1,2-dicarboxamide compounds as kinase inhibitors

Abstract

The present invention relates to 1,2-dicarboxamide compounds of Formula (I); pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, N-oxides or combination thereof, wherein 'X', 'Y', 'Z', ring A, ring B, R1, R2, R3, R4, R5, R6, 'm' and 'n' are as defined herein. The present invention also relates to 1,2-dicarboxamide compounds that modulate cellular activities like proliferation, differentiation, adhesion, migration and apoptosis by modulating protein kinase enzymatic activity. In particular the invention relates to compounds which inhibit, regulate, and / or modulate tyrosine kinases such as FLT1 (VEGFR1), FLT4 (VEGFR3), KDR (VEGFR2), MET (C-Met), MERTK (c-Mer), RET, AXL, TEK (TIE 2) and EGFR. The present disclosure relates to 1,2-dicarboxamide compounds for use in modulating kinase enzymatic activity and accordingly modulating kinase-dependent associated diseases and conditions such as cancers like Thyroid carcinoma, Ovarian carcinoma, Pancreatic carcinoma, Prostatic carcinoma, Renal cell carcinoma, Hepatocellular carcinoma, Breast carcinoma, Colorectal carcinoma, Oral squamous cell carcinoma, Colorectal, Lung adenocarcinoma or Endometrial cancer.

Description

[0001] 1,2-DICARBOXAMIDE COMPOUNDS AS KINASE INHIBITORS

[0002] This application claims the benefit of Indian provisional application no. 202441075282 filed on 04thOctober 2024 which is hereby incorporated by reference in its entirety.

[0003] FIELD OF THE INVENTION

[0004] The present disclosure relates to 1,2-dicarboxamide compounds that modulate cellular activities like proliferation, differentiation, adhesion, migration and apoptosis by modulating protein kinase enzymatic activity. In particular the present invention relates to compounds which inhibit, regulate, and / or modulate tyrosine kinases such as FLT1 (VEGFR1), FLT4 (VEGFR3), KDR (VEGFR2), MET (c-MET), MERTK (c-Mer), RET, AXL, TEK (TIE 2) and EGFR. The present disclosure relates to 1,2-dicarboxamide compounds for use in modulating kinase enzymatic activity and accordingly modulating kinase-dependent associated diseases and conditions such as cancers like Thyroid carcinoma, Ovarian carcinoma, Pancreatic carcinoma, Prostatic carcinoma, Renal cell carcinoma, Hepatocellular carcinoma, Breast carcinoma, Colorectal carcinoma, Oral squamous cell carcinoma, Colorectal, Lung adenocarcinoma or Endometrial cancer.

[0005] BACKGROUND OF THE INVENTION

[0006] Protein tyrosine kinases (PTKs) are enzymes that catalyze the transfer of the-phosphate group of ATP to tyrosine residues of protein substrates. The activity of PTKs is controlled in a complex manner by posttranslational modifications and by inter- and intramolecular complex formations (Hubbard et al., 1998. J Biol Chem., 273(20): 11987-90; Hubbard and Till, 2000. Annu Rev Biochem., 69:373-398) . PTKs have been implicated in the regulation of a variety of biological responses such as cell proliferation, migration, differentiation, and survival. They have been demonstrated to play important roles in the development of many disease states, including immunodeficiency, atherosclerosis, psoriasis, osteoporosis, diabetes, and cancer. Enhanced activity of PTKs has been implicated in a variety of malignant and nonmalignant proliferative diseases. In addition, PTKs play a central role in the regulation of cells of the immune system. PTK inhibitors can thus impact a wide variety of oncologic and immunologic disorders. Of the many different cellular functions in which the activity of protein kinases is known to be required, some processes represent attractive targets for therapeutic intervention for certain disease states. Two examples are angiogenesis and cell-cycle control, in which protein kinases play a pivotal role; these processes are essential for the growth of solid tumors as well as for other diseases.

[0007] Angiogenesis is the process of new capillaries forming out of preexisting blood vessels in your body. It’s normally a helpful, important process that supports wound healing and supplies oxygen-rich blood to organs and tissues. If required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. (Merenmies etal., 1997. Cell Growth & Differentiation, 8, 3-10). On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors). (Folkman, 1995. Nature Med., 1(1), 27-31). In particular, people with cancer, angiogenesis supports tumor growth and spread by feeding tumors with oxygen and nutrients.

[0008] Protein kinases which are involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor). FGF-R (fibroblast growth factor receptor); and TEK (Tie-2). VEGF-R2, which is expressed only on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity. Thus, it is expected that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis (Strawn et al., 1996. Cancer Research, 56(15), 3540-3545) .

[0009] TEK (TIE2) receptor tyrosine kinase is expressed in vascular endothelial cells, tumor- associated macrophages, and tumor cells and has been a major focus of research in therapies targeting the tumor microenvironment. The most extensively studied Tie2 ligands are Angiopoietin 1 and 2 (Angl, Ang2). Angl plays a critical role in vessel maturation, endothelial cell migration, and survival. Ang2, depending on the context, may function to disrupt connections between the endothelial cells and perivascular cells, promoting vascular regression. However, in the presence of VEGF-A, Ang2 instead promotes angiogenesis. TIE 2-expressing macrophages play a critical role in both tumor angiogenesis and the dissemination of tumor cells from the primary tumor to secondary sites. Therefore, Ang-TIE 2 signaling functions as an angiogenic switch during tumor progression and metastasis (Duran etal., 2021. Cancers (Basel), v; 13(22): 5730). Only a small number of studies have reported TIE2 expression in tumor cells of both an epithelial and a non-epithelial origin. Kukk et al, (1997) investigated Tie2 signaling in hematopoietic progenitors and leukemic cells. High Tie2 expression has also been shown to be a prognostic factor for poor survival and increased metastases in several cancers. In high grade serous ovarian cancer, high TIE2 expression predicted a shorter overall survival and distal omental metastasis. TIE2 expression was also increased in metastatic lesions compared with primary tumors (PLoS ONE. 2020:15: eO24 I484). In gastric cancer, an evaluation of TIE 2 expression through immunohistochemistry found that TIE2 expression increased with increasing tumor grade, the presence of lymph node metastases, higher recurrence rates, and poor patient survival (Yang et al., 2018. Oncol. Lett, 15(5) : 8027-8033). c-MET receptor, which belongs to the receptor tyrosine kinase (RTK) family, plays essential roles in controlling a number of critical cellular processes such as cell proliferation, survival, motility, and morphogenesis (Birchmeier et al., 2003. Nat. Rev. Mol. Cell Biol., 4(12):915-925; Organ and Tsao, 2011. Ther. Adv. Med. Oncol., 2011. 3(1 Suppl): S7- S19). Aberrant activation of c-MET can lead to both tumour growth and metastatic progression of cancer cells, making it an important drug target for cancer treatments (Benedetta and Donald, 2006. Clin. Cancer Res., 12(12):3657-3660; Joseph et al., 2009. Clin. Cancer Res., 15 (7):2207-2214). High c-MET expression is closely associated with poor prognosis in cancer patients. Studies have shown that abnormal activation of c-MET is critical for resistance to targeted therapies such as tyrosine kinase inhibitors and drugs that act against associated signalling pathways. Therefore, as abnormal c-MET function can increase the difficulty associated with tumour treatment, understanding its role in cancer is extremely important (Zhu et al., 2016. J Cell Sci., 129(22): 4238-51; Caenepeel et al., 2017. Oncotarget., 8(11): 17795- 809).

[0010] AXL is involved in various cellular processes including cell growth, proliferation, survival, apoptosis, and adhesion. Given this, the involvement of AXL in cancer progression is not unexpected (AXL as a Target in Breast Cancer Therapy. J. Oncol. 2020). It has been associated with different high-grade cancers and correlated with poor prognosis (ColavitoS.A., 2020. J. Oncol., 14:5291952) . Furthermore, higher levels of AXL expression are found in highly invasive cancer cell lines compared to less invasive cancer cell lines indicating an association with migration and invasiveness of cancer cells. It is a promising therapeutic target, and several inhibitors directed to AXL are currently in clinical trials. The understanding of AXL’s role in the development of resistance can lead to improved and new cancer therapeutic strategies (Martha et al. , 2021. Cancers (Basel)., 13(7): 1521). Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances binds ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity (Mahato and Sidorova, 2020. Ini. J. Mol. Sci., 21(19): 7108). Moreover, recent development of RET-specific kinase inhibitors contributed significantly to progress in the treatment of patients with RET-altered cancer.

[0011] Epidermal growth factor receptor (EGFR) is a receptor tyrosine protein kinase, and a transmembrane protein in the ErbB receptor family. EGFR regulates proliferation, survival, adhesion, migration and differentiation of cells, which is hyperactivated or sustained in a variety of tumor cells, such as lung cancer cells, breast cancer cells, prostate cancer cells and the like. Abnormal activation of EGFR plays a key role in tumor transformation and growth. Blocking activation of EGFR has been clinically proven as one of the effective targeted therapies for treating cancer.

[0012] EGFR downstream signalling is implicated in the development and progression of various cancers, including non-small cell lung cancer (NSCLC), breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, and glioblastoma. EGFR mutations or overexpression can drive cancer cell proliferation, survival, and metastasis by activating downstream signalling pathways like PI3K / AKT / mT0R, RAS / RAF / MEK / ERK, and others. Inhibiting the EGFR (Epidermal Growth Factor Receptor) downstream signalling pathway primarily prevents the cell from receiving external growth signals and can disrupt cellular processes like proliferation, survival, and differentiation. This can lead to a decrease in cell growth and even cell death in certain cases, making it a potential therapeutic target in cancer.

[0013] W02000042012A1 describes cn-carboxyaryl substituted diphenyl ureas as RAF kinase inhibitors; W02001060814A1 describes pyrrole substituted 2-indolinone protein kinase inhibitors; W02001032651 Al describes quinazoline derivatives as VEGF inhibitors; W02002059110A1 describes pyrimidineamines as angiogenesis modulators; W02004078746A2 describes 2-oxo-l,3,5-perhydrotriazapine derivatives useful in the treatment of hvper-proliferative, angiogenesis, and inflammatory disorders; WO 2005030140 A2 describes C-MET modulators and methods of use; VV02007075869 A2 describes bicyclic heteroaryl compounds, US5521184A describes pyrimidine derivatives and processes for the preparation thereof; US6762180B1 describes substituted indolines which inhibit receptor tyrosine kinases; US7253286B2 describes nitrogen-containing aromatic derivatives; WO2009137391A2 describes Benzene sulfonamide thiazole and oxazole compounds; W02007109120A2 describes Imidazolothiazole compounds for the treatment of disease; US20030087907A1 describes Quinoline derivatives and quinazoline derivatives having azolyl group; W02001002369 A2 describes indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use; WO2019148044 Al describes quinoline compounds as AXL and TAM family receptor tyrosine kinase inhibitors. US11702425 B2 discloses Bicyclic compounds as kinase modulators in particular to treatment of Hepta Cellular Carcinoma (HCC) and compounds disclosed herein are having less inhibitory activity towards c-Kit, inhibition of c-Kit causes adverse effects such as myelosuppression (Galants and Levis, 2015. Haematologica, J 00(3): e77~e79).

[0014] Based on these proof-of-principle results, still there is a need of development for clinically applicable multi-kinase inhibitors to provide significant benefits, in overcoming the challenge associated with lack of knowledge of the target specificity of multi-kinase inhibitors, to overcome the resistance developed in the existing therapies and to overcome the side effects associated with the existed therapies.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention relates to the compound of the Formula (I):

[0017] Formula (I) wherein,

[0018] ‘X’ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or -C(O)-R?; wherein the substituents are selected form hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or amino; ‘Y’ is -ORc;

[0019] ‘Z’ is selected from ‘-O-’ or ‘-S-’;

[0020] ( A ) ring — is substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted heteroaryl; ring is selected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl;

[0021] Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, haloalkyloxy, cycloalkyloxy, cyano, nitro, or amino;

[0022] R2 and R3 are independently selected from hydrogen or Ci-Ce alkyl or R2 and R3 are taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein one or more substituents are independently selected from halogen or Ci-Ce alkyl;

[0023] R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;

[0024] R5 is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;

[0025] Re is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;

[0026] R7 is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl, - wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or ammo;

[0027] Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;

[0028] Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;

[0029] Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;

[0030] Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;

[0031] ‘— ’ is an optional bond;

[0032] ‘m’ is an integer selected from 0, 1, 2, 3 or 4;

[0033] ‘n’ is an integer selected from 1, 2, 3, 4 or 5; and

[0034] ‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

[0035] According to one embodiment, there is provided a compound of Formula (I), wherein

[0036] ‘Z’ is ‘O’ or ‘S’.

[0037] According to another embodiment, there is provided a compound of Formula (I),

[0038] According to yet another embodiment, there is provided a compound of Formula (I),

[0039]

[0040] According to yet another embodiment, there is provided a compound of Formula (I), wherein ‘X’ is -C(O)-R? and the said R7 is -N(Ra)(Rb).

[0041] According to yet another embodiment, there is provided a compound of Formula (I), wherein the above said -N(Ra)(Rb) is selected from

[0042] According to yet another embodiment, there is provided a compound of Formula (I), wherein ‘X’ is -C(O)-R? and the said

[0043] According to yet another embodiment, there is provided a compound of Formula (I),

[0044] According to yet another embodiment, there is provided a compound of Formula (I), wherein ‘ Y’ is -ORc; wherein the said Rc is selected from hydrogen, methyl, propyl, isopropyl, tert-butyl, deuteromethyl, 1 -methoxy ethyl, 4-methylpiperidinyl, 4-methylmorpholinyl, 4- ethylmorpholinyl, 4-propylmorpholin, tert-butyl 4-methylpiperidinyl- 1 -carboxylate or 2- ethoxy-2-methylpropanyl .

[0045] According to yet another embodiment, there is provided a compound of Formula (I), wherein R5 and Re are hydrogen.

[0046] According to yet another embodiment, there is provided a compound of Formula (I), wherein R5 and Re are methyl.

[0047] According to yet another embodiment, there is provided a compound of Formula (I), wherein R2 and R3 are taken together with the carbon atom to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl.

[0048] According to yet another embodiment, there is provided a compound of Formula (I), wherein the above said cycloalkyl is selected from

[0049] (includes isomers

[0050] Accordingly, to yet another embodiment the compound of Formula (I) is a compound of Formula (IA): wherein, ‘X’, ‘Y’, ring A, ring B, Ri, R2, R3, R4, R5, Re ‘m’ and ‘n’ are as defined in compound Formula (I).

[0051] Accordingly, to yet another embodiment the compound of Formula (I) is a compound of Formula (IB): wherein, ring A, ring B, Ri, R2, R3, R4, Rs, Re, R7, Rc ‘m’ and ‘n’ are as defined in compound Formula (I).

[0052] Accordingly, to yet another embodiment the compound of Formula (I) is a compound of Formula (IC): wherein, Ri, R2, R3, R4, R5, Re, R7, Rc ‘m’ and ‘n’ are as defined in compound Formula (I).

[0053] Accordingly, to yet another embodiment the compound of Formula (I) is a compound of Formula (ID): wherein, Ri, R4, R7, Rc ‘m’ and ‘n’ are as defined in compound Formula (I).

[0054] * Represents chiral centre.

[0055] Accordingly, to yet another embodiment the compound of Formula (I) is a compound of Formula (IE): wherein, Ri, R4, R7, ‘m’ and ‘n’ are as defined in compound Formula (I). * Represents chiral centre.

[0056] In further yet another embodiment, the compounds of Formula (I) structurally encompass all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the general formula (I) described herein.

[0057] The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of Formula (I) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of Formula (I) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.

[0058] The compounds of the Formula (I) are existed in stereoisomeric form at specified stereo centers as “R” or “S” isomers. The stereospecificity at particular stereocenters were controlled in the precursor synthesis (Intermediates) by using chiral resolution agents like (S)-l- phenylethan-1 -amine and (R)-l-phenylethan-l -amine and the like. The isomers can also be separated by using chiral HPLC separation techniques in the final step of synthesis. The stereospecificity at the particular stereocenter are confirmed by using the technique single crystal XRD. The single crystals of the corresponding molecules were developed by using appropriate solvents like methanol, ethyl acetate, dichloromethane, ethanol, acetonitrile, acetone, THF, isopropanol, diethyl ether or in the combination of solvents. The stereochemistry at the particular stereocenter, structurally can be represented as follows.

[0059] The present invention also provides a pharmaceutical composition that includes at least one compound of Formula (I) as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, or other container.

[0060] The compounds and pharmaceutical compositions described herein are useful in modulating kinase enzymatic activity and accordingly modulating kinase-dependent associated diseases and conditions such as cancers.

[0061] Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from ChemBioDraw Ultra 23.1.2 version): methyl 4-(2-fluoro-4-((l S,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,

[0062] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0063] 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid,

[0064] (lS,2R)-Nl-(4-((6-(dimethylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carbonyl)piperazine- 1 -carboxylate,

[0065] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(piperazine-l-carbonyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0066] (lS,2R)-Nl-(4-((6-(4-acryloylpiperazine-l-carbonyl)-7-methoxyquinolin-4-yl)oxy)-

[0067] 3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0068] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(4-propionylpiperazine-l-carbonyl)quinolin-

[0069] 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0070] (lS,2R)-Nl-(4-((6-((2-acrylamidoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide

[0071] ((2R,3S,4R)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl 4-(2-fluoro- 4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,

[0072] (lR,2S)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (2R,3S,4R)-2-(((4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carbonyl)oxy)methyl)-6-methoxytetrahydro-2H-pyran-3,4-diyl diacetate, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate,

[0073] (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetate,

[0074] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-propionamidoethyl)carbamoyl)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, isopropyl 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate, 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxy-6-(methylcarbamoyl)quinoline 1-oxide, (lS,2R)-Nl-(4-((6-(l,l-dioxidothiomorpholine-4-carbonyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropyl)carbamate,

[0075] (lS,2R)-Nl-(4-((6-((l-amino-2-methylpropan-2-yl)carbamoyl)-7-methoxy quinolin- 4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- dicarboxamide 2,2,2-trifluoroacetate, tert-butyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropan-2-yl)carbamate,

[0076] ( 1 S,2R)-N 1 -(4-((6-((2-amino-2-methylpropyl)carbamoyl)-7-methoxy quinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide

[0077] 2.2.2-trifluoroacetate,

[0078] (lS,2R)-Nl-(4-((6-((2-(l,l-dioxidothiomorpholino)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0079] 1.2-dicarboxamide, (lS,2R)-Nl-(4-((6-((2-(l,l-dioxidothiomorpholino)-2-methylpropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1 ,2-dicarboxamide,

[0080] (lS,2R)-Nl-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropyl)piperazine- 1 -carboxylate,

[0081] ( 1 S,2R)-N 1 -(3 -fluoro-4-((7-methoxy-6-((2-methyl- 1 -(piperazin- 1 -yl)propan-2- yl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2- dicarboxamide 2,2,2-trifluoroacetic acid,

[0082] (lS,2R)-Nl-(3-fluoro-4-((6-((l-hydroxy-2-methylpropan-2-yl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1 ,2- dicarboxamide,

[0083] (lS,2R)-Nl-(4-((6-(((2R,3R)-2-(l,l-dioxidothiomorpholino)-3- hydroxybutyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0084] (lS,2R)-Nl-(4-((6-((l-(l,l-dioxidothiomorpholino)-2-methylpropan-2- yl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0085] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(2,2,2- trifluoroacetamido)ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0086] (lS,2R)-Nl-(3-fluoro-4-((6-((2-hydroxyethyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((6-((2-(isopropylamino)ethyl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1 ,2- dicarboxamide,

[0087] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-pivalamidoethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, ethyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate, tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)piperazine- 1 -carboxylate,

[0088] ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2-(piperazin- 1 - yl)ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetate,

[0089] (lS,2R)-Nl-(4-((6-((2-(tert-butyl(4-methoxybenzyl)amino)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0090] 1 ,2-dicarboxamide,

[0091] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-methoxyethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, isobutyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate, isopropyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)(methyl)carbamate, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(methylamino)ethyl)carbamoyl)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid,

[0092] ( 1 S,2R)-N 1 -(4-((6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0093] 1 ,2-dicarboxamide,

[0094] (lS,2R)-Nl-(4-((6-((3-(dimethylamino)propyl)(methyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0095] 1 ,2-dicarboxamide, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-N-methylquinoline-6- carboxamido)ethyl)carbamate, (lS,2R)-Nl-(3-fluoro-4-((6-((3-hydroxypropyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(4-((6-((2-aminoethyl)(methyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide

[0096] 2.2.2-trifluoroacetate,

[0097] (lS,2R)-Nl-(4-((6-((3-(l,l-dioxidothiomorpholino)propyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0098] 1.2-dicarboxamide, tert-butyl 4-(3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)piperazine-l -carboxylate, (lS,2R)-Nl-(4-((6-((2-(dimethylamino)ethyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((3 -(piperazin- 1 - yl)propyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid,

[0099] (lS,2R)-Nl-(4-((6-((3-(dimethylamino)propyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)carbamate, (lS,2R)-Nl-(4-((6-((3-aminopropyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid, tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)(methyl)carbamate,

[0100] ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((3 - (methylamino)propyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid,

[0101] (lS,2R)-Nl-(4-((6-((3-(l,3-dioxoisoindolin-2-yl)propyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0102] 1 ,2-dicarboxamide,

[0103] (lS,2R)-Nl-(4-((6-((2-(l,3-dioxoisoindolin-2-yl)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0104] 1 ,2-dicarboxamide, ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2-(3 -methyl-4-oxo-3 ,4- dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carboxamido)ethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0105] (lS,2R)-Nl-(4-((6-((2-(5-amino-lH-imidazole-4-carboxamido)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-

[0106] 1.2-dicarboxamide,

[0107] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((3-methoxypropyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0108] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((oxetan-3-ylmethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-N-methylquinoline-6- carboxamido)propyl)carbamate,

[0109] (lS,2R)-Nl-(4-((6-((3-aminopropyl)(methyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide

[0110] 2.2.2-trifluoroacetic acid,

[0111] (lS,2R)-Nl-(4-((6-(ethylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0112] (lS,2R)-Nl-(3-fluoro-4-((6-(isopropylcarbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0113] (lS,2R)-Nl-(4-((6-(tert-butylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(4-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)phenyl)piperazine- 1 -carboxylate,

[0114] ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((4-(piperazin- 1 - yl)phenyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid,

[0115] ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((4-(4-methylpiperazin- 1 - yl)phenyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0116] 3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl acetate, 3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl (tert-butoxycarbonyl)-L-valinate, ethyl 4-(2-fluoro-4-((l S,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,

[0117] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((methyl-d3)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, 2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)ethyl (tert-butoxycarbonyl)-L-valinate,

[0118] 2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)ethyl L-valinate 2,2,2-trifluoroacetic acid,

[0119] (lS,2R)-Nl-(4-((6-((2-benzamidoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0120] 3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl L-valinate 2,2,2-trifluoroacetic acid,

[0121] (lS,2R)-Nl-(3-fluoro-4-((6-((2-(2-hydroxybenzamido)ethyl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- di carb oxami de,

[0122] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methoxycarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0123] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N4-(4- fluorophenyl)maleamide,

[0124] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-fluorophenyl)-N2-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrimidin-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0125] 4-(2-fluoro-4-(3-(4-fluorobenzamido)propanamido)phenoxy)-7-methoxy-N- methylquinoline-6-carboxamide, (lS,2R)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)thio)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0126] (lR,2S)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)thio)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0127] (lS,2R)-Nl-(2-chloro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-fluorophenyl)-N2-(3-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0128] (lS,2R)-Nl-(3-chloro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(2-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-hydroxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0129] (lS,2R)-Nl-(4-((7-(2-(tert-butoxy)ethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-

[0130] 3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0131] (lS,2R)-Nl-(3-fluoro-4-((6-(hydrazinecarbonyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0132] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(l,3,4-oxadiazol-2-yl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(((4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)piperidine- 1 -carboxylate, (lS,2R)-Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(piperidin-4-ylmethoxy)quinolin-

[0133] 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid,

[0134] (1 S,2R)-N1 -(3-fluoro-4-((7-(2 -methoxy ethoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0135] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(5-methyl-l,3,4-oxadiazol-2-yl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-(methoxy-d3)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-N2,3,3-trimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-N2,3,3-trimethylcyclopropane-l,2-dicarboxamide,

[0136] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N4-(4- fluorophenyl)fumaramide,

[0137] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-phenylcyclopropane-l,2-dicarboxamide,

[0138] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-phenylcyclopropane-l,2-dicarboxamide,

[0139] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)cyclopropane-l,2-dicarboxamide,

[0140] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)cyclopropane-l,2-dicarboxamide,

[0141] (lS,2R)-Nl-(4-((6-carbamoyl-7-hydroxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0142] (lR,2S)-Nl-(2,4-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0143] ( 1 S,2R)-N 1 -(2,4-difluorophenyl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2 dicarboxamide,

[0144] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(pyridin-3-yl)cyclopropane-l,2-dicarboxamide,

[0145] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(pyridin-3-yl)cyclopropane-l,2-dicarboxamide,

[0146] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(5-fluoropyridin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0147] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(5-fluoropyridin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0148] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(5-methyl-l,3,4-thiadiazol-2-yl)cyclopropane-l,2- di carb oxami de,

[0149] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(5-methyl-l,3,4-thiadiazol-2-yl)cyclopropane-l,2- di carb oxami de,

[0150] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)- 3,3-dimethyl-N2-(2-methylbenzo[d]thiazol-6-yl)cyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-

[0151] 3,3-dimethyl-N2-(2-methylbenzo[d]thiazol-6-yl)cyclopropane-l,2-dicarboxamide,

[0152] (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-

[0153] N2-(4-fluorobenzyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0154] (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-

[0155] N2-(4-fluorobenzyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0156] (lS,2R)-Nl-(2,5-difluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0157] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(p-tolyl)cyclopropane- 1 ,2-dicarboxamide,

[0158] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-

[0159] (fluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0160] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0161] Nl-(2,3-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0162] Nl-(2,5-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0163] Nl-(2,6-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0164] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,3,4-trifluorophenyl)cyclopropane-l,2-dicarboxamide,

[0165] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3,4,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,

[0166] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,3,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,

[0167] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,4,6-trifluorophenyl)cyclopropane-l,2-dicarboxamide,

[0168] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,4,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,

[0169] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(perfluorophenyl)cyclopropane-l,2-dicarboxamide,

[0170] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide,

[0171] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide,

[0172] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluoro-4-(trifluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0173] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluoro-6-(trifluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0174] Nl-(3-chloro-2-fluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-

[0175] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0176] N 1 -(4-chloro-2-fluorophenyl)-N2-(3 -fluoro-4-((7 -methoxy-6-

[0177] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0178] Nl-(2-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0179] Nl-(3-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0180] Nl-(2,3-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0181] Nl-(2,4-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0182] Nl-(2,5-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0183] Nl-(2,6-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0184] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- hydroxyphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0185] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- methoxyphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0186] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- (methoxy-d3)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0187] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,

[0188] N 1 -(2-(difluorom ethoxy )phenyl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-(difluoromethoxy)phenyl)-N2-(3-fluoro-4-((7-methoxy-6-

[0189] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0190] N 1 -(4-(difluorom ethoxy )phenyl)-N2-(3 -fluoro-4-((7 -methoxy-6-

[0191] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0192] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-

[0193] (fluoromethoxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0194] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,

[0195] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,

[0196] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(lH-pyrazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0197] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-lH-pyrazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0198] N 1 -( 1 , 3 -dimethyl- 1 H-pyrazol-5 -yl)-N2-(3 -fluoro-4-((7 -methoxy-6-

[0199] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0200] Nl-(l,5-dimethyl-lH-pyrazol-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0201] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0202] Nl-(1 -ethyl- lH-pyrazol-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0203] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0204] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(l- isopropyl-lH-pyrazol-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0205] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(lH- imidazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0206] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-

[0207] (isoxazol-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0208] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylisoxazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0209] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisoxazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0210] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(oxazol-2-yl)cyclopropane- 1 ,2-dicarboxamide,

[0211] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyloxazol-2-yl)cyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyloxazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0212] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)oxazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0213] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-l,3,4-oxadiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0214] Nl-(5-(tert-butyl)-l,3,4-oxadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0215] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0216] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,2,5-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0217] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyl-l,2,5-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0218] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-l,2,4-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0219] Nl-(3-(tert-butyl)-l,2,4-oxadiazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0220] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylthiophen-2-yl)cyclopropane-l,2-dicarboxamide,

[0221] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(thiazol-2-yl)cyclopropane- 1 ,2-dicarboxamide,

[0222] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylthiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0223] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylthiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0224] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)thiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0225] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyl-5-(trifluoromethyl)thiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0226] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)cyclopropane-l,2- di carb oxami de, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2- (isothiazol-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0227] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisothiazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0228] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisothiazol-4-yl)cyclopropane-l,2-dicarboxamide,

[0229] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0230] Nl-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0231] Nl-(5-ethyl-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0232] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0233] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- isopropyl-l,3,4-thiadiazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0234] Nl-(5-(tert-butyl)-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0235] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4H- 1 ,2,4-triazol-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0236] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(lH-l,2,4-triazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0237] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methyl-2H-tetrazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0238] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-( 1 -methyl- lH-tetrazol-5-yl)cyclopropane- 1 ,2-dicarboxamide,

[0239] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,2,4-triazin-3-yl)cyclopropane-l,2-dicarboxamide,

[0240] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridin-2-yl)cyclopropane- 1 ,2-dicarboxamide,

[0241] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-methylpyridin-2-yl)cyclopropane-l,2-dicarboxamide,

[0242] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylpyridin-2-yl)cyclopropane-l,2-dicarboxamide,

[0243] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-methylpyridin-3-yl)cyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridin-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0244] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylpyridin-4-yl)cyclopropane-l,2-dicarboxamide,

[0245] Nl-(2,6-dimethylpyridin-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0246] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0247] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrazin-2-yl)cyclopropane-l,2-dicarboxamide,

[0248] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridazin-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0249] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethyl)pyridazin-3-yl)cyclopropane-l,2-dicarboxamide,

[0250] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- methoxypyridazin-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0251] Nl-(6-ethylpyridazin-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-

[0252] 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0253] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrimidin-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0254] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrimidin-2-yl)cyclopropane- 1 ,2-dicarboxamide,

[0255] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylpyrimidin-2-yl)cyclopropane-l,2-dicarboxamide,

[0256] Nl-(4-ethylpyrimidin-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-

[0257] 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0258] Nl-(4,6-dimethylpyrimidin-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0259] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0260] Nl-(benzo[d]oxazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin- 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0261] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- methoxybenzo[d]oxazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0262] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- fluorobenzo[d]oxazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0263] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-nitrobenzo[d]oxazol-2-yl)cyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- fluorobenzo[d]isoxazol-3-yl)-3, 3 -dimethyl cyclopropane- 1,2-dicarboxamide,

[0264] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(lH- indazol-3-yl)-3, 3 -dimethylcyclopropane- 1,2-dicarboxamide,

[0265] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-(trifluoromethyl)-lH-indazol-3-yl)cyclopropane-l,2-dicarboxamide,

[0266] N 1 -( 1 -ethyl- 1 H-indazol-3 -yl)-N2-(3 -fluoro-4-((7 -methoxy-6-

[0267] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0268] Nl-(lH-benzo[d]imidazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0269] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0270] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-( 1 -methyl- lH-benzo[d]imidazol-2-yl)cy cl opropane- 1 ,2-dicarboxamide,

[0271] Nl-(benzo[d]thiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin- 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0272] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylbenzo[d]thiazol-2-yl)cyclopropane-l,2-dicarboxamide,

[0273] Nl-(benzo[d]isothiazol-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0274] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0275] Nl-(benzo[b]thiophen-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0276] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0277] Nl-(benzo[d]isoxazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin- 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0278] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylbenzo[d]isoxazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0279] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylbenzo[d]oxazol-6-yl)cyclopropane-l,2-dicarboxamide,

[0280] Nl-(2-(tert-butyl)benzo[d]oxazol-6-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0281] Nl-(benzo[d]oxazol-7-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin- 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0282] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-phenylbenzo[d]oxazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0283] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylbenzo[d]oxazol-5-yl)cyclopropane-l,2-dicarboxamide, N 1 -( 1 H-benzo[d]imidazol -7 -yl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0284] N 1 -( 1 H-benzo[d]imidazol -5 -yl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0285] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-

[0286] (imidazof 1 ,2-a]pyridin-6-yl)-3 ,3 -dimethylcyclopropane- 1 ,2-dicarboxamide,

[0287] Nl-(benzo[d]isothiazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-

