RU2777980C2 - Bicyclic compounds as pd1/pd-l1 interaction/activation inhibitors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to compounds of the formula I, their stereoisomers and pharmaceutically acceptable salts, which are inhibitors of PD-1/PD-L1 activation. In the formula (I), X₁ is selected from -CH₂O-; R₄ is selected from hydrogen; X is selected from CR₃ or N; R₁, R₂, R₃, R₆, and R₇ are independently selected from hydrogen, halogen, C_1-6 alkyl, (4-10-element heterocycloalkyl)-C_1-4 alkyl-, OR^a or C(O)OR^a, where C_1-6 alkyl and (4-10-element heterocycloalkyl)-C_1-4 alkyl- are optionally substituted with 1, 2, or 3 R^b substitutes, and 4-10-element heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R^a is selected from C_1-6 alkyl, C_1-4 haloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10-element heteroaryl)-C_1-4 alkyl-, or (4-10-element heterocycloalkyl)-C_1-4 alkyl-, where C_1-6 alkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10-element heteroaryl)-C_1-4 alkyl-, and (4-10-element heterocycloalkyl)-C_1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 R^d substitutes, and 4-10-element heterocycloalkyl and 5-10-element heteroaryl have 1-3 heteroatoms selected from nitrogen; R^b is selected from hydroxy, amino, C_1-4 alkyl, 4-10-element heterocycloalkyl, OR^c, C(O)NR^cR^c, C(O)OR^c, NHR^c, NR^cR^c, or NR^cC(O)R^c, where C_1-4 alkyl and 4-10-element heterocycloalkyl are optionally substituted with 1, 2, or 3 R^d substitutes, and 4-10-element heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R^c is selected from hydrogen, C_1-6 alkyl, or C_3-10 cycloalkyl, where C_1-6 alkyl and C_3-10 cycloalkyl are optionally substituted with 1, 2, or 3 R^f substitutes; R^d is selected from cyano, halogen, C_6-10 aryl, 5-10-element heteroaryl, C_3-10 cycloalkyl, 4-10-element heterocycloalkyl, C(O)NR^eR^e, or C(O)OR^e, where C_6-10 aryl, 5-10-element heteroaryl, C_3-10 cycloalkyl, and 4-10-element heterocycloalkyl are optionally substituted with 1, 2, or 3 R^f substitutes, and 4-10-element heterocycloalkyl and 5-10-element heteroaryl have 1-3 heteroatoms selected from nitrogen; R^f is selected from C_1-4 alkyl, halogen, CN, OR^g, C(O)NR^gR^g, C(O)OR^g, or NR^gC(O)R^g; R^g is selected from hydrogen or C_1-6 alkyl; R^e is selected from hydrogen; m is 1 or 2; ring A is selected from C_6-10 aryl substituted with C_1-4 alkyl, cyano, or C_1-4 haloalkyl, and ring B is selected from C_6-10 aryl. The invention also relates to options of compounds of the formula (I), a method for their production, a pharmaceutical composition, use for the treatment and methods for the treatment of various diseases associated with the activation of PD-1/PD-L1, including cancer.

EFFECT: obtaining compounds for the treatment of PD-1/PD-L1-associated diseases.

13 cl, 5 tbl, 99 ex

Description

REGION TECHNIQUES, To WHICH RELATED INVENTION

The present invention relates to substituted bicyclic compounds of formula I, together with their polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts, which are inhibitors of the PD1/PD-L1 interaction. The present invention also relates to a process for the synthesis of compounds of formula I.

The compounds described herein are inhibitors of PD1/PD-L1 activation and may be used in the treatment of cancer and other diseases or conditions associated with PD1/PD-L1 activation.

LEVEL TECHNIQUES

Tumor development and survival involves interactions 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 (Th1) cells arrest cancer progression through mechanisms typically involving interferon (IFN)-γ production and cytotoxins (Zamarron BF et al. , Intl. J. Biol. Sciences, 2011, 7(5): 651-658). However, many mechanisms have evolved in tumors to avoid being killed by the immune system. The PD-1/PD-L1 molecular pathway is one such primary mechanism of cancer immune evasion.

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 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 on resting T cells but is induced on 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 killing 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).

PD-1 has two ligands, PD-L1 (also called B7-H1; CD274) and PD-L2 (B7-DC; CD273), both of which are co-inhibitory (Flies DB et al. , Yale J. Biology Medicine, 2011, 84(4): 409-421). PD-L1, expressed on almost all mouse tumor cells, is the main ligand for PD-1 mediated immune suppression. They are constantly expressed on APCs and can be widely induced on cells in both lymphoid tissues and non-lymphoid peripheral tissues after 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-γ cytokine is particularly effective in activating PD-L1 expression due to IFN-γ 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). Expression of B7-DC/PD-L2 is largely restricted to myeloid dendritic cells (DCs) and macrophages in lymphoid compartments and is slightly 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 cancer 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 PD-L1 test correlates with poor 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). Conversely, normal human tissues rarely express 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).

The cancer microenvironment governs the PD-1/PD-L1 pathway; initiation of PD-L1 expression is associated with the inhibition of named responses against cancer, thereby allowing the cancer to develop 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 H. et al. , Nature Medicine, 2002, 8(8):793-800; Curiel TJ et al. , Nature Medicine, 2003, 9(5 ):562-567), promotes anegria and T cell depletion (Barber DL et al ., Nature, 2005, 439(7077):682-687), improves 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 N. et al. , Cell Cycle, 2012, 11 (23):4305-4309). Therefore, blocking this pathway restores CTL proliferation and cytotoxicity, inhibiting the function of regulatory T cells (Tregs) and causing a decrease in T cell apoptosis.

Blockade of the PD-1/PD-L1 pathway with therapeutic antibodies has been shown to prevent the inhibitory signal from cancer cells and allow CTL to mount an immune response against 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 anti-cancer immunotherapeutic agents targeting PD-1 have been developed to date and approved for the treatment of a number of malignancies, including melanoma, lung cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer, and urothelial cancer. The first therapeutic antibody against PD-L1 was approved by the FDA in May 2016 for the treatment of patients with metastatic urothelial carcinoma and non-small cell lung cancer, with a number of additional therapies in development. There are currently at least 500 clinical trials of anti-PD-1/PD-L1 antibodies against 20 types of solid and hematologic malignancies. However, there is still a need for potent and selective small molecule inhibitors of the PD-1/PD-L1 pathway.

Common drug side effects (AEs) of both anti-PD-1 and anti-PD-L1 antibodies include fatigue, rash, diarrhea, pruritus, decreased appetite, arthralgia, and nausea. Immune-related PE (iPE) such as dermatitis, colitis, hepatitis, vitiligo, and thyroiditis have been described, and about 10% of patients develop grade 3 or 4 uPE (Hamanishi J. et al. , Int. J. Clin. Oncol ., 2016, 21:462-473). The long residence time of monoclonal antibodies (mAbs) may play a role in these AEs, which can be partially bypassed with the use of a small molecule inhibitor. In addition, studies using smaller cell-penetrating biological agents and DNA aptamers have shown that they have antibody-mimicking functions and are superior to antibody due to their chemically synthetic nature, low immunogenicity, and efficient tissue penetration (Lai WY et al . , Mol Therapy-Nucl Acids, 2016, 5:e397). Small molecule inhibitors, therefore, may provide increased oral bioavailability, increased bioefficacy, and a shorter active half-life for more controlled treatment, particularly in the event of autoimmune or other side effects.

As discussed, PD-1/PD-L1 inhibitory compounds are of great utility in activating the immune system to effectively fight cancer. Therefore, it is necessary to identify the chemical group, especially small molecule inhibitors, which contributes to this inhibition, if necessary. Therefore, the identification and development of new compounds that inhibit PD-1/PD-L1 for the treatment of cancer and other diseases or conditions associated with PD-1/PD-L1 activation will open up new possibilities in the field of cancer treatment.

ESSENCE INVENTIONS

In one aspect of this disclosure, a compound of formula I is provided.

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts, where X_one choose from -CH₂O-, -OCH₂-, -C(O)NH- or -NHC(O)-; R_four selected from hydrogen, hydroxyl, C_1-6 alkyl, amino, -C(O)OR_a1, C(O)NR_b1R_c1, C_5-6 aryl or C_1-6 heteroaryl, where C_1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR_a1, C(O)NR_b1R_c1, C_5-6 aryla and C_1-6 heteroaryl; R_a1, R_b1 and R_c1 independently selected from hydrogen or C_1-6 alkyl; X choose from CR₃ or N; R_one, R₂, R₃, R₆ and R₇ independently selected from hydrogen, halogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_6-10 arila, C_3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-14 membered heteroaryl)-C_1-4 alkyl-, (4-10-membered heterocycloalkyl)-C_1-4 alkyl-, CN, NO₂,OR^a, SR^a, NHOR^a, C(O)R^a, C(O)NR^aR^a, C(O)OR^a, OC(O)R^a, OC(O)NR^aR^a, NHR^a, NR^aR^a, NR^aC(O)R^a, NR^aC(O)OR^a, NR^aC(O)NR^aR^a, C(=NR^a)R^a, C(=NR^a)NR^aR^a, NR^aC(=NR^a)NR^aR^a, NR^aS(O)R^a, NR^aS(O)₂R^a, NR^aS(O)₂NR^aR^a, S(O)R^a, S(O)NR^aR^a, S(O)₂R^a or S(O)₂NR^aR^a, where C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-,C_3-10 cycloalkyl-C_1-4 alkyl-, (5-14 membered heteroaryl)-C_1-4 alkyl- and (4-10-membered heterocycloalkyl)-C_1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R^b deputies; R^a selected from hydrogen, cyano, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 arila, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10-membered heteroaryl)-C_1-4 alkyl- or (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, where C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl- and (4-10-membered heterocycloalkyl)-C_1-4 alkyl- independently optionally substituted with 1, 2, 3, 4 or 5 R^d deputies; R^b selected from halogen, hydroxy, cyano, amino, nitro, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, C_1-4 haloalkoxy, C_6-10 arila, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10-membered heteroaryl)-C_1-4 alkyl-, (4-10-membered heterocycloalkyl)-C_1-4 alkyl-, NHOR^c,OR^c, SR^c, C(O)R^c, C(O)NR^cR^c, C(O)OR^c, OC(O)R^c, OC(O)NR^cR^c, C(=NR^c)NR^cR^c, NR^cC(=NR^c)NR^cR^c, NHR^c, NR^cR^c, NR^cC(O)R^c, NR^cC(O)OR^c, NR^cC(O)NR^cR^c, NR^cS(O)R^c, NR^cS(O)₂R^c, NR^cS(O)₂NR^cR^c, S(O)R^c, S(O)NR^cR^c, S(O)₂R^c or S(O)₂NR^cR^c; where C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, C_1-4 haloalkoxy, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl- and (4-10-membered heterocycloalkyl)-C_1-4 alkyl- optionally substituted with 1, 2 or 3 R^d deputies; R^c selected from hydrogen, C_1-6 alkyl, C_1-4 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 arila, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10-membered heteroaryl)-C_1-4 alkyl- or (4-10 membered heterocycloalkyl)-C_1-4 alkyl-, where C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10 aryl-C_1-4 alkyl-, C_3-10 cycloalkyl-C_1-4 alkyl-, (5-10 membered heteroaryl)-C_1-4 alkyl- and (4-10-membered heterocycloalkyl)-C_1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R^f deputies;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycle oalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^{o and} R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6-membered heteroaryl, 4-6-membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; m is 1 or 2; ring A is selected from substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In another aspect of this description provides a compound of formula II

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

where X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl, and C _1-6 heteroaryl;

R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl;

R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents;

R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents;

R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^{r or} S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^{o and} R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents;

R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl;

Ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In yet another aspect of this disclosure, a compound of formula III is provided.

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

where X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl;

R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl;

R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents;

R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents;

R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents;

R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

In one aspect of this disclosure, a compound of formula IV is provided.

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

where R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents;

R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents;

R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^{r or} S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycle oalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^{o and} R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents;

R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

In one aspect of this disclosure, a compound of formula V is provided.

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

where R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl;

R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents;

R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents;

R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^{o and} R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents;

R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

In one aspect of this disclosure, a compound of formula VI is provided.

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

where R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl;

R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents;

R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents;

R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents;

R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

This specification further describes a process for the preparation of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.

This specification also describes a method for treating and/or preventing various diseases, including cancer and infectious diseases, comprising administering to a subject suffering from a proliferative disease or cancer a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or a pharmaceutical composition containing a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.

This description also describes the use of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or a pharmaceutical composition containing compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, for the treatment and/or prevention of various diseases, including a proliferative disorder or cancer; or cancer treatment together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

This description also describes a method for the treatment of cancer, where this method includes the introduction of a combination of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or a pharmaceutical composition containing compounds of Formula I, Formula II, Formula III, Formula IV , Formula V or Formula VI, with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.

This description further describes a method of treating cancer, where this method includes the introduction of a combination of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or a pharmaceutical composition with other clinically relevant immunomodulatory agents to a subject in need thereof.

These and other features, aspects and advantages of the subject matter of the present invention will become more apparent with reference to the following description. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to define key features or essential features of the description, nor is it intended to be used to limit the scope of the subject matter.

DETAILED DESCRIPTION

Those skilled in the art will recognize that this disclosure is subject to changes and modifications other than those specifically described. It is to be understood that this disclosure includes all such changes and modifications. The disclosure also includes all such steps, features, compositions, and compounds mentioned or identified herein, individually or collectively, and any and all combinations of any or more of such steps or features.

Definitions

For convenience, before further description of the present disclosure, some of the terms used in the description and examples are collected here. These definitions should be considered in light of the remainder of the disclosure and understood by one of ordinary skill in the art. The terms used herein have the meanings recognized and known to those skilled in the art, however, for convenience and completeness, specific terms and their meanings are set forth below.

The articles "a", "an" and "the" are used to denote one or more than one (that is, at least one) grammatical object of an article.

Throughout the description and the following claims, unless the context otherwise requires, the word "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of the specified integer or step or group of integers, but not excluding any other integer or stage or group of integers or stages.

The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

In the structural formulas given here and throughout this disclosure, the following terms have the meanings given, unless specifically indicated otherwise.

In addition, the compound of formula I, formula II, formula III, formula IV, formula V, formula VI can be its derivatives, analogs, stereoisomers, diastereomers, geometric isomers, polymorphs, solvates, co-crystals, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts and compositions.

Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts and their metabolites may also be referred to as "compounds in accordance with this disclosure" .

Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI may contain one or more asymmetric centers (also called chiral centers) and therefore may exist as individual enantiomers, diastereoisomers or other stereoisomeric forms or 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 a chiral center present in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or any chemical structure illustrated herein is not specified, that structure is intended to include any stereoisomer and all mixtures thereof. Thus, compounds of formula I-VI 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.

The compounds described herein include the isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine, and sulfur, which can be included in compounds such as, but not limited to, ² H (D), ³ H (T), ¹¹ C, ¹³ C , ¹⁴ C, ¹⁵ N, ¹⁸ F, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Compounds according to the invention in which atoms have been labeled with isotopes, for example radioisotopes such as ³ H, ¹³ C, ¹⁴ C and the like, can be used in metabolic studies and kinetic studies. Compounds of this invention in which hydrogen is replaced by deuterium can improve the metabolic stability and pharmacokinetic properties of the drug, such as in vivo half-life.

Individual stereoisomers of a compound of formula I-VI that contain one or more asymmetric centers can be separated by methods known to those skilled in the art. For example, such separation may be carried out by (1) the formation of diastereomeric salts, complexes, or other derivatives; (2) selective reaction with a stereoisomer-specific reagent, such as enzymatic oxidation or reduction; or (3) gas-liquid or liquid chromatography in a chiral medium, for example, on a chiral support such as silicon dioxide with an associated chiral ligand or in the presence of a chiral solvent. It will be understood that if the desired stereoisomer is converted to another chemical compound using one of the separation techniques described above, an additional step is required to release the desired form.

Alternatively, certain stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another by asymmetric conversion.

It should be understood that references herein to compounds of formulas I-VI and their salts encompass compounds of formulas I-VI in the form of free bases or their salts, for example, in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the invention relates to compounds of formulas I-VI in the form of a free base. In another embodiment, the invention relates to compounds of formulas I-VI and their salts. In an additional embodiment, the invention relates to compounds of formulas I-VI and their pharmaceutically acceptable salts.

It should be understood that pharmaceutically acceptable salts of compounds of formula I, formula II, formula III, formula IV, formula V, or formula VI can be prepared. Indeed, in some embodiments of the invention, pharmaceutically acceptable salts of the compounds of formulas I-VI may be preferred over the corresponding free base, since such salts impart greater stability or solubility to the molecule, thereby facilitating the preparation of the dosage form. Accordingly, the invention is further directed to the compounds of formulas I-VI and their pharmaceutically acceptable salts.

Included within the scope of "compounds of this invention" are all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabeled derivatives and stereoisomers of the compounds of formulas I-VI and their salts.

Compounds in accordance with this invention may exist in solid or liquid form. In the solid state, the compounds of this invention may exist in crystalline or non-crystalline form, or as a mixture thereof. For compounds of this invention that are in crystalline form, one skilled in the art will appreciate that pharmaceutically acceptable solvates can be formed if the solvent molecules are included in 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 included in the crystal lattice. Solvates in which water is the solvent that is 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 includes all such solvates.

In addition, it should be understood that some compounds in accordance with this invention that exist in crystalline form, including their various solvates, may exhibit polymorphism (ie, the ability to form different crystal structures). These various crystalline forms are commonly known as "polymorphs". The invention includes such polymorphs. The polymorphs have the same chemical composition but differ in packaging, geometric arrangement, and other descriptive properties of the crystalline solid state. Polymorphs can therefore have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs usually have different melting points, IR spectra, and X-ray powder patterns that can be used for identification. It should be understood that various polymorphs can be obtained, for example, by changing or adjusting the reaction conditions or reagents used in the preparation of the compound. For example, changes in temperature, pressure, or solvent can lead to the formation of polymorphs. In addition, one polymorph can spontaneously transform into another polymorph under certain conditions. The term "polymorphs" refers to crystalline forms of the same molecule, and different polymorphs may have different physical properties, such as, for example, melting points, heats of fusion, solubility, dissolution rates, and/or vibrational spectra as a result of the arrangement or conformation of molecules in crystal lattice.

The term "substituted" in relation to a group indicates that the hydrogen atom attached to an atom in the group is substituted. It should be understood that the term "substituted" includes the provision, implied by the meaning, that such a substitution must correspond to the allowable valency of the substituted atom and substituent, and that the substitution gives a stable compound (i.e., one that does not undergo spontaneous transformations, such as rearrangement, cyclization or removal). In certain embodiments, one atom may be replaced by more than one substituent, provided that such substitution corresponds to the allowable valency of the atom. Suitable substituents are defined here for each substituted or optionally substituted group.

The term "prodrugs" refers to a precursor compound of formula Ia and formula I, which, when administered, undergoes a chemical transformation as a result of metabolic processes before becoming an active pharmacological substance. Typically, such prodrugs will be functional derivatives of a compound of this invention that are easily converted in vivo to a compound of this invention.

The term "alkyl" refers to a saturated hydrocarbon chain having a specific number of carbon atoms. As an example, which is not limited, C _1-6 alkyl refers to an alkyl group having 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.

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

The term "haloalkyl" refers to a halogen in an alkyl group, as defined above, attached via an alkyl bond to the rest of the molecule. For example, C _1-6 haloalkyl refers to an alkyl group having 1-6 carbon atoms or 1-4 carbon atoms, where one or more hydrogen atoms are replaced by the same number of the same or different halogen atoms. Preferred haloalkyl groups include, without limitation, -CH ₂ Cl, -CHCl ₂ , trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

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

The term "halo" or "halogen" refers to a halogen radical, such as fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" refers to a saturated hydrocarbon ring having a certain number of carbon atoms, which may be monocyclic or polycyclic. For example, without limitation, C _3-10 cycloalkyl refers to a cycloalkyl group containing 3-10 atoms or 3-6 atoms. Polycyclic ring refers to hydrocarbon systems containing two or more ring systems with one or more ring carbons in common, ie spiro, fused or bridged structures. By way of example, which is not limited, C _3-6 cycloalkyl refers to a cycloalkyl group having 3-6 atoms. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl, and norbornyl groups, bridged cyclic groups, or spirobicyclic groups, such as spiro[4.4]non-2-yl, and the like.

The term "aryl" refers to an aromatic ring having a certain number of carbon atoms. For example, C _5-6 aryl refers to an aryl group having 5 or 6 atoms or 6 atoms. C _6-10 aryl refers to an aryl group containing 6-10 atoms. Preferred aryl groups include, without limitation, phenyl and the like.

The term "heteroaryl" refers to aromatic rings containing 1-3 heteroatoms per ring. "Heteroaryl" groups may be substituted with one or one or more substituents, as defined herein. "C _1-6 heteroaryl" rings contain 1 or 6 carbon atoms. The term "5-14 membered heteroaryl" contains 5-14 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.

The term "heterocyclic" refers to either saturated or unsaturated monocyclic aliphatic rings containing 5, 6 or 7 ring members including 1-3 heteroatoms or saturated or unsaturated bicyclic, tricyclic, tetracyclic aliphatic rings containing 5, 6 or 7 ring members. ring, including 1-3 heteroatoms, which may include spiro, fused or bridged ring systems. In some embodiments, "heterocyclic" groups are saturated. In other embodiments, "heterocyclic" groups are unsaturated. "Heterocyclic" groups containing more than one heteroatom may contain different heteroatoms. "Heterocyclic" groups may be substituted with one or more substituents, as defined here. "Heterocyclic" includes piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl.

The term "heterocycloalkyl" refers to a heterocyclic group, as defined above, additionally attached through an alkyl bond to the rest of the molecule. For example, 4-10 membered heterocycloalkyl refers to a heterocyclic group, as defined above, further attached via an alkyl bond to the rest of the molecule.

The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and dosage forms which, within the limits of reasonable medical judgement, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, or other problems or complications, commensurate with a reasonable ratio benefit/risk.

The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the desired biological activity of the compound in question 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.

Salts and solvates containing pharmaceutically unacceptable 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 I, formula II, formula III, formula IV, formula V, formula VI and their pharmaceutically acceptable salts. Thus, one embodiment of the invention covers compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and their salts. The compounds of formula I, formula II, formula III, formula IV, formula V, formula VI contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts when treated 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, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, almond, 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.

The term "PD-1/PD-L1 inhibitor or inhibitory compounds" or "PD-1/PD-L1 activation inhibitors" is used to identify a compound that is capable of blocking the PD-1/PD-L1 pathway to prevent an inhibitory signal from being sent from cancer cells. and allowing CTL to elicit an immune response against target/cancer cells and thus treat cancer and other diseases or conditions associated with PD1/PD-L1 activation.

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 stop the growth and division of cancer cells and may cause tumor shrinkage.

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

The term "immune checkpoint inhibitor agents" or "immune modulatory agents" is used to identify any agent or inhibitor that blocks certain proteins produced by certain types of cells in the immune system, such as T cells and certain cancer cells. These proteins help control the immune response and stop T cells from killing cancer cells. When these proteins are blocked, the brakes on the immune system are released 20 and T cells are better able to kill cancer cells. Immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, 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 “immunomodulatory agents” and “immune checkpoint inhibitors” are used interchangeably in this disclosure.

As discussed in the Background section, 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 will open up new possibilities in the field of cancer treatment.

A term once described has the same meaning to it throughout the disclosure.

In one embodiment of this disclosure, a compound of formula I is provided.

Formula (I)

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl, and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; X is selected from CR ₃ or N; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl, independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; m is 1 or 2; Ring A is selected from substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In one embodiment of this disclosure, there is provided a compound of formula I, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or - NHC(O)-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl, and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; X is CR ₃ ; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalka l) -C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; m is 1 or 2; ring A is selected from substituted or unsubstituted C _5-10 aryl; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In one embodiment of this disclosure, a compound of formula II is provided

Formula II

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl, and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In one embodiment of this disclosure, there is provided a compound of formula II, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or - NHC(O)-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl, and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₃ is independently selected from hydrogen, halogen, C(O)OR ^a _, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl or C _3-10 cycloalkyl; R ₁ , R ₂ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{6 -10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O) R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a ) NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl , 5-14-membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)- C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _{1 -4} alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents;

R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O.

In one embodiment of this disclosure, a compound of formula III is provided

Formula III

its polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalka l) -C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10-membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6-membered heteroaryl, 4-6-membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, there is provided a compound of formula III, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein X ₁ is selected from -CH ₂ O-, -OCH ₂ - or -C(O)NH-; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₃ is independently selected from hydrogen, halogen, C(O)OR ^a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl or C _3-10 cycloalkyl; R ₁ , R ₂ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{6 -10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O) R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a ) NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl , 5-14-membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)- C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _{1 -4} alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents;

R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents;

R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;

R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, a compound of formula IV is provided

Formula IV

polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents;

R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f substituents ;

R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, there is provided a compound of formula IV, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano, or C _1-4 haloalkyl; R ₃ is independently selected from hydrogen, halogen, C(O)OR ^a _, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl or C _3-10 cycloalkyl; R ₁ , R ₂ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{6 -10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O) R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a ) NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl , 5-14-membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)- C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _{1 -4} alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, a compound of formula V is provided

Formula V

polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, there is provided a compound of formula V, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano, or C _1-4 haloalkyl; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₃ is independently selected from hydrogen, halogen, C(O)OR ^a _, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl or C _3-10 cycloalkyl; R ₁ , R ₂ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{6 -10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O) OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a )NR ^a R ^a , NR ^a S (O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a , where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10- the membered heterocycloalkyl is independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S(O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O)NR ^e R ^e , S(O ) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl or 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC(O)R ^g , OC(O )NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC (O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S(O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o , where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7-membered heterocycloalkyl , C _6-10 aryl, 5-6 membered heteroaryl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _1-4 haloalkyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O)OR ^r , OC(O) R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C (=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN)NR ^r R ^r , S(O )R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r , where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10- membered heteroaryl, 4-10 membered heterocycloalkyl, optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, a compound of formula VI is provided

Formula VI

polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl;

R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _1-6 heteroaryl; where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C (O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C( O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(= NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O) NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-14 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalka l) -C _1-4 alkyl- independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10-membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment of this disclosure, there is provided a compound of formula VI, polymorphs, stereoisomers, tautomers, prodrugs, solvates and pharmaceutically acceptable salts thereof, wherein R ₅ is selected from C _1-4 alkyl, cyano, or C _1-4 haloalkyl; R ₄ is selected from hydrogen, hydroxyl, C _1-6 alkyl, amino; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; R ₃ is independently selected from hydrogen, halogen, C(O)OR ^a _, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl or C _3-10 cycloalkyl; R ₁ , R ₂ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _{6 -10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O) OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a )NR ^a R ^a , NR ^a S (O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a , where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10- the membered heterocycloalkyl is independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S(O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ^d substituents; R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O)NR ^e R ^e , S(O ) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl or 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents; R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC(O)R ^g , OC(O )NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC (O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S(O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o , where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7-membered heterocycloalkyl , C _6-10 aryl, 5-6 membered heteroaryl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _1-4 haloalkyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ^p substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O)OR ^r , OC(O) R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C (=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN)NR ^r R ^r , S(O )R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r , where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10- membered heteroaryl, 4-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl.

In one embodiment, this disclosure relates to compounds of formula I, formula II, formula III, formula IV, formula V, formula VI or their polymorphs, stereoisomers, tautomers, prodrugs, solvates and their pharmaceutically acceptable salts, which are selected from the group consisting of :

(S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine- 2-carboxylic acid (1),

N-(2-(((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (2),

(S)-1-((7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)- 2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (3),

(S)-1-((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (4),

(S)-1-((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (5),

Methyl 7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5 -carboxylate (6),

(S)-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (7),

(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (8),

(S)-1-((5-((5-Fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (9)

N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (10)

(S)-5-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (11)

(S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (12)

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)-N-methylacetamide(13)

N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)amino)ethyl)acetamide (14)

N-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)piperidin-3-yl)acetamide (15)

N-(2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino) ethyl)acetamide (16)

6-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6 -azaspiro[3.3]heptane (17)

2-(hydroxymethyl)-2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl )amino)propane-1,3-diol (18)

1-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)cyclopropan-1 -carboxylic acid (19)

((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine (20)

3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propanoic acid ( 21)

N-methyl-N-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine ( 22)

3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid ( 23)

((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)alanine (24)

(2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (25)

(S)-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (26)

1-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidine-2-carboxylic acid (27)

N-(2-(((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (28)

(2S,4R)-4-hydroxy-1-((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (29)

N-(2-(((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (30)

(2S,4R)-1-((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (31)

N-(2-(((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (32)

(2S,4R)-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]- 3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (33)

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)acetamide (34)

(2S,4R)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (35)

(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (36)

(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxamide (37)

3-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (38)

3-(((4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy )-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (39)

3-(((4-((3-hydroxypiperidin-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)benzonitrile (40)

((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl )methyl)glycine (41)

(S)-5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)-5-azaspiro[2.4]heptan-6-carboxylic acid (42)

rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (43)

4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)butanoic acid (44)

(1R,6S)-2-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (45)

(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (46)

(2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (47)

N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (48)

5-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (49)

(S)-4-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (50)

rac-(1R,6S)-2-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (51)

(S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (52)

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)(methyl)amino)ethyl)acetamide (53)

N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)acetamide (54)

(S)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (55)

N-(2-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (56)

(2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (57)

3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-6-methoxy-2,3-dihydro-1H-inden-4-yl) hydroxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (58)

(S)-4-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)morpholine-3-carboxylic acid (59)

((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)glycine (60)

(S)-5-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (61)

rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden- 4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (62)

2-(1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl )piperidin-2-yl)acetic acid (63)

N-(2-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)(methyl)amino)ethyl)-N-methylacetamide (64)

5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-5-yl)oxy)pentanoic acid (65)

5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-5-yl)oxy)pentanamide (66)

(S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxylic acid (67)

(S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (68)

(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (69)

(2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (70)

(R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-3-carboxylic acid (71)

rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis; racemic) (72)

methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (73)

4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (74)

(S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)piperidine-2-carboxylic acid (75)

(2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (76)

(2S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (77)

(S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxylic acid (78)

N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)ethyl)acetamide (79)

(S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxamide (80)

(2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (81)

(S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (82)

(1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylic acid (83)

(S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3- dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (84)

(2S,4R)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2, 3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (85)

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3- dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (86)

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (87)

(S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (88)

3-(((4-(aminomethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy )methyl)benzonitrile (89)

N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)acetamide (90)

6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)hexanamide (91)

3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)methyl)benzonitrile (92)

5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)nicotinic acid (93)

5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)nicotinamide (94)

3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)benzamide (95)

(S)-1-((3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine- 4-yl)methyl)piperidine-2-carboxylic acid (96)

N-(2-(((3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine- 4-yl)methyl)amino)ethyl)acetamide (97)

(S)-4-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)morpholine-3-carboxylic acid (98)

5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (99)

In one embodiment, the present disclosure relates to a process for preparing compounds of formula I, formula II, formula III, formula IV, formula V, and formula VI as described herein, or their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts.

