Replacement tricyclic compound

Abstract

Disclosed is a compound of the following general formula (I), a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, or a solvate thereof for use as an SOS1 inhibitor in the treatment of proliferative, infectious, and rasopathy diseases or disorders. [C115] TIFF2023504113000169.tif60129In formula, ring A, R 1 ~R 5 , X, Y, m, and n are as defined herein. Also disclosed are methods of synthesizing compounds of formula I, pharmaceutical compositions containing compounds of formula I, methods of treating proliferative, infectious, and rasopathy diseases or disorders, such as cancer, by administering said compounds, and combinations of compounds of formula I with other active ingredients.

Description

[Technical Field]

[0001] The present invention relates to a compound of the following general formula (I):

[0002] [ka]

[0003] It relates to its tautomers, its stereoisomers, its pharmaceutically acceptable salts, its crystalline polymorphs, its solvates, its combination with appropriate pharmaceuticals, its pharmaceutical compositions, methods for making the compounds, their use as SOS1 inhibitors, and their therapeutic utility in various pathological conditions.

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Indian Provisional Patent Application Nos. IN201921049157, filed November 29, 2019, and IN202021035414, filed August 17, 2020, the disclosures of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0005] Multiple signaling pathways regulate cancer initiation, progression, spread, metastasis, and immune evasion. Key signaling pathways include the RTK / RAS pathway, PI3K pathway, Wnt pathway, Myc pathway, and cell cycle pathway (Francisco Sanchez-Vega et al., Cell, 2018, 173(2):321-337.e10). RAS family proteins (KRAS, HRAS, and NRA, as well as their respective variants) are small GTPases present in cells in either a GTP-bound (inactive) or GDP-bound (active) state (Siqi Li et al., Nat. Rev. Cancer, 2018, 18(12):767-777). The activity of RAS proteins is regulated by proteins known as GTPase-activating proteins (GAPs) or guanine nucleotide exchange factors (GEFs). GAP proteins belonging to the RAS family include members such as NF1, TSC2, and IQGAP1, which activate the GTPase function of RAS proteins and thereby terminate signal transduction by catalyzing the hydrolysis of GTP to GDP. In contrast, GEFs in the RAS family include proteins such as SOS1, SOS2, RASGRP, and RASGRF2, which activate RAS proteins by exchanging GTP for GDP (Johannes L. Bos et al., Cell, 2007, 129(5):865-77).

[0006] Ras-GTP binds to effector proteins such as Raf and PI3K, resulting in 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). Induction of one or more of these intracellular signaling pathways results in the emergence and maintenance of a tumorigenic phenotype, accompanied by enhanced cell proliferation, increased cell survival, altered metabolism, angiogenesis, migration, and immune evasion, ultimately leading to cancer establishment and metastasis (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). Point mutations occur at several amino acid residues in RAS proteins, with key hotspots at positions G12, G13, and Q61. These mutations render RAS proteins constitutively active, since the majority of the protein is in the GTP-bound, activated 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). Interactions between RAS proteins and GEFs, such as Son of Sevenless1 (SOS1), play an important role in relaying signals to downstream effectors. The SOS1 protein contains several domains, including a Dbl homology domain (DH), a Pleckstrin homology domain (PH), a RAS exchange motif (REM), a 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 and an allosteric site.The catalytic site preferentially binds RAS-GDP, whereas the allosteric site binds RAS-GTP with higher 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 et al., Nat. Commun., 2012;3:1168). The catalytic function of SOS1 (guanine nucleotide exchange) is essential for the oncogenicity of KRAS 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 an important role in signal transduction following cell 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). In addition, receptors on lymphocytes (B-cell and T-cell receptors) (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).

[0007] The role of SOS1 in RAS-mediated signaling makes it an attractive target for cancer therapy. Pharmacological intervention with SOS1 inhibitors has been shown to attenuate or eliminate downstream effector events in RAS-mediated pathways (Roman C. Hillig et al., Proc. Natl. Acad. Sci. US A. 2019, 12;116(7):2551-2560; Chris R. Evelyn et al., J. Biol. Chem., 2015, 15;290(20):12879-98).

[0008] In addition to cancer, inherited SOS1 mutations have been implicated in the pathogenesis of lasopathies such as Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56).

[0009] In addition, other diseases associated with hSOS1 expression include significant upregulation in whole blood cell extracts of pediatric patients with acute community-acquired Staphylococcus aureus infection, as well as in patients with acute respiratory distress syndrome (ARDS) / acute lung injury (ALI) and sepsis (FC Baltanas, et al. BBA-Reviews on Cancer 1874(2020)188445).

[0010] In addition, several patent applications related to SOS1 have been published, such as WO2004003152, WO2014144148, WO2016077793, WO2018115380, WO2018172250, WO2019122129, WO2019201848, WO2020180768 and WO2020180770.

[0011] The above demonstrates that there is an unmet need for SOS1 inhibitory compounds for treating diseases or disorders in which SOS1 is involved, particularly cancers that are SOS1 dependent. Summary of the Invention

[0012] The present invention provides compounds of the following general formula (I), their pharmaceutically acceptable salts, tautomers, stereoisomers, crystalline polymorphs, solvates, combinations thereof with appropriate medicaments, or medicaments and pharmaceutical compositions thereof, and their uses in the treatment of various diseases or disorders, including cancer:

[0013] [ka]

[0014] In the formula, rings A, R 1 ~R 5 , X, Y, m and n are described in detail below.The compounds of the present invention are potent inhibitors of SOS1.

[0015] According to one aspect of the present invention, there is provided a compound represented by general formula (I), its tautomers, its stereoisomers, its crystalline polymorphs, its solvates, its pharmaceutically acceptable salts, its combination with a suitable drug, and its pharmaceutical composition, wherein: 1 ~R 5 , X, Y, m and n are described in more detail below.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of general formula (I), its tautomers and stereoisomers, its crystalline polymorphs, its solvates, or its pharmaceutically acceptable salts as defined herein, in combination with a conventional pharmaceutically used carrier, diluent, etc., which is useful for the treatment of an SOS1-mediated disease or disorder.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of general formula (I), its tautomer, its stereoisomer, its crystalline polymorph, its solvate, or a pharmaceutically acceptable salt thereof as defined herein, in combination with a conventional pharmaceutically used carrier, diluent, etc., which is useful in the treatment of a disease or disorder, such as cancer, an infectious disease or disorder, or a rasopathy disease or disorder.

[0018] In yet another aspect, the present invention provides a compound of Formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, a solvate thereof, in combination with a suitable pharmaceutical agent, or a pharmaceutical composition thereof for the treatment of a disease characterized by excessive or abnormal cell proliferation, such as cancer.

[0019] In another aspect, the present invention provides a compound of Formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, a solvate thereof, a combination thereof with a suitable medicament, or a pharmaceutical composition thereof for treating diseases such as pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF mutant cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, pure mucosal neuroma syndrome, epulis fibrosus, and sarcoma.

[0020] In another aspect, the present invention provides a compound of Formula I, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, a crystalline polymorph, a solvate, a combination thereof with an appropriate medicament, or a pharmaceutical composition thereof 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, epulis fibrosa, acute respiratory distress syndrome / acute lung injury and sepsis, Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC syndrome).

[0021] In another aspect, the present invention provides a compound of formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, a solvate thereof, in combination with a suitable medicament, or a pharmaceutical composition thereof for use in a treatment regimen in the first-line, second-line, or any further line of treatment setting.

[0022] In another aspect, the present invention provides a compound of formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, a solvate thereof, in combination with a suitable medicament, or a pharmaceutical composition thereof for use in the prevention, short-term treatment or long-term treatment of the above-mentioned diseases, optionally in combination with radiation therapy and / or surgery.

[0023] In yet another aspect, the present invention provides a compound of formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a crystalline polymorph thereof, a solvate thereof, a combination thereof with a suitable medicament, or a pharmaceutical composition thereof for treating various cancers mentioned above in which a signal transduction pathway involving RAS protein and / or SOS1 protein is enhanced or abnormally activated.

[0024] In another aspect, the present invention provides the use of a compound of Formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its crystalline polymorph, or its solvate in combination with other agents, such as radiation, chemotherapeutic agents, and / or targeted agents, in the treatment of cancers and their subtypes, such as those described above. Agents that can be used in combination therapy include targeted agents, such as RTK inhibitors, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanisms (such as histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), and 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. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention relates to compounds of general formula (I), their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, their solvates, their combinations with one or more other appropriate pharmaceutical agents, their pharmaceutical compositions, methods for making the compounds, their use as SOS1 inhibitors, and their therapeutic utility in the treatment or amelioration of various pathological conditions. The compounds of formula (I) are as shown below:

[0026] [ka]

[0027] During the ceremony, Ring A is selected from aryl, heteroaryl, and heterocyclyl; "----" is either a single or double bond, X and Y are independently C, O, and NR c with the proviso that X and Y cannot both be O; R 1 is selected from hydrogen and substituted or unsubstituted alkyl; R 2 is selected from hydrogen, halogen, alkyl and cycloalkyl; R 3 -OR 6 , -NR a R b , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl-substituted alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 is selected from oxo, and substituted or unsubstituted alkyl; R 5 -Halo, Cyano, -NR c R d, substituted or unsubstituted alkyl, alkyl substituted with —C(═O) or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and optionally, two R bonded to adjacent carbon atoms. 5 The groups form a substituted or unsubstituted heterocyclic ring, R 6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, and alkyl substituted with a substituted heterocyclyl; Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; R c and R d are independently selected from hydrogen and alkyl; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, and 4; When an alkyl group is substituted, the alkyl group may be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7 , -C(=O)OH, -C(=O)O(alkyl), -NR 8 R 8a , -NR 8 C(=O)R 9 and -C(=O)NR 8 R 8a and is substituted with 1 to 5 substituents independently selected from When a cycloalkyl group is substituted, the cycloalkyl group can be oxo (=O), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR 7 , -C(=O)OH, -C(=O)O(alkyl), -NR 8 R 8a , -NR 8 C(=O)R 9 and -C(=O)NR 8 R 8a and is substituted with 1 to 4 substituents independently selected from When an aryl group is substituted, the aryl group may be substituted with halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR 7 , -NR 8 R 8a , -NR 8 C(=O)R 9 , -C(=O)R 9 , -C(=O)NR 8 R 8a , -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl; When a heteroaryl group is substituted, the heteroaryl group may be substituted with any of halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 7 , -NR 8 R 8a , -NR 7 C(=O)R 9 , -C(=O)R 9 , -C(=O)NR 8 R 8a , -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl; When a heterocyclic group is substituted, the heterocyclic group is substituted on either a ring carbon atom or a ring heteroatom, and when the heterocyclic group is substituted on a ring carbon atom, the heterocyclic group is substituted with any of the following: oxo (=O), halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR 7 , -C(=O)NR 8 R 8a , -C(=O)OH, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R 8 and -N(alkyl), and when the heterocyclic group is substituted on a ring nitrogen, the heterocyclic group is not limited to alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -SO(alkyl), -C(=O)R9 and -C(=O)O(alkyl), and when the heterocyclic group is substituted on the ring sulfur, the heterocyclic group is substituted with one or two oxo (=O) groups; R 7 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl; R 8 and R 8a are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9 is selected from alkyl and cycloalkyl.

[0028] According to an embodiment of the present invention, A is selected from aryl and heteroaryl.

[0029] In certain embodiments, A is selected from phenyl and pyridyl.

[0030] In any of the above embodiments, R 1 is a substituted or unsubstituted alkyl.

[0031] In certain embodiments, R 1 is methyl.

[0032] In any of the above embodiments, R 2 is hydrogen.

[0033] In any of the above embodiments, R 3 -OR 6 , -NR a R b , substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl.

[0034] In certain embodiments, R 3 teeth, -OCH 3、

[0035] [ka] and

[0036] [ka] is selected from the group consisting of:

[0037] In any of the above embodiments, R 4 is selected from oxo and methyl.

[0038] In any of the above embodiments, R 5 is halogen, cyano, -NR c R d , substituted or unsubstituted alkyl, and alkyl or unsubstituted alkyl substituted with —C(═O), and the two R 5 The group forms a substituted or unsubstituted heterocyclyl.

[0039] In certain embodiments, R 5 are fluorine, -CH3, -CF3, -NH2, -CHF2, -CN, -COCF3,

[0040] [ka] and

[0041] [ka] and the carbon atom bonded thereto and the two adjacent R 5 The base is

[0042] [ka] and

[0043] [ka] Form.

[0044] In any of the above embodiments, R 6 is methyl, tetrahydrofuran-3-yl and

[0045] [ka] is selected from the group consisting of:

[0046] In any of the above embodiments, R a and R b are independently hydrogen, methyl,

[0047] [ka] and

[0048] [ka] is selected from the group consisting of:

[0049] In any of the above embodiments, R c and R d is independently selected from hydrogen and methyl.

[0050] If a range of atoms in the structure is given (e.g., C1-C 20It is specifically contemplated that any subrange or individual number of carbon atoms within a recited range can be used, including alkyl, etc. Thus, for example, when used with respect to any chemical group (e.g., alkyl, etc.) referred to herein, a recited range of 1 to 6 carbon atoms (e.g., C1-C6), 2 to 6 carbon atoms (e.g., C2-C6), or 3 to 6 carbon atoms (e.g., C3-C6) includes and is specifically recited as appropriate, 1, 2, 3, 4, 5, and / or 6 carbon atoms, and all subranges 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).

[0051] General terms used in the formulas may be defined as follows, however the meanings given should not be construed as limiting the scope of the terms themselves.

[0052] The term "alkyl," as used herein, means a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms. Preferably, the alkyl chain may contain 1 to 10 carbon atoms. More preferably, the alkyl chain may contain up to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0053] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, wherein at least one of the alkyl group's hydrogen atoms has been replaced with a halogen. Haloalkyl groups are exemplified by chloromethyl, 1-chloroethyl, and the like.

[0054] The term "perhaloalkyl," as used herein, means an alkyl group, as defined above, where all of the alkyl group's hydrogen atoms have been replaced with halogens. Perhaloalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.

[0055] The term "cycloalkyl," as used herein, refers to a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing 3 to 14 carbon atoms, preferably a 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 systems fused through a bond to another ring system, which may be an alicyclic or aromatic ring. Bicyclic rings also include spirocyclic systems, in which a second ring is attached at one carbon atom. Bicyclic ring systems are also exemplified by bridged monocyclic ring systems, in which two non-adjacent carbon atoms of a monocyclic ring are connected 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]heptane, octahydro-1H-indene, spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2,1′-cyclopentane], hexahydro-2′H-spiro[cyclopropane-1,1′-pentalene]. A tricyclic ring system is a bicyclic ring system as described above, further comprising a third ring, which may be an alicyclic ring or an aromatic ring. Tricyclic ring systems are also exemplified by bicyclic ring systems in which two non-adjacent carbon atoms of the bicyclic ring are connected by a bond or an alkylene bridge. Representative examples of tricyclic ring systems include tricyclo[3.3.1.0]. 3.7 ]nonane and tricyclo[3.3.1.1 3.7] Examples include, but are not limited to, decane (adamantane).

[0056] The term "cycloalkenyl," as used herein, refers to a cycloalkyl group, as defined above, which contains at least one double bond.

[0057] 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 groups also include partially saturated bicyclic and tricyclic aromatic hydrocarbons, such as tetrahydronaphthalene. Aryl groups also include bicyclic systems such as 2,3-dihydro-inden-5-yl and 2,3-dihydro-1-indenon-5-yl.

[0058] 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, the remaining ring atoms being carbon (along with the appropriate hydrogen atoms, unless otherwise indicated), and at least one ring in the ring system being aromatic. As used herein, the term "heteroaryl" also includes partially saturated bicyclic and tricyclic aromatic ring systems, such as 2,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-1-isobenzofuranon-5-yl, 2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl, and 2,3-dihydro-1-isoindolinon-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 1H-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, and the like. Zolyl, 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, 1H-pyrazolo[5,1-c]-1,2,4-triazolyl, pyrrolo[3,4-d]-1,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4-c]isothiazolyl, benzo[b ... oxazolyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzo[1,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-1-isobenzofuranon-5-yl, 2,3-dihydro-1H-indol-5-yl, 2,3-dihydro- Examples include, but are not limited to, dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl, 2,3-dihydro-1H-indol-7-yl, 2,3-dihydro-1-isoindolinone-5-yl, benzo[1,3]dioxol-4-yl, benzo[1,3]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.

[0059] The terms "heterocycle" or "heterocyclic" or "heterocyclyl," as used herein, refer to a "cycloalkyl" or "cycloalkenyl" group in which one or more of the carbon atoms is replaced by a heteroatom / heterogroup selected from N, S, SO, and O. A heterocycle can be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of monocyclic heterocycles include 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, o- ... Examples include, but are not limited to, xazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycles include, but are not limited to, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-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 includes 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[3.1.1]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, 1-methylpyridin-2(1H)-one-5-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, pyridin-2(1H)-one-5-yl, pyridin-2(1H)-one-4-yl, and the like.

[0060] "Halogen" means fluorine, chlorine, bromine or iodine.

[0061] The term "oxo" means a divalent oxygen (=O) bonded to a parent group. For example, oxo bonded to carbon forms a carbonyl, oxo substituted on cyclohexane forms cyclohexanone, etc.

[0062] The term "annulated" means that another ring is attached to a ring system at a carbon atom of the ring system or through a bond of the ring system, such as in the case of a fused or spiro ring system.

[0063] The term "bridged" means that the ring system includes an alkylene bridge having from 1 to 4 methylene units connecting two non-adjacent ring atoms.

[0064] In the compounds as described above, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, their solvates, their combination with suitable drugs, and their pharmaceutical compositions, the compound of general formula (I)

[0065] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-methoxypiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-1),

[0066] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-2),

[0067] 2-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-3),

[0068] 2-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-4),

[0069] N-(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-5),

[0070] 2-methyl-2-(3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-1-ol (Compound-6),

[0071] 1,1-difluoro-2-methyl-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-7),

[0072] N-(1-(2-amino-6-(trifluoromethyl)pyridin-4-yl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-8),

[0073] (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-(3-(methoxymethyl)azetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-9),

[0074] (R)-1,1-difluoro-1-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-10),

[0075] 2,2-difluoro-2-(2-fluoro-3-((R)-1-((2-methyl-6-(((S)-tetrahydrofuran-3-yl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-11),

[0076] (R)-N 4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-dimethyl-N 6 -(oxetan-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-12),

[0077] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-oxa-8-azaspiro[4.5]decan-8-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-13),

[0078] N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-14),

[0079] (S)-1-(4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-15),

[0080] (R)-1-(4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-16),

[0081] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-17),

[0082] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-18),

[0083] N 4 -((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N 6 -((S)-tetrahydrofuran-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-19),

[0084] N-(1-(3-amino-5-methylphenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-20),

[0085] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N 6 -(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-21),

[0086] (S)-1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-22),

[0087] (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-23),

[0088] (R)—N-(1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-24),

[0089] (S)-1-(4-(((R)-1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-25),

[0090] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3-(methoxymethyl)azetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-26),

[0091] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-27),

[0092] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N 6 -(oxetan-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-28),

[0093] (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-(oxetan-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-29),

[0094] (R)-1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-30),

[0095] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-isopropylpiperazin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-31),

[0096] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((S)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-32),

[0097] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-33),

[0098] N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-34),

[0099] 2,2-difluoro-2-(2-fluoro-3-((R)-1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-35),

[0100] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3-methoxyazetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-36),

[0101] 1'-methyl-4'-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one (Compound-37),

[0102] N-(1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-38),

[0103] N-((S / R)1-(3-(difluoro((S / R)-tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-39),

[0104] 2,2-difluoro-2-(2-fluoro-5-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-40),

[0105] 2,2-difluoro-2-(2-methyl-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-41),

[0106] 2,2-difluoro-2-(3-(1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-methylphenyl)ethan-1-ol (Compound-42),

[0107] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(2-Methoxyethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-43),

[0108] (R)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-44),

[0109] 2,2-difluoro-2-(2-methyl-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-45),

[0110] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-46),

[0111] (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-47),

[0112] (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-ol (Compound-48),

[0113] (R)-(1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-yl)methanol (Compound-49),

[0114] (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-methylpiperidin-4-ol (Compound-50),

[0115] (R)-2-(1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-yl)propan-2-ol (Compound-51),

[0116] (R)-2-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-2-azaspiro[3.3]heptan-6-ol (Compound-52),

[0117] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperazin-2-one (Compound-53),

[0118] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-(methoxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-54),

[0119] 1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-55),

[0120] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpiperazin-2-one (Compound-56),

[0121] (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(methoxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-57),

[0122] 1,1-difluoro-1-(2-fluoro-3-((R)-1-((6-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-58),

[0123] (R)-1,1-difluoro-1-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-59),

[0124] (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-60),

[0125] 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-61),

[0126] 1,1-difluoro-1-(2-fluoro-3-((R)-1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-62),

[0127] (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-63),

[0128] (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-64),

[0129] (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-ol (Compound-65),

[0130] (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperazin-2-one (Compound-66),

[0131] 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-67),

[0132] (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-68),

[0133] (R)-1-(4-((1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-69),

[0134] (R)-3,3-difluoro-3-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-1-ol (Compound-70),

[0135] (R)-1-(4-((1-(3-(1,1-difluoro-3-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-71),

[0136] 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-72),

[0137] 1,1-difluoro-1-(2-fluoro-3-((R)-1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-73),

[0138] 1-(1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound-74),

[0139] (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-75),

[0140] N-(1-(3-amino-5-fluorophenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-76),

[0141] N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-77),

[0142] N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-78),

[0143] 3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)benzonitrile (Compound-79),

[0144] N-(1-(3-amino-5-methylphenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-80),

[0145] N-(1-(indolin-4-yl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-81),

[0146] 3,3-difluoro-3-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound-82),

[0147] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (Compound-83),

[0148] (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (Compound-84),

[0149] (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (Compound-85),

[0150] 2,2-difluoro-2-(2-fluoro-3-((R)-1-((6-((R)-2-(hydroxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-86),

[0151] (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-87),

[0152] (R)-5-(4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-88),

[0153] 1-methyl-5-(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-89),

[0154] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-90),

[0155] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-91),

[0156] 1-(4-(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-92),

[0157] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-93),

[0158] (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-94),

[0159] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-95),

[0160] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-96),

[0161] (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-97),

[0162] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-98),

[0163] tert-butyl-(R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound-99),

[0164] (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)(cyclopropyl)methanone (Compound-100),

[0165] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methylpiperidin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-101),

[0166] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)ethan-1-one (Compound-102),

[0167] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(1-isopropylpiperidin-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-103),

[0168] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-104),

[0169] (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)piperidin-1-yl)ethan-1-one (Compound-105),

[0170] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(4,5-dihydrooxazol-2-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-106),

[0171] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((3-methyloxetan-3-yl)methoxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-107),

[0172] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-108),

[0173] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-109),

[0174] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine (Compound-110),

[0175] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine (Compound-111),

[0176] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-112),

[0177] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-113),

[0178] (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-114),

[0179] (R)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-115),

[0180] N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-116),

[0181] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-117),

[0182] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-118),

[0183] (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)tetrahydro-2H-pyran-4-ol (Compound-119),

[0184] 2,2,2-trifluoro-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-one (Compound-120),

[0185] (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-121),

[0186] (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one (Compound-122),

[0187] (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (Compound-123),

[0188] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)cyclohexan-1-one (Compound-124) and

[0189] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)cyclohexan-1-ol (Compound-125), is selected from the group consisting of:

[0190] According to a feature of the present invention, compounds of general formula (I), all symbols being as defined above, can be prepared by the methods illustrated in the schemes and examples set out hereinafter, however, the disclosures thereof should not be construed as limiting the scope of the invention to reach compounds of formula (I) as disclosed hereinabove.