[0288] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0289] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)cyclopropane-l,2-dicarboxamide,

[0290] N 1 -( 1 -acetyl- 1 H-indol-5 -yl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0291] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrrolo[ 1 ,2-b]pyridazin-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0292] Nl-(3,3-dimethyl-2-oxoindolin-6-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0293] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(naphthalen- 1 -yl)cyclopropane- 1 ,2-dicarboxamide,

[0294] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinazolin-4-yl)cyclopropane-l,2-dicarboxamide,

[0295] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinazolin-2-yl)cyclopropane-l,2-dicarboxamide,

[0296] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-5-yl)cyclopropane-l,2-dicarboxamide,

[0297] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- methoxyquinolin-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0298] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(8-methylquinolin-5-yl)cyclopropane-l,2-dicarboxamide,

[0299] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(3- methoxyquinolin-6-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0300] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylquinolin-7-yl)cyclopropane-l,2-dicarboxamide,

[0301] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-

[0302] (isoquinolin-6-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-6-yl)cyclopropane- 1 ,2-dicarboxamide,

[0303] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methyl-l,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-l,2-dicarboxamide,

[0304] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-l,2-dicarboxamide,

[0305] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-5-yl)cyclopropane-l,2-dicarboxamide,

[0306] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroisoquinolin-6-yl)cyclopropane-l,2-dicarboxamide,

[0307] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-6-yl)cyclopropane-l,2-dicarboxamide, tert-butyl 4-(3-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)-3,4- dihydroisoquinoline-2(lH)-carboxylate,

[0308] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-4-yl)cyclopropane- 1 ,2-dicarboxamide,

[0309] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-2-yl)cyclopropane- 1 ,2-dicarboxamide,

[0310] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-3-yl)cyclopropane-l,2-dicarboxamide,

[0311] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinoxalin-6-yl)cyclopropane-l,2-dicarboxamide,

[0312] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(phthalazin-5-yl)cyclopropane-l,2-dicarboxamide,

[0313] Nl-(cinnolin-7-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0314] Nl-(cinnolin-6-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0315] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(phthalazin-6-yl)cyclopropane- 1 ,2-dicarboxamide,

[0316] Nl-(cinnolin-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylcinnolin-5-yl)cyclopropane-l,2-dicarboxamide,

[0317] Nl-(cinnolin-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0318] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylquinoxalin-2-yl)cyclopropane-l,2-dicarboxamide,

[0319] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,5-naphthyridin-2-yl)cyclopropane-l,2-dicarboxamide,

[0320] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,7-naphthyridin-3-yl)cyclopropane-l,2-dicarboxamide,

[0321] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- methoxy-l,5-naphthyridin-4-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0322] Nl-(acridin-9-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0323] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclobutane- 1 ,2-dicarboxamide,

[0324] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclopentane- 1 ,2-dicarboxamide,

[0325] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclohexane-l,2-dicarboxamide,

[0326] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)-Nl,3,3-trimethylcyclopropane-l,2-dicarboxamide,

[0327] Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)-Nl,N2,3,3-tetramethylcyclopropane-l,2-dicarboxamide,

[0328] Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)-2- methylphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0329] Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- methylphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0330] Nl-(4-fluorophenyl)-N2-(6-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyridin-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0331] Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyri din-2 -yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0332] Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrimidin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrazin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0333] (lS,2R)-Nl-(2-fluoro-5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-

[0334] N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0335] Nl-(3-fluoro-4-((7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-

[0336] N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0337] Nl-(3-fluoro-4-((7-(2-hydroxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0338] Nl-(3-fluoro-4-((7-(2-isopropoxyethoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0339] Nl-(3-fluoro-4-((7-(3-hydroxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0340] Nl-(3-fluoro-4-((7-(3-methoxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0341] Nl-(3-fluoro-4-((7-(3-isopropoxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0342] Nl-(4-((7-(3-(tert-butoxy)propoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0343] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0344] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-tetrahydrofuran-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0345] Nl-(3-fluoro-4-((7-(((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)oxy)-6-

[0346] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0347] Nl-(3-fluoro-4-((7-(((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl)oxy)-6-

[0348] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0349] Nl-(4-((7-(((R)-l,4-dioxan-2-yl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0350] Nl-(4-((7-(((S)-l,4-dioxan-2-yl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0351] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-2-oxopyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-2-oxopyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-pyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-pyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 3-(((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)azetidine- 1 -carboxylate,

[0352] Nl-(4-((7-(azetidin-3-ylmethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0353] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(trifluoromethoxy)quinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0354] Nl-(4-((7-(difluoromethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0355] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2,2,2-trifluoroethoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane- l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7-yl)oxy)piperidine-l -carboxylate, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(piperidin-4-yloxy)quinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0356] Nl-(4-((7-((l-acryloylpiperidin-4-yl)oxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (2-((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)ethyl)carbamate,

[0357] Nl-(4-((7-(2-aminoethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0358] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2-(piperazin-l-yl)ethoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0359] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2-(4-methylpiperazin-l-yl)ethoxy)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0360] Nl-(4-((7-(3-aminopropoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(3-(piperazin-l-yl)propoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0361] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (l-(((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)cyclopropyl)carbamate,

[0362] Nl-(4-((7-((l-aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-((tetrahydro-2H-pyran-4- yl)methoxy)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- di carb oxami de,

[0363] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-((3-methyloxetan-3-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0364] Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-oxetan-2-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-oxetan-2-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0365] Nl-(3-fluoro-4-((6-((2 -hydroxy ethoxy)carbamoyl)-7-methoxy quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0366] Nl-(3-fluoro-4-((7-methoxy-6-((methoxy-d3)carbamoyl)quinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0367] Nl-(4-((6-(((R)-2,3-dihydroxypropoxy)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0368] Nl-(4-((6-(((S)-2,3-dihydroxypropoxy)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,

[0369] N 1 -(3 -fluoro-4-((7 -methoxy-6-(( 1 -(2-methyl- 1 -(neopentylamino)propan-2-yl)- 1 H- imidazol-4-yl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,

[0370] (lS,2R)-Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(3-morpholinopropoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, and (lS,2R)-Nl-(3-fluoro-4-((6-(hydroxycarbamoyl)-7-methoxyquinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or combination thereof.

[0371] DETAILED DESCRIPTION OF THE INVENTION

[0372] The present invention provides quinoline compounds, which are modulating kinase enzymatic activity and processes for the synthesis of these compounds and their pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of cancer.

[0373] The following definitions apply to the terms as used herein:

[0374] The term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 2-methylpropyl (isobutyl), n-pentyl, and 1,1 -dimethylethyl (t-butyl). Alkyl group can be substituted or unsubstituted with one or more suitable groups.

[0375] The term “alkenyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms having at least one -C=C-, for example, a C2-C6 alkenyl group may have from 2 to 6 (inclusive) -C=C- atoms in it. Examples of C2-C6 alkenyl groups include, but are not limited to ethylene, prop-l-ene, but-1- ene, but-2-ene, pent-l-ene, pent-2-ene, hex-l-ene, hex-2-ene and the like.

[0376] The term “alkoxy” refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon and hydrogen atoms, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., methyloxy, ethyloxy, n-propyloxy, 1 -methylethyloxy (isopropyl oxy), n-butyloxy, n-pentyloxy, and 1,1 -dimethylethyloxy (t-butyloxy).

[0377] The term “aryl” refers to an aromatic radical having from 6 to 14 carbon atoms such as but are not limited to, phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. The aryl group can be substituted or unsubstituted. If it is substituted the substituents are independently selected from one or more alkyl, deuteroalkyl, haloalkyoxy, alkenyl, cycloalkyl, halo, hydroxyl, alkoxy, cyano, nitro, amino, acetyl, -N(H)-acetyl, S(O)2-alkyl, thiol, thioalkyl, aminoalkyl or heterocyclyl.

[0378] The term "arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with aryl group as defined above. Representative examples of arylalkyl group include, but are not limited to phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl and the like. Arylalkyl group can be substituted or unsubstituted with one or more suitable groups.

[0379] The term “cyano” group refers to a -CN group.

[0380] The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl. Cycloalkyl group can be substituted or unsubstituted with one or more suitable groups.

[0381] The term "Cycloalkylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with cycloalkyl group as defined above. Representative examples of a cycloalkylalkyl group include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. A cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.

[0382] The term, "cycloalkyloxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Representative examples of a cycloalkyloxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and the like.

[0383] The term “Deuteroalkyl” refers to an alkyl group in which one or more hydrogen atoms have been replaced by deuterium (2H or D). In some embodiments, "deuteroalkyl" specifically refers to a trideuteriomethyl group ( — CDs), that is, a methyl group where all three hydrogen atoms are replaced with deuterium. Unless otherwise indicated, the term "deuteroalkyl" includes both partially and fully deuterated alkyl groups, with particular emphasis on fully deuterated methyl ( — CDs) groups.

[0384] The term, "deuteroalkyloxy" refers to an -O-deuteroalkyl group, wherein the deuteroalkyl group is as defined above. Representative examples of a deuteroalkyloxy group include -OCD3, -OC(H)D2, -OCD2(H) and the like.

[0385] The term “amino” represents -NH2.

[0386] The term “alkylamino” refers to an amino group substituted with one or more “alkyl” group, wherein the alkyl group and amino group is as defined above. Examples of “alkylamino” groups include but are not limited to -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CEE)(CE12CEE) and the like.

[0387] As used herein, the term “alkylaminoalkyl” means alkyl substituted with one or more “alkylamino” groups, wherein the alkyl group and alkylamino group is as defined above. Examples of “alkylaminoalkyl” groups include but are not limited to -CH2NH(CH3), - (CH2)n- NH(CH3), -CH2CH(CH3)N(CH3)2, - (CH2)n-N(CH3)2, -CH2NHCH3, -CH2NHCH2CH3, - (CH2)nN(CH3)2, -CH2N(CH3)(CH2CH3) and the like.

[0388] The term “nitro” represents -NO2.

[0389] The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.

[0390] The term “hydroxy” group refers to an -OH group.

[0391] The term “hydroxyalkyl” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl group. In one embodiment, hydroxyalkyl contains (Ci-Ce)alkyl and preferably (Ci-C4)alkyl. Examples of hydroxyalkyl moieties include but are not limited to -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, -CH(CH3)CH2OH, CH3CH(CH3)CH2-OH, CH3CH(OH)-CH-CH2-

[0392] The term “haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). Example haloalkyl groups include CF3, CH2-CF3, C2F5, CHF2, CH2F, CC13, CHCh, C2CI5 and the like.

[0393] The term “haloalkyloxy” refers to an -O-haloalkyl group, wherein the haloalkyl group is as defined above. Representative examples of a haloalkyloxy group include -OCF3, -O- CH2CF3, -OCHF2, -OCH2F and the like.

[0394] The term “heteroaryl” refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples, of heteroaryl groups are acridinyl, furyl, thienyl, benzothienyl, cinnolinyl, isoxazolyl, benzothiazolyl, thiadiazolyl, thiazolyl, imidazolyl, imidazopyridinyl, oxazolyl, oxadiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrrolopyridazine, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, purinyl, carbazolyl, phthalazinyl, benzothiophenyl, lH-imidazol-5-amine, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 1,5-naphthyridinyl, 1,7-naphthyridinyl, 4,5,6,7-tetrahydrothiazolo[5,4- c]pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2,3,4- tetrahydroisoquinolinyl, indolinyl, indazolyl, indolyl, isoindolyl, thiophenyl, pyrazinyl, pyridazinyl, diazinyl, triazinyl, and tetrazinyl. A cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups. If it is substituted the substituents are selected from alkyl, alkenyl, cycloalkyl, halo, hydroxyl, alkoxy, cyano, nitro, amino, acetyl, -N(H)- acetyl, S(O)2-alkyl, thiol, thioalkyl, aminoalkyl or heterocyclyl. The term "heterocyclyl" refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, or NH with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A monocyclic heterocyclyl may typically contain 4 to 7 ring atoms. Examples of “Heterocyclyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 1 -methyl piperazinyl, ppyrrolidin-2-one, tetrahydropyranyl, morpholinyl, thiomorpholinedioxide, oxapiperazinyl, tert-butyl piperazine- 1 -carboxylate, isoindoline-1, 3-dione, 3-methylimidazo[5,l- d] [ 1 ,2,3 , 5 ]tetrazin-4(3H)-one, 1 -(piperazin- 1 -yl)prop-2-en- 1 -one, 1 -(piperazin- 1 -yl)propan- 1-one , oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl, pyrrolidin-2-one, 1,2,3,4-tetrahydroisoquinolinyl, 2,3- dihydro-l,4-dioxinyl, 1,4,7,10-tetraoxacyclododecanyl, (3as,6as)-hexahydrofuro[2,3- b]furanyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via either a carbon atom or a heteroatom. A cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.

[0395] The term “heterocyclylalkyl” is same as “heterocyclyl” refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, or NH with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, sulfur and the heterocyclyl group was linked to alkyl chain. The examples of alkyl chain include but not limited to methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n- butyl, n-pentyl, and 1,1 -dimethylethyl (t-butyl). The Examples of “Heterocyclylalkyl” include, but are not limited to propylpyperazinyl, (S)-2-methyl-l,4-di oxane, 4-methylpiperidinyl, 3- methyloxetanyl, ethylpyperazinyl, (S)-2-methyloxetanyl, 4-methyltetrahydro-2H-pyranyl, methylazetidinyl, 3-methylazetidinyl, 2-methyltetrahydro-2H-pyranyl, and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via either a carbon atom or a heteroatom. A heterocyclylalkyl group can be unsubstituted or substituted with one or more suitable groups.

[0396] The term “substituted” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but are not limited to: hydroxy, halo, carboxyl, cyano (CN), nitro, oxo (=0), thio (=S), alkyl, methyl sulfonyl, haloalkyl, alkoxy, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, amino, -C(O)O-alkyl, heterocyclyl, CH3-C(O)-, methoxy, heteroaryl, heterocyclylalkyl, heteroarylalkyl, alkylthio, arylthio, aryloxy, amino carbonyl, alkoxycarbonyl, alkylamino, arylamino, acyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, and aliphatic. It is understood that the substituent may be further substituted.

[0397] The term "prodrug" denotes a derivative of a compound, which derivative, when administered to warm blooded animals, e.g. humans, is converted into the compound (drug). The enzymatic and / or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. For example, a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0398] The term "treating" or "treatment" of a state, disease, disorder or condition includes:

[0399] (1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;

[0400] (2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or

[0401] (3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.

[0402] The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.

[0403] The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

[0404] A "therapeutically effective amount" means the amount of a compound that, when administered to a subj ect for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.

[0405] The compounds of the present invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the formula (I), the present invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereo isomeric forms of the present invention may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

[0406] In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labelled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H ("D"),3H,nC,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36C1,123I and125I. Particular isotopes are -CD3 or -C(D2)-. Isotopically-labelled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an isotopically-labelled reagent for a non- isotopically-labelled reagent.

[0407] PHARMACEUTICAL COMPOSITIONS

[0408] The pharmaceutical compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.

[0409] The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.

[0410] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.

[0411] The carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0412] The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick-, sustained-, or delayed-release of the active ingredient after administration to the subject by employing procedures known in the art.

[0413] The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20thEd., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, or sachet. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.

[0414] The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.

[0415] The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is specifically suitable.

[0416] Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Exemplary carriers for tablets, dragees, or capsules include lactose, cornstarch, and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

[0417] A typical tablet that may be prepared by conventional tableting techniques.

[0418] Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

[0419] For parenteral application, particularly suitable are injectable solutions or suspensions, specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

[0420] METHODS OF TREATMENT

[0421] The compounds of the present invention can inhibit, regulate, and / or modulate tyrosine kinases such as KDR (VEGFR2), MET (C-MET), RET, AXL, TEK (Tie 2), EGFRs. The present disclosure relates to quinoline compounds for use in modulating kinase enzymatic activity and accordingly modulating kinase-dependent associated diseases and conditions such as cancers like Lung, Thyroid carcinoma, Ovarian carcinoma, Pancreatic carcinoma, Prostatic carcinoma, Renal cell carcinoma, Liver, Skin cancer, Hepatocellular carcinoma, Breast carcinoma, Colorectal carcinoma, Oral squamous cell carcinoma, Lung adenocarcinoma or Endometrial cancer. Gastro intestinal cancers (GIST), colon cancer or Brain cancer.

[0422] In certain embodiments, the present invention provides uses of a compound of the present invention for the preparation of a medicament, e.g., for the treatment of cancer.

[0423] In certain embodiments, the present invention provides methods for treating cancer, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

[0424] In certain embodiments, the present invention provides methods for inhibiting growth of tumor cells and / or metastasis by administering a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

[0425] Representative tumor cells include cells of a cancer such as but not limited to breast cancer, prostate cancer, melanoma, renal cancer, colon cancer and lung cancer, skin cancer, bone cancer, pancreatic cancer, head and neck cancer, intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of the cervix, Hodgkin's lymphoma, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethra cancer, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney cancer, renal pelvis carcinoma, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), SCLC, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer.

[0426] The compounds of the present invention may be used as single drugs (monotherapy) or combination with one or more other agents (Combination therapy). The compounds may be used by themselves, or preferably, in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials.

[0427] The compounds of the present invention may be administered in combination with one or more other drugs (1) to complement and / or enhance effect of the compound of the present invention, (2) to modulate pharmacodynamics, improve absorption, or reduce dosage of the compound of the present invention, and / or (3) to reduce or ameliorate the side effects of the compound of the present invention. As used herein, the phrase "Combination administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. The respective compounds may be administered by the same or different route and the same or different method.

[0428] The compounds of the present invention directed to the treatment of cancer, the compound of the present invention can be used with an existing chemo therapeutic conjointly using a single pharmaceutical composition or a combination of different pharmaceutical compositions concomitantly or in a mixture form. Examples of the chemotherapeutic include an alkylation agent, nitrosourea agent, antimetabolite, anticancer antibiotics, vegetable-origin alkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist, aromatase inhibitor, P- glycoprotein inhibitor, platinum complex derivative, other immunotherapeutic drugs and other anticancer drugs. Further, it a compound of the invention can be used administered conjointly with a cancer treatment adjunct, such as a leucopenia (neutropenia) treatment drug, thrombocytopenia treatment drug, antiemetic and cancer pain intervention drug, concomitantly or in a mixture form. Chemotherapeutic agents that may be conjointly administered with compounds of the invention, with one or more of the drugs , but not limited to : amsacrine, aminoglutethimide, asparaginase, anastrozole, Apalutamide, Enzalutamide, bicalutamide, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

[0429] In certain embodiments, the compound of the present invention of Formula (I), (IA), (IB), (IC), (ID) and (IE) conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be conjointly administered with radiation therapy. In certain embodiments, a compound of the invention may be conjointly administered with surgery, with radiofrequency, microwave, laser, high-intensity focused ultrasound, cryoablation, and irreversible electroporation or with any combination of these.

[0430] In certain embodiments, the compound of the present invention of Formula (I), (IA), (IB), (IC), (ID) and (IE) may be administered in combination with one or more other kinase inhibitors like MEK, EGFR, CDK, Bruton kinase, KRAS, ALK, PI3K, BRAF, BCR-ABL, ROS1, FGFR, JAK, PARP, or any which show better efficacy / outcome, complimentarily, in combinations in certain cancers, where two or more MOA.

[0431] The drugs for combination therapy include, for example, antibiotics, antifungal agents, sedatives, anesthetics, antiulcer drugs, antidepressants, anti arrhythmic agents, antiprotozoal agents, tranquilizers, hypotensive diuretic drugs, anticoagulants, antipsychotics, muscle relaxants, antiepileptic drugs, hypotensive diuretics, antitussives and expectorant drugs, antiallergic drugs, antinarcotics, cardiac stimulants, therapeutic drugs for arrhythmia, vasodilators, vasoconstrictors, therapeutic drugs for diabetes, vitamins, antiasthmatics, therapeutic agents for atopic dermatitis, antipruritic drugs, therapeutic agents for allergic rhinitis, hyper tensors, endotoxin-antagonists or -antibodies, signal transduction inhibitors, inhibitors of anti-inflammatory mediator activity, inhibitors of inflammatory mediator activity, antibodies to inhibit inflammatory mediator activity, antibodies to inhibit anti-inflammatory mediator activity and the like.

[0432] In any one of the foregoing embodiments, the cancer or proliferative disorder is selected from a solid tumor, malignant tumor, brain cancer, kidney cancer, liver, stomach, vagina, ovaries, gastric tumors, endometrial cancer breast, bladder colon, prostate, pancreas, lung, cervix, testis, skin, bone or thyroid; sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, Hodgkins and Non-Hodgkins lymphomas, a mammary carcinoma, follicular carcinoma, papillary carcinoma, seminoma.

[0433] In certain embodiments the compounds of the present invention can be chemically linked to monoclonal antibody or Bispecific Antibodies generally called as Antibody Drug Conjugates (ADCs). Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. ADCs combine the targeting properties of monoclonal antibodies with the cancer-killing capabilities of cytotoxic drugs. Unlike conventional chemotherapy treatments, which can damage healthy cells, antibody drug conjugates (ADCs) are targeted medicines that deliver chemotherapy agents to cancer cells. ADCs deliver the chemotherapy via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. After binding to the target (cancer protein or receptor), the ADC releases a cytotoxic drug into the cancer cell. Such examples of cleavable or non- cleavable linkers are (6-maleimidocaproyl) hydrazone, 4-(4-acetylphenoxy) butanoic acid, a disulfide-containing ADC, Peptide-based linkers, also known as lysosomal protease-sensitive linkers, such as valine-citrulline (Val-Cit), phenylalanine-lysine (Phe-Lys), and valinealanine (Vai-Ala) dipeptide linkers, are the most widely used linkers in ADC design, Glycosidase-Sensitive Linkers like P-Glucuronidase-cleavable linkers, Phosphatase-Cleavable Linkers and Non-cleavable linkers like thioether or maleimidocaproyl (MC).

[0434] In certain embodiments the compounds of the present invention can be linked to protein degraders through a linker generally called as proteolysis-targeting chimera (PROTAC) protein degraders. A major class of molecules that enable such proteins to be modulated through TPD (Target Protein Degraders) are known as proteolysis-targeting chimera (PROTAC) protein degraders. These are hetero bifunctional small molecules consisting of two ligands joined by a linker: one ligand recruits and binds a protein of interest (POI) while the other recruits and binds an E3 ubiquitin ligase. Simultaneous binding of the POI and ligase by the PROTAC induces ubiquitylation of the POI and its subsequent degradation by the ubiquitin-proteasome system (UPS), after which the PROTAC is recycled to target another copy of the POI. It is this catalytic-type mechanism of action (MoA) and event-driven pharmacology that distinguishes PROTACs from classical inhibitors, which have a one-to-one relationship with the POI and whose pharmacology is driven by stoichiometry and, usually, by interactions with a catalytic site; (Nature Reviews Drug Discovery volume 21, page 181 200; 2022).

[0435] METHODS OF PREPARATION

[0436] Compounds of the present invention can be prepared by using synthetic methods which are well established in chemical synthesis of organic compounds. Key intermediates required for synthesizing analogues are either commercially available, or can be prepared by the methods published in the literature. For example, the key intermediates in the present invention were prepared by modifying the procedures published in Front Chem. 2022; 10: 1074331, HETEROCYCLES, Vol. 93, No. 1, 2016. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and / or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

[0437] Another embodiment of the present invention provides process for preparation of the compounds of present invention are set forth in the below generalized schemes. One of skilled in the art will recognize that below generalised schemes can be adapted to produce the compounds of present invention and pharmaceutically acceptable salts according to the present invention. Wherein all symbols / variables are as defined earlier unless otherwise stated.

[0438] Scheme-I:

[0439] Ri, R2, R3, R4, Re, ring A, ring B, ‘m’ and ‘n’ are as defined in compound of formula (I).

[0440] * Represents chiral centres.

[0441] The compound of formula (i) was converted to the compound of formula (ii) with reagents like thionyl chloride and catalytic amount of DMF under reflux conditions or the like. The chloroquinoline compounds of formula (ii) was converted to the compounds of formula (iv) by reacting with compounds of formula (iii) with bases such as DIPEA or the like in solvents such as N-Methyl-2-pyrrolidone or the like at heating conditions. The compounds of formula (iv) were converted to the compounds of formula (v) with reducing agent such as Iron powder, under acidic conditions with reagents like acetic acid or ammonium chloride in solvents such as methanol or ethanol and water or the like at heating conditions. The compounds of formula (v) were converted to the compounds of formula (vi) by reacting with reagent such as 30 or 40% aqueous methylamine or the like in solvent such as N-Methyl-2- pyrrolidone or the like. The compounds of formula (vi) were converted to the compounds of Formula (I) by coupling with compounds of formula (vii) with reagents such as EDC.HC1 or T3P or the like and catalyst such as 4-Dimethylamino pyridine (DMAP) or the like in solvents such as Dichloromethane (DCM) or N-Methyl-2-pyrrolidone (NMP) or the like. Both the isomers of the compounds of formula (A) are separated by using the technique chiral HPLC. Scheme-II:

[0442] Ri, R4, Ra, Rb, ring B, ‘m’ and ‘n’ are as defined in compound of formula (I).

[0443] * Represents chiral centres.

[0444] The compound of formula (i) was converted to the compound of formula (ii) with reagents like thionyl chloride and catalytic amount of DMF under reflux conditions or the like. The chloroquinoline compounds of formula (ii) was converted to the compounds of formula (iv) by reacting with compounds of formula (iii) with bases such as DIPEA or the like in solvents such as N-Methyl-2-pyrrolidone or the like at heating conditions. The compounds of formula (iv) were converted to the compounds of formula (v) with reducing agent such as Iron powder, under acidic conditions with reagents like acetic acid or ammonium chloride in solvents such as methanol or ethanol and water or the like at heating conditions. The compounds of formula (v) were converted to the compounds of formula (vii) by coupling with compounds of formula (vi) with reagents such as EDC.HC1 or T3P or the like and catalyst such as 4-Dimethylamino pyridine (DMAP) or the like in solvents such as Dichloromethane (DCM) orN-Methyl-2-pyrrolidone (NMP) or the like. The compounds of formula (vii) were converted to the compounds of formula (viii) by using the bases such as LiOH, NaOH or KOH in solvents such as combination of Methanol, THF and water or the like. The compounds of formula (viii) were converted to the compounds of Formula (B) by coupling with compounds of formula (ix) with reagents such as HATU, EDC.HC1 or T3P or the like and bases such as DIPEA or the like and catalysts such as 4-Dimethylamino pyridine (DMAP) or the like in solvents such as DMF, Dichloromethane (DCM) or N-Methyl-2-pyrrolidone (NMP) or the like. Scheme-Ill:

[0445] Ri, R4, Rc, Rd, Re, Rf, ring B, ‘m’, ‘n’ and ‘p’ are as defined in compound of formula (I).

[0446] * Represents chiral centres.

[0447] The compounds of formula (i) were converted to the compounds of formula (C) by coupling with compounds of formula (ii) with reagents such as HATU, EDC.HC1 or T3P or the like and bases such as DIPEA or the like and catalysts such as 4-Dimethylamino pyridine (DMAP) or the like in solvents such as DMF, Dichloromethane (DCM) or N-Methyl-2- pyrrolidone (NMP) or the like.

[0448] Scheme-IV:

[0449] Ri, R4, RC ring B, ‘m’ and ‘n’ are as defined in compound of formula (I).

[0450] * Represents chiral centres and ‘LG’ leaving groups

[0451] The compounds of formula (i) were converted to the compounds of formula (iii) by coupling with compounds of formula (ii) with reagents such as EDC.HC1 or T3P or the like and catalysts such as 4-Dimethylamino pyridine (DMAP) or the like in solvents such as Dichloromethane (DCM) or N-Methyl-2-pyrrolidone (NMP) or the like. The compounds of formula (iii) were converted to the compounds of formula (iv) by reacting with reagent such as BCh (1.0M) or BBn (1.0M) in solvents such as DCM or the like. The compounds of formula (iv) were converted to the compounds of Formula (D) by coupling with compounds of formula (v) with bases such as Potassium carbonate or Cesium carbonate or the like in solvents such as Acetonitrile or DMF or DMA or the like under heating conditions.

[0452] ABBREVIATIONS:

[0453] The abbreviations used in the entire specification may be summarized herein below with their particular meaning:TH NMR (Proton Nuclear Magnetic Resonance); Hz (hertz); MHz (megahertz); 5 (delta); ppm (parts per million); CDCls (deuterated chloroform or chloroform-d), CD3OD (methanol-d4); DMSO-de (Dimethylsulfoxide-de); s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet of doublet(s)); dt (doublet of triplet(s)); J (coupling constant); JAB (coupling constant); ABq (AB quartet); brs (broad singlet); ml (millilitre); °C (degree Celsius); mol (mole(s)); mmol (millimole(s)); M (Molar solution); N (Normal solution); g (gram(s)); pH (Potential of Hydrogen); eq (equivalent(s)); psi (pound per square inch); ES-MS (Electrospray ionization mass spectrometry); m / z (mass-to-charge ratio of an ion); M-H- (parent mass spectrum peak minus hydrogen-); M+Na+ (parent mass spectrum peak plus sodium+); M+H+ (parent mass spectrum peak with an added proton); DCM (Dichloromethane); DMF (N,N-dimethylformamide); DMA (N,N-dimethylacetamide); THF (Tetrahydrofuran); Na2SO4 (sodium sulphate); IN HC1 (1 Normal Hydrochloric acid); TLC (Thin Layer Chromatography); % (percentage); RB flask (Round bottom flask); TBAF (Tetra- n-butylammonium fluoride); NaOH (sodium hydroxide); KOH (potassium hydroxide); EDC.HC1 (1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide Hydrochloride); MTBE (Methyl tert-butyl ether); HATU (l-H-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); h (or) hrs (hour(s)); H (Hydrogen); APCLMS (Atmospheric-pressure Chemical ionization mass spectroscopy); DMAP (4-Dimethylaminopyridine); TBDMSC1 (tert-butyldimethylsilyl chloride); T3P (Propanephosphonic acid anhydride or 1-propanephosphonic anhydride); DIPEA (N,N-Diisopropylethylamine or N-ethyl-N-isopropylpropan-2-amine); EtsN (Triethylamine); HPLC (High-Performance Liquid Chromatography); Pd / C (Palladium on Carbon); ACN (Acetonitrile); BCh (boron trichloride); TBAI (Tetrabutylammonium iodide); BCh (boron tribromide); XRD (X-ray Diffraction); EtOAc (Ethyl acetate); POCI3 (phosphorous oxychloride): Ltr (Liter / Litre), NaHCCh (sodium bicarbonate); SOCh (Thionyl chloride); NMP (N-methyl-2-pyrrolidone); 2M (2 Molar); TFA (Trifluoroacetic acid); VEGFR (Vascular Endothelial Growth Factor Receptor); EGFR (Epidermal Growth Factor Receptor)

[0454] EXPERIMENTAL PROCEDURES The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.

[0455] INTERMEDIATES

[0456] Intermediate 1 : i-2,2- dimethylcyclopropane-l -carboxylic acid:

[0457] Step 1: Synthesis of Racemic 3-((4-jluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxylic acid:

[0458] Method 1 :

[0459] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (100 g, 713.57 mmol, 1.0 eq) in THF (1000 ml) was added 4-methylbenzenesulfonic acid (13.5 g, 71.35 mmol, 0.1 eq) followed by 4-fluoroaniline (79.2 g, 713.57 mmol, 1.0 eq) slowly over a period of 1 hour. The reaction mixture was stirred at room temperature for about 5 hours. TLC indicated starting material was completed and the desired product was observed. The reaction mixture was evaporated under reduced pressure. Water was added to the residue, stirred at room temperature for about 3 hours. The precipitate formed was filtered, washed with water and dried under vacuum. The obtained solid was further purified by treating with Methyl-ter- butyl ether: Hexane (1000 ml, 1 :9 ratio), stirred at room temperature for about 1 hour. Solid was filtered, washed with n-Hexane and dried under vacuum to obtain the title compound (150 g, yield: 83.7%) as an off-white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 12.16 (s, 1H), 10.14 (s, 1H), 7.57 (dd, J = 9.0, 5.0 Hz, 2H), 7.11 (t, .7= 9,0 Hz, 2H), 1.98 (d, J = 9.5 Hz, 1H), 1.88 (d, J= 9.0 Hz, 1H), 1.32 (s, 3H), 1.19 (s, 3H); Mass: m / z 252.22 (M+H)+.

