RU2783211C2 - Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to new compounds of the formula I, their stereoisomers and their pharmaceutically acceptable salts, where R₁, R₂, R₃, and R₄ are independently selected from hydrogen, C_1-10 alkyl, C_1-10 alkoxy, C_1-6 halogenalkyl, C₆ aryl, and 6 or 10-element monocyclic or bicyclic heteroaryl with 1-2 heteroatoms selected from N or O, where C_1-10 alkyl, C₆ aryl, and 6 or 10-element monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C_1-6 alkyl, or C_1-6 alkoxy, where C_1-6 alkoxy is optionally substituted with C_4-5 heterocyclyl with one nitrogen heteroatom, where C_4-5 heterocyclyl is optionally substituted with one or more groups selected from halogen; O is absent or is oxygen; R₅ is selected from

; and R₆ is selected from a group consisting of hydrogen, C(O)C_1-6 alkyl. A method for the production of compounds of the formula I is also described.

EFFECT: described compounds are 2-(benzyloxy)pyrimidine derivatives, which are inhibitors of PD-1/PD-L1 activation.

formula I

11 cl, 1 dwg, 4 tbl, 8 ex

Description

The field of technology to which the invention belongs

[0001] The present invention relates to substituted 2-(benzyloxy)pyrimidine derivatives of formula Ib, formula Ia, and formula I, including their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and their pharmaceutically acceptable salts, which are inhibitors of PD-1/PD activation -L1. The present invention also relates to a process for the synthesis of compounds of formula Ib, formula Ia and formula I.

[0002] The compounds described herein are inhibitors of PD-1/PD-L1 activation, and they can be used in the treatment of cancer and other diseases or conditions associated with PD-1/PD-L1 activation.

Prerequisites for the creation of the invention

[0003] Tumor development and survival is a chaotically regulated process involving interaction between cancer cells, normal stromal cells, and host defense mechanisms (Vinay DS et al., Seminars in Cancer Biology, 2015, 35: S185-S198). In general, CD8+ cytotoxic T cells (CTL) and CD4+ helper T cells (THI cells) inhibit the development of cancer cells through mechanisms normally associated with the production of interferon (IFN) γ and cytotoxins (Zamarron BF et al., Intl. J. Biol Sciences, 2011, 7(5):651-658). However, tumors have developed a number of mechanisms to avoid immune destruction. The PD-1/PD-L1 molecular pathway is one such primary mechanism for cancer evasion by immune response.

[0004] PD-1 is a type 1 transmembrane protein encoded by the PDCD1 gene. It is a member of the extended CD28/CTLA-4 immunoglobulin family and is one of the most important inhibitory co-receptors expressed by T cells (He J et al., Scientific Reports, 2015, 5: 1-9). PD-1 is absent in resting T cells, but it is induced in activated T cells. It is also expressed on B cells, NK cells, dendritic cells (DC) and macrophages. The programmed cell death protein (PD-1) suppresses the immune system and prevents it from destroying cancer cells present in the body. In cancer, high levels of PD-1 are found in tumor-infiltrating T cells, and this expression is associated with impaired CD8+ T cell function (Leung J et al., Immune Network, 2014, 14 (6): 265-276).

[0005] PD-1 has two ligands, PD-L1 (also referred to as B7-H1; CD274) and PD-L2 (B7-DC; CD273), which are both co-inhibitory (Flies DB et al., Yale J. Biology Medicine, 2011, 84(4): 409-421). PD-L1, expressed on almost all tumor cells in mice, is the main ligand for PD-1 mediated immune suppression. It is constitutively expressed on APC, and can be widely induced on cells in lymphoid tissues and non-lymphoid peripheral tissues, followed by cellular activation (Flies DB et al., Yale J. Biology Medicine, 2011, 84(4): 409-421; Dong Y et al., Oncotarget, 2017, 8(2): 2171-2186). The IFN-α cytokine is particularly effective in upregulating PD-L1 expression due to IFN-β response elements in the PD-L1 promoter region (Lee SJ et al., FEBS Letters, 2006, 580: 755-762; Flies DB et al., Immunotherapy , 2007, 30(3): 251-260). B7-DC/PD-L2 expression is largely restricted to myeloid dendritic cells (DCs) and macrophages in lymphoid compartments, and is marginally expressed in peripheral tissues (Flies DB et al., Yale J. Biology Medicine, 2011, 84(4): 409 -421). In cancer, PD-L1 is expressed on the surface of tumor cells in various solid malignancies such as head and neck squamous cell carcinoma, melanoma, carcinomas of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colon and rectum intestines, liver, pancreas, kidneys, etc. (Topalian SL et al., Curr. Opin. Immunol., 2012, 24(2): 207-212; Wang X et al., Oncotargets and Therapy, 2016, 9: 5023-5039). In hepatocellular carcinoma, melanoma, and breast cancer, a positive response to the presence of PD-L1 correlated with worse prognosis (Muenst S et al., Breast Cancer Res. Treat., 2014, 146 (1): 15-24; Leung J et al. , Immune Network, 2014, 14(6): 265-276; Wang Q et al., Medicine (Baltimore), 2017, 96(18): e6369). In contrast, normal human tissues rarely express the PD-L1 protein on their cell surface, indicating that PD-L1 may be a selective target for anticancer therapy (Chen L et al., J Clin. Invest, 2015, 125(9) : 3384-3391).

[0006] The cancer microenvironment affects the PD-1/PD-L1 pathway; induction of PD-L1 expression is associated with inhibition of immune responses against cancer, which allows cancer to progress and metastasize (He J et al., Scientific Reports, 2015, 5: 1-9; Bardhan K et al., Frontiers in Immunology, 2016, 7 (550): 1-17). Activation of the PD-1/PD-L1 pathway induces apoptosis of activated T cells (Dong Het al., Nature Medicine, 2002, 8(8): 793-800; Curiel TJ et al., Nature Medicine, 2003, 9(5) : 562-567), promotes anergy and T cell depletion (Barber DL et al., Nature, 2005, 439(7077): 682-687), enhances regulatory T cell function (Francisco LM et al., J. Exp Med., 2009, 206(13): 3015-3029) and inhibits T cell proliferation (Sheppard KA et al., FEBS Letters, 2004, 574: 37-41; Patsoukis H. et al., Cell Cycle, 2012 , 11(23): 4305-4309). Thus, blocking this pathway will restore the proliferation and cytotoxicity of CTLs that inhibit the function of regulatory T cells (Treg) and also lead to a decrease in T cell apoptosis.

[0007] Blockade of the PD-1/PD-L1 signaling pathway by therapeutic antibodies has been shown to prevent inhibitory signaling from cancer cells and allow CTL to elicit an immune system response against the target cancer cells (Zou W et al., Sci. Transl. Med., 2016, 8(328):328rv4 Smahel M, Int. J. Mol. Sci., 2017, 18(6):1331). A number of anticancer immunotherapies targeting PD-1 have been previously developed and approved for use in a range of cancers, including melanoma, lung cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer, and urothelial cancer. The first therapeutic anti-PD-L1 antibody was approved by the FDA in May 2016, and additional therapies are currently under development (https://www.fda.gov/). However, there are at least 500 clinical trials of PD-1/PD-L1 antibodies against 20 types of solid tumors and hematological malignancies. However, there is still a need for effective and selective small molecule inhibitors of the PD-1/PD-L1 signaling pathway.

[0008] Common side effects (AE) associated with the administration of drugs such as anti-PD-1 antibodies and anti-PD-L1 antibodies include fatigue, rash, diarrhea, itching, decreased appetite, joint pain, and nausea. . Immune AEs (irAEs) such as dermatitis, colitis, hepatitis, vitiligo, and thyroiditis have been reported, and approximately 10% of patients developed irAE levels 3 or 4 (Hamanishi J et al., Int. J. Clin. Oncol., 2016 , 21: 462-473). Long-term use of monoclonal antibodies (mAbs) may contribute to these AEs, which can be partially bypassed using a small molecule inhibitor. In addition, studies using smaller cell-penetrating biologics and DNA aptamers have shown that they exhibit antibody-mimicking functions and are superior to antibodies due to their artificial chemistry, low immunogenicity, and efficient tissue penetration (Lai WY et al., Mol. Therapy - Nucl. Acids, 2016, 5: e397). Therefore, small molecule inhibitors may provide increased oral bioavailability, increased bioefficacy, and a shorter half-life, allowing for more controlled treatment, especially in the event of autoimmune or other adverse effects.

[0009] As described above, PD-1/PD-L1 inhibitory compounds are of great benefit in upregulating the immune system to effectively fight cancer. Therefore, it is necessary to identify the chemical moiety, especially small molecule inhibitors, that contributes to this inhibition. Therefore, the identification and preparation of new Pd-1/PD-L1 inhibitory compounds for the treatment of cancer and other diseases or conditions associated with PD-1/PD-L1 activation will open new possibilities in the field of cancer treatment.

The essence of the invention

[00010] As one aspect of the present invention, there is provided a compound of formula Ib

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₂ , R ₃ , R ₄ , and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted en one or more groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C(O)(CH ₂ ) _n NHC(O)CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH and NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00011] In another aspect, the present invention provides a compound of formula 1a

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and their pharmaceutically acceptable salts, where X is selected from -CH ₂ O, -OCH ₂ , C(O)NH or NHC(O); R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _2-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR _a where C _2-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more its groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _{1 -6} heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O)(CH ₂ ) _n NHC(O)CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00012] In another aspect of the present invention, a compound of formula I is provided.

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _{1 -6} haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 -membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _2-6 alkylamino, C _1-6 alkoxyamino , C _1-6 acylamino, C _1-10 heterocyclyl, -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy and COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O)R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ , 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N , S or O, where C _1-6 alkyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring are independently substituted with one or more e substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C(O)(CH ₂ ) _n NHC(O)CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00013] In one aspect, the present invention provides a process for the preparation of compounds of formula Ib, formula Ia and formula I, or polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.

[00014] In one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula Ib, Formula Ia, Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[00015] In one aspect, the present invention provides a method for the treatment and/or prevention of various diseases, including malignant tumors and infectious diseases, comprising administering to a subject in need thereof suffering from a proliferative disease or cancer, a therapeutically effective amount of a compound of formula Ib, formula Ia , formula I or a pharmaceutical composition, optionally with other clinically relevant cytotoxic agents or non-cytotoxic agents.

[00016] In one aspect of the present invention, there is provided a method for treating and/or preventing various diseases, including malignant tumors and infectious diseases, comprising administering to a subject in need thereof suffering from infectious diseases such as HIV, influenza, herpes, hepatitis A, hepatitis B, hepatitis C, hepatitis D, a therapeutically effective amount of a compound of formula Ib, formula Ia, formula I, or a pharmaceutical composition, optionally with other clinically relevant antiviral drugs.

[00017] In one aspect, the present invention provides the use of compounds of formula Ib, formula Ia, formula I, or a pharmaceutical composition for the treatment and/or prevention of various diseases, including a proliferative disorder or cancer; or for the treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

[00018] These and other features, aspects and advantages of the present invention will become more apparent with reference to the following description. The above summary is provided for the general concept of the essence of the invention in a simplified form. This summary is not intended to identify key or essential features of the invention, nor is it intended to limit the scope of the invention. Brief description of the figures

[00019] Figure 1 illustrates the in vivo efficacy of Compound 45 in the RENCA renal model, in accordance with an embodiment of the present invention. Detailed description

[00020] Specialists in the art it is clear that the present invention may be subject to changes and modifications other than specifically described options. It should be understood that the present description covers all such variations and modifications. The description also includes all steps, steps, features, compositions and compounds that are mentioned or indicated in this description individually or collectively, as well as any and all combinations of any or all such steps or features.

Definitions

[00021] For ease of understanding, before further description of the present invention, here are the terms and definitions used in the description and in the examples. These definitions are to be understood by one of ordinary skill in the art in light of the rest of the disclosure. The terms used herein have the meanings recognized and known to those skilled in the art, however, for convenience and completeness of disclosure, these specific terms and their meanings are set forth below.

[00022] Singular nouns are used to refer to both one entity and more than one (i.e., at least one) entity.

[00023] Throughout the description and the claims that accompany the description, unless the context otherwise requires, the word "comprises"/"includes" and options such as "comprising"/"comprising" are intended to include the indicated integer value or an indicator of a group of integer values or indicators, without excluding any other integer value or group of integer values or indicators.

[00024] The term "including" is used to mean "including without limitation". "Including" and "including without limitation" are used interchangeably herein.

[00025] In the structural formulas herein and throughout the text of the description, the following terms are used, but they can mean otherwise, if specifically indicated.

[00026] In addition, the compounds of formula Ib, formula Ia and formula I can be their derivatives, analogs, stereoisomers, diastereomers, geometric isomers, polymorphs, solvates, co-crystals, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts and pharmaceutical compositions.

[00027] The compounds of formula Ib, formula Ia, formula I and their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts and metabolites may also be referred to here as "compounds of the invention".

[00028] Compounds of formula Ib, formula Ia, and formula I may have one or more asymmetric centers (also referred to as chiral centers), and therefore they may exist as single enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof . Chiral centers, such as chiral carbon atoms, may also be present in a substituent, such as an alkyl group. If the stereochemistry of the chiral center present in the structure of the compounds of formula Ib, formula Ia and formula I, or in any other chemical structure presented here, is not indicated, then such a structure is understood to cover any stereoisomers and all mixtures thereof. Thus, compounds of formula Ib, formula Ia and formula I containing one or more chiral centers can be used as racemic modifications, including racemic mixtures and racemates, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

[00029] Individual stereoisomers of a compound of formula Ib, formula Ia, and formula I that contain one or more asymmetric centers can be separated using methods known to those skilled in the art. For example, such resolution may be accomplished by (1) formation of diastereomeric salts, complexes, or other derivatives; (2) selective interaction with a stereoisomer-specific reagent, for example, by enzymatic oxidation or reduction; or (3) gas-liquid or liquid chromatography in a chiral medium, for example, on a chiral carrier such as silicon dioxide with an associated chiral ligand, or in the presence of a chiral solvent. It will be understood that when the desired stereoisomer is converted to another chemical entity by one of the separation procedures mentioned above, an additional step is required to isolate the desired form.

[00030] Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another using asymmetric transformation.

[00031] References to compounds of formula Ib, formula Ia, formula I and their salts are to be understood to encompass compounds of formula Ib, formula Ia and formula I in the form of free bases or in the form of their salts, for example, in the form of their pharmaceutically acceptable salts . Thus, in one embodiment, the present invention relates to compounds of formula Ib, formula Ia and formula I in the form of a free base. In another embodiment, the present invention relates to compounds of formula Ib, formula Ia, formula I and their salts. In an additional embodiment, the present invention relates to compounds of formula Ib, formula Ia, formula I and their pharmaceutically acceptable salts.

[00032] It should be understood that pharmaceutically acceptable salts of compounds of formula Ib, formula Ia and formula I can be prepared. Indeed, in some embodiments of the present invention, pharmaceutically acceptable salts of compounds of formula Ib, formula Ia and formula I may be preferred over with the corresponding free bases, since such salts provide greater stability or solubility of the molecules, thereby facilitating the preparation of dosage forms. Accordingly, the present invention also relates to compounds of formula Ib, formula Ia, formula I and their pharmaceutically acceptable salts.

[00033] The scope of the definition of "compounds of the invention" includes all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabelled derivatives, as well as stereoisomers of compounds of formula Ib, formula Ia, formula I and their salts.

[00034] The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof. With respect to compounds of the invention that are in crystalline form, it will be understood by one skilled in the art that pharmaceutically acceptable solvates can be formed when solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may include water as a solvent that is introduced into the crystal lattice. Solvates in which the solvent is water incorporated into the crystal lattice are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The invention covers all such solvates.

[00035] It will further be understood that some compounds of the invention that exist in crystalline form, including various solvates, may exhibit polymorphism (ie, the ability to be in different crystalline structures). These various crystalline forms are commonly known as "polymorphs". The invention covers such polymorphs. Polymorphs have the same chemical composition, but differ in packaging, geometric arrangement, and other properties characteristic of a solid crystalline state. Therefore, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically have different melting points, IR spectra, and X-ray patterns that can be used to identify them. It is understood that various polymorphs can be obtained, for example, by changing or adjusting the reaction conditions or the reagents used in the preparation of the compound. For example, changes in temperature, pressure, or solvent can result in different polymorphs. In addition, under certain conditions, one polymorph can spontaneously transform into another polymorph.

[00036] The term "polymorphs" refers to crystalline forms of the same molecule, and different polymorphs, as a result of the arrangement or conformation of the molecules in the crystal lattice, may have different physical properties, such as, for example, melting point, heat of fusion, solubility, dissolution rate and/or vibrational spectrum.

[00037] The term "substituted" in relation to a group means that the hydrogen atom in this group is replaced. It should be understood that the term "substituted" includes the implicit indication that such a substitution must correspond to the allowable valence of the substituted atom and substituent, and that the substitution results in a stable compound (i.e., one that does not undergo spontaneous transformation, such as permutation, cyclization or removal). In certain embodiments of the invention, one atom may be replaced by more than one substituent, if such a substitution corresponds to the allowable valency of the atom. Suitable substituents are defined here for each substituted or optionally substituted group.

[00038] The term "prodrug" refers to a precursor compound of formula Ib, formula Ia and formula I, which, after administration, undergoes chemical transformations through metabolic processes before becoming active pharmacological substances. Typically, such prodrugs are functional derivatives of a compound of the invention that are easily converted under in vivo conditions to a compound of the invention.

[00039] The term "effective amount" refers to the amount or concentration of a compound of formula Ib, formula Ia, and formula I that elicits a biological response, either alone or when present in a pharmaceutical composition. The terms effective amount and effective dose may be used interchangeably when measurements are made under in vivo or in vitro conditions.

[00040] The term "alkyl" refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, without limitation, C _1-10 alkyl refers to an alkyl group having 1-10 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. The alkyl groups may be straight or branched chain groups. Typical branched alkyl groups have one, two or three branches. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and t-butyl.

[00041] The term "alkoxy" refers to an alkyl group attached through an oxygen bond to the rest of the molecule. Thus, for example, C _1-10 alkoxy refers to an alkyl group having from 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, attached through an oxygen atom associated with the rest of the molecule. Preferred alkoxy groups include, without limitation, -OCH ₃ (methoxy), -OC ₂ H ₅ (ethoxy) and the like.

[00042] The term "alkylamino" refers to an alkyl group, as defined above, attached through an amino group to the rest of the molecule. For example, C _1-6 alkylamino refers to an alkyl group having 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via an amino group to the rest of the molecule. Preferred alkylamino groups include, without limitation, -NHCH ₃ , -N(CH ₃ ) ₂ and the like.

[00043] The term "acylamino" refers to an acyl group attached via an amino group to the rest of the molecule. For example, C _1-6 acylamino refers to an acyl group having 1 to 6 carbon atoms or 1 to 3 carbon atoms attached via an amino group to the rest of the molecule. Preferred acylamino groups include, without limitation, CH ₃ (CO)NH- and the like.

[00044] The term "haloalkyl" refers to an alkyl group, as defined above, containing a halogen and attached through an alkyl bond to the rest of the molecule. For example, C _1-6 haloalkyl refers to an alkyl group having 1 to 6 carbon atoms or 1 to 3 carbon atoms attached to the rest of the molecule. Preferred haloalkyl groups include, without limitation, -CH ₂ Cl, -CHCl ₂ , and the like.

[00045] The term "haloalkoxy" refers to an alkoxy group, as defined above, containing a halogen and attached through an oxygen atom via an alkoxy bond to the rest of the molecule. For example, C _1-6 haloalkoxy refers to an alkoxy group having 1 to 6 carbon atoms or 1 to 3 carbon atoms attached to the rest of the molecule. Preferred haloalkoxy groups include, without limitation, -OCH ₂ Cl, -OCHCl ₂ and the like.

[00046] The term "halogen" refers to a halogen radical, such as fluorine, chlorine, bromine, or iodine. "Haloalkyl" refers to an alkyl group, as defined herein above, wherein at least one of the hydrogen atoms has been replaced by a halogen radical. "C _1-6 haloalkyl" refers to a C _1-6 alkyl group where at least one of the hydrogen atoms is replaced by a halogen atom. An example of "haloalkyl" is trifluoromethyl or 2,2,2-trifluoroethyl.

[00047] The term "cycloalkyl" refers to a saturated hydrocarbon ring having a certain number of carbon atoms. For example, without limitation, C _3-10 cycloalkyl refers to a cycloalkyl group having 3 to 10 atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantane groups, and the like.

[00048] The term "aryl" refers to an aromatic ring having a specific number of carbon atoms. Thus, for example, C _5-10 aryl refers to an aryl group having 5 to 10 atoms. Preferred aryl groups include, without limitation, phenyl, benzyl, naphthyl, and the like.

[0004 9] The term "heteroaryl" refers to aromatic rings containing from 1 to 3 heteroatoms in the ring. "Heteroaryl" groups may be substituted with one or more substituents as defined herein. "C _1-6 heteroaryl" rings contain 1-6 carbon atoms. "Heteroaryl" includes pyridinyl, tetrazolyl and pyrazolyl. "Heteroatom" refers to a nitrogen, sulfur or oxygen atom, such as a nitrogen atom or an oxygen atom.

[00050] The terms "heterocyclic" and "heterocyclyl" refer to saturated or unsaturated monocyclic aliphatic rings containing 5, 6 or 7 ring atoms, including 1 or 2 heteroatoms, or to saturated or unsaturated bicyclic aliphatic rings containing 5, 6 or 7 ring atoms, including 1-5 heteroatoms. In certain embodiments, the "heterocyclyl" groups are saturated. In other embodiments, the "heterocyclyl" groups are unsaturated. "Heterocyclyl" groups containing more than one heteroatom may contain different heteroatoms. "Heterocyclyl" groups may be substituted with one or more substituents as defined herein. "Heterocyclyl" includes piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl. In some embodiments, the implementation of the heterocyclic ring is a monocyclic or bicyclic or spirocyclic ring, which may be saturated or unsaturated. In some other embodiments, the monocyclic or bicyclic or spirocyclic heterocyclic ring may contain one or more heteroatoms selected from N, S, or O.

[00051] The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and dosage forms that are medically suitable for use in contact with human and animal tissues without undue toxicity, irritation, and other problems or complications, in proportion to a reasonable ratio benefit/risk.

[00052] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in free base form with an appropriate acid.

[00053] Salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula Ib, formula Ia, formula I and their pharmaceutically acceptable salts. Thus, one embodiment of the present invention includes a compound of formula Ib, formula Ia, formula I, and salts thereof. Compounds of formula Ib, formula Ia, formula I contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Typical pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenyl acetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate , salicylate, glycolite, lactate, heptanoite, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate , pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2-sulfonate.