[0191] Scheme A illustrates the synthesis of compounds of formula (A5).

[0192] [ka]

[0193] Metal-catalyzed cross-coupling of compounds of formula (A1) with alkoxyvinylstannanes, such as tributyl(1-ethoxyvinyl)tin, in the presence of a palladium catalyst such as Pd(PhP)Cl, Pd(dba), and the like, optionally using a base (triethylamine, N,N-diisopropylethylamine, and the like) in a hydrocarbon solvent such as toluene or an ethereal solvent such as 1,4-dioxane, provides an alkoxyvinyl intermediate, which is subsequently afforded under acidic conditions by using an aqueous mineral acid (such as hydrochloric acid) in an ethereal solvent such as THF, 1,4-dioxane, and the like, to provide compounds of formula (A2).

[0194] Subsequently, the compound of formula (A2) was reacted with the chirally pure corresponding tert-butanesulfinamide in the presence of a Lewis acid (titanium alkoxide, e.g., titanium tetraethoxide, titanium isopropoxide, etc.) in an ether solvent such as 1,4-dioxane, THF, etc. to give the compound of formula (A3).

[0195] Reaction of the compound of formula (A3) with a reducing agent such as a metal halide, e.g., sodium borohydride, L-selectride, etc., in a solvent such as THF, 1,4-dioxane, methanol, etc., optionally in the presence of water, provided the compound of formula (A4). After reduction, the major diastereomer in the compound of formula (A4) was separated or taken as is for the next step.

[0196] In compounds of formula (A4) under acidic conditions, the sulfinyl derivative is cleaved to produce amines of formula (A5) as free bases or salts. The acid used in the transformation may include mineral acids such as hydrochloric acid, or organic acids such as trifluoroacetic acid.

[0197] Scheme-B illustrates the synthesis of compounds of formula (I) and (IA).

[0198] [ka]

[0199] Compounds of formula (B1) were either commercially available or prepared by following the procedure reported in Russian Journal of Organic Chemistry, 2002, vol. 38, #12, pp. 1764-1768. Carboxylic acids (B1) were halogenated using N-halosuccinimide reagents (such as, but not limited to, NBS, NIS, and NCS) to give the corresponding dihalo compounds of formula (B2), which were then coupled with various amidines of formula (B3) to give compounds of formula (B4) (wherein R 1 is alkyl).

[0200] Compounds of formula (B4) could be directly converted to compounds of formula (B6) using various benzylamines (A5) and coupling reagents (such as, but not limited to, BOP) in polar solvents (such as, but not limited to, ACN, DMF, and DMSO), or compounds of formula (B4) could be further halogenated to give compounds of formula (B5) by using reagents (such as, but not limited to, chlorinating agents such as POCl, POBr, oxalyl chloride, or SOCl) and bases (such as, but not limited to, DIPEA, TEA, and N,N-dimethylaniline) in solvents (such as, but not limited to, chloroform, dichloroethane, and chlorobenzene).

[0201] Compounds of formula (B5) undergo nucleophilic substitution with various benzylamines (A5) to give compounds of formula (B6). Compounds of formula (B6) can be further acylated using Stille reaction conditions to give compounds of formula (B7), which can be further converted to compounds of formula (IA) via reductive amination with an appropriate substituted amine. Compounds of formula (B6) can be further functionalized to give compounds of formula (I), for example, by transition metal-catalyzed C-C coupling, C-N bond-forming reactions, or C-O bond-forming reactions (such as Suzuki or Buchwald reactions) with the corresponding substrates, i.e., substituted amines or substituted boronates.

[0202] Scheme C illustrates the synthesis of the compound of formula (B4).

[0203] [ka]

[0204] Compounds of formula (C1) are commercially available or can be obtained by following the procedures reported in WO2017139778 and Helvetica Chimica Acta, 1981, vol. 64, #2, p. 572-578.

[0205] Compounds of formula (C1) were treated with chloral hydrate and hydroxylamine to give compounds of formula (C2) at an appropriate temperature.

[0206] Compounds of formula (C2), when treated with inorganic acids such as HSO, can undergo cyclization at suitable temperatures to give isatin derivatives as compounds of formula (C3), which can be coupled with various amidines (B3) to give compounds of formula (B4), where R 1 is alkyl).

[0207] Scheme-D illustrates the synthesis of compounds of formula (IB).

[0208] [ka]

[0209] The compound of formula (D1) can be synthesized by acetylating the corresponding aniline compound of formula (B6) as described in Scheme B above.

[0210] Compounds of formula (D1) can be converted to the corresponding carbamate compounds of formula (D2) using transition metal catalyzed cross-coupling (e.g., via Buchwald-Hartwig coupling), which can then be deprotected to provide intermediate compounds of formula (D3).

[0211] Compounds of formula (D3) can be prepared by reacting the corresponding isocyanates (wherein R h =R i =H, CH3) to afford the urea compounds of formula (D4).

[0212] Compounds of formula (D4) can be prepared by reacting a base (KO) in a polar aprotic solvent such as DMF, DMSO, etc. t Further cyclization using methyl methyl ethers such as methyl ether, ...

[0213] Scheme-E illustrates the synthesis of compounds of formula (IC).

[0214] [ka]

[0215] Compounds of formula (B6) as prepared according to Scheme-B can be converted to the corresponding hydroxy derivatives of compounds of formula (E1) by, for example, transition metal catalyzed cross-coupling.

[0216] Compounds of formula (E1) could be further alkylated to compounds of formula (IC) by using bases such as K2CO3, Na2CO3.

[0217] Scheme-F illustrates the formation of a compound of formula (ID) starting from a compound of formula (F1), which is commercially available.

[0218] [ka]

[0219] Alkylation of a compound of formula (F1) with propargyl bromide gives the corresponding compound of formula (F2).

[0220] Nitration of a compound of formula (F2) with a nitrating reagent (such as, but not limited to, nitric acid, potassium nitrate, etc.) in an acid (such as, but not limited to, tin(IV) chloride, sulfuric acid, trifluoroacetic acid, acetic acid, etc.), an anhydride such as acetic anhydride, trifluoroacetic anhydride, etc., or mixture(s) thereof, gives a compound of formula (F3), which undergoes Claisen rearrangement and in situ cyclization at an appropriate temperature to give a compound of formula (F4). Such reactions can be carried out either neat or in the presence of a high boiling point solvent (such as, but not limited to, NMP, diphenyl ether, xylene, N,N-diethylaniline, etc., or mixtures thereof) in combination with a base (such as, but not limited to, cesium fluoride) and a high boiling point solvent (such as, but not limited to, N,N-diethylaniline, NMP, diphenyl ether, xylene, etc., or mixtures thereof).

[0221] The compound of formula (F4) is converted to the corresponding aniline derivative of the compound of formula (F5) through selective reduction of the nitro group using a reducing agent, including, but not limited to, hydrogenation with palladium on carbon, reduction with metals such as iron, tin, or tin chloride, etc. Such reduction can be carried out under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, etc., or mixtures thereof, in one or more solvents, for example, ethers such as THF, 1,4-dioxane, etc., alcohols such as methanol, ethanol, etc.

[0222] Compounds of formula (F5) can be further cyclized to give compounds of formula (F6) as tricyclic building blocks. Such reactions can be carried out in polar solvents such as acetonitrile using acids (such as, but not limited to, methanesulfonic acid or hydrochloric acid) at appropriate temperatures.

[0223] Compounds of formula (F6) are treated with triisopropylbenzenesulfonyl chloride in a solvent (such as an ether such as THF or 1,4-dioxane) at a suitable temperature to give the corresponding sulfonate derivatives of compounds of formula (F7).

[0224] Compounds of formula (F7) undergo a nucleophilic substitution reaction with an appropriate chiral benzylamine using an organic base reagent (such as, but not limited to, DIPEA or TEA) in a polar aprotic solvent such as dioxane or THF at a suitable temperature to provide compounds of formula (F8).

[0225] Compounds of formula (F8) are demethylated to the corresponding hydroxy derivatives of compounds of formula (F9) by using reagents such as Lewis acids (such as, but not limited to, BBr3, AlCl3) and basic reagents (such as, but not limited to, NaSEt) in polar solvents (such as, but not limited to, DMF, CA, etc., or mixtures thereof) and halogenated solvents (such as, but not limited to, chloroform, dichloromethane, etc., or mixtures thereof).

[0226] Compounds of formula (F9) can be further alkylated to give final compounds of formula (ID) using inorganic bases (such as, but not limited to, K2CO3, Na2CO3 and Cs2CO3) in polar aprotic solvents such as DMF, DMSO, etc. at appropriate temperatures.

[0227] Scheme-G illustrates the formation of a compound of formula (IE) starting from a compound of formula (G1) (Reference: CN105884699).

[0228] [ka]

[0229] Alkylation of a compound of formula (G1) with 3-chloro-2-methylprop-1-ene gives a compound of formula (G2). Such a reaction can be carried out using inorganic bases (such as, but not limited to, K2CO3, Cs3CO3, Na2CO3), organic bases (such as, but not limited to, DIPEA, TEA, diisopropylamine), and polar aprotic solvents (such as, but not limited to, acetone, acetonitrile, and DMF, or mixture(s) thereof).

[0230] Compounds of formula (G2) undergo Claisen rearrangement at an appropriate temperature to give hydroxyl derivatives of compounds of formula (G3). Such reactions can be carried out either neat or in the presence of high boiling point solvents such as, but not limited to, NMP, diphenyl ether, xylene, N,N-diethylaniline, etc., or mixtures thereof.

[0231] Compounds of formula (G3) are cyclized under acidic conditions (such as, but not limited to, formic acid, acetic acid, hydrochloric acid, and mixture(s) thereof) in solvents (such as, but not limited to, THF, diethyl ether, dioxane, and ACN) at a suitable temperature to give compounds of formula (G4).

[0232] The compound of formula (G4) can be further converted to the corresponding aniline derivative of the compound of formula (G5) through selective reduction of the nitro group using a reducing agent, including, but not limited to, hydrogenation with palladium on carbon, reduction with metals such as iron, tin, or tin chloride, etc. Such reduction reactions can be carried out in one or more solvents, for example, ethers such as THF, 1,4-dioxane, etc., alcohols such as methanol, ethanol, etc., under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, etc., or mixture(s) thereof.

[0233] Compounds of formula (G5) can be further cyclized to give compounds of formula (G6) as tricyclic building blocks. Such reactions can be carried out in polar solvents such as acetonitrile using acids (such as, but not limited to, methanesulfonic acid, hydrochloric acid, etc.) at appropriate temperatures.

[0234] Compounds of formula (G6) could be halogenated using a reagent (such as, but not limited to, POCl or POBr) in combination with an organic base (such as, but not limited to, DIPEA, TEA) in a halogenated solvent (such as, but not limited to, chlorobenzene, chloroform, DCM) at an appropriate temperature to give compounds of formula (G7).

[0235] Compounds of formula (G7) undergo nucleophilic substitution reactions with various chiral benzylamines (A5) using organic base reagents (such as, but not limited to, DIPEA, TEA, etc.) in polar aprotic solvents such as dioxane, THF, etc. at appropriate temperatures to give compounds of formula (G8).

[0236] Compounds of formula (G8) are demethylated using reagents (such as, but not limited to, BBr3, NaSEt) in polar solvents (such as DMF, ACN), halogenated solvents (such as chloroform, dichloromethane) to give the corresponding hydroxy derivatives of compounds of formula (G9).

[0237] Compounds of formula (G9) can be further alkylated to form ether compounds of general formula (IE) by using an organic base (such as, but not limited to, DIPEA, TEA, etc.) at an appropriate temperature, or the alkylation can be carried out by using a base (such as K2CO3, Na2CO3, Cs2CO3, etc.) in a polar aprotic solvent such as DMF, DMSO, etc. at an appropriate temperature. Compounds of formula (G9) could also be converted to ether compounds of general formula (IE) by Mitsunobu reaction.

[0238] However, compounds of formula (G9) can also be converted to the corresponding triflates with trifluoromethanesulfonic anhydride in halogenated solvents (such as, but not limited to, DCM, CHCl), and the triflate intermediate can be further reacted with a suitable aliphatic amine or boronic acid to give compounds of general formula (IE). This reaction can be carried out in the presence of a suitable catalyst, such as, for example, Pd(PPh)Cl, Pdddba, Pd(PPh), Pd(OAc) or mixture(s) thereof, a suitable ligand, such as, but not limited to, Xantphos, BINAP, Ru-Phos or mixture(s) thereof, a suitable base, preferably an inorganic base (e.g., KCO, NaCO, CsCO, NaO). t The reaction can be mediated in the presence of solvents such as, but not limited to, ammonium nitrate, potassium phosphate, potassium phosphate, or mixture(s) thereof. Such reactions can be carried out in solvents such as, for example, ethers (THF, dioxane, etc.), hydrocarbons such as toluene, amides (DMF, DMA, etc.), or mixture(s) thereof.

[0239] Scheme-H illustrates the formation of a compound of formula (IF) starting from a compound of formula (F4).

[0240] [ka]

[0241] The compound of formula (F4) can be reduced to the corresponding aniline derivative (H1) through selective reduction of the nitro group and aromatic double bond using a reducing agent, including, but not limited to, hydrogenation with palladium on carbon, reduction with metals such as iron, tin, or tin chloride, etc. Such reduction reactions can be carried out under either neutral or acidic conditions with ammonium chloride, acetic acid, hydrochloric acid, etc., or mixture(s) thereof, in one or more solvents (e.g., but not limited to, ethers such as THF, 1,4-dioxane, etc., alcohols such as methanol, ethanol, etc.).

[0242] Compounds of formula (H1) can be further cyclized to give compounds of formula (H2) as tricyclic building blocks. Such reactions can be carried out in polar solvents such as acetonitrile using acids (such as, but not limited to, methanesulfonic acid, hydrochloric acid, etc.) at appropriate temperatures.

[0243] Compounds of formula (H2) can be halogenated to give compounds of formula (H3) using a reagent (such as, but not limited to, POCl3 or POBr3) in combination with an organic base (such as, but not limited to, DIPEA, TEA) in a halogenated solvent such as chlorobenzene, chloroform, DCM, etc. at an appropriate temperature.

[0244] Compounds of formula (H3) undergo nucleophilic substitution reactions with various chiral benzylamines of formula (A5) using organic base reagents (such as, but not limited to, DIPEA, TEA, etc.) in polar aprotic solvents such as dioxane, THF, etc. at appropriate temperatures to give compounds of formula (H4).

[0245] Compounds of formula (H4) are demethylated to the corresponding hydroxy derivatives of compounds of formula (H5) by using Lewis acid reagents (such as, but not limited to, BBr3, AlCl3) and basic reagents (such as, but not limited to, NaSEt) in polar solvents (such as, but not limited to, DMF, CA), halogenated solvents (such as, but not limited to, chloroform, dichloromethane).

[0246] Compounds of formula (H5) can be further alkylated to form ether compounds of general formula (IF) using an organic base (such as, but not limited to, DIPEA, TEA, etc.) at an appropriate temperature, which can be carried out using a base (such as K2CO3, Na2CO3, Cs2CO3, etc.) in a polar aprotic solvent such as DMF, DMSO, etc. at an appropriate temperature. Compounds of formula (H5) can also be converted to ether compounds of general formula (IF) by Mitsunobu reaction.

[0247] However, compounds of formula (H5) can also be converted to the corresponding triflates with trifluoromethanesulfonic anhydride in halogenated solvents (such as, but not limited to, DCM, CHCl), and the triflate intermediate can be further reacted with an appropriate aliphatic amine or boronic acid to give compounds of general formula (IF). This reaction can be carried out in the presence of a suitable catalyst, such as, for example, Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof, a suitable ligand, such as, but not limited to, Xantphos, BINAP, Ru-Phos, or mixture(s) thereof, in the presence of a suitable base, preferably an inorganic base (e.g., K2CO3, Na2CO3, Cs2CO3, NaO t Such reactions can be mediated in the presence of solvents such as, but not limited to, ethers (THF, dioxane, etc.), hydrocarbons such as toluene, amides (DMF, DMA, etc.), or mixture(s) thereof.

[0248] Scheme-I illustrates the synthesis of compounds of formula (IG) and (IH).

[0249] [ka]

[0250] A compound of formula (B5) undergoes a nucleophilic substitution reaction with a compound of formula (A5) in the presence of an organic base (such as, but not limited to, TEA, pyridine, DIPEA, or DMAP) to give a compound of formula (I1). Such reactions can be carried out in polar protic solvents (such as MeOH, EtOH, or IPA), amides (such as DMF or DMA), ethers (such as THF or 1,4-dioxane), halogenated solvents (such as CHCl3, DCE, or chlorobenzene), or polar aprotic solvents (such as DMSO or CAN).

[0251] The compound of formula (I1) undergoes a controlled oxidation process using a reagent (such as, but not limited to, a combination of oxalyl chloride and DMSO) in an organic solvent (such as, but not limited to, DCM, CHCl3, DCE) in the presence of an organic base (such as, but not limited to, triethylamine, N,N-diisopropylethylamine) to give the aldehyde compound of formula (I2).

[0252] Subsequently, the compound of formula (I2) was subjected to an olefination reaction using a reagent (such as, but not limited to, alkyltriphenylphosphonium halide) in the presence of a base (such as, but not limited to, KHMDS, LDA) in the presence of an ether solvent (such as, but not limited to, THF, 1,4-dioxane) to give a compound of formula (I3).

[0253] Compounds of formula (I3) undergo hydroboration using reagents (such as, but not limited to, borane-THF complex, borane-DMS complex, or peracids such as hydrogen peroxide) in ethereal solvents (such as, but not limited to, THF, 1,4-dioxane) to give two regioisomers of compounds of formula (I4) and a racemic mixture (I5).

