(EXTRACTED FROM WIPO PAGE)
TITLE: SUBSTITUTED TRICYCLIC COMPOUNDS
FIELD OF THE INVENTION
The present invention is related to a compound of the general formula (I),

its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in various pathological conditions.
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit of Indian Provisional Patent Application Nos. IN 201921054254, filed on 27th December 2019, IN 201921049099, 29* December 2019, IN 202021022668 filed on 29th May 2020, IN 202021032769 filed on 30* July 2020 and IN 202021035200 filed on 14th August 2020, the disclosures of which are incorporated herein by reference in their entirety for all purposes.
BACKGROUND OF THE INVENTION
Multiple signaling pathways control the initiation, progression, spread, metastasis, immune evasion of cancer. Key signaling pathways include RTK/RAS pathway, PI3K pathway, Wnt pathway, Myc pathway and the cell cycle pathway (Francisco Sanchez-Vega et al., Cell, 2018, 173(2):321-337.el0). RAS-family proteins (KRAS, HRAS and NRAs and their respective mutants) are small GTPases that exist in cells in either GTP-bound (inactive) or GDP-bound (active) states (Siqi Li et al, Nat. Rev. Cancer, 2018, 18(12):767-777). The activity of RAS proteins is modulated by proteins known as GTPase Activating Proteins (GAPs) or Guanine Nucleotide
Exchange Factors (GEFs). The GAP proteins belonging to the RAS family include members such as NF1,
TSC2, IQGAP1, etc. which activate the GTPase function of the RAS proteins and thus terminate the signaling by catalyzing the hydrolysis of GTP to GDP. In contrast, the RAS family GEFs include proteins such as SOS1, SOS2, RASGRP, RASGRF2, etc. which activate the RAS proteins by exchanging GTP for GDP (Johannes L. Bos etal, Cell, 2007, 129(5):865-77).
Ras-GTP binds to effector proteins such as Raf and PI3K which in turn leads to activation of the RAF-MEK-ERK (MAPK) and PI3K-mTOR-AKT (PI3K) signaling pathways (Suzanne Schubbert et al., Nat. Rev. Cancer, 2007, 7(4):295-308). Triggering of one or more of these cellular signaling pathways leads to the initiation and maintenance of the oncogenic phenotype involving enhanced cell proliferation, increased cell survival, altered metabolism, angiogenesis, migratory potential and immune evasion eventually leading to establishment and metastasis of cancers (Yousef Ahmed Fouad et al., Am. J. Cancer Res., 2017, 1;7(5): 1016-1036; Douglas Hanahan et al., Cell, 2011, 4;144(5):646-74). RAS proteins undergo point mutations at several amino acid residues - the key hot spots being positions G12, G13 and Q61. These mutations render the RAS proteins constitutively active since the proteins are predominantly in the active GTP -bound form (Ian A. Prior et al., Cancer Res.2012, 15; 72(10): 2457-2467; Adrienne D. Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11):828-51). Interaction of RAS proteins with GEFs such as Son of Sevenless 1 (SOS 1) plays a crucial role in relaying the signals to downstream effectors. The SOS1 protein harbors several domains such as the Dbl homology domain (DH), a Pleckstrin homology domain (PH), RAS exchanger motif (REM), CDC25 homology domain and a C-terminal proline rich domain (PxxP) (Pradeep Bandaru et al., Cold Spring Harb Perspect Med., 2019, 1;9(2). pii: a031534). SOS1 has been shown to have a catalytic site as well as an allosteric site. The catalytic site is preferentially bound by RAS-GDP whereas RAS-GTP binds with the allosteric site with better affinity than RAS-GDP (S. Mariana Margarit et al., Cell, 2003, 7;112(5):685-95; Hao-Hsuan Jeng et al., Nat. Commun., 2012; 3:1168). Furthermore, binding of oncogenic KRAS to SOS1 promotes the activation of wild type HRAS and NRAS (Hao-Hsuan Jeng etal., Nat. Commun., 2012;3:1168). The catalytic (guanine nucleotide exchange) function of SOS1 is critical for KRAS oncogenic activity in cancer cells (You X et al., Blood. 2018, 13;132(24):2575-2579; Erin Sheffels et al., Sci Signal. 2018, 4;11(546). pii: eaar8371). SOS1 plays a key role in signal transmission following cellular activation by Receptor Tyrosine Kinases (RTKs) (Frank McCormick et al., Nature, 1993, 6;363(6424):45-51; Stephane Pierre et al., Biochem Pharmacol. 2011, 1;82(9): 1049-56). Additionally, receptors on lymphocytes (B cell and T cell receptor) (Mateusz Poltorak et al., Eur J Immunol.
2014, 44(5): 1535-40; Stephen R. Brooks et al., J Immunol. 2000, 15; 164(6):3123-31) and hematopoietic cells (Mario N. Lioubin et al. , Mol Cell Biol., 1994, 14(9):5682-91).
The role of SOS1 in the RAS-mediated signaling pathways make it an attractive target for cancer therapy. Pharmacological intervention with SOS1 inhibitors has been shown to attenuate or eliminate the downstream effector events of the RAS-mediated pathways (Roman C. Hillig et al., Proc. Natl. Acad. Sci. U S A. 2019, 12;116(7):2551-2560; Chris R. Evelyn et al., J Biol Chem., 2015, 15; 290(20): 12879-98).
In addition to cancer, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g. Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre eta/., Biochem. Pharmacol., 2011,82(9): 1049-56).
In addition, the other diseases associated with hSOSl expression is significantly upregulated in whole blood cell extracts of pediatric patients with acute community -acquired Staphylococcus aureus infection and in patients with Acute Respiratory Distress Syndrome (ARDS)/Acute Lung Injury (ALI) and Sepsis (F.C. Baltanas, et al. BBA - Reviews on Cancer 1874 (2020) 188445).
In addition, several patent applications related to SOS1 are published which are as follows: W02004003152, WO2014144148, WO2016077793, WO2018115380, WO2018172250, WO2019122129, WO2019201848, W02020180768, and W02020180770.
The foregoing shows that there exists an unmet need for SOS1 inhibitory compounds for treating diseases or disorders involving SOS1, particularly cancer that are dependent on the SOS1.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compound of the general formula (I), its pharmaceutically acceptable salts, its tautomeric forms, its stereoisomers, its polymorphs, its solvates, its combinations with suitable other medicament or medicaments, its pharmaceutical compositions thereof, and its use thereof in treating various diseases or disorders including cancers,

wherein, ring A, ring B, R1 to R4, and n are as described hereinbelow. The compounds of the present invention are potent inhibitors of SOS1.
According to one aspect of the present invention, there is provided a compound represented by the general formula (I), its tautomeric form, its stereoisomer, its polymorph, its solvate, its pharmaceutically acceptable salt, its combinations with suitable medicament and its pharmaceutical compositions.
In other aspect the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, and its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder mediated through SOS1.
In another aspect the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
In yet other aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating disease characterized by excessive or abnormal cell proliferation such as cancer.
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases like pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Hereditary Gingival Fibromatosis (HGF), Capillary Malformation-Arteriovenous Malformation Syndrome
(CM-AVM), Legius Syndrome, Acute Staphylococcus aureus infection (Pediatric Patients), Pure mucosal neuroma syndrome, Fibrous Epulis, Acute Respiratory Distress syndrome/Acute Lung injury and Sepsis, Costello Syndrome (CS), and Cardio-Facio-cutaneous Syndrome (CFC Syndrome).
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in therapeutic regimens in the context of first line, second line, or any further line of treatments.
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in the prevention, short-term or long term treatment of the above-mentioned diseases optionally in combination with radiotherapy and/or surgery.
In yet another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating various cancers mentioned above which harbor hyperactive or aberrantly activated signaling pathways involving RAS and or SOS1 proteins.
In another aspect the present invention provides use of the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or its solvate in combination with other agents such as radiation, chemotherapeutic agents and/or targeted agents in multiple cancers and their subtypes as mentioned above. The agents that can be used for combination therapy include targeted agents such as inhibitors of RTKs, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), protein arginine methyltransferases (PRMTs), RAS inhibitors, KRAS inhibitors, MEK inhibitors, ERK1/2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
DETAIL DESCRIPTION OF THE INVENTION
The present invention is related to a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable one or more other medicaments, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in treating, or ameliorating various pathological conditions. The compound of formula (I) is as shown below:

wherein,
Ring A is selected from aryl, heteroaryl, and heterocyclyl;
Ring B is selected from substituted or unsubstituted 5 or 6 membered carbocyclic ring and substituted or unsubstituted 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from S, O, and N;
when ring B is carbocyclic ring, it is substituted with 1 to 8 substituents independently selected from Rc and
Rd;
when ring B is heterocyclic ring, it is substituted with 1 to 7 substituents; when it is substituted on a ring nitrogen atom, it is substituted with substituents selected from Ra and Rb; and when it is substituted on a ring carbon atom, it is substituted with substituents selected from Rc and Rd;
R1 and Rb are independently selected from hydrogen, -C(=0)R8, -C(=0)NRb(Ri), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
Rc and Rd are independently selected from hydrogen, halogen, oxo, -C(=0)R8, -NRh(Ri), -C(=0)NRh(Ri), -ORj, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocyclic ring and substituted or unsubstituted heterocycle;
R1 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
R2 and R3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
R4 is selected from halogen, cyano, -NRcRVORj, -C(=0)R8, -C(=0)NRh(Ri), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and heterocyclyl substituted with substituted alkyl;
Re and Rf are independently selected from hydrogen, -C(=0)R8, -C(=0)NRh(Ri), substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
Rh and R' are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
optionally Rh and R' groups together with the nitrogen atom to which they are attached forming a substituted or unsubstituted heterocycle;
Rj is selected from hydrogen, substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkyl;
‘n’ is an integer selected from 0, 1, 2, and 3;
when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, -C(=0)0(alkyl), -NR6R61, -NR6C(=0)R7, and -C(=0)NR6R6‘;
when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from
0X0 (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, -C(=0)0(alkyl), -NR6R6a, -NR6C(=0)R7, and -C(=0)NR6R6*;
when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR5, -NR6R61, -NR6C(=0)R7, -C(=0)R7,-C(=0)NR6R6*, -S02-alkyl, -C(=0)0H, -C(=0)0-alkyl, and haloalkyl;
when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -NR6R6a, -NR5C(=0)R7, -C(=0)R7, -C(=0)NR6R6a, -SO2-alkyl, -C(=0)0H, and -C(=0)0-alkyl;
when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR5, -C(=0)NR6R6l, -C(=0)0H, -C(=0)0-alkyl, -N(H)C(=0)(alkyl), -N(H)R6, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloalkyl, aryl, heteroaryl, -S02(alkyl), -C(=0)R7, and -C(=0)0(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);
R5 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;
R6 and R6* are each independently selected from hydrogen, alkyl, and cycloalkyl;
or R6 and R6* together with nitrogen to which they are attached form a heterocyclyl ring; and
R7 is selected from alkyl and cycloalkyl.
In accordance with an embodiment of the invention, ring A is aryl and heteroaryl.
In certain embodiments, ring A is phenyl and

