PRIORITY AND CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage Application under 35 U.S.C. § 371 of International Application No. PCT/IN2019/050203, filed Mar. 13, 2019, designating the U.S. and published in English as WO 2019/175897 A1 on Sep. 19, 2019, which claims the benefit of Indian Patent Application No. IN 201841009252, filed Mar. 13, 2018. Any and all applications for which a foreign or a domestic priority is claimed is/are identified in the Application Data Sheet filed herewith and is/are hereby incorporated by reference in their entireties under 37 C.F.R. § 1.57.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to substituted bicyclic compounds of Formula I along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof which are inhibitors of PD1/PD-L1 interaction. The present invention also relates to method of synthesizing the 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 activation of PD1/PD-L1.

BACKGROUND OF THE INVENTION

Tumour development and survival involves the interplay between cancer cells, normal stromal cells and host defence mechanisms (Vinay D. S. et al., Seminars in Cancer Biology, 2015, 35: S185-S198). Generally, CD8+ cytotoxic T cells (CTLs) and CD4+ helper T (Th1) cells curb cancer development via mechanisms commonly involving the production of interferon (IFN)-γ and cytotoxins (Zamarron B F et al., Intl. J. Biol. Sciences, 2011, 7(5):651-658). Tumours have, however evolved a number of mechanisms to escape immune eradications. The PD-1/PD-L1 molecular pathway is one such primary mechanism of cancer immune evasion.

PD-1 is a type 1 trans-membrane 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 (DCs) and macrophages. The programmed cell death protein (PD-1) down regulates the immune system and prevents it from killing cancerous cells present in the body. In cancer, high levels of PD-1 are detected in tumour infiltrating T cells and this expression has been 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 named B7-H1; CD274) and PD-L2 (B7-DC; CD273), that are both co-inhibitory (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421). PD-L1, expressed on almost all murine tumour cells, is the major ligand for PD-1 mediated immune suppression. It is constitutively expressed on APCs and can be broadly induced on cells in both lymphoid tissues and non-lymphoid peripheral tissues following cellular activation (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421; Dong Y. et al., Oncotarget, 2017, 8(2):2171-2186). The cytokine IFN-γ is particularly effective in up-regulating PD-L1 expression due to IFN-γ response elements in the PD-L1 promoter region (Lee S. J. et al., FEBS Letters, 2006, 580:755-762; Flies D. B. et al., Immunotherapy, 2007, 30(3):251-260). The expression of B7-DC/PD-L2 is largely restricted to myeloid dendritic cells (DCs) and macrophages in lymphoid compartments and is not broadly expressed in peripheral tissues (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421). In cancer, PD-L1 is expressed on the surface of tumour cells in various solid malignancies such as squamous cell carcinoma of the head and neck, melanoma, carcinomas of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colorectum, liver, pancreas, kidney etc. (Topalian S. L. 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, PD-L1 positivity was correlated with worse prognosis (Muenst S. et al., Breast Cancer Res. Treat., 2014, 146(1):15-24; Leung J. et al., Immune Network, 2014, 14(6):265-276; Wang Q. et al., Medicine (Baltimore), 2017, 96(18): e6369). In contrast, normal human tissues seldom express PD-L1 protein on their cell surface, indicating that PD-L1 can be a selective target for anti-tumour therapy (Chen L. et al., J. Clin. Invest., 2015, 125(9):3384-3391).

Cancer microenvironment manipulates the PD-1/PD-L1 pathway; induction of PD-L1 expression is associated with inhibition of immune responses against cancer, thus permitting cancer progression and metastasis (He J. et al., Scientific Reports, 2015, 5:1-9; Bardhan K. et al., Frontiers in Immunology, 2016, 7(550):1-17). Activation of PD-1/PD-L1 pathway induces apoptosis of activated T cells (Dong H. et al., Nature Medicine, 2002, 8(8):793-800; Curiel T. J. et al., Nature Medicine, 2003, 9(5):562-567), facilitates T cell anergy and exhaustion (Barber D. L. et al., Nature, 2005, 439(7077):682-687), enhances the function of regulatory T cells (Francisco L. M. et al., J. Exp. Med., 2009, 206(13):3015-3029) and inhibits the proliferation of T cells (Sheppard K. A. et al., FEBS Letters, 2004, 574:37-41; Patsoukis N. et al., Cell Cycle, 2012, 11(23):4305-4309). Therefore, blocking this pathway restores the proliferation and cytotoxicity of CTLs, inhibiting the function of regulatory T cells (Tregs), and results in decrease T cell apoptosis.