[0254] The compound of formula (IG) and the racemic mixture (IH) can be prepared by Buchwald coupling of the compound of formula (I4) and the racemic mixture (I5), respectively, with an appropriate aliphatic amine. This reaction can be mediated by a suitable catalyst (such as, but not limited to, Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof), a suitable ligand (such as, but not limited to, 2-di-t-butylphosphino-2'-(N,N-dimethylamino)biphenyl, Xantphos, BINAP, Ru-Phos, or mixture(s) thereof) in the presence of a suitable base, preferably an inorganic base (such as, but not limited to, an alkali metal carbonate, e.g., Na2CO3, K2CO3, Cs2CO3, sodium tert-butoxide, potassium phosphate, or mixture(s) thereof). Such reactions could be carried out in solvents such as ethers (THF, dioxane, etc.), hydrocarbons such as toluene, amides (DMF, DMA, etc.) or mixture(s) thereof. Final separation by chiral chromatography would provide the pure diastereomers of compounds of formula (IG).

[0255] Scheme J illustrates the formation of a compound of formula (II) starting from a compound of formula (L1) (Reference: CN105884699).

[0256] [ka]

[0257] Compounds of formula (J1) are esterified using a chlorinating reagent (such as, but not limited to, thionyl chloride, oxalyl chloride, etc.) in methanol to give compounds of formula (J2).

[0258] Nitration of a compound of formula (J2) with a nitrating reagent (such as, but not limited to, nitric acid, potassium nitrate, etc.) in an acid (such as, but not limited to, tin(IV) chloride, sulfuric acid, trifluoroacetic acid, acetic acid, etc.), an anhydride such as acetic anhydride, trifluoroacetic anhydride, etc., or mixture(s) thereof, provides a compound of formula (J3).

[0259] Compounds of formula (J3) are selectively demethylated to the corresponding hydroxy derivatives of compounds of formula (J4) by using reagents such as, but not limited to, AlCl, BBr, NaSEt, etc. in polar solvents such as DMF, CHCl, halogenated solvents such as chloroform, dichloromethane, etc.

[0260] Ether formation can be carried out with compounds of formula (J4) using a protected amino alcohol such as tert-butyl(2-hydroxyethyl)carbamate to give compounds of formula (J5). Such reactions can be carried out using reagents (such as, but not limited to, DIAD, DEAD, triphenylphosphine, etc.) and solvents (such as, but not limited to, ethers such as THF, dioxane, etc., hydrocarbons such as toluene, or mixture(s) thereof).

[0261] The compound of formula (J5) is cyclized to give the compound of formula (J6). This reaction can be carried out in the presence of a suitable base, preferably an inorganic base (e.g., K2CO3, Na2CO3, Cs2CO3, NaO tThe reaction can be mediated by a suitable catalyst (such as, but not limited to, Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof), a suitable ligand (such as, but not limited to, Xantphos, BINAP, Ru-Phos, or mixture(s) thereof) in the presence of a suitable catalyst (such as, but not limited to, Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof). Such reactions can be carried out in a solvent such as, for example, an ether (such as THF, dioxane), a hydrocarbon such as toluene, an amide (such as DMF, DMA), or mixture(s) thereof.

[0262] Deprotection of a compound of formula (J6) under acidic conditions produces a compound of formula (J7). The acid used in the transformation may include a mineral acid, such as hydrochloric acid, or an organic acid, such as trifluoroacetic acid.

[0263] The compound of formula (J7) is alkylated with an alkyl halide or reductively aminated with an aldehyde to give a compound of formula (J8). Such reactions could be carried out using inorganic bases (such as, but not limited to, K2CO3, Cs2CO3, and Na2CO3) and polar aprotic solvents (such as, but not limited to, acetone, acetonitrile, and DMF, or mixture(s) thereof) in the case of alkylation, and reducing agents (such as NaCNBH4, Na(CH3COO)3BH, etc.) in solvents such as polar protic solvents (such as, but not limited to, methanol, ethanol, acetic acid, and DME).

[0264] The compound of formula (J8) can be further converted to the corresponding aniline derivative of the compound of formula (J9) through selective reduction of the nitro group using a reducing agent, including, but not limited to, hydrogenation with palladium on carbon, reduction with metals such as iron, tin, or tin chloride, etc. Such reduction reactions can be carried out in one or more solvents, for example, ethers such as THF, 1,4-dioxane, etc., alcohols such as methanol, ethanol, etc., under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, etc., or mixture(s) thereof.

[0265] Compounds of formula (J9) are coupled with various amidines of formula (B3) to give compounds of formula (J10) as tricyclic building blocks.

[0266] Compounds of formula (J10) could be halogenated to give compounds of formula (J11) using a combination of reagents (such as, but not limited to, POCl3 and POBr3) or organic bases (such as, but not limited to, DIPEA and TEA) in halogenated solvents (such as, but not limited to, chlorobenzene, chloroform and DCM) at appropriate temperatures.

[0267] Compounds of formula (J11) undergo nucleophilic substitution reactions with various chiral benzylamines of formula (A5) using organic base reagents (such as, but not limited to, DIPEA and TEA) in polar aprotic solvents such as dioxane and THF at appropriate temperatures to give compounds of formula (II).

[0268] Scheme-K illustrates the formation of a compound of formula (IJ) starting from a compound of formula (M1) (Reference: CN105884699).

[0269] [ka]

[0270] Alkylation of a compound of formula (K1) with ethyl 2-bromo-2-methylpropanoate gives a compound of formula (K2). Such a reaction can be carried out using an inorganic base (such as, but not limited to, K2CO3, Cs3CO3, and Na2CO3), an organic base (such as, but not limited to, DIPEA, TEA, diisopropylamine), and a polar aprotic solvent (such as, but not limited to, acetone, acetonitrile, and DMF, or a mixture(s) thereof).

[0271] The compound of formula (K2) can be further converted to the corresponding cyclized derivative of the compound of formula (K3) through selective reduction of the nitro group using a reducing agent, including, but not limited to, hydrogenation with palladium on carbon, reduction with metals such as iron, tin, or tin chloride, etc. Such reduction reactions can be carried out in one or more solvents, for example, ethers such as THF, 1,4-dioxane, etc., alcohols such as methanol, ethanol, etc., under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, etc., or mixture(s) thereof.

[0272] Compounds of formula (K3) are halogenated using N-halosuccinimide reagents (such as, but not limited to, NBS, NIS, and NCS) to give the corresponding dihalo compounds of formula (K4), which are then alkylated using alkyl halides to give compounds of formula (K5). Such reactions could be carried out using inorganic bases (such as, but not limited to, K2CO3, Cs2CO3, and Na2CO3) and polar aprotic solvents (such as, but not limited to, acetone, acetonitrile, and DMF, or mixture(s) thereof).

[0273] Compounds of formula (K5) can be coupled with various amidines of formula (B3) to give compounds of formula (K6) (wherein R 1is alkyl), which can be halogenated to give compounds of formula (K7) using reagents (such as, but not limited to, POCl3 and POBr3) in combination with organic bases (such as, but not limited to, DIPEA and TEA) in halogenated solvents (such as, but not limited to, chlorobenzene, chloroform and DCM) at an appropriate temperature.

[0274] Compounds of formula (K7) undergo nucleophilic substitution reactions with various chiral benzylamines (A5) using organic base reagents (such as, but not limited to, DIPEA and TEA) in polar aprotic solvents such as dioxane and THF at appropriate temperatures to give compounds of formula (K8).

[0275] Compounds of formula (K8) could be further functionalized, for example, by transition metal catalyzed C-C or C-N coupling reactions (such as Suzuki or Buchwald reactions) with the corresponding substrates, i.e., substituted amines or substituted boronates, to give compounds of formula (IJ).

[0276] Any intermediates used in the preparation of compounds of the present invention were prepared by approaches reported in the literature or by methods known to those skilled in the art of organic synthesis. Detailed experimental procedures for the synthesis of intermediates are provided below.

[0277] The intermediates and compounds of the present invention can be obtained in pure form by any suitable method, for example by evaporating the solvent in vacuo and / or recrystallizing the resulting residue from a suitable solvent (such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, or combinations thereof), or by one of the purification methods such as column chromatography (e.g., flash chromatography) on a suitable carrier material (alumina or silica gel) using an eluent (dichloromethane, ethyl acetate, hexane, methanol, acetone, and / or combinations thereof). Preparative LC-MS methods can also be used to purify the molecules described herein.

[0278] Unless otherwise noted, workup includes partitioning the reaction mixture into organic and aqueous phases as indicated in parentheses, separating the layers, drying the organic layer over sodium sulfate, filtering, and evaporating the solvent. Purification generally includes purification by silica gel chromatographic techniques using mobile phases of appropriate polarity and purification using selective crystallization, unless otherwise noted.

[0279] Salts of compounds of formula (I) can be obtained by dissolving the compound in a suitable solvent, such as a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol or isopropanol, and then treating the solution with the desired acid or base, as described in Berge SM et al., "Pharmaceutical Salts, a review article in Journal of Pharmaceutical Sciences, volume 66, pages 1-19 (1977)" and P. Heinrich Stahland and Camille G. Wermuth, "Handbook of Pharmaceutical Salts - Properties, Selection, and Use" (Wiley-VCH (2002)). Lists of suitable salts can also be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, the salt can be an alkali metal (eg, sodium or potassium), alkaline earth metal (eg, calcium), or ammonium salt.

[0280] The compounds of the present invention or compositions thereof can potentially be administered as pharmaceutically acceptable acid addition salts, base-neutralized salts, or base addition salts formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with inorganic bases such as sodium hydroxide or potassium hydroxide. Conversion to a salt is accomplished by treating the base compound with at least a stoichiometric amount of the appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, etc., and the acid is added to a similar solvent. The mixture is maintained at a suitable temperature (e.g., 0°C to 50°C). The resulting salt precipitates spontaneously or can be removed from solution with a less polar solvent.

[0281] Stereoisomers of the compounds of formula (I) of this invention can be prepared by stereospecific synthesis or by resolution of the racemic mixture by using optically active amines, acids or complex-forming agents and separation of the diastereomeric salts / complexes by fractional crystallization or column chromatography.

[0282] Prodrugs of the compounds of the present invention can be prepared in situ during the isolation and purification of the compound, or by separately reacting the purified compound with a suitable derivatizing agent. For example, a hydroxy group can be converted to an ester group by treatment with a carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol prodrug moieties include substituted or unsubstituted branched or unbranched lower alkyl ester moieties, such as ethyl esters, lower alkenyl esters, di-lower alkylamino lower alkyl esters, such as dimethylaminoethyl esters, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters, such as phenyl esters, aryl-lower alkyl esters, such as benzyl esters, aryl esters and aryl-lower alkyl esters optionally substituted with, for example, methyl, halo, or methoxy substituents, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides.

[0283] The compounds of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomers are contemplated as aspects of the present invention, and such tautomers may be in equilibrium or biased towards one of the variants.

[0284] The present invention also includes isotopically labeled compounds of the present invention that are identical to the compounds described herein except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the mass or mass number of the atom normally abundant in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine ( 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18F, 36 Cl and 123 I, etc.

[0285] Accordingly, the present invention further provides a pharmaceutical composition comprising a compound of general formula (I), its tautomer, its stereoisomer, its crystalline polymorph, its solvate, or its pharmaceutically acceptable salt as defined above, in combination with a pharmaceutically acceptable carrier, diluent, excipient, or the like.

[0286] The pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compounds of the present invention and has no adverse side effects or toxicity under the conditions of use. Examples of such pharmaceutically acceptable carriers or excipients include saline (e.g., 0.9% saline), Cremophor EL® (a derivative of castor oil and ethylene oxide, available from Sigma Chemical Co., St. Louis, MO) (e.g., Cremophor EL 5% / ethanol 5% / saline 90%, Cremophor EL 10% / saline 90%, or Cremophor EL 50% / ethanol 50%), propylene glycol (e.g., propylene glycol 40% / ethanol 10% / water 50%), polyethylene glycol (e.g., PEG 400 40% / saline 60%), and alcohol (e.g., ethanol 40% / water 60%). A preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will depend in part on the particular compound chosen, as well as on the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention.

[0287] Formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal, and vaginal administration of the compounds of formula (I), their tautomers, stereoisomers, polymorphs, solvates, and pharmaceutically acceptable salts can be developed.

[0288] The pharmaceutical compositions can be administered parenterally, for example, intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. Thus, the present invention provides compositions for parenteral administration comprising a solution of a compound of the present invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.

[0289] Generally, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those skilled in the art. See "Pharmaceutics and Pharmacy Practice," J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982) and "ASHP ​​Handbook on Injectable Drugs," Toissel, 4th ed., pages 622-630 (1986). Such compositions include solutions containing antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the recipient, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The compounds of the present invention can be administered in a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or mixture of liquids comprising water, saline, aqueous dextrose and related sugar solutions, alcohols (such as ethanol, isopropanol (e.g., for topical use) or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), dimethyl sulfoxide, glycerol ketals (such as 2,2-dimethyl-1,3-dioxolane-4-methanol), ethers (such as poly(ethylene glycol) 400), oils, fatty acids, fatty acid esters, or glycerides or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants (such as soaps or detergents), suspending agents (such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose), or emulsifying agents, and other pharmaceutical adjuvants.

[0290] The oils useful in parenteral formulations include petroleum oil, animal oil, vegetable oil and synthetic oil.The specific examples of oils useful in such formulations include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil.The fatty acids suitable for use in parenteral formulations include oleic acid, stearic acid and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0291] Suitable soaps for use in parenteral formulations include fatty acid alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents (such as dimethyldialkylammonium halides and alkylpyridinium halides), (b) anionic detergents (such as alkyl sulfonates, aryl sulfonates, olefin sulfonates, alkyl sulfates, olefin sulfates, ether sulfates, monoglyceride sulfates, sulfosuccinates, and the like), (c) nonionic detergents (such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers), (d) amphoteric detergents (such as alkyl-β-aminopropionates and 2-alkyl-imidazoline quaternary ammonium salts), and (e) mixtures thereof.

[0292] Parenteral formulations of the present invention will typically contain about 0.5% by weight or less and about 25% by weight or more of the compound of the present invention in solution. Preservatives and buffers can be used. To minimize or eliminate injection site irritation, the compositions can include one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations typically ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters (e.g., sorbitan monooleate) and high molecular weight adducts of ethylene oxide with hydrophobic bases formed by the condensation of propylene oxide with propylene glycol. Parenteral formulations of the present invention can be provided in unit-dose or multi-dose sealed containers (e.g., ampoules and vials) and can be stored in a lyophilized state requiring only the addition of a sterile liquid excipient, e.g., water, immediately prior to use for injection. Extemporaneous injection solutions and extemporaneous suspensions can be prepared from sterile powders, granules, and tablets.

[0293] Topical formulations are well known to those skilled in the art, including formulations useful for transdermal drug delivery, and in the context of the present invention are suitable for application to the skin.

[0294] Formulations suitable for oral administration can consist of (a) liquid solutions in which an effective amount of a compound of the present invention is dissolved in a diluent such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of a compound of the present invention as a solid or granule; (c) powders; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Liquid formulations can contain diluents (water, alcohols, e.g., ethanol, benzyl alcohol, and polyethylene alcohols) with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. Capsule forms can be, for example, conventional hard-shell gelatin capsules or soft-shell gelatin capsules containing surfactants, lubricants, and inert fillers (e.g., lactose, sucrose, calcium phosphate, and corn starch). Tablet forms can contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, coloring agents, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can contain the compound ingredients in a flavoring agent, usually sucrose and acacia or tragacanth. Pastilles containing the compound of the present invention in an inert base (such as gelatin and glycerin, or sucrose and acacia), emulsions, gels, and the like containing the compound of the present invention and the above-mentioned excipients are known in the art.

[0295] The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. The compounds of the present invention are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compounds of the present invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight. The surfactant must, of course, be nontoxic and preferably soluble in the propellant. Representative of such surfactants are esters or partial esters of fatty acids containing 6 to 22 carbon atoms (e.g., caproic acid, octanoic acid, lauric acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, olestearic acid, and oleic acid with aliphatic polyhydric alcohols or their cyclic anhydrides). Mixed esters (e.g., mixed glycerides or natural glycerides) can also be used. The surfactant can comprise about 0.1% to about 20% by weight, preferably about 0.25% to about 5% of the compositions of the present invention. The remainder of the compositions of the present invention is typically a propellant. If desired, a carrier such as lecithin can also be included for intranasal delivery.These aerosol formulations can be placed in an acceptable pressurized propellant (such as dichlorodifluoromethane, propane, nitrogen, etc.).Aerosol formulations can also be prepared as pharmaceuticals for non-pressurized preparations, such as in a nebulizer or atomizer.Such aerosol formulations can be used to spray onto mucous membranes.

[0296] In addition, the compounds of the present invention can be made into suppositories by mixing with a variety of bases (such as emulsifying bases or water-soluble bases). Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the compound of the present invention, such carriers as are known in the art to be appropriate.

[0297] The concentration of the compound in the pharmaceutical formulation of the present invention can vary, for example, from about 1% to less than about 10% by weight, to about 20% to about 50% by weight or more, and can be selected primarily by fluid volume and viscosity according to the particular method of administration selected.

[0298] For example, a typical intravenous pharmaceutical composition can be made up to contain 250 ml of sterile Ringer's solution and 100 mg of at least one compound of the invention. Actual methods for preparing compounds of the invention that can be administered parenterally will be known or apparent to those skilled in the art and can be found, for example, in Remington's Pharmaceutical Sciences (17 th ed., Mack Publishing Company, Easton, PA, 1985).

[0299] In addition to the pharmaceutical compositions described above, those skilled in the art will recognize that the compounds of the present invention can be formulated as inclusion complexes (e.g., cyclodextrin inclusion complexes) or liposomes. Liposomes can serve to target the compounds of the present invention to specific tissues (e.g., lymphatic tissue or cancerous liver cells). Liposomes can also be used to extend the half-life of the compounds of the present invention. Many methods are available for preparing liposomes, as described, for example, in Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980), and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0300] The compounds of the present invention can be administered in a dosage sufficient to treat a disease, condition, or disorder. Such dosages are known in the art (see, for example, Physicians' Desk Reference (2004)). The compounds of the present invention can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).

[0301] Suitable doses and administration regimens can be determined by conventional dose-ranging techniques known to those skilled in the art. Generally, treatment is initiated with small doses that are less than the optimal dose of the compounds of the present invention. Thereafter, the dose is gradually increased until the optimum effect under the circumstances is reached. The methods of the present invention can include administering at least one compound of the present invention at a dose of about 0.1 μg to about 50 mg per kg of body weight of the individual. For a 70 kg patient, it is more common to use a dose of about 10 μg to about 200 mg of the compounds of the present invention, depending on the patient's physiological response.

[0302] By way of example, and not intended to limit the invention, a dose of the pharmaceutically active agent(s) described herein for a method of treating a disease or condition such as those described above can be from about 0.001 to about 1 mg per kg of subject body weight per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg per kg of body weight per day. Doses of the pharmaceutically active agent(s) described herein for the methods described can be from about 1 to about 1000 mg per kg of body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg per kg of body weight per day.

[0303] The terms "treat," "prevent," and "inhibit," and words derived from these terms, as used herein, do not necessarily indicate 100% or complete treatment, amelioration, or inhibition. Rather, there are various degrees of treatment, amelioration, and inhibition that one of skill in the art would recognize as potentially beneficial or therapeutic. In this regard, the disclosed methods can treat, ameliorate, or inhibit a disorder in a mammal at any amount or level. For example, a disorder (including its symptoms or condition) may be alleviated by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. Furthermore, the treatment, amelioration, or inhibition achieved by the methods of the invention can include treating, ameliorating, or inhibiting one or more conditions or symptoms of the disorder, e.g., cancer. For purposes of the present invention, "treatment," "amelioration," or "inhibition" can also include delaying the onset of the disorder or its symptoms or condition.

[0304] In accordance with the present invention, the term subject includes "animal," and thus includes mammals such as, but not limited to, rodents, such as mice, and lagomorphs, such as rabbits. In one aspect, the mammal is from the order Carnivora, which includes Felidae (cats) and Canidae (dogs). In another aspect, the mammal is from the order Artiodactyla, which includes Bovidae (cattle) and Suidae (pigs), or Perissodactyla, which includes Equidae (horses). In a further aspect, the mammal is from the order Primates, Ceboids, or Simoids (monkeys), or the suborder Anthropoidea (humans and apes). In yet another aspect, the mammal is a human.

[0305] The compounds of the present invention can be used to treat various cancers, as described below, in which the signal transduction pathway involving the SOS1 protein is enhanced or abnormally activated.

[0306] The compounds of the present invention can be used to treat various cancers, as described below, in which the signal transduction pathway involving the RAS protein and / or SOS1 protein is increased or abnormally activated.

[0307] The compounds described below, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, or their solvates, in combination with appropriate pharmaceutical agents, and pharmaceutical compositions thereof may be suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer.

[0308] Cancers, tumors and other proliferative disorders that can be treated with the compounds of the present invention include, but are not limited to:

[0309] 1. Head and neck cancers, such as cancer of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including the lips, gums, alveolar process, retromolar trigone, floor of the mouth, tongue, hard palate, and oral mucosa), oropharynx (including the base of the tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, and pharyngeal wall), middle ear, and larynx (supraglottis, glottis, subglottis, vocal cords, hypopharynx, and salivary glands (including minor salivary glands)).