In any of the above embodiments, ring B is selected from


In certain embodiments, ring B is selected from

In any of the above embodiments, R1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.
In certain embodiments, R1 is selected from methyl, ethyl, isopropyl, and cyclopropyl.
In any of the above embodiments, R2 and R3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl.
In certain embodiments, R2 and R3 are independently selected from hydrogen, fluorine, and methyl.
In any of the above embodiments, R4 is selected from halogen, -NReRf, substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.
H
In certain embodiments, R4 is selected from fluorine, -NH2, -CH3, -CF3, -CHF2,

In any of the above embodiments, R1 and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl.
In certain embodiments, R1 and Rb are independently selected from hydrogen, methyl, ethyl, isopropyl,

In any of the above embodiments, Rc and Rd are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, -C(=0)NRh(Ri), -ORj, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycle.
In certain embodiments, Rc and Rd are independently selected from hydrogen, methyl, isopropyl, ethyl, -CH2F,
-CH2OMe, -OMe, -OH, fluorine, -OCH2CH3, -CF3, and -CH2CH2OMe; optionally
Rc and Rd groups together with the carbon atom which they are attached forming cycloproyl ring, cyclopentyl ring, tetrahydropyran ring, tetrahydrofuran ring and N-methyl oxazolidinone ring.
Re and Rf are selected from hydrogen.
In any of the above embodiments, optionally Rh and Ri groups together with the nitrogen atom to which they are attached forming a heterocycle.
In certain embodiments, optionally Rh and Ri groups together with the nitrogen atom to which they are attached
forming a

In any of the above embodiments, Rj is selected from hydrogen and alkyl.
In certain embodiments, Rj is selected from hydrogen, methyl, and ethyl.
In another aspects, the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, wherein ring A is selected from aryl and heteroaryl; ring B is selected from

; R1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R2 and R3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R4 is selected from halogen, -NR'R* substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Rc and Rd are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, -C(=0)NRh(Ri), -ORj, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocyclic ring and substituted or unsubstituted heterocycle; Re and Rf are hydrogen; optionally Rh and Ri groups together with the nitrogen atom to which they are attached forming a heterocycle; Rj is selected from hydrogen and alkyl; and ‘n’ is an integer selected from 0, 1, 2, and 3.
In another aspects, the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, wherein ring A is selected

; R1 is selected from methyl, ethyl, isopropyl, and cyclopropyl; R2 and R3 are independently
selected from hydrogen, fluorine, and methyl; R4 is selected from fluorine, -NH2, -CH3, -CF3, -CHF2,