[0460] Method 2:

[0461] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (20 g, 142.71 mmol, 1.0 eq) in THF (120 ml) was added 4-fluoroaniline (13.52 ml, 142.71 mmol, 1.0 eq) mixed in THF (20 ml) dropwise over a period of 20 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. Reaction mass was evaporated under reduced pressure until no more THF was distilled out. The resulting solid was stirred with water (200 ml) at room temperature for about 1 hour. Solid was filtered, washed with water (40 ml) and then dried under vacuum. The obtained compound was further dried under vacuum at 50-55 °C for around 2 hours to afford the title compound (30.47 g, yield: 85%) as an off-white solid.

[0462] Step 2: Synthesis of (lS,3R)-3-((4-jluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxylic acid:

[0463] Racemic 3 -((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l -carboxylic acid (Step 1, 150 g, 596.99 mmol, 1.0 eq) and propan-2-ol (3.75 Ltr) were stirred at 80-85 °C for around 1 hour. After getting clear solution, (S)-l-phenylethan-l -amine (72.3 g, 596.99 mmol, 1.0 eq) was added at 80-85 °C and stirred at same temperature for around 3 hours. Reaction mixture allowed to stir at room temperature for overnight. The obtained solid was filtered, washed with propan-2-ol (375 ml) and dried under vacuum. Solid was taken into RB flask, Isopropanol (1200 ml) was added, stirred at room temperature for about 2 hours. Solid was filtered, washed with propan-2-ol (125 ml) and dried under vacuum. Solid was cooled to 0 °C, acidified with IN HC1 and extracted with DCM (2x800 ml). The combined organic layer was washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain title compound (50 g, yield: 33.3%) as an off-white solid. Enantiomeric purity by chiral HPLC: >99%. Stereochemistry of the product was confirmed by Single crystal X-ray diffraction (XRD) analysis.1HNMR (500 MHz, DMSO-de): 5 ppm 12.17 (s, 1H), 10.15 (s, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.11 (t, J= 9.0 Hz, 2H), 1.99 (d, J= 9.5 Hz, 1H), 1.88 (d, J= 9.5 Hz, 1H), 1.33 (s, 3H), 1.19 (s, 3H); Mass: m / z 252.35 (M+H)+.

[0464] Intermediate 2: Preparation of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6- carb oxy late:

[0465] Step 1: Synthesis of methyl 4-chloro-7-methoxyquinoline-6-carboxylate:

[0466] To a stirred solution of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (6.0 g, 23.84 mmol, 1.0 eq) in thionyl chloride (15 ml) at 0 °C was added DMF (0.184 ml, 2.384 mmol, 0.1 eq). The reaction mixture was heated to reflux for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate solution and extracted with DCM (2x50 ml). The combined organic layer was washed with water, dried over sodium sulphate, filtered and concentrated under vacuum. The crude compound was washed with MTBE (50 ml), filtered and dried under vacuum to obtain the title compound (5 g, yield: 83.47%) as a solid. ’H NMR (500 MHz, CDCh): 5 ppm 8.765 (d, J = 5.0 Hz, 1H), 8.63 (s, 1H), 7.53 (s, 1H), 7.405 (d, J= 4.5 Hz, 1H), 4.05 (s, 3H), 4.0 (s, 3H); Mass: m / z 251.9 (M)+.

[0467] Step 2: Synthesis of methyl 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate :

[0468] To a stirred solution of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (Step 1, 5 g, 19.89 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (NMP) (20 ml) was added 2-fhioro-4- nitrophenol (4.117 g, 26.20 mmol, 1.31 eq) and N-ethyl-N-isopropylpropan-2-amine (12.67 ml, 70.56 mmol, 3.54 eq). The reaction mixture was stirred at 140 °C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, ice water (200 ml) was added, the precipitate formed was collected by filtration and dried under vacuum to obtain the title compound (5.8 g, yield: 78.37%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.785 (d, J = 5.0 Hz, 1H), 8.56 (s, 1H), 8.48 (dd, J = 10.5, 3.0 Hz, 1H), 8.24 (dd, J= 9.0, 1.0 Hz, 1H), 7.75 (t, J = 8.5 Hz, 1H), 7.60 (s, 1H), 6.81 (d, J= 5.5 Hz, 1H), 4.0 (s, 3H), 3.87 (s, 3H); Mass: m / z 372.79 (M)+.

[0469] Method 1 :

[0470] To a stirred solution of methyl 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate (Step 2, 5.8 g, 15.578 mmol, 1.0 eq) in ethanol (58 ml) was added Iron powder (3.48 g, 62.312 mmol, 4.0 eq) and acetic acid (1.15 ml, 20.251 mmol, 1.36 eq). The reaction mixture was heated to reflux for about 8 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through celite bed and washed with ethanol. The filtrate was evaporated under reduced pressure, basified with saturated sodium bicarbonate solution (50 ml) and extracted with DCM (2x50 ml). The combined organic layer was washed with water (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 1.5% methanol in di chloromethane eluent to afford the title compound (3.5 g, yield: 65.66%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.69 (d, J= 5.5 Hz, 1H), 8.59 (s, 1H), 7.53 (s, 1H), 7.11 (t, = 9.0 Hz, 1H), 6.57 (dd, J= 13.5, 2.5 Hz, 1H), 6.49-6.47 (m, 2H), 5.53 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H); Mass: m / z 342.73 (M)+.

[0471] Method 2:

[0472] To a suspension of methyl 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate (95 g, 255.16 mmol, 1.0 eq) in Methanol (475 ml) and water (95 ml) was added Iron powder (71.25 g, 1275.8 mmol, 5.0 eq). Acetic acid (95 ml) was slowly added over a period of 1 hour. Exothermic reaction. Internal temperature rises to 50-60 °C. Reaction mass was further heated at 50-60 °C for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to room temperature. Ethyl acetate (2 Ltr) was added, stirred at room temperature for about 1 hour. Reaction mass was filtered through celite bed and washed with 10% methanol : ethyl acetate (1 Ltr). The filtrate was basified with 5% sodium bicarbonate solution to until around pH 8.0. Organic layer was separated, and the aqueous layer was extracted with EtOAc (2x500 ml). The combined organic layer was washed with water (1 Ltr), dried over sodium sulphate, filtered and concentrated under reduced pressure. Methanol (475 ml) was added to the obtained solid, stirred at room temperature for about 2 hours. Solid was filtered, washed with methanol (95 ml) and then dried under vacuum to obtain the title compound (45 g) as a pale-yellow solid.

[0473] Intermediate 3: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline- 6-carboxamide:

[0474] To a stirred solution of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6- carboxylate (Intermediate-2, 7 g, 20.44 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (35 ml) was added 30% aqueous methylamine (49 ml). Reaction mass was stirred at room temperature for 3 hours. TLC indicated starting material was completed. Reaction mass was cooled to 0-10 °C, water (420 ml) was added, stirred at 0-10 °C for 1 hour. Solid was filtered, washed with water (350 ml) and dried in vacuo. Crude solid was stirred with methanol (35 ml) at room temperature for 1 hour. Solid was filtered, washed with methanol (7 ml) and dried in vacuo to obtain the product (5.3 g, 75.9% yield) as a brown colour solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.645 (d, J= 5.0 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J = 4.5 Hz, 1H), 7.50 (s, 1H), 7.09 (t, J = 8.5 Hz, 1H), 6.55 (dd, J= 13.5, 2.5 Hz, 1H), 6.48-6.44 (m, 2H), 5.51 (s, 2H), 4.01 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H); Mass: m / z 342.12 (M+H)+.

[0475] Intermediate 4: Preparation of 2-acrylamidoethan-l-aminium 2,2,2-trifluoroacetate:

[0476] Step 1: Synthesis of tert-butyl (2 -aminoethyl) carbamate:

[0477] A solution of di-tert-butyl dicarbonate (2.18 g, 2.29 ml, 9.98 mmol, 0.166 eq) in DCM (120 ml) was added dropwise to a solution of ethane- 1,2-diamine (3.60 g, 59.9 mmol, 1.0 eq) in DCM (30 ml) over 5 hours with vigorous stirring. Stirring was continued for further 24 hours at room temperature. After concentration to an oily residue, reaction mixture was dissolved in aqueous 2M sodium carbonate solution (60 ml) and extracted with dichloromethane (3x30 ml). The organic layer was washed with 2M sodium carbonate solution (2x40 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (2.2 g) as a yellow oil.TH NMR (500 MHz, DMSO-de): 5 ppm 6.73 (t, J= 4.5 Hz, 1H), 2.90 (dd, J= 12.5, 6.5 Hz, 2H), 2.52 (d, J= 6.5 Hz, 2H), 1.37 (s, 9H); Mass: m / z 161.32 (M+H)+.

[0478] Step 2: Synthesis of tert-butyl (2 -acrylamidoethyl) carbamate:

[0479] A solution of tert-butyl (2-aminoethyl)carbamate (Step 1, 1.4 g, 8.738 mmol, 1.0 eq), triethylamine (2.652 g, 3.65 ml, 26.21 mmol, 3.0 eq) and Tetrahydrofuran (20 ml) cooled to 0- 10 °C with an ice bath. Acryloyl chloride (1.584 g, 1.41 ml, 17.50 mmol, 2.0 eq) was added dropwise and the resulting reaction mixture was stirred at room temperature for about 2 hours. The resulting solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.68 g) as a yellow oil. Which was directly used in the next step without further purification. Mass: m / z 215.42 (M+H)+.

[0480] Step 3: Synthesis of 2 -aery lamidoethan-l-aminium 2,2,2-trifluoroacetate:

[0481] To a stirred solution of tert-butyl (2-acrylamidoethyl)carbamate (Step 2, 1 g, 4.667 mmol, 1.0 eq) in DCM (10 ml) was added Trifluoroacetic acid (10 ml). The reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was evaporated under reduced pressure. The obtained crude compound (0.608 g) was used for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 8.32 (s, 1H), 7.81 (brs, 3H), 6.19 (d, J= 10.0 Hz, 1H), 6.11 (dd, J= 12.0, 2.5 Hz, 1H), 5.64 (dd, J= 10.0, 2.0 Hz, 1H), 3.36 (dd, J= 12.0, 6.0 Hz, 2H), 2.90 (dd, J= 12.0, 6.0 Hz, 2H); Mass: m / z 114.98 (M)+.

[0482] Intermediate 5: Preparation of 4- 4-aminophenoxy)-7-methoxy-N-methylquinoline-6- carboxamide:

[0483] Step 1: Synthesis of methyl 7-methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylate :

[0484] To a stirred solution of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (20 g, 79.469 mmol, 1.0 eq) in Toluene (100 ml) was added 4-nitrophenol (18.72 g, 135.09 mmol, 1.7 eq) and N-ethyl-N-isopropylpropan-2-amine (35.94 g, 48.4 ml, 278.141 mmol, 3.5 eq). Reaction mixture was heated to reflux for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mixture was concentrated under reduced pressure. Water (1 Ltr) was added to the reaction mass, stirred at room temperature for about 1 hour. The precipitate formed was collected by filtration, washed with water and dried under vacuum to obtain the title compound (23 g, yield: 81%) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 8.79 (dd, J= 15.5, 5.0 Hz, 1H), 8.48 (d, J= 15.5 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J= 15.5 Hz, 1H), 7.59-7.50 (m, 3H), 6.82 (dd, J= 15.5, 5.0 Hz, 1H), 3.98 (d, J= 16.0 Hz, 3H), 3.84 (d, J= 15.5 Hz, 3H); Mass: m / z. 355.18 (M+H)+.

[0485] Step 2: Synthesis of methyl 4-(4-aminophenoxy)-7-methoxyquinoline-6-carboxylate : To a stirred solution of methyl 7-methoxy-4-(4-nitrophenoxy)quinoline-6- carboxylate (Step 1, 18 g, 50.788 mmol, 1.0 eq) in ethanol (393.75 ml) and water (56.25 ml) was added Iron powder (14.18 g, 253.94 mmol, 5.0 eq) and ammonium chloride (9.5 g, 177.75 mmol, 3.5 eq). The reaction mixture was stirred at reflux temperature for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mixture was filtered through celite pad, washed with ethyl acetate (1 Ltr). The filtrate was washed with saturated sodium bicarbonate solution (100 ml) and water (100 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was stirred with methanol (48 ml) at room temperature for about 1 hour. Solid was filtered, washed with methanol and dried under vacuum to obtain the title compound (12.2 g, yield: 74%) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 8.65 (d, J = 5.0 Hz, 1H), 8.59 (s, 1H), 7.50 (s, 1H), 6.96 (d, J= 8.5 Hz, 2H), 6.69 (d, J= 8.5 Hz, 2H), 6.43 (d, J = 5.5 Hz, 1H), 5.20 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H); Mass: m / z 325.13 (M+H)+.

[0486] Step 3: Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide :

[0487] To a stirred solution of methyl 4-(4-aminophenoxy)-7-methoxyquinoline-6- carboxylate (Step 2, 13 g, 40.082 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (65 ml) was added 40% aqueous methyl amine (44.9 ml). The reaction mixture was stirred at 0-10 °C for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. Water (1000 ml) was added to the reaction mixture, stirred at room temperature for about 1 hour. The precipitate formed was collected by filtration, washed with water and dried under vacuum to obtain the title compound (12.0 g, yield: 92%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.62 (d, J= 5.0 Hz, 2H), 8.36-8.33 (m, 1H), 7.48 (s, 1H), 6.94 (d, J= 9.0 Hz, 2H), 6.67 (d, J= 9.0 Hz, 2H), 6.41 (d, J= 5.0 Hz, 1H), 5.18 (s, 2H), 4.01 (s, 3H), 2.85 (d, J= 4.5 Hz, 3H); Mass: m / z 324.17 (M+H)+.

[0488] Intermediate 6: Preparation of (2R,3S,4R)-2-(hvdroxymethyl)-6-methoxytetrahvdro-2H- pyran-3.4-diyl diacetate:

[0489] Step 1: Synthesis of (2R,3S,4R)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3, 4-diol:

[0490] To a stirred solution of (3R,4S,5R)-3,4,5,6-tetrahydroxyhexanal (20 g, 0.1218 mmol, 1.0 eq) in Methanol (200 ml) was added acetyl chloride (0.95 g, 0.0121 mmol, 0.1 eq). The reaction mass was stirred at 80 °C for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was neutralized with sodium bicarbonate solution and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (20 g, yield: 92%) as a colourless liquid.TH NMR (500 MHz, DMSO-de): 5 ppm 4.84 (dd, J= 10.0, 5.0 Hz, 1H), 4.72 (d, J= 5.0 Hz, 1H), 4.67 (d, J= 2.5 Hz, 1H), 4.43 (t, J= 6.0 Hz, 1H), 3.66-3.62 (m, 1H), 3.58-3.54 (m, 1H), 3.48-3.43 (m, 1H), 3.28-3.25 (m, 1H), 3.20 (s, 3H), 3.03-2.99 (m, 1H), 1.87 (dd, J= 13.0, 5.0 Hz, 1H), 1.45-1.40 (m, 1H); Mass: m / z 178.97 (M)+.

[0491] Step 2: Synthesis of (2R,3S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxytetrahydro-

[0492] 2H-pyran-3, 4-diol:

[0493] To a stirred solution of (2R,3S,4R)-2-(hydroxymethyl)-6-methoxytetrahydro-2H- pyran-3, 4-diol (Step 1, 10 g, 56.12 mmol, 1.0 eq) in DCM (100 ml) at 0-10 °C was added Imidazole (11.4 g, 168.36 mmol, 3.0 eq) and tert-butylchlorodimethylsilane (8.4 g, 56.12 mmol, 1.0 eq). Cooling bath was removed, reaction mass stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. Reaction mass was diluted with DCM (500 ml), washed with water (500 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography using 0-3% methanol in dichloromethane gradient to obtain the title compound (11 g, yield: 67%) as a colourless liquid.XHNMR (500 MHz, CDCh): 5 ppm 4.76 (d, J= 3.5 Hz, 1H), 3.99-3.91 (m, 1H), 3.90 (d, J = 4.5 Hz, 1H), 3.78 (dd, J = 10.0, 6.5 Hz, 1H), 3.57-3.55 (m, 1H), 3.47-3.42 (m, 2H), 3.32 (s, 3H), 2.11 (dd, J= 13.0, 5.5 Hz, 1H), 1.68-1.65 (m, 1H), 0.91 (s, 9H), 0.11 (s, 6H).

[0494] Step 3: Synthesis of (2R,3S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxytetrahydro- 2H-pyran-3,4-diyl diacetate:

[0495] To a stirred solution of (2R,3S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-6- methoxytetrahydro-2H-pyran-3,4-diol (Step 2, 11 g, 37.61 mmol, 1.0 eq) in DCM (110 ml) at 0 °C was added triethylamine (26.2 ml, 188.06 mmol, 5.0 eq), N,N-dimethylpyridin-4-amine (0.919 g, 7.522 mmol, 0.2 eq) and acetic anhydride (10.6 ml, 112.84 mmol, 3.0 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (500 ml) and washed with water (500 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in dichloromethane gradient to obtain the title compound (10 g, yield: 70%) as a colourless liquid; ’H NMR (500 MHz, CDCh): 5 ppm 5.30-5.25 (m, 1H), 4.91 (t, J= 10.0 Hz, 1H), 4.80 (d, J= 3.0 Hz, 1H), 3.67-3.66 (m, 3H), 3.32 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H), 1.78-1.71 (m, 2H), 0.87 (s, 9H), 0.12 (s, 6H); Mass: m / z 377 (M+H)+.

[0496] Step 4: Synthesis of (2R,3S,4R)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4-diyl diacetate:

[0497] To a stirred solution of (2R,3S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-6- methoxytetrahydro-2H-pyran-3,4-diyl diacetate (Step 3, 10 g, 26.56 mmol, 1.0 eq) in THF (100 ml) at 0 °C was added Tetra-n-butylammonium fluoride (26.5 ml, 26.56 mmol, 1.0 eq, 1.0 M in THF). The reaction mass was stirred at room temperature for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Saturated sodium chloride solution (500 ml) was added to the reaction mass and extracted with 10% methanol: DCM (2x500 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-3% methanol in di chloromethane gradient to obtain the title compound (5 g, yield: 72%) as a brown colour liquid.

[0498] Intermediate 7: Preparation of tert-butyl (2-amino-2-methylpropyl)carbamate:

[0499] A solution of 2-methylpropane-l,2-diamine (1.1 g, 12.5 mmol, 1.0 eq) and DCM (10 ml) cooled to 0-10 °C. Di-tert-butyl dicarbonate (2.72 g, 12.5 mmol, 1.0 eq) was added and the reaction mass was allowed to stir at room temperature for about 20 hours. Reaction mass was evaporated under reduced pressure. Heptane (40 ml) was added to the solid, stirred at room temperature for about 30 minutes. Solid was filtered and dried under vacuum to obtain the title compound (2.1 g) as a white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 4.92 (s, 1H), 3.01 (d, J= 6.0 Hz, 2H), 1.45 (s, 9H), 1.09 (s, 6H).

[0500] Intermediate 8: Preparation of 2-(((benzyloxy)carbonyl)amino)-2-methylpropan-l-aminium

[0501] 2,2,2trifluoroacetate:

[0502] A solution of tert-butyl (2-amino-2-methylpropyl)carbamate (Intermediate 7, 1.6 g, 8.497 mmol, 1.0 eq) and DCM (32 ml) cooled to 0 °C. Triethylamine (4.347 g, 42.95 mmol, 5.0 eq), N,N-dimethylpyridin-4-amine (0.05 g, 0.849 mmol, 0.1 eq) and benzyl carb onochlori date (1.74 g, 10.19 mmol, 1.2 eq) were added to the reaction mass and allowed to stir at room temperature for overnight. DCM (100 ml) was added to the reaction mass, washed with 0.5N HC1 (20 ml), water (50 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The obtained compound (1.5 g) was used for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 7.36-7.30 (m, 5H), 6.87-6.82 (m, 1H), 4.96 (s, 2H), 4.49 (d, J = 5.5 Hz, 1H), 3.07 (d, J= 6.5 Hz, 2H), 1.38 (s, 9H), 1.15 (s, 6H); Mass: m / z 323.18 (M+H)+.

[0503] Step 2: Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-methylpropan-l-aminium 2, 2, 2trijluoroacetate:

[0504] A solution of benzyl tert-butyl (2-methylpropane-l,2-diyl)dicarbamate (Step 1, 1.5 g, 4.652 mmol, 1.0 eq) and DCM (12 ml) was cooled to 0 °C. Trifluoroacetic acid (8 ml) was added, stirred at 0 °C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Heptane (20 ml) was added to the residue, stirred at room temperature for about 30 minutes. Heptane layer was decanted. Diisopropyl ether (20 ml) was added to the residue, stirred at room temperature for about 30 minutes. Solid was filtered, washed with diisopropyl ether (10 ml) and dried under vacuum at 50 °C for about 30 minutes to obtain the title compound (1.0 g) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.83 (brs, 3H), 7.39-7.32 (m, 5H), 7.24 (brs, 1H), 5.0 (s, 2H), 3.08 (s, 2H), 1.24 (s, 6H); Mass: m / z 223.20 (M+H)+.

[0505] Intermediate 9: Preparation of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide 2,2,2- trifluoroacetate:

[0506] To a solution of tert-butyl (2-aminoethyl)carbamate (1 g, 6.242 mmol, 1.0 eq) in ethanol (10 ml) was added divinylsulfone (1.47 g, 1.25 ml, 12.48 mmol, 2.0 eq) and triethylamine (2.52 g, 3.42 ml, 24.96 mmol, 4.0 eq). The reaction mass was refluxed for about 4 hours. TLC indicated starting material was completed and the desired product was observed. Ethanol was evaporated under reduced pressure. Reaction mass was diluted with DCM (50 ml), washed with 0.3N HC1 (15 ml), 5% sodium bicarbonate solution (20 ml), water (20 ml) and 25% sodium chloride solution (20 ml). Organic layer was dried with sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in dichloromethane gradient to obtain the title compound (0.810 g, yield: 46%), which was used as such for next step.XH NMR (500 MHz, CDCh): 5 ppm 4.72 (s, 1H), 3.25-3.22 (m, 2H), 3.06-3.02 (m, 8H), 2.62 (t, J = 6.0 Hz, 2H), 1.45 (s, 9H); Mass: m / z 279.13 (M+H)+.

[0507] Step 2: Synthesis of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide 2,2,2-trifluoroacetate :

[0508] To a stirred solution of tert-butyl (2-(l,l-dioxidothiomorpholino)ethyl)carbamate (Step 1, 0.750 g, 2.693 mmol, 1.0 eq) in DCM (9 ml) at 0 °C was added Trifluoroacetic acid (6 ml). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Diisopropyl ether (30 ml) was added to the residue, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with Diisopropyl ether and dried under vacuum to obtain the title compound (0.670 g) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.68 (brs, 3H), 3.12 (t, J= 5.5 Hz, 4H), 2.95-2.90 (m, 6H), 2.68 (t, J= 5.5 Hz, 2H); Mass: m / z 179.10 (M+H)+.

[0509] Intermediate 10: Preparation of 4-(l-amino-2-methylpropan-2-yl)thiomorpholine 1,1-dioxide

[0510] 2,2,2-trifluoroacetate:

[0511] Step 1: Synthesis of tert-butyl (2-( 1 , l-dioxidothiomorpholino)-2-methylpropyl)carbamate : To a solution of tert-butyl (2-amino-2-methylpropyl)carbamate (1 g, 5.31 mmol, 1.0 eq) in ethanol (10 ml) was added (vinyl sulfonyl)ethene (1.255 g, 1.06 ml, 10.62 mmol, 2.0 eq) and tri ethylamine (2.15 g, 2.96 ml, 21.24 mmol, 4.0 eq). The reaction mass was refluxed for about 4 hours. TLC indicated starting material was completed and the desired product was observed. Ethanol was evaporated under reduced pressure. Reaction mass was diluted with DCM (50 ml), washed with 0.3N HC1 (15 ml). The organic layer was washed with 5% sodium bicarbonate solution (20 ml), water (20 ml) and 25% sodium chloride solution (20 ml). Organic layer was dried with sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in dichloromethane gradient. The obtained compound (0.830 g, yield: 50%) was used for next step.XH NMR (500 MHz, DMSO-de): 5 ppm 4.79 (s, 1H), 3.48 (s, 2H), 3.12 (m, 2H), 3.05- 3.04 (m, 6H), 1.45 (s, 9H), 1.08 (s, 6H); Mass: m / z 307.11 (M+H)+.

[0512] Step 2: Synthesis of 4 -(l-amino-2 -me thy lpropan-2-y I) thiomorpholine 1,1-dioxide 2,2,2- trijluoroace tate :

[0513] To a stirred solution of tert-butyl (2-(l,l-dioxidothiomorpholino)-2- methylpropyl)carbamate (Step 1, 0.800 g, 2.61 mmol, 1.0 eq) in DCM (9.6 ml) at 0 °C was added Trifluoroacetic acid (6.4 ml). The reaction mass was stirred at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Hexane (30 ml) was added to the residue, stirred at room temperature for about 30 minutes. Hexane layer was decanted. Diisopropylether (30 ml) was added to the residue, stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with Diisopropyl ether (20 ml) and dried under vacuum to obtain the title compound (0.693 g, yield: 83%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.59 (brs, 3H), 3.13-3.12 (m, 4H), 2.89-2.85 (m, 6H), 1.06 (s, 6H); Mass: m / z 207.20 (M+H)+.

[0514] Intermediate 11 : Preparation of tert-butyl 4-(2-amino-2-methylpropyl)piperazine-l- carboxylate:

[0515] Step 1: Synthesis of tert-butyl piperazine- 1 -carboxylate:

[0516] To a stirred solution of piperazine (15 g, 174.21 mmol, 1.0 eq) in DCM (250 ml) at 0 °C was added di-tert-butyl dicarbonate (19 g, 87.10 mmol, 0.5 eq) dissolved in DCM (200 ml). The reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (3000 ml), washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (9 g, yield: 27.7%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 3.20 (t, J = 4.5 Hz, 4H), 2.59 (t, J= 5.0 Hz, 4H), 2.35 (t, J= 5.0 Hz, 1H), 1.40 (s, 9H); Mass: m / z 187.17 (M+H)+.

[0517] Step 2: Synthesis of tert-butyl 4-(2-methyl-2-nitropropyl)piperazine-l-carboxylate:

[0518] To a stirred solution of tert-butyl piperazine- 1 -carboxylate (Step 1, 3 g, 16.10 mmol, 1.0 eq) in Aqueous 2N NaOH solution (24 ml) was added 30% formaldehyde solution (4.92 g, 16.4 ml, 164.25 mmol, 10.2 eq) and 2-nitropropane (6.6 g, 75.68 mmol, 4.7 eq). The reaction mass was stirred at 60 °C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with ice cold water (400 ml) and extracted with EtOAc (2x400 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (4 g, yield: 86.9%) as an off-white solid.XHNMR (500 MHz, CDCh): 5 ppm 3.38-3.34 (m, 4H), 2.83 (s, 2H), 2.48 (t, J= 5.0 Hz, 4H), 1.59 (s, 3H), 1.56 (s, 3H), 1.44 (s, 9H); Mass: m / z 288.23 (M+H)+.

[0519] Step 3: Synthesis of tert-butyl 4-(2-amino-2-methylpropyl)piperazine-l-carboxylate: To a suspension of Raney Nickel (1.5 g) in methanol (50 ml) was added tert-butyl 4- (2-methyl-2-nitropropyl)piperazine-l -carboxylate (Step 2, 3 g, 10.438 mmol, 1.0 eq). Reaction mass was hydrogenated in parr shaker apparatus at 70 psi hydrogen pressure for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was filtered through celite bed, washed with methanol (100 ml). The filtrate was concentrated under reduced pressure. The obtained compound (1.8 g, yield: 69%) was used for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 3.28 (t, J = 5.0 Hz, 4H), 2.44 (t, J = 5.0 Hz, 4H), 2.11 (s, 2H), 1.39 (s, 9H), 0.95 (s, 6H); Mass: m / z 258.28 (M+H)+.

[0520] Intermediate 12: Preparation of 4-((2R,3R)-l-amino-3-((tert-butyldimethylsilyl)oxy)butan-2- vDthiomorpholine 1,1 -di oxide:

[0521] Step 1: Synthesis of 2-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(l,l- dioxidothiomorpholino)butyl)isoindoline- 1,3-dione:

[0522] To a stirred solution of isoindoline-1, 3-dione (0.500 g, 3.40 mmol, 1.0 eq) in THF (5 ml) was added 4-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-l-hydroxybutan-2- yl)thiomorpholine 1,1-dioxide (1.262 g, 3.738 mmol, 1.1 eq) (Synthesis was reported in WO2020 / 165741) and triphenylphosphine (0.98 g, 3.74 mmol, 1.1 eq). The reaction mass was cooled to 0 °C, diisopropylazodicarboxylate (0.756 g, 3.74 mmol, 1.1 eq) was added and the reaction mass was allowed to stir at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. Reaction mass was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layer was washed with water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in dichloromethane gradient to obtain the title compound (0.720 g, yield: 45.4%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.91-7.84 (m, 4H), 4.06-4.04 (m, 1H), 3.887 (dd, J = 14.0, 6.3 Hz, 1H), 3.44 (dd, J = 14.5, 4.0 Hz, 1H), 3.27-3.24 (m, 2H), 3.04-2.96 (m, 3H), 2.81-2.74 (m, 4H), 1.22 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); Mass: m / z 467.25 (M+H)+.

[0523] Step 2: Synthesis of 4-((2R,3R)-l-amino-3-((tert-butyldimethylsilyl)oxy)butan-2- y I) thiomorpholine 1, 1 -dioxide:

[0524] To a stirred solution of 2-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(l, 1- dioxidothiomorpholino)butyl)isoindoline-l, 3-dione (Step 1, 2.3 g, 4.928 mmol, 1.0 eq) in

[0525] Propane-2-ol (60 ml) and water (6 ml) was added sodium borohydride (0.932 g, 24.64 mmol, 5.0 eq). The reaction mass was stirred at room temperature for about 24 hours. Acetic acid (5.32 g, 5.07 ml, 88.7 mmol, 18 eq) was added, reaction mass was heated at 80 °C for about 2 hours. Reaction mass pH adjusted to 7.5 to 8.0 and extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with water (50 ml) and brine solution (50 ml). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude compound (0.720 g) was used as such for next step without further purification. ’H NMR (500 MHz, DMSO-de): 5 ppm 4.60-4.59 (m, 1H), 3.99-3.94 (m, 1H), 3.24-3.21 (m, 3H), 3.12-3.08 (m, 1H), 3.05-3.03 (m, 3H), 2.99-2.97 (m, 1H), 2.66-2.57 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.087 (s, 3H), 0.081 (s, 3H); Mass: m / z 337.20 (M+H)+.

[0526] Intermediate 13: Preparation of 4-(2-amino-2-methylpropyl)thiomorpholine 1,1 -dioxide: A solution of tert-butyl (2-amino-2-methylpropyl)carbamate (2.3 g, 12.21 mmol, 1.0 eq) and DCM (40 ml) was cooled to 0 °C. Triethylamine (3.7 g, 5.1 ml, 36.64 mmol, 3.0 eq), N,N-dimethylpyridin-4-amine (0.149 g, 1.221 mmol, 0.1 eq) followed by benzyl chloroformate (2.5 g, 5 ml, 14.66 mmol, 1.2 eq) were added to the reaction mass and allowed to stir at room temperature for overnight. Reaction mass was diluted with DCM (100 ml), washed with 0.5N HC1 (20 ml), 5% sodium bicarbonate solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in dichloromethane gradient to obtain the title compound (2.0 g, yield: 50.78%) as a liquid.XH NMR (500 MHz, DMSO-de): 5 ppm 7.37-7.30 (m, 5H), 6.86 (s, 1H), 4.96 (s, 2H), 3.07 (d, J= 6.5 Hz, 2H), 1.37 (s, 9H), 1.15 (s, 6H); Mass: m / z 340.35 (M+NH4)+.

[0527] Step 2: Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-methylpropan-l-aminium 2,2,2- trifluoroace tate :

[0528] To a solution of benzyl tert-butyl (2-methylpropane-l,2-diyl)dicarbamate (Step 1, 1.4 g, 4.342 mmol, 1.0 eq) in DCM (12 ml) at 0 °C was added trifluoroacetic acid (8 ml). The reaction mass was allowed to stir at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Residue was stirred with heptane (20 ml) and decanted. Diisopropyl ether (40 ml) was added to the residue, stirred at room temperature for about 30 minutes. Solid was filtered, washed with diisopropylether (20 ml) and dried under vacuum at 50-60 °C for about 1 hour to afford the title compound (0.900 g) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.79 (brs, 3H), 7.39-7.30 (m, 5H), 7.24 (s, 1H), 5.0 (s, 2H), 3.08 (s, 2H), 1.24 (s, 6H); Mass: m / z 223.2 (M+H)+.