In one embodiment, this disclosure relates to a process for the preparation of formula I, comprising the steps of: (a) reacting compounds of formula I(a) with substituted amines to obtain compounds of formula

In one embodiment, this disclosure relates to a process for preparing formula I, comprising the steps of: (a) reacting compounds of formula I(a), where X _{1 of} formula I (a) and formula I are selected from -CH ₂ O-, -OCH ₂ -, -C(O)NH- or -NHC(O)-; R ₄ of formula I (a) and formula I are selected from hydrogen, hydroxyl, C _1-6 alkyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl or C _{1- 6} heteroaryl, where C _1-6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, hydroxyl, amino, -C(O)OR _a1 , C(O)NR _b1 R _c1 , C _5-6 aryl and C _1-6 heteroaryl; R _a1 , R _b1 and R _c1 are independently selected from hydrogen or C _1-6 alkyl; X of formula I (a) and formula I are selected from CR ₃ or N; R ₁ , R ₂ , R ₆ and R ₇ of formula I (a) and formula I are independently selected from hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyla-, C _3-10 cycloalkyl -C _1-4 alkyl-, (5-14-membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, CN, NO ₂ , OR ^a , SR ^a , NHOR ^a , C(O)R ^a , C(O)NR ^a R ^a , C(O)OR ^a , OC(O)R ^a , OC(O)NR ^a R ^a , NHR ^a , NR ^a R ^a , NR ^a C(O)R ^a , NR ^a C(O)OR ^a , NR ^a C(O)NR ^a R ^a , C(=NR ^a )R ^a , C(=NR ^a )NR ^a R ^a , NR ^a C(=NR ^a )NR ^a R ^a , NR ^a S(O)R ^a , NR ^a S(O) ₂ R ^a , NR ^a S(O) ₂ NR ^a R ^a , S(O)R ^a , S(O)NR ^a R ^a , S(O) ₂ R ^a or S(O) ₂ NR ^a R ^a , where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{6- 10} aryl, C _3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, ( 5-14-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered this heterocycloalkyl)-C _1-4 alkyl- is independently optionally substituted with 1, 2, 3 or 4 R ^b substituents; R ^a is selected from hydrogen, cyano, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 -membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents; R ^b is selected from halo, hydroxy, cyano, amino, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 -membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^c , OR ^c , SR ^c , C(O)R ^c , C(O)NR ^c R ^c , C(O)OR ^c , OC(O)R ^c , OC(O)NR ^c R ^c , C(=NR ^c )NR ^c R ^c , NR ^c C(=NR ^c )NR ^c R ^c , NHR ^c , NR ^c R ^c , NR ^c C(O)R ^c , NR ^c C(O)OR ^c , NR ^c C(O)NR ^c R ^c , NR ^c S(O)R ^c , NR ^c S( O) ₂ R ^c , NR ^c S(O) ₂ NR ^c R ^c , S(O)R ^c , S(O)NR ^c R ^c , S(O) ₂ R ^c or S(O) ₂ NR ^c R ^c ; where C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and ( 4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^d substituents; R ^c is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ^f substituents;

R ^d is selected from cyano, amino, C _1-6 alkyl, C _1-6 haloalkyl, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _{6 -10} aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^e , OR ^e , SR ^e , C(O)R ^e , C(O)NR ^e R ^e , C(O)OR ^e , OC(O)R ^e , OC(O)NR ^e R ^e , NHR ^e , NR ^e R ^e , NR ^e C(O)R ^e , NR ^e C(O)NR ^e R ^e , NR ^e C(O)OR ^e , C(=NR ^e )NR ^e R ^e , NR ^e C(=NR ^e )NR ^e R ^e , NR ^e C(=NOH)NR ^e R ^e , NR ^e C(=NCN)NR ^e R ^e , S(O)R ^e , S(O) NR ^e R ^e , S(O) ₂ R ^e , NR ^e S(O) ₂ R ^e , NR ^e S(O) ₂ NR ^e R ^e or S(O) ₂ NR ^e R ^e , where C _1-6 alkyl, C _1-6 haloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _{3- 10} cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^f deputies;

R ^f is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 -membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl-, (4-10 -membered heterocycloalkyl)-C _1-4 alkyl-, halogen, CN, NHOR ^g , OR ^g , SR ^g , C(O)R ^g , C(O)NR ^g R ^g , C(O)OR ^g , OC( O)R ^g , OC(O)NR ^g R ^g , NHR ^g , NR ^g R ^g , NR ^g C(O)R ^g , NR ^g C(O)NR ^g R ^g , NR ^g C(O)OR ^g , C(=NR ^g )NR ^g R ^g , NR ^g C(=NR ^g )NR ^g R ^g , S(O)R ^g , S(O)NR ^g R ^g , S(O) ₂ R ^g , NR ^g S(O) ₂ R ^g , NR ^g S(O) ₂ NR ^g R ^g or S(O) ₂ NR ^g R ^g ; where C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl , C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloalkyl )-C _1-4 alkyl- optionally substituted with 1, 2, 3, 4 or 5 R ⁿ substituents; R ^g is selected from hydrogen, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10-membered heteroaryl)-C _1-4 alkyl- or (4 -10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^p substituents; R ⁿ is selected from cyano, halogen, C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _{1 -6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, R ^o , NHOR ^o , OR ^o , SR ^o , C(O)R ^o , C(O)NR ^o R ^o , C(O)OR ^o , OC(O)R ^o , OC(O)NR ^o R ^o , NHR ^o , NR ^o R ^o , NR ^o C(O)R ^o , NR ^o C(O)NR ^o R ^o , NR ^o C(O)OR ^o , C(=NR)NR ^o R ^o , NR ^o C(=NR ^o )NR ^o R ^o , S(O)R ^o , S(O)NR ^o R ^o , S (O) ₂ R ^o , NR ^o S(O) ₂ R ^o , NR ^o S(O) ₂ NR ^o R ^o or S(O) ₂ NR ^o R ^o where C _1-4 alkyl, C _3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5 -6-membered heteroaryl)-C _1-4 alkyl-, (4-7-membered heterocycloalkyl)-C _1-4 alkyl-, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl and C _{1 -4} haloalkyl optionally substituted with 1, 2 or 3 R ^q substituents; R ^p is selected from halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl-, (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, NHOR ^r , OR ^r , SR ^r , C(O)R ^r , C(O)NR ^r R ^r , C(O )OR ^r , OC(O)R ^r , OC(O)NR ^r R ^r , NHR ^r , NR ^r R ^r , NR ^r C(O)R ^r , NR ^r C(O)NR ^r R ^r , NR ^r C(O)OR ^r , C(=NR ^r )NR ^r R ^r , NR ^r C(=NR ^r )NR ^r R ^r , NR ^r C(=NOH)NR ^r R ^r , NR ^r C(=NCN) NR ^r R ^r , S(O)R ^r , S(O)NR ^r R ^r , S(O) ₂ R ^r , NR ^r S(O) ₂ R ^r , NR ^r S(O) ₂ NR ^r R ^r or S(O) ₂ NR ^r R ^r where C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3 -10} cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10-membered heterocycloa alkyl)-C _1-4 alkyl- optionally substituted with 1, 2 or 3 R ^q substituents; R ^e , R ⁱ , R ^k , R ^o and R ^r are independently selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl , C _1-4 haloalkyl, C _2-4 alkenyl or C _2-4 alkynyl, where C _1-4 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5 or 6 membered heteroaryl, 4-6 membered heterocycloalkyl, C _2-4 alkenyl and C _2-4 alkynyl are optionally substituted with 1, 2 or 3 R ^q substituents; R ^q is selected from hydroxy, cyano, amino, halogen, COOH, C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _5-6 aryl, 5-6 membered heteroaryl , 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, NHR ⁸ , NR ⁸ R ⁸ and C _1-4 haloalkoxy, where C _1-6 alkyl, C _5-6 aryl, C _3-6 cycloalkyl, 4-6 -membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with halogen, hydroxy, cyano, COOH, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _5-6 aryl, C _3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R ⁸ is C _1-6 alkyl; m is 1 or 2; ring A is selected from substituted or unsubstituted C _5-10 aryl, substituted or unsubstituted C _3-6 cycloalkyl, and substituted or unsubstituted 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O; ring B is selected from C _5-10 aryl, C _3-6 cycloalkyl, 5-10 membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, with substituted amines in the presence of solvents with obtaining compounds of formula I.

In one embodiment, this disclosure relates to a pharmaceutical composition comprising a compound of formula I or formula II or formula III or formula IV or formula V or formula VI as described herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

In another embodiment, this disclosure relates to 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.

In one embodiment of this disclosure, compounds of formula I, formula II, formula III, formula IV, formula V and formula VI are provided, or a pharmaceutically acceptable salt thereof, as described herein, wherein the selected pharmaceutically acceptable salt is derived from inorganic bases such as Li, Na , K, Ca, Mg, Fe, Cu, Zn and Mn; compounds of organic bases 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 and the like. 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 possible, which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.

In one embodiment, this disclosure relates to a method of treating and/or preventing a proliferative disorder or cancer, comprising administering to a subject in need thereof, suffering from a proliferative disorder or cancer, a therapeutically effective amount of compounds of formula I or formula II or formula III or formula IV or formula V or formula VI or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, with other clinically relevant cytotoxic agents or non-cytotoxic agents.

In one embodiment, this disclosure relates to the use of compounds of formula I or formula II or formula III or formula IV or formula V or formula VI or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of a proliferative disorder or cancer; or cancer treatment together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

In one embodiment, this disclosure relates to the use of compounds of formula I or formula II or formula III or formula IV or formula V or formula VI or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of various diseases, including proliferative disorder or cancer; or cancer treatment together with other clinically relevant cytotoxic agents or non-cytotoxic agents, where 30 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, denileukine, diftitox, dextrazoxane, docetaxel, doxorubicin, dromostanolone propionate, cyclophosphamide, 5-fluorouracil, imatinib, methotrexate, irinotecan, toptecan, vinblastine, etoposide, vincristine, carmustine, paclitaxel, vorinostat, belinostat, romiostatinamide, romiostatinamide, romiostatinamide , Atatiniba, Bosutiniba, Cetuximab, Enterctiniba, Lapatinib, Nilotinib, Pasopaniba, Educatiniba, Sorafeniba, Sunitiniba, Vermoratiniba, Axytiniba, Gephitiniba, Kobimetinib, Karbosantiniba, Temoizolomide, Ausomin, Altoritus, Altoritus, Altoritusa, Altoritusa, Altoritusa paraginase, bexarotene, baricitinib, bleomycin, busulfan, capecitabine, cladribine, clofarabine, cytarabine, dacarbazine, dactinomycin, sodium, dasatinib, letrozole, tamoxifen, oxaliplatin, procarbazine, zoleronate, and combinations thereof.

In one embodiment, this disclosure relates to a method of treating cancer as described herein, which method includes the introduction of a combination of compounds of formula I or formula II or formula III or formula IV or formula V or formula VI or their pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier, with other clinically relevant cytotoxic agents or non-cytotoxic agents, to a subject in need thereof.

In one aspect of this disclosure, a method is provided for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administration to a subject suffering from viral infectious diseases such as HIV, influenza, herpes virus, hepatitis A, hepatitis B, hepatitis C and hepatitis D , a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV, formula V and formula VI, or a pharmaceutical composition with other clinically relevant antiviral drugs, to a subject in need thereof.

In one embodiment, this disclosure relates to a method of treating cancer as described herein, which method includes the introduction of a combination of compounds of formula I or formula II or formula III or formula IV or formula V or formula VI or their pharmaceutical composition with other clinically relevant immunomodulatory agents, the subject in need of such.

EXAMPLES

The symbols used here and the conventions used in these processes, diagrams, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard one-letter or three-letter abbreviations are generally used to refer to 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 may be used in the examples and throughout the description:

The symbols used here and the conventions used in these processes, diagrams, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard one-letter or three-letter abbreviations are generally used to refer to 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 may be used in the examples and throughout the description:

Abbreviations:

AC Acetyl _Ac2O Acetic anhydride ACN Acetonitrile AIBN Azobis(isobutyronitrile) BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BMS Borane-dimethylsulfide complex bn Benzyl Boc tert-Butoxycarbonyl Boc _2O Di-tert-butyl dicarbonate BuLi butyllithium CsF cesium fluoride EDC 1,2-dichloroethane DXM dichloromethane DDH 2,3-dichloro-5,6-dicyano-1,4-benzoquinone VHI dimethyl sulfide ATP Adenosine triphosphate Bis-pinacolatodiborone 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane ABS bovine serum albumin C18 Refers to 18-carbon alkyl groups on silica in HPLC stationary phase CH ₃ CN Acetonitrile Cy Cyclohexyl DIPEA Hunig's base, N-ethyl-N-(1-methylethyl)-2-propanamine dioxane 1,4-dioxane DMAP 4Ddimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DFFA Diphenylphosphorylazide EtOAc ethyl acetate EtOH ethanol _Et2O diethyl ether HOAC Acetic acid HPLC HPLC GMDS Hexamethyldisilazide IPS Isopropyl alcohol AHL lithium aluminum hydride DAL Lithium diisopropylamide GMDSL Lithium hexamethyldisilazide MeOH methanol HCSD Medium pressure liquid chromatography MTBE Methyl tert-butyl ether mHPBC m-Chloroperbenzoic acid Na HMDS Sodium hexamethyldisilazide NBS N-bromosuccinimide NMR Nuclear magnetic resonance Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium(0) Complex Pd(dppf)Cl ₂ .DCM [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex RP HPLC Reversed phase high pressure liquid chromatography CT Room temperature Sat. Saturated HSG Chromatography on silica gel THEM Raw material TLC Thin layer chromatography TEA Triethylamine TFK Trifluoroacetic acid THF Tetrahydrofuran

The following examples provide detailed information on the synthesis, activity and uses of the compounds in accordance with this invention. It should be understood that the following is only representative and that the invention is not limited to the details set forth in these examples.

Compounds in accordance with this invention can be obtained by various methods, including standard chemistry. Any previously defined variable will continue to have the previously defined value unless otherwise specified. Illustrative general synthesis methods are presented in the following schemes and can be easily adapted to obtain other compounds in accordance with this invention.

Also provided is the process shown in the following Scheme 1 for the preparation of compounds of formula I wherein all groups are as previously defined.

General methods synthesis compounds, disclosed in formula I:

Compounds in accordance with this invention ( VI ) receive, basically, according to scheme 1.

Scheme one:

Compound B is obtained from dimethoxyphenylpropionic acid A by reaction with polyphosphoric acid. Selective demethylation of compound B is carried out using BBr ₃ to give compound C . Decarbonylation of C using a reducing agent gives compound D. Formylation of compound D using dichloro(methoxy)methane and titanium tetrachloride gives compound E. O-alkylation of E using substituted biphenylmethyl bromides E1 gives compound F. In some instances of the present invention, biphenylmethyl alcohol E1a is used instead of biphenylmethyl bromide E1a , and further Mitsunobu reaction conditions are used to obtain intermediate F. Reductive amination of intermediate E with various substituted aliphatic, aromatic, heterocyclic and cyclic amines ( E1 ) gives compounds of general formula (VI) according to the present invention. Alternatively, modifications of R ₁ such as O-benzyl-substituted compounds of general formula VI are obtained by demethylation of E to give 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde. Selective benzylation of 7-hydroxy using E1 followed by a second benzylation of 5-hydroxy using E5 or E5a gives intermediate E6 . Reductive amination of E6 with various amines gives compounds of general formula ( VI ).

Alternatively, the unsubstituted indane base is prepared according to Scheme 2. Decarbonylation of G is carried out using trifluoroacetic acid and triethylsilane to give intermediate H . The subsequent stages are carried out according to the method described in scheme 1, with the receipt of compounds of General formula V and VI .

Scheme 2:

Alkyl-substituted indan derivatives are prepared according to Scheme 3. Formylation of o-cresol gives compound L. Reaction of intermediate L with acetic acid gives compound M , which is hydrogenated to give 8-methylchroman-2-one N. Compound N is treated with aluminum chloride to give the indenone derivative O. Decarbonylation of O followed by formylation gives intermediate Q. The subsequent stages are carried out according to the procedure described in scheme 1 to obtain compounds of general formula VI .

Biphenylmethyl bromides ( E1 ) or the corresponding alcohols are prepared by Suzuki coupling using the appropriate substituted phenylboronic acid and substituted bromobenzene.

Scheme 3:

Halogenated indan derivatives are prepared according to Scheme 4. Decarbonylation of 4-hydroxy-2,3-dihydro-1H-inden-1-one S followed by chlorination gives 5-chloro-2,3-dihydro-1H-inden-4-ol U. Intermediate U is formylated to give 6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde V. The subsequent stages are carried out according to the procedure described in scheme 1 to obtain compounds of general formula VI .

Scheme four:

Ester-substituted indane derivatives are prepared according to Scheme 5. O-alkylation of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehyde gives intermediate Y. Oxidation of an aldehyde to an acid using sodium dihydrogen phosphate and hydrogen peroxide gives intermediate Z. Intermediate Z is converted to the corresponding ester Z1 using methyl iodide in the presence of potassium carbonate. Intermediate Z1 is treated with TFA and hexamine to give the deprotected benzylaldehyde compound methyl 7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate Z2 . The subsequent stages are carried out according to the procedure described in scheme 1, with the receipt of compounds of General formula VI .

Scheme 5:

Compounds in accordance with this invention ( VI ) are also obtained according to scheme 6:

Scheme-6:

Compound E6 is reduced with sodium borohydride to give E7 which is reacted with phthalimide in the presence of TPP and DIAD to give intermediate E8 . Deprotection of the phthalimide group gives the free amine of general formula ( VI ). An amine of general formula VI is reacted with alkyl halides in the presence of a base or reductive amination using aldehydes gives alkylamines of general formula VI . Amides of general formula VI are obtained by reacting the reactive amine with substituted acids or acid chlorides.

The nitrogen-containing bicyclic heterocyclic compounds of formula I are prepared according to Scheme 7. Reaction of cyclopentanone with malanonitrile and carbon disulfide gives the bicyclic heterocyclic intermediate E11 . Hydrolysis and decarboxylation is carried out using a base to give E12 . Methylation of the thiol group using a base and methyl iodide and O-alkylation using an alkyl halide in the presence of silver oxide or base gives intermediate E14 . Bromination gives intermediate E15 . Sulfoxidation of E15 gives intermediate E16 . Nucleophilic substitution of E6 with E1a gives intermediate E17 . The conversion of bromine to vinyl is carried out by a Still coupling, the vinyl group is oxidized to an aldehyde to give E19 . Reductive amination of E19 with various amines gives compounds of general formula I.

Scheme 7:

Some of the intermediate compounds used in accordance with this invention, receive according to the method described in the following schemes.

Scheme eight: Synthesis 5-(chloromethyl)nicotinonitrile

Step 1: A stirred solution of 5-bromonicotinonitrile (22 g, 0.120 mol) and tributylvinyltin (95.3 g, 0.300 mol) in DMF (200 ml) was purged with nitrogen for 10 minutes. To this mixture was added Pd(PPh ₃ ) ₄ (13.84 g, 0.012 mol) and again purged with nitrogen for 20 minutes. The mixture is then heated at 80° C. for 4 hours. After completion, the reaction mixture is 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 to give 5-vinylnicotinonitrile as an off-white solid (Yield: 10.5 g, 67%). ¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 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).

Step 2: To a stirred solution of 5-vinylnicotinonitrile (10.5 g, 0.081 mol) in acetone (200 ml) and water (40 ml) at 0°C was added OsO ₄ (82 ml, 2.5 wt% solution in tert -butanol, 0.0081 mol) and N-methylmorpholine N-oxide (29 g, 0.242 mol) and stirred for 3 h. NaIO ₄ (60 g, 0.282 mol) was added to this mixture and the reaction mixture was stirred at room temperature within 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 is dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was chromatographed on a Combiflash system using 30% ethyl acetate in hexane as eluent to give 5-formylnicotinonitrile ( 3 ) as a yellow solid (Yield: 7.9 g, 74%). ¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.77 (s, 1H), 9.29 (s, 1H), 9.31 (s, 1H), 10.12 (s, 1H).

Step 3: To a stirred solution of 5-formylnicotinonitrile (12 g, 0.091 mol) in methanol (100 ml) at 0°C, sodium borohydride (5.12 g, 0.136 mol) was added portionwise over 30 minutes and the mixture was stirred at 0°C over 2 hours. The reaction mixture was concentrated and the residue was diluted with water (100 ml) and DCM (200 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 1% MeOH in DCM to give 5-(hydroxymethyl)nicotinonitrile as a yellow solid (Yield: 7.4 g, 60.7%). ¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ, 8.91 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 5, 54 (s, 2H), 4.50 (br, 1H).

Step 4: To a stirred solution of 5-(hydroxymethyl)nicotinonitrile (3 g, 0.022 mol) in DCM (30 ml), add 4M HCl in 1,4-dioxane (5 ml) and concentrate the mixture in vacuo. Thionyl chloride (20 ml) was added to the resulting residue and the mixture was stirred at 60°C for 3 hours. After completion, the reaction mixture was cooled to room temperature and diluted with toluene (150 ml) and the precipitated solid was filtered off. The filtrate was diluted with DCM (200 ml) and washed with saturated sodium bicarbonate solution (200 ml). The organic layer was dried over sodium sulfate and concentrated to give 5-(chloromethyl)nicotinonitrile (Yield: 1.2 g, 35%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm): δ 4.86 (s, 2H), 8.42 (s, 1H), 8.94 (d, J= 2.0 Hz , 1H), 8.99 (d, J = 2.0 Hz, 1H).

Scheme 9: Synthesis of 3-(hydroxymethyl)-[ 1,1'-biphenyl]-2-carbonitrile

Step 1: A solution of 2-amino-3-bromobenzoic acid (10.0 g, 0.046 mol) in dry THF (100 ml) at 0°C, add borane-DMS (118 ml, 1M in THF, 5 eq.) and stir mixture at room temperature for 24 h. After completion, the reaction is quenched with methanol (20 ml) and concentrated under vacuum. The residue was diluted with EtOAc (500 ml) and washed with water (300 ml), saturated sodium bicarbonate solution (300 ml), brine (200 ml) and concentrated to give (2-amino-3-bromophenyl) methanol (Yield: 7, 3 g, 78%) as an off-white solid. LCMS (ER) m/z=183.96 [MH ₂ O+H] ⁺ & 185.93 [M+2-H ₂ O+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ ppm: 4.43 (m, 2H), 5.05 (brine, 2H), 5.21 (m, 1H ), 6.50 (t, J= 7.6 Hz, 1H), 7.10 (d, J= 7.2 Hz, 1H), 7.29 (d, J= 7.6 Hz, 1H).

Step 2: Solution of (2-amino-3-bromophenyl)methanol (9.70 g, 0.048 mol) and phenylboronic acid (7.65 g, 0.062 mol) in water (60 ml), toluene (60 ml) and methanol ( 70 ml) degassed with nitrogen for 15 minutes. Pd(PPh ₃ ) ₂ Cl ₂ (3.37 g, 0.0048 mol) and sodium carbonate (13.4 g, 0.127 mol) were added to this mixture, and the mixture was stirred at 80° C. for 8 hours. , the mixture is filtered over celite and washed with EtOAc (2×200 ml). The filtrate was washed with brine (20 ml) and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge using 0-30% EtOAc in hexane as eluent to give (2-amino-[1,1'-biphenyl]-3-yl)methanol (Yield: 8 .2 g, 85%) as an off-white solid LCMS (ER) m/z=200.34 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ : 4.46 (m, 2H), 4.57 (brs, 2H), 5.14 (m, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.93 (d, J= 7.6Hz, 1H), 7.05(d, J= 7.2Hz, 1H), 7.34-7.39(m, 3H), 7.47(t, J =7.6 Hz, 2H).

Step 3: To a solution of (2-amino-[1,1'-biphenyl]-3-yl)methanol (2.5 g, 12.5 mmol) in water (15 ml) and toluene (15 ml) was added conc. HCl (6 ml) and cool the mixture to 0°C. To this mixture was slowly added a solution of sodium nitrite (1.7 g, 18.8 mmol) in water (5 mL) and stirring continued at 0°C for 1.5 h. The pH of the solution was adjusted to 6.0 using a carbonate solution. sodium. This diazonium solution is slowly added to a solution of CuSO ₄ (2.3 g, 15 mmol) and sodium cyanide (3.07 g, 62.5 mmol) in water (15 ml) and toluene (15 ml) at 60°C. After stirring at 60°C for 2 h, the reaction mixture is cooled to room temperature and filtered and washed with EtOAc (100 ml). The organic layer of the filtrate was washed with brine (20 ml) and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge using 0-20% EtOAc in hexanes as eluent to give 3-(hydroxymethyl)-[1,1'-biphenyl]-2-carbonitrile (Yield: 450 mg , 17%) as a brown liquid LCMS (ER) m/z=210.36 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ: 4.73 (m, 2H), 5.63 (m, 1H), 7.47-7.56 (m, 6H), 7.67 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H).

Step 4 : To a stirred solution of 3-(hydroxymethyl)-[1,1'-biphenyl]-2-carbonitrile (3.5 g, 16.7 mmol) in DCM (50 ml) at 0°C was added triphenylphosphine (6, 5 g, 25.1 mmol) and carbon tetrabromide (8.31 g, 25.1 mmol) and stirred at room temperature for 4 h. After completion, the reaction mixture was diluted with water (50 ml) and extracted with DCM (3×200 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g SNAP) using 0-20% EtOAc in hexane to give 3-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile (Yield: 3.05 g, 66%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ: 4.87 (s, 2H), 7.49-7.59 (m, 6H), 7.75-7.80 ( m, 2H).

Scheme ten: Synthesis 3-(chloromethyl)-5-fluoropyridine

Step 1: To a stirred solution of methyl 5-fluoronicotinate (9.2 g, 59 mmol) in dry THF (40 ml) under nitrogen at -78° C., a 2.5M solution of LiAlH ₄ in THF (31 ml, 77 mmol) and the mixture was stirred at the same temperature for 40 minutes. Upon completion, the reaction mixture was quenched at the same temperature with saturated ammonium chloride (10 ml) and poured into ice water (100 ml). The mixture was extracted with EtOAc (3×100 ml) and the organic layer was dried over anhydrous sodium sulfate and concentrated to give (5-fluoropyridin-3-yl)methanol (Yield: 7.1 g, 95%) as a red liquid. LCMS (ER) m/z=128.30[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.57 (m, 2H), 5.46 (t, J =5.6 Hz, 1H), 7.62 (d, J = 10.0 Hz, 1H), 8.41 (s, 1H), 8.45 (d, J= 2.8 Hz, 1H).

Step 2: To a solution of (5-fluoropyridin-3-yl)methanol (0.5g, 3.93mmol) in DCM (20mL) at 0°C was added triethylamine (1.63mL, 11.80mmol) and p -tosyl chloride (2.24 g, 5.90 mmol) and then the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (25 ml) and extracted with DCM (3×40 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexane as eluent to give 3-(chloromethyl)-5-fluoropyridine (Yield: 502 mg, 87%) as an off-white solid. LCMS (ER) m/z=146.28[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.85 (s, 2H), 7.85 (d, J= 9.2 Hz, 1H), 8.55 (s, 1H), 8.57 (d, J= 2.4 Hz, 1H).

Scheme eleven: Synthesis N-(2-aminoethyl)-N-methylacetamide

Step 1: To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (4.2 g, 25.7 mmol) in ethanol (60 ml) is added N-hydroxyphthalimide (4.50 g, 25.7 mmol), and stir the mixture at 60° C. for 6 hours. After completion, concentrate the mixture in vacuo. The residue was washed with diethyl ether (2×10 ml) to obtain tert-butyl (2-(1,3-dioxoindolin-2-yl)ethyl)(methyl)carbamate (Yield: 5.8 g, 74%) as a white solid substances. LCMS (ER) m/z=305.42 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.97 (s, 6H), 1.09 (s, 3H), 2.77 (s, 3H), 3.43 ( m, 2H), 3.72 (t, J =5.2 Hz, 2H), 7.86 (m, 4H).