[00054] The term "PD-1/PD-L1 inhibitor", "inhibitory compounds", or "PD-1/PD-L1 activation inhibitor" is used to identify a compound that is capable of blocking the PD-1/PD-L1 signaling pathway to prevent inhibitory signaling of cancer cells and allow CTL to elicit an immune response against the target cancer cells and thus provide treatment for cancer and other diseases or conditions associated with PD1/PD-L1 activation.

[00055] A term that was once described is used in this sense throughout the text of the description.

[00056] As discussed above in the description of the prior art, the identification and development of new PD-1/PD-L1 inhibitor compounds for the treatment of cancer and other diseases or conditions associated with PD-1/PD-L1 activation opens up new opportunities in the field cancer treatment.

[00057] The term "cytotoxic agents" or "inhibitors" is used to identify any agents or drugs that are capable of killing cells, including cancer cells. These agents or inhibitors may interfere with the growth and division of cancer cells and may result in shrinkage of tumors.

[00058] The term "non-cytotoxic agents" or "inhibitors" is used to identify any agents or inhibitors that do not directly kill cells, but instead interfere with cellular transport and metabolic functions, ultimately leading to cell death.

[00059] The term "immune checkpoint inhibitors" or "immunomodulators" is used to identify any agents or inhibitors that block certain proteins produced by certain cell types of the immune system, such as T cells, and certain cancer cells. These proteins help control immune responses and may keep T cells from killing cancer cells. When these proteins are blocked, the brakes on the immune system are released and T cells are better able to kill cancer cells. Immune checkpoint inhibitors include inhibitors that act against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 ( also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. The terms "immunomodulators" and "immune checkpoint inhibitors" are used interchangeably herein.

[00060] In one embodiment, the present invention provides compounds of formula Ib

their polymorphs, stereoisomers, tautomers, prodrugs, solvates and their pharmaceutically acceptable salts,

where X is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₂ , R ₃ , R ₄ , and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted en one or more groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C 3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms as selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent we are with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC(O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00061] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₂ , R ₃ , R ₄ , and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted en one or more groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C(O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00062] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₂ , R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino , amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl , C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₉ is C _1-6 alkoxy, where C _1-6 alkoxy, is optionally substituted with one or more groups selected from hydroxy, C _1-4 haloalkyl, C _5-6 aryl, or C _1-6 heteroaryl, where C _{5- 6} aryl or C _1-6 heteroaryl is optionally substituted with one or more groups selected from halo or cyano; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00063] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₂ , R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino , amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl , C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₉ is C _1-6 alkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or

a bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where the 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl , halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C (O) NHR ₆ , C (O) NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH, or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00064] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₂ and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C amino _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _{1- 10} alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _{1 -6} alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more more groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl and C _1-6 alkoxy; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00065] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to the aryl ring, and 0-attached to the heteroaryl ring; R ₃ , R ₄ and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino , amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl , C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one and whether more than groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₂ is selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, halogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _{1- 6} heterocyclyl or C _1-6 alkoxy, where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C(O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00066] In one embodiment, the present invention provides a compound of formula Ib, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group in -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₂ , R ₃ , R ₄ , and R ₉ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more groups selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted en one or more groups selected from hydroxy, halogen or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; R ₅ selected from

and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00067] In one embodiment, the present invention provides compounds of formula Ia

their polymorphs, stereoisomers, tautomers, prodrugs, solvates and their pharmaceutically acceptable salts,

where X is selected from -CH ₂ O -, -OCH ₂ -, - C(O)NH- or -NHC(O)-; R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected mi from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ , CN, NHR ₆ , COOH, COOR ₆ , NHC( O)R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms , selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring, independently substitution still with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00068] In one embodiment, the present invention provides a compound of formula Ia, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is -CH ₂ O-, wherein the CH ₂ group is from -CH ₂ O- attached to an aryl ring and O-attached to a heteroaryl ring; R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy, or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00069] In one embodiment, the present invention provides a compound of formula Ia, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X is -OCH ₂ -, wherein O of -OCH ₂ is attached to an aryl ring, and the CH ₂ group is attached to a heteroaryl ring; R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy, or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent enes with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , - C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00070] In one embodiment, the present invention provides a compound of formula Ia, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X is -OCH ₂ -, where O in -OCH ₂ is attached to an aryl ring and a CH ₂ group is attached to a heteroaryl ring; R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _{1 -6} alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy, or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ selected from

; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C (O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00071] In one embodiment, the present invention provides a compound of formula Ia, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is C(O)NH-, wherein the -C(O) group is from - C(O)NH is attached to an aryl ring and an NH- group is attached to a heteroaryl ring; R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy, or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from oxo, cyano, halo, hydroxy, morpholino, C(O)NH ₂ , C(O)CH ₂ , CN, NHR ₆ , COOH, COOR ₆ , NHC (O)R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituted with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, hydroxyl, halogen, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ , and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH, or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00072] In one embodiment, the present invention provides a compound of formula Ia, its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X is NH(O)-, where the -NH group is from -NHC(O) - is attached to the aryl ring and the C(O)- group is attached to the heteroaryl ring; R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR, where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy, or COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O )R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms, selected from N, S or O, where C _1-6 alkyl and 5-10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring independently substituent ene substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from the group consisting of oxo, halogen, hydroxyl, C _1-6 alkyl, COOH, COOR ₆ , R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00073] In one embodiment, the present invention provides a compound of formula I

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _{1 -6} haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 -membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino , C _1-6 acylamino, C _1-10 heterocyclyl, -COOR, where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are substituted with one or more groups selected from C _1-6 alkyl, C _{3 -6} cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy and COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₅ is -NR ₇ R ₈ where R ₇ and R ₈ are selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with substituents selected from oxo, cyano, halo, hydroxy, morpholino, C(O)NH ₂ , C(O)CH ₂ , CN, NHR ₆ , COOH, COOR ₆ , NHC(O)R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ , 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where C _1-6 alkyl and a 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring are independently substituted with one or more e substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or

a bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where the 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl , C _1-6 alkyl, COOH, COOR ₆ , Re, NHR ₆ , C (O) NHR ₆ , C (O) NHSO ₂ R ₆ , C (O) (CH ₂ ) _n NHC (O) CH ₃ and their combinations where C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl, and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00074] In one embodiment, the present invention provides a compound of formula I, polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen , cyano, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkyl amino, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl is optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxyamino, C _1-6 acylamino, C _1-6 heterocyclyl, -COOR _a where C _1-6 alkyl, C _1-6 alkoxy, and C _{1 -6} heterocyclyl substitution are one or more groups selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy and COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo, or cyano, and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00075] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-4 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _5-6 aryl and 5 -10-membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-6 alkyl, C _5-6 aryl, and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, C _{1 -6} alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl, -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy, C _1-10 heterocyclyl are optionally substituted with one or more groups selected from C _{1- 6} alkyl, C _3-6 cycloalkyl, C _1-6 hetero ocyclyl, C _1-6 alkoxy and COOR _a where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano and R _a is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl , C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; and R ₅ is selected from

R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents selected from from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00076] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-4 alkyl, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen , hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl or C _1-4 haloalkoxy; R ₂ is selected from hydrogen, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{3 -6} cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-8 heterocyclyl, COOR _a , where C _1-4 alkyl, C _1-4 alkoxy , C _1-8 heterocyclyl optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a ; where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _{5- 6} arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C amino _1-4 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _{5- 6} aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _{1- 4} haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino, or C _1-6 heterocyclyl; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00077] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ and R ₂ are independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 haloalkyl, C _{1- 4} haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-4 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-6 alkyl, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , where C _1-4 alkyl, C _1-4 alkoxy, and C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halogen or cyano, and R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl , C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl or C _1-6 heteroarylalkyl; R ₃ and R ₄ are independently selected from the group consisting of hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino and combinations thereof; and R ₅ is selected from

where R ₆ is selected from hydrogen, C _1-6 alkyl and C(O)C _1-6 alkyl.

[00078] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-4 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino C _5-9 aryl and 5- 10-membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-6 alkyl, C _5-9 aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups, selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl or -COOR _a , where C _1-4 alkyl, C _1-4 alkoxy, C _1-9 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl , C _3-6 cycloalkyl, C _1-6 hetero cyclyl, C _1-4 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; and R _a is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00079] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-4 alkyl, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen , hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, or C _1-6 heterocyclyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{3 -6} cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-8 heterocyclyl or COOR _a , where C _1-4 alkyl, C _1-4 alkoxy , and C _1-8 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy, and COOR _a ; where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; and R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₃ and R ₄ are independently selected from the group consisting of hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino and combinations thereof; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00080] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-4 alkyl, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen , hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-6 heterocyclyl or COOR _a , where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{3 -6} cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , where C _1-4 alkyl, C _1-4 alkoxy , C _1-6 heterocyclyl is optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl and C _1-4 alkoxy, where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _{1 -4} alkoxyamino or C _1-4 acylamino; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00081] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-4 alkyl, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, or C _1-6 heterocyclyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _{3 -6} cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , where C _1-4 alkyl, C _1-4 alkoxy , C _1-6 heterocyclyl is optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl and C _1-4 alkoxy, where C _1-6 heterocyclyl is optionally substituted with one or more groups selected from hydroxy, halo or cyano; R ₃ and R ₄ are independently selected from hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _{1 -4} alkoxyamino or C _1-4 acylamino; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00082] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-6 alkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen , halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-8 heterocyclyl or COOR _a , where C _1-4 alkyl, C _{1- 4} alkoxy, C _1-8 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a , where R _a is independently selected from hydrogen , C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₂ is selected from C _5-6 aryl, where C _5-6 aryl is optionally substituted with one or more groups selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl and cyano; R ₃ and R ₄ are independently selected from the group consisting of hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino and combinations thereof; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00083] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxyl , cyano, C _1-4 alkyl, C _1-4 alkoxy, haloalkyl, C _1-4 haloalkoxy, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy , and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy , and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₃ is selected from hydrogen, cyano, C _1-4 alkyl and C _1-4 haloalkyl; R ₄ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _1-4 alkoxyamino, C _1-4 acylamino and combinations thereof; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00084] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxyl , cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₃ is selected from the group consisting of hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _{1 -4} alkoxyamino, C _1-4 acylamino and combinations thereof; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00085] In one embodiment, the present invention provides a compound of formula I as described herein, wherein R ₁ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxyl , cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₂ is selected from hydrogen, C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _5-6 aryl and 5-9 membered monocyclic or bicyclic heteroaryl is optionally substituted with one or more groups selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, amino C _1-6 alkyl, C _1-4 alkoxyamino, C _1-4 acylamino, C _1-6 heterocyclyl, COOR _a , and combinations thereof; where C _1-4 alkyl, C _1-4 alkoxy, C _1-6 heterocyclyl are optionally substituted with one or more groups selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-4 alkoxy , and COOR _a ; where R _a is independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _1-6 heteroarylalkyl; R ₃ is selected from the group consisting of hydrogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _1-4 alkylamino, C _{1 -4} alkoxyamino, C _1-4 acylamino and combinations thereof; R ₄ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino; and R ₅ is selected from

where R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, where C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00086] In one embodiment, the present invention relates to a compound of formula I or its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, which are selected from the group consisting of the following compounds:

N-(2-(((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 1),

N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 2),

N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 3),

(1R,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2- azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 4),

(1S,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2- azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 5),

N-(2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 6)

(S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 7),

(S)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)piperidine-2-carboxylic acid (Compound 8),

(S)-1-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)methyl )piperidine-2-carboxylic acid (Compound 9),

(S)-1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 10),

(2S,4R)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 11),

(S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)piperidine-2-carboxylic acid (Compound 12),

(S)-1-((2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 13),

N-(2-(((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound fourteen),

(R)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 15),

(S)-1-((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 16),

(S)-1-((2-((3'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 17),

N-(2-(((2-((3'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 18),

(S)-1-((2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 19),

N-(2-(((2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 20),

N-(2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 21),

(S)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 22),

1-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)cyclopropane-1-carboxylic acid (Compound 23),

(3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)propionic acid (Compound 24),

2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propan- 1,3-diol (Compound 25),

(2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)(methyl)amino)-2-( hydroxymethyl)propane-1,3-diol (Compound 26),

(S)-3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)butyric acid (Compound 27),

((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-D-alanine (Compound 28),

((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)asparagine (Compound 29),

(2R,4R)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine- 2-carboxylic acid (Compound 30),

1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)azetidine-2-carboxylic acid (Compound 31),

N-(2-(((4-(benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 32),

1-((4-(Benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 33 ),

(2S,4R)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 34),

2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 35),

((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-L-proline (Compound 36),

Methyl 4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylate (Compound 37 ),

4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 38 ),

(2S,4R)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 39),

((S)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- carboxylic acid (Compound 40),

2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 41),

2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 42),

(S)-4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 43),

2-(4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholin-3-yl) acetic acid (Compound 44),

(S)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 45),

(S)-5-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[ 2.4]heptane-6-carboxylic acid (Compound 46),

7-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5] decan-1-he (Compound 47),

rac-(1R,6S)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)- 2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 48),

(S)-4-acetyl-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazin-2 -carboxylic acid (Compound 49),

(S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid ( Compound 50),

(S)-5-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[2.4] heptane-6-carboxylic acid (Compound 51),

7-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5]decan- 1-one (Compound 52),

N-(2-(((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)amino)ethyl)acetamide (Compound 53),

(2S,4R)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 54),

(S)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)piperidine-2-carboxylic acid (Compound 55),

N-(2-(((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)amino)ethyl)acetamide (Compound 56),

N-(2-(((2-((3',4'-dimethoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5-yl) methyl)amino)ethyl)acetamide (Compound 57),

((2S,4R)-1-((2-((3',4'-dimethoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5 -yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 58),

(2S,4R)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 59),

(S)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl) acetic acid (Compound 60),

(R)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl) acetic acid (Compound 61),

(S)-4-(6-acetamidohexanoyl)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )piperazine-2-carboxylic acid (Compound 62),

(S)-4,4-difluoro-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine -2-carboxylic acid (Compound 63),

(S)-1-((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Connection 64) and

N-(2-(((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 65).

[00087] In one embodiment, the present invention provides a process for preparing compounds of formula Ib, formula Ia and formula I described herein, or their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and their pharmaceutically acceptable salts.

[00088] In one embodiment, the present invention provides a process for preparing compounds of formula Ib, formula Ia, formula I described herein, wherein said process comprises the steps of: (a) reacting a compound of formula IV and formula B3 in the presence of a base, a solvent and optionally a coupling reaction reagent to give compounds of formula V or formula XIII; (b) processing compounds of formula V and formula XIII to obtain compounds of formula VII; and (c) reacting compounds of formula VII with substituted amines in the presence of a reducing agent and a third solvent to give compounds of formula I, Ia or Ib:

where X in formula V, formula VI, formula VII, formula Ia and formula Ib is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₉ , R ₂ , R ₃ and R ₄ in formula Ib, formula IV, formula V, formula VI, formula VII and formula XIII are independently selected from hydrogen, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _{1 -6} haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino, amino C _1-6 alkyl, C _1-6 alkoxyamino, C _1-6 acylamino, C _5-10 aryl and 5-10 -membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O, where C _1-10 alkyl, C _1-10 alkoxy, C _5-10 aryl and 5-10-membered monocyclic or bicyclic heteroaryl are optionally substituted one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkylamino , C _1-6 alkoxyamino, C _1-6 acylamino, C _1-10 heterocyclyl or -COOR _a , where C _1-6 alkyl, C _1-6 alkoxy and C _1-10 heterocyclyl are optionally substituted with one or more substituents selected from hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heterocyclyl, C _1-6 alkoxy or COOR _a , where C _1-6 heterocyclyl is optionally substituted with one or more substituents selected from hydroxy, halo or cyano; and R _a is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _5-6 aryl, C _5-6 arylalkyl, C _2-6 heterocyclyl, C _1-6 heteroaryl, or C _{1- 6} heteroarylalkyl; X in formula Ib, formula Ia, formula V, formula VI, formula VII and formula XIII is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₅ in formula Ib is -NR ₇ R ₈ where R ₇ and R ₈ are independently selected from the group consisting of hydrogen, C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, 5-10- a membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, where C _3-10 cycloalkyl, C _1-6 alkyl, C _2-6 alkenyl, and 5-10 -membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH ₂ , C(O)CH ₂ CN, NHR ₆ , COOH, COOR ₆ , NHC(O)R ₆ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _5-6 aryl, SR ₆ or 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where C _1-6 alkyl and 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic e ring is independently substituted with one or more substituents selected from hydroxyl and R ₆ ; or R ₇ and R ₈ together may form a 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, where 4-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C _1-6 alkyl, COOH, R ₆ , NHR ₆ , C(O)NHR ₆ , C(O)NHSO ₂ R ₆ , C(O ) (CH ₂ ) _n NHC (O) CH ₃ and combinations thereof, wherein C _1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR ₆ ; n is 1-6; and R ₆ is selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)C _1-6 alkyl and combinations thereof, wherein C _1-6 alkyl and C(O)C _1-6 alkyl are optionally substituted with substituents, selected from the group consisting of hydroxyl, COOH, NHR ₆ , NHC(O)NHR ₆ and combinations thereof.

[00089] In one embodiment, the present invention provides a process for preparing compounds of formula Ib, formula Ia and formula I as described herein, wherein the processing of compounds of formula V to obtain compounds of formula VII comprises: a) alkenylating compounds of formula V in the presence of a second base and a second solvent to give compounds of formula VI; and (b) oxidizing compounds of formula VI to give compounds of formula VII.

[00090] In one embodiment, the present invention provides a process for preparing compounds of formula Ib, formula Ia, and formula I as described herein, wherein the processing of compounds of formula XIII, to form compounds of formula VII, comprises formatting compounds of formula XIII, to obtain a compound of formula VII.

[00091] In one embodiment, the present invention provides a process for the preparation of compounds of formula Ib, formula Ia, formula I as described herein, wherein said process comprises the steps of: (a) reacting compounds of formula IV and formula B3 in the presence of a base, a solvent and optionally a coupling reaction reagent to give compounds of formula V or formula XIII; (b) alkenylating compounds of formula V in the presence of a second base and a second solvent to give compounds of formula VI; (c) oxidizing compounds of formula VI to give compounds of formula VII; and (d) reacting compounds of formula VII with substituted amines in the presence of a reducing agent and a third solvent to give compounds of formula I, Ia or Ib.

[00092] In one embodiment, the present invention provides a process for the preparation of compounds of formula Ib, formula Ia, formula I as described herein, wherein said process comprises the steps of: (a) reacting a compound of formula IV and formula B3 in the presence of a base, a solvent and optionally a coupling reaction reagent to give compounds of formula V or formula XIII; (b) formatting compounds of formula XIII to obtain compounds of formula VII; and (c) reacting compounds of formula VII with substituted amines in the presence of a reducing agent and a third solvent to give compounds of formula I, Ia or Ib.

[00093] In one embodiment, the present invention provides a process for preparing compounds of formula Ib, formula Ia, formula I as described herein, wherein the coupling reagent is selected from 1-[bis(dimethylamino)methylene]-1H-1,2,3 hexafluorophosphate -triazole[4,5-b]pyridinium-3-oxide (HATU), N,N'-dicyclohexylcarbodiimide (DCC) or propylphosphonic anhydride; the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, dichloromethane, ethyl acetate, dioxane, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, and combinations thereof; the base is selected from the group consisting of sodium hydride, butyllithium, lithium diisopropylamide, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, and combinations thereof; the second base is selected from the group consisting of butyllithium, sodium hydride, lithium diisopropylamide, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, and combinations thereof; the second solvent is selected from the group consisting of N,N-dimethylformamide, dichloromethane, ethyl acetate, dioxane, isopropyl alcohol, diethyl ether, t-butyl alcohol, N,N-dimethylformamide, dimethyl sulfoxide and combinations thereof, the third solvent is selected from the group consisting of acetic acid, methanol, N,N-dimethylformamide and combinations thereof, and the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and combinations thereof.

[00094] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula Ib, Formula Ia, Formula I as described herein, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[00095] In another embodiment, the present invention provides a pharmaceutical composition as described herein, wherein the composition is in a form selected from the group consisting of tablet, capsule, powder, syrup, solution, aerosol, and suspension.

[00096] In one embodiment, the present invention provides compounds of formula Ib, formula Ia, formula I, or pharmaceutically acceptable salts thereof, as described herein, wherein the pharmaceutically acceptable salt is selected from salts of inorganic bases such as salts of Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; organic base salts such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts , aluminum salts, etc. Salts also include salts of amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine and guanidine. Salts may include acid addition salts, where appropriate, which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates. , ascorbates, glycerophosphates, ketoglutarates.

[00097] In one embodiment, the present invention provides a method for the treatment and/or prevention of various diseases, including malignant tumors and infectious diseases, wherein the method comprises administering to a subject suffering from a proliferative disorder or cancer in need thereof a therapeutically effective amount of a compound of Formula Ib , formula Ia, formula I, or a pharmaceutical composition as described herein with other clinically relevant cytotoxic agents or non-cytotoxic agents.

[00098] In one embodiment, the present invention provides a method for treating and/or preventing a proliferative disorder, or cancer, or HIV, or hepatitis B, hepatitis C, hepatitis D, or infections of both a bacterial or viral nature, comprising administering to a subject suffering from from a proliferative disorder or cancer or viral disease, a therapeutically effective amount of a compound of formula Ib, formula Ia, formula I, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, with other clinically relevant cytotoxic agents or non-cytotoxic agents.

[00099] The present invention provides a method of treating a disorder caused by, associated with, or accompanied by disorders of cell proliferation and/or angiogenesis followed by metastasis, wherein the method comprises administering a therapeutically effective amount of a compound of Formula I.

[000100] The present invention provides a method of treating cancer in a patient comprising administering an effective amount of compounds of Formula Ib, Formula Ia, and Formula I. The cancer may be a hematologic malignancy or a solid tumor. The hematologic malignancy is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, and leukemia. In the case of solid tumors, the tumors are selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head cancer, neck cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.

[000101] The compounds of the invention are capable of slowing down tumor growth, arresting tumor growth, or inducing regression of tumors and preventing the formation of tumor metastases (including micrometastases) and the growth of metastases (including micrometastases). In addition, they can be used in hyperproliferation of the epidermis.