[0529] Step 3: Synthesis of benzyl (l-(l,l-dioxidothiomorpholino)-2-methylpropan-2-yl)carbamate:

[0530] To a solution of 2-(((benzyloxy)carbonyl)amino)-2-methylpropan-l-aminium 2,2,2- trifluoroacetate (Step 2, 0.900 g, 2.676 mmol, 1.0 eq) in ethanol (10 ml) was added (vinylsulfonyl)ethene (0.632 g, 0.537 ml, 5.352 mmol, 2.0 eq) and triethylamine (0.812 g, 1.12 ml, 8.028 mmol, 3.0 eq). Reaction mass was stirred at 80-90 °C for about 4 hours. TLC indicated starting material was completed and the desired product was observed. Ethanol was evaporated under reduced pressure. Reaction mass was diluted with DCM (50 ml), washed with 0.3N HC1 (15 ml). The organic layer was washed with 5% sodium bicarbonate solution (20 ml), water (20 ml) and 25% sodium chloride solution (20 ml). The organic layer was dried with sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using dichloromethane eluent to obtain the title compound (0.900 g, yield: 98.79%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.38-7.28 (m, 5H), 6.90 (s, 1H), 4.96 (s, 2H), 2.98-2.94 (m, 8H), 2.64 (s, 2H), 1.16 (s, 6H); Mass: m / z 341.17 (M+H)+.

[0531] Step 4: Synthesis of 4-(2-amino-2-methylpropyl) thiomorpholine 1,1 -dioxide:

[0532] To a stirred solution of benzyl (l-(l,l-dioxidothiomorpholino)-2-methylpropan-2- yl)carbamate (Step 3, 0.900 g, 2.643 mmol, 1.0 eq) in ethyl acetate (20 ml) and methanol (20 ml) was added 10% Pd / C (0.135 g). The reaction mass was stirred at room temperature under hydrogen atmosphere for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was filtered through celite bed, washed with EtOAc : Methanol (40 ml, 1 : 1). The filtrate was evaporated under reduced pressure. The crude compound (0.540 g) was used for next step without further purification.TH NMR (500 MHz, DMSO-de): 5 ppm 3.06-3.02 (m, 8H), 2.29 (s, 2H), 0.95 (s, 6H); Mass: m / z 207.20 (M+H)+.

[0533] Intermediate 14: Preparation of tert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate:

[0534] Step 1: Synthesis of 2-(2-bromoethyl)isoindoline-l , 3-dione : To a suspension of pthalimide (5 g, 33.94 mmol, 1.0 eq) in DMF (50 ml) was added potassium carbonate (9.38 g, 67.88 mmol, 2.0 eq), 1,2-dibromoethane (25.5 g, 11.75 ml, 135.78 mmol, 4.0 eq) and tetra-n-butylammonium bromide (0.765 g, 2.373 mmol, 0.07 eq). Reaction mass was stirred at 40 °C for about 7 hours. TLC indicated starting material was completed. Water (150 ml) was added to the reaction mass and extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with water (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 0-2% methanol in di chloromethane gradient to obtain the title compound (4.75 g, yield: 55%) as a solid.TH NMR (500 MHz, DMSO-de): 5 ppm 7.92-7.86 (m, 4H), 3.99 (t, J= 6.5 Hz, 2H), 3.72 (t, J= 6.0 Hz, 2H); Mass: m / z 255.97 (M+H)+.

[0535] Step 2: Synthesis of tert-butyl 4-(2-(l,3-dioxoisoindolin-2-yl)ethyl)piperazine-l -carboxylate:

[0536] To a stirred solution of tert-butyl piperazine- 1 -carboxylate (Intermediate 11 -step 1, 1.466 g, 7.86 mmol, 1.0 eq) in DMF (15 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.22 g, 1.64 ml, 9.44 mmol, 1.2 eq) and 2-(2-bromoethyl)isoindoline-l, 3-dione (Step 1, 2.0 g, 7.87 mmol, 1.0 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mass was poured into water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layer was washed with water (20 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2% methanol in di chloromethane gradient to obtain the title compound (1.697 g, yield: 60%) as a solid. ‘H NMR (500 MHz, DMSO-de): 5 ppm 7.88-7.83 (m, 4H), 3.70 (t, J= 6.5 Hz, 2H), 3.22-3.20 (m, 4H), 2.54 (t, J= 6.5 Hz, 2H), 2.37-2.35 (m, 4H), 1.38 (s, 9H); Mass: m / z 360.26 (M+H)+.

[0537] Step 3: Synthesis of tert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate:

[0538] To a solution of tert-butyl 4-(2-(l,3-dioxoisoindolin-2-yl)ethyl)piperazine-l- carboxylate (Step 2, 1.0 g, 2.782 mmol, 1.0 eq) in ethanol (15 ml) was added hydrazine hydrate (0.445 g, 13.91 mmol, 5.0 eq). The reaction mass was stirred at room temperature for about 7 hours. TLC indicated starting material was completed and the desired product was observed. Reaction mass was filtered through celite bed, washed with diisopropyl ether (30 ml). The filtrate was evaporated under reduced pressure. The crude compound (0.618 g) was used for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 3.29 (t, J = 5.0 Hz, 4H), 2.61 (t, J= 6.5 Hz, 2H), 2.30-2.28 (m, 6H), 1.39 (s, 9H); Mass: m / z 230.12 (M+H)+.

[0539] Intermediate 15: Preparation of Nl-(tert-butyl)-Nl-(4-methoxybenzyl)ethane-l,2-diamine:

[0540] Dissolve tert-butyl amine (2.6 g, 36.72 mmol, 1.0 eq) and 4-methoxybenzaldehyde (5 g, 36.72 mmol, 1.0 eq) in methanol (50 ml). The reaction mass was stirred at room temperature for about 3 hours. Sodium borohydride (6.9 g, 183.6 mmol, 5.0 eq) was added portion wise at 0 °C and warm to room temperature. After 2 hours, reaction mass was quenched with water (30 ml) and extracted with DCM (2x100 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (6.5 g) as a colourless liquid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.23 (d, J = 8.5 Hz, 2H), 6.83 (d, J= 8.5 Hz, 2H), 3.71 (s, 3H), 3.56 (s, 2H), 1.07 (s, 9H); Mass: m / z 194.09 (M+H)+.

[0541] Step 2: Synthesis of 2-(tert-butyl(4-methoxybenzyl)amino)acetonitrile :

[0542] Potassium carbonate (10 g, 72.426 mmol, 2.0 eq), potassium iodide (6.0 g, 36.213 mmol, 1.0 eq) and chloroacetonitrile (10.93 g, 9.16 ml, 140.85 mmol, 4.0 eq) were added to a solution of N-(4-methoxybenzyl)-2-methylpropan-2-amine (Step 1, 7.0 g, 36.213 mmol, 1.0 eq) in acetonitrile (35 ml). The reaction mass was stirred at 75-80 °C for about 6 hours. Reaction mass was cooled to room temperature, concentrated under reduced pressure. DCM (200 ml) was added to the reaction mass, washed with water (100 ml) and brine solution (100 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate and hexane as eluent to obtain the title compound (11.4 g) as a colourless oil. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.21 (d, J= 8.5 Hz, 2H), 6.90 (d, J= 8.5 Hz, 2H), 3.73 (s, 3H), 3.68 (s, 2H), 3.46 (s, 2H), 1.20 (s, 9H); Mass: m / z 233.13 (M+H)+.

[0543] Step 3: Synthesis ofNl-(tert-butyl)-Nl-(4-methoxybenzyl)ethane-l,2-diamine:

[0544] A suspension of Lithium aluminium hydride (3.75 g, 99.0 mmol, 4.6 eq) and THF (30 ml) was cooled to 0-10 °C. 2-(tert-butyl(4-methoxybenzyl)amino)acetonitrile (Step 2, 5 g, 21.52 mmol, 1.0 eq) dissolved in THF (20 ml) was added slowly to the reaction mass. Cooling bath was removed, reaction mass was stirred at room temperature for about 2 hours. Reaction mass was cooled to 0-10 °C, water (1.9 ml), IN sodium hydroxide solution (3.8 ml) and water (1.9 ml) were added sequentially. The reaction mass stirred at room temperature for about 1 hour. Reaction mass filtered through celite bed, washed with THF (10 ml). The filtrate was concentrated under reduced pressure to obtain the title compound (4.89 g, yield: 96%) as a pale-yellow oil. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.24 (d, J= 8.5 Hz, 2H), 6.84 (d, J= 8.5 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 2H), 2.55 (t, J= 7.0 Hz, 2H), 2.29 (t, J= 7.0 Hz, 2H), 1.07 (s, 9H); Mass: m / z 237.17 (M+H)+.

[0545] Intermediate 16: Preparation of 4-(3-aminopropyl)thiomorpholine I -dioxide:

[0546] Step 1: Synthesis of 2-(3-bromopropyl)isoindoline-l, 3-dione:

[0547] Phthalimide (20 g, 135.96 mmol, 1.0 eq), 1,3 -dibromopropane (116.7 g, 577.83 mmol, 4.25 eq), Acetone (167 ml) and potassium carbonate (60 g, 434 mmol, 3.19 eq) were added in to the RB flask. The mixture was refluxed for overnight. Cooled to room temperature and filtered to remove inorganic salts. The filtrate was Concentrated under reduced pressure. Ethanol (100 ml) was added to the residue, heated at 70 °C for around 1 hour until to get clear solution. Heating bath was removed, reaction mass was allowed to reach to room temperature. Reaction mass was cooled to 0-10 °C and stirred at below 10 °C for about 1 hour. Solid was filtered, washed with ice cooled ethanol (20 ml). Solid was dried in vacuo to obtain the title compound (16 g) as a white crystalline solid. ’H NMR (300 MHz, DMSO-de): 5 ppm 7.88- 7.81 (m, 4H), 3.70 (t, J= 6.6 Hz, 2H), 3.56 (t, J= 6.6 Hz, 2H), 2.19-2.10 (m, 2H).

[0548] Step 2: Synthesis of 2-(3-( 1, 1 -dioxidothiomorpholino)propyl)isoindoline- 1,3-dione:

[0549] To a solution of thiomorpholine 1,1 -dioxide hydrochloride (2.0 g, 11.65 mmol, 1.0 eq) in N,N-dimethylacetamide (20 ml) was added Potassium carbonate (4.83 g, 34.96 mmol, 3.0 eq). Reaction mass was stirred at room temperature for about 10 minutes. 2-(3-bromopropyl)isoindoline-l, 3-dione (Step 1, 6.25 g, 23.31 mmol, 2.0 eq) and Tetra-n-butyl ammonium iodide (0.430 g. 1.165 mmol, 0.1 eq) were added, stirred at 50-60 °C for overnight. Water (200 ml) was added to the reaction mass, extracted with ethyl acetate (3x50 ml). The combined organic layer was washed with water (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 40-60% ethyl acetate in hexanes gradient to obtain the title compound (2.1 g, yield: 56%) as a solid. 'H NMR (300 MHz, CD3OD): 5 ppm 7.88-7.83 (m, 4H), 3.74 (t, J= 5.0 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.13 (t, J= 5.0 Hz, 1H), 2.93 (t, J= 5.5 Hz, 4H), 2.81 (t, J= 5.5 Hz, 4H), 1.75-1.71 (m, 2H); Mass: m / z 323.12 (M+H)+.

[0550] Step 3: Synthesis of 4-(3-aminopropyl)thiomorpholine 1,1 -dioxide:

[0551] To a solution of 2-(3-(l,l-dioxidothiomorpholino)propyl)isoindoline-l, 3-dione (Step 2, 2.0 g, 6.203 mmol, 1.0 eq) in ethanol (20 ml) was added hydrazine hydrate (1.552 g, 31.017 mmol, 5.0 eq). The reaction mass was stirred at 60-70 °C for about 2 hours. TLC indicated starting material was completed and the desired product was observed. Reaction mass was cooled to room temperature, filtered through celite bed, washed with ethanol (10 ml). The filtrate was evaporated under reduced pressure. DCM (20 ml) was added to the residue, stirred at room temperature for about 1 hour. Solid was filtered and discarded; filtrate was concentrated under reduced pressure. Crude compound (0.596 g) was used for next step without further purification. ’H NMR (500 MHz, CD3OD): 5 ppm 3.10 (t, J= 5.5 Hz, 4H), 2.99-2.97 (m, 4H), 2.73 (t, J= 7.0 Hz, 2H), 2.58 (t, J= 7.0 Hz, 2H), 1.70-1.65 (m, 2H).

[0552] Intermediate 17: Preparation of 2-(3-aminopropyl)isoindoline-l, 3-dione 2,2,2-trifluoroacetic acid:

[0553] To a solution of isobenzofuran- 1,3-dione (2 g, 13.5 mmol, 1.0 eq) in ethanol (20 ml) was added tert-butyl (3-aminopropyl)carbamate (2.3 g, 13.5 mmol, 1.0 eq). Reaction mass was refluxed for around 2 hours. After completion of the reaction monitored by TLC, reaction mass was evaporated under reduced pressure. Reaction mass was diluted with DCM (50 ml) washed with 6% sodium bicarbonate solution (30 ml) and water (50 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (1.8 g, yield: 43.80%) as a white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 7.87-7.82 (m, 4H), 6.80 (d, J= 5.5 Hz, 1H), 3.56 (t, J= 7.0 Hz, 2H), 2.96-2.92 (m, 2H), 1.71-1.69 (m, 2H), 1.35 (s, 9H).

[0554] Step 2: Synthesis of 2-(3-aminopropyl)isoindoline- 1,3-dione 2,2,2-trifluoroacetic acid:

[0555] To a stirred solution of tert-butyl (3-(l,3-dioxoisoindolin-2-yl)propyl)carbamate (Step 1, 1.6 g, 5.257 mmol, 1.0 eq) in DCM (6 ml) was added Trifluoroacetic acid (TFA) (4 ml). The reaction mass was stirred at room temperature for overnight. Reaction mass was evaporated under reduced pressure. Heptane (20 ml) was added to the residue, stirred at room temperature for about 1 hour. Heptane layer was decanted. Methyl -tert-butyl ether (20 ml) was added to the residue, stirred at room temperature for about 2 hours. Solid was filtered, washed with methyltert-butyl ether (10 ml) and then dried under vacuum to afford the title compound (1.5 g, yield: 89.66%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.89-7.81 (m, 7H), 3.64 (t, J= 7.0 Hz, 2H), 2.85 (t, J= 7.0 Hz, 2H), 1.89-1.86 (m, 2H); Mass: m / z 205.0 (M+H)+.

[0556] Intermediate 18: Preparation of 2-(2-aminoethyl)isoindoline-E3-dione 2,2,2-trifluoroacetic acid:

[0557] To a stirred solution of Phthalic anhydride (2.0 g, 13.5 mmol, 1.0 eq) in Ethanol (40 ml) was added tert-butyl (2-aminoethyl)carbamate (2.16 g, 13.5 mmol, 1.0 eq). The reaction mass was refluxed for about 4 hours. TLC indicated starting material was completed. Reaction mixture was evaporated under reduced pressure. The obtained compound was purified by column chromatography using 0-3% methanol in dichloromethane gradient to afford the title compound (1.5 g, yield: 38.26%) as a solid.TH NMR (500 MHz, CDCh): 5 ppm 7.85 (dd, J = 5.5, 3.0 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 4.82 (s, 1H), 3.83 (t, J= 5.5 Hz, 2H), 3.43- 3.42 (m, 2H), 1.33 (s, 9H).

[0558] Step 2: Synthesis of 2-(2-aminoethyl)isoindoline-l ,3-dione 2,2,2-trifluoroacetic acid:

[0559] To a stirred solution of tert-butyl (2-(l,3-dioxoisoindolin-2-yl)ethyl)carbamate (Step 1, 1.0 g, 3.44 mmol, 1.0 eq) in DCM (6 ml) was added Trifluoroacetic acid (TFA) (4 ml). The reaction mass was stirred at room temperature for around 4 hours. Reaction mass was evaporated under reduced pressure, co-distilled with DCM (2x20 ml). Heptane (20 ml) was added to the residue, stirred at room temperature for about 1 hour. Heptane layer was decanted, and the residue was dried under vacuum. The obtained compound (0.850 g) was used for next step without further purification. ’H NMR (500 MHz, CD3OD): 5 ppm 9.91 (dd, J = 5.5, 3.0 Hz, 2H), 7.84 (dd, J= 5.5, 3.0 Hz, 2H), 3.99 (t, J= 5.5 Hz, 2H), 3.25 (t, J= 5.5 Hz, 2H).

[0560] Intermediate 19: of 3-methyl-4-oxo-3,4-di

[0561] 8-carboxylic acid:

[0562] 3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carboxamide (2 g, 10.30 mmol, 1.0 eq) was stirred in concentrated H2SO4 (16 ml). To the mixture was dropwise added sodium nitrite (2.6 g, 37.68 mmol, 3.65 eq) in water (10.4 ml) on an ice bath at temperature below 15 °C, and then the mixture was kept stirring for about 16 hours at room temperature. Ice water (40 ml) was added into the reaction mixture and cooled on ice bath for about 1 hour. The precipitated solid was collected kept a side and the filtrate was extracted with 20% methanol in DCM (3x50 ml). The combined organic layer was washed with water, dried over sodium, filtered and concentrated under reduced pressure. The earlier collected solid was combined and dried under vacuum to obtain the title compound (1.0 g, yield: 49.75%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 8.80 (s, 1H), 3.87 (s, 3H).

[0563] Intermediate 20: Preparation of 3-: - 1 -aminium 2,2,2-trifluoroacetate :

[0564] Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)propyl acetate:

[0565] To a solution of tert-butyl (3-hydroxypropyl)carbamate (10 g, 57.06 mmol, 1.0 eq) in DCM (100 ml) at 0-10 °C were added N,N-Diisopropylethylamine (15 ml, 85.60 mmol, 1.5 eq) and acetyl chloride (4.5 ml, 62.77 mmol, 1.1 eq). Cooling bath was removed, and the reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with Ethyl acetate (100 ml), washed with water (100 ml) and brine solution (100 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using 0-2% methanol in dichloromethane gradient to obtain the title compound (10 g, yield: 80.64%) as a colourless liquid.TH NMR (500 MHz, DMSO-de): 5 ppm 4.75 (brs, 1H), 4.13 (t, J= 6.0 Hz, 2H), 3.20-3.19 (m, 2H), 2.05 (s, 3H), 1.84-1.79 (m, 2H), 1.44 (s, 9H); Mass: m / z 240.07 (M+Na)+.

[0566] Step 2: Synthesis of 3-acetoxypropan-l-aminium 2,2,2-trijluoroacetate:

[0567] To a stirred solution of 3-((tert-butoxycarbonyl)amino)propyl acetate (Step 1, 10 g, 46.02 mmol, 1.0 eq) in DCM (60 ml) was added Trifluoroacetic acid (TFA) (40 ml). Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure, co-distilled with toluene to remove the excess TFA and then dried under vacuum. The obtained compound (10 g) was used for next step without further purification. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.71 (brs, 3H), 4.05 (t, J= 6.5 Hz, 2H), 2.89-2.83 (m, 2H), 2.02 (s, 3H), 1.88-1.82 (m, 2H); Mass: m / z 118.02 (M+H)+.

[0568] Intermediate 21 : of N-(2-aminoethyl)benzamide:

[0569] To a cooled (0-10 °C) stirred solution of ethane- 1,2-diamine (2.65 g, 44.20 mmol, 2.0 eq) and potassium carbonate (3.054 g, 22.10 mmol, 1.0 eq) in acetonitrile (270 ml), a solution of benzoic anhydride (5 g, 22.10 mmol, 1.0 eq) in acetonitrile (80 ml) was slowly added dropwise. The reaction mixture was stirred for 7 hours at the same temperature. After completion of the reaction, solids were filtered and washed with DCM. The mother liquor was distilled under reduced pressure to a residue which was filtered through a column using 20% methanol in dichloromethane to afford the product (1.88 g, yield: 52%) as an oil.1H NMR (500 MHz, DMSO-de): 5 ppm 8.49 (brs, 1H), 7.86 (d, J= 8.0 Hz, 2H), 7.53-7.50 (m, 1H), 7.45 (td, J= 6.5, 1.5 Hz, 2H), 3.34-3.30 (m, 2H), 2.75 (t, J= 6.5 Hz, 2H); Mass: m / z 163.09 (M-H)'.

[0570] Intermediate 22: Preparation of N-(2-aminoethyl)-2-hvdroxybenzamide 2,2,2-trifluoroacetic acid:

[0571] Step 1: Synthesis of tert-butyl (2-(2-hydroxybenzamido)ethyl)carbamate:

[0572] To a solution of 2-hydroxybenzoic acid (4 g, 28.96 mmol, 1.0 eq) in DCM (40 ml) was added EDC.HC1 (8.883 g, 46.33 mmol, 1.6 eq) and DMAP (0.884 g, 7.24 mmol, 0.25 eq). Reaction mass was stirred at room temperature for 10 minutes, tert-butyl (2- aminoethyl)carbamate (5.56 g, 34.7 mmol, 1.2 eq) was added, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (100 ml), washed with 7% acetic acid solution (40 ml), water (40 ml) and brine solution (40 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using 0-1.5% methanol in dichloromethane gradient to obtain the title compound (5.63 g, yield: 69.35%) as an oil. ’H NMR (500 MHz, DMSO-de): 5 ppm 12.60 (s, 1H), 8.80 (t, 1H), 7.81 (d, J= 8.0 Hz, 1H), 7.39 (dd, J= 15.5, 1.5 Hz, 1H), 6.93 (t, J= 5.0 Hz, 1H), 6.87 (t, J= 8.5 Hz, 2H), 3.34-3.32 (m, 2H), 3.13-3.10 (m, 2H), 1.36 (s, 9H).

[0573] Step 2: Synthesis ofN-(2-aminoethyl)-2-hydroxybenzamide 2,2,2-trifluoroacetic acid:

[0574] To a stirred solution of tert-butyl (2-(2-hydroxybenzamido)ethyl)carbamate (Step 1, 5.6 g, 19.97 mmol, 1.0 eq) in DCM (33.6 ml) at 0-10 °C was added Trifluoroacetic acid (TFA) (22.4 ml). Cooling bath was removed, and the reaction mass was stirred at room temperature for around 5 hours. Reaction mass was evaporated under reduced pressure, co-distilled with DCM (3x20 ml). Hexane (40 ml) was added to the residue stirred at room temperature for about 1 hour. Hexane layer was decanted and dried under vacuum. Methyl -tert-butyl ether (40 ml) was added to the residue, stirred at room temperature for about 1 hour. MTBE layer was decanted and dried under vacuum. The obtained compound (5.2 g) was used for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 8.90 (t, J = 5.0 Hz, 1H), 7.82 (dd, J= 8.0, 1.5 Hz, 4H), 7.42 (dd, J= 15.5, 1.5 Hz, 2H), 6.93-6.89 (m, 2H), 3.54 (dd, J = 12.0, 6.0 Hz, 2H), 3.01 (dd, J= 11.5, 6.0 Hz, 2H).

[0575] Intermediate 23: Preparation of (Z)-4-((4-fluorophenyl)amino)-4-oxobut-2-enoic acid:

[0576] A solution of furan-2,5-dione (5 g, 50.99 mmol, 1.0 eq) in THF (25 ml) was cooled to 0-10 °C. 4-Fluoroaniline (5.66 g, 4.83 ml, 50.99 mmol, 1.0 eq) mixed in THF (5 ml) was added dropwise over a period of 5 minutes. The reaction mass was stirred at 0-10 °C for about 1 hour. Cooling bath was removed and the reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure until no more THF was distilled out. Water (50 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (50 ml) and then dried under vacuum. Solid was further dried under vacuum at 50-60 °C for about 2 hours to obtain the product (7.89 g, yield: 74%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 13.07 (brs, 1H), 10.42 (s, 1H), 7.64 (dd, J= 9.0, 5.0 Hz, 2H), 7.17 (t, J= 9.0 Hz, 2H), 6.46 (d, J= 12.0 Hz, 1H), 6.30 (d, J = 12.0 Hz, 1H). Mass: m / z 232.08 (M+Na)+.

[0577] Intermediate 24: Preparation of (lR,3S)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-1 -carboxylic acid:

[0578] Racemic 3 -((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l -carboxylic acid (Intermediate 1-step 1, 100 g, 397.99 mmol, 1.0 eq) and propan-2-ol (2.5 Ltr) were stirred at 80-85 °C for around 1 hour. After getting clear solution, (R)-l-phenylethan-l -amine (48.22 g, 50.76 ml, 397.99 mmol, 1.0 eq) was added at 80-85 °C and stirred at same temperature for around 5 hours. Heating bath was removed, and the reaction mixture was allowed to stirred at room temperature for overnight. The obtained solid was filtered, washed with propan-2-ol (250 ml) and dried under vacuum. Solid was taken into RB flask, Isopropanol (800 ml) was added, stirred at room temperature for about 2 hours. Solid was filtered, washed with propan-2-ol (100 ml) and then dried under vacuum. Solid was cooled to 0 °C, IN HC1 (2 Ltr) and DCM (2 Ltr) were added, stirred at room temperature around 1 hour. After getting clear solution, organic layer was separated, and the aqueous layer was extracted with DCM (2x800 ml). The combined organic layer was washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain title compound (31.8 g, yield: 31.8%) as an off-white solid. Enantiomeric purity by chiral HPLC: >99%. Stereochemistry of the product was confirmed by Single crystal X-ray diffraction (XRD) analysis. ’H NMR (500 MHz, DMSO-de): 5 ppm 12.16 (s, 1H), 10.14 (s, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.11 (t, J= 9.0 Hz, 2H), 1.98 (d, J= 9.5 Hz, 1H), 1.88 (d, J= 9.5 Hz, 1H), 1.33 (s, 3H), 1.19 (s, 3H); Mass: m / z 274.04 (M+Na)+.

[0579] Intermediate 25: Preparation of (lS,3R)-3-((4-chlorophenyl)carbamoyl)-2,2- dimethylcyclopropane-1 -carboxylic acid:

[0580] Step 1: Synthesis of 3-((4-chlorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxylic acid:

[0581] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 71.35 mmol, 1.0 eq) in THF (100 ml) was added 4-chloroaniline (9.1 g, 7.78 ml, 71.35 mmol, 1.0 eq) dropwise over a period of 10 minutes. Reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. Reaction mixture was evaporated under reduced pressure. Water (100 ml) was added to the residue, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (50 ml) and then dried under vacuum to obtain the title compound (16.2 g, yield: 84.2%) as a pale-yellow solid.1HNMR (500 MHz, DMSO-de): 5 ppm 12.11 (s, 1H), 10.2 (s, 1H), 7.58 (d, J= 8.5 Hz, 2H), 7.32 (d, J= 9.0 Hz, 2H), 1.99 (d, = 9.0 Hz, 1H), 1.88 (d, J= 9.5 Hz, 1H), 1.32 (s, 3H), 1.19 (s, 3H); Mass: m / z 290.13 (M+Na)+.

[0582] Step 2: Synthesis of (lS,3R)-3-((4-chlorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxylic acid:

[0583] A suspension of the 3-((4-chlorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxylic acid (Step 1, 8 g, 29.88 mmol, 1.0 eq) in Isopropanol (200 ml) was heated to reflux for about 1 hour to achieve a clear solution. (S)-phenylethyl amine (3.621 g, 29.88 mmol, 1.0 eq) was added and the reflux was continued for about 5 hours. The reaction mixture was changed to room temperature and stirred for overnight. Solid was filtered, washed with Isopropanol (40 ml) and then dried under vacuum. The solid was taken into RB flask, isopropanol (120 ml) was added and stirred at room temperature for about 2 hours. Solid was filtered, washed with Isopropanol (40 ml) and then dried under vacuum. The wet solid was again taken into RB flask, Isopropanol (80 ml) was added, stirred at room temperature for about 2 hours. Solid was filtered, washed with isopropanol (16 ml) and then dried under vacuum. DCM (180 ml) and IN HC1 (180 ml) were added to the obtained solid, stirred at room temperature for about 30 minutes, until get a clear solution. Organic layer was separated, and the aqueous layer was extracted with DCM (3x80 ml). The combined organic layer was washed with water (180 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (2.52 g, yield: 31.5%) as a solid. Enantiomeric purity by chiral HPLC: >99%.XHNMR (500 MHz, DMSO-de): 5 ppm 12.11 (s, 1H), 10.20 (s, 1H), 7.58 (d, J= 8.5 Hz, 2H), 7.32 (d, J= 9.0 Hz, 2H), 1.99 (d, = 9.0 Hz, 1H), 1.88 (d, J= 9.5 Hz, 1H), 1.32 (s, 3H), 1.19 (s, 3H); Mass: m / z 268.18 (M+H)+.

[0584] Intermediate 26: Preparation of 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxy-N- methylquinoline-6-carboxamide:

[0585] Step 1: Synthesis of methyl 7-methoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline-6-carboxylate:

[0586] To a solution of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (8 g, 34.30 mmol, 1.0 eq) in DMF (80 ml) was added triethylamine (4.165 g, 5.73 ml, 41.16 mmol, 1.2 eq) and 2-chloro-5-nitropyrimidine (5.472 g, 34.30 mmol, 1.0 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. Reaction mass was poured into water (800 ml), stirred at room temperature for around 1 hour. Solid was filtered, washed with water (200 ml) and then dried under vacuum. DCM (24 ml) was added to the obtained solid, stirred at room temperature for about 1 hour. Solid was filtered, washed with DCM (5 ml) and then dried under vacuum to afford the title compound (6.2 g, yield: 50.73%) as a pale-yellow solid.TH NMR (500 MHz, DMSO-de): 5 ppm 9.79 (s, 2H), 8.61 (d, J= 8.5 Hz, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H); Mass: m / z 357.11 (M+H)+.

[0587] Step 2: Synthesis of methyl 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxyquinoline-6- carboxylate:

[0588] To a stirred suspension of methyl 7-methoxy-4-((5-nitropyrimidin-2-yl)oxy)quinoline- 6-carboxylate (Step 1, 6.0 g, 16.84 mmol, 1.0 eq) in Methanol (30 ml) and water (6 ml) was added Iron powder (4.70 g, 84.20 mmol, 5.0 eq) and acetic acid (6 ml). The reaction mass was stirred at 60-65 °C for around 4 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was allowed to cool to room temperature. DCM (120 ml) was added to the reaction mass, stirred at room temperature for around 30 minutes. Reaction mass was filtered through celite bed, washed with DCM (60 ml). The filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution. Organic layer was separated, and the aqueous layer was extracted with 10% methanol in DCM (50 ml). The combined organic layer was washed with water (60 ml) and brine solution (60 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Methyl tert-butyl ether (30 ml) was added to the obtained solid, stirred at room temperature for 1 hour. Solid was filtered, washed with MTBE (10 ml) and then dried under vacuum. Methanol (30 ml) was added to the resulting solid, stirred at room temperature for around 2 hours. Solid was filtered, washed with methanol (6 ml) and then dried under vacuum to obtain the title compound (2.03 g, yield: 37%) as a pale-yellow solid.1HNMR (500 MHz, DMSO-de): 5 ppm 8.53 (s, 1H), 8.27 (s, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.16 (d, J = 7.5 Hz, 1H), 6.07 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H); Mass: m / z 327.17 (M+H)+.

[0589] Step 3: Synthesis of 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxy-N-methylquinoline-6- carboxamide:

[0590] To a stirred solution of methyl 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxyquinoline- 6-carboxylate (Step 2, 0.400 g, 1.225 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (2 ml) at 10- 20 °C was added 40% aqueous methyl amine (1.6 ml). The reaction mixture was stirred at 10- 20 °C for about 1 hour and then stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to 10-20 °C, Water (30 ml) was added, stirred at same temperature for about 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum. The crude compound was purified by column chromatography using 0-5% methanol in dichloromethane gradient to afford the title compound (0.320 g, yield: 80.4%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.55 (s, 1H), 8.27 (s, 2H), 8.19 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 7.10 (s, 1H), 6.14 (d, J= 8.0 Hz, 1H), 6.05 (s, 2H), 3.80 (s, 3H), 2.81 (d, J= 3.5 Hz, 3H); Mass: m / z 326.21 (M+H)+.

[0591] Intermediate 27: i-4-oxobutanoic acid:

[0592] To a solution of succinic anhydride (3.0 g, 29.98 mmol, 1.0 eq) in THF (30 ml) was added 4-Fluoroaniline (3.33 g, 2.84 ml, 29.98 mmol, 1.0 eq). The reaction mass was refluxed for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure until no more THF was distilled out. Water (60 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. Solid was filtered, washed with water (15 ml) and then dried under vacuum. The solid was further dried under vacuum at 50 °C for about 1 hour to obtain the product (5 g, yield: 79%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 12.12 (brs, 1H), 10.0 (s, 1H), 7.60-7.57 (m, 2H), 7.12 (t, J= 9.0 Hz, 2H), 2.56-2.51 (m, 4H); Mass: m / z 210.13 (M-H)-.