In another aspects, the invention provides a pharmaceutical composition comprising a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, and a pharmaceutically acceptable carrier.
In another aspects, the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof.
In yet another aspects, the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting the interaction of SOS1 and RAS family protein in a subject,
comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof.
In another aspects, the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease, disorder, and/or condition is a cancer.
In certain embodiments, a method for the treatment and/or prevention of a disease, disorder, and/or a condition is a cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
In another aspects, the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
In another aspects, the invention provides a method for the treatment and/or prevention of a disease, disorder, and/or a condition, wherein the said disease, disorder, and/or condition is a RASopathy.
In certain embodiments, a method for the treatment and/or prevention of a disease, disorder, and/or a condition is a RASopathy, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary Gingival Fibromatosis (HGF)•
In another aspects, the invention provides the method, wherein the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, is administered before, after, or together with at least one or more pharmacologically active substance.
In another aspects, the invention provides use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
In another aspects, the invention provides use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for the treatment and/or prevention of a disease, disorder, and/or condition by inhibiting the interaction of SOS 1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
In another aspects, the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said disease, disorder, and/or condition is cancer.
In certain embodiments, the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition is cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
In another aspects, the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
In another aspects, the invention provides the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition, wherein the said the disease is a RASopathy.
In certain embodiments, the use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition is a RASopathy, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary gingival fibromatosis (HGF).
In another aspects, the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for treatment and/or
prevention of cancer, wherein said compound is administered in combination with at least one more pharmacologically active substance.
In another aspects, the invention provides the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, for treatment and/or prevention of cancer, wherein the compound is administered before, after, or together with at least one other pharmacologically active substance.
Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci to C20 alkyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-6 carbon atoms (e.g., Ci to Ce), 2-6 carbon atoms (e.g., C2 to Ce), 3-6 carbon atoms (e.g., C3 to Ce), as used with respect to any chemical group (e.g., alkyl etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, and/or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, as appropriate).
General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.
The term ‘alkyl’, as used herein, means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably, the alkyl chain may contain 1 to 10 carbon atoms. More preferably, alkyl chain may contain up to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tot-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term ‘haloalkyl’, as used herein means an alkyl group as defined hereinabove wherein at least one of the hydrogen atoms of the said alkyl group is substituted with halogen. The haloalkyl group is exemplified by chloromethyl, 1-chloroethyl, and the like.
The term ‘perhaloalkyV, as used herein, means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
The term ‘carbocycle’ or ‘carbocyclic ring’ as used herein, means a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic
cycloalkyl ring containing 3 to 6 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring. Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene, spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2,l '-cyclopentane], hexahydro-2H-spiro [cyclopropane- 1,1'-pentalene]. Tricyclic ring systems are the systems wherein the bicyclic systems as described above are further annulated with third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.13.7]nonane, and tricyclo[3.3.1.13.7]decane (adamantane).
The term "cycloalkyl" as used herein, means a monovalent carbocyclic ring.
The term ‘aryl’, as used herein, refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also include partially saturated bicyclic and tricyclic hydrocarbon ring systems with at least one aromatic ring, e.g. tetrahydro-naphthalene. Aryl group also include bicyclic systems like 2,3-dihydro-indene-5-yl, and 2,3-dihydro-1-indenone-5-yl.
The term ‘heteroaryl’, as used herein, refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic. The term ‘heteroaryl’ as used herein, also include partially saturated bicyclic and tricyclic aromatic ring system, e.g. 2,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-1-isobenzofuranone-5-yl, 2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl, and 2,3-dihydro-1-isoindolinone-5-yl. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include, but not limited to, IH- 1 ,2,3-triazolyl, 2H- 1,2,3 -triazolyl, pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, imidazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-thiadiazolyl, lH-pyrazolo[5,l-c]-l,2,4-triazolyl, pyrrolo[3,4-d]-l,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4-c] isoxazolyl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-dihydro-benzo[l,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-4-yl, 2 , 3 -dihy dro-benzofuran- 6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-1-isobenzofuranone-5-yl, 2,3-dihydro-1H-indol-5-yl, 2,3-dihydro-1H-indol-4-yl, 2,3-dihydro- lH-indol-6-yl, 2,3-dihydro-1H-indol-7-yl,
2,3-dihydro-1-isoindolinone-5-yl, benzo[l,3]dioxol-4-yl, benzo[l,3]dioxol-5-yl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.
The term ‘heterocycle’ or ‘heterocyclic ring’ or ‘heterocyclyl’ as used herein, means a ‘carbocycle’ or ‘carbocyclic ring’ or ‘cycloalkyl’ group wherein one or more of the carbon atoms are replaced by heteroatoms/groups selected from N, S, SO2, and O. The heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
1.3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include, but are not limited to, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroquinolm-1-yl, 1,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro-l,4-benzodioxinyl,
2.3-dihydro- 1 -benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1 ,2,3,4-tetrahydroquinolinyl. The term heterocycle also includes bridged and spiro heterocyclic systems such as azabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 6-oxa-3-azabicyclo[3.1. l]heptan-3-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-azabicyclo[3.2.1]octan-3-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 6-azaspiro[2.5]octan-6-yl, 5-azaspiro[2.5]octan- 5-yl, 4-azaspiro[2.4]heptan-4-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, tetrahydrofuran-3-yl, oxetan-3-yl, 1-oxa-8-azaspiro[4.5]decan-8-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, tetrahydro-2H-pyran-4-yl, 2-azaspiro[3.3]heptan- 6-ol-2-yl, morpholin-3-one-4-yl, l-methylpyridin-2(lH)-one-5-yl, l-methyl-l,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, pyridin-2(lH)-one-5-yl, pyridin-2(lH)-one-4-yl, and the like.
The ‘halogen’ means fluorine, chlorine, bromine, or iodine.
The term ‘oxo’ means a divalent oxygen (=0) attached to the parent group. For example, oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a cyclohexanone, and the like.
The term ‘annulated’ means the ring system under consideration is either simulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
The term ‘bridged’ means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring atoms.
A compound, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, its pharmaceutical composition thereof as described hereinabove wherein the compound of general formula (I), is selected from the group consisting of:
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 1);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 2);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)ainino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 3);
4-((l-(3-(l,l -difluoroethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H- [ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 4);
4-((l-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin- 7(8H)-one (Compound 5);
4-((l-(3-(l,l-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)amino)-2,6-diinethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 6);
2,6-dimethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)ainino)-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 7);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 8);
4-(( 1 -(3 ,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2,6-dimethyl-6H-[l ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 9);
(R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,6-dimethyl-7,8-dihydro-6H-[l,4]oxazmo[3,2-g]quinazolin-4-amine (Compound 10);
4-(((R)-1-(3-aniino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-6-((tetrahydrofuran-3-yl)methyl)-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 11);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-6-(cyclopropylmethyl)-2-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 12);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-6-ethyl-2-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 13);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-ethyl-6-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one. (Compound 14);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2-ethyl-6-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 15);
(R)-2-cyclopropyl-4-((l-(3-(l,l-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-6-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 16);
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-8,9-dihydio-7H-pyrano[2,3-g]quinazolin-7-yl)(pyrrolidin-1-yl)methanone (Compound 17);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 18);
2,6,8,8-tetiamethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)aniino)-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 19);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 20);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazmo[3,2-g]quinazolin-7(8H)-one (Compound 21);
4-(( 1 -(2-fluoro-3-(l , 1 ,l-trifluorO-2,3-dihydroxypropan-2-yl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 22);
4-(( l-(3-(l ,l-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 23);
(R)-N-(l-(3-aniino-5-(trifluoromethyl)phenyl)ethyl)-2,6,8,8-tetramethyl-7,8-dihydio-6H-[l,4]oxazmo[3,2-g]quinazolin-4-amine (Compound 24);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethylspiio[cyclopropane-l,8'-[l,4]oxazino[3,2-g]quinazolin]-7'(6'H)-one (Compound 25);
(R)- 1 , 1 -Difluoro- l-(2-fluoro-3-(l -((2,8,8-trimethyl-7-morpholino-8H [ 1 ,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 26);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,9-tetramethyl-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-one (Compound 27);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2, 6,8,8, 9-pentamethyl-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-one (Compound 28);
(R)-9-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-l,3,7-trimethylpyrimido[4,5-g]quinazoline-2,4(lH,3H)-dione (Compound 29);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8-trimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 30);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 31);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-isopropyl-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 32);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 33);
(R)- 1 , 1 -Difluoro- l-(2-fluoro-3-(l -((2,6,8,8-tetramethyl-7,8-dihydro-6H-[ 1 ,4]oxazino [3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 34);
(R)-2,2-Difluoro-2-(2-fluoro-3-(l-((2,6,8,8-tetramethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 35);
2,2-difluoro-2-(2-fluoro-3-((lR)-1-((2,6,8-trimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 36);
(R)-1,1-Difluoro-1-(2-fluoro-3-(l-((2,6,7,7-tetramethyl-7,8-dihydio-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 37);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethylpyrido[2,3-g]quinazolin-7(6H)-one (Compound 38);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethylpyrazino[2,3-g]quinazolin-7(6H)-one (Compound 39);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-2,6,9-trimethyl-6,9-dihydropyrazino[2,3-g]quinazoline-7,8-dione (Compound 40);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2,8,8-trimethyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 41);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,9,9-tetramethyl-8,9-dihydropyrido[2,3-g]quinazolin-7(6H)-one (Compound 42);
N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((R/S)-tetrahydrofuran-3-yl)methyl)-7,8-dihydro-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-4-amine (Compound 43);
N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S/R)-tetrahydrofuran-3-yl)methyl)-7,8-dihydro-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-4-amine (Compound 44);
(R)-1-(3-(l-((2,6-dimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-!, l-difluoro-2-methylpropan-2-ol (Compound 45);
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8-trimethyl-6H-[l,4]oxazmo[3,2-g]quinazolin-7(8H)-one (Compound 46);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)- 10-fluoro-2,6-dimethyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 47);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxyethyl)-2-methyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 48);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-6-ethyl-2-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 49);
(R)-1-(3-(l-((6-ethyl-2,8,8-trimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-!, l-difluoro-2-methylpropan-2-ol (Compound 50);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 51);
(R)-N-(l-(3-(l ,l-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2,6,8,8-tetramethyl-7,8-dihydro-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-4-amine (Compound 52);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-3-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 53);
4-(((lR)-1-(2-fluoro-3-( 1 , 1 ,3-trifluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 54);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methyl-3-(methylamino)propyl)-2-fluorophenyl)ethyl)animo)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 55);
(R)-2,2-difluoro-2-(2-fluoro-3-(l-((2-methyl-7,8-dihydro-6H-pyrano[3,2-g]quinazohn-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 56);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H- [ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 57);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2',8'-dimethylspiro[cyclopentane-l,6'-pyrrolo[3,2-g]quinazolin]-7,(8'H)-one (Compound 58);
4'-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2',8'-dimethylspiro[cyclopentane-l,6'-pyrrolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 59);
2,,8'-dimethyl-4'-((l-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)aniino)spiio[cyclopentane-l,6,-pyrrolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 60);
4'-((l-(3-(difluoromethyl)-2-methylphenyl)ethyl)aniino)-2,,8,-diniethylspiro[cyclopentane-l,6,-pyriolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 61);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,,8,-dimethylspiro[cyclopentane- 1 ,6'-pyrrolo[3 ,2-g]quinazolin]-7'(8'H)-one (Compound 62);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-6-(2-methoxyethyl)-2,8,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 63);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2, 8, 8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 64);
(R)-6-cyclopropyl-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-2,8,8-trimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 65);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,,8,-dimethylspiio [cyclopropane-1 ,6'-pyrrolo[3 ,2-g]quinazolin]-7'(8'H)-one (Compound 66);
(R)-4'-((l-(3-( 1 , 1 -difluoΓO-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aπliIlo)-2,,8,-dimethylspiro[cyclopropane-l,6'-pyn"olo[3,2-g]quinazolin]-7,(8,H)-one (Compound 67);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 68);
4-((l-(3-amino-5-(difluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyiTolo[2,3-g]quinazolin-7-one (Compound 69);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-pyiTolo[2,3-g]quinazolm-7(8H)-one (Compound 70);
(S)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 71);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)animo)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 72);
4-(( l-(3-(l ,l-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 73);
4-(( 1 -(2-fluoro-3-(l , 1 ,l-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 74);
(R)-1,1-difluoro-1-(2-fluoro-3-(l-((2,6,8,8-tetramethyl-7,8-dihydrO-6H-pyrrolo[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 75);
4-(((lR)-1-(3-(l,l -difluoro-2,3 -dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)animo)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 76);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-2,8,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 77);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-6-isopropyl-2,8,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 78);
(R)-4'-((l-(3-( 1 , 1 -difluoΓO-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aπliIlo)-2,,6,-dimethylspiro[cyclopropane-l,8'-pyrrolo[2,3-g]quinazolin]-7,(6,H)-one (Compound 79);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)animo)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 80);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 81);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 82);
2,6,6,8-tetramethyl-4-((l-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)aniino)-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 83);
4-((l-(3-(l,l-difluoroethyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 84);
4-((l-(3-(difluoro(tetrahydrofuran-3-yl)methyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 85);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2-ethyl-6,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 86);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-isopropyl-6,6,8-trimethyl-6H-pyrrolo[3,2-g]quinazolin-7(8H)-one (Compound 87);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)animo)-8-ethyl-2,6,6-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 88);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-8-ethyl-2,6,6-trimethyl-6H-pyrrolo[3,2-g]quinazolin-7(8H)-one (Compound 89);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,6,8,9-pentamethyl- 6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 90);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6,6-diethyl-2, 8-dimethyl- 6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 91);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6,6-bis(fluoromethyl)- 2,8-dimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 92);
4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-6-ethyl-2,6, 8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 93);
4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(methoxymethyl)- 2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 94);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 95);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 96);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-hydroxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 97);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-(methoxymethyl)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolm-7-one (Compound 98);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 99);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-hydroxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 100);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 101);
(S/R)-4-(((R/S)-1-(3-((S/R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 102);
(S/R)-4-(((R/S)-1-(3-((R/S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 103);
(R)-8-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 -ethyl-3 ,6-dimethyl-l,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 104);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)- 1 -isopropyl-3, 6-dimethyl-l,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 105);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-1-(2,2-difluoroethyl)-3,6-dimethyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (Compound 106);
(R)- 1 , 1 -difluoro- l-(2-fluoro-3-(l -((2,2,3 ,6-tetramethyl-2,3-dihydro- lH-imidazo[4,5-g]quinazolin-8-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 107);
(R)-1,1-difluoro-1-(2-fluoro-3-(l-((l,2,2,3,6-pentamethyl-2,3-dihydro-1H-imidazo[4,5-g]qumazolin-8-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 108);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 ,3,6-trimethyl- 1,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 109);
(R)-2-cyclopropyl-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-6,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 110);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 ,6-dimethyloxazolo[4,5-g]quinazolin-2( lH)-one (Compound 111);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-pyrrolo[2,3-g]quinazoline-7,8-dione (compound 112);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 113);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,6,7-tetramethyl-6,7-dihydro-8H-pyrrolo[3,4-g]quinazolin-8-one (Compound 114);
4-(( 1 -(2-fluoro-3-(l -(hydroxymethyl)cyclopropyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 115);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 116);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8,8-difluoro-2,6-dimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 117);
(R)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,7,8,8-tetramethyl-7,8-dihydro-6H-pyrrolo[3,4-g]quinazolin-6-one (Compound 118);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-3,6-dimethyl-l,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 119);
(S)-4-(((S)-1-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-8-methoxy-2,6,8-trimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolm-7-one (Compound 120);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-ethoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 121);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethyl-2,3 ,5,6-tetrahydrospiro[pyran-4,8'-pyrrolo[2,3-g]quinazolin]-7,(6'H)-one (Compound 122);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-(2-methoxyethyl)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 123);
4'-(((R)-1-(3-( 1 , 1 -difluoro^-hydroxy^-methylpropyl^-fluorophenyl^thytyanimo)-^^-trimethylspiro[oxazolidine-5,8'-pyrrolo[2,3-g]quinazoline]-2,7'(6'H)-dione (Compound 124);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2, 6-dimethyl-8-(trifluoromethyl)-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 125);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-ethyl-8-methoxy-2,6-dimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (compound 126);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-3-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2, 6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 127);
4'-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethyl-4,5-dihydro-2H-spiro[furan-3,8,-pyrrolo[2,3-g]quinazolin]-7,(6,H)-one (Compound 128);
4-(((lR)-1-(3-(3-(dimethylamino)-1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazohn-7-one (Compound 129);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methyl-3-(methylamino)propyl)-2-fluorophenyl)ethyl)animo)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 130);
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-8-methoxy-2,6,8-trimethyl-6,8-dihydio-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 131);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-8-(2-methoxyethyl)-2,6-dimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 132);
4-(((lR)-1-(2-fluoro-3-(piperidin-3-yl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 133);
(R)-4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyiiolo[2,3-g]quinazolin-7-one (Compound 134);
4-(((lR)-1-(3-(3-(dimethylamino)-1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 135);
2,6,8,8-tetramethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)amino)-6,8-dihydro-7H-pyrrolo[2,3-g]qumazolm-7-one (Compound 136);
4-(((R)-1-(3-ainino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 137);
(R)-4'-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2',6'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,8,-pyrrolo[2,3-g]quinazolin]-7'(6,H)-one (Compound 138); and
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)ainino)-8-ethyl-8-methoxy-2,6-dimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 139).
According to a feature of the present invention, the compounds of general formula (I) where all the symbols are as defined earlier, can be prepared by methods illustrated in the schemes and examples provided herein below. However, the disclosure should not be construed to limit the scope of the invention arriving at compound of formula (I) as disclosed hereinabove. 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 scope of 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 isomers of the compound of formula in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
The corresponding o-methyl amine derivatives represented as formula (A5) could be prepared by following the sequential transformations as depicted in Scheme - A herein below-