[000102] The compound of formula I of the present invention can be used as a prophylactic or therapeutic agent for the treatment of cancer. Examples of cancer include, without limitation, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, neuroma , non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor , vascular fibroma, retinoblastoma, penile cancer, childhood solid cancer, lymphoma, myeloma, and leukemia (including, for example, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia ( CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia).

[000103] "Combination therapy" includes administering the compounds of the invention in combination with other biologically active ingredients, such as, but not limited to, various anticancer agents, and with non-drug therapy, such as, but not limited to, surgery or radiation therapy. The compounds described herein may be used in combination with other pharmaceutically active compounds which will preferably enhance the effects of the compounds of the invention. The compounds can be administered simultaneously or sequentially with respect to other drug therapy.

[000104] In one embodiment, the present invention relates to the use of compounds of formula Ib, formula Ia, formula I, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of various diseases, including a proliferative disorder or cancer; or for the treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

[000105] In one embodiment, the present invention relates to the use of compounds of formula Ib, formula Ia, formula I, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of various diseases, including a proliferative disorder or cancer; or for the treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents, where the other clinically relevant cytotoxic agents or non-cytotoxic agents are selected from the group consisting of carboplatin, bortezomib, carfilzomib, lenalidomide, pomalidomide, doxorubicin, daunorubicin, decitabine, denileukin, denileukin diphytox , dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, cyclophosphamide, 5-fluorouracil, imatinib, methotrexate, irinotecan, toptecan, vinblastine, etoposide, vincristine, carmustine, paclitaxel, vorinostat, belinostat, panbinostat, romidepsin, chiatinastatin, moceentinastatin bosutinib, cetuximab, enterztinib, lapatinib, nilotinib, pazopanib, ruxlotinib, sorafeenib, sunitinib, vermurafenib, axitinib, gefitinib, cobimetinib, carbozantinib, temozolomide, idarubicin, abarelix, aldesleukin, alemtuzumab, basparagtaminol, allopurinol exarotin, baricitinib, bleomycin, busulfan, capecitabine, cladribine, clofarabine, cytarabine, dacarbazine, dactinomycin, sodium, dasatinib, letrozole, tamoxifen, oxaliplatin, procarbazine, zoleronate, and combinations thereof.

[000106] In one embodiment, the present invention provides a method of treating cancer as described herein, wherein said method comprises administering to a subject in need thereof a combination of a compound of Formula Ib, Formula Ia, Formula I, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier and other clinically significant cytotoxic agents or non-cytotoxic agents.

[000107] In one embodiment, the present invention relates to a method for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administration to a subject in need thereof suffering from viral infectious diseases such as HIV, influenza, herpes, hepatitis A, hepatitis B, hepatitis C, hepatitis D, a therapeutically effective amount of a compound of formula Ib, formula Ia and formula I, or a pharmaceutical composition as described herein, with other clinically relevant antiviral drugs.

[000108] In one embodiment, the present invention provides a method of treating cancer as described herein, wherein the method comprises administering a combination of a compound of formula Ib, formula Ia, formula I, or a pharmaceutical composition with other clinically relevant immune checkpoint inhibitors. In another embodiment of the present invention, immune checkpoint inhibitors are selected from the group consisting of CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 ( 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, PD-L2, and combinations thereof.

[000109] In one embodiment, the present invention provides a method of treating cancer as described herein, wherein the method comprises administering to a subject in need a combination of a compound of Formula Ib, Formula Ia, Formula I, or a pharmaceutical composition with other clinically relevant immune checkpoint inhibitors, such as nivolumab, pembrolizumab, pidilimumab, bms-986016, epacadostat, tremelimumab, CD73 inhibitors and arginase inhibitors.

[000110] In another embodiment, the compounds disclosed herein may be combined with anticancer agents (e.g., small molecules, cytotoxic agents, non-cytotoxic agents, monoclonal antibodies, antisense RNAs, and fusion proteins) that inhibit one or more biological targets. Such a combination may enhance therapeutic efficacy beyond that achieved by any single agent and may prevent or delay the emergence of resistant variants.

[000111] In another embodiment, the compounds disclosed herein may be combined with immunocancer drugs such as, but not limited to, PD-1, IDO, TDO, arginase, CD73, TIM3, CTLA4, or any other drug, which are involved in the process of immune modulation.

[000112] In another embodiment of the invention, the compounds disclosed herein can be combined with CART therapy with T cells, enhancing the effect of CART therapy with T cells.

EXAMPLES

[000113] The symbols and conventions used herein in describing processes, in the diagrams, and in the examples are consistent with those used in current scientific literature, such as in the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard one-letter or three-letter abbreviations are generally used to denote amino acid residues that are assumed to be in the L-configuration, unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. In particular, the following abbreviations and abbreviations may be used in the examples and description.

Abbreviations:

Ac acetyl;

Ac ₂ O acetic anhydride;

ACN acetonitrile;

AIBN azobis(isobutyronitrile);

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

BMS complex borane-dimethyl sulfoxide;

Bn benzyl;

Boc tert-butoxycarbonyl;

Boc ₂ O di-tert-butyl dicarbonate;

BuLi butyllithium;

CSF cesium fluoride;

DCE 1,2-dichloroethane;

DCM dichloromethane;

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;

DMS dimethyl sulfide;

ATP ATP, adenosine triphosphate;

Bis-pinacolatodiborone 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane;

BSA bovine serum albumin;

C18 denotes alkyl groups with 18 carbon atoms on silicone, used in the stationary phase for HPLC (HPLC);

CH ₃ CN acetonitrile;

Su cyclohexyl;

DCC N,N'-dicyclohexylcarbodiimide;

DIPEA Hunig's base, N-ethyl-N-(1-methylethyl)-2-propanamine;

Dioxane 1,4-dioxane;

DMAP 4-dimethylaminopyridine;

DME 1,2-dimethoxyethane;

DMF N,N-dimethylformamide, DMF;

DMSO dimethyl sulfoxide;

DPPA diphenylphosphoryl azide;

EtOAc ethyl acetate;

EtOH ethanol;

Et ₂ O diethyl ether;

HATU hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide;

HOAc acetic acid;

HPLC high pressure liquid chromatography;

HMDS hexamethyldisilazide;

IPA isopropyl alcohol;

LAH lithium aluminum hydride;

LDA lithium diisopropylamide;

LHMDS lithium hexamethyldisilazide;

MeOH methanol;

MPLC medium pressure liquid chromatography;

MTBE methyl tert-butyl ether;

mCPBA m-chloroperbezoic acid;

NaHMDS sodium hexamethyldisilazide;

NBS N-bromosuccinimide;

NMR nuclear magnetic resonance;

Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium (0);

Pd(dppf)Cl complex ₂ DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) and dichloromethane;

RPHPLC reverse phase high pressure liquid chromatography;

RT room temperature;

sat. saturated, saturated;

SGC chromatography on silica gel;

CM starting material;

T3P propylphosphonic anhydride;

TCL thin layer chromatography;

TEA triethylamine;

TFA trifluoroacetic acid; and

THF tetrahydrofuran, THF.

[000114] The following examples provide details and details regarding the synthesis, activity and uses of the compounds of the invention. It should be understood that the following materials are for illustrative purposes only, and the present invention cannot be limited to the specific details set forth in these examples.

[000115] the Compounds of the invention can be obtained in various ways, including standard chemistry. Any previously defined variable will have a previously defined value, unless otherwise specified. Illustrative general synthesis methods are shown in the following schemes and can be easily adapted to obtain other compounds of the invention.

[000116] It also provides a method, which is shown in Scheme 1 and Scheme 1a, providing compounds of formula I, where all groups have the definitions presented above.

General procedure for the synthesis of compounds of formula I

Scheme 1

Said process for the preparation of compounds of formula I comprises the following steps:

Step 1: Compound A (5-bromo-2,4-dichloropyrimidine) was reacted with a sodium or potassium salt of an alkoxide in a suitable solvent to give the corresponding 5-bromo-2-chloro-4-alkoxypyrimidine (Compound B).

Step 2: Compound B3 (2,3-substituted benzyl alcohol) was synthesized by palladium-catalyzed Suzuki coupling of substituted bromobenzene B1 with the corresponding boronic acids B2 to give B3.

Step 3: Intermediate B3 was further reacted with Compound B in the presence of a base such as sodium hydride to give 2-benzyloxy-4-alkoxy-5-bromopyrimidine (Compound C).

Step 4a: Intermediate C was reacted with tributyl(vinyl)tin (Compound C1) to give the corresponding vinyl derivative D.

Step 4b: Compound D was oxidized with sodium metaperiodate and osmium tetroxide to give the corresponding aldehyde E.

Step 4: Aldehyde E can alternatively be synthesized by lithiating compound C with n-BuLi and quenching with N,N-dimethylformamide.

Step 5: Reductive amination of intermediate E with various substituted aliphatic, aromatic, heterocyclic and cyclic amines (E1) to give compounds (Compound F) of the present invention.

General procedure for the synthesis of compounds of formula I

Scheme 1a

Step 1: Intermediate C2 was reacted with compound B3 in the presence of a base such as sodium hydride to give 2-benzyloxy-4-alkoxy-5-bromopyrimidine (Compound C3).

Step 2: Formatting of Intermediate C3 was performed using POCl ₃ and DMF to give Intermediate C4.

Step 3: Reductive amination of intermediate C4 with various substituted aliphatic, aromatic, heterocyclic and cyclic amines (E1) obtained with the compounds (Compound F) of the present invention.

General procedure for the synthesis of compounds of formula Ib

Compounds of general formula Ib, where R9 is alkyl or aryl, can be prepared according to the following scheme.

Scheme 1b

Step 1: B3 was reacted with compound D10 in the presence of a base such as sodium hydride to give a pyrimidine derivative of compound D11.

Step 2: Intermediate D11 was reacted with tributyl(vinyl)tin (Compound C1) to give the corresponding vinyl derivatives D12.

Step 3: Compound D12 was oxidized with sodium metaperiodate and osmium tetroxide to give the corresponding aldehyde D13.

Step 4: Reductive amination of intermediate D13 with various substituted aliphatic, aromatic, heterocyclic and cyclic amines (E1) to give compounds (Compound F2) of the present invention.

General information and analytical methods

[000117] Commercially available compounds were used in the reactions unless otherwise noted. NMR data were obtained on a Varian 400 MHz spectrometer. All compounds were characterized by 1H NMR, HPLC and mass spectrometry (LCMS (ES), liquid chromatography - mass spectrometry). All ¹ H chemical shifts are in parts per million (ppm) and are measured relative to TMS or residual deuterated DMSO solvent. LCMS (ES) measurements were performed on an Agilent-LCMS D-SL (G1456B) mass spectrometer. The yield of compounds is given for pure compounds.

[000118] The examples below are for illustrative purposes only and should therefore not be construed as limiting the scope of the invention.

[000119] In addition, a class of compounds of formula I was obtained using the general procedure described in scheme 1 or scheme 2 above.

General procedure for the synthesis of intermediates

Synthesis of (4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (intermediate for compounds 1, 5-9)

[000120] To a stirred solution of (3-bromo-2-methylphenyl)methanol (1.1 g, 5 mmol), (4-fluorophenyl)boronic acid (2.1.4 g, 10 mmol) in toluene (12 mL) and EtOH (4 mL) PdCl ₂ (dppf)⋅DCM (0.04 g, 0.05 mmol) and 2M aqueous NaHCO ₃ (4 mL) were added and the reaction mixture was degassed with N ₂ gas for 10 minutes. The reaction mixture was then heated in a sealed tube at 80° C. for 12 hours. The reaction mixture was filtered through celite; the filtrate was diluted with water and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by MPLC on Combiflash using 20% ethyl acetate in hexane as eluent to give (4'-fluoro-2-methyl[1,1'-biphenyl]-3-yl )methanol as an off-white solid (3, yield: 0.81 g, 73%).

LCMS (ES) m/z=199.1 [M+H-OH] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.08 (s, 3H), 4.52 (d, J=5.6 Hz, 2H), 5.09 (t, J =5.2 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 7.18-7.25 (m, 3H), 7.27-7.31 (m, 2H) , 7.38 (d, J=7.6 Hz, 1H).

Synthesis of (2-methyl-[1,1'-biphenyl]-3-yl)methanol (intermediate for compounds 2-4, 10-15)

[000121] To a stirred solution of (3-bromo-2-methylphenyl)methanol (4.1 g, 5 mmol), phenylboronic acid

(5, 1.4 g, 10 mmol) in toluene (12 ml) and EtOH (4 ml) was added PdCl ₂ (dppf)⋅DCM (0.04 g, 0.05 mmol) and 2M aqueous NaHCO ₃ solution (4 ml), and the reaction mixture was degassed with nitrogen gas for 10 minutes. The reaction mixture was then heated in a sealed tube at 80° C. for 12 hours. The reaction mixture was filtered through celite; the filtrate was diluted with water and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by MPLC on Combiflash using 20% ethyl acetate in hexane as eluent to give (2-methyl-[1,1'-biphenyl]-3-yl)methanol as off-white solid (6, yield: 0.81 g, 73%). LCMS (ES) m/z=199.1 [M+H] ⁺ .

Synthesis of N-(2-(((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino) ethyl)acetamide

(Compound 1)

Step 1: Preparation of 5-bromo-2-chloro-4-methoxypyrimidine (A1)

[000122] NaOMe (1.6 g, 28.88 mmol) was added to a stirred solution of 5-bromo-2,4-dichloropyrimidine (A, 5 g, 22.2 mmol) in MeOH (100 ml) at 0°C. , and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated; the crude product was taken up in water and extracted with ethyl acetate (2×150 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by MPLC on Combiflash using 2% ethyl acetate in hexane as eluent to give 5-bromo-2-chloro-4-methoxypyrimidine as a white crystalline solid (A1, yield: 4 g, 82%).

LCMS (ES) m/z=222.9, 224.9 [M] ⁺ , [M+2H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.01 (s, 3H), 8.69 (s, 1H).

Step 2: Preparation of 5-bromo-2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidine (A2)

[000123] To a stirred solution of (4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (intermediate 3, 0.5 g, 2.31 mmol) in THF (15 ml ) at 0°C was added 60% NaH in mineral oil (0.184 g, 4.61 mmol) and the reaction mixture was stirred at this temperature for 0.5 hour. Then, 5-bromo-2-chloro-4-methoxypyrimidine (A1, 0.51 g, 2.31 mmol) in THF (3 ml) was added to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice, extracted with ethyl acetate. The organic layer was washed with ice water, brine and dried over sodium sulfate. The organic layer was then evaporated, the crude product was purified by MPLC on Combiflash using 2.5% ethyl acetate in hexane as eluent to give 5-bromo-2-((4'-fluoro-2-methyl-[1,1'- biphenyl])-3-yl)methoxy)-4-methoxypyrimidine as a white solid (A2, yield; 0.8 g, 86%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.17 (s, 3H), 3.97 (s, 3H), 5.45 (s, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7, 22-7, 27 (m, 3H), 7.31-7.35 (m, 2H), 7.42 (d, J=7.6 Hz, 1H) , 8.51 (s, 1H).

Step 3: Preparation of 2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidine-5-carbaldehyde (A3)

[000124] To a stirred solution of 5-bromo-2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidine (A2, 0.3 g, 0.74 mmol) in THF (5 ml) at -78°C was added H-BuLi (1.2 M solution in hexane, 0.61 ml, 0.74 mmol) and stirred at -78°C for 10 minutes The reaction mixture turned dark brown and the resulting anion was quenched with DMF (0.15 mL, 1.48 mmol). The reaction mixture was allowed to warm to 0° C. and quenched with saturated NH ₄ Cl solution (3 ml). The reaction mixture was diluted with ethyl acetate (20 ml) and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated to give a crude residue which was purified by MPLC on Combiflash using 10% ethyl acetate in hexane as eluent to give 2-((4'-fluoro-2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-4-methoxypyrimidine-5-carbaldehyde as a colorless viscous liquid (A3, yield: 0.12 g, 46%).

LCMS (ES) m/z=353.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.19 (s, 3H), 4.04 (s, 3H), 5.56 (s, 2H), 7.20 (d , J=7.6 Hz, 1H), 7, 23-7, 29 (m, 3H), 7, 32-7, 35 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 8.78 (s, 1H), 10.03 (s, 1H).

Step 4: Preparation of N-(2-(((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl )amino)ethyl)acetamide (Compound 1)

[000125] To a solution of 2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidine-5-carbaldehyde (A3, 0.12 g, 0 .34 mmol) in MeOH (2 ml) and DMF (2 ml) at 0°C, N-(2-aminoethyl)acetamide (A4, 0.2 g, 2.04 mmol) and acetic acid (0.05 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., NaCNBH ₃ (0.065 g, 1.02 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, the crude product was taken up in DCM (15 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give a crude residue which was purified by MPLC on Combiflash using 7% methanol in dichloromethane as eluent to give N-(2-(((2-((4'-fluoro-2 -methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 1) as a viscous solid (yield 0.06 g, 41%).

LCMS (ES) m/z=439.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.78 (s, 3H), 2.18 (s, 3H), 2.61-2.69 (m, 1H), 3.16 (d, J=5.6 Hz, 2H), 3.70 (br s, 2H), 3.92 (s, 3H), 5.43 (s, 2H), 7.17 (d , J=6.8 Hz, 1H), 7, 23-7, 27 (m, 3H), 7.31-7.35 (m, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.82 (br s, 1H), 8.27 (s, 1H); HPLC at 280 nm, 98.33%.

Synthesis of N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 2))

Stage 1: Obtaining 5-bromo-2-chloro-4-ethoxypyrimidine (B1)

[000126] To a stirred solution of 5-bromo-2,4-dichloropyrimidine (A, 2 g, 8.85 mmol) in EtOH (20 ml) was added NaOEt (21% in EtOH, 3.4 ml, 10.62 mmol ) at 0°С. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated; the crude product was taken up in water and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by MPLC on Combiflash using 2% ethyl acetate in hexane as eluent to give 5-bromo-2-chloro-4-ethoxypyrimidine as a white crystalline solid (B1, yield: 1.6 g, 80%).

LCMS (ES) m/z=237, 239 [M] ⁺ , [M+2H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.46 (t, J=7.2 Hz, 3H), 4.53 (d, J=7.2 Hz, 2H), 8, 41 (s, 1H).

Step 2: Preparation of 5-bromo-4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine (B2)

[000127] To a stirred solution of (2-methyl-[1, 1'-biphenyl]-3-yl) methanol (6, 0.83 g, 4.21 mmol) in THF (20 mL) was added 60% NaH in mineral oil (0.36 g, 8.42 mmol) at 0° C. and the reaction mixture was stirred at this temperature for 0.5 hour. Then, 5-bromo-2-chloro-4-ethoxypyrimidine (B1, 1.0 g, 4.21 mmol) in THF (5 mL) at 0°C was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice, extracted with ethyl acetate. The organic layers were washed with ice water, brine and dried over sodium sulfate. The organic layer was then evaporated, the crude product was purified by MPLC on Combiflash using 2% ethyl acetate in hexane as eluent to give 5-bromo-4-ethoxy-2-((2-methyl-[1,1'-biphenyl]- 3-yl)methoxy)pyrimidine as a white solid (B2, yield: 0.6 g, 32%).

LCMS (ES) m/z=399, 401 [M+2H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.44 (t, J=7.6 Hz, 3H), 2.27 (s, 3H), 4.50 (q, J=7 .2 Hz, 2H), 5.44 (s, 2H), 7.21-7.23 (m, 2H), 7.29 (d, J=7.2 Hz, 2H), 7.32-7 .35 (m, 1H), 7.39-7.44 (m, 3H), 8.32 (s, 1H).

Step 3: Preparation of 4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine (B4)

[000128] To a stirred solution of 5-bromo-4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine (B2, 4.4 g, 11.03 mmol ) in B DMF (60 ml) was added tributylvinyltin (B3, 5 ml, 16.48 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. Then Pd(PPh ₃ ) ₄ (1.3 g, 1.13 mmol) was added and the reaction mixture was heated at 100° C. for 16 hours. The reaction mixture was filtered through celite; the filtrate was diluted with water and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by MPLC on Combiflash using 10% ethyl acetate in hexane as eluent to give 4-ethoxy-2-((2-methyl[1,1'-biphenyl]-3 -yl)methoxy)-5-vinylpyrimidine as a yellow oily liquid (B4, yield: 1.7 g, 32%).

LCMS (ES) m/z=347.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.34 (t, J=7.2 Hz, 3H), 2.18 (s, 3H), 4, 39-4, 45 (m, 2H), 5.27-5.30 (m, 1H), 5.44 (s, 2H), 5.85-5.90 (m, 1H), 6.57-6.65 ( m, 1H), 7.16-7.30 (m, 4H), 7-34-7.46 (m, 4H), 8.46 (s, 1H).

Step 4: Preparation of 4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde (B5)

[000129] To a stirred solution of 4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine (B4, 2.2 g, 6.36 mmol) in THF (40 ml) and water (20 ml), was added OsO ₄ (4 ml, 0.63 mmol) and stirred at 0°C for 15 minutes followed by the addition of NaIO ₄ (2.8 g, 13.14 mmol ). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by MPLC on Combiflash using 13% ethyl acetate in hexane as eluent to give 4-ethoxy-2-((2-methyl[1,1'-biphenyl]-3 -yl)methoxy)pyrimidine-5-carbaldehyde as an off-white solid (B5, yield: 1.1 g, 50%).

LCMS (ES) m/z=349.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.36 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 4.50-4.55 (m, 2H), 5.55 (s, 2H), 7.19-7.30 (m, 4H), 7.35-7.45 (m, 4H), 8.77 (s, 1H), 10.03 (s, 1H).

Step 5: Preparation of N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 2 )

[000130] To a solution of 4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-carbaldehyde (B5, 0.15 g, 0.43 mmol) in MeOH (2 ml) and DMF (2 ml) at 0°C, methylglycine (B6, 0.12 g, 1.35 mmol) and acetic acid (0.1 ml) were added simultaneously, and the reaction mixture was stirred at room temperature in within 1 hour. The reaction mixture was cooled to 0°C, NaCNBH3 (0.08 g, 1.29 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated; the crude product was taken up in DCM (15 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give a crude residue which was purified by MPLC on Combiflash using 10% methanol in dichloromethane as eluent to give N-((4-ethoxy-2-((2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 2) as a viscous solid (yield 0.035 g, 19%).

LCMS (ES) m/z=422.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22-1.31 (m, 3H), 2.18 (s, 3H), 2.28 (s, 3H), 3 .15 (s, 2H), 3.59 (s, 3H), 4.34-4.39 (m, 2H), 5.41(s, 2H), 7.16-7.18 (m, 1H ), 7.23-7.30 (m, 3H) 7.36-7.48 (m, 4H), 8.23 (s, 1H): HPLC at 254 nm: 99.38%.