[0310] 2. Lung cancer, such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma), class 3 BRAF-mutated lung cancer

[0311] 3. Mediastinal neoplasms, such as neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, and paraganglioma), germ cell tumors (including seminoma, teratoma, and non-seminoma), thymic tumors (including thymic tumor, thymolipoma, thymic carcinoma, and thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, and lymphangioleiomyoma)

[0312] 4. Cancers of the gastrointestinal (GI) tract, such as cancer of the esophagus, cancer of the stomach (gastric cancer), esophagogastric adenocarcinoma, cancers of the pancreas, liver and biliary system (hepatocellular carcinoma (HCC), such as pediatric HCC, fibrolamellar HCC, composite HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC, hepatoblastoma, cholangiocarcinoma)

[0313] 5. cholangiocarcinoma, hepatic cystadenocarcinoma, angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), cancer of the gallbladder, cancer of the extrahepatic bile duct, cancer of the small intestine (including the duodenum, jejunum, and ileum), cancer of the large intestine (including the cecum, colon, rectum, and anus, colorectal cancer, and gastrointestinal stromal tumor (GIST)), cancer of the genitourinary system (cancer of the kidney, e.g., renal pelvis cancer, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland tumor, Grabitz tumor, cancer of the ureter, cancer of the bladder, e.g., urachal carcinoma, urothelial carcinoma, cancer of the urethra, e.g., distal bulbomembranous carcinoma, cancer of the prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, and hormone-resistant), cancer of the penis)

[0314] 6. Testicular cancer, e.g., seminoma, non-seminoma

[0315] 7. Gynecological cancers, such as cancer of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterus (including endometrium and fundus)

[0316] 8. Breast cancer, such as breast cancer (invasive ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, tubular adenocarcinoma, adenocystic carcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), Her2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast

[0317] 9. Cancers of the endocrine system, such as cancer of the endocrine glands, cancer of the thyroid gland (thyroid cancer / tumor, papillary carcinoma, follicular carcinoma, undifferentiated carcinoma, medullary carcinoma), cancer of the parathyroid gland (parathyroid carcinoma / tumor), cancer of the adrenal cortex (adrenocortical cell carcinoma / tumor), cancer of the pituitary gland (including prolactinoma and craniopharyngioma), cancer of the thymus, cancer of the adrenal gland, cancer of the pineal gland, cancer of the carotid body, islet cell tumors, paraganglioma, pancreatic endocrine tumors (PET, non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors

[0318] 10. Sarcomas of soft tissues, for example, fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanotic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor

[0319] 11. Bone sarcomas, for example, myeloma, reticulum cell sarcoma, chondrosarcoma (including central chondrosarcoma, peripheral chondrosarcoma, clear cell chondrosarcoma, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal osteosarcoma, periosteal osteosarcoma, high-grade superficial osteosarcoma, small cell osteosarcoma, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma

[0320] 12. Mesothelioma, e.g., pleural mesothelioma, peritoneal mesothelioma

[0321] 13. Skin cancers, such as basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentigo melanoma, nodular melanoma, and intraocular melanoma), actinic keratosis, eyelid cancer, and class 3 BRAF-mutated melanoma

[0322] 14. Neoplasms of the central nervous system and brain, for example, astrocytoma (cerebral astrocytoma, cerebellar astrocytoma, diffuse astrocytoma, fibrillary astrocytoma, anaplastic astrocytoma, pilocytic astrocytoma, protoplasmic astrocytoma, hypertrophic astrocytoma), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic neurinoma), spinal axis tumor

[0323] 15. Lymphomas and leukemias, such as B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), and Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult human T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma B-SLL, cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, and lymphopenic HD (LDHD)), large granular lymphocyte leukemia (LGL), and chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML)

[0324] 16. Carcinoma of unknown primary site (CUP)

[0325] 17. Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive carcinoma, verrucous carcinoma, pseudosarcoma, undifferentiated carcinoma, transitional cell carcinoma, lymphoepithelial carcinoma), adenocarcinoma (AC) (well differentiated adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, pleomorphic giant cell adenocarcinoma, ductal adenocarcinoma, small cell, mark ring cell, spindle cell adenocarcinoma, clear cell adenocarcinoma, oat cell adenocarcinoma, glenoid adenocarcinoma, adenosquamous cell carcinoma, mucoepidermoid adenocarcinoma, adenoid cystadenocarcinoma), mucinous cystadenocarcinoma, acinic cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid), oncocytic cell carcinoma

[0326] 18. Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinoma

[0327] All of the above cancers that are characterized by a particular location or origin within the body are intended to include both the primary tumor and metastatic tumors originating from that location or origin.

[0328] All of the above cancers can be further differentiated by histopathological classification.

[0329] The compounds of formula I as described herein above, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, their solvates, in combination with an appropriate medicament, or pharmaceutical compositions thereof may be suitable 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, epulis fibrosa, acute respiratory distress syndrome / acute lung injury and sepsis, Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC syndrome).

[0330] The compounds of formula I as described above, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, their solvates, in combination with an appropriate medicament, or pharmaceutical compositions thereof may be used in treatment regimens in the first-line, second-line or any further line of treatment setting.

[0331] The compounds of formula I as described above, their tautomers, their stereoisomers, their pharmaceutically acceptable salts, their crystalline polymorphs, their solvates, in combination with suitable medicaments, or pharmaceutical compositions thereof, optionally in combination with radiation therapy and / or surgery, may be used for the prevention, short-term treatment or long-term treatment of the above-mentioned diseases.

[0332] The compounds of Formula I, their tautomers, stereoisomers, pharmaceutically acceptable salts, polymorphs, and solvates of the present invention can be combined with other drugs, such as radiation, chemotherapeutic agents, and / or targeted agents, in the treatment of cancers and their subtypes, as described above. Drugs that can be used in combination therapy include targeted agents, such as RTK inhibitors, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanisms (such as histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), and 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.

[0333] The following examples are presented for the purpose of further illustrating the present invention and should not be construed as limiting the scope of the invention in any way.

[0334] Either 1 HNHR spectra were also obtained in the solvents indicated, chemical shifts are given in units of δ downfield from the chemical shifts of the internal standard tetramethylsilane (TMS), and interproton coupling constants are given in Hertz (Hz).

[0335] Some of the representative examples of the present invention were prepared by following one or more of the reaction schemes described above. [Example]

[0336] The present invention is further illustrated by the following examples, which are presented as merely illustrative of the present invention and are not intended to limit the scope of the present invention. The examples presented below provide synthetic procedures for preparing related compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. All patents and patent applications mentioned herein are incorporated by reference.

[0337] The designations "or1," "or2," and "or3" in a structural formula indicate that a chiral center is assigned either R or S, and that the absolute configuration is undetermined in that formula.

[0338] Synthesis of intermediates: Intermediate-1: (R / S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0339] [ka]

[0340] Step-1: 4'-Bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0341] To a stirred solution of 4'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (10 g, 42.0 mmol) (commercially available) in dry DMF (100 ml), NaH (1.210 g, 50.4 mmol) was added at 0°C and stirred for 15 minutes. After that, MeI (3.94 ml, 63.0 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was quenched with an ice-water solution. The formed solid was filtered and dried under vacuum to give 4'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (9.0 g, 85% yield) as a brown solid.

[0342] MS(ES+)m / z=254.21(M+2) 1 H NMR(400MHz,DMSO-d6)δ7.25-7.10(m,3H),3.21(s,3H),2.17(q,J=3.9Hz,2H),1.40(q,J=3.9Hz,2H)

[0343] Step-2: 4'-acetyl-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0344] A mixture of 4'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (9.0 g, 35.7 mmol), tributyl(1-ethoxyvinyl)stannane (16.76 g, 46.4 mmol), PdCl(PPh) (2.506 g, 3.57 mmol), and triethylamine (9.95 mL, 71.4 mmol) in 1,4-dioxane (50 mL) was stirred at 100 °C for 16 h. After completion of the reaction, the mixture was cooled to room temperature and filtered through a bed of Celite. The filtrate was concentrated, and the residue was suspended in 2 N HCl (20 mL) and THF (50 mL). The suspension was stirred for 30 min and then extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (7.3 g). The crude residue was purified by column chromatography using an eluent of ethyl acetate in hexane (0→30%) to give 4′-acetyl-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (5.1 g, 66.4% yield) as a light brown solid.

[0345] MS(ES+)m / z=216.45(M+) 1 H NMR(400MHz,DMSO-d6)δ7.57(dd,J=7.9,1.1Hz,1H),7.42(t,J=7.9Hz,1H),7.31(dd ,J=7.8,1.1Hz,1H),3.23(s,3H),2.56(s,3H),2.17-2.05(m,2H),1.35-1.38(m,2H)

[0346] Step-3: (R)-2-methyl-N-((R / S)-1-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl)ethyl)propane-2-sulfinamide

[0347] To a stirred solution of 4'-acetyl-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (5.0 g, 23.23 mmol) and (R)-2-methylpropane-2-sulfinamide (3.38 g, 27.9 mmol) in THF (50 ml) was added titanium(IV) isopropoxide (17.02 ml, 58.1 mmol) under a nitrogen atmosphere. The resulting reaction mass was heated to 80°C for 16 hours. After completion of the reaction, the reaction mixture was allowed to cool to -78°C, and then sodium borohydride (3.08 g, 81 mmol) was added. The mixture was then allowed to warm gradually to room temperature and stirred for 2 hours. The reaction mass was then poured into ice-cold water (50 ml), followed by the addition of ethyl acetate (500 ml) and stirring for 30 minutes. The residue was filtered and washed with ethyl acetate, and the organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using 60% ethyl acetate in hexane as an eluent to give (R)-2-methyl-N-((R / S)-1-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl)ethyl)propane-2-sulfinamide (1.9 g, 25.5% yield) as a viscous liquid.

[0348] MS(ES+)m / z=320.53(M+) 1 H NMR(400MHz,DMSO-d6)δ7.31-7.26(m,1H),7.20(dd,J=8.1,1.1Hz,1H),6.97(dd,J=7.6,1.1Hz,1H),5.53(d,J=5.9Hz,1H), 4.07-4.01(m,1H),3.20(s,3H),2.11-2.04(m,1H),1.69-1.74(m,1H),1.55-1.46(m,2H),1.36(d,J=6.7Hz,3H),1.09(s,9H)

[0349] Step-4: (R / S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0350] To a stirred solution of (R)-2-methyl-N-((R / S)-1-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-4'-yl)ethyl)propane-2-sulfinamide (1.9 g, 5.93 mmol) in DCM (20 ml) was added dropwise a solution of 4 M HCl in dioxane (7.41 ml, 29.6 mmol) at 0°C under nitrogen atmosphere and stirring was continued for 3 h. After completion of the reaction, the solvent was evaporated under reduced pressure at 35°C, and the resulting residue was triturated with diethyl ether (15 ml), filtered, and the solid was dried in vacuo to give (R / S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride (0.5 g, 33.4% yield) as a yellow solid.

[0351] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,2H),7.39(d,J=1.8Hz,1H),7.38(s,1H),7.13-7.08(m,1H),3.84-3.8 8(m,1H),3.22(s,3H),2.10-2.05(m,1H),1.71-1.73(m,1H),1.50-1.56(m,2H),1.48(d,J=6.7Hz,3H)

[0352] Intermediate-2: (R / S)-2-(3-(1-aminoethyl)-2-fluorophenyl)propan-2-ol hydrochloride

[0353] [ka]

[0354] Step-1: 2-(3-bromo-2-fluorophenyl)propan-2-ol

[0355] Methyl 3-bromo-2-fluorobenzoate (9.5 g, 40.8 mmol) (commercially available) was taken in THF (40 mL) and cooled in an ice bath, and methylmagnesium chloride (40.8 mL, 122 mmol) in diethyl ether was added dropwise to it. After stirring at room temperature for 1.5 hours, a saturated aqueous solution of ammonium chloride (5 mL) and water (20 mL) were added sequentially to the reaction mixture, which was then extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by flash column chromatography using an eluent of 0 to 10% ethyl acetate in hexane to give 2-(3-bromo-2-fluorophenyl)propan-2-ol (7.0 g, 73.7% yield) as a colorless liquid.

[0356] 1 H NMR(400MHz,DMSO-d6)δ7.65-7.60(m,1H),7.59-7.54(m,1H),5.42(s,1H),1.48(d,J=1.4Hz,6H)

[0357] Step-2: 1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethan-1-one

[0358] The title compound was synthesized by using 2-(3-bromo-2-fluorophenyl)propan-2-ol and following a similar reaction protocol as described in step-2 of intermediate-1.

[0359] 1 H NMR(400MHz,DMSO-d6)δ7.90-7.83(m,1H),7.70-7.61(m,1H),7.27(t,J=7.7Hz,1H),5.41(s,1H),2.58(s,3H),1.52(d,J=1.4Hz,6H)

[0360] Step-3: (R)—N-(1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0361] To a stirred solution of 1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethan-1-one (3.9 g, 19.88 mmol) and (R)-2-methylpropane-2-sulfinamide (3.13 g, 25.8 mmol) in THF (30 ml) was added titanium(IV) isopropoxide (14.56 ml, 49.7 mmol) under a nitrogen atmosphere. The resulting reaction mixture was heated at 80° C. for 16 hours. After complete consumption of the starting material, the reaction mixture was brought to room temperature and diluted with ethyl acetate (100 ml). Water (10 ml) was added dropwise, and the resulting white precipitate was filtered through Celite, and the residue was washed with ethyl acetate (30 ml × 2). The filtrate was washed with water (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mass was purified by flash column chromatography using 0→30% ethyl acetate in hexane to give (R)-N-(1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 84%) as a colorless liquid.

[0362] Step-4: (R)-N-((R / S)-1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0363] To a solution of (R)-N-(1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 16.70 mmol) in MeOH (30 ml) was added NaBH (0.634 g, 16.70 mmol) at 0 °C and stirred at 27 °C for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (50 × 2 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (0 → 40% ethyl acetate in hexane) to give (R)-N-((R / S)-1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.3 g, 45.7% yield) as a brown viscous solid.

[0364] MS(ES+)m / z=324.15(M+Na) 1 H NMR(400MHz,DMSO-d6)δ7.54-7.47(m,1H),7.43-7.36(m,1H),7.17-7.09(m,1H),5.75( s,1H),5.23(s,1H),4.72-4.63(m,1H),1.48(s,6H),1.39(d,J=6.8Hz,3H),1.09(s,9H)

[0365] Step-5: (R / S)-2-(3-(1-aminoethyl)-2-fluorophenyl)propan-2-ol hydrochloride

[0366] The title compound was synthesized by using (R)-N-((R / S)-1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0367] 1 H NMR(400MHz,DMSO-d6)δ8.36(s,2H),7.69-7.62(m,1H),7.50-7.43(m,1H),7.29-7.23(m,1H),5.36(s,1H),4.72-4.56(m,1H),1.56-1.44(m,9H)

[0368] Intermediate-3: (R / S)-3-(1-aminoethyl)-5-methylaniline

[0369] [ka]

[0370] Step-1: (R)-2-methyl-N-((R / S)-1-(3-methyl-5-nitrophenyl)ethyl)propane-2-sulfinamide

[0371] The title compound was synthesized by using 1-(3-methyl-5-nitrophenyl)ethan-1-one (commercially available) and following a similar reaction protocol as described in step-3 of intermediate-1.

[0372] 1 H NMR (400 MHz, chloroform-d): δ 8.06-8.01 (m, 1H), 8.00-7.97 (m, 1H), 7.52-7.50 (m, 1H), 4.66-4.57 (m, 1H), 2.49 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H), 1.26 (s, 9H)

[0373] Step-2: (R / S)-1-(3-methyl-5-nitrophenyl)ethan-1-amine hydrochloride

[0374] The title compound was synthesized by using (R)-2-methyl-N-((R / S)-1-(3-methyl-5-nitrophenyl)ethyl)propane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0375] 1 H NMR(400MHz,DMSO-d6)δ8.72(s,3H),8.29-8.26(m,1H),8.10-8.07(m,1H),7.88-7.85(m,1H),4.60-4.51(m,1H),2.46(s,3H),1.55(d,J=6.8Hz,3H)

[0376] Step-3: (R / S)-3-(1-aminoethyl)-5-methylaniline

[0377] A mixture of (R / S)-1-(3-methyl-5-nitrophenyl)ethan-1-amine hydrochloride (4.6 g, 21.23 mmol), 10% wet Pd—C (0.226 g, 2.123 mmol), and MeOH (50 mL) was stirred on a Parr shaker under a hydrogen atmosphere (40 psi) at 27° C. for 5 hours. The reaction mixture was filtered and concentrated. The resulting residue was dissolved in water, basified with sodium carbonate, and extracted with DCM (100 mL × 2). The organic layer was dried over sodium sulfate, filtered, and concentrated to give (R / S)-3-(1-aminoethyl)-5-methylaniline (2.8 g, 88% yield) as a red liquid.

[0378] 1 H NMR(400MHz,DMSO-d6)δ6.36-6.34(m,1H),6.33-6.31(m,1H),6.22-6.20(m ,1H),4.83(s,2H),3.76(q,J=6.6Hz,1H),2.13(s,3H),1.17(d,J=6.6Hz,3H)

[0379] Intermediate-4: (R / S)-4-(1-aminoethyl)-6-(trifluoromethyl)pyridin-2-amine

[0380] [ka]

[0381] Step-1: tert-butyl (4-acetyl-6-(trifluoromethyl)pyridin-2-yl)carbamate

[0382] A mixture of 1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)ethan-1-one (2.8 g, 12.52 mmol) (commercially available), tert-butyl carbamate (1.761 g, 15.03 mmol), Pd(dba) (1.147 g, 1.252 mmol), CsCO (8.16 g, 25.05 mmol), and Xantphos (1.449 g, 2.505 mmol) in 1,4-dioxane (4 mL) was stirred at 90 °C for 12 h. Upon completion, the reaction mixture was concentrated and purified by column chromatography using an eluent of 0 → 20% ethyl acetate in hexane to give tert-butyl (4-acetyl-6-(trifluoromethyl)pyridin-2-yl)carbamate (1.4 g, 36.7% yield) as a yellow solid.

[0383] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.52-8.50(m,1H),7.95-7.72(m,1H),2.67(s,3H),1.49(s,9H)

[0384] Step-2: t-butyl (4-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-6-(trifluoromethyl)pyridin-2-yl)carbamate

[0385] The title compound was synthesized by following the similar reaction protocol as described in step-3 of intermediate-1 by using tert-butyl (4-acetyl-6-(trifluoromethyl)pyridin-2-yl)carbamate. MS(ES+)m / z=410.3(M+1)

[0386] Step-3: (R / S)-4-(1-aminoethyl)-6-(trifluoromethyl)pyridin-2-amine

[0387] To a stirred solution of t-butyl (4-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-6-(trifluoromethyl)pyridin-2-yl)carbamate (1.0 g, 5.50 mmol) in DCM (20 ml) was added 4 M HCl in dioxane (5 ml) dropwise at 0° C. and stirring was continued at 0° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated at 35° C. The resulting residue was dissolved in water, basified with sodium carbonate, and extracted with ethyl acetate (100 ml×2). The organic layer was dried over sodium sulfate and concentrated to give (R / S)-4-(1-aminoethyl)-6-(trifluoromethyl)pyridin-2-amine (0.4 g, 80.0% yield) as a yellow liquid.