Step 2: To a solution of tert-butyl (2-(1,3-dioxoindolin-2-yl)ethyl)(methyl)carbamate (6 g, 19.7 mmol) in 1,4-dioxane (100 ml) was added 4M HCl in 1,4-dioxane (50 ml) and stir the mixture at room temperature for 3 h. When complete, concentrate the mixture in vacuo. The resulting residue was washed with diethyl ether (2×10 ml) to give 2-(2-(methylamino)ethyl)isoindoline-1,3-dione HCl salt (Yield: 4.0 g, 98%) as a white solid. LCMS (ER) m/z=205.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.56 (s, 3H), 3.18 (m, 2H), 3.89 (t, J =5.6 Hz, 2H), 7.88 (m, 4H), 8.83 (br, 1H).

Step 3: Triethylamine (5.2 g, 51.3 mmol) and acetyl chloride (2 g, 25 mmol) and stirred for 2 h at room temperature. Upon completion, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×100 ml). The organic layer is dried over sodium sulfate and concentrated. The residue was washed with diethyl ether and pentane to give N-(2-(1,3-dioxoindolin-2-yl)ethyl)-N-methylacetamide (Yield: 2.5 g, 59%) as a white solid. LCMS (ER) m/z=247.20 [M+H] ⁺ .

Step 4: Hydrazine hydrate (0. 58 g, 11.6 mmol) and stir the mixture for 6 hours at room temperature. Upon completion, the mixture is concentrated. The resulting residue was diluted with pentane (50 ml) and filtered. Concentration of the filtrate gave N-(2-aminoethyl)-N-methylacetamide (Yield: 106 mg, 10.2%) as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.78 (s, 3H), 2.25 (s, 3H), 2.48 (m, 2H), 3.09 ( m, 2H), 3.22 (m, 2H).

Scheme -12: Synthesis N-(2-aminoethyl)-N-methylacetamide

Step 1: To a stirred solution of 3-acetylbenzonitrile (2.0 g, 13.7 mmol) in methanol (30 ml) was added sodium borohydride (0.62 g, 15.5 mmol) and stirred at room temperature for 6 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The organic layer is dried and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 20% EtOAc in hexane to give 3-(1-hydroxyethyl)benzonitrile (Yield: 1.8 mg, 91%) as a colorless liquid. LCMS (ER) m/z=146.05 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.32 (d, J= 6.4 Hz, 3H), 4.77 (m, 1H), 5.39 (d, J= 4.4 Hz, 1H), 7.53 (t, J= 7.6 Hz, 1H), 7.69 (d, J= 7.6 Hz, 2H), 7.76 (s, 1H) .

Step 2: To a stirred solution of 3-(1-hydroxyethyl)benzonitrile (1.0 g, 6.8 mmol) in DCM (20 ml) was added carbon tetrabromide (2.67 g, 10 mmol) and triphenylphosphine (3.37 g , 10 mmol) and stir the mixture at room temperature for 4 hours. After completion, the reaction mixture is diluted with water (10 ml) and the layers are separated. The aqueous layer is then extracted with DCM (2×20 ml) and the combined organic layer is dried and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 20% EtOAc in hexanes to give 3-(1-bromoethyl)benzonitrile (Yield: 600 mg, 42%) as a colorless liquid. LCMS (ER) m/z=146.05 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.0 (d, J= 6.8 Hz, 3H), 5.54 (m, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.87 (d, J= 7.6 Hz, 1H), 8.07 (s, 1H) .

Scheme 13: Synthesis N-(piperidin-3-yl)acetamide

Step 1: To a stirred solution of 3-aminopyridine (3.0 g, 31.9 mmol) in THF (25 ml) at 0°C was added acetic anhydride (3.70 g, 38 mmol) and the mixture was stirred at room temperature for 8 hours After completion, the reaction mixture was diluted with water (25 ml) and extracted with EtOAc (3×50 ml). The combined organic layer was dried over sodium sulfate and concentrated to give N-(pyridin-3-yl)acetamide (Yield: 2.5 g, 58%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.07 (s, 3H), 7.32 (m, 1H), 8.02 (m, 1H), 8.23 ( m, 1H), 8.70 (s, 1H), 10.13 (s, 1H).

Step 2: A solution of N-(pyridin-3-yl)acetamide (1.5 g, 11.0 mmol), HCl (3 ml) in ethanol (50 ml) was degassed with nitrogen for 10 minutes. PtO ₂ (300 mg, 22 mmol) is added to this mixture and the mixture is hydrogenated at 100 psi. within 24 hours. Upon completion, the mixture is filtered and the filtrate is concentrated in vacuo. The resulting residue was washed with EtOAc (10 ml) to give N-(piperidin-3-yl)acetamide (Yield: 1.0 g, 64%) as an off-white solid. LCMS (ER) m/z=143.18 [M+H] ⁺ .

Scheme 14: Synthesis of 3-(bromomethyl)-2-(trifluoromethyl)-1,1' -biphenyl

Stage 1: A mixture of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (15 g, 62 mmol), phenylboronic acid (22.7 g, 186 mmol), 2M sodium carbonate (150 ml), toluene (225 ml ) and MeOH (75 ml) are degassed with nitrogen for 10 minutes. To this mixture was added PdCl ₂ (dppf)DCM complex (5.75 g, 8.21 mmol) and degassed for another 5 minutes with nitrogen. The vessel is sealed, the mixture is heated at 90°C for 12 hours After completion, the reaction mixture is diluted with water (300 ml) and extracted with EtOAc (3×300 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-1% EtOAc in hexane to give 3-fluoro-2-(trifluoromethyl)-1,1'-biphenyl (Yield: 17 g, 39%) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.21 (d, J= 7.6 Hz, 1H) 7.31-7.34 (m, 2H), 7.44 -7.50 (m, 3H), 7.65 (d, J = 7.6 Hz, 1H), 7.72-7.78 (m, 1H).

Step 2: To a solution of 3-fluoro-2-(trifluoromethyl)-1,1'-biphenyl (17.0 g, 70.83 mmol) in DMSO (30 ml) is added KCN (4.6 g, 70.83 mmol ) and stir the mixture at 150°C for 16 h. After completion, the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3×100 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-5% EtOAc in hexane to give 2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile (Yield: 10.0 g , 58%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.31-7.34 (m, 2H), 7.44-7.50 (m, 3H), 7.74 (d , J= 6.4 Hz, 1H), 7.91 (t, J= 8.0 Hz, 1H), 8.19 (d, J= 7.6 Hz, 1H).

Step 3: To a solution of 2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile (1.0 g, 4.0 mmol) in dry DCM (5 ml) at -65°C, DIBAl-H (1M solution in hexane, 6.0 ml, 6.0 mmol) was added dropwise and the mixture was stirred at -65°C for 1 h. After completion, the reaction was quenched with cold water (20 ml) and extracted with DCM (3×25 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-10% EtOAc in hexane to give 2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde (Yield: 0.4 g, 39.5%) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.35 (m, 2H), 7.47 (m, 3H), 7.67 (d, J= 6.4 Hz, 1H), 7.89 (t, J= 8.0 Hz, 1H), 7.99 (d, J= 7.6 Hz, 1H), 10.37 (s, 1H).

Step 4: To a solution of 2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde (3.0 g, 12 mmol) in EtOH (30 ml) and THF (10 ml) at 0°C is added borohydride sodium (0.90 g, 24 mmol) and stirred at room temperature for 2 h. After completion of the reaction, the reaction is quenched with water (50 ml) and extracted with EtOAc (3×100 ml). The organic layer was dried over sodium sulfate and concentrated to give (2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methanol (Yield: 2.70 g, 90%) as a yellow sticky liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.73 (s, 2H), 5.53 (m, 1H), 7.21 (d, J= 7.6 Hz, 1H), 7.25 (d, J= 6.8 Hz, 2H), 7.38-7.43 (m, 3H), 7.66 (t, J= 8.0 Hz, 1H), 7, 83 (d, J= 7.6 Hz, 1H).

Step 5: Triphenylphosphine ( 0.25 g, 0.99 mmol) and carbon tetrabromide (0.33 g, 0.99 mmol) and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×20 ml). The organic layer was dried over sodium sulfate and concentrated to give 3-(bromomethyl)-2-(trifluoromethyl)-1,1'-biphenyl (Yield: 100 mg, 80%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.87 (s, 1H), 4.95 (s, 1H), 7.26-7.28 (m, 2H), 7.30-7.36(m, 1H), 7.42(m, 3H), 7.68-7.76(m, 2H).

Scheme fifteen: Synthesis methyl (1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate

Step 1: To a stirred solution of dimethyl (1R,2S)-cyclopropane-1,2-dicarboxylate (2.0 g, 12.6 mmol) in THF (40 ml) was slowly added a solution of lithium hydroxide monohydrate (0.53 g, 12 .6 mmol) in water (40 ml) and stirred for about 1 hour. The reaction mixture was cooled to 0° C. and the pH was adjusted to 5-6. The aqueous mixture was extracted with 5% MeOH in DCM (3×50 ml) and the combined organic layer was dried over sodium sulfate and concentrated to give (1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (Yield: 0.80 g, 44%) as a colorless liquid. LCMS (ER) m/z=143 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.17 (m, 1H), 1.32 (m, 1H), 1.99-2.03 (m, 1H), 2.10-2.16 (m, 1H), 3.56 (s, 3H), 12.33 (s, 1H).

Step 2: To a solution of (1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.80 g, 5.5 mmol) in THF (15 ml) under nitrogen atmosphere at 0° C. is added borane-DMS (0.84 g, 11.1 mmol) and the reaction mixture was stirred at room temperature for 6 h. After completion, the reaction was quenched with MeOH (10 ml) at 0° C. and concentrated in vacuo. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 5% MeOH in DCM as eluent to give methyl (1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (Yield: 0.550 g, 76 %) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.82 (m, 1H), 1.05 (m, 1H), 1.50 (m, 1H), 1.72 ( m, 1H), 3.38 (m, 1H), 3.58 (s, 3H), 3.62 (m, 1H), 4.51 (m, 1H).

Step 3: Triethylamine (0.58 g, 5.7 mmol) and DMAP (23 mg, 0.19 mmol) and stirred for 10 minutes. To this mixture is added tosyl chloride (0.55 g, 2.8 mmol) and the mixture is stirred at room temperature for 6 h. After completion, the reaction mixture is diluted with water (10 ml) and extracted with DCM (3×15 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 5% MeOH in DCM as eluent to give methyl (1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate (Yield: 0.330 g, 60%) as a colorless liquid.

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather serve as a guide to the skilled artisan in the preparation and use of the compounds, compositions and methods in accordance with this invention. While specific embodiments of the present invention have been described, the skilled artisan will appreciate that various changes and modifications may be made without departing from the spirit and scope of the invention.

Table one: Ways prep-HPLC:

Way Column mobile phase Compounds purified prep. HPLC A Xbridge Shield C-18, 19x250mm, 10u 5 mm ammonium acetate in water: Acetonitrile 32, 12, 86 B Xselect CSH phenylhexyl, 19x250mm, 5u 5 mm ammonium acetate in water: Acetonitrile 46, 49, 85, 56, 93, 94 C Xselect CSH phenylhexyl, 19x250mm, 5u 0.1% TFA in water: Acetonitrile 47 D Sunfire C18, 19x250mm, 10μ 5 mM ammonium acetate in water: Acetonitrile. 76, 52, 81 E Sunfire C18, 19x250mm, 10μ 0.1% formic acid in water: Acetonitrile. 79 F XTERRA C18, 19×250mm, 10μ 5 mM ammonium bicarbonate in water: Acetonitrile 63

Example one

(S)-1-((7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine- 2-carboxylic acid (1)

Step 1: Triethylsilane (5.3 ml, 33.72 mmol). The mixture is stirred at 100° C. for 16 hours. The reaction mixture is cooled to room temperature and concentrated. The residue is quenched with sodium bicarbonate solution, extracted into ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 10% EtOAc in hexane as eluent to give 2,3-dihydro-1H-inden-4-ol (1.8 g, crude) as a pale brown liquid, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 1.90-1.96 (m, 2H), 2.71 (t, J= 7 .4 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.89 (t, J =7.8 Hz, 1H), 9.04 (s, 1H).

Step 2: To a mixture of 2,3-dihydro-1H-inden-4-ol (1.8 g, 13.43 mmol) in DCM (20 ml) is added TiCl ₄ (2.7 ml, 24.17 mmol) at 0°C and the reaction mixture is stirred for 15 min. Dichloro(methoxy)methane (1.3 ml, 14.77 mmol) was added to the reaction mixture at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with cold water and extracted with DCM. The combined organic layer was dried over sodium sulfate and evaporated to give the crude product which was purified by HPLC on a Combiflash system using 20% EtOAc in hexane as eluent to give 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0 .31 g, crude) as a white solid. LCMS (ER) m/z =163.1 [M+H.] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.00-2.04 (m, 2H), 2.73 (t, J =7.4 Hz, 2H), 3, 16 (t, J =7.4 Hz, 2H), 6.75 (d, J =8.0 Hz, 1H), 7.52 (d, J =8.0 Hz, 1H), 9.86 ( s, 1H), 10.34 (s, 1H).

Step 3: Potassium carbonate (0.39 g, 2.87 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 15 minutes. 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.5 g, 1.91 mmol, 1.0 eq.) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched water and extracted with DCM. The combined organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 10% EtOAc in hexane as eluent to give 7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (0.6 g, 92%) as a white solid. LCMS (ER) m/z =343.2 [M+H.] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.02-2.09 (m, 2H), 2.19 (s, 3H), 2.81 (t, J =7 .4 Hz, 2H), 3.20 (t, J =7.6 Hz, 2H), 5.28 (s, 2H), 7.18 (t, J =9.0 Hz, 2H), 7, 25-7.31 (m, 3H), 7.34-7.38 (m, 1H), 7.42-7.46 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H), 9.95 (s, 1H).

Step 4: To a mixture of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (0.1 g, 0. 29 mmol) and (S)-piperidine-2-carboxylic acid (0.045 g, 0.35 mmol) in DMF:MeOH (10 mL) one drop of acetic acid was added at room temperature and the reaction mixture was stirred for 15 min. Sodium cyanoborohydride (0.054 g, 0.87 mmol) is added to the reaction mixture and the mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with water and extracted with DCM. The combined organic layer was washed with sodium bicarbonate solution and dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 20% MeOH in DCM as eluent to give (S)-1-((7-((2 -methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (15 mg, 11%) as white solid. LCMS (ER) m/z =456.2 [M+H. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.35-1.46 (m, 3H), 1.71-1.73 (m, 2H), 1.95-1 .99 (m, 2H), 2.18-2.25 (m, 4H), 2.78-3.05 (m, 6H), 3.41-3.71 (m, 2H), 3.81 -4.45 (m, 2H), 5.12 (s, 2H), 6.87 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H) , 7.17 (d, J = 7.6 Hz, 1H), 7.24-7.31 (m, 3H), 7.34-7.37 (m, 1H), 7.42-7.45 (m, 3H).

Example 2

N-(2-(((5-methoxy-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (2)

Step 1: A solution of 3-(3,5-dimethoxyphenyl)propanoic acid (10.0 g, 147.61 mmol) in polyphosphoric acid (100 ml) was stirred for 16 hours at 80°C. The reaction mixture is cooled to room temperature and quenched with water, extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated to give the crude product, which is purified by HPLC on a Combiflash system using 20% EtOAc in hexane as eluent to give 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one (4.0 g, 43%) as a pale brown solid. LCMS (ER) m/z =193.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.63-2.69 (m, 2H), 3.00-3.03 (m, 2H), 3.86 (s , 3H), 3.90 (s, 3H), 6.29 (s, 1H), 6.48 (s, 1H).

Step 2: To a solution of 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one (3.5 g, 18.22 mmol) in DCM (50 ml) was added BBr ₃ 17.18 mmol) dropwise over 5 min at 0°C and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 20% EtOAc in hexane as eluent to give 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-1 -one (3.5 g, crude) as a pale brown solid. LCMS (ER) m/z= 179.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.48-2.52 (m, 2H), 2.92-2.95 (m, 2H), 3.77 (s , 3H), 6.24 (s, 1H), 6.51 (s, 1H), 9.85 (s, 1H).

Step 3: To a mixture of sodium borohydride (2.24 g, 58.98 mmol) in THF (50 ml) is added BF ₃ .Et ₂ O (24.2 ml, 196.66 mmol) dropwise over 10 min at 0° C. After stirring at 0° C. for 1 h, 7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (3.5 g, 19.66 mmol) in THF (20 ml) was added to the reaction mixture, which was then stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water, extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 20% EtOAc in hexane as eluent to give 6-methoxy-2,3-dihydro-1H-inden-4-ol (2 .5 g, crude) as a pale brown solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.89-1.96 (m, 2H), 2.61- 2.65 (m, 2H), 2.72-2.76 (m, 2H), 3.62 (s, 3H), 6.12 (s, 1H), 6.25 (s, 1H), 9 .08 (s, 1H).

Step 4: To a solution of 6-methoxy-2,3-dihydro-1H-inden-4-ol (2.5 g, 15.24 mmol) in DCM (50 ml) was added TiCl ₄ (3.0 ml, 27 13 mmol) at 0°C and stirred for 15 min. Dichloro(methoxy)methane (1.5 ml, 16.76 mmol) was added to the reaction mixture at 0° C. and stirred for an additional 2 hours at room temperature. The reaction mixture was quenched with cold water and extracted with DCM. The combined organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 20% EtOAc in hexane as eluent to give 7-hydroxy-5-methoxy-2,3-dihydro-1H-inden- 4-carbaldehyde (0.1 g, crude) as a white solid. LCMS (ER) m/z =193.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.91-1.97 (m, 2H), 2.60-2.64 (m, 2H), 3.04-3 .08 (m, 2H), 3.78 (s, 3H), 6.34 (s, 1H), 10.22 (s, 1H), 10.41 (s, 1H).

Step 5: Potassium carbonate (0.10 g, 0.78 mmol) at room temperature. The mixture is stirred for 15 min and 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.13 g, 0.52 mmol) is added to the reaction mixture at room temperature. The reaction mixture is then stirred for 5 hours. The reaction mixture is quenched with water and extracted with DCM. The combined organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 10% EtOAc in hexane as eluent to give 5-methoxy-7-((2-methyl-[1,1'- biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (0.1 g, crude) as a white solid. LCMS (ER) m/z =373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.96-2.00 (m, 2H), 2.21 (s, 3H), 2.65-2.70 (m , 2H), 3.08-3.11 (m, 2H), 3.92 (s, 3H), 5.31 (s, 2H), 6.78 (s, 1H), 7.19-7, 21 (m, 1H), 7.27-7.38 (m, 4H), 7.42-7.50 (m, 3H), 10.29 (s, 1H).

Step 6: To a mixture of 5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (0.05 g, 0.13 mmol) and N-(2-aminoethyl)acetamide (0.02 g, 0.20 mmol) in DMF:MeOH (10 ml) add one drop of acetic acid at room temperature. The mixture is stirred for 15 minutes and sodium cyanoborohydride (0.025 g, 0.40 mmol) is added to the reaction mixture. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was washed with sodium bicarbonate solution and dried over sodium sulfate and evaporated to give the crude product, which was purified by HPLC on a Combiflash system using 20% MeOH in DCM as eluent to give N-(2-(((5-methoxy-7 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (10 mg, 16% ) as a white solid. LCMS (ER) m/z =459.2 [M+H.] ⁺ . HPLC purity 98.29%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22 (br, 2H), 1.75 (s, 3H), 1.94-1, 97 (s, 2H), 2.20 (s, 3H), 2.71-2.75 (m, 2H), 2.82-2.86 (s, 2H), 3.08-3.09 ( s, 2H), 3.57(s, 2H), 3.77(s, 3H), 5.15(s, 2H), 6.61(s, 1H), 7.16-7.38(m , 5H), 7.42-7.47 (m, 3H), 7.73 (br, 1H).

Example 3

(S)-1-((7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)- 2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid acid (3)

Step 1: To a solution of 5-bromoindole (1 g, 5.1 mmol) in DMF (60 ml) was added NaH (0.22 g, 5.6 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. Then 1-bromo-3-chloropropane (0.88 g, 5.6 mmol) was added to the reaction mixture at 0°C and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with water and extracted into ethyl acetate (2 ×100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a crude residue which was purified by HPLC on a Combiflash system using 9% ethyl acetate in hexane to give 4-bromo-1-(3-chloropropyl)-1H-indole in as a yellow viscous liquid (1.2 g, 86%). LCMS (ER) m/z =272.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.18 (t, J =5.4 Hz, 2H), 3.53 (t, J =6.0 Hz, 2H) , 4.31 (t, J =6.8 Hz, 2H)), 6.40(brs, 1H), 7.07 (t, J =8.0 Hz, 1H), 7.23 (d, t , J = 7.6 Hz, 1H), 7.49-7.54 (m, 2H).

Step 2: To a stirred solution of 4-bromo-1-(3-chloropropyl)-1H-indole (0.9 g, 3.3 mmol) and (2-methyl-3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.98 g, 3.97 mmol) in dioxane:water (20 ml:4 ml) Xphos (0.3 g, 0.33 mmol), CsF (1 g, 6.6 mmol) and Pd ₂ (dba) ₃ (0.27 g, 0.33 mmol) and the reaction mixture was purged with nitrogen for 15 min. The reaction mixture is then heated at 85° C. for 14 hours in a sealed tube. The reaction mixture is filtered over celite, the filtrate is diluted with water and extracted into ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a crude residue which was purified by HPLC on a Combiflash system using 10% ethyl acetate in hexane to give (3-(1-(3-chloropropyl)-1H-indole- 4-yl)-2-methylphenyl)methanol as a brown viscous liquid (0.8 g, 96%). LCMS (ER) m/z =314.1 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 1.13-1.22 (m, 4H), 1.99 (s, 3H), 2.19-2.24 (m, 2H), 3.58 (t, J = 6 Hz, 2H), 4.32 (brs, 2H), 4.54-4 .55 (m, 2H), 5.07 (brs, 1H), 6.00 (s, 1H), 6.84 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.6Hz, 1H), 7.20(q, J =8Hz, 2H), 7.33-7.34(m, 1H), 7.40(d, J =7.6Hz, 1H) , 7.47 (d, J = 8.4 Hz, 1H).

Step 3: To a solution of (3-(1-(3-chloropropyl)-1H-indol-4-yl)-2-methylphenyl)methanol (0.2 g, 0.6 mmol) in DMF (10 ml) was simultaneously added 3,3-difluoropyrrolidine hydrochloride (0.133 g, 0.95 mmol), sodium iodide (0.143 g, 0.95 mmol) and K ₂ CO ₃ (0.172 g, 1.27 mmol), and the reaction mixture is heated at 80°C within 16 hours the Reaction mixture is cooled to room temperature, diluted with ice water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a crude residue which was purified by HPLC on a Combiflash system using 15% ethyl acetate in hexane to give (3-(1-(3-(3,3-difluoropyrrolidine-1 -yl)propyl)-1H-indol-4-yl)-2-methylphenyl)methanol as a brown viscous liquid (0.13 g, 43%); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 1.90-1.97 (m, 2H), 2.00 (s, 3H), 2.12-2.18 (m , 2H), 2.37-2.48 (m, 2H), 2.62-2.64 (m, 2H), 2.81-2.87 (m, 2H), 4.18-4.25 (brs, 2H), 451-4.52 (m, 2H), 5.12-5.20 (m, 1H), 5.97 (s, 1H), 6.83 (d, J =7.2 Hz, 1H), 7.11(d, J =7.6Hz, 1H), 7.16-7.23(m, 2H), 7.32(brs, 1H), 7.39(d, J = 7.6 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H).

Step 4: To a stirred solution of (3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylphenyl)methanol (0.3 g, 0 .78 mmol) in DCM (20 mL) PBr ₃ (0.42 g, 1.56 mmol) was added dropwise at 0° C. and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture is quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated to give 4-(3-(bromomethyl)-2-methylphenyl)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H -indole in the form of a colorless viscous liquid (0.2 g, 59%). LCMS (ER) m/z =447.449 [M, M+2H] ⁺ .

Step 5: To a stirred solution of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.13 mmol) and 4-(3-(bromomethyl)-2-methylphenyl)-1 -(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indole (0.2, 0.34 mmol) in ACN (10 ml) K ₂ CO ₃ (0.07 g, 0. 41 mmol) and the reaction mixture was stirred for 14 h at room temperature. The reaction mixture is quenched with water, extracted into ethyl acetate (2×50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by HPLC on a Combiflash system using 20% ethyl acetate in hexane as eluent to give 7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol- 4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-indene-4-carbaldehyde as a colorless viscous oil (0.09 g, 36%). LCMS (ER) m/z =529.3, [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 1.14-1.18 (m, 3H), 1.91-1.94 (m, 2H), 1.97 (s , 2H), 2.05-2.10(m, 5H), 2.19-2.26(m, 2H), 2.81-2.88(m, 4H), 4.23(brs, 2H ), 5.31 (s, 2H), 5.99 (s, 1H), 6.88 (d, J = 7.2 Hz, 1H), 7.16-7.28 (m, 4H), 7 .35-7.36 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.72-7.25 (m, 1H), 9.95 (s, 1H).

Step 6: To a solution of 7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2.3 -dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.09 mmol) in MeOH (2 ml) and DMF (2 ml) simultaneously add (S)-piperidine-2-carboxylic acid (0.037 g, 0.037 g, 28 mmol) and acetic acid (0.05 ml) and the reaction mixture was stirred at 50°C for 2 h. The reaction mixture was then cooled to 0°C, NaCNBH ₃ (0.030 g, 0.283 mmol) was added and the reaction mixture was stirred at k.t. within 16 hours the Reaction mixture is evaporated; the crude product is taken up in DCM (15 ml) and washed with water and brine. The organic layer was dried over sodium sulfate, concentrated to give a crude residue which was purified by HPLC on a Combiflash system using 5% methanol in dichloromethane as eluent to give 1-((4-((2-methyl-[1,1'- biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperidine-2-carboxylic acid as a white crystalline solid (0.006 g, 10%). LCMS (ER) m/z =642.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.35-1.55 (m, 5H), 1.72 (brine, 2H), 1.92-1.99 (m , 5H), 2.09 (s, 3H), 2.21-2.26 (m, 3H), 2.31-2.37 (m, 4H), 2.81-2.91 (m, 7H ), 3.81-3.84 (m, 1H), 4.22 (brs, 2H), 5.14 (s, 2H), 5.99 (s, 1H), 6.87 (d, J = 7.2 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.20-7.28 (m, 3H), 7.35 (s, 1H), 7.45- 7.48 (m, 2H).

Example four

( S )-1-((6-methyl-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-yl )methyl)piperidine-2-carboxylic acid (4)

Step 1: To a solution of o -cresol (4.0 g, 0.0369 mol) in acetonitrile (100 ml) was added magnesium chloride (5.2 g, 0.055 mol) and triethylamine (9.35 g, 0.092 mol) and the mixture stirred for 15 minutes. Paraformaldehyde (5.5 g, 0.185 mol) was added and the mixture was heated at 90° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was diluted with aqueous 1N HCl (100 ml). The aqueous mixture is extracted with EtOAc (2×100 ml) and the organic layer is washed with saturated salt solution (50 ml), dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g) using 4% EtOAc in hexane as eluent to give 2-hydroxy-3-methylbenzaldehyde (Yield: 1.7 g, 34%) as a light green solid . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.28 (s, 3H), 6.93 (t, J= 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 9.88 (s, 1H), 11.27 (s, 1H).

Step 2: To a solution of 2-hydroxy-3-methylbenzaldehyde (10 g, 70 mmol) in acetic anhydride (15 g, 146 mmol) is added sodium acetate (15 g, 183 mmol). The mixture is heated at 180°C for 10 hours After completion of the reaction, the mixture is cooled and diluted with water (300 ml). The mixture is extracted with EtOAc (3×500 ml) and the combined extracts are washed with saturated sodium bicarbonate solution (250 ml), water (100 ml), brine (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude mixture was purified by flash chromatography (silica gel, 40 g) using 15% EtOAc in hexane as eluent to give 8-methyl-2H- chromen -2-one (Yield: 4.1 g, 35%) as whitish solid, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.46 (s, 3H), 6.41 (t, J= 9.6 Hz, 1H), 7.18 ( t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H).

Step 3: To a solution of 8-methyl-2H- chromen -2-one (8.0 g, 50 mmol) in AcOH (60 ml) was added 10% palladium on charcoal (50% wet, 4.0 g) under nitrogen and the resulting mixture was hydrogenated using a hydrogen balloon for 4 hours at room temperature. After completion of the reaction, the reaction mixture is filtered over a layer of celite and the layer is washed with EtOAc (20 ml). The filtrate was washed with saturated sodium bicarbonate (10 ml), water (10 ml), brine (10 ml), dried over sodium sulfate and concentrated in vacuo to give 8-methylchroman-2-one (3.40 g, crude) . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.30 (s, 3H), 2.77 (m, 2H), 2.98 (m, 2H), 6.97-7, 02 (m, 2H), 7.10 (d, J = 6.0 Hz, 1H).

Step 4: A mixture of 8-methylchroman-2-one (2.0 g, 13.5 mmol) and anhydrous AlCl ₃ (5.4 g, 40.5 mmol) is heated at 180° C. for 2 hours. After completion of the reaction , the mixture is cooled and quenched with ice water (100 ml). The aqueous mixture is extracted with EtOAc (3×100 ml) and the EtOAc extract is dried over sodium sulfate and concentrated. The resulting residue was triturated with pentane and filtered to give 4-hydroxy-5-methyl-2,3-dihydro- 1H -inden-1-one (Yield: 1.7 g, 67%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.24 (s, 3H), 2.59 (m, 2H), 2.95 (m, 2H), 7.04 ( d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 9.19 (s, 1H).