Synthesis of N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 3)

Step 1: Preparation of 4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine

[000131] NaH (0.2 4 g, 6 vol. mmol) and the reaction mixture was stirred for 30 minutes at room temperature. Then, 2-chloro-4,b-dimethoxypyrimidine (0.97 g, 5.55 mmol) in DMF (5 ml) was added to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with ice water, brine and dried over sodium sulfate. The organic layer was then evaporated, the crude product was purified by MPLC on Combiflash using 3% ethyl acetate in hexane as eluent to give 4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)pyrimidine as a colorless viscous oil (1.4 g, 83%).

LCMS (ES) m/z=337 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.16 (s, 3H), 3.86 (s, 6H), 5.42 (s, 2H), 5.87 (s, 1H), 7.18 (d, J=7.2 Hz, 1H ), 7.24-7.30 (m, 3H), 7.36-7.37 (m, 1H), 7.39-7.43 (m, 3H).

Step 2: Preparation of 4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde

[000132] To a stirred solution of 4,3-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine (0.8 g, 2.38 mmol) in DMF ( 6 ml) POCl ₃ (5 ml 16.48 mmol) was added and the reaction mixture degassed with N ₂ gas for 10 minutes, Pd(Pph ₃ ) ₄ (0.7 ml, 7.82 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice and made basic with saturated NaHCO ₃ solution. The precipitated solid was filtered off and dried under vacuum to give the crude product. The crude product was purified by MPLC on Combiflash using 20% ethyl acetate in hexane as eluent to give 4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) pyrimidine-5-carbaldehyde as a white solid (0.38 g, 44%).

LCMS (ES) m/z=365.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.21 (s, 3H), 3.99 (s, 6H), 5.55 (s, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.26-7.30 (m, 3H), 7.34-7.38 (m, 1H), 7.42-7.47 (m, 3H), 10.05 (s, 1H).

Step 3: Preparation of N-(2-(((4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino )ethyl)acetamide

[000133] To a solution of 4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde (0.19 g, 0.52 mmol) in MeOH (3 ml) and 3 ml DMF) at 0° C. were added simultaneously N-(2-aminoethyl)acetamide (0.203 g, 1.56 mmol) and acetic acid (0.1 ml) and the reaction mixture was stirred at room temperature. temperature for 1 hour. The reaction mixture was cooled to 0° C., NaCNBH ₃ (0.09 g, 1.56 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, the crude product was taken up in DCM (15 ml) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give a crude residue which was purified by MPLC on Combiflash using 10% methanol in dichloromethane as eluent to give N-(2-(((4,b-dimethoxy-2- ((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide as an off-white solid (0.05g, 23%) .

LCMS (ES) m/z=451.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.76(s, 3H), 2.20(s, 3H), 3.14(s, 1H), 2.52-2.54(m, 2H), 3.10(kv, J=6Hz , 2H), 3.58 (s, 2H), 3.89 (s, 6H), 5.44 (s, 2H), 7.17 (d, J=7.2 Hz, 1H), 7, 23 -7.29 (m, 3H) 7.33-7.37 (m, 1H), 7.43 (t, J=7.6 Hz, 3H), 7.76 (br s, 1H): HPLC at 254 nm: 98.47%.

Synthesis of (1R,6R)-2-((4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2 -azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 4) and (1S,6R)-2-((4,b-dimethoxy-2-((2-methyl-[1,1'-]) biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 5)

[000134] To a solution of 4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde (0.2 g, 0.54 mmol) rac-(1R,6S)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid hydrochloride (97 mg, 0.54 mmol), triethylamine (81 mg , 0.81 mmol) and stirred for 5 minutes. To this mixture was added acetic acid (0.1 ml) and the reaction mixture was stirred at room temperature for 2 hours. NaCNBH ₃ (101 mg, 1.6 mmol) was added to this reaction mixture and stirring was continued at room temperature for 16 hours. The reaction mixture was diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×150 ml). The combined organic layer was washed with water (40 ml) and brine (40 ml), dried over sodium sulfate and concentrated to give a crude residue which was purified by Combiflash chromatography using 8% methanol in dichloromethane as eluent to give rac( 1R,6S)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2-azabicyclo [4.1.0]heptane-1-carboxylic acid as a light white solid (yield: 165 mg, 62%). The racemic mixture was purified by supercritical fluid chromatography (Waters SFC 200q, column: CHIRALCEL OJ-H (250×21 mm), 5 µm) using CO2 and 0.2% TEA in MeOH as mobile phase (method: 60 g ( CO2) 15% (co-solvent) 100 bar (ABPR)), loading 5.0 mg/injection in a 5-minute cycle. Two peaks were collected at 6.8 minutes (peak-1, isomer-1) and 8.3 minutes (peak-2, isomer-2) and concentrated to give compound 4 (73 mg) and compound 5 (82 mg). Peak-1:

(1R,6R)-2-((4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2- azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 4)

[000135] LCMS (ES) m/z=490.39 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.09-1.18 (m, 1H), 1.26-1.22 (m, 2H), 1.35-1.36 (m, 1H), 1.51-1.59 (m, 1H), 1.77-1.83 (m, 2H), 2.22 (s, 3H), 2.49 (m, 2H), 3.36 (m, 1H), 3.65 (m, 1H), 3.92 (s, 6H), 5.46 (s, 2H), 7.19-7.21 (m, 1H), 7.26- 7.32 (m, 3H), 7.35-7.39 (m, 1H), 7.44-7.48 (m, 3H), 11.82 (br s, 1H); HPLC at 214 nm: 98.96%.

Peak-2: (1S,6R)-2-((4,b-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 5)

[000136] LCMS (ES) m/z=490.39 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMS0-d ₆ ): δ 1.15-1.26 (m, 3H), 1.35-1.36 (m, 1H), 1.51-1.59 (m, 1H), 1.77-1.83(m, 2H), 2.22(s, 3H), 2.49(m, 2H), 3.36(m, 1H), 3.65(m, 1H ), 3.92 (s, 6H), 5.46 (s, 2H), 7.19-7.21 (m, 1H), 7.26-7.32 (m, 3H), 7.35- 7.39 (m, 1H), 7.44-7.48 (m, 3H), 11.82 (br s, 1H), HPLC at 214 nm: 99.23%.

Synthesis of N-(2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl) acetamide (Compound 6)

Step 1: Preparation of 4,6-diethoxy-2-(methylthio)pyrimidine [000137] To a stirred solution of 4,6-dichloro-2-(methylthio)pyrimidine (5 g, 25 mol) in EtOH (30 ml) at 0 °C was added NaOEt (21% in EtOH, 20 ml, 56 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated and the crude product was taken up in water (100 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give 4,b-diethoxy-2-(methylthio)pyrimidine as a white solid (yield: 4.7 g, 85.5%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.37 (d, J=7.04 Hz, 6H), 2.51 (s, 3H), 4.32-4.37 (t, J=7 .04 Hz, 4H), 5.67 (s, 1H).

Step 2: Preparation of 4,6-diethoxy-2-(methylsulfonyl)pyrimidine

[000138] To a stirred solution of 4,6-diethoxy-2-(methylthio)pyrimidine (51 g, 4 mmol) in DCM (30 ml) at 0°C was added mCPBA (4.31 g, 24 mmol), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with ice water (30 ml) and extracted with DCM (3×100 ml). The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using 8% ethyl acetate in hexane as eluent to give 4,6-diethoxy-2-(methylsulfonyl)pyrimidine as a white solid (yield: 1 g, 81%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.41 (d, J=7.08 Hz, 6H), 3.30 (s, 3H), 4.32-4.48 (t, J=7 .12 Hz, 4H), 6.12 (s, 1H).

Step 3: Preparation of 4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine

[000139] To a stirred solution of 4,b-diethoxy-2-(methylsulfonyl)pyrimidine (4.5 g, 18.2 mmol) in DMF (40 ml) -yl)methanol (3.62 g, 18.2 mmol) and potassium carbonate (2.53 g, 18.2 mmol). The reaction mixture was heated at 80°C for 8 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate and evaporated to give the crude product. The crude product was purified by flash chromatography using 10% ethyl acetate in hexane as eluent to give 4,b-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine in as a white solid (yield: 3.5 g, 52%).

LCMS (ES) m/z=365.21 [M+H] ⁺ , purity at 214 nm: 89.77%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.30 (m, 6H), 2.20 (s, 3H), 4.29-4.33 (m, 4H), 5 .40 (s, 2H), 7.20 (m, 1H), 7.25-7.30 (m, 3H), 7.39 (m, 1H), 7.44-7.48 (m, 4H ).

Step 4: Preparation of 4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde

[000140] A solution of phosphoryl chloride (5 ml) in DMF (10 ml) was stirred at 0° C. under nitrogen for 1 hour. A solution of 4,b-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine (3.5g, 9.6mmol) in DCE (30mL) was added dropwise. ). Then the reaction mixture was stirred at room temperature for 30 minutes, after which it was heated at 80°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo and diluted with DCM (50 ml). The organic layer was washed with water (25 ml), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (10% EtOAc in hexane) to give 4,6-diethoxy-2 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde as a white solid (yield: 1.5 g, 39%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.34 (t, J=7.08 Hz, 6H), 2.22 (s, 3H), 4.46-4.51 (m, 4H ), 5.52 (s, 2H), 7.21 (m, 1H), 7.26-7.30 (m, 3H), 7.40 (m, 1H), 7.44-7.48 ( m, 3H), 10.07 (s, 1H).

Step 5: Preparation of N-(2-(((4,b-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino )ethyl)acetamide

[000141] To a solution of 4,b-diethoxy-2-((2-methyl-[1, 1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde (0.15 g, 0.38 mmol) in MeOH (3 ml) and DMF (3 ml) at room temperature were added N-(2-aminoethyl)acetamide (60 mg, 0.57 mmol) and acetic acid (0.1 ml) at the same time, and the reaction mixture was stirred at room temperature temperature for 2 hours. To this reaction mixture was added NaCNBH ₃ (0.08 g, 1.29 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 ml) and was extracted with a mixture of DCM:MeOH (9:1) (3×2 5 ml). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to give a crude residue which was purified by flash chromatography using 8% methanol in dichloromethane as eluent to give N-(2-(((4,b-diethoxy- 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide as a white solid (yield 0.091 g, 49%).

LCMS (ES) m/z=479.24 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.19-1.30 (t, 6H), 1.82 (s, 3H), 2.19 (s, 3H), 2.93 (m , 2H), 3.30(m, 2H), 3.89(s, 2H), 4.35-4.40(q, 4H), 5.43(s, 2H), 7.21(m, 1H), 7.26 -7.30 (m, 3H), 7.40 (m, 1H), 7.44-7.48 (m, 3H), 8.03 (s, 1H), 8.23 (broad s, 1H), HPLC at 214 nm: 98.19%.

Synthesis of (S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 7)

Stage 1: Synthesis of 5-bromo-4-methoxy-2-(methylthio)pyrimidine

[000142] NaOMe (21% in MeOH, 30 ml, 136 mmol), and the reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo. The crude product was diluted with water (500 ml) and extracted with ethyl acetate (2×900 ml). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate and evaporated to give 5-bromo-4-methoxy-2-(methylthio)pyrimidine as a white solid (yield: 22 g, 89%).

LCMS (ES) m/z=235.19 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.54 (s, 3H), 4.05 (s, 3H), 8.34 (s, 1H).

Stage 2: Synthesis of 5-bromo-4-methoxy-2-(methylthio)pyrimidine

[000143] To a stirred solution of 5-bromo-4-methoxy-2-(methylthio)pyrimidine (140 g, 595 mmol) in DCM (2 L) at 0°C was added meta-chloroperbenzoic acid (308 g, 1780 m mol), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with ice water (1 L) and extracted with DCM (3×2 L). The combined organic layer was washed with saturated sodium bicarbonate solution (1 L), brine (500 ml) and dried over sodium sulfate. The organic layer was evaporated and the crude product was purified by Combiflash chromatography using 8% ethyl acetate in hexane as eluent to give 5-bromo-4-methoxy-2-(methylsulfonyl)pyrimidine as a white solid (yield: 72 g, 45.38%).

LCMS (ES) m/z=267.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.40 (s, 3H), 4.11 (s, 3H), 9.02 (s, 1H).

Stage 3. Synthesis of 5-bromo-4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine

[000144] To a stirred solution of 5-bromo-4-methoxy-2-(methylsulfonyl)pyrimidine (80 g, 299 mmol) in DMF (400 ml) -yl)methanol (59.49 g, 300 mmol) and potassium carbonate (123 g, 900 mmol) and the reaction mixture was heated at 80° C. for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2×2 L). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by Combiflash chromatography using 10% ethyl acetate in hexane as eluent to give 5-bromo-4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl) methoxy)pyrimidine as a white solid (yield: 47 g, 40.8%).

LCMS (ES) m/z=385.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.28 (s, 3H), 4.05 (s, 3H), 5.46 (s, 2H), 7.21-7.25 (m, 2H ), 7.31-7.34 (m, 2H), 7.36-7.39 (m, 1H), 7.41-7.46 (m, 3H), 8.33 (s, 1H).

Step 4: Synthesis of 4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine

[000145] To a stirred solution of 5-bromo-4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)ptrimidine f (48 g, 124 mmol) in DMF (150 ml) was added tributylvinyltin (71.1 g, 220 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. Pd(PPh ₃ ) ₄ (7.1 g, 6.2 mmol) was added to this mixture, and the reaction mixture was heated at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was diluted with water (500 ml) and was extracted with ethyl acetate (2×1 l). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 3% ethyl acetate in hexane as eluent to give 4-methoxy-2-((2-methyl-[1,1'- biphenyl)]-3-yl)methoxy)-5-vinylpyrimidine as a yellow oily liquid (yield: 30 g, 72.8%).

LCMS (ES) m/z=333.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 3.92 (s, 3H), 5.31 (d, J=11.6 Hz, 1H), 5, 55 (s, 2H), 5.89 (d, J=16.6 Hz, 1H), 6.62-6.69 (m, 1H), 7.21-7.31 (m, 4H), 7 .37-7.46 (m, 4H), 8.51 (s, 1H).

Step 5: Synthesis of 4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde

[000146] To a stirred solution of 4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine (24 g, 72 mmol) in THF (80 ml) and water (80 ml) at 0°C was added OsO ₄ (73 ml, solution of 2.5% by weight in tert-butanol, 7.2 mmol) and stirred for 15 minutes. To this mixture was added NaIO ₄ (23 g, 108 mmol) and the reaction mixture was allowed to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (2×800 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by Combiflash chromatography using 12% ethyl acetate in hexane as eluent to give 4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-carbaldehyde as an off-white solid (yield: 18 g, 60%).

LCMS (ES) m/z=335.38 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.29 (s, 3H), 4.13 (s, 3H), 5.58 (s, 2H), 7.24-7.31 (m, 3H ), 7.35-7.45 (m, 5H), 8.81 (s, 1H), 10.18 (s, 1H).

Step 6: Synthesis of (S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2 -carboxylic acid

[000147] To a solution of 4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-carbaldehyde (30 g, 89 mmol) in EtOH (45 ml) and DMF (45 ml) were added simultaneously (S)-piperidine-2-carboxylic acid (11.58 g, 89 mmol) and acetic acid (0.3 ml) and the reaction mixture was stirred at room temperature for 2 hours. NaCNBH ₃ (16.91 g, 269 mmol) was added to this reaction mixture and stirring continued at room temperature for 16 hours. The reaction mixture was diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×150 ml). The combined organic layer was washed with water (40 ml) and brine (40 ml), dried over sodium sulfate and concentrated to give the crude product (16 g) which was purified by Combiflash chromatography using 8% methanol in dichloromethane as eluent, to give (S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid as a light yellow solid (yield: 10.5 g, 26.1%).

LCMS (ES) m/z=448.24 [M+H] ⁺ and purity at 214 nm: 99.36%; ¹ H NMR (400 MHz, DMSO-d6): 5 1.35 (m, 1H), 1.46 (m, 3H), 1.70 (m, 2H), 2.20 (m, 4H), 2 .89 (m, 1H), 3.07 (w, 1H), 3.55 (d, 1H), 3.66 (d, 1H), 3.90 (s, 3H), 5.43 (s, 2H), 7.21 (m, 1H), 7.26-7.30 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 3H), 8.25 (s, 1H).

Synthesis of (S)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5 -yl)methyl)piperidine-2-carboxylic acid (Compound 8)

Stage 1: Synthesis of 2-fluoro-5-(hydroxymethyl)benzonitrile (2)

[000148] To a stirred solution of 2-fluoro-5-formylbenzonitrile (10 g, 67 mmol) in ethanol (100 ml) at 0°C was added sodium borohydride (3.0 g, 80 mmol) and continued stirring at 0°C within 2 hours. After TLC indicated completion of the reaction, the reaction mixture was quenched with ice water (50 ml) and extracted with DCM (2×50 ml). The organic layer was dried over sodium sulfate and concentrated to give 2-fluoro-5-(hydroxymethyl)benzonitrile as a white solid (yield: 10 g, 100%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.33 (s, 1H), 4.69 (s, 2H), 7.21 (s, 1H), 7.57-7.63 (m, 2H ).

Stage 2: Synthesis of 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)-2-fluorobenzonitrile

[000149] Sodium hydride (1.36 g, 60% in mineral oil, 34 mmol) and the mixture was stirred at 0° C. for 1 hour. To this mixture was added 5-bromo-2,4-dichloropyrimidine (7.5 g, 34 mmol) and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was quenched with ice water (100 ml) and was extracted with 10% IPA in chloroform (4×100 ml). The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 20% EtOAc in hexane to give 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)-2- fluorobenzonitrile as a white solid (yield: 4.9 g, 65%).

LCMS (ES) m/z=342.19 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.51 (s, 2H), 7.59 (m, 1H), 7.91 (m, 1H), 8.06 (m, 1H), 8.78 (broad s, 1H).

Step 3: Synthesis of 5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)-2-fluorobenzonitrile

[000150] Sodium hydride (0. 67 g, 60% in mineral oil, 17 mmol) and the mixture was stirred at room temperature for 30 minutes. To this mixture was added 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)-2-fluorobenzonitrile (5.5 g, 16 mmol) and left to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 15% ethyl acetate in hexane as eluent to give 5-(((5-bromo-2-((2-methyl-[1,1' -)biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)-2-fluorobenzonitrile as a white solid (yield: 2.8 g, 41%).

LCMS (ES) m/z=504.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 5.38 (s, 2H), 5.53 (s, 2H), 7.21-7.23 (m , 1H), 7.31-7.34 (m, 3H), 7.36-7.39 (m, 1H), 7.41-7.45 (m, 3H), 7.56 (m, 1H ), 7.89 (m, 1H), 8.05 (m, 1H), 8.58 (s, 1H). HPLC purity at 214 nm: 88.94%.

Step 4: Synthesis of 2-fluoro-5-(((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)benzonitrile

[000151] To a stirred solution of 5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)-2 -fluorobenzonitrile (2.8 g, 5.5 m, mol) in DMF (30 ml) was added tributylvinyltin (4.4 g, 13 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh _{3) 4} (0.6 g, 0.5 mmol) and the reaction mixture was heated at 100° C. for 3 hours. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 25% ethyl acetate in hexane as eluent to give 2-fluoro-5-(((2-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)benzonitrile as an off-white solid (yield: 1.6 g, 66.6%).

LCMS (ES) m/z=452.42 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.26 (s, 3H), 5.30 (d, J=11.6 Hz, 1H), 5.42 (s, 2H), 5.52 ( s, 2H), 5.80 (d, J=16.8 Hz, 1H), 6.68 (m, 1H), 7.21-7.23 (m, 1H), 7.31-7.34 (m, 3H), 7.36-7.39 (m, 1H), 7.41-7.45 (m, 4H), 7.72 (m, 1H), 7.78 (m, 1H), 8.32 (s, 1H); HPLC purity at 214 nm: 94.70%.

Step 5: Synthesis of 2-fluoro-5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl) benzonitrile

[000152] To a stirred solution of 2-fluoro-5-(((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl )benzonitrile (1.6 g, 3 mmol) in acetone (80 ml) and water (16 ml) at 0°C was added OsO ₄ (3 ml, 2.5 wt.% solution in tert-butanol, 0.3 mmol ) and N-methylmorpholine N-oxide (1.0 g, 8.7 mmol) and stirred for 15 minutes. To this mixture was added NaIO ₄ (2.1 g, 10 mmol) and the reaction mixture was left to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 ml) and extracted with DCM (2×100 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by Combiflash chromatography using 30% ethyl acetate in hexane as eluent to give 2-fluoro-5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl ]-3)yl)methoxy)pyrimidin-4-yl)oxy)methyl)benzonitrile as a dark solid (yield: 0.2 g, 15.3%).

LCMS (ES) m/z=454.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.23 (s, 3H), 5.55 (s, 2H), 5.62 (s, 2H), 7.22-7.32 (m , 4H), 7.38 (m, 1H), 7.46 (m, 2H), 7.52 (m, 1H), 7.59 (m, 1H), 7.93 (m, 1H), 8 .08 (m, 1H), 8.85 (s, 1H), 10.07 (s, 1H).

Step 6: Synthesis of (S)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid

[000153] To a solution of 2-fluoro-5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl )benzonitrile (1 g, 0.22 mmol) in MeOH (2 ml) and DMF (2 ml), (S)-piperidine-2-carboxylic acid (20 mg, 0.19 mmol) and acetic acid (1 drop ). The reaction mixture was stirred at room temperature for 2 hours. To this reaction mixture was added NaCNBH ₃ (30 mg, 0.6 mmol) and continued stirring at room temperature for 16 hours. The reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (2×10 ml). The combined organic layer was washed with water (3 ml) and brine (3 ml), dried over sodium sulfate and concentrated to give the crude product, which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to give (S) -1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )piperidine-2-carboxylic acid as a white solid (yield: 20 mg, 16.1%).

LCMS (ES) m/z=567.29 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (m, 1H), 1.39 (m, 3H), 1.72 (m, 2H), 2.19 (s, 3H), 2.30 (m, 1H), 2.87 (m, 1H), 3.20 (m, 1H), 3.55 (d, J=14.4 Hz, 1H), 3.66 (d, J =14.4 Hz, 1H), 5.40 (s, 2H), 5.48 (s, 2H), 7.21 (m, 1H), 7.26-7.30 (m, 3H), 7 .37 (m, 1H), 7.43-7.47 (m, 3H), 7.55 (t, J=9.2 Hz, 1H), 7.89 (m, 1H), 8.04 ( m, 1H), 8.26 (s, 1H); HPLC purity at 214 nm: 91.83%.