[0388] 1 H NMR(400MHz,DMSO-d6)δ6.95(d,J=1.2Hz,1H),6.65(d,J=1.3Hz,1H),6.42(s,2H),3.87(q,J=6.6Hz,1H),3.34(s,2H),1.20(d,J=6.7Hz,3H)

[0389] Intermediate-5: (R / S)-2-(3-(1-aminoethyl)phenyl)-2-methylpropan-1-ol hydrochloride

[0390] [ka]

[0391] Step-1: Methyl 2-(3-acetylphenyl)-2-methylpropanoate

[0392] The title compound was synthesized by using methyl 2-(3-bromophenyl)-2-methylpropanoate (Journal of Medicinal Chemistry, 51(3), 392-395; 2008) according to the same reaction protocol as that described in Step-2 of Intermediate-1. MS(ES+)m / z=221.2(M+1)

[0393] Step-2: Isopropyl 2-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)phenyl)-2-methylpropanoate

[0394] The title compound was synthesized by using methyl 2-(3-acetylphenyl)-2-methylpropanoate and following the similar reaction protocol as described in step-3 of intermediate-1. MS(ES+)m / z=354.3(M+1)

[0395] Step-3: (R)-N-((R / S)-1-(3-(1-hydroxy-2-methylpropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0396] To a solution of isopropyl 2-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)phenyl)-2-methylpropanoate (3 g, 8.49 mmol) in MeOH (30 ml) was added LAH (0.322 g, 8.49 mmol) at 0° C. and stirred at 27° C. for 2 hours. After completion of the reaction, the reaction mixture was quenched with aqueous sodium hydroxide solution (50 ml) and extracted with ethyl acetate (100 ml × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-N-((R / S)-1-(3-(1-hydroxy-2-methylpropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.9 g, 75% yield) as a colorless liquid. MS(ES+)m / z=298.3(M+1)

[0397] Step-4: (R / S)-2-(3-(1-aminoethyl)phenyl)-2-methylpropan-1-ol hydrochloride

[0398] The title compound was synthesized by using (R)-N-((R / S)-1-(3-(1-hydroxy-2-methylpropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0399] 1 H NMR(400MHz,DMSO-d6)δ8.51(s,2H),7.57-7.53(m,1H),7.47-7.22(m,3H),4.48-4.26(m,1H),3.44(s,2H),1.57-1.46(m,3H),1.24(s,6H)

[0400] Intermediate-6: (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol

[0401] [ka]

[0402] Step-1: Ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate

[0403] A suspension of ethyl 2-bromo-2,2-difluoroacetate (33.7 g, 166 mmol) (commercially available) and copper (10.56 g, 166 mmol) in DMSO (200 ml) was stirred at room temperature for 30 minutes under a nitrogen atmosphere. 1-Bromo-2-fluoro-3-iodobenzene (20 g, 66.5 mmol) in DMSO (50 ml) was added dropwise to the reaction mixture, and the reaction was then stirred at 50° C. for 15 minutes. After completion of the reaction, the reaction was quenched with water (100 ml) and extracted with diethyl ether (500 ml). The organic layer was separated, filtered through Celite, dried over sodium sulfate, and evaporated to give the crude compound (16 g). The crude compound was purified by column chromatography using an eluent of 5% ethyl acetate in hexane to give ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate (12 g, 60.8% yield) as a colorless liquid.

[0404] 1 H NMR (400 MHz, chloroform-d) δ 7.77-7.70 (m, 1H), 7.65-7.59 (m, 1H), 7.21-7.15 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H)

[0405] Step-2: 1-(3-bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol

[0406] The title compound was synthesized by using ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step-1 of intermediate-2.

[0407] 1 H NMR (400 MHz, chloroform-d) δ 7.70-7.65 (m, 1H), 7.45-7.40 (m, 1H), 7.14-7.08 (m, 1H), 1.38-1.36 (m, 6H)

[0408] Step-3: 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one

[0409] The title compound was synthesized by using 1-(3-bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol and following the similar reaction protocol as described in step-2 of intermediate-1.

[0410] 1 H NMR (400 MHz, chloroform-d) δ 7.99-7.94 (m, 1H), 7.68-7.63 (m, 1H), 7.34-7.27 (m, 1H), 2.68 (d, J = 5.3 Hz, 3H), 1.40-1.36 (m, 6H)

[0411] Step-4: (R)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0412] The title compound was synthesized by using 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2.

[0413] MS(ES+)m / z=372.28(M+23) 1 H NMR(400MHz,DMSO-d6)δ7.77-7.70(m,1H),7.61-7.55(m,1H),7.41-7.34(m,1H),5.41(s,1H),2.80-2.57(m,3H),1.22(s,15H)

[0414] Step-5: (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0415] To a stirred solution of (R)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (29 g, 83 mmol) in THF (450 ml) and ethanol (45 ml) was added NaBH4 (6.28 g, 166 mmol) in portions at -40°C. The resulting reaction mixture was stirred at -40°C for 1 h, slowly brought to room temperature, and stirred for 3 h, 25 o The mixture was stirred at room temperature for 1 hour at rt. After complete consumption of the starting material, the reaction mass was diluted with ethyl acetate (200 ml) and quenched with a saturated solution of ammonium chloride (50 ml). The organic layer was washed with water (100 ml) and brine (100 ml). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mass was purified by flash column chromatography using 0→70% ethyl acetate in hexane to give (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 29.9 mmol, 36.0% yield) as a sticky colorless solid.

[0416] MS(ES+)m / z=352.28(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.70-7.63(m,1H),7.37-7.31(m,1H),7.30-7.25(m,1H),5.84(d,J= 7.7Hz,1H),5.33(s,1H),4.74-4.62(m,1H),1.40(d,J=6.8Hz,3H),1.20(s,6H),1.10(s,9H)

[0417] Step-6: (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol

[0418] The title compound was synthesized by using (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-3 of intermediate-4.

[0419] 1 H NMR(400MHz,DMSO-d6)δ7.73-7.67(m,1H),7.36-7.19(m,2H),5.30(s,1H),4.28(q,J=6.6Hz,1H),1.25(d,J=6.6Hz,3H),1.22-1.18(m,6H)

[0420] Intermediate-7: (R / S)-2-(3-(1-aminoethyl)-2-methylphenyl)-2,2-difluoroethan-1-ol hydrochloride

[0421] [ka]

[0422] Step-1: Ethyl 2-(3-acetyl-2-methylphenyl)-2,2-difluoroacetate

[0423] The title compound was synthesized by using 1-(3-iodo-2-methylphenyl)ethan-1-one (commercially available) and following a similar reaction protocol as described in step-1 of intermediate-6. MS(ES+)m / z=257.2(M+1)

[0424] Step-2: (R)-N-((R / S)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

[0425] The title compound was synthesized by using ethyl 2-(3-acetyl-2-methylphenyl)-2,2-difluoroacetate and following the similar reaction protocol as described in step-3 of intermediate-1.

[0426] MS(ES+)m / z=320.03(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.64-7.59(m,1H),7.40-7.35(m,1H),7.30(t,J=7.8Hz,1H),5.75-5.63(m ,2H),4.77-4.65(m,1H),3.95-3.83(m,2H),2.40-2.37(m,3H),1.38(d,J=6.7Hz,3H),1.09(s,9H)

[0427] Step-3: (R / S)-2-(3-(1-aminoethyl)-2-methylphenyl)-2,2-difluoroethan-1-ol hydrochloride

[0428] The title compound was synthesized by using (R)-N-((R / S)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0429] 1 H NMR(400MHz,DMSO-d6)δ8.72-8.58(m,3H),7.86-7.73(m,1H),7.53-7.45(m,1H),7.44-7. 36(m,1H),4.72-4.54(m,1H),3.90(t,J=14.5Hz,2H),2.43-2.39(m,3H),1.49-1.46(m,3H)

[0430] Intermediate-8: (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol

[0431] [ka]

[0432] Step-1: Ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate

[0433] The title compound was synthesized by using ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step-2 of intermediate-1.

[0434] GCMS (m / z) = 260.20 (M+) 1 H NMR (400 MHz, chloroform-d): δ 8.09-8.00 (m, 1H), 7.91-7.79 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 2.67 (d, J = 5.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0435] Step-2: Isopropyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate

[0436] The title compound was synthesized by using ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step-3 of intermediate-2.

[0437] 1 H NMR(400MHz,DMSO-d6)δ7.97-7.90(m,1H),7.88-7.82(m,1H),7.54-7.46(m,1H) ),5.24-5.06(m,1H),2.70(d,J=2.2Hz,3H),1.25(d,J=6.2Hz,6H),1.21(s,9H)

[0438] Step-3: (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0439] The title compound was synthesized by using isopropyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step 5 of intermediate 6.

[0440] MS(ES+)m / z=324.34(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=7.0Hz,1H),7.47-7.41(m,1H),7.31(t,J=7.7Hz,1H),5.87(d,J=7.7 Hz,1H),5.71(t,J=6.5Hz,1H),4.74-4.63(m,1H),3.97-3.84(m,2H),1.41(d,J=6.8Hz,3H),1.11(s,9H)

[0441] Step-4: (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol

[0442] The title compound was synthesized by using (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-3 of intermediate-4.

[0443] 1 H NMR(400MHz,DMSO-d6)δ7.80-7.71(m,1H),7.43-7.37(m,1H),7.31-7.27(m,1H) ),5.69(brs,1H),4.36-4.27(m,1H),3.91(t,J=14.4Hz,2H),1.33-1.19(m,3H)

[0444] Intermediate-9: (R / S)-2-(5-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol hydrochloride

[0445] [ka]

[0446] Step-1: Ethyl 2-(5-bromo-2-fluorophenyl)-2,2-difluoroacetate

[0447] The title compound was synthesized by using 4-bromo-1-fluoro-2-iodobenzene (commercially available) and following a similar reaction protocol as described in step-1 of intermediate-6.

[0448] 1 H NMR(400MHz,DMSO-d6)δ7.97-7.83(m,2H),7.49-7.42(m,1H),4.36(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H)

[0449] Step-2: Ethyl 2-(5-acetyl-2-fluorophenyl)-2,2-difluoroacetate

[0450] The title compound was synthesized by using ethyl 2-(5-bromo-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step-2 of intermediate-1.

[0451] GCMS (m / z) = 260.13. 1 H NMR(400MHz,DMSO-d6)δ8.32-8.26(m,1H),8.19(dd,J=7.1,2.3Hz,1H),7.65-7.85(m,1H),4.37(q,J=7.1Hz,2H),2.65(s,3H),1.24(t,J=7.1Hz,3H)

[0452] Step-3: Isopropyl (R)-2-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate

[0453] The title compound was synthesized by using ethyl 2-(5-acetyl-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step-3 of intermediate-2.

[0454] MS(ES+)m / z=378.22(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.24-8.19(m,1H),8.18-8.14(m,1H),7.61-7.56(m,1H),5.20-5.10(m,1H),2.77(s,3H),1.26(d,J=6.3Hz,6H),1.23(s,9H)

[0455] Step-4: (R)-N-((R / S)-1-(3-(1,1-difluoro-2-hydroxyethyl)-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0456] The title compound was synthesized by using isopropyl (R)-2-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate and following a similar reaction protocol as described in step 5 of intermediate 6.

[0457] MS(ES+)m / z=324.03(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.63-7.55(m,2H),7.34-7.25(m,1H),5.79(d,J=7.3Hz,1H),5.71(t ,J=6.8Hz,1H),4.45(p,J=6.9Hz,1H),3.97-3.83(m,2H),1.40(d,J=6.8Hz,3H),1.12(s,9H)

[0458] Step-5: (R / S)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethan-1-ol hydrochloride

[0459] The title compound was synthesized by using (R)-N-((R / S)-1-(3-(1,1-difluoro-2-hydroxyethyl)-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0460] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,3H),7.86-7.71(m,2H),7.45-7.40(m,1H),5 .82-5.79(m,1H),4.55-4.44(m,1H),3.95-3.92(m,2H),1.52(d,J=6.8Hz,3H)

[0461] Intermediate-10: (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline

[0462] [ka]

[0463] Step-1: (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide

[0464] The title compound was synthesized by following the similar reaction protocol as described in step-3 of Intermediate 1 by using 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one (commercially available).

[0465] 1H NMR(400MHz,DMSO-d6)δ8.66-8.62(m,1H),8.43-8.37(m,1H),8.32-8.29(m,1H) ),6.09(d,J=8.7Hz,1H),4.74-4.66(m,1H),1.46(d,J=6.9Hz,3H),1.14(s,9H)

[0466] Step-2: (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride

[0467] The title compound was synthesized by using (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0468] 1 H NMR(400MHz,DMSO-d6)δ8.99(s,3H),8.81(t,J=1.9Hz,1H),8.63-8.40(m,2H),4.82-4.69(m,1H),1.60(d,J=6.8Hz,3H)

[0469] Step-3: (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline

[0470] To a stirred solution of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (14 g, 51.7 mmol) in MeOH (100 mL) in a Parr shaker, 10% wet Pd—C (1.101 g, 10.35 mmol) was added. The resulting reaction mixture was stirred for 3 hours at room temperature under hydrogen pressure (40 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was dissolved in dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (6 g, 56.8% yield).

[0471] MS(ES+)m / z=205.82,(M+1) 1 H NMR(400MHz,DMSO-d6)δ6.83-6.78(m,2H),6.69-6.65(m,1H),5.45(bs,2H),3.93-3.86(m,1H),1.79(bs,2H),1.20(d,J=6.6Hz,3H)

[0472] Intermediate-11: (R / S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride

[0473] [ka]

[0474] Step-1: (R)-2-methyl-N-((R / S)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide

[0475] The title compound was synthesized by using 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (WO200740382007) and following a similar reaction protocol as described in step-3 of intermediate-1.

[0476] 1 H NMR(400MHz,DMSO-d6)δ7.93-7.87(m,1H),7.71-7.65(m,1H),7.46-7.40(m,1H) ),5.92(d,J=7.8Hz,1H),4.79-4.67(m,1H),1.44(d,J=6.8Hz,3H),1.11(s,9H)

[0477] Step-2: (R / S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride

[0478] The title compound was synthesized by using (R)-2-methyl-N-((R / S)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0479] 1 H NMR(400MHz,DMSO-d6)δ8.94(s,3H),8.21-8.09(m,1H),7.90-7.75(m,1H),7.52(t,J=7.8Hz,1H),4.74-4.64(m,1H),1.58(d,J=6.8Hz,3H)

[0480] Intermediate-12: (R / S)-3-(1-aminoethyl)-5-(difluoromethyl)aniline

[0481] [ka]

[0482] Step 1: 3-Bromo-5-nitrobenzaldehyde

[0483] The experimental and analytical data were those reported in Journal of Medicinal Chemistry, 2018, vol. 61, #12, pp. 5235-5244 and WO201175515.

[0484] Step-2: 1-Bromo-3-(difluoromethyl)-5-nitrobenzene

[0485] 3-Bromo-5-nitrobenzaldehyde (35 g, 152 mmol) was dissolved in DCM (350 ml), and DAST (101 ml, 761 mmol) was added dropwise at 0° C. The reaction was allowed to reach room temperature and stirring was continued for 18 hours. After completion of the reaction, the resulting solution was poured onto ice and extracted with dichloromethane (400 ml). The organic layer was washed with water (500 ml × 2) and brine (300 ml). The separated organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude mass was purified by flash column chromatography using an eluent of 0 to 5% ethyl acetate in hexane to obtain 1-bromo-3-(difluoromethyl)-5-nitrobenzene (36.0 g, 94% yield) as a brown oil.

[0486] 1 H NMR(400MHz,DMSO-d6)δ8.59-8.57(m,1H),8.42-8.39(m,1H),8.31-8.28(m,1H),7.20(t,J=55.0Hz,1H)

[0487] Step-3: 1-(3-(difluoromethyl)-5-nitrophenyl)ethan-1-one

[0488] The title compound was synthesized by using 1-bromo-3-(difluoromethyl)-5-nitrobenzene and following a similar reaction protocol as described in step-2 of intermediate-1.

[0489] 1 H NMR(400MHz,DMSO-d6)δ8.78-8.76(m,1H),8.66-8.63(m,1H),8.55-8.53(m,1H),7.27(t,J=55Hz,1H),2.74(s,3H)

[0490] Step-4: (R)-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0491] The title compound was synthesized by using 1-(3-(difluoromethyl)-5-nitrophenyl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2.

[0492] 1 H NMR(400MHz,DMSO-d6)δ8.76-8.74(m,1H),8.57-8.54(m,1H),8.49-8.46(m,1H),7.30(t,J=55.1Hz,1H),2.84(s,3H),1.26(s,9H)

[0493] Step-5: (R)-N-((R / S)-1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0494] The title compound was synthesized by using (R)-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-2.

[0495] 1 H NMR(400MHz,DMSO-d6)δ8.53-8.51(m,1H),8.29-8.31(m,1H),8.12-8.10(m,1H),7.22(t,J =55.3Hz,1H),6.05(d,J=8.3Hz,1H),4.70-4.58(m,1H),1.45(d,J=6.9Hz,3H),1.14(s,9H)

[0496] Step-6: (R / S)-1-(3-(difluoromethyl)-5-nitrophenyl)ethan-1-amine hydrochloride

[0497] The title compound was synthesized by using the product of (R)-N-((R / S)-1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-5 of intermediate-2.

[0498] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,3H),8.69-8.66(m,1H),8.45-8.41(m,1H),8.3 0-8.28(m,1H),7.26(t,J=55.1Hz,1H),4.75-4.66(m,1H),1.58(d,J=6.8Hz,3H)

[0499] Step-7: (R / S)-3-(1-aminoethyl)-5-(difluoromethyl)aniline

[0500] To a stirred solution of (R / S)-1-(3-(difluoromethyl)-5-nitrophenyl)ethan-1-amine hydrochloride (2 g, 7.92 mmol) in EtOH (25 mL):water (5 mL) was added iron (0.884 g, 15.83 mmol) and ammonium chloride (0.847 g, 15.83 mmol) at room temperature. The resulting reaction mixture was heated at 95°C for 1 hour. After complete consumption of the starting material, the reaction mixture was brought to room temperature and the magnetic beads were removed by iron force. The reaction mixture was diluted with water (50 mL), and the product was extracted into ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude mass was purified by flash column chromatography using 0→70% ethyl acetate in hexane as eluent to give (R / S)-3-(1-aminoethyl)-5-(difluoromethyl)aniline (1.4 g, 95% yield) as a thick brown oil.

[0501] 1 H NMR(400MHz,DMSO-d6)δ6.80(t,J=55Hz,1H),6.71-6.67(m,2H),6.57-6.54(m ,1H),5.28(s,2H),3.91-3.83(m,1H),1.92-1.71(m,2H),1.20(d,J=6.5Hz,3H)

[0502] Intermediate-13: (R / S)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine hydrochloride

[0503] [ka]

[0504] Step 1: 3-Bromophenyl(tetrahydrofuran-2-yl)methanone

[0505] To a stirred solution of 1,3-dibromobenzene (6.45 ml, 53.4 mmol) in THF (50.0 ml), nBuLi (21.36 ml, 53.4 mmol) was slowly added at −78° C., and the mixture was stirred for 30 minutes at −78° C. To this was slowly added a solution of N-methoxy-N-methyltetrahydrofuran-2-carboxamide (5.0 g, 31.4 mmol) in THF (30.0 ml) at −78° C. The reaction mixture was stirred for 1 hour until it reached room temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (200 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by flash chromatography using an eluent of 0→5% ethyl acetate in hexane to afford the title compound 3-bromophenyl(tetrahydrofuran-2-yl)methanone (2.0 g, 24.96%). MS(ES+) m / z = 255.51.

[0506] Step-2: 2-((3-bromophenyl)difluoromethyl)tetrahydrofuran

[0507] To a stirred solution of (3-bromophenyl)(tetrahydrofuran-2-yl)methanone (2.00 g, 7.84 mmol), DAST (10.36 ml, 78 mmol) was added and heated at 50° C. for 48 hours. The reaction mixture was slowly quenched in ice water, then basified with aqueous sodium bicarbonate and extracted with ethyl acetate (75.0 ml × 2). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue (2.3 g). The crude residue was purified by flash chromatography using an eluent of 0→5% ethyl acetate in n-hexane to give 2-((3-bromophenyl)difluoromethyl)tetrahydrofuran (1.5 g, 69%).

[0508] 1 H NMR (400 MHz, chloroform-d) δ 7.72-7.69 (m, 1H), 7.62-7.57 (m, 1H), 7.51-7.46 (m, 1H), 7.35-7.30 (m, 1H), 4.38-4.27 (m, 1H), 3.88-3.82 (m, 2H), 2.10-2.02 (m, 2H), 1.94-1.82 (m, 2H)

[0509] Step-3: 1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-one

[0510] The title compound was synthesized by using 2-((3-bromophenyl)difluoromethyl)tetrahydrofuran and following the similar reaction protocol as described in step-2 of intermediate-1.

[0511] 1 H NMR (400 MHz, chloroform-d): δ 8.16-8.12 (m, 1H), 8.08-8.04 (m, 1H), 7.79-7.74 (m, 1H), 7.60-7.54 (m, 1H), 4.45-4.28 (m, 1H), 3.91-3.80 (m, 2H), 2.66 (s, 3H), 2.14-2.05 (m, 2H), 1.93-1.83 (m, 2H).

[0512] Step-4: (R)—N-(1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0513] The title compound was synthesized by using 1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2.

[0514] 1 H NMR (400 MHz, chloroform-d): δ 8.06-8.03 (m, 1H), 8.01-7.95 (m, 1H), 7.70-7.65 (m, 1H), 7.54-7.48 (m, 1H), 4.42-4.40 (m, 1H), 3.87-3.81 (m, 2H), 2.81 (s, 3H), 2.11-2.02 (m, 2H), 1.97-1.79 (m, 2H), 1.35 (s, 9H).

[0515] Step-5: (R)-N-((R / S)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0516] The title compound was synthesized by using (R)-N-(1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-2.