Step 5: To a solution of 4-hydroxy-5-methyl-2,3-dihydro- 1H -inden-1-one (0.70 g, 4.3 mmol) in 1,2-dichloroethane (20 ml) at room temperature temperature under nitrogen atmosphere slowly add sodium cyanoborohydride (0.8 g, 12.9 mmol) and ZnI ₂ (5.5 g, 17 mmol) and the resulting mixture is heated at 80°C for 16 h. After completion, the reaction mixture is quenched water (50 ml) and filtered through a pad of celite. The layer was washed with EtOAc (200 ml) and the filtrate was dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 20% EtOAc in hexane to give 5-methyl-2,3-dihydro- 1H -inden-4-ol (Yield: 0.50 g, 72%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.10 (m, 2H), 2.23 (s, 3H), 2.82 (m, 2H), 2.90 (m, 2H), 6.73 (d, J =7.2 Hz, 1H), 6.92 (d, J =7.2 Hz, 1H).

Step 6: To a solution of 5-methyl-2,3-dihydro- 1H -inden-4-ol (0.50 g, 3.3 mmol) in TFA (12.5 ml) is added hexamine (0.56 g, 4.0 mmol) and the mixture was stirred at 120°C for 3 hours. After cooling the mixture to 0°C, 10% aqueous H ₂ SO ₄ solution (12.5 ml) was added and the mixture was heated at 100°C for 2 hours The reaction mixture is cooled to room temperature and quenched with solid sodium bicarbonate until gas evolution stops. After diluting the mixture with water (50 ml), it is extracted with DCM (3×50 ml) and the organic extract is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 20% EtOAc in hexane to give 7-hydroxy-6-methyl-2,3-dihydro-1 H -indene-4-carbaldehyde (Yield: 220 mg, 38%) as a yellow solid. LCMS (ER) m/z=177.24 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.18 (m, 2H), 2.29 (s, 3H), 2.82 (t, J= 7.2 Hz, 2H), 3.29 (t, J= 7.2 Hz, 2H), 5.05 (m, 1H), 7.46 (s, 1H), 9.97 (s, 1H).

Step 7: To a solution of 7-hydroxy-6-methyl-2,3-dihydro- 1H -indene-4-carbaldehyde (0.22 g, 1.25 mmol) in acetonitrile (5 ml) was added potassium carbonate (0 25 g, 1.86 mmol) and the reaction mixture was stirred for 30 minutes. 3-(Bromomethyl)-2-methyl-1,1'-biphenyl (0.32 g, 1.25 mmol) was added and the reaction mixture was stirred for 5 hours. Upon completion, the reaction mixture was diluted with water (10 ml) and extracted EtOAc (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% EtOAc in hexane as eluent to give 6-methyl-7-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-2,3-dihydro-1 H -indene-4-carbaldehyde (Yield: 0.35 g, 79%) as a white solid. LCMS (ER) m/z=357.19 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ ppm: 2.07 (m, 2H), 2.24 (s, 6H), 2.99 (m, 2H), 3.19 (m , 2H), 5.14 (s, 2H), 7.19 (d, J = 7.2 Hz, 1H), 7.27-7.32 (m, 3H), 7.38 (m, 1H) , 7.44-7.49 (m, 3H), 7.56 (s, 1H), 10.01 (s, 1H).

Step 8: Solution of 6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-carbaldehyde (100 mg, 0.28 mmol), ( S )-piperidine-2-carboxylic acid (50 mg, 0.42 mmol) and acetic acid (1 drop) in DMF (2 ml) and MeOH (2 ml) were stirred at room temperature for 2 hours Sodium cyanoborohydride (50 mg, 0.84 mmol) is added and the mixture is stirred for 16 hours. After completion, the reaction mixture is concentrated and the residue is diluted with water (10 ml). The aqueous mixture is extracted with 10% MeOH in DCM (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% MeOH in DCM as eluent to give ( S )-1-((6-methyl-7-((2-methyl-[1, 1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 62 mg, 46%) as white solid .

LCMS (ER) m/z=470.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.78 (m, 2H), 1.99 (m, 2H), 2.19 (s, 3H), 2.23 (s, 3H), 2.83 (m, 1H), 2.88 (m, 4H), 3.09 (m , 1H), 3.41 (d, J =12.8 Hz, 1H), 3.81 (d, J =12.8 Hz, 1H), 4.94 (s, 2H), 6.97 (s , 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m, 1H), 7.44-7.49 ( m, 3H).

Example 5

( S )-1-((6-chloro-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-yl )methyl)piperidine-2-carboxylic acid (5)

Step 1: To a solution of 4-hydroxy-2,3-dihydro- 1H -inden-1-one (5.0 g, 33.7 mmol) in 1,2-dichloroethane (500 ml) at room temperature under nitrogen Sodium cyanoborohydride (8.48 g, 135 mmol) and ZnI ₂ (43 g, 135 mmol) are added slowly and the resulting mixture is heated at 80° C. for 5 hours. After completion of the reaction, the reaction mixture is filtered through a plug of silica gel under warm conditions and washed with warm DCM (500 ml). The filtrate was concentrated in vacuo to give 2,3-dihydro-1 H -inden-4-ol (Yield: 3.3 g, 75%) as a brown viscous solid which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.99 (m, 2H), 2.67 (m, 2H), 2.82 (m, 2H), 6.54 (d, J=7.6Hz, 1H), 6.65(d, J =7.6Hz, 1H), 6.91(t, J =7.6Hz, 1H), 9.15(s, 1H) .

Step 2: To a solution of 2,3-dihydro- 1H -inden-4-ol (3.3 g, 24.6 mmol) in chloroform (150 ml) at 60°C was added N-chlorosuccinimide (3.2 g, 24.6 mmol). After stirring at room temperature for 1 hour, conc. HCl (1 ml) and the mixture is refluxed for 10 hours After completion, the reaction mixture is cooled and diluted with water (100 ml). The aqueous mixture is extracted with DCM (2×100 ml) and the combined organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g) using 0-40% EtOAc in hexane as eluent to give 5-chloro-2,3-dihydro- 1H -inden-4-ol (Yield: 1.3 g, 32%) as yellow liquid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.99 (m, 2H), 2.82 (m, 4H), 6.69 (d, J =8.0 Hz, 1H), 7.07 (d, J =8.0 Hz, 1H), 9.24 (s, 1H).

Step 3: To a solution of 5-chloro-2,3-dihydro- 1H -inden-4-ol (1.3 g, 7.7 mmol) in TFA (50 ml) is added hexamine (940 mg, 9.25 mmol ) and the mixture is heated at 120°C for 2 hours. After completion, the reaction mixture is quenched with solid sodium bicarbonate (5 g). After dilution with water (30 ml), the mixture was extracted with EtOAc (2×50 ml) and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel) using 0-40% EtOAc in hexane as eluent to give 6-chloro-7-hydroxy-2,3-dihydro- 1H -indene-4-carbaldehyde (Yield: 0. 6 g, 40%) as a yellow liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.06 (m, 2H), 2.83 (t, J =7.6 Hz, 2H), 3.16 (t, J = 7.6 Hz, 2H), 7.69 (s, 1H), 9.87 (s, 1H), 10.52 (br, 1H).

Step 4: Potassium carbonate ( 0.63 g, 4.6 mmol) and the reaction mixture was stirred for 30 minutes. To this mixture was added 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.79 g, 3.06 mmol) and continued for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-40% EtOAc in hexane as eluent to give 6-chloro-7-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 0.70 g, 64%) as a yellow solid. LCMS (ER) m/z=377.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.08 (m, 2H), 2.27 (s, 3H), 2.99 (t, J =7.6 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H), 5.14 (s, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.27-7, 30 (m, 3H), 7.36 (m, 1H), 7.44-7.48 (m, 3H), 7.82 (s, 1H), 10.00 (s, 1H).

Step 5: Solution of 6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-carbaldehyde (120 mg, 0.30 mmol), (S)-piperidine-2-carboxylic acid (60 mg, 0.40 mmol) and acetic acid (1 drop) in DMF (2 ml) and MeOH (2 ml) were stirred at room temperature for 2 h. Sodium cyanoborohydride (54 mg, 0.90 mmol) is added and the reaction mixture is stirred for an additional 16 h. After completion of the reaction, the reaction mixture is concentrated and the residue is diluted with water (10 ml) and saturated sodium bicarbonate solution (2 ml). The aqueous mixture is extracted with EtOAc (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% MeOH in DCM as eluent to give ( S )-1-((6-chloro-7-((2-methyl-[1, 1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 80 mg, 57%) as white solid . LCMS (ER) m/z=490.14 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.22-1.34 (m, 2H), 1.48 (m, 3H), 1.75 (m, 2H), 2.01 (m, 2H), 2.26 (s, 3H), 2.82-2.88 (m, 5H), 3.08 (m, 1H), 3.36 (d, J =13, 6 Hz, 1H), 3.74 (d, J =13.6 Hz, 1H), 5.04 (s, 2H), 7.20 (d, J= 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (m, 1H), 7.44-7.49 (m, 3H).

Example 6

Methyl 7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[ 1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydro-1 H - inden- 5-carboxylate (6)

Step 1: Potassium carbonate (0.64 g, 4 .6 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. After stirring, 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.79 g, 3.08 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was diluted water (25 ml) and extracted with EtOAc (3×25 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% EtOAc in hexane as eluent to give 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) -2,3-dihydro- 1H -indene-5-carbaldehyde (Yield: 1.05 g, 99.5%) as a sticky solid. LCMS (ER) m/z=343.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.13 (m, 2H), 2.28 (s, 3H), 2.98 (t, J =7.2 Hz, 2H) , 3.03 (t, J =7.2 Hz, 2H), 5.16 (s, 2H), 7.17 (d, J =7.2 Hz, 1H), 7.31 (m, 2H) , 7.35-7.38 (m, 2H), 7.38-7.44 (m, 4H), 7.70 (d, J= 7.6 Hz, 1H), 10.29 (s, 1H ).

Step 2: To a solution of 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-5-carbaldehyde (0.80 g, 2 .3 mmol) in acetonitrile (30 ml) and water (2 ml) at 0°C NaH ₂ PO ₄ (112 mg, 0.9 mmol), 30% hydrogen peroxide (4 ml) and sodium chlorite (0. 63 g, 7.0 mmol). After stirring at 0°C for 3 h, the reaction mixture was diluted with water (50 ml) and extracted with DCM (3×50 ml). The organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo to give 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1 H -indene-5-carboxylic acid (Yield: 0.80 g, 95%) as a white solid. LCMS (ER) m/z=357.43 [MH] ^- ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.02 (m, 2H), 2.22 (s, 3H), 2.87 (m, 4H), 5.06 ( s, 2H), 7.04 (d, J=7.2 Hz, 1H), 7.17 (d, J =7.2 Hz, 1H), 7.24-7.31 (m, 3H), 7.38(m, 1H), 7.43-7.47(m, 2H), 7.49-7.52(m, 2H), 12.77(brs, 1H).

Step 3: To a solution of 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -indene-5-carboxylic acid (0.30 g, 0.837 mmol) in acetone (10 ml) potassium carbonate (0.29 g, 2.09 mmol) and methyl iodide (0.18 g, 1.26 mmol) are added. The reaction mixture is heated to reflux for 4 hours. After completion of the reaction, the reaction mixture is cooled and filtered. The filtrate was concentrated and the resulting crude product was purified by flash chromatography (silica gel) using 5% EtOAc in hexane as eluent to give methyl 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)- 2,3-dihydro-1 H -indene-5-carboxylate (Yield: 0.30 g, 96%) as a white solid. LCMS (ER) m/z=373.18 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.04 (m, 2H), 2.23 (s, 3H), 2.92 (m, 4H), 3.74 ( s, 3H), 5.03 (s, 2H), 7.10 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.27 ( m, 1H), 7.31 (d, J = 7.6 Hz, 2H) 7.38 (m, 1H), 7.44-7.48 (m, 3H), 7.54 (d, J = 7.6 Hz, 1H).

Step 4: To a solution of methyl 4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -indene-5-carboxylate (0.20 g, 0.537 mmol) in TFA (5 ml) was added hexamine (0.112 g, 0.805 mmol). The mixture was stirred at 120°C for 3 hours. After cooling the mixture to 0°C, 10% aqueous H ₂ SO ₄ solution (5 ml) was added and heated at 100°C for 2 hours. The reaction mixture was cooled to room temperature and quenched solid sodium bicarbonate until gas evolution stops. After diluting the mixture with water (25 ml), it is extracted with DCM (3×50 ml) and the organic extract is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 10% EtOAc in hexane to give methyl 7-formyl-4-hydroxy-2,3-dihydro-1 H -indene-5-carboxylate (Yield: 80 mg , 67.6%) as a white solid. LCMS (ER) m/z=221.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.10 (m, 2H), 2.83 (t, J =7.6 Hz, 2H), 3.25 (t, J =7.6Hz, 2H), 3.94(s, 3H), 8.22(s, 1H), 9.96(s, 1H), 11.13(brs, 1H).

Step 5: To a solution of methyl 7-formyl-4-hydroxy-2,3-dihydro- 1H -indene-5-carboxylate (0.12 g, 0.54 mmol) in acetonitrile (5 ml) was added potassium carbonate (0 11 g, 0.82 mmol). The reaction mixture is stirred for 30 minutes. To this mixture was added 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.14 g, 0.54 mmol). The reaction mixture was stirred for 6 hours. After completion of the reaction, the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3×25 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-10% EtOAc in hexane as eluent to give methyl 7-formyl-4-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1 H -indene-5-carboxylate (Yield: 70 mg, 58%) as an off-white solid. LCMS (ER) m/z=401.14 [M+H] ⁺ .

Step 6: Solution of methyl 7-formyl-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -indene-5-carboxylate (70 mg , 0.175 mmol), N-(2-aminoethyl)acetamide (30 mg, 0.26 mmol) and acetic acid (1 drop) in DMF (2.5 ml) and MeOH (2.5 ml) were stirred at room temperature in over 8 h. To this reaction mixture was added sodium cyanoborohydride (33 mg, 0.525 mmol) and the reaction mixture was stirred further for 8 h. ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% MeOH in DCM as eluent to give methyl 7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl- [1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-5-carboxylate (Yield: 33 mg, 41%) as a sticky solid. LCMS (ER) m/z=487.21 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.88 (s, 3H), 2.03 (m, 2H), 2.23 (s, 3H), 2.56 ( m, 2H), 2.91 (m, 4H), 3.14 (m, 2H), 3.64 (s, 2H), 3.76 (s, 3H), 5.01 (s, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7.26-7.32 (m, 3H), 7.38 (m, 1H), 7.44-7.48 (m, 3H) , 7.55 (s, 1H), 7.77 (m, 1H).

Example 7

( S )-1-((7-((3 '-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2' -dimethyl-[ 1,1'- biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1 H -inden-4-yl)methyl)piperidine-2-carboxylic acid (7)

Step 1: To a solution of 3-bromo-2-methylphenol (9.8 g, 52 mmol) in DMF (80 ml) was added 1,3-dichloropropane (11.73 g, 10 mmol) and potassium carbonate (21.5 g , 156 mmol). The reaction mixture is stirred at 80° C. for 12 hours under nitrogen. After 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 is 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 to give 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (Yield: 10 .1 g, 73.7%) as a yellow liquid, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 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: 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 is heated at 80°C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture is cooled to room temperature and diluted with EtOAc (100 ml), washed with ice water (50 ml), brine (50 ml) and the organic phase is dried over sodium sulfate and concentrated under vacuum to obtain the crude product. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 15% EtOAc in hexane to give 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (7.1 g, 56.3%) as a yellow liquid, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 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: To a solution of 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (2 g, 0.059 mol) 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) potassium carbonate was added at room temperature (2.47 g, 17 mmol) and the reaction mixture was purged with nitrogen for 15 minutes. To this mixture was added Pd(dppf)Cl ₂ DCM (0.24 g, 0.29 mmol) and the reaction mixture was again purged with nitrogen for 10 min and heated at 95° C. for 12 h. 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 (100 ml) and the 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 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 (Yield: 2 g, 90%) as an off-white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ hours/ ppm: 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: To a stirred solution of (3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (0 .55 g, 14 mmol) and 7-hydroxy-5-methoxy-2,3-dihydro- 1H -indene-4-carbaldehyde (0.28 g, 14 mmol) in dry THF (20 ml) under nitrogen at 0°C add triphenylphosphine (0.96 g, 35 mmol) and DEAD (1.15 g, 66 mmol) and the reaction mixture is stirred at room temperature for 24 h. After completion of the reaction, the mixture is diluted with EtOAc (50 ml) and washed with ice-cold water (20 ml) and brine (20 ml). The organic phase is dried over sodium sulfate, concentrated in vacuo to give the crude product, which is purified by column chromatography (silica gel, 100-200 mesh) using 30% EtOAc in hexane to give 7-((3'-(3-(3, 3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1 H -inden-4 -carbaldehyde (Yield: 0.110 g, 13%) as a white solid. LCMS (ER) m/z=550.25 [M+H] ⁺ .

Step 5: Solution of 7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy) -5-methoxy-2,3-dihydro- 1H -indene-4-carbaldehyde (100 mg, 0.185 mmol), ( S )-piperidine-2-carboxylic acid (36 mg, 0.27 mmol) and acetic acid ( 1 drop) in DMF (2 ml) and MeOH (2 ml) was stirred at room temperature for 2 h. Sodium cyanoborohydride (34 mg, 0.55 mmol) was added to this mixture and the reaction mixture was stirred for 16 h. completion of the reaction, the reaction mixture was diluted with ice water (10 ml) and the aqueous mixture was extracted with 10% MeOH in DCM (3×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by prep-TLC using 10% MeOH in DCM as solvent system to give ( S )-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy )-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1 H -inden-4-yl)methyl)piperidin-2- carboxylic acid (36, Yield: 50 mg, 44%) as a white solid. LCMS: (ER) m/z=663.31 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.76 (m, 2H), 1.82 (s, 3H), 1.90-2.00 (m, 9H), 2.19 (m, 4H), 2.50-2.72 (m, 7H), 2.75-2.89 (m, 5H), 2.98-3.11 (m, 2H), 3. 73 (m, 1H), 3.80 (s, 3H), 3.89 (m, 1H), 4.05 (m, 2H), 5.18 (s, 2H), 6.63 (s, 1H ), 6.86 (d, J =7.48 Hz, 1H), 6.96 (d, J =8.16 Hz, 1H), 7.06 (d, J =7.36 Hz, 1H), 7.17-7.28 (m, 2H), 7.47 (d, J = 7.52 Hz, 1H).

Example eight

( S )-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-yl)methyl)piperidine-2-carboxylic acid (8)

Stage 1: Mixture of 7-hydroxy-5-methoxy-2,3-dihydro- 1H -inden-1-one (20 g, 0.1122 mol) in DCE (200 ml), zinc iodide (107.48 g, 0.337 mol) and sodium cyanoborohydride (28.21 g, 0.448 mol) are heated at 75° C. for 8 hours. The reaction mixture is filtered and the residue is washed with DCM (200 ml). The filtrate was washed with water (100 ml), brine (100 ml) and dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 30% EtOAc in hexane as eluent to give 6-methoxy-2,3-dihydro- 1H -inden-4-ol (Yield: 17 g, 92%) as a white solid. LCMS (ER) m/z=165.04 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95 (m, 2H), 2.65 (t, J =7.2 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 3.64 (s, 3H), 6.14 (s, 1H), 6.27 (s, 1H), 9.11 (s, 1H).

Step 2: To a solution of 6-methoxy-2,3-dihydro- 1H -inden-4-ol (1 g, 0.006 mol) in 10% NaOH aqueous solution (45 ml) was added β-cyclodextrin (8 g, 0.007 mol) and the mixture is heated to 60°C. Chloroform (6 ml, 0.125 mol) was slowly added to this mixture over 3 hours. After consumption of the starting material, the reaction mixture was cooled to room temperature and acidified with 1N HCl solution to pH=2. The aqueous layer is extracted with EtOAc (3×200 ml) and the combined organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in hexane as eluent to give 7-hydroxy-5-methoxy-2,3-dihydro- 1H -indene-4-carbaldehyde (Yield: 200 mg, 17 %) as an off-white solid. LCMS (ER) m/z=193.03 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.99 (m, 2H), 2.64 (t, J =7.2 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 3.80 (s, 3H), 6.36 (s, 1H), 10.24 (s, 1H), 10.45 (s, 1H).

Step 3: To a solution of 7-hydroxy-5-methoxy-2,3-dihydro- 1H -indene-4-carbaldehyde (600 mg, 3.12 mmol) in DCM (100 ml) at 0°C, slowly add a 1M solution BBr ₃ in DCM (4.7 ml, 4.68 mmol) and the solution was stirred at room temperature for 6 h. Upon completion, the reaction mixture was quenched with water (100 ml) and extracted with DCM (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography using 30% EtOAc in hexane as eluent to give 5,7-dihydroxy-2,3-dihydro-1 H -indene-4-carbaldehyde (Yield: 405 mg, 71%) as white solid. LCMS (ER) m/z=177.28 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.00 (m, 2H), 2.63 (t, J =7.2 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 6.177 (s, 1H), 9.97 (s, 1H), 10.59 (s, 1H), 11.10 (s, 1H).

Step 4: To a solution of 5,7-dihydroxy-2,3-dihydro- 1H -indene-4-carbaldehyde (0.40 g, 2.247 mmol) in acetonitrile (20 ml) was added potassium carbonate (0.37 g, 2. 69 mmol) and 3-(bromomethyl)-2-methyl-1,1'-biphenyl (0.59 g, 2.25 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g) using 0-20% EtOAc in hexane as eluent to give 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-2,3-dihydro-1 H -indene-4-carbaldehyde (Yield: 0.70 g, 87%) as a white solid. LCMS (ER) m/z=359.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.05 (m, 2H), 2.19 (s, 3H), 2.71 (t, J =7.2 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H), 5.24 (s, 2H), 6.55 (s, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.28-7.33(m, 3H), 7.38(m, 1H), 7.44-7.48(m, 3H), 10.05(s, 1H), 11.31 (s, 1H).

Step 5: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-carbaldehyde (0, 50 g, 1.39 mmol) in acetonitrile (20 ml) are added potassium carbonate (0.35 g, 2.5 mmol) and 3-(chloromethyl)benzonitrile (0.41 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent to give 3-(((4-formyl-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-5-yl)oxy)methyl)benzonitrile (Yield: 0.505 g, 75%) as a white solid. LCMS (ER) m/z=474.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.00 (m, 2H), 2.21 (s, 3H), 2.70 (t, J =7.2 Hz, 2H), 3.13 (t, J =7.2 Hz, 2H), 5.30 (s, 2H), 5.38 (s, 2H), 6.92 (s, 1H), 7.22 ( d, J = 7.6 Hz, 1H), 7.27-7.33 (m, 3H), 7.38 (m, 1H), 7.44-7.48 (m, 3H), 7.63 (t, J = 7.6 Hz, 1H), 7.85 (m, 2H), 8.01 (s, 1H), 10.39 (s, 1H).

Step 6: A solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-5- yl)oxy)methyl)benzonitrile (100 mg, 0.21 mmol), ( S )-piperidine-2-carboxylic acid (40.8 mg, 0.32 mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2 drops) in DMF (5 ml) was stirred at 70°C for 4 h. After completion, the reaction mixture was poured into ice water (10 ml). The solid is filtered and dissolved in DCM. The organic solvent is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give ( S )-1-((5-((3-cyanobenzyl)oxy)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 26 mg, 46%) as a white solid. LCMS (ER) m/z=587.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.32-1.45 (m, 4H), 1.78 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.32 (m, 1H), 2.73 (m, 2H), 2.81 (m, 1H), 2.94-3.03 (m, 2H), 3 .14 (m, 1H), 3.71 (d, J = 12.4 Hz, 1H), 3.88 (d, J = 12.4 Hz, 1H), 5.14 (s, 2H), 5 .23 (s, 2H), 6.73 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.37 ( m, 1H), 7.44-7.49 (m, 3H), 7.61 (t, J = 7.6 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H).

Example 9

Synthesis of (S)-1-((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-carbaldehyde (0, 40 g, 1.117 mmol) in DMF (20 ml) add potassium carbonate (0.46 g, 3.38 mmol) and 3-(chloromethyl)-5-fluoropyridine (0.325 g, 2.25 mmol) and stir at room temperature within 16 hours Upon completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using DCM as eluent to give 5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (Yield: 0.201 g, 38%) as a white solid. LCMS (ER) m/z=468.16 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.99-2.00 (m, 2H), 2.22 (s, 3H), 2.71 (m, 2H), 3.13 (m, 2H), 5.32 (s, 2H), 5.40 (s, 2H), 6.95 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H ), 7.27-7.40 (m, 4H), 7.44-7.48 (m, 3H), 7.92 (d, J =9.2 Hz, 1H), 8.58 (s, 1H), 8.62 (s, 1H), 10.35 (s, 1H).

Step 2: To a solution of 5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-indene-4-carbaldehyde (50 mg, 0.11 mmol), ( S )-piperidine-2-carboxylic acid (52 mg, 0.32 mmol) in MeOH (3 mL) and DMF (3 mL) cyanoborohydride is added sodium (19 mg, 0.32 mmol) and acetic acid (2 drops) and the mixture was stirred at room temperature for 8 h. After completion, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×30 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-1-((5-((5-fluoropyridin-3-yl)methoxy) -7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 30 mg, 48%) as a white solid. LCMS (ER) m/z=581.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m, 2H), 2.32 (m, 3H), 2.49 (m, 1H), 2.74 (m, 2H), 2.81-3.05 (m, 3H), 3.14 (m, 1H), 3 .68 (d, J =12.8 Hz, 1H), 3.88 (d, J =12.4 Hz, 1H), 5.16 (s, 2H), 5.26 (m, 2H), 6 .78 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.39 (m, 1H), 7.44- 7.47 (m, 3H), 7.92 (d, J =9.6 Hz, 1H), 8.54 (s, 1H), 8.61 (s, 1H).

Example ten

N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1 H -inden-4-yl)methyl)amino)ethyl)acetamide

obtained by a method similar to example 9

LCMS (ER) m/z=554.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.75 (s, 3H), 1.97-2.01 (m, 2H), 2.20 (m, 3H), 2.61 (m, 2H), 2.76 (m, 2H), 2.89 (m, 2H), 3.13 (m, 2H), 3.71 (s, 2H), 5.16 (s , 2H), 5.26 (m, 2H), 6.77 (s, 1H), 7.19 (d, J =7.6 Hz, 1H), 7.25-7.33 (m, 3H) , 7.39(m, 1H), 7.44-7.47(m, 3H), 7.80(brs, 1H), 7.86(d, J =9.2Hz, 1H), 8, 55 (s, 1H), 8.59 (s, 1H).

Example eleven

Synthesis of (S)-5-((5-methoxy-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl )methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid

Step 1: To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (1.0 g, 3.6 mmol) in 1,4-dioxane (10 ml ) at 0°C, 4M HCl in 1,4-dioxane (15 mL) was added dropwise and the mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated in vacuo to give (S)-5-azaspiro[ 2,4]heptane-6-carboxylic acid (700 mg, crude) as an off-white solid. LCMS (ER) m/z=142.28 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.64 (m, 4H), 1.97-2.02 (m, 1H), 2.22 (m, 1H), 3.12(m, 2H), 4.44(m, 1H), 8.91(brs, 1H), 10.24(brs, 1H).

Step 2: 5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde solution (200 mg, 0 .42 mmol), (S)-5-azaspiro[2,4]heptane-6-carboxylic acid hydrochloride (89 mg, 0.50 mmol) and acetic acid (2 drops) in MeOH (2.5 ml) and DMF (2.5 ml) stirred at room temperature for 30 minutes. Sodium cyanoborohydride (39 mg, 0.63 mmol) is added to this mixture and stirring is continued at room temperature for 16 hours. After completion, the reaction mixture is diluted with water (10 ml) and extracted with 10% MeOH in DCM (3×15 ml) . The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give ( S )-5-((5-methoxy-7-((2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (Yield: 90 mg , 45%) as a white solid. LCMS (ER) m/z=498.43 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.46 (m, 1H), 0.58-0.64 (m 3H), 1.81-1.99 (m, 1H), 1.99-2.04 (m, 2H), 2.22 (s, 3H), 2.36 (m, 1H), 2.75 (m, 2H), 2.86-3.06 (m, 4H), 3.85 (m, 1H), 3.86 (s, 3H), 4.15 (m, 2H), 5.21 (s, 2H), 6.72 (s, 1H) , 7.20 (d, J = 7.6 Hz, 1H), 7.28-7.33 (m, 3H), 7.39 (m, 1H), 7.44-7.50 (m, 3H ).

Example 12

Synthesis of (S)-1-((7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro -1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1: Triethylamine (1.5 g, 15 mmol) is added to a solution of trifluoroethanol (500 mg, 5.0 mmol) in DCM (10 ml) and cooled to 0°C. To this mixture was added p-toluenesulfonyl chloride (1.2 g, 6.0 mmol) and the reaction mixture was stirred at room temperature for 6 h. After completion, the reaction mixture was diluted with water (10 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×10 ml) and the combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexane as eluent to give 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (Yield: 405 mg, 31%) as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.44 (s, 3H), 4.86 (m, 2H), 7.52 (d, J =8.0 Hz, 2H), 7.86 (d, J =8.0 Hz, 2H).

Step 2: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (0.40 g, 1.12 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (0.34 g, 1.34 mmol) in DMF (8 ml) potassium carbonate (0.28 g, 2.0 mmol) was added and stir the mixture at room temperature for 16 h. After completion, the mixture is diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexane as eluent to give 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5 -(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 102 mg, 21%) as a white solid. LCMS (ER) m/z=441.57 [M+H] ⁺ .