Synthesis of (S)-1-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl) methyl)piperidine-2-carboxylic acid (Compound 9)

Stage 1: Synthesis of 5-bromo-2-(methylsulfonyl)-4-(2,2,2-trifluoroethoxy)pyrimidine

[000154] To a stirred solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (6 g, 25 mmol) in THF (200 ml) at 0°C was added NaH (1.48 g, 60% in mineral , 37 mmol), and the reaction mixture was stirred at 0°C for 1 hour. To this mixture was added a solution of 2,2,2-trifluoroethan-1-ol (5.7 g, 25 mmol) in THF (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with ice water (250 ml) and extracted with ethyl acetate (2×500 ml). The combined organic layer was washed with brine (200 ml), dried over sodium sulfate and evaporated to give 5-bromo-2-(methylsulfonyl)-4-(2,2,2-trifluoroethoxy)pyrimidine as a white solid (yield: 8 g, crude).

LCMS (ES) m/z=303.26; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.50 (s, 3H), 5.12-5.19 (m, 2H), 8.69 (s, 1H).

Stage 2: Synthesis of 5-bromo-2-(methylsulfonyl)-4-(2,2,2-trifluoroethoxy)pyrimidine

[000155] Meta- chloroperbenzoic acid (11.4 g, 66 mmol) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with ice water (100 ml) and extracted with DCM (3×200 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (300 ml), brine (100 ml) and dried over sodium sulfate. The organic layer was evaporated and the crude product was purified by combined flash chromatography using 8% ethyl acetate in hexane as eluent to give 5-bromo-2-(methylsulfonyl)-4-(2,2,2-trifluoroethoxy)pyrimidine in as a white solid (yield: 8.4 g, 95%).

LCMS (ES) m/z=335.23 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.34 (s, 3H), 5.23-5.29 (m, 2H), 9.16 (s, 1H).

Step 3: Synthesis of 5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine

[000156] To a stirred solution of 5-bromo-2-(methylsulfonyl)-4-(2,2,2-trifluoroethoxy)pyrimidine (5 g, 25 mmol) in DMF (70 ml) was added 1'-biphenyl]-3-yl) methanol (8.4 g, 25 mmol) and potassium carbonate (5.1 g, 37.5 mol) and the reaction mixture was heated at 80° C. for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2×250 ml). The combined organic layer was washed with ice water (250 ml), brine (250 ml) and dried over sodium sulfate. The organic layer was evaporated and the crude product was purified by Combiflash chromatography using 10% ethyl acetate in hexane as eluent to give 5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine as a colorless viscous liquid (yield: 5.6 g, 53%).

LCMS (ES) m/z=453.29 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 5.10-5.22 (m, 2H), 5.58 (s, 2H), 7.19-7 .21 (m, 1H), 7.24-7.27 (m, 3H), 7.31-7.37 (m, 1H), 7.39-7.47 (m, 3H), 8.67 (s, 1H).

Step 4: Synthesis of 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)-5-vinylpyrimidine

[000157] To a stirred solution of 5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine (5.5 g, 12 mmol) in DMF (50 ml) was added tributylvinyltin (9.6 g, 30 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh _{3) 4} (1.3 g 1.2 mmol) and the reaction mixture was heated at 100° C. for 8 hours. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was diluted with water (200 ml) and extracted with ethyl acetate (2×500 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 3% ethyl acetate in hexane as eluent to give 2-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-4-(2,2,2-trifluoroethoxy)-5-vinylpyrimidine as a yellow oily liquid (yield: 3.1 g, 64.5%).

LCMS (ES) m/z=401.13 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 5.10-5.18 (m, 2H), 5.42 (d, J=12 Hz, 1H), 5, 49 (s, 2H), 5.99 (d, J=16.6 Hz, 1H), 6.60-6.71 (m, 1H), 7.21-7.19 (m, 1H), 7 .26-7.31 (m, 3H), 7.36-7.39 (m, 1H), 7.43-7.47 (m, 3H), 8.51 (s, 1H).

Step 5: Synthesis of 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine-5-carbaldehyde

[000158] To a stirred solution of 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)-5-vinylpyrimidine (7, 0, 5 g, 1.2 mmol) in THF (20 ml) and water (6 ml) at 0°C was added OsO ₄ (1 ml, 2.5 wt.% solution in tert-butanol, 0.12 mmol), and stirred for 15 minutes. To this mixture was added NaIO ₄ (0.21 g, 1.87 mmol) and the reaction mixture was allowed to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×200 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 12% ethyl acetate in hexane as eluent to give 2-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine-5-carbaldehyde as a gray solid (yield: 0.45 g, 95%).

LCMS (ES) m/z=403.57 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 5.19-5.26 (m, 2H), 5.61 (s, 2H), 7.22-7.7 .23 (m, 1H), 7.27-7.32 (m, 3H), 7.38-7.40 (m, 1H), 7.44-7.47 (m, 3H), 8.92 (s, 1H), 10.05 (s, 1H).

Step 6: (S)-1-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine-5- yl)methyl)piperidine-2-carboxylic acid

[000159] To a solution of 2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidine-5-carbaldehyde (0.2 g , 0.51 mmol) in MeOH (3 ml) and DMF (3 ml) were simultaneously added (S)-piperidine-2-carboxylic acid (0.1 g, 0.77 mmol) and acetic acid (0.1 ml) , and the reaction mixture was stirred at room temperature for 2 hours. To this reaction mixture was added NaCNBH ₃ (97 mg, 15 mmol) and continued stirring at room temperature for 16 hours. The reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (2×20 ml). The combined organic layer was washed with water (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated to give a crude residue which was purified by Combiflash chromatography using 8% methanol in dichloromethane as eluent to give ( S)-1-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)methyl) piperidine-2-carboxylic acid as a white solid (yield: 50 mg, 18.7%).

LCMS (ES) m/z=516.35 [M+H] ⁺ and purity at 214 nm: 99.86%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.40-1.44 (m, 4H), 1.74 (m, 2H), 2.20 (s, 3H), 2.32 (m , 1H), 2.88 (m, 1H), 3.21 (m, 1H), 3.55 (d, J=14.4 Hz, 1H), 3.68 (d, J=14.4 Hz , 1H), 5.01-5.10 (m, 2H), 5.46 (s, 2H), 7.19-7.21 (m, 1H), 7.26-7.30 (m, 3H ), 7.37 (m, 1H), 7.44-7.48 (m, 3H), 8.37 (s, 1H).

Synthesis of (S)-1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin- 2-carboxylic acid (Compound 10)

Stage 1: Synthesis of 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-chloropyrimidine

[000160] Sodium hydride (2.5 g, 60% in mineral oil, 62.7 mmol) and the reaction mixture was stirred for 10 minutes. To this mixture was added 5-bromo-2,4-dichloropyrimidine (9.5 g, 41.73 mmol) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was quenched with ice water (100 ml) and the mixture was extracted with EtOAc (3×100 ml). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using 20% EtOAc in hexane as eluent to give 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-chloropyrimidine as a sticky solid (yield: 16 g, 97%).

Step 2: Synthesis of 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine

[000161] Sodium hydride ( 2.42 g, 60% in mineral oil, 60.6 mmol) and stirred at room temperature for 30 minutes. To this mixture was added 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-chloropyrimidine (16 g, 40.4 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 20% ethyl acetate in hexane as eluent to give 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2- ((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine as a yellow viscous liquid (yield: 11.04 g, 49%).

LCMS (ES) m/z=557.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 0.016 (s, 6H), 0.83 (s, 9H), 1.60 (m, 2H), 1.72 (m, 2H), 2, 20 (s, 3H), 3.62 (m, 2H), 4.44 (m, 2H), 5.47 (s, 2H), 7.21-7.23 (m, 1H), 7.25 -7.31 (m, 3H), 7.37-7.49 (m, 4H), 8.47 (s, 1H).

Step 3: Synthesis of 4-((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)butan-1-ol

[000162] To a solution of 5-bromo-4-(4-((tert-butyldimethylsilyl)oxy)butoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine ( 5.5 g, 9.86 mmol) in THF (50 ml) at 0°C was added TBAF (1M solution in THF, 1 eq.) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×100 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 20% ethyl acetate in hexane as eluent to give 4-((5-bromo-2-((2-methyl-[1,1'- biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)butan-1-ol as a yellow viscous liquid (yield: 2.03 g, 46%).

LCMS (ES) m/z=443.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.65 (m, 2H), 1.76 (m, 2H), 2.19 (s, 3H), 3.44 (m, 2H), 4.42(m, 2H), 4.46(m, 1H), 5.43(s, 2H), 7.21-7.23(m, 1H), 7.25-7.31(m, 3H), 7.39-7.52 (m, 4H), 8.53 (s, 1H); HPLC purity at 214 nm: 98.91%.

Step 4: Synthesis of 4-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)butan-1-ol

[000163] To a stirred solution of 4-((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)butan-1-ol (1.0 g, 2.26 mmol) in DMF (15 ml) was added tributylvinyltin (1.79 g, 5.64 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh _{3) 4} (0.3 g, 0.23 mmol) and the reaction mixture was heated at 100° C. for 3 hours. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 25% ethyl acetate in hexane as eluent to give 4-((2-((2-methyl-[1,1'-biphenyl ]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)butan-1-ol as a yellow solid (yield: 0.7 g, 79%).

LCMS (ES) m/z=391.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.56 (m, 2H), 1.77 (m, 2H), 2.20 (s, 3H), 3.43 (m, 2H), 4.40 (m, 2H), 4.45 (m, 1H), 5.30 (d, J=12 Hz, 1H), 5.45 (s, 2H), 5.90 (d, J=17 .6 Hz, 1H), 6.62 (m, 1H), 7.19 (m, 1H), 7.25-7.32 (m, 3H), 7.36-7.39 (m, 1H) , 7.43-7.47 (m, 3H), 8.48 (s, 1H).

Step 5: Synthesis of 4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde

[000164] To a stirred solution of 4-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)butan-1-ol ( 0.7 g, 1.79 mmol) in THF (10 ml) and water (10 ml) at 0°C was added OsO ₄ (1.8 ml, 2.5 wt.% solution in tert-butanol, 0.18 mmol) and stirred for 15 minutes. To this mixture was added NaIO ₄ (0.57 g, 2.7 mmol) and the reaction mixture was allowed to stir at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with water (30 ml) and extracted with DCM (2×50 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 40% ethyl acetate in hexane as eluent to give 4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'- biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde as a sticky oily compound (yield: 0.5 g, 62%).

LCMS (ES) m/z=393.38 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.56 (m, 2H), 1.77 (m, 2H), 2.22 (s, 3H), 3.44 (m, 2H), 4.42(m, 1H), 4.51(m, 2H), 5.56(s, 2H), 7.21(m, 1H), 7.27-7.33(m, 3H), 7 .36 (m, 1H), 7.39-7.46 (m, 3H), 8.79 (s, 1H), 10.06 (s, 1H); HPLC purity at 214 nm: 99.52%.

Step 6: Synthesis of (S)-1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )piperidine-2-carboxylic acid

[000165] To a solution of 4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde (0.24 g, 0.61 mmol) in MeOH (2 ml) and DMF (2 ml) were added simultaneously (S)-piperidine-2-carboxylic acid (79 mg, 0.61 mmol) and acetic acid (1 drop) and the reaction mixture was stirred at room temperature within 2 hours. To this reaction mixture was added NaCNBH ₃ (115 mg, 1.83 mmol) and continued stirring at room temperature for 16 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml) and extracted with DCM (2×25 ml). The combined organic layer was washed with water (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated to give the crude product, which was purified by flash chromatography using 10% methanol in dichloromethane as eluent to give (S)- 1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid in as a white solid (yield: 250 mg, 80.8%).

LCMS (ES) m/z=506.43 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33-1.54 (m, 7H), 1.74 (m, 4H), 2.20 (s, 3H), 2.30 (m , 1H), 2.91 (m, 1H), 3.17 (m, 1H), 3.43 (m, 2H), 3.55 (d, J=14 Hz, 1H), 3.66 (d , J=14 Hz, 1H), 4.33 (m, 2H), 5.42 (s, 2H), 7.18 (m, 1H), 7.25-7.32 (m, 3H), 7 .37 (m, 1H), 7.43-7.47 (m, 3H), 8.23 (s, 1H); HPLC purity at 214 nm: 97.43%.

Synthesis of (2S,4R)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine -5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 11)

Step 1: Synthesis of (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol

[000166] To a solution of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin (b g, 0.027 mol) and (2-methyl-3-(4,4,5,5-tetramethyl)- 1,3,2-dioxaborolan-2-yl)phenyl)methanol (8.3 g, 33 mmol) in toluene:ethanol:water (1:1:1) (120 ml) was added potassium carbonate (11 .5 g, 83 mmol) and the mixture was degassed at room temperature for 15 minutes using nitrogen. To this mixture was added Pd(dppf)Cl ₂ ⋅DCM complex (1.4 g, 1.3 mmol) and the reaction mixture was degassed again for 10 minutes using nitrogen. After stirring the reaction mixture at 95°C for 12 hours, the mixture was cooled to room temperature, and filtered through a pad of celite. The filtrate was diluted with water (100 ml) and the aqueous mixture was extracted with EtOAc (2×500 ml). The organic layer was washed with brine (500 ml), dried over sodium sulfate and concentrated to give the crude compound. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh), using hexane as eluent, to give (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 2-methylphenyl)methanol as a light red liquid (yield: 7 g, 97.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.12 (s, 3H), 4.27 (m, 4H), 4.52 (m, 2H), 5.75 (s, 1H), 6.90 (m, 2H), 7.05 (m 1H), 7.16 (m, 1H), 7.20 (m, 1H), 7.36 (m, 1H).

Step 2: Synthesis of 2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine

[000167] To a stirred solution of (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (8.2 g, 32 mmol) in DMF (40 mL) 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (7 g, 32 mmol) and potassium carbonate (13.2 g, 96 mmol) were added and the reaction mixture was heated at 80° C. for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2×250 ml). The combined organic layer was washed with ice water (250 ml), brine (250 ml), dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 10% ethyl acetate in hexane as eluent to give 2-( (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine as a colorless viscous liquid (yield: 9 g, 71.4 %).

Step 3: Synthesis of 2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5-carbaldehyde

[000168] A solution of phosphoryl chloride (8 ml) in DMF (8 ml) at 0° C. under nitrogen was stirred for 1 hour and added dropwise to a solution of 2-((3-(2,3-dihydrobenzo)[b ][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine (3 g, 7.6 mmol) in DCE (30 mL). The reaction mixture was stirred at room temperature for 30 minutes and then heated at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo, and diluted with DCM (100 ml). The organic mixture was washed with water (25 ml), brine (25 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (10% EtOAc in hexane) to give 2- ((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5-carbaldehyde as a light yellow solid ( yield: 1.5 g, 46.8%).

LCMS (ES) m/z=423.36 [M+H] ⁺ and purity at 214 nm: 98.13%; 1 H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 4.00 (s, 6H), 4.28 (s, 4H), 5.54 (s, 2H), 6, 73-6.77 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.17-7.19 (m, 1H), 7.22-7.26 (m, 1H), 7.44 (d, J=7.6 Hz, 1H), 10.07 (s, 1H).

Step 4: Preparation of (2S,4R)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4, 6-dimethoxypyrimidin-5-yl)methyl)-4-hydroxypyrrolidin-2-carboxylic acid

[000169] To a solution of 2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5-carbaldehyde (0 .5 g, 1.1 mmol) in DMF (8 ml) was simultaneously added (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (0.15 g, 1.1 mmol), NaCNBH ₃ (0.2 g , 3.3 mmol) and acetic acid (0.1 ml). The reaction mixture was heated at 70°C for 4 hours. The reaction mixture was diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×150 ml). The combined organic layer was washed with water (40 ml) and brine (40 ml), dried over sodium sulfate and concentrated to give a crude residue which was purified by Combiflash chromatography using 8% methanol in dichloromethane as eluent to give (2S,4R)-1-((2-((3-(2,3-dihydro[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid as a white solid (yield: 0.29 g, 49%).

LCMS (ES) m/z=538.34 [M+H] ⁺ and purity at 214 nm: 98.13%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.91 (m, 2H), 2.23 (s, 3H), 3.25-3.41 (m, 3H), 3.78-3 .86 (m, 2H), 3.90 (s, 6H), 4.16 (m, 1H), 4.27 (s, 4H), 4.98 (br s, 1H), 5.44 ( s, 2H), 6.73-6.77 (m, 2H), 6.92 (d, J=8.12 Hz, 1H), 7.15-7.17 (m, 1H), 7.22 -7.26 (m, 1H), 7.44 (d, J=7.16 Hz, 1H).

Synthesis of (S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5 -yl)methyl)piperidine-2-carboxylic acid (Compound 12).

Stage 1: Synthesis of 5-vinylnicotinonitrile

[000170] A stirred solution of 5-bromonicotinonitrile (2 g, 0.12 mol) and tributylvinyltin (95.3 g, 300 mmol) in DMF (200 ml) at room temperature was purged with nitrogen for 10 minutes. To this mixture was added Pd(PPh ₃ ) ₄ (13.84 g, 12 mmol) and again purged with nitrogen for 20 minutes. The mixture was then heated at 80° C. for 4 hours. After completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with EtOAC (3×200 ml). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 10% EtOAc in hexane as eluent to give 5-vinylnicotinonitrile as an off-white solid (yield: 10.5 g, 67%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.55 (d, J=10.8 Hz, 1H), 6.17 (d, J=17.6 Hz, 1H), 6.80 ( m, 1H), 8.52 (s, 1H), 8.90 (s, 1H), 9.03 (s, 1H).

Stage 2: Synthesis of 5-formylnicotinonitrile

[000171] To a stirred solution of 5-vinylnicotinonitrile (10.5 g, 81 mmol) in acetone (200 ml) and water (40 ml) was added O ₃ O ₄ (82 ml, 2.5 wt.% solution in tert-butanol, 8.1 mmol) and N-methylmorpholine N-oxide (29 g, 242 mmol) and stirred for 3 hours. To this mixture was added NaIO ₄ (60 g, 282 mmol) and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (300 ml) and extracted with DCM (2×400 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by Combiflash chromatography using 30% ethyl acetate in hexane as eluent to give 5-formylnicotinonitrile as a yellow solid (yield: 7.9 g, 74%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.77 (s, 1H), 9.29 (s, 1H), 9.31 (s, 1H), 10.12 (s, 1H).

Stage 3: Synthesis of 5-(hydroxymethyl)nicotinonitrile

[000172] To a stirred solution of 5-formylnicotinonitrile (12 g, 91 mmol) in methanol (100 ml) at 0°C was added portionwise sodium borohydride (5.12 g, 136 mmol) over 30 minutes and the mixture was stirred at 0° C within 2 hours. After completion of the reaction with TLC control, the reaction mixture was concentrated and the residue was diluted with water (100 ml) and DCM (200 ml). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh), using 1% MeOH in DCM as eluent, to give 5-(hydroxymethyl)nicotinonitrile as a yellow solid (yield: 7.4 g, 60 .7%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 4.50 (br s, 1H), 5.54 (s, 2H), 8.19 (s, 1H), 8.80 (s, 1H ), 8.91 (s, 1H).

Step 4: Synthesis of 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)nicotinonitrile

[000173] Sodium hydride (0.26 g, 60% in mineral oil, 6, 5 mmol) and the mixture was stirred at 0° C. for 30 minutes. To this mixture was added a solution of 5-bromo-2,4-dichloropyrimidine (1.0 g, 4.3 mmol) in THF (5 ml) and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, it was quenched with ice water (100 ml) and extracted with 10% IPA in chloroform (4×100 ml). The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 5% MeOH in DCM as eluent to give 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)nicotinonitrile as a yellow solid (yield: 1.0 g, 70%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.59 (s, 2H), 8.43 (s, 1H), 8.80 (s, 1H), 9.00 (s, 1H), 9.05 (s, 1H); HPLC purity at 214 nm: 97.07%.

Step 5: Synthesis of 5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile

[000174] Sodium hydride ( 0.184 g, 60% in mineral oil, 4.6 mmol) and stirred at room temperature for 30 minutes. To this mixture was added 5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)nicotinonitrile (1 g, 3.1 mmol) and left to stir at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride solution (20 ml), and then diluted with water (50 ml). The aqueous mixture was extracted with ethyl acetate (2×100 ml) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by flash chromatography (silica gel) using 50% ethyl acetate in hexane as eluent to give 5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]- 3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile as a sticky solid (yield: 0.7 g, 47%).

LCMS (ES) m/z=487.21 [M+H] ⁺ ;] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 5.50 (s, 2H) , 5.53 (s, 2H), 7.21-7.23 (m, 1H), 7.27-7.31 (m, 3H), 7.36-7.38 (m, 1H), 7 .44-7.47(m, 3H), 8.43(m, 1H), 8.59(s, 1H), 8.98(s, 1H), 9.01(s, 1H); HPLC purity at 254 nm: 97.78%.

Step 4: Synthesis of 5-(((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)nicotinonitrile

[000175] To a stirred solution of 5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile ( 0.3 g, 0.62 mmol) in DMF (10 ml) was added tributylvinyltin (0.57 g, 1.86 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh ₃ ) ₄ (72 mg, 0.061 mmol) and the reaction mixture was heated at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 30% ethyl acetate in hexane as eluent to give 5-(((2-((2-methyl-[1,1' -]biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)nicotinonitrile as sticky oil (yield: 0.225 g, 75%).

LCMS (ES) m/z=435.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 5.32 (d, J=11.2 Hz, 1H), 5.52 (s, 4H), 5. 89 (d, J=17.6 Hz, 1H), 6.67 (m, 1H), 7.21-7.23 (m, 1H), 7.27-7.31 (m, 3H), 7 .36-7.38(m, 1H), 7.42-7.45(m, 3H), 8.43(m, 1H), 8.55(s, 1H), 8.98(s, 1H ), 9.01 (s, 1H); HPLC purity at 254 nm: 92.44%.

Step 5: Synthesis of 5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile

[000176] To a stirred solution of 5-(((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)nicotinonitrile (220 mg, 0.43 mmol) in acetone (8 ml) and water (2 ml) at 0°C was added OsO ₄ (0.44 ml, 2.5 wt.% solution in tert-butanol, 0.043 mmol) and N- N-methylmorpholine oxide (152 mg, 1.35 mmol) and stirred for 2 hours. To this mixture was added NaIO ₄ (324 mg, 1.513 mmol) and the reaction mixture was allowed to stir at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (25 ml) and extracted with DCM (2×25 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by Combiflash chromatography using 30% ethyl acetate in hexane as eluent to give 5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy))pyrimidin-4-yl)oxy)methyl)nicotinonitrile as a yellow solid (yield: 95 mg, 47%).