Blockade of the PD-1/PD-L1 pathway by therapeutic antibodies has been shown to prevent inhibitory signalling from cancer cells and enabling CTLs to elicit an immune response against the target/cancer cells (Zou W. et al., Sci. Transl. Med., 2016, 8(328):328rv4; Smahel M., Int. J. Mol. Sci., 2017, 18(6):1331). A number of cancer immunotherapy agents targeting PD-1 have been developed till date and approved for a number of malignancies including melanoma, lung cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer and urothelial cancer. The first therapeutic anti-PD-L1 antibody was approved by the FDA in May 2016, for the treatment of patients with metastatic urothelial carcinoma and non-small cell lung cancer, with a number of additional therapies in the pipeline. Currently, there are at least 500 clinical studies on-going with PD-1/PD-L1 antibodies against 20 types of solid and haematological malignant tumours. However, there is still a need for potent and selective small molecule inhibitors of the PD-1/PD-L1 pathway.

Common drug-related adverse effects (AEs) of both anti-PD-1 and anti-PD-L antibodies include fatigue, rash, diarrhoea, pruritus, decrease appetite, arthralgia and nausea. Immune-related AEs (irAEs) such as dermatitis, colitis, hepatitis, vitiligo and thyroiditis have been reported and about 10% of patients develop grade 3 or 4 irAEs (Hamanishi J. et al., Int. J. Clin. Oncol., 2016, 21:462-473). The long residence time of the monoclonal antibodies (mAbs) could contribute to these AEs, which may be partially circumvented using a small molecule inhibitor. In addition, studies using smaller cell penetrating biologicals and DNA aptamers have shown to exert antibody-mimic functions and are advantageous over antibody for its chemically synthetic nature, low immunogenicity, and efficient tissue penetration (Lai W. Y. et al., Mol. Therapy-Nucl. Acids, 2016, 5: e397). Small molecule inhibitors, therefore, can provide increased oral bioavailability, increased bio-efficiency and shortened half-life activity for a more controllable treatment, particularly in the case of auto-immune or other adverse events.

As discussed, the PD-1/PD-L1 inhibitory compounds have vast utility in up-regulating the immune system for efficiently combating cancer. Therefore, the identification of a chemical moiety, especially small molecule inhibitors, that facilitates this inhibition is necessary. Therefore, the identification and development of new PD-1/PD-L1 inhibitor compounds treating cancer and other diseases or conditions associated with activation of PD-1/PD-L1 would open new opportunities in the realm of cancer treatment.

SUMMARY OF INVENTION

In an aspect of the present disclosure there is provided a compound of Formula I


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X1is selected from —CH2O—, —OCH2—, —C(O)NH— or —NHC(O)—; R4is selected from hydrogen, hydroxyl, C1-6alkyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, or C1-6heteroaryl, wherein C1-6alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, and C1-6heteroaryl; Ra1, Rb1, and Rc1are independently selected from hydrogen or C1-6alkyl; X is selected from CR3or N; R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents; Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents; Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents; Rcis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent; Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents; Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents; Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents; Rnis selected from cyano, halo, C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents; Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents; Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents; Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl; R8is C1-6alkyl; m is 1 or 2; Ring A is selected from substituted or unsubstituted C5-10aryl, substituted or unsubstituted C3-6cycloalkyl, 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 C5-10aryl, C3-6cycloalkyl, 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 the present disclosure there is provided a compound of Formula II


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof,
wherein X1is selected from —CH2O—, —OCH2—, —C(O)NH— or —NHC(O)—;
R4is selected from hydrogen, hydroxyl, C1-6alkyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, or C1-6heteroaryl, wherein C1-6alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, and C1-6heteroaryl;
Ra1, Rb1, and Rc1are independently selected from hydrogen or C1-6alkyl;
R5is selected from C1-4alkyl, cyano, or C1-4haloalkyl;
R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents; Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents;
Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents;
Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents;
Rcis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent;
Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents; Rnis selected from cyano, halo, C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3_10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents;
Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents;
Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
R8is C1-6alkyl;
Ring B is selected from C5-10aryl, C3-6cycloalkyl, 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 the present disclosure there is provided a compound of Formula III


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof,
wherein X1is selected from —CH2O—, —OCH2—, —C(O)NH— or —NHC(O)—;
R4is selected from hydrogen, hydroxyl, C1-6alkyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, or C1-6heteroaryl; wherein C1-6alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, and C1-6heteroaryl;
Ra1, Rb1, and Rc1are independently selected from hydrogen or C1-6alkyl;
R5is selected from C1-4alkyl, cyano, or C1-4haloalkyl;
R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents;
Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents;
Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents;
Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents;
Rfis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent;
Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents;
Rnis selected from cyano, halo, C1_4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents;
Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents;
Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
R8is C1-6alkyl.