[0593] Intermediate 28: Preparation of 4- 4-aminophenyl)thio)-7-methoxy-N-methylquinoline-6- carboxamide:

[0594] Step 1: Synthesis of methyl 7-methoxy-4-((4-nitrophenyl)thio)quinoline-6-carboxylate:

[0595] To a stirred suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (7 g, 27.81 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (NMP) (35 ml) was added 4-nitrobenzenethiol (6.47 g, 41.72 mmol, 1.5 eq). N-ethyl-N-isopropylpropan-2-amine (10.78 g, 14.53 ml, 83.43 mmol, 3.0 eq) was added dropwise slowly over a period of 10 minutes. Due to Exothermic nature, internal temperature rises to 40 to 50 °C. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to 0-10 °C, water (875 ml) was added, stirred at same temperature for about 30 minutes. Solid was filtered, washed with water (120 ml) and then dried under vacuum to afford the title compound (7.2 g, yield: 69.9%) as a pale-yellow colour solid.XH NMR (500 MHz, DMSO-de): 5 ppm 8.83 (d, J= 4.5 Hz, 1H), 8.45 (s, 1H), 8.24 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 9.0 Hz, 2H), 7.63 (s, 1H), 7.31 (d, J = 4.5 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 3H); Mass: m / z 371.1 (M+H)+.

[0596] Step 2: Synthesis of methyl 4-((4-aminophenyl)thio)-7-methoxyquinoline-6-carboxylate:

[0597] To a suspension of methyl 7-methoxy-4-((4-nitrophenyl)thio)quinoline-6-carboxylate (Step 1, 5.0 g, 13.5 mmol, 1.0 eq) in Methanol (25 ml) and water (5 ml) was added Iron powder (3.77 g, 67.49 mmol, 5.0 eq) and acetic acid (5 ml). Reaction mass was stirred at 60-65 °C for around 4 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach to room temperature. DCM (100 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. Reaction mass was filtered through celite bed, washed with DCM (100 ml). Filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution. Organic layer was separated, and the aqueous layer was extracted with DCM (2x100 ml). The combined organic layer was washed with water (100 ml) and brine solution (50 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using 0-2% methanol in dichloromethane gradient to afford the title compound (3.7 g, yield: 80.52%) as a pale-yellow colour solid. _XH NMR (500 MHz, DMSO-de): 5 ppm 8.57 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 7.50 (s, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.72 (d, J= 8.5 Hz, 2H), 6.56 (d, J = 5.0 Hz, 1H), 5.75 (d, J = 5.0 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H); Mass: m / z 341.18 (M+H)+.

[0598] Step 3: Synthesis of 4-((4-aminophenyl)thio)-7-methoxy-N-methylquinoline-6-carboxamide :

[0599] To a stirred solution of methyl 4-((4-aminophenyl)thio)-7-methoxyquinoline-6- carboxylate (Step 2, 3.5 g, 10.28 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (17.5 ml) was added 40% aqueous methyl amine (10.5 ml). The reaction mixture was stirred at 0-10 °C for about 1 hour. Cooling bath was removed and the reaction mass stirred at room temperature for overnight. After completion of the reaction monitored by TLC, reaction mass was diluted with water (262 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layer was again washed with water (100 ml), dried over sodium sulphate, filtered and evaporated under reduced pressure. The obtained solid was stirred with Hexane: Methyl -tert-butyl ether (40 ml, 1 : 1) at room temperature for about 1 hour. Solid was filtered, washed with Hexane and then dried under vacuum to obtain the title compound (2.9 g, yield: 83.1%) as a pale-yellow solid.1H NMR (500 MHz, DMSO-de): 5 ppm 8.53 (d, = 5.0 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J= 4.5 Hz, 1H), 7.48 (s, 1H), 7.26 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.54 (d, J= 5.0 Hz, 1H), 5.73 (s, 2H), 4.01 (s, 3H), 2.85 (d, J= 4.5 Hz, 3H); Mass: m / z 340.20 (M+H)+.

[0600] Intermediate 29: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxy-N-methylquinoline- 6-carboxamide:

[0601] To a stirred solution of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (1 g, 3.98 mmol, 1.0 eq) in DMA (20 ml) was added sodium tert-butoxide (0.76 g, 7.96 mmol, 2.0 eq) and 4-amino-3-chlorophenol (1.14 g, 7.96 mmol, 2.0 eq). The reaction mixture was stirred at 80-85 °C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature, water (200 ml) was added and extracted with ethyl acetate (3x50 ml). The combined organic layer was washed with water (2x100 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (1.1 g, yield: 77%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.63 (d, J= 5.0 Hz, 1H), 8.59 (s, 1H), 8.34 (m, 1H), 7.49 (s, 1H), 7.23 (d, J= 3.0 Hz, 1H), 7.01 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.46 (d, J= 5.0 Hz, 1H), 5.45 (s, 2H), 4.01 (s, 3H), 2.84 (d, J= 5.0 Hz, 3H); Mass: m / z 358.15 (M+H)+.

[0602] Intermediate 30: Preparation of 4-(3-aminophenoxy)-7-methoxy-N-methylquinoline-6- carb oxami de:

[0603] Step 1: Synthesis of methyl 7-methoxy-4-(3-nitrophenoxy)quinoline-6-carboxylate :

[0604] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (6 g, 23.84 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (36 ml) was added N-ethyl-N-isopropylpropan-2- amine (10.78 g, 14.53 ml, 83.44 mmol, 3.5 eq) and 3-nitrophenol (5.638 g, 40.53 mmol, 1.7 eq). The reaction mass was stirred at 130-140 °C for around 7 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Reaction mass was cooled to 10-20 °C, water (540 ml) was added, stirred at same temperature for about 1 hour. Solid was filtered, washed with water (100 ml) and then dried under vacuum. Methanol (30 ml) was added to the resulting solid, stirred at room temperature for around 1 hour. Solid was filtered, washed with methanol and then dried under vacuum to obtain the title compound (6.1 g, yield: 72.21%) as a pale-yellow solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 8.74 (d, J= 5.5 Hz, 1H), 8.58 (s, 1H), 8.23-8.21 (m, 1H), 8.20-8.18 (m, 1H), 7.85-7.82 (m, 2H), 7.57 (s, 1H), 8.68 (d, J= 5.0 Hz, 1H), 3.99 (s, 3H), 3.87 (s, 3H); Mass: m / z 377.14 (M+Na)+.

[0605] Step 2: Synthesis of methyl 4-(3-aminophenoxy)-7-methoxyquinoline-6-carboxylate:

[0606] To a suspension of methyl 7-methoxy-4-(3-nitrophenoxy)quinoline-6-carboxylate (Step 1, 6 g, 16.93 mmol, 1.0 eq) in Methanol (30 ml) and water (6 ml) was added Iron powder (4.7 g, 84.65 mmol, 5.0 eq) and acetic acid (6 ml). Reaction mixture was stirred at 60-65 °C for around 4 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Ethyl acetate (180 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The reaction mass was filtered through celite bed, washed with ethyl acetate (120 ml). Filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution, stirred at room temperature for about 30 minutes. Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with water (100 ml) and brine solution (50 ml). Organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. Methanol (30 ml) was added to the obtained solid, stirred at room temperature for about 30 minutes. Solid was filtered, washed with methanol and then dried under vacuum to afford the title compound (4.9 g, yield: 89.2%) as a pale-yellow solid.XH NMR (500 MHz, DMSO-de): 5 ppm 8.69 (d, J= 5.0 Hz, 1H), 8.55 (s, 1H), 7.52 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.56 (d, J = 5.5 Hz, 1H), 6.52 (d, J= 8.0 Hz, 1H), 6.40 (s, 1H), 6.36 (d, J= 7.5 Hz, 1H), 5.40 (s, 2H), 3.98 (s, 3H), 3.86 (s, 3H); Mass: m / z 325.20 (M+H)+.

[0607] Step 3: Synthesis of 4-(3-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide:

[0608] To a stirred solution of methyl 4-(3-aminophenoxy)-7-methoxyquinoline-6- carboxylate (Step 2, 4.8 g, 14.80 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (24 ml) was added 40% aqueous methyl amine (9.6 ml). The reaction mixture was stirred at 0-10 °C for about 1 hour and then stirred at room temperature for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Water (360 ml) was added to the reaction mixture, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (120 ml) and then dried under vacuum. Methanol (20 ml) was added to the obtained solid, stirred at room temperature for about 1 hour. Solid was filtered, washed with methanol and then dried under vacuum to obtain the product (1.6 g, yield: 33.43%) as a pale-yellow solid.1H NMR (500 MHz, DMSO-de): 5 ppm 8.66 (d, J= 5.5 Hz, 1H), 8.56 (s, 1H), 8.35 (d, J= 4.5 Hz, 1H), 7.50 (s, 1H), 7.13 (t, = 8.0 Hz, 1H), 6.56 (d, J= 5.0 Hz, 1H), 6.52-6.50 (m, 1H), 6.38 (t, J= 2.5 Hz, 1H), 6.35 (dd, J= 8.0, 1.5 Hz, 1H), 5.39 (s, 2H), 4.01 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H); Mass: m / z 346.17 (M+Na)+. Intermediate 31 : Preparation of 4-(4-amino-2-chlorophenoxy)-7-methoxy-N-methylquinoline- 6-carboxamide:

[0609] Step 1: Synthesis of methyl 4-(2-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate :

[0610] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (5 g, 19.86 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (25 ml) was added N-ethyl-N-isopropylpropan-2- amine (8.987 g, 12.11 ml, 69.53 mmol, 3.5 eq) and 2-chloro-4-nitrophenol (5.861 g, 33.77 mmol, 1.7 eq). The reaction mass was stirred at 110-120 °C for around 18 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Reaction mass was cooled to 10-20 °C, water (375 ml) was added, stirred at same temperature for about 1 hour. Solid was filtered, washed with water (100 ml) and then dried under vacuum. The crude compound was purified by column chromatography using 0-40% Ethyl acetate in hexanes gradient to obtain the title compound (6.6 g, yield: 85.45%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.77 (d, J= 5.0 Hz, 1H), 8.61 (d, J= 3.0 Hz, 1H), 8.55 (s, 1H), 8.33 (dd, J= 9.0, 2.5 Hz, 1H), 7.71 (d, J= 8.5 Hz, 1H), 7.60 (s, 1H), 6.70 (d, J= 5.0 Hz, 1H), 4.0 (s, 3H), 3.87 (s, 3H); Mass: m / z 389.12 (M+H)+.

[0611] Step 2: Synthesis of methyl 4-(4-amino-2-chlorophenoxy)-7-methoxyquinoline-6-carboxylate :

[0612] To a suspension of methyl 4-(2-chloro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate (Step 1, 6.5 g, 16.72 mmol, 1.0 eq) in Methanol (32.5 ml), water (6.5 ml) was added Iron powder (4.67 g, 83.6 mmol, 5.0 eq) and acetic acid (6.5 ml). Reaction mixture was stirred at 60-65 °C for around 4 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Ethyl acetate (180 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The reaction mass was filtered through celite bed, washed with ethyl acetate (100 ml). Filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution, stirred at room temperature for about 30 minutes. Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with water (100 ml) and brine solution (50 ml). Organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude compound was purified by column chromatography using 0-3% methanol in dichloromethane gradient to afford the title compound (4.7 g, yield: 78.36%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.67 (d, J= 5.0 Hz, 1H), 8.60 (s, 1H), 7.52 (s, 1H), 7.13 (d, J= 8.5 Hz, 1H), 6.79 (d, J= 2.5 Hz, 1H), 6.63 (dd, J= 8.5, 2.5 Hz, 1H), 6.35 (d, J= 5.0 Hz, 1H), 5.51 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H); Mass: m / z 381.13 (M+Na)+.

[0613] Step 3: Synthesis of 4-(4-amino-2-chlorophenoxy)-7-methoxy-N-methylquinoline-6- carboxamide:

[0614] To a stirred solution of methyl 4-(4-amino-2-chlorophenoxy)-7-methoxyquinoline-6- carboxylate (Step 2, 4.5 g, 12.54 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (22.5 ml) was added 40% aqueous methyl amine (13.5 ml). The reaction mixture was stirred at 10-20 °C for about 1 hour and then stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Water (337 ml) was added to the reaction mixture, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (135 ml) and then dried under vacuum. The crude compound was purified by column chromatography using 0-5% methanol in dichloromethane gradient to afford the title compound (4.0 g, yield: 89.14%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.63 (d, .7= 5.5 Hz, 1H), 8.61 (s, 1H), 8.37-8.33 (m, 1H), 7.50 (s, 1H), 7.11 (d, = 8.5 Hz, 1H), 6.79 (d, J= 2.5 Hz, 1H), 6.63 (dd, 1H), 6.33 (d, J = 5.0 Hz, 1H), 5.50 (s, 2H), 4.02 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H); Mass: m / z 380.14 (M+Na)+. Intermediate 32: of 4-(4-amino-3- i-7-methoxv-N-

[0615] 6-carboxamide:

[0616] Step 1: Synthesis of methyl 4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate:

[0617] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (4.5 g, 17.88 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (22.5 ml) was added N-ethyl-N-isopropylpropan-2- amine (8.088 g, 10.90 ml, 62.58 mmol, 3.5 eq) and 3-fluoro-4-nitrophenol (5.618 g, 35.76 mmol, 2.0 eq). The reaction mass was stirred at 120-130 °C for around 16 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Reaction mass was cooled to 10-20 °C, water (340 ml) was added, stirred at same temperature for about 1 hour. Solid was filtered, washed with water (100 ml) and then dried under vacuum. The crude compound was purified by column chromatography using 0-50% Ethyl acetate in hexanes gradient to obtain the title compound (2.30 g, yield: 34.55%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 4.83 (d, J= 5.5 Hz, 1H), 8.46 (s, 1H), 8.31 (t, J= 9.0 Hz, 1H), 7.69 (dd, J= 12.0, 2.5 Hz, 1H), 7.60 (s, 1H), 7.33 (dd, J= 9.0, 2.5 Hz, 1H), 6.95 (d, J= 5.5 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H); Mass: m / z 373.17 (M+H)+.

[0618] Step 2: Synthesis of methyl 4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylate:

[0619] To a suspension of methyl 4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate (Step 1, 2.1 g, 5.909 mmol, 1.0 eq) in Methanol (10.5 ml), water (2.1 ml) was added Iron powder (1.575 g, 28.20 mmol, 5.0 eq) and acetic acid (2.1 ml). Reaction mixture was stirred at 60-65 °C for around 4 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Ethyl acetate (30 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. Reaction mass was filtered through celite bed, washed with 10% methanol in ethyl acetate (50 ml). Filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution. Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2x30 ml). The combined organic layer was washed with water (50 ml) and brine solution (30 ml). Organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude compound was purified by column chromatography using 0-3% methanol in dichloromethane gradient to afford the title compound (1.35 g, yield: 69.94%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.66 (d, .7= 5.0 Hz, 1H), 8.57 (s, 1H), 7.51 (s, 1H), 7.10 (dd, J= 12.0, 2.0 Hz, 1H), 6.88- 6.87 (m, 2H), 6.48 (d, J = 5.0 Hz, 1H), 5.23 (s, 2H), 3.97 (s, 3H), 3.86 (s, 3H); Mass: m / z 365.14 (M+Na)+.

[0620] Step 3: Synthesis of 4-(4-amino-3-fluorophenoxy)-7-methoxy-N-methylquinoline-6- carboxamide:

[0621] To a stirred solution of methyl 4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline-6- carboxylate (Step 2, 1.3 g, 3.797 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (6.5 ml) was added 40% aqueous methyl amine (3.9 ml). The reaction mixture was stirred at 0-10 °C for about 1 hour and then stirred at room temperature for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Water (60 ml) was added to the reaction mixture, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum to obtain the title compound (1.14 g, yield: 87.96%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 8.63 (d, J= 5.5 Hz, 1H), 8.59 (s, 1H), 8.37-8.32 (m, 1H), 7.49 (s, 1H), 7.08 (dd, 1H), 6.88-6.86 (m, 2H), 6.47 (d, J= 5.0 Hz, 1H), 5.21 (s, 2H), 4.01 (s, 3H), 2.84 (d, J= 5.0 Hz, 3H); Mass: m / z 364.18 (M+Na)+.

[0622] Intermediate 33: Preparation of 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate:

[0623] To an ice cooled solution of 2-(tert-butoxy)ethan-l-ol (3 g, 25.38 mmol, 1.0 eq) in DCM (30 ml) was added triethylamine (5,137 g, 7.0 ml, 50.76 mmol, 2.0 eq), 4- (dimethylamino)pyridine (0.31 g, 2.537 mmol, 0.1 eq) and para-Toluene sulfonyl chloride (7.25 g, 38.03 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (50 ml), washed with saturated ammonium chloride solution (40 ml) and water (40 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using DCM as an eluent to afford the title compound (4.3 g, yield: 60.75%) as a pale blue colour oil. 'H NMR (500 MHz, DMSO-de): 5 ppm 7.78 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 4.06 (t, J= 4.5 Hz, 2H), 3.45 (t, J= 4.5 Hz, 2H), 2.42 (s, 3H), 1.05 (s, 9H).

[0624] Intermediate 34:

[0625] To a solution of tert-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (2.0 g, 9.29 mmol, 1.0 eq) in DCM (20 ml) at 0-10 °C was added Triethylamine (1.88 g, 18.57 mmol, 2.0 eq), DMAP (0.226 g, 1.857 mmol, 0.2 eq) and 4-methylbenzenesulfonyl chloride (1.948 g, 10.218 mmol, 1.1 eq). Cooling bath was removed, and the reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (20 ml), washed with 2% citric acid solution (15 ml) and water (50 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using DCM as an eluent to afford the title compound (3.0 g) as a liquid. Mass: m / z 392.17 (M+Na)+.

[0626] Intermediate 35: Preparation of 2-methoxy ethyl 4-methylbenzenesulfonate: To a stirred solution of 2-methoxyethan-l-ol (2.5 g, 32.85 mmol, 1.0 eq) in DCM (25 ml) at 0-10 °C was added triethylamine (6.648 g, 9.15 ml, 65.69 mmol, 2.0 eq) and para- Toluene sulfonyl chloride (7.51 g, 39.42 mmol, 1.2 eq). Cooling bath was removed, and the reaction mass was stirred at room temperature for overnight. The reaction mass was diluted with DCM (60 ml), washed with 0.5N HC1 solution (20 ml), 5% sodium bicarbonate solution (20 ml), water (20 ml) and brine solution (20 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by column chromatography using dichloromethane as an eluent to afford the title compound (2 g, yield: 26.43%) as a liquid. ’H NMR (500 MHz, DMSO-de): 5 ppm 7.78 (d, J = 8.0 Hz, 2H), 7.48 (d, J= 8.0 Hz, 2H), 4.11 (t, J= 4.5 Hz, 2H), 3.48 (t, J= 4.5 Hz, 2H), 3.17 (s, 3H), 2.42 (s, 3H).

[0627] Intermediate 36: i-2,2- ;-l -carboxylic acid:

[0628] To a solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (5 g, 35.67 mmol, 1.0 eq) in THF (30 ml) was added 4-fhioro-N-methylaniline (4.46 g, 4.3 ml, 35.67 mmol, 1.0 eq) mixed in THF (20 ml) dropwise over a period of 10 minutes. The reaction mass was stirred at 50-60 °C for around 3 hours. After completion of the reaction monitored by TLC, Reaction mass was evaporated under reduced pressure. Water (100 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum. Solid was further dried under vacuum at 50-60 °C for about 2 hours to afford the title compound (8.23 g, yield: 87%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 12.43 (s, 1H), 7.35-7.29 (m, 4H), 3.16 (s, 3H), 1.59 (d, J= 8.5 Hz, 1H), 1.54 (d, J= 8.5 Hz, 1H), 1.24 (s, 6H); Mass: m / z 288.04 (M+Na)+.

[0629] Intermediate 37: Preparation of (E)-4-((4- i-4-oxobut-2-enoic acid:

[0630] Step 1: Synthesis of methyl (E)-4-((4-jluorophenyl)amino)-4-oxobut-2-enoate:

[0631] A solution of (E)-4-methoxy-4-oxobut-2-enoic acid (3.0 g, 23.05 mmol, 1.0 eq) and 4- Fluoroaniline (2.8 g, 25.36 mmol, 1.1 eq) in DMF (30 ml) was cooled to 0 °C. N-Ethyl diisopropyl amine (7.4 g, 10 ml, 57.62 mmol, 2.5 eq) and HATU (17.52 g, 46.1 mmol, 2.0 eq) were added, reaction mass was stirred at 0-10 °C for about 1 hour. Cooling bath was removed and the reaction mass stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to 0-20 °C, Water (450 ml) was added, stirred at 0-20 °C for about 1 hour. Solid was filtered, washed with water (150 ml) and then dried under vacuum. The obtained solid was purified by column chromatography (silica gel, 60-120 mesh) using 0-5% methanol in dichloromethane gradient to obtain the product (4.87 g, yield: 94%) as a solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.62 (s, 1H), 7.71-7.68 (m, 2H), 7.22-7.17 (m, 2H), 7.19 (d, J= 15.5 Hz, 1H), 6.73 (d, J = 15.5 Hz, 1H), 3.76 (s, 3H); Mass: m / z 224.17 (M+H)+.

[0632] Step 2: Synthesis of (E)-4-((4-fluorophenyl)amino)-4-oxobut-2-enoic acid:

[0633] To a solution of methyl (E)-4-((4-fluorophenyl)amino)-4-oxobut-2-enoate (Step 1, 4.5 g, 20.161 mmol, 1.0 eq) in methanol (22.5 ml) and THF (22.5 ml) was added IN KOH solution (140.8 ml, 141.13 mmol, 7.0 eq). The reaction mass was stirred at 10 to 20 °C for around 5 hours. TLC indicated starting material was completed. Reaction mass was cooled to 10 to 20 °C, IN HC1 was added till reaction mass pH reaches to 8.0. Reaction mass was evaporated under reduced pressure at bath temperature below 40 °C. Reaction mass was cooled to 10-20 °C, pH adjusted to 3.0 with IN HC1. The resulting solid was filtered, washed with water (40 ml) and then dried under vacuum to obtain the title compound (3.9 g) as a solid; ’H NMR (500 MHz, DMSO-de): 5 ppm 13.07 (s, 1H), 10.57 (s, 1H), 7.71-7.68 (m, 2H), 7.19 (t, J = 9.0 Hz, 2H), 7.11 (d, J= 15.5 Hz, 1H), 6.66 (d, J= 15.5 Hz, 1H). Mass: m / z 210.23 (M+H)+.

[0634] Intermediate 38: Preparation of 2,2-dimethyl-3-(phenylcarbamoyl)cyclopropane-l -carboxylic acid:

[0635] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 71.35 mmol, 1.0 eq) in THF (50 ml) was added aniline (6.645 g, 6.51 ml, 71.35 mmol, 1.0 eq) mixed in THF (50 ml) dropwise over a period of 20 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. THF was evaporated under reduced pressure. Water (200 ml) was added to the residue, stirred at room temperature for around 1 hour. Solid was filtered, washed with water (50 ml) and then dried under vacuum to obtain the title compound (13.65 g, yield: 82%) as an off-white solid.1HNMR (500 MHz, DMSO-d6): 5 ppm 12.19 (s, 1H), 10.10 (s, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.27 (t, J= 8.0 Hz, 2H), 7.01 (t, J= 7.5 Hz, 1H), 2.0 (d, J= 9.5 Hz, 1H), 1.88 (d, J= 9.5 Hz, 1H), 1.32 (s, 3H), 1.19 (s, 3H); Mass: m / z 256.10 (M+Na)+.

[0636] Intermediate 39: Preparation of 2-((4-fluorophenyl)carbamoyl)cvclopropane-l-carboxylic acid:

[0637] To a solution of 3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 89.32 mmol, 1.0 eq) in THF (50 ml) was added 4-Fluoroaniline (9.914 g, 8.45 ml, 89.32 mmol, 1.0 eq) mixed in THF (10 ml) dropwise over a period of 20 minutes. The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure until no more THF was distilled out. Water (100 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (50 ml) and then dried under vacuum. Solid was further dried under vacuum at 50-60 °C for about 2 hours to obtain the product (15.53 g, yield: 78%) as an off-white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 12.14 (brs, 1H), 10.19 (s, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.12 (dd, J= 15.5, 2.0 Hz, 2H), 2.18-2.14 (m, 1H), 2.03-1.98 (m, 1H), 1.43-1.39 (m, 1H), 1.17-1.13 (m, 1H).

[0638] Intermediate 40: Preparation of 3-((2,4-difluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-1 -carboxylic acid:

[0639] To a solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (5 g, 35.67 mmol, 1.0 eq) in THF (25 ml) was added 2,4-difluoroaniline (4.606 g, 35.67 mmol, 1.0 eq) dissolved in THF (25 ml) dropwise over a period of 15 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. THF was evaporated under reduced pressure. Water (100 ml) was added to the residue, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum to afford the title compound (7.5 g, yield: 78.07%) as a white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 12.18 (s, 1H), 9.92 (s, 1H), 7.80-7.75 (m, 1H), 7.31-7.26 (m, 1H), 7.05-7.02 (m, 1H), 2.10 (d, J = 9.0 Hz, 1H), 1.89 (d, J = 9.5 Hz, 1H), 1.31 (s, 3H), 1.19 (s, 3H); Mass: m / z 292.15 (M+Na)+.

[0640] Intermediate 41 : Preparation of 2,2-dimethyl-3-(pyri din-3 -ylcarbamoyl)cvclopropane-l- carboxylic acid:

[0641] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 71.35 mmol, 1.0 eq) in THF (50 ml) was added pyri din-3 -amine (6.716 g, 71.35 mmol, 1.0 eq) mixed in THF (50 ml) dropwise over a period of 20 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. THF was evaporated under reduced pressure. Water (150 ml) was added to the residue, stirred at room temperature for around 1 hour. Solid was filtered, washed with water (100 ml) and then dried under vacuum to obtain the title compound (12.5 g, yield: 74.8%) as a solid.1HNMR (500 MHz, DMSO-de): 5 ppm 12.09 (s, 1H), 10.26 (s, 1H), 8.69 (d, J= 3.0 Hz, 1H), 8.22 (dd, J= 4.5, 1.5 Hz, 1H), 8.0 (dd, J= 8.5, 1.5 Hz, 1H), 7.30 (dd, J= 8.5, 4.5 Hz, 1H), 2.02 (d, J = 9.5 Hz, 1H), 1.90 (d, J = 9.0 Hz, 1H), 1.33 (s, 3H), 1.19 (s, 3H); Mass: m / z 233.07 (M-H)-.

[0642] Intermediate 42: Preparation of 3-((5-fluoropyridin-2-yl)carbamoyl)-2,2- dimethylcyclopropane-1 -carboxylic acid:

[0643] To a stirred solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (20 g, 142.71 mmol, 1.0 eq) in THF (100 ml) was added 5-fluoropyridin-2-amine (16 g, 142.71 mmol, 1.0 eq) mixed in THF (100 ml) dropwise over a period of 30 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was completed and the desired product was observed. THF was evaporated under reduced pressure. Water (200 ml) was added to the residue, stirred at room temperature for around 1 hour. Solid was filtered, washed with water (100 ml) and then dried under vacuum to obtain the title compound (27.36 g, yield: 76%) as a white solid.XHNMR (500 MHz, DMSO-de): 5 ppm 12.05 (s, 1H), 10.72 (s, 1H), 8.29 (d, J= 3.0 Hz, 1H), 8.06 (dd, J= 9.0, 4.0 Hz, 1H), 7.69 (td, J= 8.5, 3.0 Hz, 1H), 2.11 (d, J= 9.0 Hz, 1H), 1.89 (d, J= 9.0 Hz, 1H), 1.32 (s, 3H), 1.17 (s, 3H).

[0644] Intermediate 43: Preparation of 2,2-dimethyl-3-((5-methyl-l,3,4-thiadiazol-2-

[0645] To a solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 71.37 mmol, 1.0 eq) in THF (170 ml) was added 5-methyl-l,3,4-thiadiazol-2-amine (8.22 g, 71.37 mmol, 1.0 eq) dissolved in THF (40 ml) dropwise over a period of 15 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. THF was evaporated under reduced pressure. Water (150 ml) was added to the residue, stirred at room temperature for around 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum. The obtained solid was stirred at 60- 65 °C for around 30 minutes. Reaction mass was cooled to room temperature, solid was filtered, washed with methanol and then dried under vacuum to obtain the title compound (12.49 g) as an off-white solid. Mass: m / z 256.1 (M+H)+.

[0646] Intermediate 44: of 2,2-dimethyl-3-((2- ;-l -carboxylic acid:

[0647] To a solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (5 g, 35.67 mmol, 1.0 eq) in THF (25 ml) was added 2-methylbenzo[d]thiazol-6-amine (5.85 g, 35.67 mmol, 1.0 eq) dissolved in THF (25 ml) dropwise over a period of 15 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. THF was evaporated under reduced pressure. Water (100 ml) was added to the residue, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (20 ml) and then dried under vacuum to afford the title compound (7.5 g, yield: 69.06%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 12.15 (s, 1H), 10.31 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.53-7.45 (m, 1H), 2.75 (s, 3H), 2.04 (d, J = 9.0 Hz, 1H), 1.91 (d, J = 9.0 Hz, 1H), 1.35 (s, 3H), 1.21 (s, 3H); Mass: m / z 305.13 (M+H)+.

[0648] Intermediate 45: of 3 -((4-fluorobenzvl)carbamovl)-2,2-di :-l- carboxylic acid:

[0649] To a solution of 6, 6-dimethyl-3-oxabicyclo[3.1.0]hexane-2, 4-dione (10 g, 71.35 mmol, 1.0 eq) in THF (50 ml) was added (4-fhiorophenyl)methanamine (8.933 g, 71.35 mmol, 1.0 eq) dissolved in THF (50 ml) dropwise over a period of 10 minutes. Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was not consumed completely. Reaction mass was stirred at 50-60 °C for around 4 hours. Heating bath was removed, and the reaction mass was allowed to reach to room temperature. THF was evaporated under reduced pressure. Water (200 ml) was added to the residue, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (50 ml) and then dried under vacuum to afford the title compound (16 g, yield: 84.52%) as a white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 13.10 (s, 1H), 8.93 (t, J= 5.5 Hz, 1H), 7.31 (dd, J= 9.0, 6.0 Hz, 2H), 7.16-7.13 (m, 2H), 4.29 (d, J = 6.0 Hz, 2H), 1.89 (d, J = 8.5 Hz, 1H), 1.86 (d, J = 9.0 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H); Mass: m / z 288.10 (M+Na)+. Intermediate 46: Preparation of 4-(4-ammo-2,5-difluorophenoxy)-7-methoxy-N- methylquinoline-6-carboxamide:

[0650] Step 1: Synthesis of methyl 4-(2,5-difluoro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate:

[0651] To a suspension of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (4 g, 17.151 mmol, 1.0 eq) in N,N-Dimethylacetamide (60 ml) was added cesium carbonate (16.76 g, 51.45 mmol, 3.0 eq). Reaction mass was stirred at room temperature for about 15 minutes. 1,2,4- trifluoro-5-nitrobenzene (4.555 g, 25.72 mmol, 1.5 eq) was added, reaction mass was stirred at 100-110 °C for around 8 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Reaction mass was cooled to 10-20 °C, water (900 ml) was added, stirred at same temperature for about 1 hour. Solid was filtered and washed with water (100 ml). The filtrate was extracted with 10% methanol in ethyl acetate (3x100 ml). The combined organic layer was washed with water (100 ml), dried over sodium sulphate filtered and concentrated under reduced pressure to obtain the title compound (4.1 g) as a solid. Mass: m / z 391.13 (M+H)+.

[0652] Step 2: Synthesis of methyl 4-(4-amino-2,5-difluorophenoxy)-7-methoxyquinoline-6- carboxylate:

[0653] To a suspension of methyl 4-(2,5-difluoro-4-nitrophenoxy)-7-methoxyquinoline-6- carboxylate (Step 1, 4.0 g, 10.248 mmol, 1.0 eq) in Methanol (40 ml), water (4 ml) was added Iron powder (2.36 g, 51.24 mmol, 5.0 eq) and acetic acid (4 ml). Reaction mixture was stirred at 60-65 °C for around 5 hours. TLC indicated starting material was consumed and the desired product was observed. Heating bath was removed, and the reaction mass was allowed to reach room temperature. Ethyl acetate (500 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The reaction mass was filtered through celite bed, washed with ethyl acetate (200 ml). Filtrate was basified to around pH 8.0 with 10% sodium bicarbonate solution, stirred at room temperature for about 30 minutes. Reaction mass was again filtered through celite bed, washed with ethyl acetate. Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with water (300 ml), dried over sodium sulphate, filtered and evaporated under reduced pressure to afford the title compound (3.1 g) as a solid. Mass: m / z 361.12 (M+H)+.