LCMS (ES) m/z=437.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.22 (s, 3H), 5.61 (s, 4H), 7.21-7.23 (m, 1H), 7.27-7 .31 (m, 3H), 7.36-7.38 (m, 1H), 7.44-7.52 (m, 3H), 8.47 (m, 1H), 8.85 (s, 1H ), 9.01 (s, 1H), 9.03 (s, 1H), 10.07 (s, 1H).

Step 6: Synthesis of (S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid

[000177] To a solution of 5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile (150 mg, 0.34 mmol) in MeOH (2 ml) and DMF (2 ml) were added simultaneously (S)-piperidine-2-carboxylic acid (32 mg, 0.515 mmol) and acetic acid (2 drops) and the reaction mixture was stirred at room temperature for 3 hours. To this reaction mixture was added NaCNBH ₃ (35 mg, 1.03 mmol) and continued stirring at room temperature for 5 hours. The reaction mixture was diluted with water (10 ml) and extracted with DCM (2×25 ml). The combined organic layer was washed with water (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated to give the crude product, which was purified by flash chromatography using 10% methanol in dichloromethane as eluent to give (S)- 1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl) piperidine-2-carboxylic acid as a white solid (yield: 33 mg, 18%).

LCMS (ES) m/z=550.22 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (m, 1H), 1.39 (m, 3H), 1.72 (m, 2H), 2.19 (s, 3H), 2.32 (m, 1H), 2.89 (m, 1H), 3.23 (m, 1H), 3.54 (d, J=14.0 Hz, 1H), 3.68 (d, J =14.0 Hz, 1H), 5.48 (s, 4H), 7.21-7.22 (m, 1H), 7.24-7.31 (m, 3H), 7.36-7, 38 (m, 1H), 7.43-7.48 (m, 3H), 8.28 (s, 1H), 8.43 (s, 1H), 8.98 (s, 1H), 9.00 (s, 1H); HPLC purity at 214 nm: 99.32%.

Synthesis of (S)-1-((2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 13)

Stage 1: Obtaining 1-bromo-3-(3-chloropropoxy)-2-methylbenzene

[000178] To a stirred solution of 3-bromo-2-methylphenol (1.9.8 g, 52 mmol) in DMF (80 mL) was added 1,3-dichloropropane (73 g, 100 mmol) and potassium carbonate (21.5 g, 156 mmol) and the reaction mixture was stirred at 80° C. for 12 hours under nitrogen. After TLC showed completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (100 ml), washed with ice water (50 ml) and brine (30 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to give the crude product. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 10% EtOAc in hexane as eluent to give 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3- difluoropyrrolidine as a yellow liquid (yield: 10.1 g, 73.7%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.25-2.31 (m, 5H), 3.77 (m, 2H), 4.12 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 6.98-7.02 (m, 1H), 7.17 (d, J=8 Hz, 1H).

Step 2: Preparation of 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine

[000179] To a stirred solution of 1-bromo-3-(3-chloropropoxy)-2-methylbenzene (10.1 g, 38 mmol) in DMF (60 ml) was added 3,3-difluoropyrrolidine (11 g, 76 mmol), potassium carbonate (22.5 g, 163 mmol) and sodium iodide (8.5 g, 57 mmol) and the reaction mixture was heated at 80° C. for 12 hours under nitrogen atmosphere. After TLC showed completion of the reaction, the reaction mixture was cooled to room temperature and diluted with EtOAc (100 ml), washed with ice water (50 ml), brine (50 ml), the organic phase was dried over sodium sulfate and concentrated in vacuo, obtaining crude product. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 15% EtOAc in hexane as eluent to give 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3- difluoropyrrolidine as a yellow liquid (7.1 g, 56.3%).

LCMS (ES) m/z=334.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.96 (m, 2H), 2.22-2.33 (m, 5H), 2.66 (m, 2H), 2.75 (m, 2H ), 2.94 (m, 2H), 4.01 (m, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.96-7.00 (m, 1H), 7 , 15 (d, J=8.0 Hz, 1H).

Step 3: Preparation of (3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol

[000180] To a solution of 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (2 g, 59 mmol) and (2-methyl-3-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.78 g, 71 mmol) in toluene:ethanol:water (1:1:1) (30 ml) carbonate was added at room temperature potassium (2.47 g, 17 mmol) and the mixture was degassed for 15 minutes using nitrogen. To this mixture was added Pd(dppf)Cl ₂ ⋅DCM (0.24 g, 0.29 mmol) and the reaction mixture was again degassed for 10 minutes using nitrogen and heated at 95°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was diluted with water (50 ml) and the mixture was extracted with EtOAc (2×100 ml). The organic layer was washed with brine (20 ml), dried over sodium sulfate and concentrated to give the crude compound. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 10% EtOAc in hexane as eluent to give (3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol as an off-white solid (yield: 2 g, 90%).

LCMS (ES) m/z=376.18 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.77 (s, 3H), 1.94 (s, 3H), 2.20-2.32(m, 4H), 2.62-2.68(m, 4H), 2.92(m, 2H), 4.06(m, 2H), 4.54(m, 2H), 5.09 (m, 1H), 6.64 (d, J=7.44 Hz, 1H), 6.94 (d, J=7.84 Hz, 2H), 7.15-7, 22 (m, 2H), 7.39 (d, J=7.44 Hz, 1H).

Step 4: Preparation of 5-bromo-2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-4-methoxypyrimidine

[000181] To a stirred solution of (3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (1 .41 g, 3.7 mmol) in DMF (30 ml) was added 5-bromo-4-methoxy-2-(methylsulfonyl)pyrimidine (2 g, 7.49 mmol) and potassium carbonate (3.1 g, 22 mmol ), and the reaction mixture was heated at 80°C for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (60 ml) and extracted with ethyl acetate (2×120 ml). The combined organic layer was washed with ice water (50 ml), brine (50 ml), dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 10% ethyl acetate in hexane as eluent to give 5-bromo -2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-4- methoxypyrimidine as a sticky liquid (yield: 0.7 g, 17%).

LCMS (ES) m/z=562.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.83 (s, 3H), 1.93 (m, 2H), 2.03 (s, 3H), 2.26 (m, 2H), 2.62 (m, 2H), 2.71 (m, 2H), 2.88-2.92 (m, 2H), 3.98 (s, 3H), 4.06 (m, 2H), 5 .43 (s, 2H), 6.65 (m, 1H), 6.95 (m, 1H), 7.07 (m, 1H), 7.19-7.39 (m, 2H), 7. 43 (m, 1H), 8.53 (s, 1H).

Step 5: Preparation of 2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy) -4-methoxy-5-vinylpyrimidine

[000182] To a stirred solution of 5-bromo-2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]- 3-yl)methoxy)-4-methoxypyrimidine (0.7 g, 1.24 mmol) in DMF (10 ml) was added tributylvinyltin (1.18 g, 3.7 mmol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh _{3) 4} (140 mg, 0.12 mmol) and the reaction mixture was heated at 100° C. for 8 hours. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was diluted with water (30 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 3% ethyl acetate in hexane as eluent to give 2-((3'-(3-(3,3-difluoropyrrolidine-1 -yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxy-5-vinylpyrimidine as a sticky solid (yield: 0.32 g, 47 ,5%).

LCMS (ES) m/z=510.19 [M+H] ⁺ , purity at 214 nm: 87.14%.

Step 6: Preparation of 2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy) -4-methoxypyrimidine-5-carbaldehyde

[000183] To a stirred solution of 2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl) methoxy)-4-methoxy-5-vinylpyrimidine (0.32 g, 0.62 mmol) in acetone (10 ml) and water (2 ml) at 0°C was added OsO ₄ (0.6 ml, 2.5 wt % solution in tert-butanol, 0.062 mmol), N-methylmorpholine N-oxide (103 mg, 0.87 mmol) and stirred for 2 hours. To this mixture was added NaIO ₄ (0.22 g, 1 mmol) and the reaction mixture was allowed to stir at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 12% ethyl acetate in hexane as eluent to give 2-((3'-(3-(3,3-difluoropyrrolidine-1- yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidine-5-carbaldehyde as white sticky solid (yield: 80 mg, 53%) .

LCMS (ES) m/z=512.45 [M+H] ⁺ and purity at 214 nm: 95.24%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.83 (s, 3H), 1.93 (m, 2H), 2.00 (s, 3H), 2.17-2 .24 (m, 2H), 2.59 (m, 2H), 2.68-2.70 (m, 2H), 2.89 (m, 2H), 4.04 (m, 2H), 4. 06 (s, 3H), 5.57 (s, 2H), 6.66 (d, J=7.6 Hz, 1H), 6.95 (d, J=9.2 Hz, 1H), 7, 08 (d, J=7.36 Hz, 1H), 7.17-7.27 (m, 2H), 7.44 (d, J=7.2 Hz, 1H), 8.80 (s, 1H ), 10.04 (s, 1H).

Step 7: Preparation of (S)-1-((2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl ]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid

[000184] To a solution of 2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy )-4-Methoxypyrimidine-5-carbaldehyde (70 mg, 0.1368 mmol) in MeOH (3 ml) and DMF (3 ml) was simultaneously added (S)-piperidine-2-carboxylic acid (26 mg, 0.2052 mmol ) and acetic acid (0.1 ml), and the reaction mixture was stirred at room temperature for 2 hours. To this reaction mixture was added NaCNBH ₃ (25 mg, 0.41 mmol) and continued stirring at room temperature for 16 hours. The reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (2×20 ml). The combined organic layer was washed with water (5 ml) and brine (5 ml), dried over sodium sulfate and concentrated to give a crude residue which was purified by Combiflash chromatography using 8% methanol in dichloromethane as eluent to give (S )-1-((2-((3'-(3-(3, 3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl) methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid as a light white solid (yield: 33 mg, 39%).

LCMS (ES) m/z=625.35 [M+H] ⁺ and purity at 214 nm: 95.52%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.35-1.50 (m, 4H), 1.70-1.73 (m, 2H), 1.83 (s, 3H), 1.80-1.93 (m, 2H), 2.00 (s, 3H), 2.17-2.32 (m, 3H), 2.53-2.71 (m, 4H) , 2.92 (m, 3H), 3.12 (m, 1H), 3.54-3.66 (m, 2H), 3.89 (s, 3H), 4.06 (m, 2H), 5.43 (s, 2H), 6.67 (d, J=7.48 Hz, 1H), 6.95 (d, J=8.21 Hz, 1H), 7.05 (d, J=7 .36 Hz, 1H), 7.17-7.27 (m, 2H), 7.44 (d, J=7.48 Hz, 1H), 8.24 (s, 1H).

[000185] The following compounds were synthesized using a procedure similar to that described above for Compounds 1-13.

N-(2-(((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound fourteen)

[000186] LCMS (ES) m/z=421.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.73 (s, 3H), 2.19 (s, 3H), 3.08-3.12 (m, 2H), 3.55 (s , 3H), 3.91 (s, 3H), 5.42 (s, 2H), 7.17 (d, J=7.6 Hz, 1H), 7.24 (d, J=7.6 Hz , 1H), 7.29 (d, J=7.2 Hz, 2H), 7.36, (d, J=7.2 Hz, 1H), 7.41-7.45 (m, 3H), 7.73 (br s, 1H), 8.22 (s, 1H).

Compound 15: (R)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- carboxylic acid

[000187] LCMS (ES) m/z=448.24 [M+H] ⁺ and purity at 214 nm: 99.9%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.35 (m, 1H), 1.46 (m, 3H), 1.70 (m, 2H), 2.20 (m, 4H), 2.89 (m, 1H), 3.07 (br s, 1H), 3.55 (d, J=14 Hz, 1H), 3.66 (d, J=14 Hz, 1H), 3. 90 (s, 3H), 5.43 (s, 2H), 7.21 (m, 1H), 7.26-7.30 (m, 3H), 7.37 (m, 1H), 7.44 -7.48 (m, 3H), 8.25 (s, 1H).

(S)-1-((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 16)

[000188] LCMS (ES) m/z=466.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (br s, 1H), 1.45 (s, 3H), 1.71 (br s, 2H), 2.18 (s , 3H), 2.20-2.25 (m, 1H), 2.86-2.89 (m, 1H), 3.05-3.15 (m, 1H), 3.51-3.64 (m, 2H), 3.88 (s, 3H), 5.41 (s, 2H), 7.17 (d, J=7.6 Hz, 1H), 7.23-7.27 (m, 3H), 7.31-7.35 (m, 2H), 7.43 (d, J=7.2 Hz, 1H), 8.23 (s, 1H).

(S)-1-((2-((3'-fluoro-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidin-2- carboxylic acid (Compound 17)

[000189] LCMS (ES) m/z=466.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.35 (br s, 1H), 1.40-1.50 (m, 3H), 1.65-1.78 (m, 2H) , 2.20 (s, 3H), 2.30-2.47 (m, 1H), 2.86-2.89 (m, 1H), 3.10 (br s, 1H), 3.52 -3.55 (m, 1H), 3.61-3.64 (m, 1H), 3.88 (s, 3H), 5.42 (s, 2H), 7.14 (d, J=8 Hz, 2H), 7.19-7.20 (m, 2H), 7.27 (t, J=7.2 Hz, 2H), 7.44-7.50 (m, 2H), 8.23 (s, 1H).

N-(2-(((2-((3'-fluoro-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl) acetamide (Compound 18)

[000190] LCMS (ES) m/z=439.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.77 (s, 3H), 2.19 (s, 3H), 2.54 (t, J=6.4 Hz, 2H), 3, 12 (q, J=6.0 Hz, 2H), 3.59 (s, 2H), 3.91 (s, 3H), 5.42 (s, 2H), 7.13 (d, J=8 .0 Hz, 2H), 7.18-7.20 (m, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.44-7.50 (m, 2H), 7 .76 (br s, 1H), 8.24 (s, 1H).

(S)-1-((2-((2'-fluoro-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidin-2- carboxylic acid (Compound 19)

[000191] LCMS (ES) m/z=466.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (br s, 1H), 1.40-1.50 (m, 3H), 1.76-1.78 (m, 2H) , 2.11 (s, 3H), 2.23-2.30 (m, 1H), 2.86-2.89 (m, 1H), 3.10 (br s, 1H), 3.51 -3.54 (m, 1H), 3.61-3.65 (m, 1H), 3.88 (s, 3H), 5.42 (s, 2H), 7.18 (d, J=7 .2, 1H), 7.26-7.29 (m, 4H), 7.43-7.48 (m, 2H), 8.25 (s, 1H).

N-(2-(((2-((2'-fluoro-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl) acetamide (Compound 20)

[000192] LCMS (ES) m/z=439.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.77 (s, 3H), 2.11 (s, 3H), 2.55-2.61 (m, 2H), 3.10-3 .15 (m, 2H), 3.32 (s, 1H), 3.62 (s, 2H), 3.91 (s, 3H), 5.43 (s, 2H), 7.18 (d, J=7.2, 1H), 7.26-7.31(m, 4H), 7.41-7.47(m, 2H), 7.78(brs, 1H), 8.25( s, 1H).

N-(2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 21)

[000193] LCMS (ES) m/z=435.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.30 (t, J=7.2 Hz, 3H), 1.76 (s, 3H), 2.18 (s, 3H), 2.52 -2.53(m, 2H), 3.08-3.13(m, 2H), 3.56(s, 2H), 4.37(q, J=7.2Hz, 2H), 5, 40 (s, 2H), 7.16 (d, J=7.2 Hz, 1H), 7.23-7.29 (m, 3H) 7.35-7.37 (m, 1H), 7. 39-7, 45 (m, 3H), 7.74 (br s, 1H), 8.22 (s, 1H).

(S)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Connection 22)

[000194] LCMS (ES) m/z=462.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.28 (t, J=7.2 Hz, 3H), 1.35-1.45 (m, 3H), 1.66-1.78 (m, 2H), 2.18 (s, 3H), 2.87-2.90 (m, 2H), 3.09-3.13 (m, 2H), 3.50-3.54 (m , 1H), 3.60-3.63 (m, 1H), 4.35 (q, J=6.8 Hz, 2H), 5.40 (s, 2H), 7.17 (d, J= 6.8 Hz, 1H), 7.25-7.30 (m, 3H) 7.34-7.37 (m, 1H), 7.40-7.45 (m, 3H), 8.22 ( s, 1H).

1-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)cyclopropane-1-carboxylic acid (Compound 23)

[000195] LCMS (ES) m/z=434.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ0.88-0.89 (m, 2H), 1.05-1.09 (m, 2H), 1.30 (t, J=6.8 Hz, 3H), 2.17 (s, 3H), 3.67 (s, 3H), 4.35 (q, J=6.8 Hz, 2H), 5.39 (s, 2H) 7.16 (d, J=7.2 Hz, 1H), 7.22-7.29 (m, 3H) 7.34-7.45 (m, 5H), 8.15 (s, 1H).

(3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)propionic acid (Compound 24)

[000196] LCMS (ES) m/z=422 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.30 (t, J=6.8 Hz, 3H), 2.18-2.20 (m, 6H), 2.65 (s, 2H) , 3.58 (s, 2H), 4.37 (q, J=7.2 Hz, 2H), 5.40 (s, 2H) 7.16 (d, J=7.6 Hz, 1H), 7.23-7.29 (m, 3H) 7.34-7.45 (m, 4H), 8.23 (s, 1H).

2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propan- 1,3-diol (Compound 25)

[000197] LCMS (ES) m/z=454 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.29 (t, J=6.8 Hz, 3H), 1.77 (br s, 1H), 2.18 (s, 3H), 3 .35-3.36 (m, 6H), 3.60 (s, 2H), 4.20 (s, 3H), 4.36 (kv, J=7.2 Hz, 2H), 5.40 ( s, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.23-7.30 (m, 3H) 7.34-7.45 (m, 4H), 8.25 ( s, 1H).

(2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)(methyl)amino)-2-( hydroxymethyl)propane-1,3-diol (Compound 26)

[000198] LCMS (ES) m/z=468.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.30 (t, J=7.2 Hz, 3H), 2.18 (s, 6H), 3.50-3.51 (m, 6H) , 3.66 (s, 2H), 4.20 (s, 3H), 4.35 (q, J=6, 8 Hz, 2H), 5.40 (s, 2H), 7.17 (d, J=7.8 Hz, 1H), 7.23-7.30 (m, 3H) 7.34-7.45 (m, 4H), 8.25 (s, 1H).

(S)-3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)butyric acid (Compound 27)

[000199] LCMS (ES) m/z=436.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.09 (d, J=6.4 Hz, 3H) 1.30-1.26 (m, 2H), 1.33-1.30 ( m, 3H), 2.22-2.18 (m, 5H), 2.97-2.94 (m, 1H), 3.74-3.61 (m, 2H), 4.39-4, 37 (m, 2H), 5.42 (s, 2H), 7.18-7.16 (m, 1H), 7.30-7.23 (m, 3H) 7.45-7.40 (m , 4H), 8.28 (s, 1H).

((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-D-alanine (Compound 28)

[000200] LCMS (ES) m/z=464.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.31 (t, J=7.2 Hz, 3H), 2.18 (s, 3H), 3.38 (br s, 2H), 3.77-3.68(m, 2H), 4, 40-4, 35(m, 2H), 5.42(s, 2H), 6.93(s, 1H), 7.30-7, 23 (m, 3H) 7.50-7.34 (m, 4H), 8.28 (s, 1H).

((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)asparagine (Compound 29)

[000201] LCMS (ES) m/z=464.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.31 (t, J=7.2 Hz, 3H), 2.18 (s, 3H), 3.38 (br s, 2H), 3.77-3.68(m, 2H), 4, 40-4, 35(m, 2H), 5.42(s, 2H), 6.93(s, 1H), 7.30-7, 23 (m, 3H) 7.50-7.34 (m, 4H), 8.28 (s, 1H).

(2R,4R)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine- 2-carboxylic acid (Compound 30)

[000202] LCMS (ES) m/z=464.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (t, J=7.2 Hz, 3H), 1.98-1.90 (m, 2H), 2.13 (s, 3H ), 2.42-2.39 (m, 1H) 3.21-3.17 (m, 2H), 3.46-3.42 (m, 2H), 3.79-3.73 (m, 2H), 4.17 (s, 1H), 4.38-4.33 (m, 2H), 5.41 (s, 2H), 7.17-7.16 (m, 1H), 7.30 -7.23 (m, 3H), 7.37-7.33 (m, 1H), 7.45-7.40 (m, 3H), 8.23 (s, 1H).

1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)azetidine-2-carboxylic acid (Compound 31)

[000203] LCMS (ES) m/z=433.51 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.29 (q, J=4.2 Hz, 3H), 2.05-1.82 (m, 2H), 2.18 (s, 3H ), 3.20-3.11 (m, 4H), 3.74-3.70 (m, 1H), 4.38-4.32 (m, 2H), 5.39 (s, 2H), 7.30-7.15 (m, 5H), 7.45-7.37 (m, 5H), 8.20 (s, 1H).

N-(2-(((4-(benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 32)

[000204] LCMS (ES) m/z=496.61 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.72 (s, 3H), 2.17 (s, 3H), 2.555-2.53 (m, 3H), 3.14-3.08 (m, 2H), 3.64 (s, 2H), 5.47-5.37 (m, 4H) 7.17-7.16 (m, 2H), 7.34-7.27 (m, 3H) 7.36-7.34 (m, 5H), 7.45-7.37 (m, 4H), 8.26 (s, 1H).

1-((4-(Benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 33 )

[000205] LCMS (ES) m/z=523.63 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.21 (s, 1H), 1.43-1.39 (m, 4H), 1.72-1.70 (m, 2H), 2 .17 (s, 3H), 2.30-2.21 (m, 1H), 2.86-2.85 (m, 1H), 3.16-3.15 (m, 2H), 3.67 -3.51(m, 2H), 5.41(d, J=5.6Hz, 2H), 7.18-7.16(m, 2H), 7.34-7.27(m, 3H ), 7.36-7.34 (m, 5H), 7.45-7.37 (m, 4H), 8.25 (s, 1H).

(2S,4R)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 34)

[000206] LCMS (ES) m/z=480.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.88-1.90 (m, 2H), 2.21 (s, 3H), 3.14 (s, 1H), 3.35-3 .19 (m, 1H), 3.76-3.83 (m, 3H), 3.88 (s, 6H), 4.15 (br.s, 1H), 4.94 (br.s, 1H ), 5.44 (s, 2H), 7.18 (d, J=7.6 Hz, 1H), 7.24-7.30 (m, 3H) 7.33-7.37 (m, 1H ), 7.41-7.46 (m, 3H).