[0517] MS(ES+) m / z = 346.2. 1 H NMR (400 MHz, chloroform-d): δ 7.53-7.50 (m, 1H), 7.50-7.41 (m, 3H), 4.66-4.56 (m, 1H), 4.41-4.28 (m, 1H), 3.89-3.79 (m, 2H), 3.48-3.44 (m, 1H), 2.10-2.01 (m, 2H), 1.92-1.79 (m, 2H), 1.55 (d, J = 6.6 Hz, 3H), 1.26 (s, 9H).

[0518] Step-6: (R / S)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine hydrochloride

[0519] The title compound was synthesized by using (R)-N-((R / S)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0520] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,2H),7.73-7.63(m,2H),7.55(d,J=7.3Hz,2H),4.54-4.3 2(m,2H),3.78-3.65(m,2H),2.05-1.89(m,2H),1.85-1.65(m,3H),1.52(d,J=6.8Hz,3H)

[0521] Intermediate-14: (R / S)-3-(1-aminoethyl)-4-fluoro-5-methylaniline hydrochloride

[0522] [ka]

[0523] Step-1: 1-(2-fluoro-3-methyl-5-nitrophenyl)ethan-1-one

[0524] The title compound was synthesized following the similar reaction protocol as described in step-2 of intermediate-1 by using 1-bromo-2-fluoro-3-methyl-5-nitrobenzene (commercially available).

[0525] 1H NMR (400 MHz, chloroform-d) δ 8.67-8.54 (m, 1H), 8.35-8.21 (m, 1H), 2.72 (d, J = 5.0 Hz, 3H), 2.48-2.45 (m, 3H)

[0526] Step-2: (R)-N-((R / S)-1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0527] The title compound was synthesized by using 1-(2-fluoro-3-methyl-5-nitrophenyl)ethan-1-one and following the similar reaction protocol as described in step-3 of intermediate-1.

[0528] 1 H NMR(400MHz,DMSO-d6)δ8.36(dd,J=6.0,2.9Hz,1H),8.17(dd,J=6.4,2.9Hz,1H),6.06(d, J=8.6Hz,1H),4.79-4.61(m,1H),2.36(d,J=2.2Hz,3H),1.43(d,J=6.9Hz,3H),1.12(s,9H)

[0529] Step-3: (R / S)-1-(2-fluoro-3-methyl-5-nitrophenyl)ethan-1-amine hydrochloride

[0530] The title compound was synthesized according to the similar reaction protocol as described in step-4 of intermediate-1 by using (R)-N-((R / S)-1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide.

[0531] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,2H),8.49(dd,J=6.0,2.9Hz,1H),8.37-8.21(m,1H),4.70(s,1H),2.38(d,J=2.2Hz,3H),1.55(d,J=6.8Hz,3H)

[0532] Step-4: (R / S)-3-(1-aminoethyl)-4-fluoro-5-methylaniline hydrochloride

[0533] To a stirred solution of (R / S)-1-(2-fluoro-3-methyl-5-nitrophenyl)ethan-1-amine hydrochloride (2.2 g, 9.38 mmol) in methanol (80 ml), Pd—C (0.998 g, 0.938 mmol) was added and stirred at room temperature under a hydrogen atmosphere at 60 psi for 6 hours. After completion of the reaction, the reaction mass was filtered through Celite and evaporated to give (R / S)-3-(1-aminoethyl)-4-fluoro-5-methylaniline hydrochloride (1.8 g, 94% yield) as an off-white solid.

[0534] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,3H),6.61-6.40(m,2H),5.47(s,2H),4.54-4.36(m,1H),2.13(d,J=2.0Hz,3H),1.46(d,J=6.8Hz,3H)

[0535] By following the procedure described above for Intermediate-1 and using the corresponding starting materials, the following intermediates shown in Table 1 were prepared.

[0536] [Table 1]

[0537] Intermediate-17: (R / S)-1-(indolin-4-yl)ethan-1-amine hydrochloride

[0538] [ka]

[0539] Step-1: 1-(1H-indol-4-yl)ethan-1-one

[0540] The title compound was synthesized following the similar reaction protocol as described in step-2 of intermediate-1 by using commercially available 4-bromo-1H-indole.

[0541] MS(ES+)m / z=160.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ11.46(bs,1H),7.78-7.75(m,1H),7.72-7.68(m,1H),7.57-7.52(m,1H),7.24-7.17(m,1H),7.13-7.07(m,1H),2.65(s,3H)

[0542] Step-2: (R)—N-(1-(1H-indol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0543] The title compound was synthesized by using 1-(1H-indol-4-yl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2.

[0544] MS(ES+)m / z=263.15(M+1) 1H NMR (400MHz, chloroform-d) δ 8.67 (s, 1H), 7.81-7.77 (m, 1H), 7.66-7.62 (m, 1H), 7.60-7.55 (m, 2H), 7.27-7.25 (m, 1H), 2.92 (s, 3H), 1.39 (s, 9H)

[0545] Step-3: (R)-N-((R / S)-1-(1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[0546] The title compound was synthesized by using (R)-N-(1-(1H-indol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-3 of intermediate-1.

[0547] MS(ES+)m / z=265.21(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.34-7.27(m,2H),7.09-7.04(m,2H),6.56(d,J=3.2Hz,1H),5.45 (d,J=5.6Hz,1H),4.83-4.70(m,1H),3.45-3.37(m,1H),1.49(d,J=6.7Hz,3H),1.11(s,9H)

[0548] Step-4: (R)-N-((R / S)-1-(indolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[0549] To a stirred solution of (R)-N-((R / S)-1-(1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1.3 g, 4.92 mmol) in acetic acid (15 ml), sodium cyanoborohydride (0.618 g, 9.83 mmol) was slowly added at room temperature and stirring was continued for 1.5 hours. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated under reduced pressure to give a crude residue (1.7 g). The crude residue was purified by flash column chromatography using an eluent of 0→60% ethyl acetate in hexane to give (R)-N-((R / S)-1-(indolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 76% yield).

[0550] 1 H NMR(400MHz,DMSO-d6)δ6.89(t,J=7.7Hz,1H),6.60(dd,J=7.7,0.9Hz,1H),6.38(dd,J=7.7,0.9Hz,1H),5.46(s,1H), 5.38(d,J=5.7Hz,1H),4.32(p,J=6.6Hz,1H),3.44-3.45(m,2H),2.97-2.88(m,2H),1.34(d,J=6.7Hz,3H),1.10(s,9H)

[0551] Step-5: (R / S)-1-(indolin-4-yl)ethan-1-amine hydrochloride

[0552] The title compound was synthesized by using (R)-N-((R / S)-1-(indolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0553] 1 H NMR(400MHz,DMSO-d6)δ8.69-8.64(m,2H),7.58(d,J=7.7Hz,1H),7.44(t,J=7.8Hz,1H),7.33(d, J=7.8Hz,1H),4.47-4.34(m,1H),3.69(t,J=7.9Hz,2H),3.41-3.21(m,2H),1.52(d,J=6.8Hz,3H)

[0554] Intermediate-18: 6-Bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one Route-I:

[0555] [ka]

[0556] Step 1: 4,7-Dibromo-2,3-dihydro-1H-indene-5-carboxylic acid

[0557] To a solution of 2,3-dihydro-1H-indene-5-carboxylic acid (commercially available) (2.00 g, 12.33 mmol) in concentrated HSO (20 mL) was added NBS (5.49 g, 30.8 mmol) in portions at room temperature, and the mixture was stirred overnight at room temperature. The reaction mass was then poured into a water solution cooled with crushed ice. The solution was stirred for 30 min, and the solid was filtered, air-dried, and precipitated with EtOAc and hexane to give 4,7-dibromo-2,3-dihydro-1H-indene-5-carboxylic acid (3.81 g, 97% crude yield) as a brown solid.

[0558] MS(ES+)m / z=319.94(M+) 1 H NMR(400MHz,DMSO-d6)δ13.49(s,1H,D2O exchangeable),7.71(s,1H),3.11-3.96(m,4H),2.15-2.04(m,2H)

[0559] Step-2: 6-Bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

[0560] A mixture of 4,7-dibromo-2,3-dihydro-1H-indene-5-carboxylic acid (70 g, 219 mmol), acetamidomide hydrochloride (31.0 g, 328 mmol), copper(I) iodide (8.33 g, 43.8 mmol) and cesium carbonate (143 g, 438 mmol) in DMF (500 ml) was heated at 70° C. for 16 hours. After completion of the reaction, the reaction mass was poured into water and extracted with EtOAc, the organic layer was washed with water (100 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound (45.2 g). The crude compound was purified by column chromatography using 20→30% ethyl acetate in hexane to give the title compound 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (27 g, 44.2% yield) as a white solid.

[0561] MS(ES+)m / z=279.15(M+) 1 H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.99(s,1H),3.20(t,J=7.6Hz,2H),3.01(t,J=7.5Hz,2H),2.34(s,3H),2.20-2.09(m,2H)

[0562] Route-II:

[0563] [ka]

[0564] Step-1: N-(7-bromo-2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide

[0565] A solution of 2,2,2-trichloroethane-1,1-diol (4.29 g, 25.9 mmol) and sodium sulfate (26.8 g, 189 mmol) in DM water (140 ml) was heated to 40 °C. A suspension of 7-bromo-2,3-dihydro-1H-inden-4-amine (5 g, 23.57 mmol) (WO 2017 / 139778 A1), DM water (38 ml), and HCl (3.93 ml, 47.1 mmol) were added sequentially. To this reaction mixture was added a solution of hydroxylamine hydrochloride (4.91 g, 70.7 mmol) in DM water (21 ml). The reaction mixture was then stirred at 80 °C for 1 hour. After the reaction was completed, the mixture was cooled to 10°C, and the precipitate was filtered, washed with water and hexane, and dried to obtain N-(7-bromo-2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide (6 g, yield 90%).

[0566] MS(ES+)m / z=283.09(M+) 1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.55(s,1H),7.71(s,1H),7.46(d,J=8.5Hz,1H),7.34(d,J=8.5Hz,1H),2.99-2.86(m,4H),2.10-1.98(m,2H)

[0567] Step-2: 5-Bromo-1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione

[0568] To sulfuric acid (3.77 ml, 70.6 mmol) at room temperature was added N-(7-bromo-2,3-dihydro-1H-inden-4-yl)-2-(hydroxyimino)acetamide (1 g, 3.53 mmol) in portions, and the reaction mixture was then heated at 60° C. for 1 hour without allowing the internal temperature to rise above 60° C. The reaction mixture was then poured into an ice-water solution, and the precipitated solid was filtered. The remaining solid was dissolved in 10% MeOH / DCM, and the mixture was evacuated under vacuum. The residue was then stirred in ethyl acetate, filtered, and washed with ethyl acetate to give the desired product (900 mg, 96% yield).

[0569] MS(ES+)m / z=265.90(M+) 1 H NMR(400MHz,DMSO-d6)δ11.22(s,1H),7.48(s,1H),2.89(t,J=7.3Hz,4H),2.16-2.04(m,2H)

[0570] Step-3: 6-Bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

[0571] To a solution of 5-bromo-1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (100 mg, 0.376 mmol) in DMSO (10 mL), acetamide hydrochloride (42.6 mg, 0.451 mmol), tert-butyl hydroperoxide (0.102 mL, 0.564 mmol), and sodium carbonate (119 mg, 1.127 mmol) were added at room temperature, and stirring was continued for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with water (20 mL), brine, dried over anhydrous NaSO, and concentrated to give a crude residue (130 mg). The residue was purified by redisep® Rf column attached to a column chromatography (Rf200, Teledyne / Isco) system using gradient elution with ethyl acetate in hexane (0 to 40%) to give 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (90 mg, 86%).

[0572] MS(ES+)m / z=279.02(M+) 1 H NMR(400MHz,DMSO-d6)δ12.25(s,1H),7.99(s,1H),3.20(t,J=7.6Hz,2H),3.06-2.97(m,2H),2.34(s,3H),2.25-2.02(m,2H)

[0573] Intermediate-19: 6-Bromo-4-chloro-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline

[0574] [ka]

[0575] To a stirred solution of 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (0.290 g, 1.039 mmol) in chlorobenzene (10 mL) was added DIPEA (0.272 mL, 1.558 mmol) followed by POCl (0.116 mL, 1.247 mmol) at 0° C. and stirred at room temperature for 0.5 hours. The reaction mixture was then heated to 90° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give the crude product (0.41 g). The crude residue was purified using a Biotage purification system with an eluent of 0 to 5% ethyl acetate in hexane to give 6-bromo-4-chloro-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline (130 mg, 42.0% yield) as a pale yellow solid.

[0576] MS(ES+)m / z=299.21(M+1) 1 H NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 1.0 Hz, 1H), 3.59-3.44 (m, 2H), 3.26-3.15 (m, 2H), 2.85 (s, 3H), 2.35-2.28 (m, 2H)

[0577] Intermediate-20: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-amine

[0578] [ka]

[0579] Step-1: N-(4-bromo-5,6,7,8-tetrahydronaphthalen-1-yl)-2-(hydroxyimino)acetamide

[0580] The title compound was synthesized according to the similar reaction protocol as described in Step-1 of Route-II of Intermediate-18 by using 4-bromo-5,6,7,8-tetrahydronaphthalen-1-amine (commercially available).

[0581] 1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.45(s,1H),7.67(s,1H),7.44(d,J=8.5Hz, 1H),7.28(d,J=8.5Hz,1H),2.69-2.66(m,2H),2.61-2.58(m,2H),1.74-1.69(m,4H)

[0582] Step-2: 5-Bromo-6,7,8,9-tetrahydro-1H-benzo[g]indole-2,3-dione

[0583] The title compound was synthesized by using N-(4-bromo-5,6,7,8-tetrahydronaphthalen-1-yl)-2-(hydroxyimino)acetamide and following the same reaction protocol as described in step-2 of Route-II of Intermediate-18.

[0584] 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.53(s,1H),2.75-2.57(m,4H),1.76-1.71(m,4H)

[0585] Step-3: 6-Bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4(3H)-one

[0586] The title compound was synthesized by using 5-bromo-6,7,8,9-tetrahydro-1H-benzo[g]indole-2,3-dione and following the similar reaction protocol as described in step-3 of Route-II of Intermediate-18.

[0587] MS(ES+)m / z=293.1(M+) 1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.04(s,1H),3.02(t,J=6.1Hz,2H),2.76(t,J=6.2Hz,2H),2.35(s,3H),1.79-1.63(m,4H)

[0588] Step-4: 6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate

[0589] To a stirred suspension of 6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4(3H)-one (0.3 g, 1.023 mmol) in tetrahydrofuran (60 mL) was added potassium carbonate (0.424 g, 3.07 mmol), DMAP (0.125 g, 1.023 mmol), followed by 2,4,6-triisopropylbenzenesulfonyl chloride (0.682 g, 2.251 mmol) at 25° C. The reaction mixture was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give a crude residue (0.41 g). The crude compound was purified by flash column chromatography using a gradient eluent of 0 to 15% ethyl acetate in hexane to give 6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (0.26 g, 45.4% yield) as an off-white solid.

[0590] 1 H NMR (400MHz, chloroform-d) δ8.23(s,1H),7.22(s,2H),4.40-4.27(m,2H),3.30-3.17 (m,2H),2.97-2.88(m,3H),2.61(s,3H),1.92-1.82(m,4H),1.28(d,J=6.8Hz,18H)

[0591] Step-5: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-amine

[0592] To a stirred solution of 6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (0.25 g, 0.447 mmol) in DMSO (2.5 mL) was added (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (0.109 g, 0.536 mmol) followed by triethylamine (0.498 mL, 3.57 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was brought to room temperature, diluted with DCM (50 mL), and washed with a saturated solution of sodium bicarbonate. The separated organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a crude residue (0.321 g). The crude residue was purified by flash column chromatography using an eluent of 0→0.5% methanol in DCM to give (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-4-amine (0.14 g, 65.4% yield).

[0593] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.32(d,J=7.8Hz,1H),6.87(s,1H),6.83(d,J=1.9Hz,1H),6.69(d,J=1.9Hz,1H),5.54 (s,2H),5.50(d,J=7.2Hz,1H),3.11-3.02(m,2H),2.81-2.72(m,2H),2.40(s,3H),1.83-1.71(m,4H),1.53(d,J=7.0Hz,3H)

[0594] Intermediate-21: (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0595] [ka]

[0596] To a stirred solution of 6-bromo-4-chloro-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline (1 g, 3.36 mmol) (Intermediate-19) in 1,4-dioxane (30 ml), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (0.909 g, 3.36 mmol) and diisopropylamine (1.761 ml, 10.08 mmol) were added in a microwave vial at room temperature. The reaction mixture was heated at 120° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give 2.0 g of crude compound. The crude residue was purified by flash chromatography using a gradient elution with ethyl acetate in hexanes (0 to 50%) to give (R)-6-bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (1.5 g, 90% yield) as a sticky yellow solid.

[0597] 1 H NMR(400MHz,DMSO-d6)δ8.61(t,J=1.8Hz,1H),8.53(d,J=7.3Hz,1H),8.46(s,1H),8.36-8.30(m,2H),5.73 -5.55(m,1H),3.29-3.13(m,2H),3.13-2.85(m,2H),2.36(s,3H),2.19-2.08(m,2H),1.66(d,J=7.1Hz,3H) MS(m / z)=495.10(M+1)

[0598] Intermediate-22: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0599] [ka]

[0600] To a solution of 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (Intermediate-18) (2.0 g, 7.16 mmol) (Intermediate-18) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (4.75 g, 10.75 mmol) in DMF (60 ml), DBU (5.40 ml, 35.8 mmol) was added, followed by (R / S)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (1.975 g, 9.67 mmol) at room temperature. The resulting reaction mixture was stirred at 120° C. for 2 hours. The reaction mixture was quenched with ice-cold water (50 ml), extracted with ethyl acetate (60 ml×3), and washed with water (30 ml) and brine (30 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue (3.1 g). The crude mass was purified by flash column chromatography using a gradient elution of 0 to 30% ethyl acetate in hexane to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (1.5 g, 45.0% yield) as a colorless oil.

[0601] MS(ES+)m / z=465.1(M+) 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.35(d,J=7.8Hz,1H),6.91-6.81(m,2H),6.70(d,J=1.9Hz,1H),5.53(d,J= 11.8Hz,3H),3.23(t,J=7.7Hz,2H),3.03(t,J=7.5Hz,2H),2.39(s,3H),2.19-2.09(m,2H),1.54(d,J=7.1Hz,3H)

[0602] Following the same procedure as described above for Intermediate-22, the following intermediates disclosed in Table 2 were prepared using Intermediate-18 and the appropriate amine.

[0603] [Table 2]

[0604] Intermediate-25: (R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one

[0605] [ka]

[0606] A solution of (R)-6-bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Intermediate-21) (500 mg, 1.009 mmol), morpholin-3-one (306 mg, 3.03 mmol), KCO (279 mg, 2.019 mmol) in dioxane (20 ml) was taken and degassed with N in a microwave vial for 5 minutes before adding Cu(I)I (19.23 mg, 0.101 mmol). The resulting reaction mixture was heated at 95° C. for 16 hours. The reaction mixture was concentrated in vacuo to give crude material (0.9 g). The crude residue was purified by flash column chromatography using a gradient elution with ethyl acetate in hexanes (0 to 60%) to afford (R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (450 mg, 86% yield) as an off-white solid.

[0607] MS(ES+)m / z=516.0(M+1) 1H NMR(400MHz,DMSO-d6)δ8.62(t,J=1.8Hz,1H),8.42(d,J=7.3Hz,1H),8.37-8.30(m,2H),8.12(s,1H),5.73-5.64(m,1H),4.09-4 .00(m,2H),3.77-3.68(m,4H),3.28-3.19(m,3H),3.19-3.11(m,2H),2.95-2.85(m,2H),2.17-2.04(m,2H),1.67(d,J=7.1Hz,3H)

[0608] Intermediate-26: (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol

[0609] [ka]

[0610] To a stirred solution of 6-bromo-4-chloro-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline (Intermediate-19) (200 mg, 0.672 mmol) in dioxane (5.0 ml) was added (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol (Intermediate-8) (147 mg, 0.672 mmol) and DIPEA (0.352 ml, 2.016 mmol) in a microwave vial. The resulting reaction mixture was heated at 100° C. for 16 hours. After complete consumption of the starting material, the reaction mixture was concentrated in vacuo to give the crude product (371 mg). The crude product was purified by flash column chromatography using an eluent of 0→40% ethyl acetate in hexane to give (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol (300 mg, 93% yield).

[0611] MS(ES+)m / z=481.11(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.45(d,J=7.3Hz,1H),7.68-7.60(m,1H),7.45-7.37(m,1H),7.25(t,J=7.7Hz,1H),5.84-5.76(m,1) H),4.84-4.73(m,1H),4.00-3.87(m,2H),3.29-3.16(m,2H),3.03(t,J=7.5Hz,2H),2.35(s,3H),2.20-2.07(m,2H),1.58(d,J=7.0Hz,3H)

[0612] Using a procedure similar to Intermediate-26 above, but using Intermediate-19 and the appropriate amine, the following examples disclosed in Table 3 were prepared.