Step 3: A solution of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden- 4-carbaldehyde (100 mg, 0.23 mmol), ( S )-piperidine-2-carboxylic acid (87 mg, 0.68 mmol), sodium cyanoborohydride (42.2 mg, 0.68 mmol), and acetic acid ( 2 drops) in MeOH (2 ml) and DMF (3 ml) was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (3×25 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The residue was diluted with DCM (10 ml) and washed with DM water (4 ml). The organic layer was concentrated and purified by reverse phase HPLC using method-A to give ( S )-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5- (2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 20 mg, 16%) as a white solid. LCMS (ER) m/z=554.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.47 (m, 1H), 1.60 (m, 3H), 1.73 (m, 1H), 2.03 ( m, 3H), 2.21 (s, 3H), 2.79 (m, 2H), 2.83 (brs, 1H), 3.11 (m, 3H), 3.85 (brs, 1H), 3.95-4.02 (m, 2H), 4.84 (m, 2H), 5.20 (s, 2H), 6.86 (s, 1H), 7.21 (d, J =7, 6 Hz, 1H), 7.28-7.33 (m, 3H), 7.39 (m, 1H), 7.44-7.47 (m, 3H).

Example 13

Synthesis of N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide

Step 5: To a solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-5 -yl)oxy)methyl)benzonitrile (135 mg, 0.29 mmol) N-(2-aminoethyl)-N-methylacetamide (100 mg, 0.86 mmol) was added in a 1:1 mixture of MeOH and DMF (5 ml) , acetic acid (2 drops) and stirred for 15 minutes. To this mixture was added sodium cyanoborohydride (53 mg, 0.86 mmol) and the reaction mixture continued to be stirred at room temperature for 16 h. ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give N-(2-(((5-((3-cyanobenzyl)oxy)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)-N-methylacetamide (Yield: 46 mg , 28%) as a white solid. LCMS (ER) m/z=574.54 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.72 (s, 3H), 1.97 (m, 2H), 2.09 (s, 3H), 2.20 ( s, 3H), 2.36 (m, 2H), 2.74 (m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 3.40 (s, 2H), 5.13 (s, 2H), 5.20 (s, 2H), 6.72 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.25 (m, 1H ), 7.33 (m, 2H), 7.37 (m, 1H), 7.44-7.49 (m, 3H), 7.59-7.61 (m, 2H), 7.81 ( t, J = 8.8 Hz, 2H), 7.95 (s, 1H).

Example fourteen

Synthesis of N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3- dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -indene-4-carbaldehyde (0.250 g , 0.68 mmol) in DMF (10 ml) are added potassium carbonate (0.192 g, 1.39 mmol) and 3-(1-bromoethyl)benzonitrile (0.22 g, 1.04 mmol) and the reaction mixture is stirred at room temperature temperature for 10 minutes. Upon completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-20% EtOAc in hexane as eluent to give 3-(1-((4-formyl-7-((2-methyl-[1, 1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)benzonitrile (Yield: 0.275 g, 80%) as a white solid. LCMS (ER) m/z=488.34 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.63 (d, J =6.4 Hz, 3H), 1.97 (m, 2H), 2.18 (s, 3H), 2.65 (m, 2H), 3.08 (m, 2H), 5.10 (d, J = 12.4 Hz, 1H), 5.26 (d, J = 12.4 Hz, 1H), 5.86 (m, 1H), 6.73 (s, 1H), 7.27 (m, 2H), 7.30-7.40 (m, 4H), 7.44-7.48 (m, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz , 1H), 8.01 (s, 1H), 10.45 (s, 1H).

Step 2: To a solution of 3-(1-((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 5-yl)oxy)ethyl)benzonitrile (150 mg, 0.31 mmol) was added N N-(2-aminoethyl)acetamide (47 mg, 0.46 mmol) in a 1:1 mixture of MeOH and DMF (5 ml), acetic acid (5 drops) and stirred for 15 minutes. To this mixture, add sodium cyanoborohydride (38 mg, 0.62 mmol) and continue stirring the reaction mixture at room temperature for 16 hours. After completion, the reaction mixture is diluted with water (10 ml) and extracted with 10% MeOH in DCM (3× 25 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7 -((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (Yield: 55 mg, 31%) as a white solid. LCMS (ER) m/z=574.51 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.57 (d, J = 6.4 Hz, 3H), 1.78 (s, 3H), 1.94-1, 97 (m, 2H), 2.15 (s, 3H), 2.61 (m, 2H), 2.67-2.75 (m, 2H), 2.86 (m, 2H), 3.16 (m, 2H), 3.69 (brs, 2H), 4.89 (d, J= 12.0 Hz, 1H), 5.07 (d, J= 12.4 Hz, 1H), 5.60 (m, 1H), 6.46 (s, 1H), 7.15-7.22 (m, 2H), 7.25-7.31 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.78 (d , J = 7.6 Hz, 1H), 7.82 (brs, 1H), 7.94 (s, 1H).

Example fifteen

Synthesis of N-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidin-3-yl)acetamide

Step 1: Solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl )oxy)methyl)benzonitrile (150 mg, 0.40 mmol), N-(piperidin-3-yl)acetamide (170 mg, 1.20 mmol) in triethylamine (82 mg) and acetic acid (5 drops) are stirred in over 1 h. Add sodium cyanoborohydride (74.6 mg, 1.20 mmol) to this mixture and continue to stir the reaction mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3 ×25 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give N-(1-((5-((3-cyanobenzyl)oxy)-7-(( 2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-3-yl)acetamide (Yield: 23 mg, 9 .5%) as a white solid. LCMS (ER) m/z=600.55 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.10 (m, 1H), 1.39 (m, 1H), 1.58-1.74 (m, 6H), 1.83-1.99 (m, 3H), 2.21 (s, 3H), 2.61,2.76 (m, 4H), 2.88 (m, 2H), 3.39 (m, 2H), 3.60(m, 1H), 5.13(s, 2H), 5.20(s, 2H), 6.72(s, 1H), 7.20(d, J =7.52 Hz, 1H), 7.25-7.33(m, 3H), 7.37(m, 1H), 7.43-7.47(m, 3H), 7.63(m, 2H), 7 .80 (d, J = 7.36 Hz, 1H), 7.86 (d, J = 7.52 Hz, 1H), 7.97 (s, 1H).

The following compounds are prepared by the methods described above.

Table 2

No. Structure LCMS m/z [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16

N-(2-(((7-((2-метил-[1,1'-бифенил]-3-ил)метокси)-2,3-дигидро-1H-инден-4-ил)метил)амино)этил)ацетамид

N-(2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino) ethyl)acetamide 429.3 1.78 (s, 3H), 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.64-2.66 (m, 2H), 2.81 (t, J=7.2Hz, 2H), 2.88(t, J=7.4Hz, 2H), 3.16-3.18(m, 2H), 3.70(s, 2H), 5, 13 (s, 2H), 6.89 (d, J=8.4Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 7.17 (d, J=7.6Hz , 1H), 7.23-7.31 (m, 3H), 7.34-7.46 (m, 4H), 7.81 (s, 1H) 17

6-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6 -azaspiro[3,3]heptane 426.3 1.96-1.99 (m, 2H), 2.18 (s, 3H), 2.79-2.81 (m, 4H), 3.26-3.31 (m, 6H), 4, 58(s, 4H), 5.11(s, 2H), 6.85(brs, 1H), 6.99(brs, 1H), 7.16-7.18(m, 1H), 7.24 -7.38(m, 4H), 7.42-7.44(m, 3H) eighteen

2-(hydroxymethyl)-2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl )amino)propane-1,3-diol 448.0 1.99-2.01(m, 2H), 2.18(s, 3H), 2.81-2.89(m, 4H), 3.30(s, 6H), 3.65(brs, 2H), 4.32 (br, 3H), 5.12 (s, 2H), 6.81-6.89 (m, 1H), 7.04-7.20 (m, 2H), 7.22 -7.39(m, 4H), 7.42-7.44(m, 3H) 19

1-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)cyclopropan-1 -carboxylic acid 428.2 0.86-0.87 (m, 2H), 1.08-1.09 (m, 2H), 1.94-2.02 (m, 2H), 2.17 (s, 3H), 2, 77-2.88 (m, 4H), 3.73 (s, 2H), 5.11 (s, 2H), 6.83 (d, J=7.6 Hz, 1H), 7.03 (d , J=8.4 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.23-7.37 (m, 4H), 7.42-7.45 (m, 3H) twenty

((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine 402.1 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.80-2.94 (m, 4H), 3.08 (s, 2H), 3.86 (s, 2H), 5.15(s, 2H), 6.94(d, J=8.0Hz, 1H), 7.16-7.21(m, 2H), 7.23-7.31(m , 3H), 7.36-7.37 (m, 1H), 7.42-7.44 (m, 3H) 21

3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propanoic acid 417.2 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.25-2.28 (m, 2H), 2.80-2.91 (m, 6H), 3, 74 (s, 2H), 5.13 (s, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.09-7.17 (m, 2H), 7.23-7 .37 (m, 4H), 7.42-7.44 (m, 3H), 8.01-9.91 (br, 2H) 22

N-methyl-N-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine 417.2 1.94-1.99 (m, 2H), 2.17 (s, 3H), 2.22 (s, 3H), 2.79 (t, J=7.6 Hz, 2H), 2.84 -2.91 (m, 4H), 3.53 (s, 2H), 5.10 (s, 2H), 6.84 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 7.45(d, J=7.6Hz, 1H), 7.22-7.30(m, 3H), 7.33-7.44(m, 4H ) 23

3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid 430.2 1.15-1.16 (m, 3H), 2.00-2.05 (m, 2H), 2.10-2.25 (m, 5H), 2.81-2.95 (m, 4H ), 3.09-3.11 (m, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.87 (d, J=12.8 Hz, 1H), 5.15 (s, 2H), 6.93 (d, J=8.0 Hz, 1H), 7.12-7.18 (m, 2H), 7.24-7.37 (m, 4H), 7, 42-7.44 (m, 2H), 9.98 (br, 1H) 24

((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)alanine 415.2 1.25-1.26 (m, 3H), 1.98-2.02 (m, 2H), 2.18 (s, 3H), 2.80-2.97 (m, 4H), 3, 16-3.18 (m, 1H), 3.78-3.90 (m, 2H), 5.15 (s, 2H), 6.94 (d, J=8.0 Hz, 1H), 7 .16-7.37 (m, 6H), 7.42-7.44 (m, 2H), 7.56-8.34 (br, 1H) 25

(2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid 488.5 1.13-1.19 (m, 1H), 1-98-2.0 (m, 3H), 2.15-2.23 (m, 1H), 2.21 (s, 3H), 2, 74 (t, J=7.6 Hz, 3H), 2.89-2.97 (m, 2H), 3.19 (brs, 1H), 3.74 (brs, 1H), 3.83 (s , 3H), 4.07-4.08(m, 2H), 4.23(brs, 1H), 4.19(s, 2H), 4.21(brs, 1H), 6.69(s, 1H), 7.19-7.21(m, 1H), 7.26-7.31(m, 3H), 7.34-7.38(m, 1H), 7.42-7.49( m, 3H) 26

(S)-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid 486.5 1.35-1.51 (m, 4H), 1.75 (brs, 2H), 1.96 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.52 (s, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.68-2.78 (m, 1H), 2.79-2.93 (m, 1H), 3, 10-3.11 (m, 1H), 3.71-3.74 (m, 1H), 3.78 (s, 3H), 3.82-3.84 (m, 1H), 5.17 ( s, 2H), 6.64 (s, 1H), 7.18(d, J=7.6 Hz, 1H), 7.25-7.31 (m, 3H), 7.34-7.38 (m, 1H), 7.42-7.48 (m, 3H) 27

1-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidine-2-carboxylic acid 468.2 1.47(brs, 2H), 1.63-1.70(m, 8H), 2.03(brs, 2H), 2.18(s, 3H), 2.65(brs, 2H), 2 .80-2.89(m, 1H), 3.07(brs, 1H), 3.86(brs, 2H), 4.21(brs, 1H), 5.13(s, 2H), 6, 86-7.14 (m, 1H), 7.19-7.26 (m, 2H), 7.27-7.38 (m, 4H), 7.42-.47 (m, 3H)1, 47(brs, 2H), 1.63-1.70(m, 8H), 2.03(brs, 2H), 2.18(s, 3H), 2.65(brs, 3H), 2.80 -2.89(m, 2H), 3.07(brs, 1H), 3.86(brs, 2H), 4.21(brs, 1H), 5.13(s, 1H), 6.86- 7.14 (m, 1H), 7.19-7.26 (m, 2H), 7.27-7.38 (m, 4H), 7.42-.47 (m, 3H) 28

N-(2-(((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide 443.20 1.96-1.99 (m, 2H), 2.18 (s, 3H), 2.79-2.81 (m, 4H), 3.26-3.31 (m, 6H), 4, 58(s, 4H), 5.11(s, 2H), 6.85(brs, 1H), 6.99(brs, 1H), 7.16-7.18(m, 1H), 7.24 -7.38(m, 4H), 7.42-7.44(m, 3H) 29

(2S,4R)-4-hydroxy-1-((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid 472.18 1.99 (m, 4H), 2.19 (s, 3H), 2.23 (s, 3H), 2.43 (m, 1H), 2.83-2.93 (m, 5H), 3 .16 (m, 1H), 3.50 (m, 1H), 3.60 (d, J=12.8 Hz, 1H), 3.99 (d, J=12.8 Hz, 1H), 4 .21(brs, 1H), 4.95(s, 2H), 5.01(brs, 1H), 6.99(s, 1H), 7.19(d, J=7.2Hz, 1H) , 7.27-7.32(m, 3H), 7.37(m, 1H), 7.44-7.49(m, 3H). thirty

N-(2-(((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide 463.17 1.79 (s, 3H), 2.01 (m, 2H), 2.27 (s, 3H), 2.54 (m, 2H), 2.83 (m, 2H), 2.89 (m , 2H), 3.14 (m, 2H), 3.60 (s, 2H), 5.03 (s, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.26 -7.32(m, 4H), 7.38(m, 1H), 7.44-7.48(m, 3H), 7.80(brs, 1H). 31

(2S,4R)-1-((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 492.09 1.99 (m, 4H), 2.27 (s, 3H), 2.23 (m, 1H), 2.83-2.93 (m, 4H), 3.16 (m, 1H), 3 .50 (m, 1H), 3.60 (d, J=12.8 Hz, 1H), 3.99 (d, J=12.8 Hz, 1H), 4.21 (br, 1H), 4 .9 (brs, 1H), 5.05 (s, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.28 (s, 2H), 7.29-7.32 ( m, 2H), 7.37 (m, 1H), 7.44-7.49 (m, 3H), 11.0-13.0 (br, 1H). 32

N-(2-(((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide 636.92 1.76 (s, 3H), 1.82 (s, 3H), 1.87-2.00 (m, 5H), 2.01 (s, 3H), 2.20-2.28 (m, 4H), 2.75-2.59 (m, 6H), 2.83-2.92 (m, 4H), 3.06 (m, 2H), 3.55 (s, 2H), 3.76 (s, 3H), 4.05 (m, 2H), 5.16 (s, 2H), 6.59 (s, 1H), 6.68 (d, J=7.48 Hz, 1H), 6 .96 (d, J=8.16 Hz, 1H), 7.06 (d, J=7.36 Hz, 1H), 7.17-7.28 (m, 2H), 7.47 (brs, 1H). 33

(2S,4R)-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]- 3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 665.241 1.82 (s, 2H), 1.90-2.09 (m, 8H), 2.10-2.30 (m, 4H), 2.55-3.00 (m, 11H), 3, 10-3.49 (br, 2H), 3.60 (m, 1H), 3.83 (s, 3H), 4.00-4.09 (m, 4H), 4.11 (m, 1H) , 5.20 (m, 3H), 6.86 (m, 2H), 6.96 (d, J=8.16 Hz, 1H), 7.06 (d, J=7.36 Hz, 1H) , 7.17-7.28 (m, 2H), 7.47 (d, J=7.52 Hz, 1H). 34

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)acetamide 560.30 1.76 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.66 (m, 2H), 2.76 (m, 2H), 2.90 (m , 2H), 3.16 (m, 2H), 3.77 (s, 2H), 5.14 (s, 2H), 5.24 (s, 2H), 6.74 (s, 1H), 7 .18 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.2 Hz, 2H), 7.36 -7.48(m, 4H), 7.61(t, J=7.2Hz, 1H), 7.82(d, J=7.2Hz, 2H), 7.84(brs, 1H) 7.97 (s, 1H) 35

(2S,4R)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 589.28 1.99-2.10 (m, 4H), 2.20 (s, 3H), 2.73 (m, 2H), 2.83-3.02 (m, 3H), 3.30 (m, 2H), 3.73(m, 1H), 4.12-4.20(m, 2H), 4.26(brs, 1H), 5.16(s, 2H), 5.31(s, 2H ), 6.78 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.32 (d, J =7.2 Hz, 2H), 7.36-7.49 (m, 4H), 7.61 (t, J=7.6 Hz, 1H), 7.80 (d, J=7.6 Hz , 1H), 7.90 (d, J=7.6 Hz, 1H), 8.03 (s, 1H). 36

(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid 587.15 1.45 (m, 4H), 1.76 (m, 2H), 1.97 (m, 2H), 2.20 (s, 3H), 2.32 (m, 2H), 2.66-3 .14 (m, 4H), 3.32 (m, 1H), 3.73 (m, 1H), 3.90 (m, 1H), 5.13 (s, 2H), 5.23 (s, 2H), 6.73 (s, 1H), 7.20 (d, J=7.44 Hz, 1H), 7.24-7.32 (m, 3H), 7.37-7.45 (m , 4H), 7.60 (m, 1H), 7.80 (d, J=7.26 Hz, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.98 (s , 1H). 37

(S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxamide 586.55 1.49-1.58 (m, 4H), 1.73 (m, 1H), 1.91-1.97 (m, 4H), 2.19 (s, 3H), 2.59-2, 74 (m, 4H), 2.82 (m, 1H), 2.98 (m, 1H), 3.19 (d, J=12.5 Hz, 1H), 3.69 (d, J=12 Hz, 1H), 5.10(s, 2H), 5.24(s, 2H), 6.69(s, 1H), 6.95(brs, 1H), 7.06(brs, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.32 (m, 2H), 7.36-7.47 (m, 4H), 7.59 (m, 1H), 7 .78-7.82 (m, 2H), 7.93 (s, 1H). 38

3-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile 579.39 1.97 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.90 (m, 2H), 3.41 (s, 6H), 3.69 (br , 2H), 4.22 (br, 3H), 5.13 (s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.19 (m, 1H), 7 .25 (m, 1H), 7.32 (m, 2H), 7.36-7.47 (m, 4H), 7.59 (m, 1H), 7.78 (d, J=7.96 Hz, 1H), 7.90 (d, J=7.88 Hz, 1H), 7.97 (s, 1H). 39

3-(((4-((2-oxa-6-azaspiro[3,3]heptan-6-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile 557.41 1.97 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.86 (m, 2H), 3.23 (m, 2H), 3.31 (m , 2H), 3.45 (m, 2H), 4.55 (s, 4H), 5.13 (s, 2H), 5.22 (s, 2H), 6.72 (s, 1H), 7 .19 (m, 1H), 7.25 (m, 1H), 7.32 (m, 2H), 7.39-7.47 (m, 4H), 7.62 (m, 1H), 7. 84 (m, 2H), 7.98 (s, 1H). 40

3-(((4-((3-hydroxypiperidin-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)benzonitrile 559.41 1.23-1.33(m, 4H), 1.35(m, 1H), 1.56(m, 1H), 1.69-1.84(m, 3H), 1.98(m, 2H), 2.21(s, 3H), 2.74-2.76(m, 3H), 2.87(m, 2H), 3.45(m, 1H), 4.49(brs, 1H ), 5.13 (s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.20 (d, J=7.32 Hz, 1H), 7.25-7 .32 (m, 3H), 7.39 (m, 1H), 7.44-7.47 (m, 3H), 7.63 (m, 1H), 7.80 (d, J=7.68 Hz, 1H), 7.85 (d, J=7.85 Hz, 1H), 7.94 (s, 1H). 41

((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl )methyl)glycine 533.49 2.00 (m, 2H), 2.19 (s, 3H), 2.76 (m, 2H), 2.92 (m, 2H), 3.07 (s, 2H), 3.99 (s , 2H), 5.16 (s, 2H), 5.27 (s, 2H), 6.76 (s, 1H), 7.19 (d, J=7.44 Hz, 1H), 7.27 (m, 1H), 7.32 (d, J=7.24 Hz, 1H), 7.36-7.47 (m, 4H), 7.60 (m, 1H), 7.81 (d, J=7.52 Hz, 1H), 7.91 (d, J=7.76 Hz, 1H), 8.02 (s, 1H). 42

(S)-5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)-5-azaspiro[2,4]heptan-6-carboxylic acid 599.49 0.43-0.54 (m, 4H), 1.77 (m, 1H), 2.00 (m, 2H), 2.20 (s, 3H), 2.31 (m, 1H), 2 .75 (m, 2H), 2.88-2.92 (m, 4H), 3.60 (m, 1H), 4.12 (m, 2H), 5.16 (m, 2H), 5. 31 (m, 2H), 6.79 (s, 1H), 7.20 (d, J=7.32 Hz, 1H), 7.27 (m, 1H), 7.32 (d, J=7 .12 Hz, 2H), 7.39 (m, 1H), 7.44-7.47 (m, 3H), 7.67 (m, 1H), 7.83 (d, J=7.62 Hz , 1H), 7.91 (d, J=7.8 Hz, 1H), 8.02 (s, 1H). 43

rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid
(cis, racemic) 599.55 1.20-1.40(m, 4H), 1.58(m, 1H), 1.71-1.79(m, 2H), 1.95(m, 2H), 2.19(s, 3H), 2.32 (m, 2H), 2.72-2.79 (m, 3H), 3.00 (m, 1H), 3.60 (d, J=12.48 Hz, 1H), 3.67 (d, J=12.52 Hz, 1H), 5.11 (m, 2H), 5.31 (m, 2H), 6.72 (s, 1H), 7.19 (d, J =7.12 Hz, 1H), 7.27 (m, 1H), 7.32 (d, J=7 Hz, 2H), 7.39 (m, 2H), 7.44-7.47 (m , 2H), 7.61 (m, 1H), 7.80 (m, 2H), 7.92 (s, 1H), 11.90 (br, 1H). 44

4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)butanoic acid 561.46 1.66 (m, 2H), 2.00 (m, 2H), 2.23 (m, 6H), 2.76 (m, 4H), 2.93 (m, 2H), 3.81 (s , 2H), 5.16 (s, 2H), 5.24 (s, 2H), 6.76 (s, 1H), 7.26-7.45 (m, 9H), 7.61 (m, 1H), 7.80-7.85 (m, 2H), 7.99 (s, 1H). 45

(1R,6S)-2-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) 498.49 1.15-1.33(m, 2H), 1.37(m, 2H), 1.62(m, 1H), 1.78(m, 1H), 2.01(m, 2H), 2 .18 (m, 3H), 2.32 (m, 1H), 2.76 (m, 2H), 2.95 (m, 1H), 3.09 (s, 1H), 3.49 (m, 2H), 3.59 (m, 2H), 3.84 (s, 3H), 5.20 (s, 2H), 6.71 (s, 1H), 7.21 (d, J=7.44 Hz, 1H), 7.27-7.31(m, 3H), 7.37(m, 1H), 7.44-7.50(m, 3H)

Example 46:

Synthesis of (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-carbaldehyde (0, 20 g, 0.55 mmol) in acetonitrile (20 ml) add potassium carbonate (0.30 g, 2.23 mmol) and 5-(chloromethyl)nicotinonitrile (5, 0.25 g, 1.67 mmol) and stir the reaction mixture at RT for 16 h. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent to give 5-(((4-formyl-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Yield: 0.07 g, 26%) as a white solid. LCMS (ER) m/z=475.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.97-2.00 (m, 2H), 2.21 (s, 3H), 2.71 (m, 2H), 3.13 (m, 2H), 5.32 (s, 2H), 5.42 (s, 2H), 6.92 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H ), 7.29-7.40 (m, 3H), 7.44-7.48 (m, 3H), 8.52 (s, 1H), 9.01 (s, 2H), 10.37 ( s, 1H).

Step 6: Solution of 5-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl )oxy)methyl)nicotinonitrile (100mg, 0.21mmol), ( S )-piperidine-2-carboxylic acid (40.8mg, 0.32mmol), sodium cyanoborohydride (66.4mg, 1.06mmol ) and acetic acid (2 drops) in DMF (5 ml), the reaction mixture was stirred at 70°C for 4 h. After completion, the reaction mixture was poured into ice water (10 ml) and a white solid was collected by filtration. A solution of the white solid in DCM (20 ml) was dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The product is then purified by reverse phase HPLC using method-B to give (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 26 mg, 46%) as a white solid. LCMS (ER) m/z=588.38 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.32-1.45 (m, 4H), 1.75 (m, 2H), 1.97 (m, 2H), 2.21 (s, 3H), 2.32 (m, 1H), 2.76 (m, 2H), 2.81-3.03 (m, 3H), 3.11 (m, 1H), 3 .68 (d, J =12.28 Hz, 1H), 3.88 (d, J =12.4 Hz, 1H), 5.14 (s, 2H), 5.28 (m, 2H), 6 .77 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.39 (m, 1H), 7.44- 7.47 (m, 3H), 8.48 (s, 1H), 9.01 (m, 1H).

The following compounds were prepared by the methods described above.

Table 3

No. Structure LCMS m/z [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 47

(2S,4R)-1-((5-((5-цианопиридин-3-ил)метокси)-7-((2-метил-[1,1'-бифенил]-3-ил)метокси)-2,3-дигидро-1H-инден-4-ил)метил)-4-гидроксипирролидин-2-карбоновая кислота

(2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 590.35 1.96-2.10(m, 5H), 2.20(s, 3H), 2.73(m, 2H), 2.83-3.02(m, 2H), 3.27(brs, 1H), 3.66 (m, 1H), 4.16 (m, 2H), 4.23 (m, 1H), 5.18 (m, 3H), 5.36 (m, 2H), 6, 81 (s, 1H), 7.20 (m, 1H), 7.29 (m, 1H), 7.33 (m, 2H), 7.36-7.47 (m, 4H), 8.53 (s, 1H), 9.03 (m, 2H) 48

N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide 561.39 1.76 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.62 (m, 2H), 2.78 (m, 2H), 2.90 (m , 2H), 3.11-3.16 (m, 2H), 3.73 (s, 2H), 5.15 (s, 2H), 5.28 (s, 2H), 6.76 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.2 Hz, 2H) , 7.36-7.48(m, 4H), 7.80(brs, 1H), 8.43(s, 1H), 8.99(s, 2H). 49

5-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile 579.39 1.97 (m, 2H), 2.20 (s, 3H), 2.77 (m, 2H), 2.91 (m, 2H), 3.39 (s, 6H), 3.66 (br , 2H), 4.00-4.50 (br, 3H), 5.14 (s, 2H), 5.26 (s, 2H), 6.75 (s, 1H), 7.17 (m, 1H), 7.28 (m, 1H), 7.36 (m, 2H), 7.39 (m, 1H), 7.43-7.47 (m, 3H), 8.45 (s, 1H ), 9.00 (s, 2H). fifty

(S)-4-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid 588.42 1.98 (m, 2H), 2.21 (s, 3H), 2.87 (m, 2H), 2.92-2.94 (m, 1H), 2.96-3.00 (m, 2H), 3.09 (br, 1H), 3.43 (m, 1H), 3.50-3.64 (m, 4H), 3.80 (m, 2H), 5.14 (s, 2H ), 5.26 (m, 2H), 6.75 (s, 1H), 7.20 (d, J=7.28 Hz, 1H), 7.28 (m, 1H), 7.33 (d , J=7.04 Hz, 2H), 7.37 (m, 1H), 7.39-7.47 (m, 3H), 8.44 (s, 1H), 9.01 (d, J= 10.5 Hz, 2H), 12.32(brs, 1H). 51

rac-(1R,6S)-2-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid
(cis, racemic) 600.57 1.09-1.40(m, 4H), 1.56(m, 1H), 1.70(m, 1H), 1.78(m, 1H), 1.96-1.99(m, 2H), 2.20 (s, 3H), 2.32-2.40 (m, 2H), 2.73-2.82 (m, 3H), 2.99-3.05 (m, 1H) , 3.63 (m, 2H), 5.15 (s, 2H), 5.32 (s, 2H), 6.78 (s, 1H), 7.19 (d, J=7.28 Hz, 1H), 7.27 (m, 1H), 7.33 (d, J=7.04 Hz, 2H), 7.37-7.47 (m, 4H), 8.41 (s, 1H), 8.96 (m, 1H), 8.99 (m, 2H), 11.73 (br, 1H). 52

(S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid 600.52 0.41(m, 1H), 0.53(m, 3H), 1.75-1.79(m, 1H), 1.99-2.01(m, 2H), 2.21(s, 3H), 2.31(m, 1H), 2.76(m, 2H), 2.89-3.31(m, 4H), 3.60(m, 1H), 4.13(m, 2H ), 5.18 (m, 2H), 5.33 (m, 2H), 6.83 (s, 1H), 7.19 (m, 1H), 7.29 (m, 1H), 7.33 (m, 2H), 7.38 (m, 1H), 7.40-7.48 (m, 3H), 8.55 (s, 1H), 9.02 (m, 1H), 9.05 ( m, 1H)

Example 53:

Synthesis of N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)(methyl)amino)ethyl)acetamide

Step 1: To a stirred solution of N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (1, 0.3 g, 0.523 mmol) in DMF (8 ml) formaldehyde (64.4 mg, 2.14 mmol) is added and formic acid (98 mg, 2.14 mmol) and stirred for 15 minutes. To this mixture was added sodium cyanoborohydride (133 mg, 2.14 mmol) and the reaction mixture was stirred for 4 hours at room temperature. Upon completion, the reaction mixture was diluted with water (10 ml) and extracted with 10% DCM in MeOH (3×25 ml). The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent, then recrystallized from THF and pentane to give N-(2-(((5-((3-cyanobenzyl) hydroxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl) acetamide (Yield: 68 mg, 21%) as a white solid. LCMS (ER) m/z=574.60 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.72 (s, 3H), 1.95-1.99 (m, 2H), 2.09 (s, 3H), 2.21 (s, 3H), 2.36 (m, 2H), 2.74 (t, J= 7.2 Hz, 2H), 2.88 (t, J =7.4 Hz, 2H), 3.12 (m, 2H), 3.40 (s, 2H), 5.13 (s, 2H), 5.21 (s, 2H), 6.73 (s, 1H), 7.19 (d , J= 7.6Hz, 1H), 7.23-7.31 (m, 3H), 7.37 (m, 1H), 7.44-7.48 (m, 3H), 7.59-7 .63 (m, 2H), 7.81 (t, J = 8.4 Hz, 2H), 7.95 (s, 1H).