[0654] Step 3: Synthesis of 4-(4-amino-2,5-dijluorophenoxy)-7-methoxy-N-methylquinoline-6- carboxamide:

[0655] To a stirred solution of methyl 4-(4-amino-2, 5 -difluorophenoxy)-7-m ethoxy quinoline- 6-carboxylate (Step 2, 3.0 g, 8.326 mmol, 1.0 eq) in l-methyl-2-pyrrolidinone (15 ml) was added 40% aqueous methyl amine (6 ml). The reaction mixture was stirred at 10-20 °C for about 1 hour and then stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with water (225 ml) and extracted with ethyl acetate (3x500 ml). The combined organic layer was washed with water (300 ml), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain the title compound (1.9 g) as a solid. Mass: m / z 360.16 (M+H)+.

[0656] EXAMPLES i-2,2-

[0657] To a stirred solution of methyl 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline- 6-carboxylate (Intermediate 2, 3.5 g, 10.224 mmol, 1.0 eq) in DCM (35 ml) was added (IS, 3R)-

[0658] 3 -((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l -carboxylic acid (Intermediate 1, 3.85 g, 15.336 mmol, 1.5 eq), EDC.HC1 (4.89 g, 25.56 mmol, 2.5 eq) andN,N-dimethylpyridin-

[0659] 4-amine (0.749 g, 6.134 mmol, 0.6 eq). The reaction mixture was stirred at room temperature for overnight. Reaction mixture was diluted with DCM (25 ml) and washed with water (25 ml). The aqueous layer was extracted with DCM (20 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-3.5% methanol in dichloromethane gradient to obtain the title compound (2.0 g) as an off-white solid.TH NMR (500 MHz, DMSO- d6): 8 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.68 (d, J= 5.5 Hz, 1H), 8.60 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.59-7.54 (m, 3H), 7.44-7.38 (m, 2H), 7.13-7.09 (m, 2H), 6.52 (d, J = 5.0 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 576.13 (M+H)+. of (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6- methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2- 4-fluorophenyl)-3,3-

[0660] ;- 1 ,2-dicarboxamide:

[0661] To a stirred solution of 4-(4-amino-2-fluorophenoxy)-7-methoxy-N- methylquinoline-6-carboxamide (Intermediate 3, 5.2 g, 15.234 mmol, 1.0 eq) in DCM (104 ml) was added (1 S,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxylic acid (Intermediate- 1, 4.594 g, 18.28 mmol, 1.2 eq) and 4-dimethylaminopyri dine (0.558 g, 4.57 mmol, 0.3 eq). Reaction mass was cooled to 0-10 °C, propane phosphonic anhydride solution (T3P) (29.08 ml, 45.70 mmol, 3.0 eq, 50% in ethyl acetate) was added, stirred at same temperature for 1 hour. Cooling bath was removed, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to 0-10 °C, 5% sodium bicarbonate solution was added till to reach pH 8.0, stirred at 0-10 °C for 30 minutes. Organic layer was separated, aqueous layer was extracted with 10% methanol : DCM (2x150 ml). The combined organic layer was washed with 8% aqueous acetic acid solution (100 ml), 5% sodium bicarbonate solution (75 ml), water (75 ml) and brine solution (50 ml). Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient. The obtained solid was dissolved in acetonitrile (50 ml), stirred at room temperature for overnight. Solid was filtered, washed with acetonitrile (5 ml) and dried in vacuo to obtain the title compound (3.8 g, 43.4% yield) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.65 (d, J= 5.5 Hz, 1H), 8.60 (s, 1H), 8.37 (t, J = 4.5 Hz, 1H), 7.85 (d, J= 14.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.41 (dd, J = 16.0, 9.0 Hz, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 4.02 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 575.3 (M+H)+. .-2,2- ne-6-carboxvlic acid:

[0662] To a stirred solution of methyl 4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxylate (Example 1, 0.600 g, 1.047 mmol, 1.0 eq) in methanol (6 ml) and THF (6 ml) was added aqueous 2NNaOH solution (2.08 ml, 4.0 eq). The reaction mixture was stirred at 6-13 °C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture pH adjusted to 8.0 with IN HC1 and concentrated under reduced pressure. Again, the reaction mixture pH adjusted to 6.0 with IN HC1. The precipitate formed was collected by filtration, washed with water and dried under vacuum to obtain the title compound (0.400 g, yield: 68.02%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 13.10 (s, 1H), 10.42 (s, 1H), 10.13 (s, 1H), 8.67 (d, J= 5.5 Hz, 1H), 8.56 (s, 1H), 7.84 (d, J= 13.0 Hz, 1H), 7.58 (dd, J= 8.5, 5.5 Hz, 2H), 7.52 (s, 1H), 7.44- 7.38 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.52 (d, J= 5.0 Hz, 1H), 3.98 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 559.99 (M-H)'.

[0663] Example 4: Preparation of (lS,2R)-Nl-(4-((6-(dimethylcarbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-E2-dicarboxamide:

[0664] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-15 °C was added HATU (0.677 g, 1.780 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.230 g, 0.31 ml, 1.78 mmol, 2.0 eq). The reaction mass was stirred at same temperature for about 30 minutes. Dimethylamine hydrochloride (0.109 g, 1.068 mmol, 1.2 eq) was added, stirred at 0-15 °C for about 6 hours. TLC indicated starting material was completed. Reaction mass was poured into water (75 ml), stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (0.090 g, yield: 17.17%) as an off-white solid.XHNMR (500 MHz, DMSO- d6): 8 ppm 10.40 (s, 1H), 10.12 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.068 (s, 1H), 7.83 (d, J = 12.5 Hz, 1H), 7.58 (dd, J = 9.0, 5.5 Hz, 2H), 7.51 (s, 1H), 7.41-7.39 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 3.97 (s, 3H), 3.02 (s, 3H), 2.80 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 589.28 (M+H)+. of tert-butyl 4-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7-

[0665] :-6-i ine-l-carboxylate: To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.600 g, 1.068 mmol, 1.0 eq) in DCM (12 ml) was added EDC.HC1 (0.512 g, 2.67 mmol, 2.5 eq) and N,N-dimethylpyridin-4-amine (0.078 g, 0.64 mmol, 0.6 eq). The reaction mixture was stirred at room temperature for about 20 minutes, tert-butyl piperazine- 1- carboxylate (Intermediate 11-step 1, 0.298 g, 1.602 mmol, 1.5 eq) was added to the reaction mixture, stirred at room temperature for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. DCM (300 ml) and water (100 ml) were added to the reaction mixture, organic layer was separated, and the aqueous layer was extracted with DCM (100 ml). The combined organic layer was washed with water (100 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 2-5% methanol in dichloromethane gradient to obtain the title compound (0.450 g, yield: 58%) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J = 12.5 Hz, 1H), 7.59-7.55 (m, 2H), 7.51 (s, 1H), 7.43-7.37 (m, 2H), 7.13-7.08 (m, 2H), 6.52 (d, J = 5.0 Hz, 1H), 3.98 (s, 3H), 3.68-3.59 (m, 2H), 3.50-3.47 (m, 1H), 3.39-3.38 (m, 1H), 3.38-3.26 (m, 2H), 3.17-3.15 (m, 2H), 2.05 (s, 2H), 1.40 (s, 9H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 730.49 (M+H)+.

[0666] Example 6: Preparation of (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(piperazine-l- carbonyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcvclopropane-E2- di carb oxami de:

[0667] To a stirred solution of tert-butyl 4-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carbonyl)piperazine-l -carboxylate (Example 5, 0.450 g, 0.616 mmol, 1.0 eq) in DCM (8 ml) at 0 °C was added TFA (2 ml). The reaction mixture was stirred at 0 to 10 °C for about 2.5 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure. The reaction mixture was cooled to 0 °C, basified with saturated sodium carbonate solution and extracted with DCM. The combined organic layer was washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the title compound (0.380 g) as an off-white solid;XH NMR (500 MHz, DMSO-de): 5 ppm 10.40 (s, 1H), 10.12 (s, 1H), 8.63 (d, J= 5.5 Hz, 1H), 8.07 (s, 1H), 7.84 (d, J= 14.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.50 (s, 1H), 7.43- 7.37 (m, 2H), 7.13-7.09 (m, 2H), 6.51 (d, J = 5.0 Hz, 1H), 3.97 (s, 3H), 3.63-3.56 (m, 2H), 3.10-3.08 (m, 2H), 2.77-2.75 (m, 2H), 2.66-2.59 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 630.36 (M+H)+.

[0668] Example 7: Preparation of (lS,2R)-Nl-(4-((6-(4-acryloylpiperazine-l-carbonyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcvclopropane- E2-dicarboxamide:

[0669] To a stirred solution of (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(piperazine-l- carbonyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2- dicarboxamide (Example 6, 0.270 g, 0.420 mmol, 1.0 eq) in DCM (5.4 ml) at 0 °C was added N-ethyl-N-isopropylpropan-2-amine (0.22 ml, 1.26 mmol, 3.0 eq) and acryloyl chloride (0.01 ml, 0.50 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with DCM (50 ml) and washed with water (25 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-10% methanol in dichloromethane gradient to obtain the title compound (0.050 g, yield: 25%) as an off-white solid.XH NMR (500 Mz, DMSO-de): 5 ppm 8.64 (d, J= 5.0 Hz, 1H), 8.16 (s, 1H), 7.84 (d, J= 13.5 Hz, 1H), 7.72-7.66 (m, 1H), 7.59-7.57 (m, 3H), 7.52 (s, 1H), 7.43-7.38 (m, 2H), 7.13-7.09 (m, 3H), 6.51 (d, J= 5.0 Hz, 1H), 6.13 (dd, J= 16.5, 2.0 Hz, 1H), 5.72-5.68 (m, 1H), 3.98 (s, 3H), 3.68-3.60 (m, 5H), 3.54-3.50 (m, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 684.3 (M+H)+. 8: of (lS,2R)-Nl-(3-fhioro-4-((7-methoxv-6-(4-

[0670] >1,2-

[0671] To a stirred solution of (lS,2R)-Nl-(3-fhioro-4-((7-methoxy-6-(piperazine-l- carbonyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2- dicarboxamide (Example 6, 0.200 g, 0.317 mmol, 1.0 eq) in DCM (4 ml) was added triethylamine (0.17 ml, 1.27 mmol, 4.0 eq) followed by propionic anhydride (0.62 ml, 4.96 mmol, 16 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with DCM (300 ml) and washed with water. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-2.5% methanol in dichloromethane gradient to obtain the title compound (0.160 g) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.43 (s, 1H), 10.14 (s, 1H), 8.64 (d, J = 5.0 Hz, 1H), 8.15 (d, J= 4.5 Hz, 1H), 7.85 (d, 1H), 7.59-7.56 (m, 2H), 7.52 (s, 1H), 7.43-7.37 (m, 2H), 7.14-7.09 (m, 2H), 6.52 (d, J = 5.0 Hz, 1H), 3.98 (s, 3H), 3.69-3.52 (m, 4H), 3.48-3.40 (m, 2H), 3.20-3.11 (m, 2H), 3.11-3.05 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.18 (t, J= 7.5 Hz, 3H); Mass: m / z 686.47 (M+H)+. S,2R)-Nl-(4-((6-((2-acrvlamidoethvl)carbamovl)-7- >N2-(4-fluorophenvl)-3 , 3 -di

[0672] 1,2-dicarboxamide:

[0673] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DCM (10 ml) and THF (10 ml) was added 2- acrylamidoethan-l-aminium 2,2,2-trifluoroacetate (Intermediate 4, 0.608 g, 2.671 mmol, 3.0 eq), N-ethyl-N-isopropylpropan-2-amine (1.495 g, 2.0 ml, 11.574 mmol, 13 eq), N,N- dimethylpyridin-4-amine (0.065 g, 0.534 mmol, 0.6 eq) and EDC.HC1 (1.28 g, 6.677 mmol, 7.5 eq). The reaction mass was stirred at room temperature for about 24 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The aqueous layer was extracted with DCM (50 ml). The combined organic layer was washed with water (50 ml) and brine solution (30 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-7% methanol in di chloromethane gradient to obtain the title compound (0.120 g, yield: 20%) as a pale-yellow solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.64 (s, 1H), 8.51 (t, J= 5.5 Hz, 1H), 8.27 (t, J = 5.5 Hz, 1H), 7.84 (dd, J= 13.5, 1.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.41-7.40 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 6.22 (dd, J = 17.0, 10.0 Hz, 1H), 6.11 (dd, J= 17.0, 2.0 Hz, 1H), 5.59 (dd, J= 10.0, 2.0 Hz, 1H), 4.01 (s, 3H), 3.41 (t, J= 5.0 Hz, 2H), 3.37 (t, J= 5.0 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 658.34 (M+H)+.

[0674] Example 10: Preparation of ((2R,3S,4R)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2- vDmethyl 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcvclopropane- l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate:

[0675] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.300 g, 0.534 mmol, 1.0 eq) in DCM (20 ml) was added (2R,3S,4R)-2- (hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4-diol (Intermediate 6-step 1, 0.142 g, 0.801 mmol, 1.5 eq), EDC. HC1 (0.665 g, 3.472 mmol, 6.5 eq) and N,N-dimethylpyridin-4- amine (0.039 g, 0.320 mmol, 0.6 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (200 ml) and washed with water (200 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (0.150 g, yield: 38.9%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.13 (s, 1H), 8.68 (t, J= 5.0 Hz, 2H), 7.85 (d, J= 12.5 Hz, 1H), 7.58 (dd, J= 8.5, 5.0 Hz, 2H), 7.55 (s, 1H), 7.42 (t, J= 8.5 Hz, 2H), 7.11 (t, J= 8.5 Hz, 2H), 6.527 (d, J= 4.5 Hz, 1H), 5.22 (d, J= 5.5 Hz, 1H), 4.89 (d, J= 4.5 Hz. 1H), 4.72 (d, J= 2.0 Hz, 1H), 4.62 (d, J= 11.5 Hz, 1H), 4.327 (dd, J = 11.5, 7.0 Hz, 1H), 4.14 (t, J= 5.0 Hz, 1H), 3.98 (s, 3H), 3.68-3.59 (m, 2H), 3.22 (s, 2H), 3.17- 3.12 (m, 1H), 2.05 (s, 2H), 1.90 (dd, J = 13.0, 4.5 Hz, 1H), 1.51-1.45 (m, 1H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 722.08 (M+H)+.

[0676] Example 11 : Preparation of (lR,2S)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-E2-dicarboxamide:

[0677] To a stirred solution of (lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane- 1 -carboxylic acid (Intermediate 1, 0.186 g, 0.742 mmol, 1.2 eq) inDCM (4 ml) was added EDC.HC1 (0.652 g, 3.401 mmol, 5.5 eq) and N,N-dimethylpyridin-4-amine (0.037 g, 0.309 mmol, 0.5 eq). The reaction mixture was stirred at room temperature for about 15 minutes. 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (Intermediate 5, 0.200 g, 0.6185 mmol, 1.0 eq) was added and stirred at room temperature for about 1.5 hours. The reaction mixture was diluted with DCM (20 ml) and washed with IN HC1 (15 ml). The aqueous layer was re-extracted with DCM (3x50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (20 ml), water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.150 g, yield: 43.6%) as a solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.27 (s, 1H), 10.16 (s, 1H), 8.63 (d, = 5.0 Hz, 1H), 8.60 (s, 1H), 8.36 (d, J= 5.0 Hz, 1H), 7.71 (d, J= 9.0 Hz, 2H), 7.59-7.57 (m, 2H), 7.50 (s, 1H), 7.22 (d, J= 9.0 Hz, 2H), 7.13-7.09 (m, 2H), 6.475 (d, J= 5.5 Hz, 1H), 4.02 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H), 2.04 (d, J= 2.5 Hz, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 557.16 (M+H)+. ine-6-carbonyl)oxy)methyl)-6-methoxytetrahydro-2H-pyran-3,4-diyl di acetate:

[0678] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1 g, 1.781 mmol, 1.0 eq) in DCM (20 ml) was added N,N-dimethylpyridin-4- amine (0.130 g, 1.068 mmol, 0.6 eq), EDC.HC1 (2.2 g, 11.57 mmol, 6.5 eq) and (2R,3S,4R)- 2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4-diyl diacetate (Intermediate 6, 0.700 g, 2.671 mmol, 1.5 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mass was diluted with DCM (200 ml), washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-3% methanol in dichloromethane gradient. Solid was treated with heptane, stirred at room temperature, filtered and dried under vacuum to obtain the title compound (0.050 g) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.44 (s, 1H), 10.14 (s, 1H), 8.69 (d, J= 5.5 Hz, 1H), 8.46 (s, 1H), 7.85 (d, 12.5 Hz, 1H), 7.59-7.53

[0679] (m, 3H), 7.45-7.39 (m, 2H), 7.11 (t. J = 9.0 Hz, 2H), 6.535 (d, J= 5.0 Hz, 1H), 5.30-5.26 (m, 1H), 5.16 (t, J = 10.0 Hz, 1H), 4.90 (s, 1H), 4.375 (d, J = 5.0 Hz, 1H), 4.29 (dd, J = 12.5, 5.0 Hz, 1H), 4.13 (dd, J= 12.0, 2.0 Hz, 1H), 3.99 (m, 2H), 3.95 (s, 3H), 3.29 (s, 3H), 2.05 (s, 2H), 2.02 (s, 3H), 1.96 (s, 3H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 806.65 (M+H)+.

[0680] Example 13: Preparation of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcvclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)carbamate:

[0681] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1.8 g, 3.205 mmol, 1.0 eq) in DCM (18 ml) was added tert-butyl (2- aminoethyl)carbamate (Intermediate 4-step 1, 2.054 g, 12.82 mmol, 4.0 eq) and N-ethyl-N- isopropylpropan-2-amine (2.07 g, 2.8 ml, 16.02 mmol, 5.0 eq). The reaction mixture was cooled to 0 °C, EDC.HC1 (4.6 g, 24.04 mmol, 7.5 eq) and N,N-dimethylpyridin-4-amine (0.391 g, 3.205 mmol, 1.0 eq) were added, reaction mass was allowed to stir at room temperature for overnight. Water (36 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Organic layer was separated, aqueous layer was extracted with DCM (2x50 ml). The combined organic layer was washed with water (100 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to afford the title compound (1.19 g, yield: 52.77%) as an off-white solid.TH NMR (500 MHz, CDCk): 5 ppm 10.81 (s, 1H), 9.99 (s, 1H), 9.19 (s, 1H), 8.62 (d, = 3.5 Hz, 1H), 8.45 (s, 1H), 7.85 (d, J= 11.0 Hz, 1H), 7.55-7.52 (m, 3H), 7.42 (d, J = 6.0 Hz, 1H), 7.09 (t, J= 8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.38 (d, J= 3.5 Hz, 1H), 5.04 (s, 1H), 4.13 (s, 3H), 3.66 (m, 2H), 3.45 (m, 2H), 2.03-1.97 (m, 2H), 1.43 (s, 9H), 1.36 (s, 3H), 1.34 (s, 3H); Mass: m / z 704.25 (M+H)+. of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamovl)-7- methoxy quinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcy cl opropane-

[0682] 1,2-dicarboxamide 2,2,2-trifluoroacetate:

[0683] A solution of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-

[0684] 2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate (Example 13, 1.0 g, 1.42 mmol, 1.0 eq) and DCM (12 ml) cooled 0 °C. Trifluoroacetic acid (8 ml) was added to the reaction mass under nitrogen. Ice bath was removed, and the reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure. Hexane (20 ml) was added to the residue, stirred at room temperature for about 30 minutes. Hexane layer was decanted. Methyl -tert-butyl ether (20 ml) was added to the residue, stirred at room temperature for about 30 minutes. The precipitate formed was collected by filtration, washed with methyl -tert-butyl ether and dried under vacuum at 50 °C for about 1 hour. The obtained solid (0.917 g) was used as such for next step without further purification.XH NMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.13 (s, 1H), 8.72 (d, J= 6.0 Hz, 2H), 8.61 (brs, 1H), 7.87 (d, J = 13.0 Hz, 1H), 7.77 (s, 3H), 7.58 (dd, J = 9.0, 5.0 Hz, 3H), 7.45-7.40 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.59 (brs, 1H), 4.04 (s, 3H), 3.58-3.54 (m, 2H), 3.06-2.99 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 604.29 (M+H)+.

[0685] Example 15: Preparation of ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2- propionamidoethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide:

[0686] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.300 g, 0.418 mmol, 1.0 eq) in DCM (10 ml) at 0 °C was added triethylamine (0.75 ml, 5.375 mmol, 12.68 eq) and propionic anhydride (0.86 ml, 6.688 mmol, 16.0 eq). Reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (30 ml) and washed with water (30 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.050 g, yield: 18.18%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.64 (t, J= 5.5 Hz, 2H), 8.48 (t, J= 5.5 Hz, 1H), 7.90 (t, J= 5.5 Hz, 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.58 (dd, J = 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.43-7.40 (m, 2H), 7.11 (t, J = 8.5 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 4.03 (s, 3H), 3.36 (t, J= 6.0 Hz, 2H), 3.27 (t, J= 6.0 Hz, 2H), 2.09 (q, J = 7.5 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.0 (t, J= 7.5 Hz, 3H); Mass: m / z 660.46 (M+H)+.

[0687] Example 16: Preparation of isopropyl 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)- 2,2-dimethylcvclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate:

[0688] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.100 g, 0.178 mmol, 1.0 eq) in DCM (10 ml) and THF (10 ml) at 0-10 °C was added propan-2-ol (0.068 ml, 0.89 mmol, 5.0 eq), Dicyclohexylcarbodiimide (0.044 g, 0.213 mmol, 1.2 eq) and N,N-dimethylpyridin-4-amine (0.010 g, 0.089 mmol, 0.5 eq). Cooling bath was removed, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (200 ml) and washed with water (200 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-3% methanol in dichloromethane gradient to obtain the title compound (0.030 g, yield: 27.7% yield) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.67 (d, = 5.5 Hz, 1H), 8.49 (s, 1H), 7.84 (dd, J= 13.5, 2.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.53 (s, 1H), 7.45-7.38 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.52 (d, J = 5.0 Hz, 1H), 5.21-5.13 (m, 1H), 3.97 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H); Mass: m / z 604.22 (M+H)+.

[0689] Example 17: Preparation of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-6-(methylcarbamoyl)quinoline 1 -oxide:

[0690] To a stirred solution of (lS,2R)-Nl-(3-fhioro-4-((7-methoxy-6-

[0691] (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane-l,2-dicarboxamide (Example 2, 0.500 g, 0.87 mmol, 1.0 eq) in DCM

[0692] (10 ml) was added meta-chloroperbenzoic acid (1.05 g, 6.08 mmol, 7.0 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was cooled to 0 °C, quenched with saturated sodium sulphite solution (50 ml). Organic layer was separated, aqueous layer was extracted with DCM (2x75 ml). The combined organic layer was washed with water (75 ml) and brine solution (50 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-10% methanol in di chloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure. The obtained compound was stirred with heptane (50 ml) at room temperature for about 1 hour. Solid was filtered and dried under vacuum at 50-60 °C for about 2 hours to obtain the title compound (0.110 g, yield: 21.4%) as an off-white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.53 (s, 1H), 8.45 (dd, J = 9.0, 4.5 Hz, 1H), 8.41 (d, J= 7.0 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J= 11.5 Hz, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.42-7.36 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.53 (d, J = 7.0 Hz, 1H), 4.05 (s, 3H), 2.84 (d, J= 4.5 Hz. 3H), 2.05 (s, 2H), 1.36 (s, 3H), 1.26 (s, 3H); Mass: m / z 613.32 (M+Na)+. -

[0693] 1,2-dicarboxamide: To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.400 g, 0.712 mmol, 1.0 eq) in DCM (20 ml) was added thiomorpholine 1,1- dioxide (0.115 g, 0.855 mmol, 1.2 eq), Triethylamine (0.36 g, 3.56 mmol, 5.0 eq) and N,N- dimethylpyridin-4-amine (0.052 g, 0.427 mmol, 0.6 eq). The reaction mass was cooled to 0 °C, EDC.HC1 (1.092 g, 5.70 mmol, 8.0 eq), was added and allowed to stir at room temperature for overnight. Water (40 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Organic layer was separated and the aqueous layer was extracted with DCM (2x50 ml). The combined organic layer was washed with water (100 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.120 g, yield: 24.84%) as an off-white solid.XH NMR (500 MHz, DMSO- d6): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.64 (d, = 5.5 Hz, 1H), 8.42 (s, 1H), 7.85 (d, J= 13.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.442-7.387 (m, 2H), 7.116 (t, J= 9.0 Hz, 2H), 6.51 (d, J = 5.0 Hz, 1H), 3.98 (s, 3H), 3.74-3.70 (m, 2H), 3.65-3.47 (m, 2H), 3.21-3.18 (m, 2H), 2.99-2.96 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: 679.34 (M+H)+.

[0694] Example 19: Preparation of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)-2-methylpropyl)carbamate:

[0695] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.900 g, 1.602 mmol, 1.0 eq) in DCM (18 ml) was added tert-butyl (2-amino-2- methylpropyl)carbamate (Intermediate 7, 0.45 g, 2.404 mmol, 1.5 eq), N,N-dimethylpyridin- 4-amine (0.095 g, 0.801 mmol, 0.5 eq) and EDC.HCl (2.15 g, 11.22 mmol, 7.0 eq). The reaction mass was stirred at room temperature for about 48 hours. Reaction mass was diluted with DCM (50 ml), washed with water (100 ml). Aqueous layer was extracted with DCM (50 ml). The combined organic layer was washed with 10% citric acid solution (10 ml), 5% sodium bicarbonate solution (10 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.400 g, yield: 34.12%) as a paleyellow solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.63 (d, J= 5.0 Hz, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 7.84 (d, J= 13.5 Hz, 1H), 7.58 (dd, J = 8.5, 5.0 Hz, 2H), 7.50 (s, 1H), 7.40 (s, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.89 (t, J = 5.0 Hz, 1H), 6.49 (d, J = 5.0 Hz, 1H), 4.02 (s, 3H), 3.26 (d, = 5.5 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 9H), 1.36 (s, 6H), 1.33 (s, 6H); Mass: m / z 732.4 (M+H)+.

[0696] Example 20: Preparation of (lS,2R)-Nl-(4-((6-((l-amino-2-methylpropan-2-yl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcvclopropane-

[0697] E2-dicarboxamide 2,2,2-trifluoroacetate:

[0698] A solution of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)- 2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropyl)carbamate (Example 19, 0.300 g, 0.410 mmol, 1.0 eq) and DCM (6 ml) cooled to 0-15 °C. Trifluoroacetic acid (4 ml) was added to the reaction mass under nitrogen. Ice bath was removed, and the reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Methyl tert-butyl ether (10 ml) was added to the residue, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with Methyl tert-butyl ether (2x5 ml) and dried under vacuum to obtain the title compound (0.120 g) as a pale-yellow solid. 'H NMR (300 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.67 (d, = 5.4 Hz, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.88-7.84 (m, 4H), 7.58 (dd, J= 9.0, 5.4 Hz, 2H), 7.54 (s, 1H), 7.40 (d, J= 4.5 Hz, 2H), 7.11 (t, J= 8.7 Hz, 2H), 6.54 (d, J= 5.1 Hz, 1H), 4.0 (s, 3H), 3.30-3.28 (m, 2H), 2.05 (s, 2H), 1.40 (s, 6H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 632.48 (M+H)+. Example 21 : Preparation of tert-butyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)-2-methylpropan-2-yl)carbamate:

[0699] Step 1: Synthesis of benzyl (l-(4-(2-jluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropan-2-yl) carbamate :

[0700] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1.0 g, 1.78 mmol, 1.0 eq) in DCM (20 ml) was added 2- (((benzyloxy)carbonyl)amino)-2-methylpropan-l-aminium 2,2,2-trifluoroacetate

[0701] (Intermediate 13-step 2, 0.9 g, 2.676 mmol, 1.5 eq), N,N-dimethylpyridin-4-amine (0.108 g, 0.89 mmol, 0.5 eq) and EDC.HC1 (2.56 g, 13.35 mmol, 7.5 eq). The reaction mass was stirred at room temperature for about 24 hours. Reaction mass was diluted with DCM (50 ml) and washed with water (100 ml). Aqueous layer was extracted with DCM (50 ml). The combined organic layer was washed with 10% citric acid solution (15 ml), 5% sodium bicarbonate solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.900 g, yield: 66%) as a pale-yellow solid.TH NMR (500 MHz, CD3OD): 5 ppm 8.91 (s, 1H), 8.63 (d, J= 5.5 Hz, 1H), 7.84 (dd, J= 12.5, 2.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.49 (s, 1H), 7.41-7.23 (m, 8H), 7.04 (t, J= 9.0 Hz, 2H), 6.55 (d, J = 5.0 Hz, 1H), 5.07 (s, 2H), 4.02 (s, 3H), 3.72 (s, 2H), 2.08 (s, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.37 (s, 6H); Mass: m / z 766.44 (M+H)+. Step 2: Synthesis of (lS,2R)-Nl-(4-((6-((2-amino-2-methylpropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3, 3-dimethylcyclopropane- 1, 2-dicarboxamide :

[0702] To a suspension of 10% Pd / C (0.105 g, 50% wet) in ethyl acetate (20 ml) was added benzyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane- l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2-methylpropan-2- yl)carbamate (Step 1, 0.700 g, 0.914 mmol, 1.0 eq) dissolved in ethanol (20 ml). The reaction mass was hydrogenated in parr shaker apparatus at 50 psi for about 4 hours. TLC indicated starting material was completed and the desired product was observed. Reaction mass was filtered through celite bed, washed with EtOAc : Ethanol (100 ml, 1 : 1). The filtrate was evaporated under reduced pressure to obtain the title compound (0.548 g) as a solid, which was used for next step without further purification.TH NMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.13 (s, 1H), 8.655 (d, J= 5.0 Hz, 1H). 8.61 (s, 1H), 8.46 (t, J= 6.0 Hz, 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.58 (dd, J= 8.5, 5.0 Hz, 2H), 7.55 (s, 1H), 7.419-7.40 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.51 (d, J= 5.5 Hz, 1H), 4.04 (s, 3H), 3.26 (d, J= 6.0 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.09 (s, 6H); Mass: m / z 632.41 (M+H)+.

[0703] Step 3: Synthesis of tert-butyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropan-2-yl) carbamate :

[0704] A solution of (lS,2R)-Nl-(4-((6-((2-amino-2-methylpropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1,2-dicarboxamide (Step 2, 0.700 g, 1.108 mmol, 1.0 eq) and DCM (14 ml) was cooled to 0 °C. Triethylamine (0.336 g, 0.46 ml, 3.324 mmol, 3.0 eq) and di-tert-butyl dicarbonate (0.36 g, 0.38 ml, 1.662 mmol, 1.5 eq) were added. Cooling bath was removed, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (60 ml), washed with 0.5N HC1 (20 ml), 5% sodium carbonate solution (20 ml), water (20 ml) and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 0-5% methanol in di chloromethane gradient to obtain the title compound (0.25 g, yield: 30.8%) as a solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.66-8.64 (m, 2H), 8.46 (t, J = 6.0 Hz, 1H), 7.84 (d, J= 14.0 Hz, 1H), 7.59-7.56 (m, 3H), 7.44-7.38 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.68-6.66 (m, 1H), 6.515 (d, J = 5.0 Hz, 1H), 4.05 (s, 3H), 3.50 (d, J = 6.0 Hz, 2H), 2.05 (s, 2H), 1.38 (s, 9H), 1.37 (s, 3H), 1.33 (s, 6H), 1.27 (s, 3H); Mass: m / z 732.44 (M+H)+.