The compound of formula (Al) undergoes a metal catalyzed cross coupling with alkoxy vinyl stannane, e.g. tributyl(l-ethoxyvinyl)tin in presence of palladium catalysts such as Pd(PhgP)2Cl2, Pd2(dba)a and like; optionally using bases such as triethylamine, Ν,Ν-Diisopropylethylamine and like, in hydrocarbon solvents like toluene or ether solvents like 1,4-dioxane to furnish the alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like. The similar transformation can be carried out by reaction of compound of formula (Al) with n-alkylvinyl ether using catalysts such as palladium (Π) acetate and like, ligands such as 1 ,3-Bis(diphenylphosphino)propane and like, in presence of organic bases such as DIPEA, TEA and like in alcoholic solvents such as ethylene glycol and at elevated temperatures ,in solvents such as 1,4-dioxane, THF and mixtures thereof to give alkoxy vinyl intermediate which in turn provide compound of formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric acid in ether solvent such as THF, 1,4-dioxane and like
The compound of formula (A2) was then reacted with corresponding chirally pure t-butanesulfmamide in presence of Lewis acid such as Titanium alkoxides e.g. titanium tetraethoxide, titanium isopropoxide and the like, in ether solvents such as 1,4-dioxane, THF and like, to obtain the compound of formula (A3).
The compound of formula (A3) reacted with reducing agent such as metal hydrides e.g. sodium borohydride, L-selectride and like, in solvents such as THF, 1,4- dioxane, methanol and the like, optionally in presence of water to provide sulfinamide of formula (A4). Major diastereoisomer in the compound of formula (A4) after reduction was separated or taken ahead as such.
The compound of formula (A4) under acidic condition undergoes cleavage of reduced ketimine derivative to generate amine of formula (AS) as a free base or salt. The acids employed for the transformation may involve mineral acids such as hydrochloric acid, organic acids like trifluoroacetic acid and thereof.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-B herein below-

Compound of formula (B2) can be synthesized from compound of formula (Bl) by following the reaction protocol as mentioned in EP2243779 ( Ra= Rb = CH3) and WO2015164480 (Ra and Rb together forms a ring). Compound of formula (B2) was converted to corresponding cyclic amide of formula (B3) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (B2) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof. Nitration of compound of formula (B3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (B4). Compound of formula (B4) can be further alkylated by using corresponding alkyl halide in presence of bases such as Na2CO3, K2CO3, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 60°C leading to compound of formula (B5). An alternative synthetic route towards the compound of formula (B5) is the transformation of intermediate of compound of formula (B4) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc. Such reactions can be carried out in aprotic solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C. Compound of formula (B5) was converted to corresponding aniline derivative compound of formula (B6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (B5) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (B6) upon treatment with corresponding alkylnitriles using acids such as but not limited to Methane sulfonic acid, HC1 etc. at 25°C-120°C to afford compound of formula (B7), which could be further coupled with different chiral benzyl amine (A5) derivatives using diffaent coupling reagents such as but not limited to BOP, PyBop etc. and organic bases such as DBU, DIPEA etc. in a polar aprotic solvent like DMF, DMSO etc. at 0°-120°C to afford a compound of formula (I).
Alternatively, compound of formula (I) can be prepared from compound of formula (B7) by reacting with phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (B8).
Compound of formula (B8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. optionally neat or in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C. Carbonyl functional group in Compound of formula (I) on further reduction using different reducing reagents such as but
not limited to borane DMS, borane THF, LiA1H4 in polar aprotic solvents like THF, dioxane etc. at temperature 70 - 90°C leading to final compound of formula (I).
Compound of formula (I) allowed to react with fluorinating reagent such as DAST, martin sulfurane in solvents such as DCM, chloroform, THF, ether, 1,4-dioxane to provide compound of formula (B9).
Compound of formula (B9) undergoes epoxidation reaction to provide compound of formula (BIO). This reaction is effected by hydrogen peroxide in presence of acidic medium using organic acids such as formic acid and like.
Compound of formula (BIO) on epoxide opening by nucleophilic reagent provide compound of formula (I). Such transformations can be effected by reaction of epoxide compound with various nucleophilic reagents such as sodium alkoxides, primary or secondary amines in alcohol solvents like ethanol, methanol, and like and at room temperature or elevated temperature.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-C herein below-

Compound of formula (C2) is prepared by following a procedure reported in Chemistry - A European Journal, 2015, vol. 21, # 4, p. 1482 - 1487. The compound of formula (C2) is converted to corresponding 4-oxo chromene carboxylic ester derivative of compound of formula (C3) using corresponding alpha diketo ester and basic reagents such as but not limited to NaOMe, NaOEt, KOBu etc. in a polar aprotic solvents like DMF, DMA etc. at 0°C - 75 °C. Halogenation of compound of formula (C3) using N-halosuccinamide reagent such as but not limited to NBS , NIS and NCS gives corresponding dihalo compound of formula (C4) via e.g. benzylic halogenation in a aprotic halogenated solvents like CCl4, DCM etc. at 0°-80°C. The compound of formula (C5) aldehyde derivative can be synthesized by oxidation of compound of formula (C4). Compound of formula (C5) undergoes an acidic hydrolysis leading to compound of formula (C6), that can be further functionalized to corresponding amide of compound of formula (C7) using coupling reagent such as but not limited to PyBop in a polar aprotic solvents like DMF, DMSO etc. at temperature ranging from 0°C -30°C for about l-16h. Compound of formula (C8) can be achieved by oxidation of compound of formula (C7) with suitable oxidizing reagent such as but not limited to sulphamic acid and sodium chlorite. Compound of formula (C8) when condensed with corresponding amidine by coupling reaction affords a quinazoline enone derivative of compound of formula (C9). Reduction of enone compound of formula (C9) using reagents such as but not limited to H2-Pd/C leading to corresponding compound of formula (CIO). The compound of formula (CIO) can be transformed to the corresponding compound of formula (Cl 1) via halogenation using reagents such as phosphorus oxyhalide, thionyl chloride and like, in aprotic solvents like chlorobenzene, toluene and mixtures thereof. Compound of formula (Cl 1) undergoes a coupling with different chiral benzylic amines (A5 ) leading to the final compound of formula (I). This reaction can be effected by organic base such as DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - D herein below.

The compound of formula (Dl) is converted to corresponding acetyl derivative of compound of formula (D2) via N-acylation reaction using acetyl chloride & using organic basic reagents such as but not limited to pyridine, DIPEA, TEA etc in halogenated solvents such as, although not limited chloroform, dichloromethane, and the like mixtures thereof. Nitration of compound of formula (D2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (D3).
Acetyl deprotection of compound of formula (D3) using inorganic bases such as Na2CO3, K2CO3, CS2CO3, etc in polar protic solvents like methanol, ethanol etc at appropriate temperature afforded compound of formula
(D4).
compound of formula (D4) can be further alkylated by using alkyl halides and bases such as NaH, Na2CO3, K2CO3, Cs2CO3 etc. in polar aprotic solvents like THF, DMF, and DMSO etc. at temperature 20°C - 60°C leading to compound of formula (D5).
Compound of formula (D5) can be converted to corresponding aniline derivative, compound of formula (D6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (D6) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof.
Compound of formula (D6) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (D7).
Compound of formula (D7) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (D8).
Compound of formula (D8) was reacted with compound of formula (AS) in the presence DIPEA, TEA, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; optionally neat or in etheral solvents such as THF, 1,4 dioxane and like or polar aptotic solvents like DMF, DMA, DMSO and thereof at temperature ranging from 20-130°C. to provide compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - E herein below.

SCHEME - E
Compound of formula (El) can be synthesized following a reaction protocol described in WO200879759.Compound of formula (E2) can be synthesized by appropriate displacement of aromatic halogen with corresponding alkyl amine using appropriate bases such as TEA, NaH, Na2CO3, K2CO3, CS2CO3 etc. in polar aptotic solvents like THF, DMF, DMSO etc. at temperature 20°C - 120°C.
Compound of formula (E2) can be converted to corresponding cyclic amide of formula (E3) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (E2) can be carried out in one or more solvents, alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (E3) can be further alkylated by using bases such as NaH, Na2C03, K2CO3, CS2CO3 etc. in polar aprotic solvents like THF, DMF, and DMSO etc. at temperature 20°C - 60°C leading to compound of formula (E4). Compound of formula (E5) can be synthesized by ester hydrolysis of compound of formula (E4) using bases such as NaOH, LiOH and KOH etc.Compound of formula (E5) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (E6).Compound of formula (E6) can be converted to the corresponding compound of formula (E7) by halogenation using reagents such as POCI3, ΡΟΒΓ3, SOCI2 etc.
Compound of formula (E7) undergoes a nucleophilic substitution reaction with different chiral benzyl amine (AS) leading to compound of formula (I) using aprotic solvents like dioxane, THF and like, at temperature 0°C -130°C and bases such as but limited to DIPEA, TEA and thereof.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme -F herein below.