Example 54:

Synthesis of N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)amino)ethyl)acetamide

Step-1: Preparation of 4-(((4-formyl-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)methyl)benzonitrile

To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1 H -inden-4-carbaldehyde (1 , 0.30 g , 0.83 mmol) in DMF (10 ml) add potassium carbonate (0.34 g, 2.4 mmol) and 4-(chloromethyl)benzonitrile (0.16 g, 0.83 mmol) and stir the reaction mixture at RT within 16 hours Upon completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent to give 3-(((4-formyl-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-5-yl)oxy)methyl)benzonitrile (Yield: 0.35 g, 89.27%) as a white solid.

LCMS (ER) m/z=474.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.00 (m, 2H), 2.21 (s, 3H), 2.70 (t, J =7.2 Hz, 2H), 3.13 (t, J =7.2 Hz, 2H), 5.30 (s, 2H), 5.38 (s, 2H), 6.92 (s, 1H), 7.22 ( d, J = 7.6 Hz, 1H), 7.27-7.33 (m, 3H), 7.38 (m, 1H), 7.44-7.48 (m, 3H), 7.63 (t, J =7.6 Hz, 1H), 7.85 (m, 2H), 8.01 (s, 1H), 10.39 (s, 1H).

Step-2: N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

4-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy) solution methyl)benzonitrile (150 mg, 0.31 mmol), N-(2-aminoethyl)acetamide (32 mg, 0.31 mmol) and acetic acid (2 drops) in DMF (3 ml) and MeOH (3 ml) was stirred at RT for 2 h. Add sodium cyanoborohydride (60 mg, 0.93 mmol) to this mixture and stir the reaction mixture for 16 h. Upon completion, the reaction mixture was poured into ice water (10 ml) and the white solid collected by filtration . A solution of the white solid in DCM (20 ml) was dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give N-(2-(((5-((4-cyanobenzyl)oxy)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (Yield: 90 mg, 52% ) as a white solid. LCMS (ER) m/z=560.49 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.77 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.74- 2.78 (m, 4H), 2.90 (m, 2H), 3.21 (m, 2H), 3.85 (br, 2H), 5.14 (m, 2H), 5.29 (s , 2H), 6.74 (s, 1H), 7.20 (d, J = 7.48 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.31 (d , J= 7.08 Hz, 2H), 7.36-7.48 (m, 4H), 7.70 (d, J= 5.92 Hz, 2H), 7.87 (d, J =8, 16 Hz, 2H), 7.92 (br, 1H).

Example 55:

Synthesis of (S)-1-((7-((2-cyano-[ 1,1'- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl )methyl)piperidine-2-carboxylic acid

Step-1: To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (918 mg, 4.7 mmol) and 3-(hydroxymethyl)-[1,1'-biphenyl ]-2-carbonitrile (1.0 g, 4.7 mmol) in dry THF (30 ml) add triphenylphosphine (3 g, 0.035 mol) and cool the mixture to 0°C. To this mixture was added DEAD (266 mg, 0.014 mol) and the mixture was stirred for 2 hours. Upon completion, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×100 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-20% EtOAc in hexane as eluent to give 3-(((7-formyl-6-methoxy-2,3-dihydro-1H-indene -4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (Yield: 450 mg, 24.5%) as a white solid. LCMS (ER) m/z=384.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95-2.01 (m, 2H), 2.71 (m, 2H), 3.11 (m, 2H), 4.04 (s, 3H), 5.50 (s, 2H), 6.79 (s, 1H), 7.48-7.65 (m, 6H), 7.78-7.84 (m, 2H), 10.30 (s, 1H).

Step-2: To a solution of 3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (60 mg, 0.156 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.20 mmol) in DMF (3 ml) add acetic acid (3 drops) and stir the reaction mixture for 10 minutes. Sodium cyanoborohydride (29 mg, 0.47 mmol) was added to this mixture and stirred at 70° C. for 3 hours. After completion, the reaction mixture was diluted with ice water (10 ml) and the resulting solid was collected by filtration. The solid is further dissolved in DCM (30 ml) and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-1-((7-((2-cyano-[1,1'-biphenyl] -3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 15 mg, 19%) as a white solid. LCMS (ER) m/z=497.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.48 (m, 4H), 1.77 (m, 2H), 1.95-2.01 (m, 2H), 2.73 (m, 2H), 2.83 (m, 1H), 2.92 (m, 1H), 3.07 (m, 2H), 3.14 (m, 1H), 3.74 (m , 1H), 3.79 (s, 3H), 3.88 (m, 1H), 5.36 (s, 2H), 6.65 (s, 1H), 7.48-7.62 (m, 6H), 7.77 (t, J= 7.2 Hz, 1H), 7.82 (t, J= 7.6 Hz, 1H).

The following compounds were prepared by the methods described above.

No. Structure LCMS m/z [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 56

N-(2-(((7-((2-циано-[1,1'-бифенил]-3-ил)метокси)-5-метокси-2,3-дигидро-1H-инден-4-ил)метил)амино)этил)ацетамид

N-(2-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide 470.32 1.78 (s, 3H), 1.95-1.99 (m, 2H), 2.57 (m, 2H), 2.77 (m, 2H), 2.87 (m, 2H), 3 .14 (m, 2H), 3.64 (brs, 2H), 3.79 (s, 3H), 5.35 (s, 2H), 6.63 (s, 1H), 7.50-7, 61 (m, 6H), 7.75-7.84 (m, 3H). 57

(2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 499.31 1.95-1.99 (m, 3H), 2.09 (m, 1H), 2.77 (m, 3H), 2.87-2.99 (m, 2H), 3.26 (m, 1H), 3.65(m, 1H), 3.84(s, 3H), 4.08(m, 2H), 4.23(brs, 1H), 5.26(brs, 1H), 5, 38 (s, 2H), 6.69 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 2H). 58

3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-6-methoxy-2,3-dihydro-1H-inden-4-yl) hydroxy)methyl)-[1,1'-biphenyl]-2-carbonitrile 489.32 1.96-1.99(m, 2H), 2.78(m, 2H), 2.89(m, 2H), 3.52(brs, 7H), 3.80(s, 3H), 4 .03 (m, 2H), 4.71 (brs, 2H), 5.36 (s, 2H), 6.65 (s, 1H), 7.50-7.61 (m, 6H), 7, 75-7.84 (m, 2H). 59

(S)-4-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)morpholine-3-carboxylic acid 499.34 1.94-1.98(m, 2H), 2.27(m, 1H), 2.76(m, 2H), 2.86(m, 1H), 2.98(m, 2H), 3 .10 (m, 1H), 3.46 (m, 1H), 3.55 (m, 1H), 3.61-3.68 (m, 3H), 3.74 (m, 1H), 3. 76 (s, 3H), 5.34 (s, 2H), 6.60 (s, 1H), 7.48-7.62 (m, 6H), 7.77 (t, J=7.2 Hz , 1H), 7.82 (t, J=7.6 Hz, 1H). 60

((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)glycine 443.44 1.95-1.99(m, 2H), 2.78(m, 2H), 2.92(m, 2H), 3.09(brs, 2H), 3.84(s, 3H), 3 .93 (s, 2H), 5.39 (s, 2H), 6.69 (s, 1H), 7.50-7.62 (m, 6H), 7.75-7.84 (m, 2H ). 61

(S)-5-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid 509.45 0.48 (m, 1H), 0.61 (m, 3H), 1.87 (m, 1H), 1.97-2.01 (m, 2H), 2.36 (m, 1H), 2 .78 (m, 2H), 2.87-3.03 (m, 5H), 3.85 (s, 3H), 4.18 (m, 2H), 5.38 (s, 2H), 6, 71 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 2H). 62

rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden- 4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid
(cis, racemic) 509.39 1.19 (m, 1H), 1.25 (m, 2H), 1.37 (m, 1H), 1.62 (m, 1H), 1.78 (m, 2H), 1.97-2 .01 (m, 2H), 2.21 (m, 1H), 2.30 (m, 1H), 2.66-2.78 (m, 3H), 2.93-3.03 (m, 1H ), 3.48 (d, J=12.4 Hz, 1H), 3.58 (d, J=12.4 Hz, 1H), 3.84 (s, 3H), 5.37 (s, 2H ), 6.70 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 2H). 63

2-(1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl )piperidin-2-yl)acetic acid 511.48 1.37 (m, 3H), 1.59 (m, 2H), 1.84 (m, 1H), 1.97-2.01 (m, 2H), 2.13-2.19 (m, 1H), 2.39 (m, 1H), 2.66 (m, 1H), 2.78 (m, 3H), 2.84-2.99 (m, 3H), 3.66 (d, J =12.8 Hz, 1H), 3.78 (s, 3H), 3.85 (m, 1H), 5.36 (s, 2H), 6.64 (s, 1H), 7.50-7 .61 (m, 6H), 7.75-7.84 (m, 2H).

Example-64:

Synthesis of N-(2-(((7-((2-cyano-[ 1,1'- biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl )methyl)(methyl)amino)ethyl)-N-methylacetamide

Step-1: To a solution of 3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (250 mg, 0.65 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (115 mg, 1.30 mmol) and acetic acid (2 drops) in DMF (3 ml) and MeOH (3 ml ), the reaction mixture was stirred at RT for 30 minutes. To this mixture was added sodium cyanoborohydride (40 mg, 0.130 mmol) and stirred for 16 h. After completion, the reaction mixture was poured into ice water (10 ml) and extracted with DCM (3×50 ml) and the organic layer was dried over sodium sulfate and concentrate. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-20% MeOH in DCM as eluent to give 3-(((6-methoxy-7-((methyl(2-(methylamino)ethyl) amino)methyl)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (Yield: 100 mg, 33%) as white solid . LCMS (ER) m/z=456.30 [M+H] ⁺ .

Step-2: To a stirred solution of 3-(((6-methoxy-7-((methyl(2-(methylamino)ethyl)amino)methyl)-2,3-dihydro-1H-inden-4-yl)oxy) methyl)-[1,1'-biphenyl]-2-carbonitrile (80 mg, 0.176 mmol), AcOH (5 drops) in DMF (5 ml) add HOBt (35 mg, 0.26 mmol), EDC. HCl ( 50 mg, 0.26 mmol), N,N-diisopropylethylamine (68 mg, 0.53 mmol) and the mixture was stirred for 12 hours at room temperature. Upon completion, dilute the mixture with water (10 ml) and extract with 10% MeOH in DCM (3×20 ml). The organic layer is dried and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give N-(2-(((7-((2-cyano-[1,1'-biphenyl ]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide (Yield: 12 mg) as white solid substances. LCMS (ER) m/z=498.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.90-2.14 (m, 8H), 2.48 (m, 2H), 2.58 (m, 1H), 2.77-2.86(m, 6H), 3.32-3.37(brs, 3H), 3.76(s, 3H), 3.78(m, 1H), 5.35(s, 2H), 6.68 (s, 1H), 7.50-7.61 (m, 6H), 7.75-7.84 (m, 3H).

Example 65:

Synthesis of 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)hydroxy)pentanoic acid

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-carbaldehyde (0, 40 g, 1.12 mmol) in DMF (10 ml) are added potassium carbonate (0.46 g, 3.38 mmol) and methyl 5-bromopentanoate (0.217 g, 1.22 mmol) and the reaction mixture is stirred at 60°C within 6 hours After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexane as eluent to give methyl 5-((4-formyl-7-((2-methyl-[1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (Yield: 0.310 g, 58%) as a white solid. LCMS (ER) m/z=473.50 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.71-1.81 (m, 4H), 1.99-2.00 (m, 2H), 2.22 (s , 3H), 2.41 (m, 2H), 2.69 (m, 2H), 3.13 (m, 2H), 3.58 (s, 3H), 4.16 (m, 2H), 5 .32 (s, 2H), 6.78 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.28-7.40 (m, 4H), 7.44- 7.50 (m, 3H), 10.35 (s, 1H).

Step 2: To a solution of methyl 5-((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)pentanoate (150 mg, 0.32 mmol) in MeOH (3 mL) and DMF (3 mL) N-(2-aminoethyl)acetamide (32.7 mg, 0.48 mmol) and acetic acid ( 3 drops) and stir the reaction mixture for 10 minutes. Sodium cyanoborohydride (57 mg, 0.935 mmol) was added to this mixture and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (3×30 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (Yield: 80 mg, 45%) as white solid. LCMS (ER) m/z=559.55 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.70-1.76 (m, 4H), 1.78 (s, 3H), 1.99-2.00 (m , 2H), 2.33 (s, 3H), 2.39 (m, 2H), 2.57 (m, 2H), 2.75 (m, 2H), 2.88 (m, 2H), 3 .18 (m, 2H), 3.59 (s, 3H), 3.72 (m, 2H), 4.01 (m, 2H), 5.18 (s, 2H), 6.70 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.28-7.40 (m, 4H), 7.44-7.48 (m, 3H), 7.86 (br , 1H).

Step 3: To a stirred solution of methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-5-yl)oxy)pentanoate (70 mg, 0.125 mmol) in THF (3 ml) and water (1.5 ml) add lithium hydroxide (10.5 mg, 0.25 mmol ) and stir the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (5 ml) and acidified with 1N HCl. The aqueous mixture is extracted with EtOAc (3×20 ml) and the combined organic extract is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using an ammonia solution of 10% MeOH in DCM as eluent to give 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2 -methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoic acid (Yield: 20 mg, 29%) as white solid substances. LCMS (ER) m/z=545.46 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.67-1.74 (m, 4H), 1.76 (s, 3H), 1.95-1.98 (m , 2H), 2.21 (s, 3H), 2.28 (m, 2H), 2.55 (m, 2H), 2.74 (m, 2H), 2.85 (m, 2H), 3 .12 (m, 2H), 3.60 (s, 2H), 3.98 (m, 2H), 5.15 (s, 2H), 6.61 (s, 1H), 7.18 (d, J =7.6 Hz, 1H), 7.26-7.39(m, 4H), 7.44-7.48(m, 3H), 7.83(brs, 1H).

Example-66:

Synthesis of 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)pentanamide

Step 1: To a stirred solution of methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-5-yl)oxy)pentanoate (60 mg, 0.107 mmol) in MeOH (10 ml) at -60°C in a steel autoclave, ammonia is purged for 10 minutes, after the steel autoclave is sealed, the mixture is heated at 60°C and stirred for 16 h. After completion, excess ammonia is removed by washing with nitrogen and the reaction mixture is concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 10% MeOH in DCM as eluent to give 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl -[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanamide (Yield: 30 mg, 51%) as a white solid. LCMS (ER) m/z=544.42 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.67-1.74 (m, 4H), 1.76 (s, 3H), 1.95-1.98 (m , 2H), 2.21 (s, 3H), 2.45 (m, 2H), 2.56 (m, 2H), 2.75 (m, 2H), 2.86 (m, 2H), 3 .12 (m, 2H), 3.63 (s, 2H), 3.98 (m, 2H), 5.16 (s, 2H), 6.62 (s, 1H), 6.74 (br 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.26-7.39 (m, 5H), 7.44-7.48 (m, 3H), 7.80 (br , 1H).

Example 67:

Synthesis of (S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of methyl 5-((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- (S)-piperidine-2-carboxylic acid (102 mg, 0.79 mmol) and acetic acid ( 3 drops) and stirred for 2 h. To this mixture was added sodium cyanoborohydride (134 mg, 2.1 mmol) and the mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with 10 % MeOH in DCM (3×30 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-1-((5-((5-methoxy-5-oxopentyl)oxy) -7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 245 mg, 59%) as a light yellow solid. LCMS (ER) m/z=584.63 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.45 (m, 4H), 1.74 (m, 7H), 1.96-2.00 (m, 2H), 2.21 (s, 3H), 2.39 (m, 2H), 2.75 (m, 2H), 2.80 (m, 1H), 2.95 (m, 1H), 3.05 (m , 1H), 3.11 (m, 1H), 3.59 (s, 3H), 3.75 (d, J = 12.0 Hz, 1H), 3.88 (d, J = 12.0 Hz , 1H), 4.00 (m, 2H), 5.20 (s, 2H), 6.64 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.27 -7.40 (m, 4H), 7.44-7.49 (m, 3H).

Step 2: To a stirred solution of (S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (70 mg, 0.11 mmol) in THF (3 ml) and water (1.5 ml) hydroxide is added lithium (10.5 mg, 0.23 mmol) and stir the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 ml) and acidified with 1N HCl. The aqueous mixture is extracted with EtOAc (3×20 ml) and the combined organic extract is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using an ammoniated solution of 10% MeOH in DCM as eluent to give (S)-1-((5-(4-carboxybutoxy)-7-((2-methyl -[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 38 mg, 61%) as white solid. LCMS (ER) m/z=572.39 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.38-1.49 (m, 4H), 1.74 (m, 6H), 1.95-1.98 (m , 2H), 2.21 (s, 3H), 2.26 (m, 2H), 2.73 (m, 2H), 2.81 (m, 1H), 3.03 (m, 2H), 3 .12 (m, 2H), 3.84 (s, 2H), 3.98 (m, 2H), 5.16 (s, 2H), 6.63 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.26-7.39 (m, 4H), 7.44-7.49 (m, 3H).

Example 68:

Synthesis of (S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step-1: To a stirred solution of (S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (103mg, 0.18mmol) in MeOH (10mL) at -35°C in a steel autoclave purge ammonia for 5 minutes, after sealing the steel autoclave, the mixture is heated at 55°C and stirred for 36 hours. After completion, excess ammonia is removed by washing with nitrogen and the reaction mixture is concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 8% MeOH in DCM as eluent to give (S)-1-((5-((5-amino-5-oxopentyl)oxy)-7- ((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 60 mg, 60%) as an off-white solid. LCMS (ER) m/z=571.45 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.43-1.74 (m, 5H), 1.74 (m, 4H), 1.95-1.98 (m , 3H), 2.11-2.13(m, 2H), 2.21(s, 3H), 2.73(m, 2H), 2.83(m, 1H), 3.05(m, 2H), 3.50(m, 2H), 3.96-4.03(m, 4H), 5.19(s, 2H), 6.67(s, 1H), 6.75(brs, 1H ), 7.20 (d, J = 7.6 Hz, 1H), 7.26-7.39 (m, 5H), 7.44-7.49 (m, 3H).

Example 69:

Synthesis of (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl) methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1: Potassium carbonate (0.31 g , 2.30 mmol) and 3-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile (0.50 g, 1.92 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-20% EtOAc in hexane as eluent to give 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-indene -4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (Yield: 0.50 g, 71%) as a yellow solid. LCMS (ER) m/z=370.45 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.04 (m, 2H), 2.73 (t, J =7.2 Hz, 2H), 3.14 (t, J = 7.6 Hz, 2H), 5.41 (s, 2H), 6.53 (s, 1H), 7.51-7.63 (m, 6H), 7.75 (m, 1H), 7.83 (m, 1H), 10.08 (s, 1H), 11.22 (s, 1H).

Step 2: To a solution of 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile ( 0.75 g, 2.03 mmol) in DMF (15 ml) add potassium carbonate (0.82 g, 6.09 mmol) and 5-(chloromethyl)nicotinonitrile (0.92 g, 6.09 mmol) and stir mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with ice water (30 ml) and extracted with EtOAc (3×50 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-50% EtOAc in hexane as eluent to give 5-(((7-((2-cyano-[1,1'-biphenyl] -3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (Yield: 0.55 g, 57%) as an off-white solid. LCMS (ER) m/z=486.50 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.99-2.02 (m, 2H), 2.73 (m, 2H), 3.14 (m, 2H), 5.42 (s, 2H), 5.49 (s, 2H), 6.94 (s, 1H), 7.51-7.64 (m, 6H), 7.74 (m, 1H), 7 .82 (m, 1H), 8.51 (s, 1H), 9.01 (d, J = 5.2 Hz, 2H), 10.38 (s, 1H).

Step 3: To a solution of 5-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5- yl)oxy)methyl)nicotinonitrile (180mg, 0.37mmol), ( S )-piperidine-2-carboxylic acid (40mg, 0.33mmol) in DMF (2ml) and MeOH (2ml) add acetic acid (2 drops) and stir the mixture for 2 h. Add sodium cyanoborohydride (68 mg, 1.11 mmol) to this mixture and continue stirring at room temperature for 16 h. After completion, the reaction mixture was poured into ice water (10 ml) and extracted with 5% MeOH in DCM (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-20% MeOH in DCM as eluent to give (S)-1-((7-((2-cyano-[1,1' -biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield : 30 mg, 14%) as a white solid. LCMS (ER) m/z=599.55 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.33-1.46 (m, 4H), 1.74 (m, 2H), 1.93-2.00 (m , 2H), 2.30 (m, 1H), 2.81 (m, 2H), 2.82-3.08 (m, 4H), 3.62 (d, J = 12.4 Hz, 1H) , 3.86 (d, J =12.4 Hz, 1H), 5.28 (s, 2H), 5.33 (m, 2H), 6.76 (s, 1H), 7.50-7, 61 (m, 6H), 7.72 (d, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 8.47 (s, 1H), 8. 98 (s, 1H), 9.00 (s, 1H).

The following compounds were prepared by the methods described above.

Table four:

No. Structure LCMS m/z [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 70

(2S,4R)-1-((7-((2-циано-[1,1'-бифенил]-3-ил)метокси)-5-((5-цианопиридин-3-ил)метокси)-2,3-дигидро-1H-инден-4-ил)метил)-4-гидроксипирролидин-2-карбоновая кислота

(2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 601.50 1.96-2.09(m, 4H), 2.73-2.78(m, 3H), 2.87-3.05(m, 2H), 3.27(brs, 1H), 3, 66 (m, 1H), 4.16 (m, 2H), 4.23 (m, 1H), 5.19 (s, 1H), 5.29 (s, 2H), 5.35 (m, 2H ), 6.81 (s, 1H), 7.51-7.62 (m, 6H), 7.72 (d, J=7.2 Hz, 1H), 7.79 (t, J=7, 6 Hz, 1H), 8.51 (s, 1H), 8.99 (s, 1H), 9.01 (s, 1H). 71

(R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-3-carboxylic acid 599.45 1.33-1.42(m, 2H), 1.58(m, 1H), 1.76(m, 1H), 1.96-2.01(m, 2H), 2.10(m, 1H), 2.20 (m, 1H), 2.33 (m, 1H), 2.56 (m, 1H), 2.78 (m, 3H), 2.88 (m, 2H), 3, 42 (s, 2H), 5.26 (s, 2H), 5.33 (m, 2H), 6.76 (s, 1H), 7.49-7.61 (m, 6H), 7.72 (d, J=7.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 8.38 (s, 1H), 8.98 (s, 1H), 8.99 (s, 1H). 72

rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid
(cis; racemic) 611.48 [M+H] ⁺ 1.13-1.33(m, 4H), 1.56(m, 1H), 1.66(m, 1H), 1.76(m, 1H), 1.96-1.99(m, 2H), 2.32-2.38 (m, 2H), 2.75-2.82 (m, 3H), 2.99-3.03 (m, 1H), 3.66 (m, 2H) , 5.31 (s, 2H), 5.33 (m, 2H), 6.77 (s, 1H), 7.50-7.61 (m, 6H), 7.69 (d, J=7 .2 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 8.39 (s, 1H), 8.94 (s, 1H), 8.99 (s, 1H). 73

methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate 641.39 0.95 (m, 1H), 1.52 (m, 6H), 1.75 (m, 6H), 1.97 (m, 2H), 2.20 (s, 3H), 2.74 (m , 2H), 2.85 (m, 2H), 3.50-3.56 (m, 5H), 5.14-5.18 (m, 4H), 6.72 (s, 1H), 7, 19 (d, J=7.2 Hz, 1H), 7.24-7.32 (m, 3H), 7.39 (m, 1H), 7.43-7.47 (m, 3H), 7 .61 (t, J=8.56 Hz, 1H), 7.81 (m, 2H), 8.02 (s, 1H).

Example 74:

Synthesis of 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)amino)bicyclo[2,2,2]octane-1-carboxylic acid

Step-1: To a solution of methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (160 mg, 0.24 mmol) in THF (6 ml) and water (4 ml) was added lithium hydroxide (83 mg, 1.99 mmol) and stir the mixture at room temperature for 12 h. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (30 ml). The aqueous layer was acidified to pH 4 using 3N HCl solution and the reaction mixture was extracted with 10% MeOH in DCM (2×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give 4-(((5-((3-cyanobenzyl)oxy)-7-((2- methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)bicyclo[2,2,2]octane-1-carboxylic acid (Yield: 50 mg, 32%) as a white solid. LCMS (ER) m/z=627.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.73 (m, 12H), 2.00 (m, 2H), 2.20 (s, 3H), 2.77 ( m, 2H), 3.02 (m, 2H), 3.86 (m, 2H), 5.20-5.22 (m, 4H), 6.82 (s, 1H), 7.19 (d , J = 7.2 Hz, 1H), 7.24-7.32 (m, 3H), 7.39 (m, 1H), 7.43-7.47 (m, 3H), 7.66 ( t, J = 8.56 Hz, 1H), 7.87 (m, 2H), 8.02 (s, 1H), 8.43(brs, 1H), 12.14 (brs, 1H).

Example 75:

Synthesis of (S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[ 1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.50 g, 1.5 mmol) and 3-(bromomethyl)-2-(trifluoromethyl)- 1,1'-biphenyl (0.29 g, 1.5 mmol) in ACN (10 mL) potassium carbonate (0.31 g, 2.25 mmol) was added and the mixture was stirred at room temperature for 16 h. , the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×40 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-30% EtOAc in hexane as eluent to give 5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]- 3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (Yield: 0.3 g, 47%) as an off-white solid. LCMS (ER) m/z=427.45 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.98-2.04 (m, 2H), 2.70 (m, 2H), 3.12 (m, 2H), 3.91 (s, 3H), 5.47 (s, 2H), 6.69 (s, 1H), 7.30 (d, J= 6.0 Hz, 2H), 7.37-7.46 (m, 4H), 7.73 (t, J= 7.6 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 10.31 (s, 1H).

Step 2: To a stirred solution of 5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde ( 0.10 g, 0.23 mmol), ( S )-piperidine-2-carboxylic acid (27 mg, 0.21 mmol) in DMF (1 ml) and MeOH (1 ml) add acetic acid (2 drops) and continue to stir the mixture for 1 h. To this mixture is added sodium cyanoborohydride (40 mg, 0.69 mmol) and continue stirring at room temperature for 16 h and the mixture is heated at 50°C for 5 h. After completion, the reaction mixture poured into ice water (10 ml) and extracted with 10% MeOH in DCM (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-1-((5-methoxy-7-((2-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 30 mg, 25%) as white solid. LCMS (ER) m/z=540.36 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.33-1.46 (m, 4H), 1.77 (m, 2H), 1.97-2.00 (m , 2H), 2.42 (m, 1H), 2.76 (m, 2H), 2.84 (m, 1H), 2.91 (m, 1H), 3.02-3.09 (m, 1H), 3.14 (m, 1H), 3.73-3.76 (m, 4H), 3.88 (d, J =12.4 Hz, 1H), 5.34 (s, 2H), 6.54 (s, 1H), 7.30 (d, J= 6.4 Hz, 2H), 7.35 (d, J= 7.6 Hz, 1H), 7.41-7.46 (m , 3H), 7.71 (t, J= 7.6 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H).

The following compounds were prepared by the methods described above.

Example 76

(2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[ 1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid

LCMS (ER) m/z=542.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95-1.99 (m, 3H), 2.09 (m, 1H), 2.26-2.79 (m , 3H), 2.86-3.02 (m, 2H), 3.25 (m, 1H), 3.66 (m, 1H), 3.81 (s, 3H), 4.05-4, 12(m, 2H), 4.23(brs, 1H), 5.26(brs, 1H), 5.36(s, 2H), 6.59(s, 1H), 7.30(d, J = 6.4 Hz, 2H), 7.35 (d, J= 7.6 Hz, 1H), 7.41-7.46 (m, 3H), 7.71 (t, J= 7.6 Hz , 1H), 7.79 (d, J= 7.6 Hz, 1H).

Example 77:

Synthesis of (2S)-1-((7-((2-methyl-[1,1 ' -biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1 : To a stirred solution of 1-methyl-3-hydroxymethylpiperidine (2 g, 15.5 mmol) in DCM (30 ml) at 0°C, add triethylamine (4.9 g, 46 mmol) and tosyl chloride (4.41 g , 23.2 mmol) and the mixture was stirred at room temperature for 6 h. After completion, the reaction mixture was diluted with water (30 ml) and extracted with DCM (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-20% EtOAc in hexane as eluent to give (1-methylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (Yield: 2.50 g, 58 %) as a white solid. LCMS (ER) m/z=284.36 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.87-0.95 (m, 1H), 1.33-1.50 (m, 4H), 1.63 (m , 1H), 1.80-1.85 (m, 2H), 2.06 (s, 3H), 2.42 (s, 3H), 2.46-2.52 (m, 1H), 3, 90 (m, 2H), 7.48 (d, J =8.0 Hz, 2H), 7.78 (d, J =8.0 Hz, 2H).