[0705] Example 22: Preparation of (lS,2R)-Nl-(4-((6-((2-amino-2-methylpropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- E2-dicarboxamide 2,2,2-trifluoroacetate:

[0706] A solution of tert-butyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)- 2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- m ethylpropan -2 -yl)carbamate (Example 21, 0.150 g, 0.205 mmol, 1.0 eq) and DCM (3 ml) was cooled to 0-15 °C. Trifluoroacetic acid (2 ml) was added to the reaction mass and allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure and dried under vacuum. Residue was stirred with heptane (10 ml) and decanted. Methyl tert-butyl ether (10 ml) was added to the residue, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with Methyl tert-butyl ether and dried under vacuum to obtain the title compound (0.100 g, yield: 65.79%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.44 (s, 1H), 10.14 (s, 1H), 8.71-8.66 (m, 3H), 7.88-7.85 (m, 4H), 7.59- 7.56 (m, 3H), 7.45-7.39 (m, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.59 (d, J= 5.5 Hz, 1H), 4.03 (s, 3H), 3.48 (d, J = 6.5 Hz, 2H), 2.06 (s, 2H), 1.37 (s, 3H), 1.28 (s, 6H), 1.27 (s, 3H); Mass: m / z 632.27 (M+H)+. Example 23: Preparation of (1 S,2R)-N 1 -(4-((6-((2-( E 1 - dioxidothiomorpholino)ethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2- (4-fluorophenyl)-3, 3-dimethyl cyclopropane- E2-dicarboxamide:

[0707] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1.0 g, 1.78 mmol, 1.0 eq) in DCM (20 ml) at 0 °C was added 4-(2- aminoethyl)thiomorpholine 1,1-dioxide 2,2,2-trifluoroacetate (Intermediate 9, 0.624 g, 2.137 mmol, 1.2 eq), triethylamine (0.54 g, 5.342 mmol, 3.0 eq), N,N-dimethylpyridin-4-amine (0.108 g, 0.89 mmol, 0.5 eq) and EDC.HC1 (2.38 g, 12.46 mmol, 7.0 eq). Cooling bath was removed, and the reaction mass was stirred at room temperature for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (100 ml) and washed with water (50 ml). Aqueous layer was extracted with DCM (50 ml). The combined organic layer was washed with 10% citric acid solution (10 ml), 5% sodium bicarbonate solution (20 ml), water (30 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (0.578 g, yield: 45%) as a pale-yellow solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.655 (d, J= 5.0 Hz, 1H), 8.63 (s, 1H), 8.44 (t, J= 5.5 Hz, 1H), 7.84 (dd, J= 14.0, 1.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.54 (s, 1H), 7.43-7.38 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.51 (d, J=

[0708] 5.5 Hz, 1H), 4.04 (s, 3H), 3.44 (dd, J = 12.0, 6.5 Hz, 2H), 3.10 (t, J = 5.5 Hz, 4H), 3.0 (t, J =

[0709] 2.5 Hz, 4H), 2.71 (t, J= 6.5 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 722.24 (M+H)+.

[0710] Example 24: Preparation of (lS,2R)-Nl-(4-((6-((2-(El-dioxidothiomorpholino)-2- methylpropyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-E2-dicarboxamide:

[0711] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DCM (10 ml) at 0 °C was added 2-(l,l- dioxidothiomorpholino)-2-methylpropan-l-aminium 2,2,2-trifluoroacetate (Intermediate 10, 0.342 g, 1.068 mmol, 1.2 eq), triethylamine (0.27 g, 0.37 ml, 2.671 mmol, 3.0 eq), N,N- dimethylpyridin-4-amine (0.054 g, 0.446 mmol, 0.5 eq) and EDC.HC1 (1.194 g, 6.233 mmol, 7.0 eq). Cooling bath was removed, and the reaction mass was stirred at room temperature for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (75 ml) and washed with water (75 ml). Aqueous layer was extracted with DCM (50 ml). The combined organic layer was washed with 10% citric acid solution (15 ml), 5% sodium bicarbonate solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-7% methanol in di chloromethane gradient to obtain the title compound (0.197 g, yield: 29.6%) as a pale-yellow solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.66 (s, 2H), 8.29 (t, J = 5.0 Hz, 1H), 7.84 (d, J = 13.0 Hz, 1H), 7.59-7.57 (m, 3H), 7.42-7.40 (m, 2H), 7.11 (t, J= 7.5 Hz, 2H), 6.52 (d, J= 5.0 Hz, 1H), 4.08 (s, 3H), 3.39 (d, J = 5.0 Hz, 2H), 3.07-3.01 (m, 8H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.11 (s, 6H); Mass: m / z 750.36 (M+H)+.

[0712] Example 25: Preparation of (lS,2R)-Nl-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-3-

[0713] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid

[0714] (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) and DMF (5 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (0.46 g, 0.62 ml, 3.56 mmol, 4.0 eq) and HATU (0.507 g, 1.335 mmol, 1.5 eq) were added to the reaction mass, and stirred at 0 °C for about 1 hour. Ammonium chloride (0.095 g, 1.78 mmol, 2.0 eq) was added and the reaction mass was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Water (50 ml) was added to the reaction mass stirred at room temperature for about 1 hour. Solid was filtered, washed with water (50 ml) and dried under vacuum, the crude solid was purified by silica gel column chromatography using 0-5% methanol in di chloromethane gradient to obtain the title compound (0.100 g, yield: 20%) as an off-white solid.XHNMR (500 MHz, DMSO-de): 5 ppm 10.43 (s, 1H), 10.14 (s, 1H), 8.67 (d, J = 12.5 Hz, 2H), 7.87-7.84 (m, 2H), 7.75 (s, 1H), 7.59-7.53 (m, 3H), 7.41 (s, 2H), 7.12 (m, 2H), 6.51 (s, 1H), 4.04 (s, 3H), 2.06 (s, 2H), 1.38 (s, 3H), 1.27 (s, 3H); Mass: m / z 561.32 (M+H)+. tyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4- ;- 1 -carb oxami do)nhenoxy)-7- ine-l-carboxylate:

[0715] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DCM (10 ml) was added tert-butyl 4-(2-amino-2- methylpropyl)piperazine-l -carboxylate (Intermediate 11, 0.343 g, 1.335 mmol, 1.5 eq), N,N- dimethylpyridin-4-amine (0.054 g, 0.445 mmol, 0.5 eq) and EDC.HC1 (1.7 g, 8.90 mmol, 10 eq). Reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was diluted with DCM (200 ml) and washed with water (200 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.250 g, yield: 35%) as an off-white solid. ’H NMR (500 MHz, CDCh): 5 ppm 9.18 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 7.80 (dd, J = 11.5, 9.5 Hz, 1H), 7.56- 7.52 (m, 3H), 7.33 (d, J= 9.0 Hz, 1H), 7.14 (t, J= 9.0 Hz, 1H), 7.05-7.02 (m, 2H), 6.41 (d, J = 5.0 Hz, 1H), 4.10 (s, 3H), 3.42 (m, 4H), 2.69 (s, 2H), 2.59 (m, 4H), 2.02 (d, J= 8.5 Hz, 1H), 1.96 (d, J= 8.5 Hz, 1H), 1.50 (s, 6H), 1.45 (s, 9H), 1.40 (s, 3H), 1.25 (s, 3H); Mass: m / z 801.39 (M+H)+.

[0716] Example 27: Preparation of (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-methyl-l-(piperazin- l-yl)propan-2-yl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane-E2-dicarboxamide 2,2,2-trifluoroacetic acid:

[0717] To a stirred solution of tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- m ethoxy quinoline-6-carboxamido)-2-methylpropyl)piperazine-l -carboxylate (Example 26, 0.200 g, 0.250 mmol, 1.0 eq) in DCM (6 ml) was added Trifluoroacetic acid (4 ml). The reaction mass was stirred at room temperature for about 8 hours. Reaction mass was evaporated under reduced pressure. Methyl -tert-butyl ether (50 ml) was added to the residue stirred at room temperature for about 1 hour. Solid was filtered, washed with Methyl -tert-butyl ether and dried under vacuum to obtain the title compound (0.100 g, yield: 57%) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.13 (s, 1H), 8.69 (d, = 5.5 Hz, 1H), 8.50 (s, 3H), 8.03 (s, 1H), 7.86 (d, J = 12.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.55 (s, 1H), 7.41 (d, J= 6.5 Hz, 2H), 7.11 (t, J= 8.5 Hz, 2H), 6.57 (d, J= 5.5 Hz, 1H), 4.03 (s, 3H), 3.09- 3.07 (m, 6H), 2.76 (m, 4H), 2.05 (s, 2H), 1.37 (s, 6H), 1.36 (s, 3H), 1.27 (s, 3H); Mass: m / z 701.38 (M+H)+.

[0718] Example 28: Preparation of (lS,2R)-Nl-(3-fluoro-4-((6-((l-hvdroxy-2-methylpropan-2- yl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide:

[0719] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.200 g, 0.356 mmol, 1.0 eq) and DMF (4 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (0.138 g, 0.186 ml, 1.067 mmol, 3.0 eq) and HATU (0.270 g, 0.712 mmol, 2.0 eq) were added and the reaction mass was stirred at same temperature for about 1 hour. 2-amino-2-methylpropan-l-ol (0.047 g, 0.534 mmol, 1.5 eq) was added, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Water (40 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. Solid was filtered, washed with water (30 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-8% methanol in dichloromethane gradient to obtain the title compound (0.040 g, yield: 17.7%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.69 (s, 1H), 8.65 (d, J= 5.0 Hz, 1H), 8.19 (s, 1H), 7.85 (d, J= 14.0 Hz, 1H), 7.58 (dd, J = 9.0, 5.0 Hz, 2H), 7.53 (s, 1H), 7.43-7.40 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.505 (d, J= 5.0 Hz, 1H), 5.06 (t, J= 5.5 Hz, 1H), 4.04 (s, 3H), 3.48 (d, J = 5.5 Hz, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.35 (s, 6H), 1.27 (s, 3H); Mass: m / z 633.30 (M+H)+.

[0720] Example 29: Preparation of (lS,2R)-Nl-(4-((6-(((2R,3R)-2-(El-dioxidothiomorpholino)-3- hydroxybutyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-E2-dicarboxamide:

[0721] Step 1: Synthesis of (lS,2R)-Nl-(4-((6-(((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(l,l- dioxidothiomorpholino)butyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-

[0722] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) and DMF (5 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (0.345 g, 0.46 ml, 2.67 mmol, 3.0 eq) and HATU (0.677 g, 1.78 mmol, 2.0 eq) were added, reaction mass was stirred at same temperature for about 1 hour. 4- ((2R,3R)- 1 -amino-3 -((tert-butyldimethylsilyl)oxy)butan-2-yl)thiomorpholine 1 , 1 -dioxide

[0723] (Intermediate 12, 0.450 g, 1.325 mmol, 1.5 eq) was added, reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Water (50 ml) was added to the reaction mass, stirred at 0 °C for about 30 minutes. Solid was filtered, washed with water (50 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.270 g, yield: 34.48%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.65 (d, J= 5.5 Hz, 1H), 8.54 (s, 1H), 8.37 (t, J= 5.5 Hz, 1H), 7.84 (d, J= 14.0 Hz, 1H), 7.59-7.55 (m, 3H), 7.40- 7.39 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.515 (d, J= 5.0 Hz, 1H), 4.03 (s, 3H), 4.0-3.98 (m, 2H), 3.50-3.46 (m, 1H), 3.27-3.23 (m, 4H), 3.06-2.96 (m, 4H), 2.86-2.83 (m, 1H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.23 (d, J= 5.0 Hz, 3H), 0.88 (s, 9H), 0.096 (s, 3H), 0.086 (s, 3H); Mass: m / z 880.54 (M+H)+.

[0724] Step 2: Synthesis of (lS,2R)-Nl-(4-((6-(((2R,3R)-2-(l,l-dioxidothiomorpholino)-3- hydroxybutyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-

[0725] To a stirred solution of (lS,2R)-Nl-(4-((6-(((2R,3R)-3-((tertbutyldimethylsilyl)oxy)-2-(l,l-dioxidothiomorpholino)butyl)carbamoyl)-7-methoxyquinolin- 4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- dicarboxamide (Step 1, 0.420 g, 0.477 mmol, 1.0 eq) in THF (5 ml) was added Tetra-n-butyl ammoniumfluoride (0.25 g, 0.954 ml, 0.954 mmol, 2.0 eq, 1.0 M in THF). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was poured into water (20 ml) and extracted with DCM (2x50 ml). The combined organic layer was washed with brine solution (20 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-3% methanol in dichloromethane gradient to obtain the title compound (0.070 g, yield: 19.2%) as an off-white solid.XH NMR (500 MHz, CD3OD): 5 ppm 8.86 (s, 1H), 8.63 (d, J= 5.5 Hz, 1H), 7.84 (dd, J = 12.5, 2.0 Hz, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.53 (s, 1H), 7.40 (dd, J= 9.0, 2.0 Hz, 1H), 7.34 (t, J= 8.5 Hz, 1H), 7.04 (t, J = 8.5 Hz, 2H), 6.56 (d, J= 5.0 Hz, 1H), 4.14 (s, 3H), 3.86- 3.85 (m, 1H), 3.55-3.53 (m, 2H), 3.38-3.35 (m, 4H), 3.15-3.07 (m, 5H), 2.88-2.83 (m, 1H), 2.08 (s, 2H), 1.39 (s, 3H), 1.27 (s, 3H), 1.28 (d, J= 6.5 Hz, 3H); Mass: m / z 766.30 (M+H)+.

[0726] Example 30: Preparation of (lS,2R)-Nl-(4-((6-((l-(El-dioxidothiomorpholino)-2- methylpropan-2-yl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcvclopropane-E2-dicarboxamide:

[0727] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.600 g, 1.068 mmol, 1.0 eq) and DMF (13 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (0.414 g, 3.205 mmol, 3.0 eq) and HATU (0.812 g, 2.137 mmol, 2.0 eq) were added, reaction mass was stirred at 0 °C for about 1 hour. 4-(2-amino-2- methylpropyl)thiomorpholine 1,1-dioxide (Intermediate 13, 0.264 g, 1.282 mmol, 1.2 eq) dissolved in DMF (2 ml) was added, stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Water (130 ml) was added to the reaction mass, stirred at 0 °C for about 1 hour. The precipitate formed was filtered, washed with water and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (0.361 g) as an off-white solid. 'H NMR (500 MHz, CDCh): 5 ppm 10.47 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 8.64 (d, J= 5.0 Hz, 1H), 7.83-7.79 (m, 2H), 7.55-7.52 (m, 3H), 7.33 (d, J = 8.5 Hz, 1H), 7.16 (t, J= 9.0 Hz, 1H), 7.06-7.03 (m, 2H), 6.42 (d, J= 5.0 Hz, 1H), 4.12 (s, 3H), 3.22 (t, J= 4.5 Hz, 4H), 3.0 (t, J= 4.5 Hz, 6H), 2.03 (d, J= 8.0 Hz, 1H), 1.45 (s, 6H), 1.43 (s, 3H), 1.41 (s, 3H); Mass: m / z 750.7 (M+H)+. 31 : of (1 S,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(2,2,2- i-3,3-

[0728] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.400 g, 0.557 mmol, 1.0 eq) in DCM (8 ml) at 0 °C was added triethylamine (0.225 g, 0.311 ml, 2.223 mmol, 4.0 eq) and 2,2,2- trifluoroacetic anhydride (0.234 g, 0.155 ml, 1.114 mmol, 2.0 eq). The reaction mass was allowed to stir at room temperature for overnight. Reaction mass was diluted with DCM (75 ml), washed with 0.5N HC1 (20 ml), 5% NaHCOs solution (30 ml), water (30 ml) and brine solution (30 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.160 g, yield: 41%) as a pale-yellow solid.1HNMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.13 (s, 1H), 9.51 (t, J= 5.5 Hz, 1H), 8.66 (d, J = 5.0 Hz, 1H), 8.61 (s, 1H), 8.55 (t, J= 5.5 Hz. 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.41-7.40 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.518 (d, J= 5.5 Hz, 1H), 4.01 (s, 3H), 3.49-3.45 (m, 2H), 3.43-3.39 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H).

[0729] Example 32: Preparation of (lS,2R)-Nl-(3-fluoro-4-((6-((2-hvdroxyethyl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- di carb oxami de:

[0730] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1.5 g, 2.67 mmol, 1.0 eq) and DMF (15 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (1.03 g, 8.0 mmol, 3.0 eq) and HATU (2.03 g, 5.33 mmol, 2.0 eq) were added and the reaction mass stirred at same temperature for about 1 hour. 2-aminoethan- l-ol (0.24 g, 4.0 mmol, 1.5 eq) dissolved in DMF (4 ml) was added, and allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was poured into water (100 ml), stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (50 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-10% methanol in di chloromethane gradient to obtain the title compound (0.230 g, yield: 14.28%) as an off-white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 10.42 (s, 1H), 10.12 (s, 1H), 8.66-8.64 (m, 2H), 8.435 (t, J = 6.0 Hz, 1H), 7.86-7.83 (m, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.54 (s, 1H), 7.43-7.38 (m, 2H), 7.13-7.09 (m, 2H), 6.507 (d, J= 5.0 Hz, 1H), 4.80 (t, 1H), 4.03 (s, 3H), 3.57-3.53 (m, 2H), 3.41-3.38 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 605.25 (M+H)+.

[0731] Example 33: Preparation of ( 1 S,2R)-N 1 -(3 -fluoro-4-((6-((2-

[0732] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxy quinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3, 3-dimethylcy cl opropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.400 g, 0.557 mmol, 1.0 eq) in acetone (8 ml) was added acetic acid (0.100 g, 0.09 ml, 1.671 mmol, 3.0 eq) and sodium triacetoxy borohydride (0.354 g, 1.671 mmol, 3.0 eq). The reaction mass was stirred at room temperature for overnight. TLC indicated starting material was completed. Reaction mass was quenched with 0.5N HC1 till to reach pH 6.0. After then, pH adjusted to 8.0 with 5% NaHCCh solution. Reaction mass was evaporated under reduced pressure. Residue was diluted with DCM (100 ml), washed with water (30 ml) and brine solution (30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. Crude compound was stirred with diisopropyl ether (20 ml) at room temperature for about 30 minutes. Solid was filtered, washed with diisopropyl ether (10 ml) and dried under vacuum to obtain the title compound (0.050 g) as an off-white solid.XHNMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.66-8.64 (m, 2H), 8.52 (t, J= 5.5 Hz, 1H), 7.84 (dd, J= 13.5, 1.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.54 (s, 1H), 7.43-7.38 (m, 2H), 7.132-7.09 (m, 2H), 6.51 (d, J= 5.5 Hz, 1H), 4.03 (s, 3H), 3.41-3.39 (m, 2H), 2.76-2.73 (m, 2H), 2.63 (m, 1H), 2.05 (s, 3H), 1.37 (s, 3H), 1.27 (s, 3H), 1.03 (d, J= 6.0 Hz, 6H); Mass: m / z 646.02 (M+H)+. ethoxy-6-((2-

[0733] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxy quinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcy cl opropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.300 g, 0.418 mmol, 1.0 eq) in DCM (6 ml) was added triethylamine (0.168 g, 0.23 ml, 1.672 mmol, 4.0 eq) followed by pivaloyl chloride (0.075 g, 0.076 ml, 0.627 mmol, 1.5 eq). The reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (50 ml), washed with 0.3N HC1 (10 ml), 5% NaHCCh solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.090 g, yield: 31.36%) as an off-white solid.XH NMR (500 MHz, CD3OD): 5 ppm 8.89 (s, 1H), 8.66 (d, J= 5.5 Hz, 1H), 7.85 (dd, J= 12.5, 2.0 Hz, 1H), 7.73 (brs, 1H), 7.57 (dd, J= 9.5, 5.0 Hz, 2H), 7.51 (s, 1H), 7.41 (dd, J= 9.0, 1.5 Hz, 1H), 7.34 (t, = 8.5 Hz, 1H), 7.04 (t, J = 8.5 Hz, 2H), 6.61 (d, J= 5.5 Hz, 1H), 4.12 (s, 3H), 3.59 (dd, J= 11.0, 5.0 Hz, 2H), 3.47 (dd, J= 11.0, 5.0 Hz, 2H), 2.08 (s, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.18 (s, 9H). carboxamido)ethyl)carbamate:

[0734] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.300 g, 0.418 mmol, 1.0 eq) in DCM (10 ml) was added triethylamine (0.211 g, 0.3 ml, 2.09 mmol, 5.0 eq) followed by ethyl chloroformate (0.068 g, 0.06 ml, 0.626 mmol, 1.5 eq). The reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (50 ml), washed with 0.3N HC1 (10 ml), 5% NaHCOs solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.200 g, yield: 68.5%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.65 (d, J= 5.0 Hz, 1H), 8.60 (s, 1H), 8.47 (t, J= 5.0 Hz, 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 2H), 7.20 (t, J= 5.5 Hz, 1H), 7.11 (t, J= 9.0 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 4.01 (s, 3H), 3.99-3.96 (m, 2H), 3.37-3.35 (m, 2H), 3.21- 3.17 (m, 2H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.13 (t, J= 7.5 Hz, 3H); Mass: m / z 676.25 (M+H)+.

[0735] Example 36: Preparation of tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)piperazine-l-carboxylate:

[0736] A solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.300 g, 0.534 mmol, 1.0 eq) and DMF (5 ml) cooled to 0 °C. N-ethyl-N- isopropylpropan-2-amine (0.207 g, 1.60 mmol, 3.0 eq) and HATU (0.406 g, 1.068 mmol, 2.0 eq) were added, reaction mass was stirred at 0-10 °C for about 1 hour. Tert-butyl 4-(2- aminoethyl)piperazine-l -carboxylate (Intermediate 14, 0.184 g, 0.801 mmol, 1.5 eq) dissolved in DMF (2 ml) was added and the reaction mass was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was poured into water (50 ml), stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (50 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.270 g, yield: 65.37%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.40 (s, 1H), 10.11 (s, 1H), 8.69 (s, 1H), 8.66 (d, J= 5.5 Hz, 1H), 8.48 (m, 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.54 (s, 1H), 7.43-7.38 (m, 2H), 7.13-7.08 (m, 2H), 6.51 (d, 1H), 4.05 (s, 3H), 3.46- 3.44 (m, 2H), 3.34 (m, 4H), 2.55-2.53 (m, 2H), 2.41 (m, 4H), 2.05 (s, 2H), 1.39 (s, 9H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 773.36 (M+H)+.

[0737] Example 37: Preparation of (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(piperazin-l- in-4- i-N2-(4-fluorophenyl)-3 ,3 - dimethylcyclopropane-E2-dicarboxamide 2,2,2-trifluoroacetate:

[0738] To a stirred solution of tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)piperazine-l -carboxylate (Example 36, 0.200 g, 0.258 mmol, 1.0 eq) in DCM (6 ml) at 0 °C was added Trifluoroacetic acid (4 ml). Reaction mass was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. Reaction mass was evaporated under reduced pressure. Residue was washed with hexanes (20 ml) and hexane layer was decanted. Methyl -tert-butyl ether (20 ml) was added to the residue stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with Methyl -tert-butyl ether (10 ml) and dried under vacuum. The obtained solid was further purified by treating again with Methyltert-butyl ether (20 ml), stirred at room temperature for overnight. Solid was filtered and dried under vacuum to obtain the title compound (0.130 g, yield: 64%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.44 (s, 1H), 10.14 (s, 1H), 8.84 (s, 2H), 8.745 (d, J = 5.5 Hz, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 7.87 (d, J= 12.5 Hz, 1H), 7.59 (dd, J = 9.0, 5.5 Hz, 2H), 7.56 (s, 1H), 7.45-7.40 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.64 (d, J= 5.5 Hz, 1H), 4.05 (s, 3H), 3.58-3.57 (m, 2H), 3.25 (m, 4H), 3.07-3.0 (m, 6H), 2.06 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 673.24 (M+H)+.

[0739] Example _ 38: _ Preparation _ of _ ( 1 S,2R)-N 1 -(4-((6-((2-(tert-butyl(4- methoxybenzyl)amino)ethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2- (4-fluorophenyl)-3, 3-dimethyl cyclopropane- E2-dicarboxamide:

[0740] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid

[0741] (Example 3, 1 g, 1.781 mmol, 1.0 eq) in DMF (10 ml) at 0-10 °C was added HATU (1.35 g, 3.561 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.68 g, 0.92 ml, 5.342 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 15 minutes. Nl-(tert-butyl)-Nl-(4- methoxybenzyl)ethane-l,2-diamine (Intermediate 15, 0.63 g, 2.671 mmol, 1.5 eq) dissolved in DMF (5 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (225 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (50 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-5% methanol in di chloromethane gradient to obtain the title compound (0.800 g) as a brown solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.66-8.65 (m, 2H), 8.26 (t, J= 5.5 Hz, 1H), 7.84 (d, J= 12.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.55 (s, 1H), 7.41-7.39 (m, 1H), 7.29 (d, J= 8.5 Hz, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.79 (d, J= 9.0 Hz, 2H), 6.51 (d, J= 5.0 Hz, 1H), 4.05 (s, 3H), 3.66 (s, 2H), 3.63 (s, 3H), 3.13 (dd, J = 12.5, 6.0 Hz, 2H), 2.73 (t, J = 6.5 Hz, 2H), 2.05 (s, 3H), 1.37 (s, 3H), 1.27 (s, 3H), 1.11 (s, 9H); Mass: m / z 780.27 (M+H)+. Example 39: _ Preparation _ of _ ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2- methoxy ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3- dimethylcyclopropane- 1 ,2-dicarboxamide:

[0742] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.300 g, 0.534 mmol, 1.0 eq) in DMF (6 ml) at 0-10 °C was added HATU (0.507 g, 1.335 mmol, 2.5 eq) and N-ethyl-N-isopropylpropan-2-amine (0.207 g, 0.27 ml, 1.602 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes. 2-methoxyethan- 1-amine (0.048 g, 0.641 mmol, 1.2 eq) dissolved in DMF (1 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-3% methanol in dichloromethane gradient to obtain the title compound (0.080 g) as a light brown solid.TH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.12 (s, 1H), 8.655 (d, J = 5.5 Hz, 1H), 8.62 (s, 1H), 8.467 (t, J= 6.0 Hz, 1H), 7.84 (dd, J = 14.0, 1.5 Hz, 1H), 7.58 (dd, J = 9.0, 5.0 Hz, 2H), 7.54 (s, 1H), 7.44-7.38 (m, 2H), 7.11 (t, J = 8.5 Hz, 2H), 6.51 (d, J= 5.0 Hz, 1H), 4.03 (s, 3H), 3.49 (m, 4H), 3.30 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 619.07 (M+H)+.

[0743] Example 40: Preparation of isobutyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcvclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)carbamate:

[0744] To a stirred solution of (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1,2-dicarboxamide 2,2,2-trifluoroacetate (Example 14, 0.200 g, 0.278 mmol, 1.0 eq) in DCM (4 ml) at 0-10 °C was added triethylamine (0.0846 g, 0.116 ml, 0.836 mmol, 3.0 eq) followed by isobutyl carb onochlori date (0.0856 g, 0.081 ml, 0.627 mmol, 2.25 eq). Cooling bath was removed, reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (50 ml), washed with 0.5N HC1 (10 ml), 5% NaHCOs solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 0-4% methanol in di chloromethane gradient to obtain the title compound (0.092 g, yield: 47%) as an off-white solid. 'H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.647 (d, J= 5.0 Hz, 1H), 8.60 (s, 1H), 8.46 (t, J = 5.5 Hz, 1H), 7.84 (d, J = 13.0 Hz, 1H), 7.58 (dd, J = 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.405 (d, J = 5.0 Hz, 2H), 7.208 (t. = 5.5 Hz, 1H), 7.11 (t, J= 9.0 Hz, 2H), 6.499 (d, = 5.0 Hz, 1H), 4.01 (s, 3H), 3.727 (d, J = 6.5 Hz, 2H), 3.38-3.35 (m, 2H), 3.22-3.18 (m, 2H), 2.05 (s, 2H), 1.84-1.76 (m, 1H), 1.37 (s, 3H), 1.27 (s, 3H), 0.83 (d, J= 6.5 Hz, 6H); Mass: m / z 704.49 (M+H)+.

[0745] Example 41 : Preparation of isopropyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)carbamate:

[0746] To a (lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)- 3 -fluorophenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2-dicarboxamide 2,2,2- trifluoroacetate (Example 14, 0.200 g, 0.278 mmol, 1.0 eq) in DCM (4 ml) at 0-10 °C was added N-ethyl-N-isopropylpropan-2-amine (0.108 g, 0.836 mmol, 3.0 eq) followed by isopropyl carb onochlori date (0.0512 g, 0.418 ml, 0.418 mmol, 1.5 eq). Cooling bath was removed, reaction mass was stirred at room temperature for overnight. Reaction mass was diluted with DCM (100 ml), washed with 0.5N HC1 (10 ml), 5% NaHCCh solution (20 ml), water (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-5% methanol in dichloromethane gradient to obtain the title compound (0.040 g, yield: 20.83%) as an off-white solid.XH NMR (500 MHz, DMSO- d6): 6 ppm 10.42 (s, 1H), 10.13 (s, 1H), 8.65 (d, J= 5.0 Hz, 1H), 8.61 (s, 1H), 8.46 (t, J= 5.0 Hz, 1H), 7.85 (d, J= 14.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.40 (d, J= 5.0 Hz, 2H), 7.11 (t, J = 9.0 Hz, 2H), 6.50 (d, J= 5.0 Hz, 1H), 4.78-4.73 (m, 1H), 4.01 (s, 3H), 3.36-3.35 (m, 2H), 3.20-3.17 (m, 2H), 3.02 (s, 1H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.135 (d, J= 6.5 Hz, 6H); Mass: m / z 690.47 (M+H)+.

[0747] Example 42: Preparation of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)(methyl)carbamate:

[0748] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-10 °C was added HATU (0.677 g, 1.780 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.345 g, 0.4 ml, 2.67 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes, tert-butyl (2- aminoethyl)(methyl)carbamate (0.186 g, 1.068 mmol, 1.2 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-3% methanol in dichloromethane gradient to obtain the title compound (0.062 g, yield: 9.7%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s. 1H), 10.12 (s, 1H), 8.645 (d, J = 5.5 Hz, 1H), 8.58 (s, 1H), 8.468 (t, J = 5.5 Hz, 1H), 7.84 (d, J = 13.0 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52 (s, 1H), 7.42-7.39 (m, 2H), 7.13-7.09 (m, 2H), 6.50 (d, J= 4.5 Hz, 1H), 4.01 (s, 3H), 3.43 (m, 2H), 3.39 (t, J= 3.0 Hz, 2H), 2.84 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 1.32 (s, 9H); Mass: m / z 718.49 (M+H)+.

[0749] Example 43: Preparation of ( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2-

[0750] (methylamino)ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcvclopropane-E2-dicarboxamide 2,2,2-trifluoroacetic acid:

[0751] To a stirred solution of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7- methoxyquinoline-6-carboxamido)ethyl)(methyl)carbamate (Example 42, 0.600 g, 0.835 mmol, 1.0 eq) in DCM (12 ml) was added Trifluoroacetic acid (8 ml). The reaction mass was stirred at room temperature for overnight. Reaction mass was evaporated under reduced pressure. Methyl -tert-butyl ether (20 ml) was added to the residue, stirred at room temperature for about 2 hours. Solid was filtered, washed with methyl -tert-butyl ether (10 ml) and dried under vacuum. DCM (20 ml) was added to the solid, stirred at room temperature for overnight. DCM layer was decanted. Again, DCM was added to the residue, stirred at room temperature for about 6 hours. DCM layer was decanted, methyl -tert-butyl ether (20 ml) was added to the residue, stirred at room temperature for about 2 hours. Solid was filtered, washed with methyltert-butyl ether (10 ml) and dried under vacuum to obtain the title compound (0.130 g, yield: 21.27%) as an off-white solid.XH NMR (500 MHz, DMSO-de): 5 ppm 10.44 (s, 1H), 10.14 (s, 1H), 8.76 (d, J= 5.5 Hz, 2H), 8.68 (t, J= 5.5 Hz, 1H), 8.41 (m, 2H), 7.88 (d, J= 13.5 Hz, 1H), 7.59-7.56 (m, 3H), 7.46-7.40 (m, 2H), 7.11 (dd, J= 15.5, 2.0 Hz, 2H), 6.66 (d, J= 4.5 Hz, 1H), 4.05 (s, 3H), 3.61 (dd, J = 12.0, 6.0 Hz, 2H), 3.15-3.10 (m, 2H), 2.63-2.61 (m, 2H), 2.06 (s, 2H), 1.37 (s, 3H), 1.27 (s, 3H); Mass: m / z 618.5 (M+H)+. )(methvl)carbamovl)-

[0752] To a stirred solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-10 °C was added HATU (0.677 g, 1.780 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.230 g, 0.31 ml, 1.78 mmol, 2.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes. N1,N1,N2- trimethylethane-l,2-diamine (0.109 g, 1.068 mmol, 1.2 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at 0-10 °C for about 30 minutes. The precipitate formed was filtered, washed with water (50 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-12% methanol in dichloromethane gradient. The obtained solid was stirred with heptane (20 ml) at room temperature for about 30 minutes. Solid was filtered, washed with heptane (5 ml) and dried under vacuum to obtain the title compound (0.180 g, yield: 31.3%) as an off-white solid.1HNMR (500 MHz, CD3OD): 5 ppm 8.61 (d, = 5.5 Hz, 1H), 8.36 (s, 1H), 7.84 (dd, J= 12.5, 2.0 Hz, 1H), 7.57 (dd, J= 9.0, 5.0 Hz, 2H), 7.49 (d, J= 5.5 Hz, 1H), 7.40 (d, J= 8.5 Hz, 1H), 7.32 (t, J= 9.0 Hz, 1H), 7.06 (t, 2H), 6.56 (d, J= 5.5 Hz, 1H), 4.04 (s, 3H), 3.96 (m, 1H), 3.65 (m, 1H), 2.94 (s, 3H), 2.80 (m, 1H), 2.60-2.55 (m, 1H), 2.51 (s, 3H), 2.08 (s, 2H), 2.07 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); Mass: m / z 667.9 (M+Na)+.