Compound of formula (F2) can be synthesized by following the reaction protocol as mentioned in EP2243779 (Rc = Rd = CH3) and WO2015164480 (Rc and Rd together forms a ring). Compound of formula (F2) was converted to corresponding cychc amide of formula (F3) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (F2) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Nitration of compound of formula (F3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (F4).
Compound of formula (F4) can be treated with SOCl2 , POCI3, POBr3 and thereof using DMF to give an intermediate (Halogenation reaction intermediate), which undergoes a nucleophilic substitution reaction with appropriate amines leading to the compound of formula (F5), using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvent like dioxane, THF etc. at appropriate temperature.
Compound of formula (F5) can be converted to corresponding aniline derivative, compound of formula (F6) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (F5) can be carried out in one or more solvents, such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof. Compound of formula (F6) upon treatment with corresponding nitrile solvents such as but not limited to acetonitrile using acids such as but not limited to methane sulfonic acid, HC1 etc. at 25°C-120°C to afford compound of formula (F7), which can be transformed to intermediate (F8), via e.g. triflate or halogenation etc. of the corresponding compound of formula (F7). Compound of formula (F8) undergoes a nucleophilic substitution reaction with different chiral benzyl amine (A5), using aprotic solvents like dioxane, THF etc., at temperature 0°C-130°C and bases such as but limited to DIPEA, TEA etc. leading to final compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - G herein below.

Compound of formula (Gl) was allowed to react with corresponding carbamate in the presence of catalyst such as (tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, Bis(dibenzyhdeneacetone)2 Pd(0), rac 2,2'-Bis(diphenylphosphino)- 1 , 1 '-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, DIPEA, Potassium triphosphate and thereof; in a suitable solvent selected from THF, 1 ,4-dioxane, dimethoxyethane, DMF, DMA, toluene and the like to provide compound of formula (G2)
Cyclization of compound of formula(G2) provided compound of formula (G3), in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., Na2CO3, K2CO3, CS2CO3, NaO¾u, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
Nitration of compound of formula (G3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (G4).
The compound of formula (G4) was alkylated to give compound of formula (G5). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
Compound of the formula (G6) was obtained from compound of formula (G5) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof. This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.
Compound of formula (G6) reacted with alkylnitriles in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (G7).
Compound of formula (G7) was reacted with POCl3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (G8).
Compound of formula (G8) was reacted with compound of formula (A5) in the presence of triethyl amine, Ν,Ν-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - H herein below.

Compound of formula (HI) can be synthesized by reaction protocol as mentioned in (W0243823). Compound of formula (H2) can be synthesized from compound of formula (HI) by using oxidizing agents like MnO2, H2O2, AgNOa, DDQ and thereof.
Compound of formula (H2) undergoes alkylation reaction using alkyl halides in presence of bases such as K2CO3, Na2C03, CS2CO3 and like; in polar aprotic solvents like DMF, DMSO and thereof; at temperature 20°C - 60°C afforded compound of formula (H3).
An alternative synthetic route towards the compound of formula (H3) is the transformation of intermediate of compound of formula (H2) via Mitsunobu reaction with corresponding alcohol, using different reagents such as but not limited to DEAD, DIAD etc. Such reactions can be carried out in aprotic solvents like, e.g., ethos such as THF, Dioxane and the like; hydrocarbons, e.g., toluene or mixtures thereof, at temperature 25°C - 90°C.
Compound of formula (H4) can be synthesized by ester hydrolysis of formula (H3) using bases such as NaOH, LiOH, KOH and like; in polar protic solvents such as methanol, ethanol and like.
Compound of formula (H4) on reaction with acetamidine, formamidine and like; in polar aprotic solvents like DMF, DMSO and thereof at temperature elevated temperatures afforded compound of formula (H5).
Compound of formula (H7) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (H6).
Compound of formula (H6) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - 1 herein below.

The compound of the formula (12) obtained by treating compound of the formula (II) with oxidizing agent potassium permanganate, potassium dichromate, sodium dichromate in presence of acids like sulphuric acid, acetic acid and like, in 1:1 mixture of t-butanol and Water as Solvent.
The compound of formula (12) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (13). The compound of formula (13) was subjected to C-N coupling reaction e.g. Buchwald reaction with 1- methylurea provided compound of formula (14). This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CO3, CS2CO3, NaOtBu, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
Nitration of compound of formula (14) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (15).
The compound of formula (15) was alkylated to give compound of formula (16). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
Compound of the formula (17) was obtained from compound of formula (16) using by metal reductions using iron, tin or tin chloride or the like in solvents selected from THF, 1,4-dioxane methanol, ethanol or the like or mixtures thereof under acidic condition using ammonium chloride, acetic acid, hydrochloric acid or the like or mixture(s) thereof. This transformation can also be carried out by catalytic hydrogenation using Pd/C and thereof in solvents ethyl acetate, Methanol or mixture(s) thereof.
Compound of formula (17) reacted with acetonitrile in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (18).
Compound of formula (18) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (19).
Compound of formula (19) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - J herein below.

Compound of formula (J2) can be synthesized from compound of formula (Jl) by following the reaction protocol as mentioned in ACS Medicinal Chemistry Letters, 2018, vol. 9, # 8, p. 827 - 831 (Rb = Rc = CHa). Upon thermal cyclization at elevated temperature(s) the compound of the formula (J2) can undergo ring cyclization to produce compound of formula (J3). Such reaction can be carried out by using Lewis acids such as, although not limited to AlC3, BF3, etc., either neat or by using solvents such as DCM, DCE, chlrobenzene, toluene, xylene, etc. and the like or mixture(s) thereof. Nitration of compound of formula (J3) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (J4). Compound of formula (J4) can be further alkylated by using bases such as NaH, K2CO3, Na2CO3, CS2CO3 etc. in polar aprotic solvents like THF, DMF, DMSO etc. at appropriate temperature leading to compound of formula (J5). Compound of formula (J5) was converted to corresponding aniline derivative compound of formula (J6) through selective reduction of nitro group by using different reducing agents. Such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (J6) upon treatment with corresponding alkylnitriles using acids such as but not limited to Methane sulfonic acid, HC1 etc. at appropriate temperature to afford compound of formula (J7). The halogenation of compound of formula (J7) to produce the compound of formula (J8). Such reaction can be carried out by using neat halogenating reagents, such as but not limited to POCb, POBn, SOC12 and the like at appropriate temperature. This reaction can also
be caned out by using combination of halogenating reagents and organic bases such as POCh, POBr3, SOCI2 and the like; and organic bases like DIPEA, TEA, Ν,Ν-Dimethylaniline and the like; using solvents such as DCE, DCM, chlorobenzene, toluene and the like or mixture(s) thereof at appropriate temperature. The compound of formula (I) can be obtained by using nucleophilic substitution of benzyl amines (A5) with the compound of the formula (J8). Such reaction can be carried out at appropriate temperature in presence of bases like DIPEA, TEA and the like; in solvents such as THF, 1,4-Dioxane, DCE, ACN, DMSO, etc., and the like or mixture(s) thereof.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme -K herein below.

The compound of formula (Kl) was subjected to esterification in alcoholic solvents like methanol ethanol and thereof in presence of chlorinating agents such as thionyl chloride, oxalyl chloride and thereof, or in presence of acidic reagents such as sulfuric and methane sulfonic acid thereof to provide the compound of formula (K2). Compound of formula (K3) can be synthesized by appropriate displacement of aromatic halogen with corresponding alkyl amine in alcoholic solvents like methanol ethanol and thereof.
Compound of formula (K3) was reacted with oxalyl chloride in the presence of bases like triethyl amine, N,N- ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, or mixture(s) thereof to provide compound of formula (K4).
Compound of formula (K4) was subjected to cyclisation using dithionate salts in the presence of mixture of solvents such as THF , 1,4-Dioxane , in alcoholic solvents like methanol ethanol and water, mixture(s) thereof to provide compound of formula (K5).
The compound of formula (K5) was alkylated to give compound of formula (K6). This conversion was effected in presence alkali hydrides like sodium hydride and like; or bases such as potassium carbonate and like; and alkylating reagents alkyl halides e.g. Methyl iodide and like; in presence of solvents such as THF, DMF or mixture(s) thereof.
The compound of formula (K6) was subjected to C-N coupling reaction e.g. Buchwald reaction with tert-butyl carbamate provided compound of formula (K7). This reaction can mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixtures thereof; a suitable ligand such as Xantphos, BINAP, Ru-Phos, XPhos, or mixtures thereof; in the presence of suitable base, preferably inorganic bases such as alkali metal carbonates, e.g., K2CO3, Na2CO3, CS2CO3, NaOtBu, Potassium phosphate, or mixture thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA or mixtures thereof.
Compound of formula (K7) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (Aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (K8).
Compound of formula (K8) reacted with alkyl nitriles in presence of the reagent such as methane sulfonic acid, sulfuric acid, hydrochloric acid, or the like to obtain compound of formula (K9).
Compound of formula (K9) was reacted with POCI3 or POBr3 optionally in solvents such as toluene, xylene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (K10).
Compound of formula (K10) was reacted with compound of formula (A5) in the presence of triethyl amine, N,N-ethyldiisopropyl amine, pyridine, DBU or the like in solvents such as THF , 1,4-Dioxane, toluene, DCM, DMSO or mixture(s) thereof to provide compound of formula (I).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - L herein below.

Compound of formula (LI) allowed to react with N-hydroxyacetamide in presence of the bases such as K2CO3, Na2C03, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 80°C leading to compound of formula (L2). Nitration of compound of formula (L2) with nitrating reagents such as, although not limited to fuming nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (TV) chloride, sulphuric acid, trifluroacetic acid, acetic acid and the like, anhydrides like acetic anhydride, trifluroacetic anhydride and the like, or mixture(s) thereof to provide compound of formula (L3). Compound of formula (L3) was converted to corresponding aniline derivative compound of formula (L4) through selective reduction of nitro group by using different reducing agents. Although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction of the compound of formula (L3) can be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and the like mixtures thereof. Compound of formula (L4) allowed to react with corresponding acyl halide in presence of the organic basic reagents such as but not limited to DIPEA, TEA etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 80°C leading to compound of formula (L5). Compound of formula (L5) can be further alkylated by using bases such as K2CO3, Na2C03, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 20°C - 60°C leading to compound of formula (L6). Compound of formula (L6) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aprotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (L7).
Compound of formula (L8) can be prepared from compound of formula (L7) by reacting with phosporyl halides such as POCI3 or ΡΟΒΓ3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (L8).
Compound of formula (L8) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aptotic solvents like dioxane, THF etc. at 0°C -130°C.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - M herein below.