Step 2: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (200 mg, 0.558 mmol) in DMF (5 ml) are added potassium carbonate (231 mg, 1.67 mmol) and (1-methylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (238 mg, 0.84 mmol) and the reaction mixture is stirred at room temperature temperature for 16 hours After completion, the reaction mixture was diluted with ice water (15 ml) and extracted with 5% MeOH in DCM (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-10% MeOH in DCM as eluent to give 7-((2-methyl-[1,1'-biphenyl]-3-yl) methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (Yield: 0.15 g, 57%) as a white solid. LCMS (ER) m/z=470.54 [M+H] ⁺ ;

Step 3: To a solution of 7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro- 1H-indene-4-carbaldehyde (150 mg, 0.319 mmol), ( S )-piperidine-2-carboxylic acid (123 mg, 0.96 mmol) in DMF (2.5 ml) and MeOH (2.5 ml) , add acetic acid (3 drops) and stir the mixture for 1 h. Add sodium cyanoborohydride (60 mg, 0.96 mmol) to this mixture and continue stirring at room temperature for 16 h. water (10 ml) and extracted with 10% MeOH in DCM (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-10% MeOH in DCM as eluent to give (2S)-1-((7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield : 18 mg, 9.6%) as a white solid. LCMS (ER) m/z=583.57 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.47 (m, 5H), 1.64 (m, 4H), 1.74 (m, 2H), 1.98- 2.04 (m, 4H), 2.21 (s, 6H), 2.74 (m, 2H), 2.82 (m, 3H), 2.98-3.04 (m, 3H), 3 .15 (m, 1H), 3.72 (d, J =12.4 Hz, 1H), 3.89 (m, 3H), 5.17 (s, 2H), 6.61 (s, 1H) , 7.19 (d, J = 7.2 Hz, 1H), 7.26-7.32 (m, 3H), 7.38 (t, J = 7.2 Hz, 1H), 7.44- 7.48 (m, 3H).

Example 78:

Synthesis of (S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[ 1,1'- biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile ( 0.25 g, 0.697 mmol) in ACN (10 ml) add potassium carbonate (0.280 g, 2.03 mmol) and methyl 5-bromopentanoate (0.396 g, 2.03 mmol) and stir the mixture at room temperature for 16 h After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 30% EtOAc in hexane as eluent to give methyl 5-((7-((2-cyano-[1,1'-biphenyl]-3- yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (Yield: 0.150 g, 45%) as a white solid. LCMS (ER) m/z=484.26 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.69-1.80 (m, 4H), 1.95-2.02 (m, 2H), 2.40 (m , 2H), 2.69 (m, 2H), 3.13 (m, 2H), 3.58 (s, 3H), 4.16 (m, 2H), 5.48 (s, 2H), 6 .78 (s, 1H), 7.49-7.58 (m, 6H), 7.75 (m, 1H), 7.83 (m, 1H), 10.33 (s, 1H).

Step 2: Methyl 5-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl solution )hydroxy)pentanoate (220 mg, 0.46 mmol), ( S )-piperidine-2-carboxylic acid (176 mg, 1.366 mmol) in DMF (2 ml) and MeOH (2 ml), acetic acid (6 drops) stirred for 30 minutes. Sodium cyanoborohydride (86 mg, 1.366 mmol) is added to this mixture and stirring is continued at room temperature for 16 hours. After completion, the reaction mixture is poured into ice water (10 ml) and extracted with DCM (3×15 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-10% MeOH in DCM as eluent to give (S)-1-((7-((2-cyano-[1,1' -biphenyl]-3-yl)methoxy)-5-((5-methoxy-5-oxopentyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield : 80 mg, 29%) as a white solid. LCMS (ER) m/z=597.68 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.33-1.46 (m, 4H), 1.69-1.80 (m, 5H), 1.95-2 .02 (m, 2H), 2.45 (m, 2H), 2.78 (m, 2H), 2.82-3.08 (m, 4H), 3.12 (m, 2H), 3, 58 (s, 3H), 3.71 (d, J =12.4 Hz, 1H), 3.86 (d, J =12.8 Hz, 1H), 3.98 (m, 2H), 5. 34 (m, 2H), 6.62 (s, 1H), 7.50-7.62 (m, 6H), 7.75 (m, 1H), 7.83 (m, 1H).

Step 3: To a stirred solution of (S)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-methoxy-5-oxopentyl) hydroxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (70 mg, 0.117 mmol) in THF (3 ml) and water (1.5 ml) add lithium hydroxide ( 9.8 mg, 0.23 mmol) and stir the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 ml) and acidified with 1N HCl. The aqueous mixture is extracted with EtOAc (3×20 ml) and the combined organic extract is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-15% MeOH in DCM as eluent to give (S)-1-((5-(4-carboxybutoxy)-7-((2-cyano -[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 15 mg, 22%) as white solid. LCMS (ER) m/z=583.48 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.38-1.49 (m, 4H), 1.76 (m, 6H), 1.95-1.98 (m , 2H), 2.29 (m, 2H), 2.73 (m, 2H), 2.81 (m, 1H), 3.03 (m, 3H), 3.15 (m, 1H), 3 .78 (d, J =12.4 Hz, 1H), 3.90 (d, J =12.8 Hz, 1H), 3.99 (m, 2H), 5.35 (s, 2H), 6 .63 (s, 1H), 7.50-7.62 (m, 6H), 7.75 (m, 1H), 7.83 (m, 1H).

Example-79:

Synthesis of N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)amino)ethyl)acetamide

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-carbaldehyde (0, 50 g, 1.39 mmol) in DMF (10 ml) are added potassium carbonate (0.288 g, 2.08 mmol) and 5-bromopentanenitrile (0.25 g, 1.53 mmol) and the mixture is stirred at room temperature for 5 hours After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 20% EtOAc in hexane as eluent to give 5-((4-formyl-7-((2-methyl-[1,1'-biphenyl] -3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanenitrile (Yield: 0.425 g, 69%) as a white solid. LCMS (ER) m/z=440.51 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.74-1.80 (m, 2H), 1.86-1.90 (m, 2H), 1.97-2 .01 (m, 2H), 2.21 (s, 3H), 2.59 (m, 2H), 2.69 (m, 2H), 3.11 (m, 2H), 4.20 (m, 2H), 5.31 (s, 2H), 6.79 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.28-7.40 (m, 4H), 7.44-7.48 (m, 3H), 10.34 (s, 1H).

Step 2: To a solution of 5-((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl )hydroxy)pentanenitrile (150 mg, 0.35 mmol) in DMF (10 ml) N-(2-aminoethyl)acetamide (45 mg, 0.44 mmol) and acetic acid (2 drops) are added and the mixture is stirred for 10 minutes. Sodium cyanoborohydride (32 mg, 0.52 mmol) was added to this mixture and the mixture was stirred at room temperature for 6 hours. After completion, the reaction mixture was diluted with water (15 ml) and extracted with 10% MeOH in DCM (3×30 ml) . The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The resulting product was then purified by reverse phase HPLC using method-E to give N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (Yield: 40 mg) as a sticky liquid. LCMS (ER) m/z=526.50 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.78-1.82 (m, 5H), 1.84 (m, 2H), 1.97-1.99 (m , 2H), 2.21 (s, 3H), 2.50 (m, 2H), 2.59 (m, 2H), 2.73 (m, 2H), 2.86 (m, 2H), 3 .11 (m, 2H), 3.60 (m, 2H), 4.02 (m, 2H), 5.15 (s, 2H), 6.63 (s, 1H), 7.19 (d, J =7.6Hz, 1H), 7.26-7.40(m, 4H), 7.44-7.48(m, 3H), 7.76(brs, 1H).

The following compounds were prepared by the methods described above.

Example 80

(S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxamide, LCMS (ER) m/z=552.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.47 (m, 1H), 1.58 (m, 2H), 1.72-1.79 (m, 6H), 1.93-1.97(m, 3H), 2.21(s, 3H), 2.59(m, 3H), 2.66-2.83(m, 5H), 2.94-3, 02 (m, 1H), 3.15 (d, J = 12.0 Hz, 1H), 3.63 (d, J = 12.0 Hz, 1H), 4.02 (m, 2H), 5, 15 (s, 2H), 6.62 (s, 1H), 7.06 (bd, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.27-7.40 (m , 4H), 7.44-7.49 (m, 3H).

Example 81

(2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid, LCMS (ER) m/z=551.51 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.78-1.81 (m, 2H), 1.84-1.90 (m, 2H), 1.96-2 .05 (m, 3H), 2.13 (m, 1H), 2.22 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.74-2.81 ( m, 3H), 2.88-2.98 (m, 2H), 3.27 (m, 1H), 3.70 (t, J= 8.0 Hz, 1H), 4.03-4.18 (m, 4H), 4.25 (m, 1H), 5.19 (s, 2H), 5.29 (brs, 1H), 6.70 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.44-7.49 (m, 3H).

Example 82

Synthesis of (S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)- 2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of 5-hydroxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H -inden-4-carbaldehyde (0, 20 g, 0.55 mmol) in DMF (4 ml) was added potassium carbonate (0.227 g, 1.6 mmol) and methyl (1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate (0.321 g , 1.39 mmol) and stir the mixture at room temperature for 12 h. After completion, the reaction mixture was diluted with water (6 ml) and extracted with EtOAc (3×10 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 20% EtOAc in hexane as eluent to give methyl (1R,2S)-2-(((4-formyl-7-((2-methyl- [1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropan-1-carboxylate (Yield: 0.330 g, crude) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (m, 1H), 1.07 (m, 1H), 1.66 (m, 1H), 1.74- 1.80 (m, 2H), 1.86-1.90 (m, 2H), 1.97-2.01 (m, 2H), 2.21 (s, 3H), 2.71 (m, 2H), 3.10(m, 1H), 3.53(s, 3H), 5.31(s, 2H), 6.78(s, 1H), 7.22(d, J =7.6 Hz, 1H), 7.28-7.40 (m, 4H), 7.44-7.48 (m, 3H), 10.24 (s, 1H).

Step 2: To a solution of methyl (1R,2S)-2-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-5-yl)oxy)methyl)cyclopropan-1-carboxylate (150 mg, 0.32 mmol) in DMF (2 ml) and MeOH (2 ml) add (S)-piperidine-2-carboxylic acid (61 mg, 0.48 mmol) and acetic acid (2 drops) and stir the mixture for 30 minutes. Sodium cyanoborohydride (60 mg, 0.95 mmol) was added to this mixture and the mixture was stirred at 60°C for 4 h. After completion, the reaction mixture was diluted with water (15 ml) and extracted with 10% MeOH in DCM (3×30 ml ). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-12% MeOH in DCM as eluent to give (S)-1-((5-(((1S,2R)-2-(methoxycarbonyl )cyclopropyl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidin-2- carboxylic acid (Yield: 180 mg) as an off-white solid. LCMS (ER) m/z=584.59 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.95 (m, 1H), 1.03 (m, 1H), 1.39 (m, 1H), 1.43- 1.54 (m, 5H), 1.78-1.90 (m, 4H), 1.97-1.99 (m, 2H), 2.21 (s, 3H), 2.72 (m, 2H), 2.84 (m, 2H), 3.03 (m, 2H), 3.51 (s, 3H), 3.79 (m, 1H), 3.92 (m, 1H), 4, 34 (m, 1H), 5.16 (s, 2H), 6.59 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.26-7.40 (m , 4H), 7.44-7.48 (m, 3H).

Step 3: To a stirred solution of (S)-1-((5-(((1S,2R)-2-(methoxycarbonyl)cyclopropyl)methoxy)-7-((2-methyl-[1,1'-biphenyl] -3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (100 mg, 0.17 mmol) in THF (3 ml) and water (1, 5 ml) lithium hydroxide (14 mg, 0.35 mmol) is added and the mixture is stirred at room temperature for 6 hours. After completion, the reaction mixture is diluted with water (5 ml) and acidified with 1N HCl (pH 5-6). The aqueous mixture is extracted with 10% MeOH in DCM (3×10 ml) and the combined organic extract is dried over sodium sulfate and concentrated. The crude product is purified by column chromatography (silica gel, 100-200 mesh) using 0-30% MeOH in DCM as eluent. The resulting product was then purified by reverse phase column chromatography to obtain (S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 45 mg, 46%) as an off-white solid. LCMS (ER) m/z=570.57 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.95 (m, 1H), 1.07 (m, 1H), 1.39 (m, 1H), 1.43- 1.54 (m, 3H), 1.78-1.90 (m, 4H), 1.97-1.99 (m, 2H), 2.21 (s, 3H), 2.72 (m, 2H), 2.84 (m, 2H), 3.03 (m, 3H), 3.79 (m, 1H), 3.97 (m, 2H), 4.39 (s, 1H), 5, 17 (s, 2H), 6.65 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.26-7.40 (m, 4H), 7.44-7 .48 (m, 3H).

The following compounds are prepared by the methods described above.

Example 83

(1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylic acid, LCMS (ER) m/z=543.54 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.95 (m, 2H), 1.67 (m, 2H), 1.78 (s, 3H), 1.97- 2.00 (m, 2H), 2.20 (s, 3H), 2.73 (m, 2H), 2.88 (m, 4H), 3.26-3.32 (m, 2H), 3 .73 (m, 1H), 3.89 (m, 1H), 3.95 (d, J =12.8 Hz, 1H), 4.56 (m, 1H), 5.18 (s, 2H) , 6.69 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.27-7.39 (m, 4H), 7.44-7.49 (m, 3H ), 8.64 (br, 1H).

Example 84

Synthesis (S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3- dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acids

Stage 1: A mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxin (5 g, 0.023 mol), (2-methyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)methanol (8.6 g, 0.034 mol), potassium carbonate (9.5 g, 0.069 mol), toluene (50 ml), water (50 ml) and EtOH (50 ml) degassed with nitrogen for 15 minutes. To this mixture was added PdCl ₂ (dppf)DCM (0.93 g, 1.15 mmol) and degassed for another 5 minutes with nitrogen. The vessel is sealed, the mixture is heated at 90°C for 8 hours After completion, the reaction mixture is diluted with water (300 ml) and extracted with EtOAc (3×300 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-30% EtOAc in hexanes to give (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2 -methylphenyl)methanol (Yield: 5.8 g, 97%) as a yellow sticky liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.11 (s, 3H), 4.27 (s, 4H), 4.51 (m, 2H), 5.10 ( m, 1H), 6.69-6.74 (m, 2H), 6.89 (d, J= 7.6 Hz, 1H), 7.04 (d, J= 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H).

Step 2: To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (500 mg, 2.6 mmol) and (3-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)-2-methylphenyl)methanol (866 mg, 3.3 mmol) in dry THF (15 ml) triphenylphosphine (1.7 g, 6.5 mmol) is added at 0°C and stirred mixture for 10 minutes at 0°C. DEAD (1.355 g, 7.8 mmol) was added to this mixture and the mixture was stirred for 30 minutes. Upon completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-30% EtOAc in hexane as eluent to give 7-((3-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 350 mg, 27%) as a white solid. LCMS (ER) m/z=431.43 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95-2.01 (m, 2H), 2.23 (s, 3H), 2.71 (m, 2H), 3.11 (m, 2H), 3.94 (s, 3H), 4.28 (s, 4H), 5.31 (s, 2H), 6.73-6.79 (m, 3H), 6 .92 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.47 (d, J= 7.2 Hz, 1H), 10.30 (s, 1H).

Step 3: To a solution of 7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H -indene-4-carbaldehyde (100 mg, 0.23 mmol) and (S)-piperidine-2-carboxylic acid (36 mg, 0.27 mmol) in DMF (3 ml) add acetic acid (3 drops) and stir within 10 minutes. To this mixture, sodium cyanoborohydride (43 mg, 0.69 mmol) was added and the mixture was stirred at 80°C for 3 hours. After completion, the reaction mixture was diluted with ice water (10 ml) and extracted with 10% MeOH in DCM (3x solid the material was then dissolved in DCM (30 ml) and dried over sodium sulfate and concentrated.The residue was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent.The product was then purified by prep reverse HPLC phase using Method-B to give (S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)- 5-Methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 35 mg, 28%) as white solid LCMS (SE) m/z=544 .39 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.38 (m, 1H), 1.48 (m, 3H), 1.76 ( m, 2H), 1.95-1.98 (m, 2H), 2.22 (s, 3H), 2.42 (m, 1H), 2.73 (m, 2H), 2.82-2 .90 (m, 2H), 3.00-3.08 (m, 2H), 3.70 (d, J =12.0 Hz, 1H), 3.79 (s, 3H), 3.87 ( d, J = 12.4 Hz, 1H), 4.28 (s, 4H), 5.16 (s, 2H), 6.64 (s, 1H), 6.74-6.78 (m, 2H), 6.91 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 7.2 Hz, 1H), 7.24 (t, J =7.6 Hz, 1H), 7.44 (d, J= 7.2 Hz, 1H).

The following compounds were prepared by the methods described above.

Example 85

(2S,4R)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2, 3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid, LCMS (ER) m/z=546.31 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95-1.99 (m, 3H), 2.09 (m, 1H), 2.23 (s, 3H), 2.73-2.77(m, 3H), 2.86-2.96(m, 2H), 3.27(m, 1H), 3.67(m, 1H), 3.85(s, 3H), 4.09 (m, 2H), 4.24 (m, 1H), 4.28 (s, 4H), 5.18 (s, 2H), 5.27 (br, 1H), 6, 70 (s, 1H), 6.74-6.78 (m, 2H), 6.91 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 7.2 Hz, 1H ), 7.25 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H).

Example 86:

Synthesis of N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2' -dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide

Stage 1: Mixture of (3-bromo-2-methylphenyl)methanol (2 g, 9.95 mmol), o-tolylboronic acid (4.06 g, 29.84 mmol), sodium carbonate (12.4 g, 0.117 mol ), toluene (27 ml), water (9 ml) and MeOH (9 ml) were degassed with nitrogen for 15 minutes. To this mixture is added Pd(PPh ₃ ) ₄ (1.1 g, 0.99 mmol) and degassed for another 5 minutes with nitrogen. The vessel is sealed, the mixture is heated at 90°C for 16 hours After completion, the reaction mixture is diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The organic layer is dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 0-20% EtOAc in hexane to give (2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (Yield: 2.05 g, 97%) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.90 (s, 3H), 1.97 (s, 3H), 4.54 (m, 2H), 5.12 ( m, 1H), 6.95 (d, J= 7.6 Hz, 1H), 7.03 (d, J= 6.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.39 (d, J= 7.2 Hz, 1H).

Step 2: To a solution of (2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (1.7 g, 8.01 mmol) in DCM (5 ml) at 0°C was added PBr ₃ (2.38 g, 8.8 mmol) and stir the mixture at room temperature for 16 h. After completion, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-10 % EtOAc in hexane as eluent to give 3-(bromomethyl)-2,2'-dimethyl-1,1'-biphenyl (Yield: 1.7 g, 77%) as a colorless sticky liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.97 (s, 3H), 2.04 (s, 3H), 4.79 (s, 2H), 7.05 ( d, J= 7.2 Hz, 2H), 7.18-7.33 (m, 4H), 7.43 (d, J= 8.8 Hz, 1H).

Step 3: Potassium carbonate (0.28 g , 2.01 mmol) and 3-(bromomethyl)-2,2'-dimethyl-1,1'-biphenyl (0.47 g, 1.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent to give 7-((2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (Yield: 0.61 g, 94%) as a light yellow solid. LCMS (ER) m/z=373.16 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.97 (s, 3H), 2.02 (m, 2H), 2.04 (s, 3H), 2.71 ( t, J =7.2Hz, 2H), 3.14(t, J =7.2Hz, 2H), 5.24(s, 2H), 6.55(s, 1H), 7.05( d, J= 7.2 Hz, 2H), 7.18-7.33 (m, 4H), 7.43 (d, J= 8.8 Hz, 1H), 10.35 (s, 1H), 11.31 (s, 1H).

Step 4: To a solution of 7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde ( 0.56 g, 1.5 mmol) in DMF (10 ml) are added potassium carbonate (0.416 g, 3.0 mmol) and 3-(chloromethyl)benzonitrile (0.29 g, 1.5 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-50% EtOAc in hexane as eluent to give 3-(((7-((2,2'-dimethyl-[1,1'- biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 0.705 g, 96%) as a light yellow solid. LCMS (ER) m/z=488.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.00 (m, 2H), 2.02 (s, 3H), 2.21 (s, 3H), 2.70 ( t, J = 7.2 Hz, 2H), 3.13 (m, 2H), 5.12 (s, 2H), 5.20 (s, 2H), 6.72 (s, 1H), 7, 05-7.07(m, 2H), 7.23-7.32(m, 4H), 7.42(d, J= 7.2Hz, 1H), 7.63(t, J =7.6 Hz, 1H), 7.85 (m, 2H), 7.96 (s, 1H), 10.37 (s, 1H).

Step 5: To a solution of 3-(((7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-indene -5-yl)oxy)methyl)benzonitrile (150 mg, 0.30 mmol) in DMF (4 ml) and MeOH (4 ml) N-(2-aminoethyl)acetamide (31 mg, 0.30 mmol) was added and acetic acid (2 drops) and stir the mixture for 10 minutes. To this mixture was added sodium cyanoborohydride (56 mg, 0.90 mmol) and the mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (15 ml) and extracted with 10% MeOH in DCM (3×30 ml) . The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The resulting product was further purified by reverse phase HPLC using method-A to give N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (Yield: 100 mg, 21%) as a white solid. LCMS (ER) m/z=574.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.74 (s, 3H), 1.96-2.00 (m, 8H), 2.53 (m, 2H), 2.73 (t, J =7.2 Hz, 2H), 2.88 (t, J =7.2 Hz, 2H), 3.13 (m, 2H), 3.64 (s, 2H), 5.12 (s, 2H), 5.20 (s, 2H), 6.71 (s, 1H), 7.05-7.07 (m, 2H), 7.23-7.32 (m, 4H), 7.42 (d, J= 7.2 Hz, 1H), 7.61 (t, J =7.6 Hz, 1H), 7.75 (m, 1H), 7.80-7, 82 (m, 2H), 7.94 (s, 1H),

The following compounds were prepared by the methods described above.

Example 87

N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide, LCMS (ER) m/z=578.44 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.79 (s, 3H), 1.96-2.01 (m, 2H), 2.18 (s, 3H), 2.77 (t, J =7.2 Hz, 2H), 2.90-2.97 (m, 4H), 3.27 (m, 2H), 4.00 (s, 2H), 5.17 (s, 2H), 5.28 (s, 2H), 6.79 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.23-7.37 (m, 5H), 7.41 (d, J= 7.2 Hz, 1H), 7.62 (t, J =7.6 Hz, 1H), 7.81-7.87 (m, 2H), 8, 00 (shs, 1H), 8.07 (shs, 1H),

Example 88:

Synthesis of (S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)piperidine-2-carboxylic acid

To a solution of (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (90 mg, 0.15 mmol) in MeOH (5 ml), water (5 ml) add 1,4-dioxane (3 ml) and hydroxide sodium (10 mg) and the mixture was stirred at 90° C. for 3 hours. After completion, the reaction mixture was diluted with water (10 ml) and extracted with 10% MeOH in DCM (3×20 ml). The organic layer was concentrated and the crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-15% MeOH in DCM to give (S)-1-((5-((3-carbamoylbenzyl)oxy)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 40 mg, 44 %) as a white solid. LCMS (ER) m/z=605.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.33-1.48 (m, 4H), 1.79 (m, 2H), 1.95-1.99 (m , 2H), 2.21 (s, 3H), 2.74 (m, 2H), 2.83 (m, 1H), 2.96-3.02 (m, 3H), 3.17 (m, 1H), 3.82 (d, J =12.0 Hz, 1H), 4.04 (d, J =12.8 Hz, 1H), 5.15 (s, 2H), 5.23 (s, 2H), 6.79 (br, 1H), 7.19 (m, 1H), 7.25-7.33 (m, 4H), 7.39 (m, 1H), 7.44-7.48 (m, 4H), 7.65 (d, J= 8.0 Hz, 1H), 7.83 (d, J= 7.6 Hz, 1H), 8.12 (s, 1H), 8.31 (ws, 1H).

Example 89:

Synthesis of 3-(((4-(aminomethyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl) hydroxy)methyl)benzonitrile

Step 1: To a solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)methyl)benzonitrile (60 mg, 0.126 mmol) in MeOH (2 mL), THF (2 mL) sodium borohydride (12 mg, 0.40 mmol) was added slowly at 0°C and the mixture was stirred at RT for 3 hours After completion, the reaction is quenched with water (10 ml) and extracted with DCM (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography using 30% EtOAc in hexane as eluent to give 3-(((4-(hydroxymethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 50 mg, 83%) as a white solid. LCMS (ER) m/z=476 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.94-2.02 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.91 (m, 2H), 4.45 (m, 2H), 4.54 (m, 1H), 5.13 (s, 2H), 5.20 (s, 2H), 6.69 (s , 1H), 7.32 (d, J = 7.28 Hz, 1H) 7.35-7.47 (m, 4H), 7.60 (m, 1H), 7.81 (m, 2H), 7.95 (s, 1H).

Step 2: To a solution of 3-(((4-(hydroxymethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 5-yl)oxy)methyl) benzonitrile (250 mg, 0.526 mmol) and phthalimide (229 mg, 1.31 mmol) in dry THF (5 mL), triphenylphosphine (345 mg, 1.31 mmol) was added and the mixture was cooled to 0 °C. To this mixture is added DIAD (266 mg, 1.31 mmol) and the mixture is stirred at room temperature for 6 h. After completion, the reaction mixture is diluted with water (20 ml) and extracted with EtOAc (3×40 ml). The combined organic layer is dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography using 20% EtOAc in hexane as eluent to give 3-(((4-((1,3-dioxoindolin-2-yl)methyl)-7-((2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 300 mg, 94%) as a white solid. LCMS (ER) m/z=605.31 [M+H] ⁺

Step 3: To a solution of 3-(((4-((1,3-dioxoindolin-2-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) -2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (300 mg, 0.495 mmol) in EtOH (15 mL) hydrazine hydrate solution (2 mL) was added slowly at room temperature and the mixture was stirred at RT within 3 hours After completion, the reaction is quenched with water (10 ml) and extracted with DCM (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography using 30% EtOAc in hexane as eluent to give 3-(((4-(aminomethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 35 mg, 15%) as a white solid. LCMS (ER) m/z=475.6 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.98 (m, 2H), 2.19 (s, 3H), 2.74 (m, 2H), 2.89 ( m, 2H), 3.62 (s, 2H), 5.12 (s, 2H), 5.21 (s, 2H), 6.69 (s, 1H), 7.17 (d, J =7 .24 Hz, 1H), 7.25 (m, 1H), 7.32 (d, J = 7.04 Hz, 1H), 7.37-7.47 (m, 4H), 7.59 (m , 1H), 7.78-7.86(m, 2H), 7.91(m, 1H).

Example-90:

Synthesis of N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl ]-3-yl) methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)acetamide

Step 1: Solution of 3-(((4-(aminomethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5 -yl)oxy)methyl)benzonitrile (40 mg, 0.084 mmol), triethylamine (12.7 mg, 0.21 mmol) in DCM (5 ml) was cooled to 0°C. Acetyl chloride (16 mg, 0.021 mmol) was added to this mixture and the reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was diluted with ice water (10 ml) and the aqueous mixture was extracted with EtOAc (3×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-30% EtOAc in hexane as eluent to give N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl -[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)acetamide (Yield: 32 mg, 73%) as a white solid. LCMS (ER) m/z=517.34 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.79 (s, 3H), 1.98 (m, 2H), 2.19 (s, 3H), 2.74 ( m, 2H), 2.87 (m, 2H), 4.21 (m, 2H), 5.12 (s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.19 (d, J =7.08 Hz, 1H), 7.25 (m, 1H), 7.32 (d, J =7.04 Hz, 2H), 7.40-7.47 (m , 4H), 7.59(m, 1H), 7.78-7.82(m, 3H), 7.91(s, 1H).

Example 91:

Synthesis of 6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)hexanamide

Step 1: Solution of 3-(((4-(aminomethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5 -yl)oxy)methyl)benzonitrile (150 mg, 0.31 mmol), 6-acetamidohexanoic acid (82 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), EDC . HCl (90 mg, 0.47 mmol) and DIPEA (244 mg, 1.89 mmol) in DMF (10 ml) were stirred for 12 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with ice water (20 ml) and extracted with 10% MeOH in DCM (2×50 ml). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give 6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)hexanamide (Yield: 80 mg, 40%) as white solid. LCMS (ER) m/z=630.68 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.16-1.21 (m, 2H), 1.29-1.36 (m, 2H), 1.41-1 .49 (m, 2H), 1.75 (s, 3H), 1.93-2.06 (m, 4H), 2.19 (s, 3H), 2.66-2.74 (m, 2H ), 2.87 (m, 2H), 2.96 (m, 2H), 4.21 (m, 2H), 5.13 (s, 2H), 5.21 (s, 2H), 6.72 (s, 1H), 7.19 (d, J = 7.36 Hz, 1H), 7.25 (m, 1H), 7.32 (d, J = 7.04 Hz, 1H), 7.37 -7.47 (m, 4H), 7.59 (t, J =7.76 Hz, 1H), 7.78-7.82 (m, 4H), 7.93 (s, 1H).