[0613] [Table 3] TIFF0007629922000050.tif93131

[0614] Intermediate-35: (R)-6-bromo-N-(1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0615] [ka]

[0616] To a stirred solution of (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol (300 mg, 0.625 mmol) (Intermediate-26) in DCM (10 ml), 1,8-bis(dimethylamino)naphthalene (361 mg, 1.686 mmol), trimethyloxonium tetrafluoroborate (231 mg, 1.561 mmol) were added at 0° C. The resulting heterogeneous reaction mass was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was diluted with DCM (50 ml), filtered through Celite, and the filtrate was washed with 10% aqueous HCl. The separated organic layer was washed again with water (20 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product (500 mg), which was purified by flash column chromatography using a gradient elution with 20% ethyl acetate in hexane to give (R)-6-bromo-N-(1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (120 mg, 38.83% yield) as a colorless liquid.

[0617] MS(ES+)m / z=496.05(M+2) 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.47(d,J=7.2Hz,1H),7.65-2.60(m,1H),7.46-7.40(m,1H),7.28-7.23(m,1H),5.81-5. 73(m,1H),4.05-3.93(m,2H),3.26-3.29(m,1H),3.03(t,J=7.6Hz,2H),2.34(s,3H),2.17-1.99(m,2H),1.58(d,J=7.1Hz,3H)

[0618] Intermediate-36: (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethan-1-one

[0619] [ka]

[0620] A mixture of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (1.8 g, 3.87 mmol) (Intermediate-22), tributyl(1-ethoxyvinyl)stannane (1.075 ml, 5.03 mmol) and PdCl(PPh) (0.272 g, 0.387 mmol) in toluene (20 ml) was heated at 100° C. for 16 hours. After completion of the reaction, the reaction mass was cooled to room temperature, filtered through a Celite bed, the solvent was removed in vacuo and the residue was suspended in 2N HCl (10 ml) and THF (30 ml). The resulting mixture was stirred for 2 hours at room temperature, basified with aqueous NaHCO, and then extracted with EtOAc (3×50 ml). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5.5 g of crude compound. The crude compound was purified by flash column chromatography using a gradient elution of 20 to 30% ethyl acetate in hexane to give (R) 1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethan-1-one (1.2 g, 72.4% yield) as a colorless oil.

[0621] MS(ES+)m / z=429.1(M+1) 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.64(d,J=7.9Hz,1H),6.90-6.88(m,1H),6.87-6.85(d,J=1.9Hz,1H),6.73-6.70(m,1H),5.68-5. 61(m,1H),5.57(s,2H),3.29(t,J=7.5Hz,2H),3.09(t,J=7.7Hz,2H),2.70(s,3H),2.43(s,3H),2.13-2.04(m,2H),1.60(d,J=7.1Hz,3H)

[0622] Intermediate-37: (R)-3-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-3,3-difluoropropan-1-ol

[0623] [ka]

[0624] Step-1: (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetaldehyde

[0625] A solution of oxalyl chloride (0.087 ml, 0.999 mmol) in dichloromethane (20 ml) was taken at −78° C., and to the solution was added anhydrous DMSO (0.136 ml, 1.915 mmol). The mixture was maintained at −60° C. for 30 minutes. A solution of ((R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethan-1-ol) (400 mg, 0.833 mmol) (Intermediate-26) in dichloromethane (10 ml) was added and vigorously stirred at −60° C. for 30 minutes. Then, triethylamine (0.522 ml, 3.75 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. Upon completion, the reaction mixture was diluted with dichloromethane (100 ml) and washed with water (50 ml) and brine (50 ml). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give crude (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetaldehyde. The crude product was used as is in the next step. MS(ES+)m / z=478.05(M+)

[0626] Step-2: (R)-6-bromo-N-(1-(3-(1,1-difluoroallyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0627] To a suspension of methyltriphenylphosphonium bromide (892 mg, 2.496 mmol) in THF (20 ml) was added KHMDS (2.496 ml, 2.496 mmol) at 0° C. The yellow mixture was stirred at 0° C. for 30 minutes. A solution of (R)-2-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetaldehyde (398 mg, 0.832 mmol) in 5 ml of THF was added to the reaction mixture. The yellow suspension was again stirred at room temperature for 16 hours. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (50 ml × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by flash chromatography using a gradient elution with ethyl acetate in hexane (0 to 30%) to give (R)-6-bromo-N-(1-(3-(1,1-difluoroallyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (140 mg, 35.3% yield) as a colorless sticky solid.

[0628] MS(ES+)m / z=476.1(M+) 1 H NMR(400MHz,DMSO-d6)δ8.57-8.54(m,1H),8.48-8.45(m,1H),7.67-7.59(m,1H),7.49-7.41(m,1H),7.29-7.22(m,1H),6.47-6.34(m, 1H),5.78-5.68(m,1H),5.67-5.54(m,2H),3.24-3.17(m,2H),3.07-2.98(m,2H),2.32(s,3H),2.17-2.06(m,2H),1.57(d,J=6.6Hz,3H)

[0629] Step-3: (R)-3-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-3,3-difluoropropan-1-ol

[0630] To a solution of (R)-6-bromo-N-(1-(3-(1,1-difluoroallyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (142 mg, 0.298 mmol) in THF (10 mL) was added BH3.THF (1.491 mL, 1.491 mmol) at 0 °C. The resulting solution was allowed to warm to room temperature and stirred for 3 h. The solution was cooled to 0 °C again and treated dropwise with 10 N NaOH (0.298 mL, 1.49 mmol), followed by the slow addition of HO (0.304 mL, 2.98 mmol). The resulting mixture was allowed to warm to room temperature and stirred again for 1 h. The reaction mixture was diluted with 10% HCl (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated to give crude (R)-3-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-3,3-difluoropropan-1-ol (70 mg) as a green sticky solid, which was used as is in the next step. MS(ES+)m / z=494.11(M+)

[0631] Intermediate-38: 1-(3-((R)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoropropan-2-ol

[0632] [ka]

[0633] To a solution of (R)-6-bromo-N-(1-(3-(1,1-difluoroallyl)-2-fluorophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (800 mg, 1.679 mmol) in THF (20 mL) was added BH3.THF (8.40 mL, 8.40 mmol) at 0 °C. The solution was allowed to warm to room temperature and stirred for 3 h. The solution was cooled to 0 °C again and treated dropwise with 10 N NaOH (2.0 mL), followed by the slow addition of HO (1.715 mL, 16.79 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with 10% aqueous HCl (10 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography using a gradient elution with ethyl acetate in hexanes (0 to 30%) to give 1-(3-((R)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoropropan-2-ol (360 mg, 43.4% yield) as a white solid.

[0634] MS(ES+)m / z=494.17(M+) 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.49-8.41(m,1H),7.66-7.56(m,1H),7.41-7.32(m,1H),7.27-7.17(m,1H),5.85-5.75(m,1H),5.60-5. 55(m,1H),4.20(s,1H),3.27-3.18(m,2H),3.03(t,J=7.6Hz,2H),2.40 -2.28(m,3H),2.18-2.08(m,2H),1.62-1.54(m,3H),1.17-1.12(m,3H)

[0635] Intermediate-39: 3-(3-((R / S)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4)amino)ethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol (Compound-39a) and 3-(3-((S / R)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4)amino)ethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol (Compound-39b)

[0636] [ka]

[0637] Step-1: 1-Bromo-3-(1,1-difluoro-2-methylallyl)-2-fluorobenzene

[0638] To a solution of 1-(3-bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (12.5 g, 44.2 mmol) in dichloromethane (130 ml) was added martinsulfurane (29.7 g, 44.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 21.0 g of crude residue. The obtained crude product was purified by flash chromatography using a gradient elution with ethyl acetate in hexane (0 to 2%) to obtain 1-bromo-3-(1,1-difluoro-2-methylallyl)-2-fluorobenzene (8.1 g, 69.2% yield) as a colorless liquid.

[0639] 1 H NMR (400 MHz, chloroform-d) δ 7.72-7.64 (m, 1H), 7.55-7.47 (m, 1H), 7.17-7.08 (m, 1H), 5.36-5.21 (m, 2H), 1.91-1.84 (m, 3H) GCMS (m / z) = 264.10 (M+)

[0640] Step-2: 3-(3-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol

[0641] To a solution of 1-bromo-3-(1,1-difluoro-2-methylallyl)-2-fluorobenzene (7.0 g, 26.4 mmol) in acetone (60 ml) and water (15 ml), N-methylmorpholine N-oxide (6.19 g, 52.8 mmol) and potassium osmate dihydrate (0.584 g, 1.584 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was diluted with cold water (70 ml), and the compound was extracted with ethyl acetate (70 ml × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 14.0 g of crude product. The resulting crude product was purified by flash chromatography using a gradient elution with ethyl acetate in hexane (0 to 60%) to give 3-(3-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol (6.7 g, 85% yield) as a brown liquid.

[0642] 1 H NMR(400MHz,DMSO-d6)δ7.90-7.79(m,1H),7.54-7.42(m,1H),7.31-7.20(m,1H),4.0 7-3.98(m,1H),3.57-3.55(m,1H),3.46-3.40(m,1H),3.38-3.30(m,1H),1.18(s,3H)

[0643] Step-3: (R / S)-1-(3-(1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (Peak-1) and (S / R)-1-(3-(1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (Peak-2)

[0644] [ka]

[0645] The title compound was synthesized by using 3-(3-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol and following the similar reaction protocol as described in step-2 of intermediate-1, and was further separated by chiral chromatography (instrument method: MEOH_0.1% DEA_100_B_1.0ML_8MIN, flow rate: 1.00ml / min) to give two isomers as peak-1 and peak-2, respectively.

[0646] Peak-1: 1 H NMR(400MHz,DMSO-d6)δ7.98-7.83(m,1H),7.73-7.62(m,1H),7.45-7.34(m,1H),5.3 5(s,1H),4.74(t,J=6.0Hz,1H),3.52-3.36(m,2H),2.59(d,J=4.3Hz,3H),1.21(s,3H) Chiral purity - 99.93%, (RT - 3.75)

[0647] Peak-2: 1 H NMR(400MHz,DMSO-d6)δ7.95-7.84(m,1H),7.72-7.64(m,1H),7.44-7.35(m,1H),5.3 5(s,1H),4.74(t,J=6.1Hz,1H),3.50-3.33(m,2H),2.59(d,J=4.3Hz,3H),1.21(s,3H) Chiral purity - 93.76%, (RT - 4.28)

[0648] Step-4: (R)—N-(1-(3-((R / S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (Peak-1) and (R)—N-(1-(3-((S / R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (Peak-2)

[0649] [ka]

[0650] The title compound was synthesized according to the similar reaction protocol as described in step-3 of intermediate-1 by using (R / S)-1-(3-(1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (Peak-1) and (S / R)-1-(3-(1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (Peak-2) (Peak-1 and Peak-2 were taken separately) to give Peak-1 and Peak-2, respectively.

[0651] Peak-1: MS(ES+)m / z=366.35(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.79-7.68(m,1H),7.64-7.55(m,1H),7.42-7.32(m,1H),5.33(s,1H) ),4.73(t,J=6.0Hz,1H),3.48-3.36(m,2H),2.68(d,J=2.5Hz,3H),1.22(s,3H),1.08(s,9H)

[0652] Peak-2: MS(ES+)m / z=366.35(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.78-7.68(m,1H),7.63-7.54(m,1H),7.42-7.31(m,1H),5.33(s,1H) ),4.73(t,J=6.0Hz,1H),3.50-3.38(m,2H),2.68(d,J=2.6Hz,3H),1.23(s,3H),1.08(s,9H)

[0653] Step-5: (R)—N-((R / S)-1-(3-((R / S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (Peak-1) and (R)—N-((S / R)-1-(3-((S / R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (Peak-2)

[0654] [ka]

[0655] The title compound was synthesized by using (R)—N-(1-(3-((R / S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (Peak-1) and (R)—N-(1-(3-((S / R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (Peak-2) (Peak-1 and Peak-2 were submitted separately) and following the similar reaction protocol as described in step-4 of Intermediate-2 to give the major isomers of Peak-1 and Peak-2, respectively.

[0656] Peak-1: MS(ES+)m / z=368.35(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.69-7.63(m,1H),7.38-7.31(m,1H),7.31-7.23(m,1H),5.85(d,J=7.7Hz,1H ),5.23(s,1H),4.71-4.65(m,2H),3.48-3.35(m,2H),1.40(d,J=6.8Hz,3H),1.19(s,3H),1.11(s,9H)

[0657] Peak-2: MS(ES+)m / z=368.35(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.69-7.63(m,1H),7.38-7.31(m,1H),7.30-7.23(m,1H),5.85(d,J=7.6Hz,1H ),5.24(s,1H),4.76-4.61(m,2H),3.44-3.38(m,2H),1.40(d,J=6.8Hz,3H),1.19(s,3H),1.11(s,9H)

[0658] Step-6: (R / S)-3-(3-((R / S)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol hydrochloride (Peak-1) and (S / R)-3-(3-((S / R)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol hydrochloride (Peak-2)

[0659] [ka]

[0660] The title compound was synthesized by using (R)—N-((R / S)-1-(3-((R / S)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (Peak-1) and (R)—N-((S / R)-1-(3-((S / R)-1,1-difluoro-2,3-dihydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (Peak-2) and following the same reaction protocol as described in step-4 of Intermediate-1.

[0661] Peak-1: MS(ES+)m / z=263.95(M+1) 1H NMR(400MHz,DMSO-d6)δ8.62(s,2H),7.84-7.76(m,1H),7.52-7.45(m,1H),7.41-7.34(m,1H) ,5.43-5.21(m,1H),4.77-4.55(m,1H),3.46-3.37(m,2H),1.53(d,J=6.8Hz,3H),1.20(s,3H)

[0662] Peak-2: MS(ES+)m / z=364.15(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.60(s,2H),7.81-7.74(m,1H),7.53-7.45(m,1H),7.41-7.33(m,1H) ,5.37-5.28(m,1H),4.77-4.55(m,1H),3.46-3.37(m,2H),1.53(d,J=6.8Hz,3H),1.20(s,3H)

[0663] Step-7: (R / S)-3-(3-((R / S)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol (Peak-1) (39a) and (S / R)-3-(3-((S / R)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol (Peak-2) (39b)

[0664] [ka]

[0665] The title compound was prepared by using Intermediate-19, and (R / S)-3-(3-((R / S)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol hydrochloride (Peak-1) and (S / R)-3-(3-((S / R)-1-aminoethyl)-2-fluorophenyl)-3,3-difluoro-2-methylpropane-1,2-diol hydrochloride (Peak-2) and following a similar reaction protocol as described in the synthesis of Intermediate-21. Intermediate-39a:MS(ES+)m / z=526.32(M+2), Intermediate-39b:MS(ES+)m / z=526.30(M+2)

[0666] Intermediate-40: (R / S)-N-(3-(1-aminoethyl)-5-fluorophenyl)acetamide hydrochloride

[0667] [ka]

[0668] Step-1: N-(3-bromo-5-fluorophenyl)acetamide

[0669] To a solution of 1,3-dibromo-5-fluorobenzene (25 g, 98 mmol) (commercially available) and acetamide (7.56 g, 128 mmol) in dioxane (200 ml) in RB was added Cs2CO3 (48.1 g, 148 mmol). The mixture was thoroughly deoxygenated by purging with nitrogen for 15 minutes, after which Pd2(dba)3 (1.803 g, 1.969 mmol) and Xantphos (1.140 g, 1.969 mmol) were added. The resulting reaction mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the reaction mass was cooled to room temperature, diluted with ethyl acetate (500 ml), and filtered through Celite. The filtrate was concentrated under vacuum and the crude product (30 g) was purified by flash column chromatography with gradient elution with 30% ethyl acetate in hexane to give N-(3-bromo-5-fluorophenyl)acetamide (15 g, 65.6% yield).

[0670] MS(ES+)m / z=234.1(M+2) 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.64-7.61(m,1H),7.51-7.45(m,1H),7.21-7.18(m,1H),2.07(s,3H)

[0671] Step-2: N-(3-acetyl-5-fluorophenyl)acetamide

[0672] The title compound was synthesized by using N-(3-bromo-5-fluorophenyl)acetamide and following the similar reaction protocol as described in step-2 of intermediate-1.

[0673] GCMS (m / z) = 195.15 (M+) 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.88-7.81(m,2H),7.45-7.35(m,1H),2.56(s,3H),2.08(s,3H)

[0674] Step-3: (R)—N-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-fluorophenyl)acetamide

[0675] The title compound was synthesized by using N-(3-acetyl-5-fluorophenyl)acetamide and following a similar reaction protocol as described in step-3 of intermediate-2.

[0676] MS(ES+)m / z=299.34(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.87-7.84(m,1H),7.83-7.79(m,1H),7.39-7.32(m,1H),2.69(s,3H),2.08(s,3H),1.24(s,9H)

[0677] Step-4: N-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-fluorophenyl)acetamide

[0678] The title compound was synthesized by using (R)-N-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-fluorophenyl)acetamide and following a similar reaction protocol as described in step-4 of intermediate-2.

[0679] MS(ES+)m / z=301.28(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.52-7.45(m,1H),7.25-7.21(m,1H),6.96-6.92(m,1 H),5.71(d,J=7.0Hz,1H),4.38-7.28(m,1H),2.05(s,3H),1.38(d,J=6.7Hz,3H),1.12(s,9H)

[0680] Step-5: (R / S)-N-(3-(1-aminoethyl)-5-fluorophenyl)acetamide hydrochloride

[0681] The title compound was synthesized by using N-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-fluorophenyl)acetamide and following a similar reaction protocol as described in step-5 of intermediate-2.

[0682] MS(ES+)m / z=301.28(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.71-8.47(m,3H),7.59-7.52(m,1H),7.46-7 .43(m,1H),7.18-7.13(m,1H),4.42-4.23(m,1H),2.08(s,3H),1.50(d,J=6.8Hz,3H)

[0683] Intermediate-41: (R / S)-N-(3-(1-aminoethyl)-5-(difluoromethyl)phenyl)acetamide hydrochloride

[0684] [ka]

[0685] Step-1: 3-amino-5-bromo-N-methoxy-N-methylbenzamide

[0686] To a stirred solution of 3-amino-5-bromobenzoic acid (24 g, 111 mmol) (commercially available) in DMF (10 ml) was added N,O-dimethylhydroxylamine hydrochloride (108 g, 1111 mmol) and DIPEA (233 ml, 1333 mmol), and the mixture was stirred for 15 minutes before adding HATU (46.5 g, 122 mmol) at room temperature. The resulting reaction mass was stirred at 25° C. for 16 hours. After complete consumption of the starting material, the reaction mass was cooled to 0° C. o The mixture was cooled to 20°C and cold water was added to precipitate the solid product, which was filtered and dried under vacuum to give 3-amino-5-bromo-N-methoxy-N-methylbenzamide (28 g, 97% yield) as an off-white solid.

[0687] MS(ES+)m / z=260.96(M+2) 1 H NMR(400MHz,DMSO-d6)δ6.83-6.81(m,1H),6.78-6.73(m,1H),6.73-6.70(m,1H),5.61(s,2H),3.55(s,3H),3.21(s,3H)

[0688] Step-2: 3-acetamido-5-bromo-N-methoxy-N-methylbenzamide

[0689] To a stirred solution of 3-amino-5-bromo-N-methoxy-N-methylbenzamide (28 g, 108 mmol) in DCM (200 ml) was added DIPEA (37.7 ml, 216 mmol) and a catalytic amount of DMAP (0.660 g, 5.40 mmol) at room temperature. o After cooling to 20°C, acetyl chloride (9.22 ml, 130 mmol) was added dropwise. The resulting reaction mixture was allowed to reach room temperature and stirred for 16 hours. DCM (500 ml) was added, and it was washed with water (200 ml) and brine (200 ml). The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated under vacuum. The crude mass (32 g) was purified by flash column chromatography using 0 to 30% ethyl acetate in hexane as a gradient eluent to give 3-acetamido-5-bromo-N-methoxy-N-methylbenzamide (12 g, 36.9% yield) as a white solid.

[0690] MS(ES+)m / z=303.21(M+2) 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.01-8.00(m,1H),7.75-7.73(m,1H),7.40-7.38(m,1H),3.56(s,3H),3.25(s,3H),2.07(s,3H)

[0691] Step-3: N-(3-bromo-5-formylphenyl)acetamide

[0692] To a stirred solution of 3-acetamido-5-bromo-N-methoxy-N-methylbenzamide (12 g, 39.8 mmol) in THF (100 ml) was added 1 M DIBAL-H in toluene (47.8 ml, 47.8 mmol) dropwise over 30 min at −78° C. The resulting reaction mass was stirred for 3 h at −78° C. After complete consumption of the starting material, the reaction mass was poured into an ice-cold saturated solution of ammonium chloride and diluted with ethyl acetate (900 ml). The layers were separated, dried over anhydrous NaSO, filtered, and concentrated under vacuum. The crude mass (18 g) was purified by flash column chromatography using a gradient of 0 to 50% EtOAc in hexanes to give N-(3-bromo-5-formylphenyl)acetamide (6 g, 62.2% yield) as a white solid.