In an aspect of the present disclosure there is provided a compound of Formula IV


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof,
wherein R5is selected from C1-4alkyl, cyano, or C1-4haloalkyl;
R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents;
Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents;
Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents;
Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents;
Rfis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent;
Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents;
Rnis selected from cyano, halo, C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents;
Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents;
Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
R8is C1-6alkyl.

In an aspect of the present disclosure there is provided a compound of Formula V


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof,
wherein R5is selected from C1-4alkyl, cyano, or C1-4haloalkyl;
R4is selected from hydrogen, hydroxyl, C1-6alkyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, or C1-6heteroaryl; wherein C1-6alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, and C1-6heteroaryl;
Ra1, Rb1, and Rc1are independently selected from hydrogen or C1-6alkyl;
R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents;
Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents;
Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents;
Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents;
Rfis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent;
Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents;
Rnis selected from cyano, halo, C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents;
Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NR)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents;
Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
R8is C1-6alkyl.

In an aspect of the present disclosure there is provided a compound of Formula VI


their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof,
wherein R5is selected from C1-4alkyl, cyano, or C1-4haloalkyl;
R4is selected from hydrogen, hydroxyl, C1-6alkyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, or C1-6heteroaryl; wherein C1-6alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)ORa1, C(O)NRb1Rc1, C5-6aryl, and C1-6heteroaryl;
Ra1, Rb1, and Rc1are independently selected from hydrogen or C1-6alkyl;
R1, R2, R3, R6, and R7are independently selected from hydrogen, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, or S(O)2NRaRa, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-14 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl-, are independently optionally substituted with 1, 2, 3, or 4 Rbsubstituents;
Rais selected from hydrogen, cyano, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are independently optionally substituted with 1, 2, 3, 4, or 5 Rdsubstituents;
Rbis selected from halo, hydroxy, cyano, amino, nitro, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rcor S(O)2NRcRc; wherein the C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4haloalkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rdsubstituents;
Rdis selected from cyano, amino, C1-6alkyl, C1-6haloalkyl, halo, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, or S(O)2NReRe, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rfsubstituents;
Reis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rfsubstituent;
Rfis selected from C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, halogen, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, or S(O)2NRgRg; wherein the C1-4alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, 3, 4, or 5 Rnsubstituents;
Rnis selected from cyano, halo, C1_4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, or S(O)2NRoRo, wherein the C1-4alkyl, C3-10cycloalkyl, 4-7 membered heterocycloalkyl, C6-10aryl, 5-6 membered heteroaryl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-6 membered heteroaryl)-C1-4alkyl-, (4-7 membered heterocycloalkyl)-C1-4alkyl-, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl and C1-4haloalkyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rgis selected from hydrogen, C1-6alkyl, C1-4haloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, or (4-10 membered heterocycloalkyl)-C1-4alkyl-, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2, or 3 Rpsubstituents;
Rpis selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl-, (4-10 membered heterocycloalkyl)-C1-4alkyl-, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRror S(O)2NRrRr, wherein the C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5-10 membered heteroaryl)-C1-4alkyl- and (4-10 membered heterocycloalkyl)-C1-4alkyl- are optionally substituted with 1, 2 or 3 Rqsubstituents;
Re, Ri, Rk, Roand Rrare independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4haloalkyl, C2-4alkenyl, or C2-4alkynyl, wherein the C1-4alkyl, C3-6cycloalkyl, C6-10aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4alkenyl, and C2-4alkynyl are optionally substituted with 1, 2 or 3 Rqsubstituents;
Rqis selected from hydroxy, cyano, amino, halo, COOH, C1-6haloalkyl, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C5-6aryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6cycloalkyl, NHR8, NR8R8, and C1-4haloalkoxy, wherein the C1-6alkyl, C5-6aryl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with halo, hydroxy, cyano, COOH, amino, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C5-6aryl, C3-10cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl;
R8is C1-6alkyl.

The present disclosure further describes the process of preparation of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.

The present disclosure also discloses the method for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administering to a subject suffering from the proliferative disorder or cancer a therapeutically effective amount of the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising 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.

The present disclosure further discloses the use of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising 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 proliferative disorder or cancer; or treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

The present disclosure also discloses a method for the treatment of cancer, said method comprising administering a combination of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising 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.

The present disclosure further describes a method of treatment of cancer, said method comprising administering a combination of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition, with other clinically relevant immune modulators agents to a subject in need of thereof.

These and other features, aspects, and advantages of the present subject matter will become better understood 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 identify key features or essential features of the disclosure, nor is it intended to be used to limit the scope of the subject matter.