Example 92:

Synthesis of 3-(((4-((dimethylamino)methyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5 -yl)oxy)methyl)benzonitrile

Step 1: Solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl )oxy)methyl)benzonitrile (120 mg, 0.25 mmol), a solution of dimethylamine in methanol (4 ml) and acetic acid (1 drop) in DMF (4 ml) were stirred at room temperature for 2 hours. To this mixture was added sodium cyanoborohydride (47 mg, 0.76 mmol) and stirred for 12 h. After completion, the reaction mixture was poured into ice water (10 ml) and a white solid was collected by filtration. A solution of the white solid in DCM (20 ml) was dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give 3-(((4-((dimethylamino)methyl)-7-((2-methyl- [1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (Yield: 12 mg, 9.6%) as white solid substances. LCMS (ER) m/z=503.5 [MH]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.01 (m, 2H), 2.20 (s, 3H), 2.62-2.79 (m, 8H), 2.97 (m, 2H), 4.20 (m, 2H), 5.19 (s, 2H), 5.30 (s, 2H), 6.84 (s, 1H), 7.19 (d , J = 7.08 Hz, 1H), 7.25-7.32 (m, 3H), 7.38-7.48 (m, 4H), 7.62 (t, J = 7.04 Hz, 1H), 7.82-7.88 (m, 2H), 8.03 (s, 1H).

Example-93:

Synthesis of 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)nicotinic acid

To a solution of N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (0.12g, 0.21mmol) in ethanol (8ml) and water (8ml) add potassium hydroxide (60mg, 1 .07 mmol) and refluxed for 20 h. Upon completion, the reaction mixture was diluted with water (20 ml) and washed with EtOAc (30 ml). The aqueous layer was acidified to pH 4 using 6N HCl solution and then the mixture was extracted with 10% MeOH in DCM (2×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The compound was then purified by reverse phase HPLC using method-B to give 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]- 3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinic acid (Yield: 20 mg, 16%) as a white solid. LCMS (ER) m/z=580.58 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.76 (s, 3H), 2.00 (m, 2H), 2.20 (s, 3H), 2.74- 2.83 (m, 4H), 2.94 (m, 2H), 3.25 (m, 2H), 3.87 (s, 2H), 5.18 (s, 2H), 5.27 (s , 2H), 6.85 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.24-7.32 (m, 3H), 7.39 (m, 1H) , 7.43-7.48(m, 3H), 8.32(s, 1H), 8.40(br, 1H), 8.74(s, 1H), 8.96(s, 1H).

Example 94:

Synthesis of 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)nicotinamide

Step 1: To a solution of N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy )-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (1 , 0.15g, 0.25mmol) in ethanol (8ml) and water (8ml) add potassium hydroxide (60 mg, 1.07 mmol) and refluxed for 6 h. Upon completion, the reaction mixture was diluted with water (20 ml) and washed with EtOAc (30 ml). The aqueous layer was acidified to pH4 using 6N HCl solution and the reaction mixture was extracted with 10% MeOH in DCM (2×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent. The compound was then purified by reverse phase HPLC using method-B to give 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]- 3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide (Yield: 30 mg, 20%) as a white solid. LCMS (ER) m/z=579.6 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.74 (s, 3H), 1.84 (m, 2H), 1.97 (m, 2H), 2.20 ( s, 3H), 2.74 (m, 2H), 2.87 (m, 2H), 3.07 (m, 2H), 3.61 (s, 2H), 5.13 (s, 2H), 5.25 (s, 2H), 6.77 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.31-7.33 (m, 2H), 7.39 (m, 1H), 7.43-7.48 (m, 3H), 7.64 (m, 1H), 7.73 (m, 1H), 8.21 (br, 1H), 8.32 ( s, 1H), 8.32(s, 1H), 8.81(s, 1H), 8.99(s, 1H).

Example 95:

Synthesis of 3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[ 1,1'- biphenyl] -3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)benzamide

Step 1: To a solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- of yl)oxy)methyl)benzonitrile (0.30 g, 0.63 mmol) in ethanol (10 ml) and water (10 ml) add potassium hydroxide (0.15 g, 2.67 mmol) and reflux for 12 hours After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (30 ml). The aqueous layer was acidified to pH 4 using 6N HCl solution and the reaction mixture was extracted with 10% MeOH in DCM (2×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product gives a mixture of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)methyl)benzamide (240 mg; crude) as a yellow viscous liquid which is used in the next step without further purification.

Step 2: Solution of 3-(((4-formyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl )hydroxy)methyl)benzamide (240 mg, 0.487 mmol), N-(2-aminoethyl)acetamide (50 mg, 0.487 mmol) and acetic acid (1 drop) in DMF (4 ml) and MeOH (4 ml) were stirred at room temperature for 2 h. To this mixture was added sodium cyanoborohydride (92 mg, 1.46 mmol) and the reaction mixture was stirred for 16 h. MeOH in DCM (3×100 ml). The combined organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give 3-(((4-(((2-acetamidoethyl)amino)methyl)-7-( (2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide (32 mg) as a white solid. LCMS (ER) m/z=578.62 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.73 (s, 3H), 1.99 (m, 2H), 2.20 (s, 3H), 2.53 ( m, 2H), 2.74 (m, 2H), 2.87 (m, 2H), 3.07 (m, 2H), 3.62 (s, 2H), 5.12 (s, 2H), 5.18 (s, 2H), 6.74 (s, 1H), 7.18 (d, J = 7.26 Hz, 1H), 7.26 (m, 1H), 7.31 (d, J = 8.16 Hz, 2H), 7.36-7.48 (m, 6H), 7.61 (d, J= 7.6 Hz, 1H), 7.74 (m, 1H), 7.82 (d, J = 7.76 Hz, 1H), 8.01 (m, 2H).

Example 96:

Synthesis of (S)-1-((3-methoxy-1-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine -4-yl)methyl)piperidine-2-carboxylic acid

Step 1: To a solution of cyclopentanone (40 g, 476.19 mmol) and malononitrile (30 ml, 476.19 mmol) in MeOH (100 ml) and DMF (30 ml) is added CS ₂ (100 ml, 1664.2 mmol) and stirred for 5 minutes. Triethylamine (35 ml, 237.7 mmol) was slowly added dropwise to this mixture and the mixture was stirred at room temperature for 48 hours. Upon completion, the reaction mixture was filtered and washed with cold MeOH (30 ml) and dried under vacuum to give 3- hydroxy-1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (Yield: 13.0 g, crude) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.86-1.96 (m, 2H), 2.74 (t, J =8.0 Hz, 2H), 2, 93 (t, J = 8.0 Hz, 2H), 8.75 (s, 1H), 9.03 (s, 1H).

Step 2: A solution of 3-hydroxy-1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (13 g, 67.56 mmol) in 1N NaOH (250 ml) was stirred at 150°C within 8 h. After completion, the reaction mixture is acidified with an aqueous solution of 6N HCl and the solid is filtered. The solid was washed with cold water (20 ml) and dried under vacuum to give 1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (Yield: 6.2 g, crude) as a red solid substances. LCMS (ER) m/z=168.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.90 (t, J =8.0 Hz, 2H), 2.60 (t, J =8.0 Hz, 2H) , 2.78 (t, J =8.0 Hz, 2H), 5.94 (s, 1H), 11.50-12.76 (brs, 2H).

Step 3: Potassium carbonate (5.0 g, 36.17 mmol) and MeI (3.39 g, 2.39 mmol) and the mixture was stirred at room temperature for 6 h. After completion, the reaction was quenched with water (100 ml) and extracted with DCM (2×100 ml) . The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 0-30% EtOAc in hexane as eluent to give 1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine-3- ol (Yield: 1.9 g, 44%) as a red solid. LCMS (ER) m/z=182.31 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.96-2.01 (m, 2H), 2.49 (s, 3H), 2.57 (t, J =8 .0 Hz, 2H), 2.75 (t, J =8.0 Hz, 2H), 6.18 (s, 1H), 10.44 (s, 1H).

Step 4: Ag ₂ O ( 2.18 g, 9.40 mmol) and MeI (2.58 g, 18.23 mmol) and the mixture was stirred at 80° C. for 16 hours. After completion, the reaction was quenched with water (100 ml) and extracted with EtOAc (2 ×100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 12 g cartridge) using 10% EtOAc in hexane as eluent to give 3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine ( Yield: 2.3 g, 71%) as a white solid. LCMS (ER) m/z=196.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.06-1.99 (m, 2H), 2.49 (s, 3H), 2.60 (t, J =7 .2 Hz, 2H), 2.80 (t, J =8.0 Hz, 2H), 3.85 (s, 3H), 6.39 (s, 1H).

Step 5: Br ₂ ( 2.0 g, 11.73 mmol) and stirred at room temperature for 4 h. After completion, the reaction mixture was concentrated in vacuo to give 4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro- 5H-cyclopenta[c]pyridine (Yield: 2.0 g, 62%) as an off-white solid. LCMS (ER) m/z=274.31 [M+H] ⁺ & 276.32 [M+2H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.06-2.12 (m, 2H), 2.54 (s, 3H), 2.73 (t, J =8 Hz, 2H), 2.85 (t, J =8.0 Hz, 2H), 3.94 (s, 3H).

Step 6: To a solution of 4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (2.0 g, 10.24 mmol) in DCM (50 ml) at mCPBA (4.0 g, 25.60 mmol) was added at 0°C and the mixture was stirred at room temperature for 12 h. After completion, the reaction was quenched with aqueous saturated NaHCO ₃ solution (100 ml) and extracted with DCM (2×70 ml) . The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-3-methoxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine (Yield: 1.9 g, 80% ) as a white solid. LCMS (ER) m/z=306.25 [M+H] ⁺ & 308.21 [M+2H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.10-2.13 (m, 2H), 2.92 (t, J =8 Hz, 2H), 3.23 ( t, J = 8.0 Hz, 2H), 3.30 (s, 3H), 3.97 (s, 3H).

Step 7: NaH (0. 25 g, 6.37 mmol) and stirred at 0° C. for 30 min. To this mixture was added 4-bromo-3-methoxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine (1.3 g, 4.24 mmol) and the mixture was stirred at room temperature for 6 hours After completion, the reaction mixture is quenched with aqueous saturated NaHCO ₃ solution (100 ml) and extracted with EtOAc (2×80 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using DCM as eluent to give 4-bromo-3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Yield: 700 mg, 39%) as a white solid. LCMS (ER) m/z=424.38[M+H] ⁺ and 426.39 [M+2H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.06 (t, J =8.0 Hz, 2H), 2.16 (s, 3H), 2.83 (m, 4H), 3.91 (s, 3H), 5.46 (s, 2H), 7.16-7.18 (m, 1H), 7.24-7.27 (m, 1H), 7.29 -7.31(m, 2H), 7.35-7.39(m, 1H), 7.43-7.46(m, 3H).

Step 8: To a solution of 4-bromo-3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (0.7 g, 1.64 mmol) in DMF (20 ml) was added tributyl(vinyl)tin (1.3 g, 4.10 mmol) and degassed with nitrogen for 5 minutes. To this mixture was added Pd(PPh ₃ ) ₄ (0.2 g, 0.16 mmol) and again degassed with nitrogen for 5 minutes. The mixture was stirred at 90° C. for 16 hours. After completion, the reaction was quenched with water (30 ml) and extracted with EtOAc (2×80 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g Cartridge) using hexane as eluent to give 3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)- 4-vinyl-6,7-dihydro-5H-cyclopenta[c]pyridine (Yield: 550 mg, 89%) as a white solid. LCMS (ER) m/z=372.48 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.03-2.08 (m, 2H), 2.22 (s, 3H), 2.71-2.94 (m , 4H), 3.91 (s, 3H), 5.27 (d, J= 11.6 Hz, 1H ), 5.48 (s, 2H), 5.67 (d, J= 18.8 Hz , 1H ), 7.17(m, 1H), 7.23-7.27(m, 1H), 7.29-7.31(m, 2H), 7.35-7.38(m, 1H ), 7.43-7.47 (m, 3H).

Step 9: Solution of 3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-vinyl-6,7-dihydro-5H-cyclopenta[c]pyridine ( 0.55 g, 1.48 mmol) in THF (3 ml) and water (3 ml) are cooled to 0°C, osmium tetroxide (0.41 g, 1.62 mmol) is added and stirred at 0°C for 15 minutes. To this mixture is added NaIO ₄ (1.1 g, 5.18 mmol) and the mixture is stirred at room temperature for 16 h. After completion, the reaction is quenched with water (10 ml) and extracted with Et ₂ O (2×20 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-20% EtOAc in hexane as eluent to give 3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde (Yield: 220 mg, 40%) as a white solid. LCMS (ER) m/z=374.47 [M+H] ⁺ .

Step 10: A solution of 3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde ( 90 mg, 0.241 mmol), (S)-piperidine-2-carboxylic acid (37 mg, 0.289 mmol), sodium cyanoborohydride (44 mg, 0.71 mmol) and acetic acid (2 drops) in DMF (5 ml) are stirred at 80°C for 6 hours After completion, the reaction mixture was poured into ice water (10 ml) and extracted with 10% MeOH in DCM (2×30 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-1-((3-methoxy-1-((2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 35 mg, 30%) in form of a white solid. LCMS (ER) m/z=487.46 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.39-1.48 (m, 4H), 1.70-1.78 (m, 2H), 2.02 (t , J= 8 Hz, 2H ), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.71 (t, J= 8 Hz, 2H ), 2.85-3 .06 (m, 3H), 3.68-3.77 (m, 1H), 3.78-3.80 (m, 1H), 3.85 (s, 3H), 5.45 (s, 2H ), 7.17 (d, J= 8 Hz, 1H ), 7.25 (t, J= 8 Hz, 1H ), 7.30 (d, J= 8 Hz, 2H ), 7.37 (t, J= 8.0 Hz, 1H ), 7.44 (t, J= 8.0 Hz, 3H ).

The following compound is obtained by the methods described above.

Example 97

N-(2-(((3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine- 4-yl)methyl)amino)ethyl)acetamide, LCMS (ER) m/z=460.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.76 (s, 3H), 2.02 (t, J= 7.2 Hz, 2H ), 2.22 (s, 3H), 2.47 (t, J= 7.6 Hz, 2H ), 2.72 (t, J= 7.2 Hz, 2H ), 2.86 (t, J= 7.2 Hz, 2H ) , 3.09 (t, J= 6.0 Hz, 2H ), 3.54 (s, 2H), 3.85 (s, 3H), 5.44 (s, 2H), 7.16 (t, J = 7.6 Hz, 1H ), 7.25 (t, J= 7.6 Hz, 1H ), 7.30 (d, J= 7.6 Hz, 2H ), 7.37 (t, J= 6.8 Hz, 1H ), 7.45 (t, J= 6.8 Hz, 3H ), 7.73 (m, 1H ).

Example 98

Synthesis of (S)-4-((5-methoxy-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl )methyl)morpholine-3-carboxylic acid

Stage 1: Solution of 5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-carbaldehyde (150 mg, 0.403 mmol), ( S )-morpholine-3-carboxylic acid (158 mg, 1.209 mmol), in DMF (3 ml) and MeOH (3 ml), add AcOH (2 drops) and stir for 2 h at room temperature. Sodium cyanoborohydride (74 mg, 1.20 mmol) is added to this mixture and stirring is continued for 16 hours. After completion, the reaction mixture is poured into ice water (10 ml) and extracted with 10% MeOH in DCM (3×20 ml). The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent to give (S)-4-((5-methoxy-7-((2-methyl-[1 ,1'-Biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (Yield: 12 mg, 6%) as white solid . LCMS (ER) m/z=486.37 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.95-1.98 (m, 2H), 2.22 (m, 3H), 2.26-2.32 (m , 2H), 2.74 (m, 2H), 2.84 (m, 1H), 2.93-2.99 (m, 2H), 3.11 (m, 1H), 3.46 (m, 1H), 3.55 (m, 1H), 3.68 (m, 2H), 3.75 (s, 4H), 5.17 (s, 2H), 6.62 (s, 1H), 7, 19 (d, J = 7.6 Hz, 1H), 7.25-7.33 (m, 3H), 7.37 (m, 1H), 7.44-7.49 (m, 3H).

Example 99

5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[ 1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid

The compound is synthesized in accordance with the procedure described in example 15, LCMS (ER) m/z=625.35 [M+H] ⁺

General technique biological estimates

PD-L1 enzymatic analysis: analysis binding homogeneous fluorescence With temporary resolution (HRFW)

All binding studies were performed using the PD-1/PD-L1 Binding Assay Kit from CisBio (Catalog # 63ADK000CPAPEG) according to the manufacturer's protocol. The interaction between Tag1-PD-1 and Tag2-PD-1 is determined through anti-Tag1-Eu ³⁺ (HFVR donor) and anti-Tag2-XL665 (HFVR acceptor). When donor and acceptor antibodies approach due to PD-1 and PD-L1 binding, excitation of the donor antibody triggers resonant fluorescence energy transfer (RFET) towards the acceptor antibody, which in turn emits specifically at 665 nm. This specific signal is positively proportional to the PD-1/PD-L1 interaction. Compounds that block the PD-1/PD-L1 interaction cause a decrease in the HFVR signal. Required reagents are mixed in the following order: 2 µl compounds (or diluent buffer), 4 µl PD-L1 protein, 4 µl PD-1 protein. After incubation for 15 minutes, add 5 µl of anti-Tag1-Eu ³⁺ and 5 µl of anti-Tag2-XL665. The plate is sealed and incubated at room temperature for 1 hour. Fluorescence emission is read at two different wavelengths (665 nm and 620 nm) on a BMG PheraStar® multiplate reader. The results are calculated from the fluorescence signal at 665 nm and 620 nm and expressed as the ratio HPF=(665 nm/620 nm) x 10 ⁴ .

Grade biological activities:

Table 5 below shows the biological activity of the compounds of the invention in a PD1/PD-L1 inhibition assay. Compounds having an IC50 <100 nM are designated "A"; 100-500 nM are designated as "B"'; and >500 nM are designated as "C", respectively.

Table 5: Biochemical data inhibition PD1/PD-L1

Compound PD1/PD-L1 activity one B 2 B 3 C four B 5 B 6 C 7 C eight A 9 A ten A eleven A 12 A 13 A fourteen C fifteen A 16 C 17 C eighteen B 19 B twenty B 21 C 22 B 23 C 24 C 25 A 26 B 27 B 28 C 29 B thirty B 31 B 32 B 33 C 34 A 35 A 36 A 37 A 38 A 39 B 40 A 41 A 42 A 43 A 44 A 45 B 46 A 47 A 48 A 49 A fifty A 51 A 52 A 53 A 54 B 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 B 64 B 65 A 66 B 67 A 68 A 69 A 70 A 71 A 72 A 73 B 74 A 75 C 76 C 77 A 78 A 79 A 80 C 81 A 82 B 83 B 84 A 85 B 86 B 87 B 88 B 89 A 90 C 91 C 92 A 93 A 94 A 95 A 96 BUT 97 A 98 A 99 BUT

BUT - not determined.

The above compounds have the potential for development as drugs for attenuating PD1/PD-L1 activity and hence the treatment of cancer and other diseases or conditions associated with PD1/PD-L1 activation.

Claims (179)

1. Compound of formula I

its stereoisomers and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-; R ₄ is selected from hydrogen; X is selected from CR ₃ or N; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O) OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms, selected from nitrogen and oxygen, and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl; R ^e is selected from hydrogen; m is 1 or 2; ring A is selected from C _6-10 aryl substituted with C _1-4 alkyl, cyano or C _1-4 haloalkyl and ring B is selected from C _6-10 aryl. 2. Compound of formula II

its stereoisomers and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-; R ₄ is selected from hydrogen; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O) OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms, selected from nitrogen and oxygen, and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl; R ^e is selected from hydrogen and ring B is selected from C _6-10 aryl. 3. Compound of formula III

its stereoisomers and pharmaceutically acceptable salts, where X ₁ is selected from -CH ₂ O-; R ₄ is selected from hydrogen; R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O) OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms, selected from nitrogen and oxygen, and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl or 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl and R ^e is selected from hydrogen. 4. Compound of formula IV

its stereoisomers and pharmaceutically acceptable salts, where R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O) OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms, selected from nitrogen and oxygen, and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl and R ^e is selected from hydrogen. 5. Compound of formula V

its stereoisomers and pharmaceutically acceptable salts, where R ₅ is selected from C _1-4 alkyl, cyano or C _1-4 haloalkyl; R ₄ is selected from hydrogen; R ₁ , R ₂ , R ₃ , R ₆ and R ₇ are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O) OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms, selected from nitrogen and oxygen, and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl and R ^e is selected from hydrogen. 6. Compounds of formula I, formula II, formula III, formula IV, formula V or their stereoisomers and pharmaceutically acceptable salts according to any one of paragraphs. 1-5 selected from the group consisting of: (S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine- 2-carboxylic acid (1), N-(2-(((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (2), (S)-1-((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (4), (S)-1-((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (5), methyl 7-(((2-acetamidoethyl)amino)methyl)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5 -carboxylate (6), (S)-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (7), (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (8), (S)-1-((5-((5-Fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (9), N-(2-(((5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (10), (S)-5-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (11), (S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (12), N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)-N-methylacetamide (13), N-(2-(((5-(1-(3-cyanophenyl)ethoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)amino)ethyl)acetamide (14), N-(1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)piperidin-3-yl)acetamide (15), N-(2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino) ethyl)acetamide (16), 6-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)-2-oxa-6 -azaspiro[3,3]heptane (17), 2-(hydroxymethyl)-2-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl )amino)propane-1,3-diol (18), 1-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)cyclopropan-1 -carboxylic acid (19), ((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine (20), 3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)propanoic acid ( 21), N-methyl-N-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)glycine ( 22), 3-(((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)butanoic acid ( 23), ((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)alanine (24), (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (25), (S)-1-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (26), 1-((4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperidine-2-carboxylic acid (27) N-(2-(((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (28), (2S,4R)-4-hydroxy-1-((6-methyl-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (29), N-(2-(((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (30), (2S,4R)-1-((6-chloro-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (31), N-(2-(((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (32), (2S,4R)-1-((7-((3'-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]- 3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (33), N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)acetamide (34), (2S,4R)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro -1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (35), (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (36), (S)-1-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxamide (37), 3-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (38), 3-(((4-((2-oxa-6-azaspiro[3,3]heptan-6-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl )methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (39), 3-(((4-((3-hydroxypiperidin-1-yl)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-5-yl)oxy)methyl)benzonitrile (40), ((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl )methyl)glycine (41), (S)-5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)-5-azaspiro[2,4]heptan-6-carboxylic acid (42), rac-(1R,6S)-2-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3 -dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (43), 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)butanoic acid (44), (1R,6S)-2-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (45), (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (46), (2S,4R)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (47), N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (48), 5-(((4-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3 -yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (49), (S)-4-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)morpholine-3-carboxylic acid (50), rac-(1R,6S)-2-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (51), (S)-5-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (52), N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)(methyl)amino)ethyl)acetamide (53), N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)amino)ethyl)acetamide (54), (S)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)piperidine-2-carboxylic acid (55), N-(2-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)amino)ethyl)acetamide (56), (2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4- yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (57), 3-(((7-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-6-methoxy-2,3-dihydro-1H-inden-4-yl) hydroxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (58), (S)-4-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)morpholine-3-carboxylic acid (59), ((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)glycine (60) , (S)-5-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (61), rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden- 4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (62), 2-(1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl )piperidin-2-yl)acetic acid (63), N-(2-(((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl) methyl)(methyl)amino)ethyl)-N-methylacetamide (64), 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-5-yl)oxy)pentanoic acid (65), 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-5-yl)oxy)pentanamide (66), (S)-1-((5-(4-carboxybutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxylic acid (67), (S)-1-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (68), (S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (69), (2S,4R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (70), (R)-1-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-3-carboxylic acid (71), rac-(1R,6S)-2-((7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy) -2,3-dihydro-1H-inden-4-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (cis, racemic) (72), methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene -4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (73), 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (74), (S)-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4- yl)methyl)piperidine-2-carboxylic acid (75), (2S,4R)-4-hydroxy-1-((5-methoxy-7-((2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro- 1H-inden-4-yl)methyl)pyrrolidine-2-carboxylic acid (76), (2S)-1-((7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2.3 -dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (77), (S)-1-((5-(4-carboxybutoxy)-7-((2-cyano-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxylic acid (78), N-(2-(((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)amino)ethyl)acetamide (79), (S)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden- 4-yl)methyl)piperidine-2-carboxamide (80), (2S,4R)-1-((5-(4-cyanobutoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H- inden-4-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (81), (S)-1-((5-(((1S,2R)-2-carboxycyclopropyl)methoxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (82), (1R,2S)-2-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2 ,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylic acid (83), N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3- dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (86), N-(2-(((5-((3-cyanobenzyl)oxy)-7-((4'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (87), (S)-1-((5-((3-carbamoylbenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)piperidine-2-carboxylic acid (88), 3-(((4-(aminomethyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy )methyl)benzonitrile (89), N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)acetamide (90), 6-acetamido-N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-4-yl)methyl)hexanamide (91), 3-(((4-((dimethylamino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5- yl)oxy)methyl)benzonitrile (92), 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)nicotinic acid (93), 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)nicotinamide (94), 3-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H -inden-5-yl)oxy)methyl)benzamide (95), (S)-1-((3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine- 4-yl)methyl)piperidine-2-carboxylic acid (96), N-(2-(((3-methoxy-1-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine- 4-yl)methyl)amino)ethyl)acetamide (97), (S)-4-((5-methoxy-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl) methyl)morpholine-3-carboxylic acid (98) and 5-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4 -yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (99). 7. A method for preparing compounds of formula I according to claim 1 or their stereoisomers and pharmaceutically acceptable salts, including: (a) the interaction of compounds of formula I(a) with substituted aliphatic, aromatic, heterocyclic and cyclic amines to obtain compounds of formula I

, where X _{1 of} formula I(a) and formula I are selected from -CH ₂ O-; R ₄ of formula I(a) and formula I are selected from hydrogen; X of formula I(a) and formula I are selected from CR ₃ or N; R ₁ , R ₂ , R ₆ and R ₇ of formula I(a) and formula I are independently selected from hydrogen, halogen, C _1-6 alkyl, (4-10 membered heterocycloalkyl)-C _1-4 alkyl-, OR ^a or C(O)OR ^a , where C _1-6 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2 or 3 R ^b substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen and is mono- or bicyclic; R ^a is selected from C _1-6 alkyl, C _1-4 haloalkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl-C _1-4 alkyl-, (5-10 membered heteroaryl) -C _1-4 alkyl- or (4-10-membered heterocycloalkyl)-C _1-4 alkyl-, where C _1-6 alkyl, C _6-10 aryl-C _1-4 alkyl-, C _3-10 cycloalkyl- C _1-4 alkyl-, (5-10 membered heteroaryl)-C _1-4 alkyl- and (4-10 membered heterocycloalkyl)-C _1-4 alkyl- are independently optionally substituted with 1, 2, 3, 4 or 5 R ^d substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^b is selected from hydroxy, amino, C _1-4 alkyl, 4-10 membered heterocycloalkyl, OR ^c , C(O)NR ^c R ^c , C(O)OR ^c , NHR ^c , NR ^c R ^c or NR ^c C(O)R ^c , where C _1-4 alkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^d substituents, and 4-10 membered heterocycloalkyl has 1-3 heteroatoms selected from nitrogen and oxygen, and is mono- or bicyclic; R ^c is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl, where C _1-6 alkyl and C _3-10 cycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents; R ^d is selected from cyano, halogen, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)NR ^e R ^e or C(O)OR ^e , where C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R ^f substituents, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl have 1-3 heteroatoms selected from nitrogen; R ^f is selected from C _1-4 alkyl, halogen, CN, OR ^g , C(O)NR ^g R ^g , C(O)OR ^g or NR ^g C(O)R ^g ; R ^g is selected from hydrogen or C _1-6 alkyl; R ^e is selected from hydrogen; m is 1 or 2; ring A is selected from C _6-10 aryl substituted with C _1-4 alkyl, cyano or C _1-4 haloalkyl; ring B is selected from C _6-10 aryl, with substituted amines in the presence of solvents to give compounds of formula I. 8. Pharmaceutical composition that inhibits the activation of PD1/PD-L1, containing an effective amount of a compound of formula I, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-6 together with a pharmaceutically acceptable carrier. 9. The pharmaceutical composition of claim 8, wherein the composition is in a form selected from the group consisting of tablet, capsule, powder, syrup, solution, aerosol, and suspension. 10. A method of treating and/or preventing various diseases associated with PD1/PD-L1 activation, including cancer and infectious diseases, comprising administering to a subject suffering from a proliferative disease or cancer a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV or formula V according to any one of paragraphs. 1-6 or a pharmaceutical composition according to claim 8 or 9. 11. The use of compounds of formula I, formula II, formula III, formula IV or formula V according to any one of paragraphs. 1-6 or a pharmaceutical composition according to claim 8 or 9 for the treatment or prevention of various diseases associated with PD1/PD-L1 activation, including proliferative disease or cancer; or treatment of cancer associated with PD1/PD-L1 activation. 12. A method of treating cancer associated with PD1/PD-L1 activation, wherein said method comprises administering a compound of formula I, formula II, formula III, formula IV, or formula V according to any one of paragraphs. 1-6 or a pharmaceutical composition according to claim 8 or 9 to a subject in need thereof. 13. A method of treating cancer associated with PD1/PD-L1 activation, wherein said method comprises administering a compound of formula I, formula II, formula III, formula IV, or formula V according to any one of paragraphs. 1-6 or a pharmaceutical composition according to claim 8 or 9 to a subject in need thereof.