[0753] Example 45: Preparation of (lS,2R)-Nl-(4-((6-((3-

[0754] (dimethylamino)propyl)(methyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-

[0755] N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-L2-dicarboxamide:

[0756] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-10 °C was added HATU (0.677 g, 1.780 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.230 g, 0.31 ml, 1.78 mmol, 2.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes. N1,N1,N3- trimethylpropane- 1,3 -diamine (0.124 g, 1.068 mmol, 1.2 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at room temperature for about 30 minutes. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-10% methanol in di chloromethane gradient to obtain the title compound (0.290 g, yield: 49.4%) as an off-white solid. ’H NMR (500 MHz, CD3OD): 5 ppm 8.62 (d, J= 3.5 Hz, 1H), 8.29 (s, 1H), 7.84 (dd, J= 12.5, 2.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.51 (s, 1H), 7.40 (dd, J= 8.5, 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.04 (t, J= 8.5 Hz, 2H), 6.57 (d, J= 5.5 Hz, 1H), 4.06 (s, 3H), 3.84 (m, 1H), 3.57 (m, 1H), 3.0-2.94 (m, 1H), 2.94 (s, 3H), 2.73 (s, 3H), 2.42-2.39 (m, 1H), 2.31 (s, 2H), 2.07 (s, 3H), 1.85-1.67 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H); Mass: m / z 660.04 (M+H)+.

[0757] Example 46: Preparation of tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4- i-7-methoxy-N- methylquinoline-6-carboxamido)ethyl)carbamate:

[0758] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 1 g, 1.78 mmol, 1.0 eq) in DMF (10 ml) at 0-10 °C was added HATU (1.354 g, 3.56 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.69 g, 0.93 ml, 5.34 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes, tert-butyl (2- (methylamino)ethyl)carbamate (0.372 g, 2.137 mmol, 1.2 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (180 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-7% methanol in dichloromethane gradient to obtain the title compound (0.120 g, yield: 9.38%) as an off-white solid. ’H NMR (500 MHz, DMSO-de): 5 ppm 10.41 (s, 1H), 10.13 (s, 1H), 8.66 (d, J= 5.0 Hz, 1H), 8.11 (d, J= 14.0 Hz, 1H), 7.84 (d, J= 13.5 Hz, 1H), 7.58 (dd, J= 9.0, 5.0 Hz, 2H), 7.52-7.50 (m, 1H), 7.39 (m, 2H), 7.11 (t, J= 9.0 Hz, 2H), 6.67 (t, 1H), 6.10 (d, 1H), 3.97 (s, 3H), 3.15-3.12 (m, 2H), 3.02-3.01 (m, 2H), 2.80 (s, 3H), 2.05 (s, 2H), 1.37 (s, 3H), 1.34 (s, 9H), 1.27 (s, 3H); Mass: m / z 718.33 (M+H)+. Example 47: Preparation of (lS,2R)-Nl-(3-fluoro-4-((6-((3-hvdroxypropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-E2- di carb oxami de:

[0759] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-10 °C was added HATU (0.677 g, 1.78 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.345 g, 0.46 ml, 2.67 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes. 3 -aminopropan- l-ol (0.1 g, 1.335 mmol, 1.5 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-8% methanol in dichloromethane gradient to obtain the title compound (0.075 g, yield: 13.6%) as a light brown solid.TH NMR (500 MHz, CD3OD): 5 ppm 8.78 (s, 1H), 8.56 (m, 1H), 7.75 (dd, J= 12.5, 2.0 Hz, 1H), 7.46 (dd, J= 9.5, 5.0 Hz, 2H), 7.42 (s, 1H), 7.31 (dd, J= 9.0, 2.0 Hz, 1H), 7.25 (t, J= 9.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.51 (d, J= 5.0 Hz, 1H), 4.02 (s, 3H), 3.62 (t, J= 6.0 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 1.98 (s, 2H), 1.79-1.75 (m, 2H), 1.33 (s, 3H), 1.29 (s, 3H); Mass: m / z 641.26 (M+Na)+. of (1 S,2R)-N 1 -(4-((6-((2-aminoethyl)(methyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcvclopropane-

[0760] E2-dicarboxamide 2,2,2-trifluoroacetate: To a stirred solution of tert-butyl (2-(4-(2-fhroro-4-((lS,3R)-3-((4- fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-N- methylquinoline-6-carboxamido)ethyl)carbamate (Example 46, 0.600 g, 0.836 mmol, 1.0 eq) in DCM (12 ml) was added Tri fluoroacetic acid (8 ml). The reaction mass was stirred at room temperature for overnight. Reaction mass was evaporated under reduced pressure. Heptane (40 ml) was added to the residue stirred at room temperature for about 1 hour. Heptane layer was decanted. Methyl -tert-butyl ether (40 ml) was added to the residue, stirred at room temperature for about 2 hours. Solid was filtered, washed with methyl -tert-butyl ether (10 ml) and dried under vacuum. DCM (30 ml) was added to the solid, stirred at room temperature for overnight. DCM layer was decanted. Again, DCM was added to the residue, stirred at room temperature for about 6 hours. DCM layer was decanted and dried under vacuum. Methyl -tert-butyl ether (20 ml) was added to the residue, stirred at room temperature for about 2 hours. Solid was filtered, washed with methyl-tert-butyl ether (10 ml) and dried under vacuum to obtain the title compound (0.130 g, yield: 21.27%) as an off-white solid. ’H NMR (500 MHz, CD3OD): 5 ppm 8.77 (s, 1H), 8.58 (s, 1H), 7.89 (d, J= 12.0 Hz, 1H), 7.56 (m, 3H), 7.42-7.38 (m, 2H), 7.04 (m, 2H), 6.80 (brs, 1H), 4.10 (s, 3H), 3.55 (m, 2H), 3.19-3.12 (m, 2H), 2.97 (s, 3H), 2.09 (s, 2H), 1.43 (s, 3H), 1.38 (s, 3H); Mass: m / z 618.3 (M+H)+.

[0761] Example 49: Preparation of (lS,2R)-Nl-(4-((6-((3-(El- dioxidothiomorpholino)propyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcvclopropane-E2-dicarboxamide:

[0762] To a solution of 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid (Example 3, 0.500 g, 0.890 mmol, 1.0 eq) in DMF (5 ml) at 0-10 °C was added HATU (0.677 g, 1.78 mmol, 2.0 eq) and N-ethyl-N-isopropylpropan-2-amine (0.345 g, 0.46 ml, 2.67 mmol, 3.0 eq). The reaction mass was stirred at 0-10 °C for about 30 minutes. 4-(3- aminopropyl)thiomorpholine 1,1-dioxide (Intermediate 16, 0.342 g, 1.78 mmol, 2.0 eq) dissolved in DMF (2 ml) was added, allowed to stir at room temperature for overnight. TLC indicated starting material was completed. Water (105 ml) was added to the reaction mass, stirred at room temperature for about 1 hour. The precipitate formed was filtered, washed with water (20 ml) and dried under vacuum. The crude compound was purified by silica gel column chromatography using 0-5% methanol in di chloromethane gradient to obtain the title compound (0.060 g, yield: 9.16%) as an off-white solid.TH NMR (500 MHz, DMSO-de): 5 ppm 8.70 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.74 (dd, J = 12.5, 2.0 Hz, 1H), 7.47 (dd, J= 9.0, 4.5 Hz, 2H), 7.41 (s, 1H), 7.30 (d, J= 10.5 Hz, 1H), 7.24 (t, J= 9.0 Hz, 1H), 6.94 (t, J= 9.0 Hz, 2H), 6.46 (d, J= 5.5 Hz, 1H), 4.0 (s, 3H), 3.43 (t, J= 7.0 Hz, 2H), 3.0 (t, J= 5.5 Hz, 4H), 2.92 (m, 4H), 2.56 (t, J= 7.0 Hz, 2H), 1.98 (d, J= 4.5 Hz, 2H), 1.75 (t, J= 7.0 Hz, 2H), 1.33 (s, 3H), 1.29 (s, 3H); Mass: m / z 736.42 (M+H)+.

[0763] Example 50: Preparation o...

Claims

We Claim:

1. A compound of formula (I):Formula (I) wherein,‘X’ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or -C(O)-R?; wherein the substituents are selected form hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or amino;‘Y’ is -ORc;‘Z’ is selected from ‘-O-’ or ‘-S-’; ringis substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted heteroaryl; ring O isselected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl;Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, haloalkyloxy, cycloalkyloxy, cyano, nitro, or amino;R2 and R3 are independently selected from hydrogen or Ci-Ce alkyl or R2 and R3 are taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein one or more substituents are independently selected from halogen or Ci-Ce alkyl;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;Rs is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;Re is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;R? is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or amino;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;’ is an optional bond;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IA):Formula (I A) wherein,‘X’ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or -C(O)-R?; wherein the substituents are selected form hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or amino;‘Y’ is -ORc; ringis substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted heteroaryl; ring is selected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl;Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, haloalkyloxy, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or amino;R2 and R3 are independently selected from hydrogen or Ci-Ce alkyl or R2 and R3 are taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein one or more substituents are independently selected from halogen or Ci-Ce alkyl;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;Rs is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;Re is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;R? is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or amino;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;’ is an optional bond;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

3. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IB):Formula (IB) wherein, ringis substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted heteroaryl; ring is selected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl;Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, haloalkyloxy, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or ammo;R2 and Ra are independently selected from hydrogen or Ci-Ce alkyl or R2 and R3 are taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein one or more substituents are independently selected from halogen or Ci-Ce alkyl;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;Rs is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;Re is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;R? is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or amino;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;’ is an optional bond;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

4. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IC):Formula (IC) wherein,Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, haloalkyloxy, Ci-Ce alkoxy, cycloalkyloxy, cyano, nitro, or ammo;R2 and R3 are independently selected from hydrogen or Ci-Ce alkyl or R2 and R3 are taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein one or more substituents are independently selected from halogen or Ci-Ce alkyl;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;Rs is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;Re is selected from hydrogen or substituted or unsubstituted Ci-Ce alkyl;R7 is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl,halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or amino;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;’ is an optional bond;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

5. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (ID):formula (ID) wherein,Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, haloalkyloxy, cycloalkyloxy, cyano, nitro, or ammo;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;R7 is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or amino;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl or hydroxyalkyl;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

6. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IE):Formula (IE) wherein,Ri is selected from one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, haloalkyloxy, cycloalkyloxy, cyano, nitro, or amino;R4 is selected form one or more hydrogen, hydroxyl, halo, Ci-Ce alkyl, substituted or unsubstituted aryl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, oxo (C=O), -C(O)-alkyl, -C(O)-alkoxy, deuteroalkyloxy, haloalkyloxy, cycloalkyloxy, cyano, nitro or amino;R7 is selected from substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce haloalkyl, hydroxy, Ci-Ce alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -O-substituted or unsubstituted heterocyclylalkyl,wherein one or more substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -C(O)-alkyl,-C(O)-alkenyl, -C(O)-alkoxy, -O-C(O)-alkyl, cycloalkyloxy, cyano, heterocyclyl, nitro or ammo;Ra and Rb are independently selected from hydrogen, amino, hydroxyalkyl, substituted or unsubstituted Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce deuteroalkyl, Ci-Ce deuteroalkyloxy, hydroxy, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hetercyclylalkyl, -O- hydroxyalkyl, -(CH2)n-O-C(O)-alkyl, -(CH2)n-O-C(O)-alkyl-N(Rd)(Re); wherein the substituents are selected from hydroxy, alkylaminoalkyl, heterocyclyl or alkoxy;Rc selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce cycloalkylalkyl, Ci-Ce deuteroalkyl, hydroxyalkyl, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; wherein the one or more substituents are selected from amino, Ci-Ce alkyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkoxy, -N(H)-C(O)-alkoxy, Ci-Ce haloalkyl, hydroxy, halo or Ci-Ce alkoxy;Rd and Re are independently selected from hydrogen, substituted or unsubstituted Ci- Ce alkyl, -C(O)-alkoxy, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-alkenyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, -C(O)-substituted or unsubstituted aryl, -C(O)-substituted or unsubstituted heteroaryl, -C(O)-substituted or unsubstituted heterocyclyl, or Rd and Re are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; wherein the substituents are selected from hydroxyl, halo, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, cycloalkyloxy, -C(O)-alkoxy, -C(O)alkenyl, or - C(O)alkyl, cyano, nitro, haloalkyl or amino;Rf and Rgare independently selected from hydrogen, substituted or unsubstituted Ci-Ce alkyl or hydroxyalkyl;‘m’ is an integer selected from 0, 1, 2, 3 or 4;‘n’ is an integer selected from 1, 2, 3, 4 or 5; and ‘p’ is an integer selected from 1, 2, 3 or 4 or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or a combination thereof.

7. The compound according to claim 1, wherein ‘X’ is -C(O)-R?; wherein ‘R7’ is -11. The compound according to claim 1, wherein ‘ Y’ is -ORC; wherein Rc is selected from hydrogen, methyl, propyl, isopropyl, tert-butyl, deuteromethyl, 1 -methoxy ethyl, 4- methylpiperidinyl, 4-methylmorpholinyl, 4-ethylmorpholinyl, 4-propylmorpholin, tert-butyl 4- methylpiperidinyl-1 -carboxylate or 2-ethoxy-2-methylpropanyl.

12. The compound according to claim 1, wherein Rs and Re are independently selected from hydrogen or methyl.

13. The compound according to claim 1, wherein R2 and R3 are taken together with the carbon atom to which they are attached to form substituted or unsubstituted C3-C10 cycloalkyl; wherein the said cycloalkyl is selected from(includes14. The compound according to claim 1, wherein the compound of Formula (I) is selected from methyl 4-(2-fluoro-4-((l S,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylic acid, (lS,2R)-Nl-(4-((6-(dimethylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,tert-butyl 4-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carbonyl)piperazine- 1 -carboxylate,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(piperazine-l-carbonyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(4-((6-(4-acryloylpiperazine-l-carbonyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(4-propionylpiperazine-l-carbonyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(4-((6-((2-acrylamidoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,((2R,3S,4R)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl 4-(2-fluoro- 4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,(lR,2S)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(2R,3S,4R)-2-(((4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carbonyl)oxy)methyl)-6-methoxytetrahydro-2H-pyran-3,4-diyl diacetate, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate,(lS,2R)-Nl-(4-((6-((2-aminoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetate,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-propionamidoethyl)carbamoyl)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, isopropyl 4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2-dimethylcyclopropane-l- carboxamido)phenoxy)-7-methoxy-6-(methylcarbamoyl)quinoline 1-oxide,(lS,2R)-Nl-(4-((6-(l,l-dioxidothiomorpholine-4-carbonyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropyl)carbamate, (lS,2R)-Nl-(4-((6-((l-amino-2-methylpropan-2-yl)carbamoyl)-7-methoxy quinolin- 4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide2, 2, 2-tri fluoroacetate, tert-butyl (l-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropan-2-yl)carbamate,( 1 S,2R)-N 1 -(4-((6-((2-amino-2-methylpropyl)carbamoyl)-7-methoxy quinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide2.2.2-trifluoroacetate,(lS,2R)-Nl-(4-((6-((2-(l,l-dioxidothiomorpholino)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1.2-dicarboxamide,(lS,2R)-Nl-(4-((6-((2-(l,l-dioxidothiomorpholino)-2-methylpropyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1 ,2-dicarboxamide,(lS,2R)-Nl-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)-2- methylpropyl)piperazine- 1 -carboxylate,( 1 S,2R)-N 1 -(3 -fluoro-4-((7-methoxy-6-((2-methyl- 1 -(piperazin- 1 -yl)propan-2- yl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2- dicarboxamide 2,2,2-trifluoroacetic acid,(lS,2R)-Nl-(3-fluoro-4-((6-((l-hydroxy-2-methylpropan-2-yl)carbamoyl)-7- methoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1 ,2- dicarboxamide,(lS,2R)-Nl-(4-((6-(((2R,3R)-2-(l,l-dioxidothiomorpholino)-3- hydroxybutyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(4-((6-((l-(l,l-dioxidothiomorpholino)-2-methylpropan-2- yl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(2,2,2- trifluoroacetamido)ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((6-((2-hydroxyethyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((6-((2-(isopropylamino)ethyl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1 ,2- dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-pivalamidoethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, ethyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate, tert-butyl 4-(2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)piperazine- 1 -carboxylate,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2-(piperazin- 1 - yl)ethyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetate,(lS,2R)-Nl-(4-((6-((2-(tert-butyl(4-methoxybenzyl)amino)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane- 1 ,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-methoxyethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, isobutyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate, isopropyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)carbamate,tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)ethyl)(methyl)carbamate,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((2-(methylamino)ethyl)carbamoyl)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid,( 1 S,2R)-N 1 -(4-((6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1 ,2-dicarboxamide,(lS,2R)-Nl-(4-((6-((3-(dimethylamino)propyl)(methyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1.2-dicarboxamide, tert-butyl (2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-N-methylquinoline-6- carboxamido)ethyl)carbamate,(lS,2R)-Nl-(3-fluoro-4-((6-((3-hydroxypropyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(4-((6-((2-aminoethyl)(methyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide2.2.2-trifluoroacetate,(lS,2R)-Nl-(4-((6-((3-(l,l-dioxidothiomorpholino)propyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1.2-dicarboxamide, tert-butyl 4-(3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)piperazine-l -carboxylate, (lS,2R)-Nl-(4-((6-((2-(dimethylamino)ethyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((3 -(piperazin- 1 - yl)propyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid,(lS,2R)-Nl-(4-((6-((3-(dimethylamino)propyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)carbamate, (lS,2R)-Nl-(4-((6-((3-aminopropyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid, tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)propyl)(methyl)carbamate,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((3 - (methylamino)propyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid, (lS,2R)-Nl-(4-((6-((3-(l,3-dioxoisoindolin-2-yl)propyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1 ,2-dicarboxamide,(lS,2R)-Nl-(4-((6-((2-(l,3-dioxoisoindolin-2-yl)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1 ,2-dicarboxamide,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((2-(3 -methyl-4-oxo-3 ,4- dihydroimidazo[5,l-d][l,2,3,5]tetrazine-8-carboxamido)ethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(4-((6-((2-(5-amino-lH-imidazole-4-carboxamido)ethyl)carbamoyl)-7- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-1.2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((3-methoxypropyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((oxetan-3-ylmethyl)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxy-N-methylquinoline-6- carboxamido)propyl)carbamate, (lS,2R)-Nl-(4-((6-((3-aminopropyl)(methyl)carbamoyl)-7-methoxyquinolin-4- yl)oxy)-3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide2.2.2-trifluoroacetic acid,(lS,2R)-Nl-(4-((6-(ethylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((6-(isopropylcarbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(4-((6-(tert-butylcarbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(4-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6- carboxamido)phenyl)piperazine- 1 -carboxylate,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((4-(piperazin- 1 - yl)phenyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide 2,2,2-trifluoroacetic acid,( 1 S,2R)-N 1 -(3 -fluoro-4-((7 -methoxy-6-((4-(4-methylpiperazin- 1 - yl)phenyl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl acetate,3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl (tert-butoxycarbonyl)-L-valinate, ethyl 4-(2-fluoro-4-((l S,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxylate,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-((methyl-d3)carbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)ethyl (tert-butoxycarbonyl)-L-valinate,2-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)ethyl L-valinate 2,2,2-trifluoroacetic acid,(lS,2R)-Nl-(4-((6-((2-benzamidoethyl)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,3-(4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-7-methoxyquinoline-6-carboxamido)propyl L-valinate 2,2,2-trifluoroacetic acid,(lS,2R)-Nl-(3-fluoro-4-((6-((2-(2-hydroxybenzamido)ethyl)carbamoyl)-7- m ethoxy quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- di carb oxami de,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methoxycarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N4-(4- fluorophenyl)maleamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-fluorophenyl)-N2-(2-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrimidin-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,4-(2-fluoro-4-(3-(4-fluorobenzamido)propanamido)phenoxy)-7-methoxy-N- methylquinoline-6-carboxamide,(lS,2R)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)thio)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)thio)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(2-chloro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(4-fluorophenyl)-N2-(3-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-chloro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(2-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-hydroxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(4-((7-(2-(tert-butoxy)ethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)- 3-fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((6-(hydrazinecarbonyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(l,3,4-oxadiazol-2-yl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-(((4-(2-fluoro-4-((lS,3R)-3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)piperidine- 1 -carboxylate,(lS,2R)-Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(piperidin-4-ylmethoxy)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide 2,2,2- trifluoroacetic acid,(1 S,2R)-N1 -(3-fluoro-4-((7-(2 -methoxy ethoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(5-methyl-l,3,4-oxadiazol-2-yl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-(methoxy-d3)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-N2,3,3-trimethylcyclopropane-l,2-dicarboxamide, (lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-N2,3,3-trimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N4-(4- fluorophenyl)fumaramide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-phenylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-phenylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)cyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)cyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(4-((6-carbamoyl-7-hydroxyquinolin-4-yl)oxy)-3-fluorophenyl)-N2-(4- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(2,4-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,( 1 S,2R)-N 1 -(2,4-difluorophenyl)-N2-(3 -fluoro-4-((7 -methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2 dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(pyridin-3-yl)cyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(pyridin-3-yl)cyclopropane-l,2-dicarboxamide,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(5-fluoropyridin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(5-fluoropyridin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(5-methyl-l,3,4-thiadiazol-2-yl)cyclopropane-l,2- di carb oxami de,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(5-methyl-l,3,4-thiadiazol-2-yl)cyclopropane-l,2- di carb oxami de,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(2-methylbenzo[d]thiazol-6-yl)cyclopropane-l,2- di carb oxami de,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethyl-N2-(2-methylbenzo[d]thiazol-6-yl)cyclopropane-l,2- di carb oxami de,(lS,2R)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorobenzyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,(lR,2S)-Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorobenzyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(2,5-difluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(p-tolyl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- (fluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,3-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin- 4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,5-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,6-difluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,3,4-trifluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3,4,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,3,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,4,6-trifluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2,4,5-trifluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(perfluorophenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethyl)phenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluoro-4-(trifluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- fluoro-6-(trifluoromethyl)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-chloro-2-fluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-chloro-2-fluorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-chlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,3-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,4-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,5-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(2,6-dichlorophenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- hydroxyphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- methoxyphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- (methoxy-d3)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,N 1 -(2-(difluoromethoxy)phenyl)-N2-(3 -fluoro-4-((7 -methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-(difluoromethoxy)phenyl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,N 1 -(4-(difluoromethoxy)phenyl)-N2-(3 -fluoro-4-((7 -methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-(fluoromethoxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-(trifluoromethoxy)phenyl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(lH-pyrazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-lH-pyrazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(l,3-dimethyl-lH-pyrazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(l,5-dimethyl-lH-pyrazol-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(l-ethyl-lH-pyrazol-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(l- isopropyl-lH-pyrazol-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(lH- imidazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(isoxazol-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylisoxazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisoxazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(oxazol-2-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyloxazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyloxazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)oxazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-l,3,4-oxadiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(5-(tert-butyl)-l,3,4-oxadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,2,5-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyl-l,2,5-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-l,2,4-oxadiazol-3-yl)cyclopropane-l,2-dicarboxamide, Nl-(3-(tert-butyl)-l,2,4-oxadiazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylthiophen-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(thiazol-2-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methylthiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylthiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)thiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methyl-5-(trifluoromethyl)thiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)cyclopropane-l,2- di carb oxami de,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2- (isothiazol-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisothiazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylisothiazol-4-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl)cyclopropane-l,2-dicarboxamide, Nl-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(5-ethyl-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- isopropyl-l,3,4-thiadiazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(5-(tert-butyl)-l,3,4-thiadiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4H- 1 ,2,4-triazol-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(lH-l,2,4-triazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methyl-2H-tetrazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-( 1 -methyl- lH-tetrazol-5-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,2,4-triazin-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridin-2-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-methylpyridin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylpyridin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-methylpyridin-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridin-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylpyridin-4-yl)cyclopropane-l,2-dicarboxamide,Nl-(2,6-dimethylpyridin-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrazin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyridazin-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-(trifluoromethyl)pyridazin-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- methoxypyridazin-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(6-ethylpyridazin-3-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrimidin-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrimidin-2-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylpyrimidin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(4-ethylpyrimidin-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4,6-dimethylpyrimidin-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(benzo[d]oxazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- methoxybenzo[d]oxazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(5- fluorobenzo[d]oxazol-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5-nitrobenzo[d]oxazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- fluorobenzo[d]isoxazol-3-yl)-3, 3 -dimethyl cyclopropane- 1,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(lH- indazol-3-yl)-3, 3 -dimethylcyclopropane- 1,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(6-(trifluoromethyl)-lH-indazol-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(l-ethyl-lH-indazol-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(lH-benzo[d]imidazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-( 1 -methyl- lH-benzo[d]imidazol-2-yl)cy cl opropane- 1 ,2-dicarboxamide,Nl-(benzo[d]thiazol-2-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(4-methylbenzo[d]thiazol-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(benzo[d]isothiazol-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(benzo[b]thiophen-3-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(benzo[d]isoxazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylbenzo[d]isoxazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylbenzo[d]oxazol-6-yl)cyclopropane-l,2-dicarboxamide,Nl-(2-(tert-butyl)benzo[d]oxazol-6-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(benzo[d]oxazol-7-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-phenylbenzo[d]oxazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methylbenzo[d]oxazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(lH-benzo[d]imidazol-7-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(lH-benzo[d]imidazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(imidazof 1 ,2-a]pyridin-6-yl)-3 ,3 -dimethylcyclopropane- 1 ,2-dicarboxamide,Nl-(benzo[d]isothiazol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(1 -acetyl- lH-indol-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(pyrrolo[ 1 ,2-b]pyridazin-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3,3-dimethyl-2-oxoindolin-6-yl)-N2-(3-fluoro-4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(naphthalen- 1 -yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinazolin-4-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinazolin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(2- methoxyquinolin-5-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(8-methylquinolin-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(3- methoxyquinolin-6-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylquinolin-7-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(isoquinolin-6-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-6-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(2-methyl-l,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroisoquinolin-6-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(5,6,7,8-tetrahydroquinolin-6-yl)cyclopropane-l,2-dicarboxamide,tert-butyl 4-(3-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)carbamoyl)-2,2-dimethylcyclopropane-l-carboxamido)-3,4- dihydroisoquinoline-2(lH)-carboxylate,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-4-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-2-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinolin-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(quinoxalin-6-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(phthalazin-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(cinnolin-7-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(cinnolin-6-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(phthalazin-6-yl)cyclopropane- 1 ,2-dicarboxamide,Nl-(cinnolin-5-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylcinnolin-5-yl)cyclopropane-l,2-dicarboxamide,Nl-(cinnolin-4-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(3-methylquinoxalin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,5-naphthyridin-2-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-3,3- dimethyl-N2-(l,7-naphthyridin-3-yl)cyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(6- methoxy-l,5-naphthyridin-4-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(acridin-9-yl)-N2-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclobutane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclopentane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)cyclohexane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)-Nl,3,3-trimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4- fluorophenyl)-Nl,N2,3,3-tetramethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)-2- methylphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- methylphenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(6-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyridin-3-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyri din-2 -yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrimidin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-fluorophenyl)-N2-(5-((7-methoxy-6-(methylcarbamoyl)quinolin-4- yl)oxy)pyrazin-2-yl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(2-fluoro-5-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-(2-hydroxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-(2-isopropoxyethoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((7-(3-hydroxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-(3-methoxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-(3-isopropoxypropoxy)-6-(methylcarbamoyl)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((7-(3-(tert-butoxy)propoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-tetrahydrofuran-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-(((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)oxy)-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,Nl-(3-fluoro-4-((7-(((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl)oxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide,Nl-(4-((7-(((R)-l,4-dioxan-2-yl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((7-(((S)-l,4-dioxan-2-yl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-2-oxopyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-2-oxopyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-pyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-pyrrolidin-3-yl)oxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 3-(((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)azetidine- 1 -carboxylate,Nl-(4-((7-(azetidin-3-ylmethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(trifluoromethoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((7-(difluoromethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2,2,2-trifluoroethoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl 4-((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)piperidine-l -carboxylate,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(piperidin-4-yloxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((7-((l-acryloylpiperidin-4-yl)oxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, tert-butyl (2-((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)ethyl)carbamate,Nl-(4-((7-(2-aminoethoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3-fluorophenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2-(piperazin-l-yl)ethoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(2-(4-methylpiperazin-l-yl)ethoxy)quinolin- 4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((7-(3-aminopropoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,N 1 -(3 -fluoro-4-((6-(methylcarbamoyl)-7-(3 -(piperazin- 1 -yl)propoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,N 1 -(3 -fluoro-4-((6-(methylcarbamoyl)-7-(3 -(4-methylpiperazin- 1 - yl)propoxy)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2- di carb oxami de, tert-butyl (l-(((4-(2-fluoro-4-(3-((4-fluorophenyl)carbamoyl)-2,2- dimethylcyclopropane-l-carboxamido)phenoxy)-6-(methylcarbamoyl)quinolin-7- yl)oxy)methyl)cyclopropyl)carbamate,Nl-(4-((7-((l-aminocyclopropyl)methoxy)-6-(methylcarbamoyl)quinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-((tetrahydro-2H-pyran-4- yl)methoxy)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3, 3 -dimethylcyclopropane- 1,2- di carb oxami de,Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-((3-methyloxetan-3-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((R)-oxetan-2-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(((S)-oxetan-2-yl)methoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, Nl-(3-fluoro-4-((6-((2 -hydroxy ethoxy)carbamoyl)-7-methoxy quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(3-fluoro-4-((7-methoxy-6-((methoxy-d3)carbamoyl)quinolin-4-yl)oxy)phenyl)- N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((6-(((R)-2,3-dihydroxypropoxy)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,Nl-(4-((6-(((S)-2,3-dihydroxypropoxy)carbamoyl)-7-methoxyquinolin-4-yl)oxy)-3- fluorophenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide,N 1 -(3 -fluoro-4-((7 -methoxy-6-(( 1 -(2-methyl- 1 -(neopentylamino)propan-2-yl)- 1 H- imidazol-4-yl)carbamoyl)quinolin-4-yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3- dimethylcyclopropane- 1 ,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((6-(methylcarbamoyl)-7-(3-morpholinopropoxy)quinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide, (lS,2R)-Nl-(3-fluoro-4-((6-(hydroxycarbamoyl)-7-methoxyquinolin-4- yl)oxy)phenyl)-N2-(4-fluorophenyl)-3,3-dimethylcyclopropane-l,2-dicarboxamide or pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, or pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites or N-oxides or combination thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutically acceptable excipient is a carrier or a diluent.

17. A method of modulating the activity of a kinase, the method comprising administering to a subject an effective amount of a compound of Formula (I) according to any one of claims 1-14 or a pharmaceutical composition thereof.

18. The method according to claim 17, wherein the modulating the activity of the kinase comprises inhibition of said kinase.

19. The method according to claim 18, wherein said kinase is at least one of KDR, c-Met, RET, AXL, TEK (Tie 2), PDGFR and EGFR.

20. A method of treating diseases or disorders associated with abnormal, uncontrolled, and / or unwanted activities of kinases, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-14 or a pharmaceutical composition thereof.

21. The method according to claim 20, wherein said kinase is at least one of KDR, c-Met, RET, AXL, TEK (Tie 2), PDGFR and EGFR.

22. A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-14 or a pharmaceutical composition thereof.

23. The method of claim 22, wherein the cancer is ovarian cancer, prostate cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, pancreatic cancer, breast cancer, colorectal carcinoma, oral squamous cell carcinoma and / or lung adenocarcinoma.

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