Carbonyl functional group in Compound of formula (Ml) on further reduction using different reducing reagents such as but not limited to triethyl silane, borane DMS, borane THF, LLA1H4 in polar aptotic solvents like THF, dioxane etc or like in acids such as, although not limited to trifluroacetic acid, sulphuric acid, acetic acid and the like, or mixture(s) thereof to provide compound of formula (M2).
Compound of formula (M2) converted to compound of formula (M3) using Ftiedel craft acylation. This transformation was carried out by reaction of Compound of formula (M2) with corresponding acyl halide in presence of Lewis acids such as aluminum trichloride, zinc chloride, boron trifluoride etherate and like, in halogenated solvents like dichloromethane, dichloroethane and like.
Compound of formula (M3) was allowed to react with mixture of bromine & aqueous metal hydroxides like NaOH, KOH or the like or mixtures thereof to provide compound of formula (M4).
Compound of formula (M4) which on coupling with different amidines such as acetamidine, formamidine etc. in polar aptotic solvents like DMF, DMSO etc. at temperature 80°C - 100°C leading to compound of formula (M5).
Compound of formula (M6) can be prepared from compound of formula (M5) by reacting with phosporyl halides such as POCI3 or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (M6).
Compound of formula (M6) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the final compound of formula (I) using organic basic reagents such as but not limited to DIPEA, TEA etc. in a polar aprotic solvents like dioxane, THF etc. at 0°C -130°C.
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme - N herein below.

Compound of the formula (N2) was obtained by oxidation of compound of the formula (Nl). This transformation can be effected by oxidizing reagents such as potassium permanganate, potassium dichromate, sodium dichromate and like; in presence of acids like H2SO4, acetic acid and like.
Compound of the formula (N3) was obtained from compound of the formula (N2) by esterification reaction. This transformation can be effected by reaction of alcohols such as methanol, ethanol and like; in presence of mineral acids like sulfuric acid, organic acids like methane sulfonic acid and like, or in presence of chloride reagents like thionyl chloride, oxalyl chloride and thereof. This transformation can also be effected by Mitsonobu reaction between acid (N3) and corresponding alcohols in presence of Triaryl phosphines and azo carboxylates such as DEAD, DIAD and like.
The reaction between compound of formula (N3) and substituted dialkyl dicarboxylates (compound of the formula (N4)) in presence of base provided compound of the formula (N5). This type of transformations can be carried out either at room temperature or at elevated temperatures using alkali bases such as NaOH, KOH and like; carbonates such as potassium carbonate, cesium carbonate and like; or organic bases like Triethylamine, diisopropylethyl amine and thereof; in amidic solvents like DMF, DMA and like; etheral solvents like 1, 4-dioxane, THF and thereof.
Compound of formula (N5) undergo reductive cyclization to provide compound of formula (N6). The reduction of nitro group was carried out using different reagents; although not limited, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. These reactions are carried out in one or more solvents, e.g., ethers such as THF, 1, 4-dioxane, and the like; alcohol such as methanol, ethanol and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid and mixtures thereof.
Compound of formula (N6) undergoes N-alkylation using alkyl halides and bases such as K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DAB CO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N7).
Compound of formula (N7) allowed to react with tot-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (Π) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tot-butoxide, DIPEA, Potassium triphosphate and thoeof; in a suitable solvent selected from THF, 1, 4-dioxane, dimethoxyethane, DMF, DMA, toluene and the like to provide compound of formula (N8).
Compound of formula (N8) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like thereof to provide compound of formula (N9).
Compound of formula (N9) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like to obtain compound of formula (N10). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.
Alternatively, compound of formula (N8) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (N10)
Compound of formula (N10) can also be obtained directly from compound of formula (N8) by reaction alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid and thereof.
Compound of formula (N10) allowed to react with phosporyl halides such as POCh or POBr3 optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (N11).
Compound of formula (Nil) allowed to react with compound of formula (A5) in presence of suitable coupling reagent to provide compound of formula (N12). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1 ,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
Compound of formula (N12) converted to compound of formula (I) in presence of alkali hydroxides such as NaOH, LiOH and thereof, in solvents like methanol, ethanol and thereof or using tetrabutyl ammonium halide in etheral solvents like THF, 1,4-dioxane and thereof.
Compound of formula (N12) undergoes decarboxylation reaction to furnish compound of the formula (N13). This transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof; similar transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like; at elevated temperatures.
Compound of formula (N13) converted to compound of formula (I) using ceric ammonium nitrate, thallium nitrate and thereof in present of alcoholic solvents like methanol, ethanol and thereof.
Further, Compound of formula (N7) undergoes decarboxylation reaction to furnish compound of the formula (N14). This transformation can be achieved using sodium chloride, lithium chloride and thereof, in solvents such as dimethyl sulfoxide and like, at elevated temperatures. Similar transformation can be effected by acidic reagents such as mineral acids like sulfuric acid, organic acids like trifluoroacetic acid and thereof.
Compound of formula (N14) undergoes C-alkylation reaction with alkyl halides in presence of bases such as NaH, sodium/potassium alkoxides, K2CO3, Na2CO3, CS2CO3; organic bases like diisopropylethyl amine, DBU, DABCO and so on; in polar aprotic solvents like DMF, DMSO, acetone and like, etheral solvents such as THF, 1, 4-dioxane and like, at room temperature or elevated temperatures provide compound of formula (N15) Compound of formula (N15) can be converted to compound of formula (I) in five steps by employing analogous protocol mentioned above in scheme -N for the conversion of compound of formula (N7) to compound of formula (N12).
The compounds of formula (I) was prepared by following the sequential transformations as depicted and described in Scheme-O herein below.

Compound of formula (01) converted to compound of formula (02) using Friedel craft acylation. This transformation was carried out by reaction of Compound of formula (01) with corresponding acyl halide in presence of Lewis acids such as aluminum trichloride, zinc chloride, boron trifluoride etherate and like, in halogenated solvents like dichloromethane, dichloroethane and like.
Compound of formula (02) was allowed to react with pyridine, optionally in solvents such as THF, toluene, xylene or the like or the mixtures thereof, followed by treatment of aqueous metal hydroxides like NaOH, KOH or the like or mixtures thereof to provide compound of formula (03).
Compound of formula (03) acid derivative undergoes esterification reaction to corresponding compound of formula (04) using solvents such as methanol, ethanol, propanol, tert-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
Compound of formula (04) was undergoes coupling with alkyl/substituted alkyl halide/dihalides to the corresponding formula (05) using bases like Lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tertbutoxide, sodium ethoxide, sodium methoxide, cesium carbonate, potassium carbonate or the like possibly in the presence of additives such as N,N,N',N'-Tetramethylethane- 1,2-diamine in solvents selected from THF, 1,4-dioxane, DMF and like.
Alternatively, the compound of formula (01) undergoes alkylation/acylation reaction to give compound of formula (Oil) the reaction was carried out using alkyl halides/ acyl halide and bases like Lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tertbutoxide, sodium ethoxide, sodium methoxide, cesium carbonate, potassium carbonate or the like possibly in the presence of additives such as N,N,N',N'-Tetramethylethane-1, 2-diamine in solvents selected from THF, 1,4-dioxane, DMF and like
Compound of formula (Oil) was converted to compound of formula (013) by employing similar protocol mentioned above for conversion of compound of formula (01) to compound of formula (03).
Compound of formula (013) undergoes esterification reaction to corresponding compound of formula (05) using solvents such as methanol, ethanol, propanol, tert-butanol using acidic conditions like hydrochloric acid, sulfuric acid, thionyl chloride or the like or mixture(s) thereof.
Compound of formula (05) can be further reacted with alkyl halide, acyl chlorides using bases such as K2CO3, Na2C03, CS2CO3 etc. in polar aprotic solvents like DMF, DMSO etc. at elevated temperatures leading to compound of formula (06)
Compound of formula (06) allowed to react with tot-butyl carbamate in the presence of catalyst such as (tris(dibenzylideneacetone) dipalladium(O), palladium (Π) acetate, Bis(dibenzylideneacetone)2 Pd(0), racemic 2,2’-Bis(diphenylphosphino)-l,l’-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0) and the like; in presence of ligands such as RuPhos, Xanthphos, Davephos, BINAP, or the like; using a suitable base such as sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tot-butoxide, DIPEA, Potassium triphosphate and thoeof; in a suitable solvent selected from THF, 1,4-dioxane, dimethoxyethane, DMF, DMA, toluene and the like to provide compound of formula (07).
Compound of formula (07) undergoes deprotection using acids like organic acids such as trifluoroacetic acid, Methane sulfonic acid and like, mineral acids like hydrochloric acid, acetic acid (aqueous or in etheral solvents), sulfuric acid and the like; using solvents like dichloromethane, dichloroethane, THF, 1,4-dioxane and like, to provide compound of formula (08).
Compound of formula (08) allowed to react with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid and the like to obtain compound of formula (09). The same transformation can be carried out using trialkyl orthoacetate in presence of ammonium acetate, in corresponding polar protic solvents like ethanol, methanol and thereof.
Further, compound of formula (07) on reaction with alkylnitrile in presence of the acidic reagents such as methane sulfonic acid, sulfuric acid, hydrochloric acid or the like can directly give compound of formula (09)
Compound of formula (09) allowed to react with phosporyl halides such as POCI3 or POBrg optionally in solvents such as toluene, xylene, chlorobenzene or the like or the mixtures thereof, optionally using organic base such as triethylamine, diisopropylethylamine or the like to provide compound of formula (OIO).
Compound of formula (OIO) allowed to react with compound of formula (AS) in presence of suitable coupling reagent to provide compound of formula (I). The reaction can be carried out in presence of organic base such as diisopropylethylamine, triethylamine, DBU or the like, or using coupling reagents such as DCC, EDC, BOP, pyBOP, HBTU or the like; in etheral solvents such as THF, 1,4 dioxane and like or polar aprotic solvents like DMF, DMA, DMSO and thereof.
Further, compound of formula (OIO) converted to compound of formula (014) using halogenating reagents such as NBS, NCS, bromine and like, in polar solvents such as DMF, AcOH, DCM and like.
Compound of formula (015) was prepared from compound of formula (014) using C-C coupling reactions such as Suzuki coupling reaction using corresponding boronic acid in presence of Pd catalyst such as tris(dibenzylideneacetone) dipalladium(O), palladium(II)acetate, Bis(dibenzylideneacetone)2Pd(0), rac 2,2'-B is(diphenylphosphino)- 1 , 1 '-binaphthyl, 2,5 bis(tri-t-butylphosphine) palladium (0), Pd(PPh3)4 and like in base such as K2CO3, Na2CO3, CS2CO3, Potassium phosphate and like; in solvents such as toluene, 1,4-dioxane , DMA, DMF and like
The compound of formula (014) can be converted to compound of formula (I) using similar protocol used earlier for conversion of compound of formula (09) to compound of formula (I) in two steps.