2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 35)

[000207] LCMS (ES) m/z=470.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 3.34 (d, J=4.8 Hz, 6H), 3.54 (s, 2H), 3. 88 (s, 6H), 4.12, brs, 3H), 5.43 (s, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.24-7.30 (m , 3H), 7.34-7.39 (m, 1H), 7.43 (t, J=7.6 Hz, 3H).

((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-L-proline (Compound 36)

[000208] LCMS (ES) m/z=464.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.55-1.89 (m, 3H), 2.01-2.22 (m, 1H), 2.21 (s, 3H), 2 .65 (br.s, 1H), 3.05-3.09 (m, 1H), 3.18-3.29 (m, 1H), 3.86 (s, 2H), 3.90 (S , 6H), 5.45 (s, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.25-7.30 (m, 3H), 7.34-7.38 ( m, 1H), 7.42-7.47 (m, 3H).

Methyl 4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylate (Compound 37)

[000209] LCMS (ES) m/z=494.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 2.29-2.32 (m, 1H), 3.09 (t, J=8.4 Hz, 1H ), 3.16-3.27 (m, 1H), 3.45-3.50 (m, 1H), 3.52-3.69 (m, 7H), 3.85 (s, 6H), 5.44 (s, 2H), 7.18 (d, J=8 Hz, 1H), 7.24-7.38 (m, 3H), 7.34-7.38 (m, 1H), 7 .42-7.46 (m, 3H).

4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 38 )

[000210] LCMS (ES) m/z=480 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 2.29-2.32 (m, 1H), 2.99-3.04 (m, 1H), 3 .42-3.49 (m, 2H), 3.51-3.64 (m, 3H), 3.66-3.72 (m, 2H), 3.85 (s, 6H), 5.43 (s, 2H), 7.18 (d, J=8 Hz, 1H), 7.24-7.38 (m, 3H), 7.34-7.38 (m, 1H), 7.42- 7.46 (m, 3H).

(2S,4R)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 39)

[000211] LCMS (ES) m/z=508.19 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.30-1.32 (t, 6H), 1.93 (m, 2H), 2.21 (s, 3H), 2.66 (m , 1H), 3.23-3.27 (br.s, 1H), 3.36-3.46 (br.s, 1H), 3.82 (d, 1H), 3.92 (d, 1H ), 4.17(s, 1H), 4.35-4.38(m, 4H), 4.97(br s, 1H), 5.43(s, 2H), 7.20(m, 1H), 7.26-7.30 (m, 3H), 7.40 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 99.78%.

((S)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- carboxylic acid (Compound 40)

[000212] LCMS (ES) m/z=506.19 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.26-1.28 (m, 6H), 1.33 (m, 2H), 1.46 (m, 2H), 1.70 (s , 2H), 2.21 (s, 3H), 2.37 (m, 1H), 3.00 (s, 1H), 3.11 (s, 1H), 3.62 (d, J=13, 2 Hz, 1H), 3.74 (d, J=13.2 Hz, 1H), 4.33 (m, 4H), 5.41 (s, 2H), 7.20 (m, 1H), 7 .26-7.30 (m, 3H), 7.40 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 99.60%.

2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 41)

[000213] LCMS (ES) m/z=498.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.28 (m, 6H), 2.21 (s, 3H), 3.40 (m, 4H), 3.56 (br s, 2H ), 4.15 (brs, 2H), 4.33-4.38 (m, 4H), 5.42 (m, 2H), 7.20 (m, 1H), 7.26-7, 30 (m, 3H), 7.40 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 99.77%.

2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 42)

[000214] LCMS (ES) m/z=470.362 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.22 (s, 3H), 3.38 (m, 4H), 3.57 (m, 2H), 3.90 (s, 6H), 4.71(brs, 2H), 5.45(s, 2H), 7.20(m, 1H), 7.26-7.30(m, 3H), 7.37(m, 1H) , 7.44-7.48 (m, 3H), HPLC at 214 nm: 97.42%.

(S)-4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 43)

[000215] LCMS (ES) m/z=480.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.22 (s, 3H), 3.03 (m, 2H), 3.32 (m, 1H), 3.50 (m, 1H), 3.59 (m, 3H), 3.67 (m, 2H), 3.87 (s, 6H), 5.45 (s, 2H), 7.20 (m, 1H), 7, 26-7 , 30 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 98.9%.

2-(4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholin-3-yl) acetic acid (Compound 44)

[000216] LCMS (ES) m/z=494.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.20 (m, 5H), 2.50 (m, 1H), 2.71 (m, 2H), 3.22 (m , 2H), 3.40-3.63 (m, 4H), 3.88 (s, 6H), 5.45 (s, 2H), 7.20 (m, 1H), 7.26-7, 30 (m, 3H), 7.39 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 98.43%.

(S)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid acid (Compound 45)

[000217] LCMS (ES) m/z=478.36 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.23-1.31 (m, 4H), 1.63 (m, 1H), 1.71 (m, 1H), 2.23 (s , 3H), 2.33 (m, 1H), 3.03-2.97 (m, 2H), 3.63 (m, 1H), 3.77 (m, 1H), 3.91 (s, 6H), 5.45 (s, 2H), 7.20 (m, 1H), 7.26-7.32 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 3H), HPLC at 214 nm: 99.83%.

(S)-5-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[ 2.4]heptane-6-carboxylic acid (Compound 46)

[000218] LCMS (ES) m/z=490.39 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 0.42-0.55 (m, 4H), 1.23 (m, 2H), 1.71-1.75 (m, 1H), 2 .23 (s, 3H), 2.27 (m, 1H), 2.87 (m, 1H), 2.94 (m, 1H), 3.59 (m, 1H), 3.97 (s, 6H), 5.47 (s, 2H), 7.19-7.21 (m, 1H), 7.26-7.32 (m, 3H), 7.35-7.39 (m, 1H) , 7.43-7.47 (m, 3H), HPLC at 214 nm: 99.30%.

7-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5] decan-1-on (Compound 47)

[000219] LCMS (ES) m/z=503.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 1.33-1.47 (m, 4H), 1.78-1.97 (m, 3H), 2.07-2.05 (m, 1H), 2.22 (s, 3H), 2.39 (m, 1H), 2.72 (m, 1H), 3.09 (m, 2H), 3.33 (m, 2H), 3, 88 (s, 6H), 5.45 (s, 2H), 7.19-7.21 (m, 1H), 7.26-7.32 (m, 3H), 7.35-7.39 ( m, 1H), 7, 43-7, 47 (m, 4H), HPLC at 214 nm: 99.84%.

rac-(1R,6S)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)- 2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 48)

[000220] LCMS (ES) m/z=460.43 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 0.99-1.00 (m, 1H), 1.19-1.22 (m, 2H), 1.56-1.59 (m, 2H), 1.80-1.84 (m, 1H), 2.21 (s, 3H), 2.33-2.36 (m, 1H), 2.53 (m, 2H), 3.67 -3.55(m, 2H), 3.89(s, 3H), 5.51(s, 2H), 7.19-7.21(m, 1H), 7.26-7.32(m , 3H), 7.35-7.39 (m, 1H), 7.43-7.47 (m, 3H), 8.37 (s, 1H), 11.82 (br s, 1H), HPLC at 214 nm: 99.23%.

(S)-4-acetyl-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazin-2 -carboxylic acid (Compound 49)

[000221] LCMS (ES) m/z=491.46 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.95 (m, 3H), 2.20 (s, 3H), 2.32 (br s, 1H), 2.84-3.01 (m, 2H), 3.15 (m, 1H), 3.45 (m, 1H), 3.55-3.79 (m, 2H), 3.89 (m, 5H), 5.49 ( s, 2H), 7.17-7.19 (m, 1H), 7.26-7.32 (m, 3H), 7.35-7.39 (m, 1H), 7.43-7, 47 (m, 3H), 8.26 (br s, 1H), HPLC at 214 nm: 99.86%.

(S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid ( Compound 50)

[000222] LCMS (ES) m/z=449.23[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.21 (s, 3H), 2.49 (m, 1H), 2.66-2.88 (m, 3H), 2.98-2 .95 (m, 1H), 3.09 (m, 1H), 3.12 (m, 1H), 3.54-3.57 (m, 1H), 3.66-3.69 (m, 1H ), 3.89 (s, 3H), 5.49 (s, 2H), 7.17-7.19 (m, 1H), 7.24-7.32 (m, 3H), 7.35- 7.39 (m, 1H), 7.43-7.47 (m, 3H), 8.31 (br s, 1H), HPLC at 214 nm: 97.83%.

(S)-5-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[2, 4]heptane-6-carboxylic acid (Compound 51)

[000223] LCMS (ES) m/z=460.36 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 0.42-0.51 (m, 4H), 1.73-1.78 (m, 1H), 2.14 (m, 1H), 2 .23 (s, 3H), 2.68 (m, 1H), 2.78 (m, 1H), 3.57 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 3.91 (s, 3H), 5.51 (s, 2H), 7.19-7.21 (m, 1H), 7.24-7.32 (m, 3H), 7.35 -7.39 (m, 1H), 7.43-7.49 (m, 3H), 8.30 (s, 1H); HPLC purity at 214 nm: 99.70%.

7-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5]decan- 1-one (Compound 52)

[000224] LCMS (ES) m/z=473.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 1.33-1.51 (m, 4H), 1.76-1.89 (m, 2H), 1.95-2.03 (m, 2H), 2.21 (s, 3H), 2.43 (m, 1H), 2.76 (m, 1H), 2.96-3.06 (m, 2H), 3.36 (m, 2H ), 3.89 (s, 3H), 5.44-5.52 (m, 2H), 7.19-7.21 (m, 1H), 7.24-7.32 (m, 3H), 7.35-7.39 (m, 1H), 7.43-7.49 (m, 4H), 8.21 (s, 1H); HPLC purity at 214 nm: 95.84%.

N-(2-(((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)amino)ethyl)acetamide (Compound 53)

[000225] LCMS (ES) m/z=540.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.75 (s, 3H), 2.19 (s, 3H), 2.55 (m, 2H), 3.10 (m, 2H), 3.64 (s, 2H), 5.40 (s, 2H), 5.48 (s, 2H), 7.21 (m, 1H), 7.26-7.31 (m, 3H), 7 .37 (m, 1H), 7.43-7.47 (m, 3H), 7.55 (t, J=9.2 Hz, 1H), 7.77 (m, 1H), 7.88 ( m, 1H), 8.04 (m, 1H), 8.30 (s, 1H); HPLC purity at 214 nm: 96.36%.

(2S,4R)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 54)

[000226] LCMS (ES) m/z=569.28 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.87-2.02 (m, 2H), 2.20 (s, 3H), 2.40 (m, 1H), 3.18 (m , 1H), 3.46 (m, 1H), 3.70 (d, J=14 Hz, 1H), 3.82 (d, J=14 Hz, 1H), 4.20 (m, 1H), 4.90 (br s, 1H), 5.40 (s, 2H), 5.48 (s, 2H), 7.21 (m, 1H), 7.26-7.31 (m, 3H) , 7.37 (m, 1H), 7.43-7.47 (m, 3H), 7.55 (t, J=9.2 Hz, 1H), 7.88 (m, 1H), 8. 04 (m, 1H), 8.32 (s, 1H); HPLC purity at 214 nm: 98.12%.

(S)-1-((2-((3-(2,3-dihydro[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)piperidine-2-carboxylic acid (Compound 55)

[000227] LCMS (ES) m/z=536.26 [M+H] ⁺ and purity at 214 nm: 98.69%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.49-1.44 (m, 2H), 1.63-1.70 (m, 2H), 1.89 (s, 2H), 2 .23 (s, 3H), 2.30 (m, 1H), 2.96-3.04 (br.s, 2H), 3.63-3.76 (m, 2H), 3.87 (s , 6H), 4.27 (s, 4H), 5.43 (s, 2H), 6.73-6.77 (m, 2H), 6.92 (d, J=8.12 Hz, 1H) , 7.15-7.17 (m, 1H), 7.22-7.26 (m, 1H), 7.44 (d, J=7, 16 Hz, 1H).

N-(2-(((2-((3-(2,3-dihydro[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)amino)ethyl)acetamide (Compound 56)

[000228] LCMS (ES) m/z=509.23 [M+H] ⁺ and purity at 214 nm: 96.7%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.82 (s, 3H), 2.23 (s, 3H), 2.82 (br s, 2H), 3.24-3.25 (m, 2H), 3.83 (m, 2H), 3.94 (s, 6H), 4.27 (s, 4H), 5.47 (s, 2H), 6.73-6.77 ( m, 2H), 6.92 (d, J=8.12 Hz, 1H), 7.15-7.17 (m, 1H), 7.22-7.26 (m, 1H), 7.44 (d, J=7, 16 Hz, 1H), 7.95-7.97 (m, 1H).

N-(2-(((2-((3',4'-dimethoxy-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5-yl)methyl )amino)ethyl)acetamide (Compound 57)

[000229] LCMS (ES) m/z=511.33 [M+H] ⁺ and purity at 214 nm: 95.1%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.78 (s, 3H), 2.25 (s, 3H), 2.56 (m, 2H), 3.13 (m, 2H), 3.60 (m, 2H), 3.76 (s, 3H), 3.79 (s, 3H), 3.90 (s, 6H), 5.44 (s, 2H), 6.82 (d , J=8.12 Hz, 1H), 6.86 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 7.20-7.21 (m, 2H), 7 .45 (d, J=7 Hz, 1H), 7.81 (br.s, 1H).

((2S,4R)-1-((2-((3',4'-dimethoxy-2-methyl[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 58)

[000230] LCMS (ES) m/z=540.33 [M+H] ⁺ and purity at 214 nm: 99.69%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.85-1.91 (m, 2H), 2.25 (s, 3H), 2.50 (s, 2H), 3.35-3 .41 (m, 2H), 3.76-3.82 (m, 8H), 3.90 (s, 6H), 4.18 (m, 1H), 4.99 (br s, 1H), 5.45 (s, 2H), 6.82 (d, J=8.12 Hz, 1H), 6.86 (s, 1H), 7.08 (d, J=8, 2 Hz, 1H), 7.20-7.21 (m, 2H), 7.45 (d, J=7 Hz, 1H).

(2S,4R)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 59)

[000231] LCMS (ES) m/z=552.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.93-2.00 (m, 2H), 2.20 (s, 3H), 2.40 (m, 1H), 3.18 (m , 1H), 3.47 (m, 1H), 3.71 (d, J=14 Hz, 1H), 3.82 (d, J=14 Hz, 1H), 4.20 (m, 1H), 4.91 (br s, 1H), 5.48 (s, 4H), 7.18-7.20 (m, 1H), 7.24-7.32 (m, 3H), 7.36- 7, 38 (m, 1H), 7.43-7.47 (m, 3H), 8.32 (s, 1H), 8.43 (s, 1H), 8.98 (s, 1H), 9 .00 (s, 1H); HPLC purity at 214 nm: 99.59%.

(S)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl)acetic acid (Compound 60)

[000232] LCMS (ES) m/z=462.38 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33-1.36 (m, 2H), 1.46 (m, 3H), 1.70 (m, 1H), 2.20 (s , 3H), 2.23-2.32 (m, 2H), 2.63 (m, 2H), 2.87 (m, 1H), 3.40 (d, J=14 Hz, 1H), 3 .68 (d, J=14 Hz, 1H), 3.90 (s, 3H), 5.43 (s, 2H), 7.18 (m, 1H), 7.26-7.32 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 3H), 8.25 (s, 1H), HPLC at 214 nm: 96%.

[000233] Compounds 61-63 were prepared in a manner similar to that used for Compound 60.

(R)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl)acetic acid (Compound 61)

[000234] LCMS (ES) m/z=462.23 [M+H] ⁺ .

(S)-4-(6-acetamidohexanoyl)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )piperazine-2-carboxylic acid (Compound 62)

[000235] LCMS (ES) m/z=604.3 [M+H] ⁺ .

(S)-4,4-difluoro-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine -2-carboxylic acid (Compound 63)

[000236] LCMS (ES) m/z=484.3 [M+H] ⁺ .

Synthesis of (S)-1-((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 64)

Step 1: Synthesis of 5-bromo-4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine

[000237] Sodium hydride (1. 73 g, 60% in mineral oil, 0.043 mol) and stirred at room temperature for 30 minutes. To this mixture was added 5-bromo-2-chloro-4-methylpyrimidine (5 g, 0.024 mol) and left to stir at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh), using 10% ethyl acetate in hexane as eluent, to give 5-bromo-4-methyl-2-((2-methyl-[1,1' -biphenyl)]-3-yl)methoxy)pyrimidine as an off-white solid (yield: 1.5 g, 17%).

LCMS (ES) m/z=369.01 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.31 (s, 3H), 2.58 (s, 3H), 5.47 (s, 2H), 7.21-7.23 (m, 2H ), 7.25-7.30 (m, 2H), 7.35 (m, 1H), 7.39-7.43 (m, 2H), 7.49 (m, 1H), 8.47 ( s, 1H); HPLC purity at 214 nm: 99.78%.

Stage 2: Synthesis of 4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine

[000238] To a stirred solution of 5-bromo-4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine (1/5 g, 0.0041 mol) in DMF (20 ml) was added tributylvinyltin (3.2 g, 0.011 mol) and the reaction mixture was degassed with nitrogen gas for 10 minutes. To this mixture was added Pd(PPh ₃ ) ₄ (0.46 g, 0.4 mmol) and the reaction mixture was heated at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was diluted with water (50 ml) and was extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulfate, evaporated and the crude product was purified by Combiflash chromatography using 25% ethyl acetate in hexane as eluent to give 4-methyl-2-((2-methyl-[1,1'- biphenyl).]-3-yl)methoxy)-5-vinylpyrimidine as a yellowish liquid (yield: 1.2 g, 92%).

LCMS (ES) m/z=317.42 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.20 (s, 3H), 2.46 (s, 3H), 5.30 (d, J=11.2 Hz, 1H), 5, 45 (s, 2H), 5.78 (d, J=17.6 Hz, 1H), 6.82 (m, 1H), 7.19 (m, 1H), 7.25-7.32 (m , 3H), 7.36-7.39 (m, 1H), 7.43-7.47 (m, 3H), 8.67 (s, 1H); HPLC purity at 214 nm: 99.04%.

Stage 3: Synthesis of 4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidine-5-carbaldehyde

[000239] To a stirred solution of 4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidine (0.9 g, 0.003 mol) in THF (25 ml) and water (25 ml) at 0°C was added OsO ₄ (42 ml, 2.5 wt.% solution in tert-butanol, 0.0042 mol) and stirred for 15 minutes. NaIO ₄ (0.89 g, 0.0042 mol) was added to this mixture and the reaction mixture was allowed to stir at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with water (50 ml) and was extracted with DCM (2×50 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 20% ethyl acetate in hexane as eluent to give 4-methyl-2-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)pyrimidine-5-carbaldehyde as an off-white solid (yield: 0.64 g, 73%).

LCMS (ES) m/z=319.36 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 2.22 (s, 3H), 2.73 (s, 3H), 5.57 (s, 2H), 7.21 (m, 1H), 7.27-7.33 (m, 3H), 7.38 (m, 1H), 7.46 (m, 3H), 8.99 (s, 1H), 10.12 (s, 1H); HPLC purity at 214 nm: 97.18%.

Step 4: Synthesis of (S)-1-((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2 -carboxylic acid

[000240] To a solution of 4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-carbaldehyde (0.2 g, 0.62 mmol) in MeOH (2 ml) and DMF (2 ml) were added simultaneously (S)-piperidine-2-carboxylic acid (73 mg, 0.56 mmol) and acetic acid (1 drop) and the reaction mixture was stirred at room temperature for 2 hours . To this reaction mixture was added NaCNBH ₃ (110 mg, 1.86 mmol) and continued stirring at room temperature for 16 hours. The reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (2×10 ml). The combined organic layer was washed with water (3 ml) and brine (3 ml), dried over sodium sulfate and concentrated to give the crude product, which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to give (S) -1-((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid as a white solid substances (yield: 90 mg, 35%).

LCMS (ES) m/z=432.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33-1.42 (m, 4H), 1.72 (m, 2H), 2.16 (m, 1H), 2.20 (s , 3H), 2.49 (s, 3H), 2.78 (m, 1H), 3.08 (m, 1H), 3.39 (m, 1H), 3.75 (m, 1H), 5 .41 (s, 2H), 7.18 (m, 1H), 7.25-7.32 (m, 3H), 7.37 (m, 1H), 7.43-7.47 (m, 3H ), 8.31 (s, 1H); HPLC purity at 214 nm: 99.20%.

[000241] Compound 65 was prepared in a manner analogous to that described above for compound 64.

N-(2-(((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 65)

[000242] LCMS (ES) m/z=405.24 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.78 (s, 3H), 2.20 (s, 3H), 2.45 (s, 3H), 2.55 (m, 2H), 3.13 (m, 2H), 3.64 (s, 2H), 5.42 (s, 2H), 7.18 (m, 1H), 7.25-7.32 (m, 3H), 7 .37 (m, 1H), 7.43-7.47 (m, 3H), 7.77 (br s, 1H), 8.37 (s, 1H); HPLC purity at 214 nm: 98.84%.

Example 5

General Procedures for Biological Assessments

PD-L1 Enzyme Assay: Binding Assay Using Time-Resolved Homogeneous Fluorescence (HTRF)

[000243] All binding studies were performed using the PD-1/PD-L1 Binding Assay Kit from CisBio (Catalog # 63ADK000CPAPEG), following the manufacturer's protocol. The interaction between Tag1-PD-1 and Tag2-PD-1 was detected using anti-Tag1-Eu ³⁺ (HTRF donor) and anti-Tag2-XL665 (HTRF acceptor) antibodies. When donor and acceptor antibodies came into close proximity due to PD-1 and PD-L1 binding, excitation of the donor antibody caused fluorescent resonance energy transfer (FRET) to the acceptor antibody, which in turn specifically emitted light at a wavelength of 665 nm. This specific signal is directly proportional to the PD-1/PD-L1 interaction. Compounds that block PD-1/PD-L1 interaction cause a decrease in HTRF signal. Required reagents were mixed in the following order: 2 µl compound (or diluent buffer), 4 µl PD-L1 protein, 4 µl PD-1 protein. After a 15 minute incubation, 5 μl of anti-Tag1-Eu ³⁺ antibody and 5 μl of anti-Tag2-XL665 antibody were added. The tablet was closed and incubated at room temperature for 1 hour. Fluorescent radiation was read at two different wavelengths (665 nm and 620 nm) on a BMG PheraStar® multiplate reader. The results obtained from the fluorescence signals at 665 nm and 620 nm were used to calculate the ratio HTRF=(665 nm/620 nm)×10 ⁴ . Assessment of biological activity:

[000244] Table 1 below shows the biological activity of the compounds of the invention as determined in a PD1/PD-L1 inhibition assay. Compounds having an IC ₅₀ <100 nM are designated "A"; 100-500 nM are designated as "B"; and >500 nM are labeled "C", respectively.