CLAIMS
1. A compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof,

wherein,
Ring A is selected from aryl, heteroaryl, and heterocyclyl;
Ring B is selected from substituted or unsubstituted 5 or 6 membered carbocyclic ring and substituted or unsubstituted 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from S, O, and N;
when ring B is carbocyclic ring, it is substituted with 1 to 8 substituents independently selected from Rc and
Rd;
when ring B is heterocyclic ring, it is substituted with 1 to 7 substituents; when it is substituted on a ring nitrogen atom, it is substituted with substituents selected from R1 and Rb; and when it is substituted on a ring carbon atom, it is substituted with substituents selected from Rc and Rd;
R1 and Rb are independently selected from hydrogen, -C(=0)R8, -C(=0)NRb(Ri), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
Rc and Rd are independently selected from hydrogen, halogen, oxo, -C(=0)R8, -NRb(Ri), -C(=0)NRb(Ri), -ORj, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocychc ring and substituted or unsubstituted heterocycle;
R1 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl.
R2 and R3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
R4 is selected from halogen, cyano, -NRcRVORj, -C(=0)R8, -C(=0)NRh(Ri), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and heterocyclyl substituted with substituted alkyl;
Re and Rf are independently selected from hydrogen, -C(=0)R8, -C(=0)NRh(Ri), substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
Rh and R' are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;
optionally Rh and R' groups together with the nitrogen atom to which they are attached forming a substituted or unsubstituted heterocycle;
Rj is selected from hydrogen, substituted or unsubstituted alkyl, alkyl substituted with substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkyl;
‘n’ is an integer selected from 0, 1, 2, and 3;
when an alkyl group is substituted, it is substituted with 1 to 5 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)OH, -C(=0)0(alkyl), -NR6R61, -NR6C(=0)R7, and -C(=0)NR6R6‘;
when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR5, -C(=0)0H, -C(=0)0(alkyl), -NR6R6a, -NR6C(=0)R7, and -C(=0)NR6R6*;
when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR5, -NR6R61, -NR6C(=0)R7, -C(=0)R7,-C(=0)NR6R6*, -S02-alkyl, -C(=0)0H, -C(=0)0-alkyl, and haloalkyl;
when the heteroaiyl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -NR6R6a, -NR5C(=0)R7, -C(=0)R7, -C(=0)NR6R6a, -SO2-alkyl, -C(=0)0H, and -C(=0)0-alkyl;
when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR5, -C(=0)NR6R6“, -C(=0)0H, -C(=0)0-alkyl, -N(H)C(=0)(alkyl), -N(H)R6, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloalkyl, aryl, heteroaryl, -S02(alkyl), -C(=0)R7, and -C(=0)0(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=0) group(s);
R5 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;
R6 and R6* are each independently selected from hydrogen, alkyl, and cycloalkyl;
or R6 and R6* together with nitrogen to which they are attached form a heterocyclyl ring; and
R7 is selected from alkyl and cycloalkyl.
2. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in claim 1, wherein ring A is selected from aryl and heteroaryl.
3. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in claim 1 or 2, wherein ring A is selected from
phenyl and
4. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 3, wherein,
Ring B is selected from

Ra and Rb are independently selected from hydrogen, -C(=0)R8, -C(=0)NRb(Ri), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
Rc and Rd are independently selected from hydrogen, halogen, oxo, -C(=0)R8, -NRb(Ri), -C(=0)NRb(Ri), -ORj, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocyclic ring and substituted or unsubstituted heterocycle.
5. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 4, wherein ring B is selected from


6. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 5, wherein R1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.
7. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 6, wherein R1 is selected from methyl, ethyl, isopropyl, and cyclopropyl.
8. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 7, wherein R2 and R3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl.
9. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 8, wherein R2 and R3 are independently selected from hydrogen, fluorine, and methyl.
10. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 9, wherein R4 is selected from halogen, -NRcRf, substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.
11. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 10, wherein R4 is

12. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 11, wherein ring A is selected from aryl and heteroaryl; ring B is selected from

; R1 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R2 and R3 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R4 is selected from halogen, -NR'R* substituted or unsubstituted alkyl, cycloalkyl substituted with substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R* and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Rc and Rd are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, -C(=0)NRb(Ri), -ORj, and substituted or unsubstituted heterocyclyl; optionally Rc and Rd groups together with the carbon atom which they are attached forming a substituted or unsubstituted carbocyclic ring and substituted or unsubstituted heterocycle; Re and Rf are hydrogen; optionally Rh and Ri groups together with the nitrogen atom to which they are attached forming a heterocycle; Rj is selected from hydrogen and alkyl; and ‘n’ is an integer selected from 0, 1, 2, and 3.
13. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 12, wherein ring A is

R1 is selected from methyl, ethyl, isopropyl, and cyclopropyl; R2 and R3 are independently selected from hydrogen, fluorine, and methyl; R4 is selected from fluorine,

14. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 13, wherein the compound is selected from:
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin- 7(8H)-one (Compound 1);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-[ 1 ,4]oxazino[3,2- g]quinazolin-7(8H)-one (Compound 2);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H- [ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 3);
4-((l-(3-(l,l -difluoroethyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H- [ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 4);
4-((l-(3-amino-5-(difluoromethyl)phenyl)ethyl)ainino)-2,6-dimethyl-6H-[l,4]oxazmo[3,2-g]quinazolin-7(8H)-one (Compound 5);
4-((l-(3-(l,l-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)aniino)-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 6);
2,6-dimethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)amino)-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 7);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)aniino)-2,6-diniethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 8);
4-(( 1 -(3 ,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2,6-dimethyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 9);
(R)-N-(l-(3-animo-5-(trifluoromethyl)phenyl)ethyl)-2,6-dimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-amine (Compound 10);
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-6-((tetrahydrofuran-3-yl)methyl)-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 11);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-6-(cyclopropylmethyl)-2-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 12);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-6-ethyl-2-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 13);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-ethyl-6-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one. (Compound 14);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2-ethyl-6-methyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 15);
(R)-2-cyclopropyl-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-6-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 16);
(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2-methyl-8,9-dihydro-7H-pyrano[2,3-g]quinazolin-7-yl)(pyirolidin-1-yl)methanone (Compound 17);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 18);
2,6,8,8-tetramethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)amino)-6H-[l,4]oxazmo[3,2-g]qumazolm-7(8H)-one (Compound 19);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 20);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-[l,4]oxazmo[3,2-g]quinazolin-7(8H)-one (Compound 21);
4-(( 1 -(2-fluoro-3-(l , 1 ,l-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 22);
4-(( l-(3-(l ,l-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 23);
(R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,6,8,8-tetramethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-amine (Compound 24);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethylspiio[cyclopropane-l,8'-[l,4]oxazino[3,2-g]quinazolin]-7'(6'H)-one (Compound 25);
(R)- 1 , 1 -Difluoro- l-(2-fluoro-3-(l -((2,8,8-trimethyl-7-morpholino-8H [ 1 ,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 26);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,9-tetramethyl-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-one (Compound 27);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2, 6,8,8, 9-pentamethyl- 8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-one (Compound 28);
(R)-9-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-l,3,7-trimethylpyrimido[4,5-g]quinazoline-2,4(lH,3H)-dione (Compound 29);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 30);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 31);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-isopropyl-2,6-dimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 32);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 33);
(R)- 1 , 1 -Difluoro- l-(2-fluoro-3-(l -((2,6,8,8-tetramethyl-7,8-dihydro-6H-[ 1 ,4]oxazino [3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 34);
(R)-2,2-Difluoro-2-(2-fluoro-3-(l-((2,6,8,8-tetramethyl-7,8-dihydio-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 35);
2,2-difluoro-2-(2-fluoro-3-((lR)-1-((2,6,8-trimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 36);
(R)-1,1-Difluoro-1-(2-fluoro-3-(l-((2,6,7,7-tetramethyl-7,8-dihydio-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 37);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethylpyrido[2,3-g]quinazolin-7(6H)-one (Compound 38);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8-trimethylpyrazino[2,3-g]quinazolin-7(6H)-one (Compound 39);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl) amino)-2,6,9-trimethyl-6,9-dihydropyrazino[2,3-g]quinazoline-7,8-dione (Compound 40);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2, 8, 8-trimethyl- 6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 41);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,9,9-tetramethyl-8,9-dihydropyrido[2,3-g]quinazolin-7(6H)-one (Compound 42);
N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((R/S)-tetrahydrofuran-3-yl)methyl)-7,8-dihydro-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-4-amine (Compound 43);
N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S/R)-tetrahydrofuran-3-yl)methyl)-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-amine (Compound 44);
(R)-1-(3-(l-((2,6-dimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-!, l-difluoro-2-methylpropan-2-ol (Compound 45);
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,6,8-trimethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 46);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)- 10-fluoro-2,6-dimethyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 47);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-6-(2-methoxyethyl)-2-methyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 48);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-ethyl-2-methyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 49);
(R)-1-(3-(l-((6-ethyl-2,8,8-trimethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-!, l-difluoro-2-methylpropan-2-ol (Compound 50);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H- [l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 51);
(R)-N-(l-(3-(l ,l-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2,6,8,8-tetramethyl-7,8-dihydro-6H-[l,4]oxazino[3,2-g]quinazolin-4-amine (Compound 52);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-3-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2, 6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 53);
4-(((lR)-1-(2-fluoro-3-( 1 , 1 ,3-trifluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[ 1 ,4]oxazino[3 ,2-g]quinazolin-7(8H)-one (Compound 54);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methyl-3-(methylaniino)propyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[l,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 55);
(R)-2,2-difluoro-2-(2-fluoro-3-(l-((2-methyl-7,8-dihydro-6H-pyrano[3,2-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 56);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-[ 1 ,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 57);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2',8'-dimethylspiro[cyclopentane-l,6'-pyrrolo[3,2-g]quinazolin]-7'(8,H)-one (Compound 58);
4'-((l-(2-fluora-3-(trifluoramethyl)phenyl)ethyl)amino)-2',8'-dimethylspiro[cyclopentane-l,6'-pyrrolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 59);
2,,8'-dimethyl-4,-((l-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)aniino)spiio[cyclopentane-l,6,-pyrrolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 60);
4'-((l-(3-(difluoromethyl)-2-methylphenyl)ethyl)aniino)-2,,8,-diniethylspiro[cyclopentane-l,6,-pyriolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 61);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2,,8,-dimethylspiro[cyclopeiitane-1 ,6'-pyrrolo[3 ,2-g]quinazolin]-7'(8'H)-one (Compound 62);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-6-(2-methoxyethyl)- 2,8,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 63);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2,8,8-trimethyl- 6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 64);
(R)-6-cyclopropyl-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-2,8,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 65);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,,8,-dimethylspiio [cyclopropane-1 ,6'-pyrrolo[3 ,2-g]quinazolin]-7'(8'H)-one (Compound 66);
(R)-4'-((l-(3-( 1 , 1 -difluoΓO-2-hydrΌxy-2-methylpropyl)-2-fluorophenyl)ethyl)aπlino)-2,,8,-dimethylspiro[cyclopropane-l,6'-pyrrolo[3,2-g]quinazolin]-7'(8'H)-one (Compound 67);
(R)-4-((l-(3-( 1 , 1 -Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 68);
4-((l-(3-amino-5-(difluoromethyl)phenyl)ethyl)animo)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 69);
(R)-4-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6H-pyiTolo[2,3-g]quinazolin-7(8H)-one (Compound 70);
(S)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8,8-tetramethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 71);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 72);
4-(( 1-(3-(1 ,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 73);
4-(( 1 -(2-fluoro-3-(1 , 1 ,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 74);
(R)-1,1-difluoro-1-(2-fluoro-3-(l-((2,6,8,8-tetramethyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinazolm-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 75);
4-(((lR)-1-(3-(1,1 -difluoro-2,3 -dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 76);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-2,8,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 77);
(R)-4-((1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)-6-isopropyl-2,8,8-trimethyl-6H-pyrrolo[2,3-g]quinazolin-7(8H)-one (Compound 78);
(R)-4'-((l-(3-( 1 , 1 -difluoro-^-hydroxy^-methylpropyl^-fluorophenyl^thyyamino)-2',6'-dimethylspiro[cyclopropane-l,8'-pyrrolo[2,3-g]quinazolin]-7,(6'H)-one (Compound 79);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 80);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 81);
4-((l-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 82);
2,6,6,8-tetramethyl-4-((l-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)aniino)-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 83);
4-((l-(3-(l,l-difluoroethyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyiTolo[3,2-g]quinazolin-7-one (Compound 84);
4-((l-(3-(difluoro(tetrahydrofuran-3-yl)methyl)-2-fluorophenyl)ethyl)aniino)-2,6,6,8-tetramethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 85);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-2-ethyl-6,6,8-trimethyl- 6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 86);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-isopropyl-6,6,8-trimethyl-6H-pyrrolo[3,2-g]quinazolin-7(8H)-one (Compound 87);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)animo)-8-ethyl-2,6,6-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 88);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) ethyl)amino)-8-ethyl-2,6,6-trimethyl-6H-pyrrolo[3,2-g]quinazolin-7(8H)-one (Compound 89);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2, 6,6,8, 9-pentamethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 90);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6,6-diethyl-2, 8-dimethyl- 6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 91);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6,6-bis(fluoromethyl)- 2,8-dimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 92);
4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-ethyl-2,6, 8-trimethyl- 6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 93);
4-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(methoxymethyl)- 2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 94);
4-(((R)- 1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 95);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 96);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-6-hydroxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]qvrinazolin-7-one (Compound 97);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-(methoxymethyl)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 98);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 99);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-hydroxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 100);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazohn-7-one (Compound 101);
(S/R)-4-(((R/S)-1-(3-((S/R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 102);
(S/R)-4-(((R/S)-1-(3-((R/S)-1,1-difluoiO-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 103);
(R)-8-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 -ethyl-3 ,6-dimethyl-1 ,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 104);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluoro phenyl)ethyl)amino)- 1 -isopropyl-3,6-dimethyl- l,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 105);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-1-(2,2-difluoroethyl)-3,6-dimethyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (Compound 106);
(R)- 1 , 1 -difluoro- l-(2-fluoro-3-(l -((2,2,3 ,6-tetramethyl-2,3-dihydro- lH-imidazo[4,5-g]quinazolin-8-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 107);
(R)-1,1-difluoro-1-(2-fluoro-3-(l-((l,2,2,3,6-pentamethyl-2,3-dihydro-1H-imidazo[4,5-g]qumazolin-8-yl)aniino)ethyl)phenyl)-2-methylpropan-2-ol (Compound 108);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 ,3,6-trimethyl- 1,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 109);
(R)-2-cyclopropyl-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-6,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 110);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 1 ,6-dimethyloxazolo[4,5-g]quinazolin-2(lH)-one (Compound 111);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6H-pyrrolo[2,3-g]quinazoline-7,8-dione (compound 112);
(R)-4-(( 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6-dimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 113);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,6,6,7-tetramethyl-6,7-dihydro-8H-pyrrolo[3,4-g]quinazolin-8-one (Compound 114);
4-(( 1 -(2-fluoro-3-(l -(hydroxymethyl)cyclopropyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 115);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2, 6, 8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 116);
(R)-4-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8,8-difluoro-2,6-dimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazohn-7-one (Compound 117);
(R)-4-((l-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,7,8,8-tetramethyl-7,8-dihydro-6H-pyrrolo[3,4-g]quinazolin-6-one (Compound 118);
(R)-8-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-3,6-dimethyl-l,3-dihydro-2H-imidazo[4,5-g]quinazolin-2-one (Compound 119);
(S)-4-(((S)-1-(3-(l,l-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 120);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-ethoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 121);
(R)-4'-((l-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethyl-2,3 ,5,6-tetrahydrospiro[pyran-4,8,-pyrrolo[2,3-g]quinazolin]-7'(6,H)-one (Compound 122);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-(2-methoxyethyl)-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 123);
4'-(((R)-1-(3-( 1 , 1 -difluoΓO-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aπliIlo)-2,,3,6,-trimethylspiro[oxazolidine-5,8'-pyrrolo[2,3-g]quinazoline]-2,7'(6'H)-dione (Compound 124);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-8-methoxy-2, 6-dimethyl- 8-(trifluoromethyl)-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 125);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-ethyl-8-methoxy-2,6-dimethyl-6, 8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (compound 126);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-3-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 127);
4'-(((R)- 1 -(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,,6,-dimethyl-4,5 -dihydro-2H-spiro[furan-3,8,-pyrrolo[2,3-g]quinazolin]-7,(6'H)-one (Compound 128);
4-(((lR)-1-(3-(3-(dimethylamino)-1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 129);
4-(((lR)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methyl-3-(methylamino)propyl)-2-fluorophenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 130);
4-(((R)-1-(3-amino-5-(trifluoromethyl)plienyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 131);
4-(((R)-1-(3-( 1 , 1 -difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-8-(2-methoxyethyl)-2,6-dimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 132);
4-(((lR)-1-(2-fluoro-3-(piperidin-3-yl)phenyl)ethyl)amino)-2,6,8,8-tetramethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 133);
(R)-4-((l-(2-fluoro-3-(trifluoroniethyl)phenyl)ethyl)aniino)-2,6,8,8-tetramethyl-6,8-dihydio-7H-pyiiolo[2,3-g]quinazolin-7-one (Compound 134);
4-(((lR)-1-(3-(3-(dimethylamino)-1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 135);
2,6,8,8-tetramethyl-4-((l-(3-(trifluoromethyl)phenyl)ethyl)aniino)-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 136);
4-(((R)-1-(3-amino-5-(trifluoromethyl)plienyl)ethyl)amino)-6-methoxy-2,6,8-trimethyl-6,8-dihydro-7H-pyrrolo[3,2-g]quinazolin-7-one (Compound 137);
(R)-4'-((l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2',6'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,8,-pyrrolo[2,3-g]quinazolin]-7'(6,H)-one (Compound 138); and
4-(((R)-1-(3-amino-5-(trifluoromethyl)plienyl)ethyl)amino)-8-ethyl-8-methoxy-2,6-dimethyl-6,8-dihydro-7H-pyrrolo[2,3-g]quinazolin-7-one (Compound 139).
15. A pharmaceutical composition comprising a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 14 and a pharmaceutically acceptable carrier.
16. A method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof as claimed in any one of claims from 1 to 14.
17. A method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting the interaction of SOS1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof as claimed in any one of claims from 1 to 14.
18. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 16 or 17, wherein the said disease, disorder, and/or condition is a cancer.
19. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim
18, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
20. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 16 or 17, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/Acute Lung injury, and Sepsis.
21. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim
16 or 17, wherein the said disease, disorder, and/or condition is a RASopathy.
22. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 21, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary Gingival Fibromatosis (HGF).
23. The method as claimed in claims 15 to 22, wherein the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, is administered before, after, or together with at least one or more pharmacologically active substance.
24. Use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 14, for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
25. Use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 14, for the treatment and/or prevention of a disease, disorder, and/or condition by inhibiting the interaction of SOS 1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
26. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 24 or 25, wherein the said disease, disorder, and/or condition is cancer.
27. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 26, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
28. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 24 or 25, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/ Acute Lung injury, and Sepsis.
29. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 24 or 25, wherein the said the disease is a RASopathy.
30. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 29, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation- Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary gingival fibromatosis (HGF).
31. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 14, for treatment and/or prevention of cancer, wherein said compound is administered in combination with at least one more pharmacologically active substance.
32. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 14, for treatment and/or prevention of cancer, wherein the compound is administered before, after, or together with at least one other pharmacologically active substance.