[000245] Table 1 shows the results that most tested compounds effectively block PD1/PD-L1 when assessed by the analysis of binding with homogeneous fluorescence over time (HTRF). The IC ₅₀ values indicate the effectiveness of the compounds in inhibiting PD1/PD-L1 activation. The IC ₅₀ value indicates how much of a particular drug or compound is needed to inhibit the PD1/PD-L1 interaction by 50%. A low IC ₅₀ value indicates a high inhibitory efficacy of the test compound (compounds 1-65 described above). In Table 1 above, the efficiency level is designated by the letters "A", "B" and "C", where "A" corresponds to the lowest IC ₅₀ value, and thus the highest efficiency.

[000246] The above compounds have sufficient potency to recognize their potential for use as drugs to reduce PD1/PD-L1 activity, and thus their acceptability for the treatment of cancer and other diseases or conditions associated with PD1/ activation. PD-L1.

Example 6

Evaluation of the pharmacokinetics of Compound 45: an overview of animal experiments

[000247] The Jubilant Biosys Institutional Animal Care and Ethics Committee (IAEC) (IAEC/JDC/2018/158), appointed by the State Committee for the Control and Supervision of Animal Experimentation (CPCSEA), has approved pharmacokinetic experiments in mice. Male Balb/c mice (~6-8 weeks old, body weight range 22-25 g) were purchased from Vivo Biotech, Hyderabad, India. Animals were quarantined in the Jubilant Biosys Animal House for 7 days with light:dark cycles of 12:12 hours, and prior to the study, the animals were distributed according to body weight. The animals had free access to food (Altromin Spezialfutter GmbH & Co. KG., Im Seelenkamp 20, D-32791, Lage, Germany) and water ad libitum.

[000248] An intravenous and oral pharmacokinetic study was performed for doses of 2 and 10 mg/kg, at a dose volume of 10 ml/kg. Serial blood samples (200 µl) were taken from the retroorbital plexus at time points corresponding to 0.083 (for IV only), 0.15, 0.5, 1, 2, 4, 8, 10 (for PO only) and 24 hours. Blood samples were collected in tubes containing K ₂ EDTA as an anticoagulant and centrifuged for 5 minutes at 14,000 rpm in a refrigerated centrifuge (Biofuge, Heraeus, Germany) at 4°C to separate plasma.

[000249] Group I (oral administration, po) (body weight 22-25 g) received compound 45 at a dose of 10 mg/kg (suspension composition prepared using 0.5% methylcellulose and Tween-80; dose volume: 10 ml/kg), while group II (body weight 24-25 g) received compound 45 intravenously (IV) [5% DMSO, 5% Solutol:absolute alcohol (1:1/v/v) and 90% saline; load: 0.2 mg/ml; dose volume: 10 ml/kg] at a dose of 2.0 mg/kg. After dosing, serial blood samples (200 μl) were taken, selective sampling was performed (three mice were used for blood sampling at each time point) at regular intervals using heparinized capillaries for blood sampling through the retroorbital plexus into polypropylene tubes containing K ₂ EDTA solution as an anticoagulant. Animals were allowed to feed 2 hours after dosing Compound 45. Compound 45 blood concentration versus time data were analyzed non-compartmentally using Phoenix WinNonlin Version 7.0 software.

[000250] The results obtained are shown in Table 2 below.

Example 7

ADME (absorption, distribution, metabolism and excretion) and pharmacokinetics Compound 45

Metabolic stability in liver microsomes

[000251] Procedure: Potassium phosphate buffer (66.7 mM, pH 7.4) containing mouse or rat, dog or monkey or human liver microsomes (0.5 mg/mL) was pre-incubated separately with test compound (1 µM) and a positive control (verapamil, 1 µM) in a water bath at 37°C for 5 minutes. Reactions were initiated by adding 20 μl of 10 mM NADPH. Reactions without NADPH (0 and 30 minutes) were also incubated to rule out non-NADPH related metabolism or chemical instability in the incubation buffer. All reactions were terminated using 200 μl of ice-cold acetonitrile containing an internal standard at 0, 5, 15 and 30 minutes. The vials were centrifuged at 3000 rpm for 15 minutes. Reaction mixtures (obtained from the above studies) were recovered, processed and analyzed by LC-MS [Shimadzu SIL LC series unit (Kyoto, Japan) with API-4000 mass spectrometer (MDS Sciex, Toronto, Canada)] to monitor the disappearance of the compound.

Conclusion

Metabolic stability of Compound 45: High stability (>80%) was found for different types of microsomes of Compound 45 in the liver of mice, rats, dogs and humans.

Permeability to Caco-2 cells

[000252] Procedure: Caco-2 human intestinal epithelial cells were seeded in 24-Transwell® dual chamber plates (Millipore, Billerica, MA, USA) (cell density 80,000 cells/cm ² on day 1). Permeability studies were performed with monolayers cultured for 21-22 days in cell culture. The integrity of each monolayer of Caco-2 cells was confirmed by the transepithelial electrical resistance (TEER) test (preliminary experiment) and by determination of the permeability of the reference compound, ie Lucifer yellow. For the experiments we used monolayers of Caco-2 cells with TEER values of more than 500 Ohm⋅cm ² . Digoxin (5 μM) was used as a positive control for the P-gp substrate. The concentrations of the compound used in the assay were 5 μM. HBSS buffer was used as the transfer assay medium and the final concentration of DMSO in solution after additions was 0.05%. The bidirectional permeability study was initiated by adding an appropriate volume of compound-containing HBSS buffer to the appropriate apical and basolateral chambers (n=3). An aliquot of the sample (100 μl) was taken from both chambers at 0 and 60 minutes after incubation. Acetonitrile was added to this equal volume, mixed gently and centrifuged at 4000 rpm for 10 minutes. An aliquot of 100 µl was transferred to an autosampler and 10 µl was injected into the setup for LC-MS/MS analysis.

Conclusion:

Compound 45 was found to be moderately permeable and high efflux/excretion in the Caco-2 cell assay and may be an active efflux transporter substrate.

Plasma protein binding

Procedure:

[000253] To evaluate the ability of a compound of the invention to bind plasma proteins, the most common method of assaying plasma protein binding using equilibrium dialysis was used. The test compound was evaluated at a final concentration of 3 μM in mouse, rat, human or dog plasma. A 150 μl aliquot of plasma containing the compound was added to the first half (plasma side) of a well of a 96-well microequilibrium dialysis device. A 150 μl aliquot of 100 mM sodium phosphate buffer, pH 7.4, was added to the other half (buffer side) of a well of a 96-well HT-equilibrium dialysis device. The plate containing plasma and buffer was equilibrated at 37+1°C for 4.5 hours with constant shaking at 120 rpm on an orbital shaker. After completion of the incubation time, samples were taken from the respective halves. Proteins were precipitated with organic solvents. Samples were subjected to centrifugation and supernatants were analyzed on the LC-MS/MS unit.

Conclusion:

Compound 45 showed high plasma binding in mice, with an unbound fraction of 0.039. The stability and resilience of Compound 45 in plasma was good.

CYP inhibition

Procedure:

[000254] The CYP inhibition efficacy of a compound of the invention was evaluated in human liver microsomes (obtained from GIBCO Invitrogen) against CYP3A4, 2D6, 2C9, 2C19 and 1A2 by a method comprising the following sequential steps. The standard reaction mixture (final volume 300 µl) contained 66.7 M potassium phosphate buffer (pH 7.4), protein (concentrations 0.1, 0.25, 0.5, 0.5 and 0.5 mg/ml for CYP3A4, 2D6, 2C9 2C19 and 1A2, respectively) and test compound (at eight different concentration levels ranging from 0.091 to 20.0 µM, added to 0.9 µl of DMSO solution with a final DMSO concentration of 0.1%). The mixtures were pre-incubated at 37±1°C for 5 minutes. The reaction (in duplicate) was initiated by adding 30 μl of NADPH (10 mM). The reaction was terminated after 10 minutes by adding 300 μl of acetonitrile. The activity of liver microsomes was confirmed by positive controls, i.e. controlling midazolam hydroxylation for CYP 3A4, bufuralol hydroxylation for CYP 2D6, diclofenac hydroxylation for CYP 2C9, omeprazole hydroxylation for CYP2C19, and O-deethylation for CYP 1A2. Reaction mixtures (obtained from the above studies) were extracted, processed and analyzed by LC-MS method [Shimadzu SIL LC series setup (Kyoto, Japan) connected to an API-4000 mass spectrometer (MDS Sciex, Toronto, Canada)].

Conclusion:

The expected IC ₅₀ values for Compound 45 are determined for CYP-specific hydroxylation of midazolam, bufuralol, diclofenac and omeprazole for CYP 3A4, 2D6 and 2C9, respectively. Compound 45 showed no significant inhibition against these enzymes and Compound 45 was found to have predicted IC ₅₀ values for these proteins of >10 μM, respectively, indicating that it is a weak inhibitor of the CYPs tested.

Pharmacokinetic profile:

t _1/2 , _β : final half-life;

AUC _0-t : area under the plasma concentration-time curve from zero to the last measured time point;

AUC _0-∞ : area under the plasma concentration-time curve from zero to infinity;

C _max : maximum observed plasma concentration;

t _max : time to maximum observed plasma concentration;

CL: clearance;

C ₀ : extrapolated concentration at time zero;

V _d : volume of distribution;

V _dss : volume of distribution in the equilibrium phase;

T _last : time of the last quantifiable point;

F: oral bioavailability.

[000255] Compound 45 plasma concentration profiles after single oral and intravenous administration to mice. In mice, plasma concentrations of Compound 45 after an intravenous dose of 1 mg/kg decreased monoexponentially. Clearance was 6.77 ml/min/kg [8% hepatic blood flow (HBF)]. In vivo clearance was slightly higher than predicted from in vitro results (on microsomes). Compound 45 had a high volume of distribution in mice, which was 0.74 l/kg, which is 40 times the total body water (TBW). The time corresponding to the final half-life (t _1/2 ) was 1.27 hours. After oral administration, maximum plasma concentrations (C _max : 4841 ng/ml) were reached after 0.5 hours, indicating rapid absorption from the gastrointestinal tract. The final t _1/2 value (6.32 hours) determined after oral administration was greater than after intravenous administration (1.27 hours), which may indicate multiple sites of absorption. The AUC _0-∞ achieved after oral dosing was 21117 ng·h/mL. Oral bioavailability in mice for a dose of 10 mg/kg was 91%.

Example 8

In vivo efficacy of Compound 45 in the renal RENCA model (Figure 1)

[000256] The RENCA kidney cancer cell line used was purchased from ATCC, USA and grown in recommended media and under recommended culture conditions. Cells in the exponential growth phase were mixed with an equal volume of matrigel in a ratio of 1:1, followed by subcutaneous implantation of cells (1×10 ⁶ cells/100 μl) into the right flank of immunocompetent Balb/c mice (1 injection per mouse). Tumor cells engrafted at the injection site within 1-2 weeks after implantation, and treatment was initiated by randomization of mice into study groups (N=10) when the mean tumor volume reached 100 mm ³ . Tumor mice received vehicle (oral, po), vehicle (ip, ip), Compound B (oral, 30 mg/kg, twice daily) or anti-PD-L1 monoclonal antibody (mAb). (clone 10F.9G2, BioXcell) at a dose of 0.1 mg/mouse, in Q4D mode. Tumor volume and mouse body weight were measured three times per week during treatment until tumor volume reached a maximum of 2000 mm ³ . Tumor volume (mm ³ ) was calculated using the formula: (tumor length) × (tumor width) ² /2. To evaluate the pharmacokinetic parameters of Compound B, plasma and tumors were isolated at the end of the study and analyzed. Tumor growth inhibition (TGI) was calculated after normalization of tumor volume on a given day (TV _Final ) / compared to volume on day 1 (TV _Initial ) / using the formula below:

% TGI = [1-(TV _Final (under treatment) - TV _Initial (under treatment)) / (TV _Final (vehicle) - TV _Initial (vehicle))] × 100

[000257] As shown in FIG. 1, compound 45 showed better or similar efficacy compared to anti-PD-L1 monoclonal antibody (anti-PD-L1 mAb) when administered orally (po). No significant weight loss was observed during treatment.

Advantages and technical results

[000258] The small molecule compounds of the invention are quite stable in mouse, rat and dog liver microsomes and have very good solubility. These compounds have shown very good oral activity and are effective in a syngeneic oral model. Some of the side effects associated with toxicity, which have been observed due to low clearance when using the anti-PD-L1 monoclonal antibody, can be overcome using small molecular weight compounds of the invention.

Claims (115)

1. Compound of formula I

Formula I its stereoisomers, and their pharmaceutically acceptable salts, where R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C ₆ aryl and 6 or 10-membered monocyclic or bicyclic heteroaryl with 1 -2 heteroatoms selected from N or O, where C _1-10 alkyl, C ₆ aryl and 6- or 10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl or C _1-6 alkoxy, where C _1-6 alkoxy is optionally substituted with C _4-5 heterocyclyl with one nitrogen heteroatom, where C _4-5 heterocyclyl is optionally substituted with one or more groups selected from halogen; O is absent or is oxygen; R ₅ selected from

and R ₆ is selected from the group consisting of hydrogen, C(O)C _1-6 alkyl. 2. The compound of formula I according to claim 1, its stereoisomers and their pharmaceutically acceptable salts, where R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 haloalkyl, C ₆ aryl, and 6- or 10-membered monocyclic or bicyclic heteroaryl with 1 -2 heteroatoms selected from N or O, where C _1-6 alkyl, C ₆ aryl and 6- or 10-membered monocyclic or bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _{1 -4} alkyl or C _1-4 alkoxy, where C _1-4 alkoxy is optionally substituted with C _4-5 heterocyclyl with one nitrogen heteroatom, where C _4-5 heterocyclyl is optionally substituted with one or more groups selected from halogen; O is absent or is oxygen; R ₅ selected from

; and R ₆ is selected from the group consisting of hydrogen or C(O)C _1-6 alkyl. 3. The compound of formula I according to claim 1, its stereoisomers and their pharmaceutically acceptable salts, where R ₁ is selected from hydrogen, C _1-4 alkyl, C ₆ aryl and 6-membered monocyclic heteroaryl with 1 heteroatom selected from N, where C _1-4 alkyl, C ₆ aryl and 6-membered monocyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-4 alkyl or C _1-4 alkoxy; R ₂ is selected from hydrogen, C ₆ aryl and 10-membered bicyclic heteroaryl with 1-2 heteroatoms selected from O, where C ₆ aryl and 10-membered bicyclic heteroaryl are optionally substituted with one or more groups selected from hydrogen, fluorine, hydroxyl, cyano, C _1-4 alkyl or C _1-4 alkoxy, where C _1-4 alkoxy is optionally substituted with C _4-5 heterocyclyl with one nitrogen heteroatom, where C _4-5 heterocyclyl is optionally substituted with one or more groups selected from halogen; R ₃ and R ₄ are independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy; O is absent or is oxygen; R ₅ selected from

and R ₆ is selected from the group consisting of hydrogen or C(O)C _1-6 alkyl. 4. The compound or its stereoisomers and their pharmaceutically acceptable salts, selected from the group consisting of the following compounds: N-(2-(((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 1), N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 2), N-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methylglycine (Compound 3), (1R,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2- azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 4), (1S,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2- azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 5), N-(2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 6) (S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 7), S)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl )methyl)piperidine-2-carboxylic acid (Compound 8), (S)-1-((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)methyl )piperidine-2-carboxylic acid (Compound 9), (S)-1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 10), (2S,4R)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 11), (S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)piperidine-2-carboxylic acid (Compound 12), (S)-1-((2-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 13), N-(2-(((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound fourteen), (R)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 15), (S)-1-((2-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 16), (S)-1-((2-((3'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 17), N-(2-(((2-((3'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 18), (S)-1-((2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2 -carboxylic acid (Compound 19), N-(2-(((2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl )acetamide (Compound 20), N-(2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 21), (S)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Compound 22), 1-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)cyclopropane-1-carboxylic acid (Compound 23), (3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)propionic acid (Compound 24), 2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propan- 1,3-diol (Compound 25), (2-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl) (methyl)amino)-2-( hydroxymethyl)propane-1,3-diol (Compound 26), (S)-3-(((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)butyric acid (Compound 27), ((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-D-alanine (Compound 28), ((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)asparagine (Compound 29), (2R,4R)-1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine- 2-carboxylic acid (Compound 30), 1-((4-ethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)azetidine-2-carboxylic acid (Compound 31), N-(2-(((4-(benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 32), 1-((4-(Benzyloxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 33 ), (2S,4R)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 34), 2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 35), ((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-L-proline (Compound 36), methyl 4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylate (Compound 37), 4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 38 ), (2S,4R)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4- hydroxypyrrolidine-2-carboxylic acid (Compound 39), ((S)-1-((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- carboxylic acid (Compound 40), 2-(((4,6-diethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 41), 2-(((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl) propane-1,3-diol (Compound 42), (S)-4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 43), 2-(4-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholin-3-yl) acetic acid (Compound 44), (S)-1-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 45), (S)-5-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[ 2.4]heptane-6-carboxylic acid (Compound 46), 7-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5] decan-1-he (Compound 47), rac-(1R,6S)-2-((4,6-dimethoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)- 2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 48), (S)-4-acetyl-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazin-2 -carboxylic acid (Compound 49), (S)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid ( Compound 50), (S)-5-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[2.4] heptane-6-carboxylic acid (Compound 51), 7-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5]decan- 1-one (Compound 52), N-(2-(((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5- yl)methyl)amino)ethyl)acetamide (Compound 53), (2S,4R)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 54), (S)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)piperidine-2-carboxylic acid (Compound 55), N-(2-(((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidine-5- yl)methyl)amino)ethyl)acetamide (Compound 56), N-(2-(((2-((3',4'-dimethoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5-yl) methyl)amino)ethyl)acetamide (Compound 57), ((2S,4R)-1-((2-((3',4'-dimethoxy-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5 -yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 58), (2S,4R)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin- 5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 59), (S)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl) acetic acid (Compound 60), (R)-2-(1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2- yl) acetic acid (Compound 61), (S)-4-(6-acetamidohexanoyl)-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl )piperazine-2-carboxylic acid (Compound 62), (S)-4,4-difluoro-1-((4-methoxy-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine -2-carboxylic acid (Compound 63), (S)-1-((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid ( Connection 64) and N-(2-(((4-methyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 65). 5. The method of obtaining compounds of formula I according to any one of paragraphs. 1-4 or their stereoisomers and their pharmaceutically acceptable salts, where the method includes a) the interaction of compounds of formula IV and formula B3 in the presence of a base, a solvent and, optionally, a coupling reagent, to obtain compounds of formula V or formula XIII; (b) treating compounds of formula V and formula XIII to give compounds of formula VII; and (c) reacting compounds of formula VII with substituted amines in the presence of a reducing agent and a third solvent to give compounds of formula I:

where X in formula I, formula V, formula VI, formula VII and formula XIII is selected from -CH ₂ O-; R ₁ , R ₂ , R ₃ and R ₄ in formula I, formula IV, formula V, formula VI, formula VII and formula XIII are independently selected from hydrogen, C _1-10 alkyl, C _1-10 alkoxy, C _1-6 haloalkyl, C ₆ aryl and 6- or 10-membered monocyclic or bicyclic heteroaryl with 1-2 heteroatoms selected from N or O, where C _1-10 alkyl, C ₆ aryl and 6- or 10-membered monocyclic or bicyclic heteroaryl optionally substituted with one or more groups selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl or C _1-6 alkoxy, where C _1-6 alkoxy is optionally substituted with C _4-5 heterocyclyl, where C _4-5 heterocyclyl is optional substituted with one or more groups selected from halo; O in formula I, formula IV, formula V, formula VI, formula VII and formula XIII is absent or is oxygen, R ₅ in formula I is

and R ₆ is selected from the group consisting of hydrogen or C(O)C _1-6 alkyl. 6. The method according to p. 5, where the processing of compounds of formula V, obtaining compounds of formula VII includes: (a) alkenylation of compounds of formula V in the presence of a second base and a second solvent, to obtain compounds of formula VI; and (b) oxidizing compounds of formula VI to give compounds of formula VII. 7. The method according to claim 5, wherein the processing of compounds of formula XIII to obtain compounds of formula VII comprises formylation of compounds of formula XIII to obtain compounds of formula VII. 8. The method according to any one of paragraphs. 5-7, wherein the coupling reagent is selected from 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5- b ]pyridinium-3-oxide hexafluorophosphate (HATU), N ,N '-dicyclohexylcarbodiimide (DCC) or propylphosphonic anhydride; the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert - butyl alcohol, dichloromethane, ethyl acetate, dioxane, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and combinations thereof; the base is selected from the group consisting of sodium hydride, butyllithium, lithium diisopropylamide, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, and combinations thereof; the second base is selected from the group consisting of butyllithium, sodium hydride, lithium diisopropylamide, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, and combinations thereof; the second solvent is selected from the group consisting of N,N-dimethylformamide, dichloromethane, ethyl acetate, dioxane, isopropyl alcohol, diethyl ether, t - butyl alcohol, N,N-dimethylformamide, dimethyl sulfoxide and combinations thereof, the third solvent is selected from the group consisting of acetic acid, methanol, N,N-dimethylformamide and combinations thereof, and the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and combinations thereof. 9. A method of treating and/or preventing diseases associated with PD1/PD-L1 activation selected from a proliferative disorder or cancer, comprising administering to a subject suffering from a proliferative disorder or cancer a therapeutically effective amount of a compound according to any one of paragraphs. 1-4. 10. The use of compounds according to any one of paragraphs. 1-4 for the treatment and/or prevention of various diseases associated with PD1/PD-L1 activation, including a proliferative disorder or cancer. 11. A method of treating and/or preventing infectious diseases associated with PD1/PD-L1 activation, wherein the method comprises administering to a subject suffering from infectious diseases selected from HIV, influenza, herpes virus, hepatitis A, hepatitis B, hepatitis C, and hepatitis D, a therapeutically effective amount of a compound according to any one of paragraphs. 1-4.

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