[0693] MS(ES+)m / z=244.1(M+2) 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.93(s,1H),8.18-8.15(m,1H),8.07-8.02(m,1H),7.77-7.75(m,1H),2.09(s,3H)

[0694] Step-4: N-(3-bromo-5-(difluoromethyl)phenyl)acetamide

[0695] To a cooled (-15°C) solution of N-(3-bromo-5-formylphenyl)acetamide (5 g, 20.66 mmol) in DCM (100 ml), DAST (13.64 ml, 103 mmol) was added dropwise. The mixture was stirred for 15 minutes and then allowed to reach room temperature. After completion of the reaction, the mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution (100 ml), and the product was extracted into DCM (100 ml x 2). The combined organic layer was washed with water (100 ml) and brine (100 ml). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The crude mass was purified by flash column chromatography using 0 to 10% ethyl acetate in hexane as a gradient eluent to give N-(3-bromo-5-(difluoromethyl)phenyl)acetamide (0.7 g, 12.83% yield).

[0696] MS(ES+)m / z=266.1(M+2) 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.02-8.00(m,1H),7.79-7.76(m,1H),7.44-7.42(m,1H),7.03(t,J=55.6Hz,1H),2.08(s,3H)

[0697] Step-5: N-(3-acetyl-5-(difluoromethyl)phenyl)acetamide

[0698] The title compound was synthesized by using N-(3-bromo-5-(difluoromethyl)phenyl)acetamide and following a similar reaction protocol as described in step-2 of intermediate-1.

[0699] MS(ES+)m / z=228.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.25-8.20(m,1H),8.18-8.14(m,1H),7.83-7.81(m,1H),7.12(t,J=55.6Hz,1H),2.60(s,3H),2.09(s,3H)

[0700] Step-6: (R)—N-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(difluoromethyl)phenyl)acetamide

[0701] The title compound was synthesized by using N-(3-acetyl-5-(difluoromethyl)phenyl)acetamide and following a similar reaction protocol as described in step-3 of intermediate-2.

[0702] MS(ES+)m / z=331.34(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.24-8.21(m,1H),8.12-8.10(m,1H),7. 74-7.71(m,1H),7.11(t,J=55.7Hz,1H),2.73(s,3H),2.09(s,3H),1.24(s,9H)

[0703] Step-7: N-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-(difluoromethyl)phenyl)acetamide

[0704] The title compound was synthesized by using (R)-N-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(difluoromethyl)phenyl)acetamide and following a similar reaction protocol as described in step-4 of intermediate-2.

[0705] MS(ES+)m / z=333.40(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.81-7.79(m,1H),7.63-7.61(m,1H),7.29-7.27(m,1H),7.00(t, J=55.9Hz,1H),5.75(d,J=6.5Hz,1H),4.40-4.37(m,1H),2.06(s,3H),1.40(d,J=6.7Hz,3H),1.12(s,9H)

[0706] Step-8: (R / S)-N-(3-(1-aminoethyl)-5-(difluoromethyl)phenyl)acetamide hydrochloride

[0707] The title compound was synthesized by using N-(3-((R / S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-(difluoromethyl)phenyl)acetamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0708] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.53-8.36(m,3H),7.85-7.79(m,2H),7.43-7.4 1(m,1H),7.05(t,J=55.7Hz,1H),4.55-4.31(m,1H),2.09(s,3H),1.51(d,J=6.8Hz,3H)

[0709] Intermediate-42: (R / S)-N-(3-fluoro-5-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0710] [ka]

[0711] Step-1: 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

[0712] To a stirred solution of 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (5 g, 17.91 mmol) (Intermediate-18) in NMP (200 ml) was added Pd(dba) (1.640 g, 1.791 mmol), BINAP (2.231 g, 3.58 mmol), and sodium tert-butoxide (3.44 g, 35.8 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was diluted with water (100 ml) and extracted with ethyl acetate (150 ml × 2). The organic layer was washed with water (100 ml) and brine (100 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (5.4 g). The crude product was purified by flash column chromatography using a gradient elution with 0 to 80% ethyl acetate in hexane to give 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (1.8 g, 35.2% yield) as a gray solid.

[0713] MS(ES+)m / z=286.34(M+1) 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),7.33(s,1H),3.79-3.74(m,4H),3.07(t,J=7.3Hz,2H),3.00-2.91(m,6H),2.32(s,3H),2.12-2.04(m,2H)

[0714] Step-2: (R / S)—N-(3-fluoro-5-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0715] To a stirred solution of 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (0.25 g, 0.876 mmol) in DMF (10 ml), DBU (1.321 ml, 8.76 mmol) and BOP (0.581 g, 1.314 mmol) were added sequentially and stirred for 15 minutes at room temperature, after which (R / S)-N-(3-(1-aminoethyl)-5-fluorophenyl)acetamide hydrochloride (0.306 g, 1.314 mmol) (Intermediate-40) was added. The resulting mixture was heated at 120° C. for 2 hours. The reaction mass was allowed to reach room temperature and poured into ice-cold water (20 ml). The yellow solid was precipitated, filtered, and dried. The residue was dissolved in DCM (50 ml), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude mass (300 mg) was purified by flash column chromatography using 0 to 100% ethyl acetate in hexane as a gradient eluent to give (R / S)—N-(3-fluoro-5-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4yl)amino)ethyl)phenyl)acetamide (0.2 g, 49.2% yield) as a brown solid. MS(ES+)m / z=464.23(M+1)

[0716] Intermediate-43: (R / S)-N-(3-(difluoromethyl)-5-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0717] [ka]

[0718] The title compound was synthesized by using 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one and following a similar reaction protocol as described in step-2 of Intermediate-42. MS(ES+)m / z=496.24(M+1)

[0719] Intermediate-44: 1-(3-((R / S)-1-aminoethyl)phenyl)-2,2,2-trifluoroethan-1-ol hydrochloride

[0720] [ka]

[0721] Step 1: 1-(3-bromophenyl)-2,2,2-trifluoroethan-1-ol

[0722] To a stirred solution of 3-bromobenzaldehyde (12 g, 64.9 mmol) in tetrahydrofuran (100 ml), (trifluoromethyl)trimethylsilane (13.83 g, 97 mmol) and a catalytic amount of TBAF (12.97 ml, 12.97 mmol) were added at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was diluted with 3N HCl solution (30 ml) and stirred for 30 minutes. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (100 ml × 3). The combined organics were washed with brine (100 ml), dried over NaSO, filtered, and concentrated to give the crude product (22 g). The crude residue was purified by flash column chromatography using 0→20% ethyl acetate in hexane as eluent to give 1-(3-bromophenyl)-2,2,2-trifluoroethan-1-ol (13 g, 79% yield) as a light brown liquid.

[0723] GCMS (m / z) = 255.97 (M+) 1 H NMR(400MHz,DMSO-d6)δ7.72-7.67(m,1H),7.63-7.59(m,1H),7.54-7.49(m,1H),7.43-7.37(m,1H),7.00(d,J=5.7Hz,1H),5.29-5.21(m,1H)

[0724] Step-2: 1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethan-1-one

[0725] The title compound was synthesized by using 1-(3-bromophenyl)-2,2,2-trifluoroethan-1-ol and following the similar reaction protocol as described in step-2 of intermediate-1.

[0726] GCMS (m / z) = 218.13 (M+) 1 H NMR(400MHz,DMSO-d6)δ8.11-8.05(m,1H),8.04-7.97(m,1H),7.79-7.72(m, 1H),7.63-7.55(m,1H),6.99(d,J=5.7Hz,1H),5.36-5.24(m,1H),2.60(s,3H)

[0727] Step-3: (R / S)-2-methyl-N-(1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethylidene)propane-2-sulfinamide

[0728] The title compound was synthesized by using 1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2. MS(ES+)m / z=321.28(M+)

[0729] Step-4: (R / S)-2-methyl-N-(1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethylidene)propane-2-sulfinamide

[0730] The title compound was synthesized by using (R / S)-2-methyl-N-(1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethylidene)propane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-2.

[0731] MS(ES+) m / z=323.97(M+) 1 H NMR(400MHz,DMSO-d6)δ7.52-7.47(m,1H),7.45-7.40(m,1H),7.38-7.33(m,2H),6.89-6.76(m, 1H),5.74-5.67(m,1H),5.18-5.05(m,1H),4.46-4.33(m,1H),1.40(d,J=6.8Hz,3H),1.11(s,9H)

[0732] Step-5: 1-(3-((R / S)-1-aminoethyl)phenyl)-2,2,2-trifluoroethan-1-ol hydrochloride

[0733] The title compound was synthesized by using (R / S)-2-methyl-N-(1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)ethylidene)propane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-1.

[0734] 1 H NMR(400MHz,DMSO-d6)δ8.57-8.26(m,3H),7.64-7.61(m,1H),7.56-7.52(m,1H) ,7.51-7.47(m,2H),6.99(s,1H),5.18(s,1H),4.44(s,1H),1.50(d,J=6.8Hz,3H)

[0735] Intermediate-45: (R / S)-1-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol

[0736] [ka]

[0737] Step-1: 1-(3-bromophenyl)-1,1-difluoro-2-methylpropan-2-ol

[0738] The title compound was synthesized from commercially available ethyl 2-(3-bromophenyl)-2,2-difluoroacetate by following the similar reaction protocol as described in step-1 of intermediate-2.

[0739] 1H NMR(400MHz,DMSO-d6)δ7.73-7.69(m,1H),7.64-7.61(m,1H),7.52-7.41(m,2H),5.41(s,1H),1.18(s,3H),1.15(s,6H)

[0740] Step-2: 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethan-1-one

[0741] The title compound was synthesized by using 1-(3-bromophenyl)-1,1-difluoro-2-methylpropan-2-ol and following a similar reaction protocol as described in step-2 of intermediate-2.

[0742] 1H NMR(400MHz,DMSO-d6)δ8.13-8.07(m,1H),8.04-7.99(m,1H),7.76-7.72(m ,1H),7.67-7.60(m,1H),5.41(s,1H),2.62(s,3H),1.21(s,3H),1.14(s,6H)

[0743] Step-3: (R / S)—N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0744] The title compound was synthesized by using 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethan-1-one and following a similar reaction protocol as described in step-3 of intermediate-2. LCMS m / z=332.28(M+1)

[0745] Step-4: (R / S)-2-methyl-N-((R / S)-1-(3-(1,1,2,2-tetrafluoro-2-hydroxyethyl)phenyl)ethyl)propane-2-sulfinamide

[0746] The title compound was synthesized by using (R / S)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide and following a similar reaction protocol as described in step-4 of intermediate-2. LCMS m / z=334.11(M+1)

[0747] Step-5: (R / S)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride

[0748] The title compound was synthesized by using (R / S)-2-methyl-N-((R / S)-1-(3-(1,1,2,2-tetrafluoro-2-hydroxyethyl)phenyl)ethyl)propane-2-sulfinamide and following a similar reaction protocol as described in step-5 of intermediate-2.

[0749] 1H NMR(400MHz,DMSO-d6)δ8.68-8.53(m,3H),7.69-7.64(m,1H),7.63-7.59(m,1H),7.55 -7.45(m,2H),5.32(s,1H),4.57-4.38(m,1H),1.53(d,J=6.8Hz,3H),1.22-1.13(m,6H)

[0750] Step-6: (R / S)-1-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol

[0751] The title compound was synthesized by using (R / S)-1-(3-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride and Intermediate-19 and following a similar reaction protocol as described in Intermediate-21. LCMS m / z=492.11(M+2)

[0752] Example 1: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-methoxypiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 1)

[0753] [ka]

[0754] A solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (200 mg, 0.430 mmol) (Intermediate-22), 4-methoxypiperidine (49.5 mg, 0.430 mmol), sodium tert-butoxide (83 mg, 0.860 mmol), and 2-di-t-butylphosphino-2'-(N,N-dimethylamino)biphenyl (29.4 mg, 0.086 mmol) in dioxane (10 mL) was degassed with N for 15 min, and then Pd(dba) (79 mg, 0.086 mmol) was added at room temperature. The resulting reaction mixture was heated at 100 °C for 1 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (40 ml), filtered through Celite, and the residue was washed with ethyl acetate (20 ml × 2). The filtrate was concentrated under vacuum to give the crude product (291 mg). The crude product was purified by flash column chromatography using a gradient elution of 0 to 0.5% MeOH in DCM to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-methoxypiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (21 mg, yield 9.78%).

[0755] MS(ES+)m / z=500.24(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.54(bs,1H),6.88-6.87(m,1H),6.86-6.83( s,1H),6.71-6.68(m,1H),5.63-5.56(m,1H),5.54(s,2H),3.30(s,3H),3.27-3.17 (m,2H),3.10(t,J=7.6Hz,2H),2.95(t,J=7.3Hz,2H),2.85-2.78(m,2H),2.37(s,3 H),2.13-2.04(m,2H),2.03-1.91(m,3H),1.75-1.65(m,2H),1.56(d,J=7.1Hz,3H)

[0756] Using procedures similar to those described above in Example-1 and using the appropriate commercially available amines, the examples disclosed in Table 4 were prepared.

[0757] [Table 4] TIFF0007629922000069.tif255160TIFF0007629922000070.tif255157TIFF0007629922000071.tif255154TIFF00076299220 00072.tif255161TIFF0007629922000073.tif255157TIFF0007629922000074.tif255153TIFF0007629922000075.tif255164 TIFF0007629922000076.tif255153TIFF0007629922000077.tif255156TIFF0007629922000078.tif255153TIFF00076299220 00079.tif255153TIFF0007629922000080.tif246168TIFF0007629922000081.tif255154TIFF0007629922000082.tif255154 TIFF0007629922000083.tif255155TIFF0007629922000084.tif255153TIFF0007629922000085.tif255152TIFF00076299220 00086.tif255152TIFF0007629922000087.tif255161TIFF0007629922000088.tif255154TIFF0007629922000089.tif249168 TIFF0007629922000090.tif238168TIFF0007629922000091.tif255153TIFF0007629922000092.tif249170TIFF00076299220 00093.tif255152TIFF0007629922000094.tif255153TIFF0007629922000095.tif255153TIFF0007629922000096.tif188170

[0758] Example 74: 1-((R / S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound 74a) and 1-((S / R)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound 74b)

[0759] [ka]

[0760] To a stirred solution of ((R)1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethan-1-one) (0.2 g, 0.467 mmol) (Intermediate-36) and azetidine-3-carbonitrile hydrochloride (0.077 g, 0.654 mmol) in MeOH (15 mL), acetic acid (0.053 mL, 0.934 mmol) was added at room temperature, and the reaction mixture was stirred for 10 minutes. Subsequently, NaCNBH3 (0.059 g, 0.934 mmol) was added at room temperature, and the reaction mixture was heated to 75°C for 16 hours in a sealed tube. After completion of the reaction, the reaction mass was distilled under reduced pressure to obtain a brown semi-solid, which was then poured into water (50 ml) and basified with 10% aqueous NaHCO3 solution (50 ml). The product was extracted with ethyl acetate (100 ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using an eluent of 0-3% MeOH in DCM, and then purified by reverse-phase preparative HPLC to obtain two diastereomers.

[0761] Peak-1: 1-((R / S)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound-74a)

[0762] MS(ES+)m / z=495.24(M+1), RT:2.37min, [GENERIC_BASIC_CT_aghp_4.5minIW, flow rate: 0.60ml / min]

[0763] 1 H NMR(400MHz,DMSO-d6)δ8.34(d,J=8.2Hz,1H),8.10(s,1H),6.91(s,1H),6.85(s,1H),6.72-6.69(m,1H),5.62-5.56(m,1H),5.55(s,2H),3.64-3 .54(m,1H),3.55-3.34(m,3H),3.26-3.17(m,2H),3.16-3.06(m,4H),2.3 9(s,3H),2.16-2.04(m,2H),1.56(d,J=7.1Hz,3H),1.19(d,J=6.4Hz,3H)

[0764] Peak-2: 1-((S / R)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound-74b)

[0765] MS(ES+)m / z=495.24(M+1), RT:2.40min, [GENERIC_BASIC_CT_aghp_4.5minIW, flow rate: 0.60ml / min]

[0766] 1H NMR(400MHz,DMSO-d6)δ8.34(d,J=8.2Hz,1H),8.10(s,1H),6.91(s,1H),6.85(s,1H),6.72-6.69(m,1H),5.62-5.56(m,1H),5.55(s,2H),3.64-3 .54(m,1H),3.55-3.34(m,3H),3.26-3.17(m,2H),3.16-3.06(m,4H),2.3 9(s,3H),2.16-2.04(m,2H),1.56(d,J=7.1Hz,3H),1.19(d,J=6.4Hz,3H)

[0767] Example 75: (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 75)

[0768] [ka]

[0769] The title compound was synthesized by using 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one and Intermediate-8 and following a similar reaction protocol as described in Step-2 of Intermediate-42.

[0770] MS(ES+)m / z=487.17(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=7.4Hz,1H),7.67-7.60(m,1H),7.57(s,1H),7.45-7.37(m,1H),7.27-7.21(m,1H),5.88-5.80(m,1H),5.76 (s,1H),4.00-3.88(m,2H),3.83-3.76(m,4H),3.14-3.02(m,6H),2.97 (t,J=7.3Hz,2H),2.32(s,3H),2.14-2.02(m,2H),1.60(d,J=7.1Hz,3H)

[0771] Example 76: (R / S)—N-(1-(3-amino-5-fluorophenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 76)

[0772] [ka]

[0773] To a stirred solution of (R / S)—N-(3-fluoro-5-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide (0.2 g, 0.431 mmol) (Intermediate-42) in MeOH (2 ml) was added concentrated HCl (0.360 ml, 4.31 mmol) at room temperature. The resulting reaction mixture was heated at 50° C. for 16 hours. The consumption of the starting material was monitored by TLC and concentrated in vacuo. The residue was neutralized with a saturated solution of sodium bicarbonate, and the product was extracted in ethyl acetate (50 ml), which was washed with water (20 ml) and brine (20 ml). The separated organic layer was dried over anhydrous NaSO and concentrated in vacuo. The crude product (100 mg) was purified by column chromatography using 0→5% MeOH in EtOAc as a gradient eluent to give (R / S)—N-(1-(3-amino-5-fluorophenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (0.095 g, 52.2% yield).

[0774] MS(ES+)m / z=422.04(M+1) 1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.53(s,1H),6.44-6.42(m,1H),6.36-6.33(m,1H),6.20-6.12(m,1H),5.62-5.52(m,1H),5.36(s,2H) ,3.80-3.76(m,4H),3.11(t,J=7.5Hz,2H),3.05-3.00(m,4H),2.97(t,J=7.3Hz,2H),2.39(s,3H),2.12-2.03(m,2H),1.53(d,J=7.1Hz,3H)

[0775] Example 77: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 77)

[0776] [ka]

[0777] The title compound was synthesized by using Intermediate-43 and following a similar reaction protocol as described in Example-76.

[0778] MS(ES+)m / z=454.17(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.27(m,1H),7.56(s,1H),6.83(t,J=56Hz,1H),6.76(s,1H),6.75(s,1H),6.58(s,1H),5.64(p,J=7.4Hz,1H),5.36(s, 2H),3.80-3.77(m,4H),3.11(t,J=7.5Hz,2H),3.06-3.00(m,4H),2.98 (t,J=7.3Hz,2H),2.41(s,3H),2.14-2.05(m,2H),1.59(d,J=7.1Hz,3H)

[0779] Example 78: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 78)

[0780] [ka]

[0781] Step-1: (R / S)-6-bromo-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0782] The title compound was synthesized by using Intermediate-19 and the product of Step-6 of Intermediate-12 and following the same reaction protocol as described in the synthesis of Intermediate-21.

[0783] MS(ES+)m / z=479.11(M+2) 1 H NMR(400MHz,DMSO-d6)δ8.53(d,J=7.3Hz,1H),8.51-8.47(m,2H),8.29-8.25(m,1H),8.15-8.12(m,1H),7.22(t,J=55.3 Hz,1H),5.71-5.59(m,1H),3.28-3.16(m,2H),3.09-2.99(m,2H),2.37(s,3H),2.20-2.05(m,2H),1.65(d,J=7.1Hz,3H)

[0784] Step-2: (R / S)—N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0785] The title compound was synthesized by using (R / S)-6-bromo-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine and following the same reaction protocol as described in the synthesis of Example-1.

[0786] MS(ES+)m / z=496.24(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.52-8.45(m,1H),8.31-8.24(m,1H),8.15-8.12(m,1H),8.11(d,J=7.6Hz,1H),7.40-7.04(m,1H),6.96-6.90(m,1H) ),5.73-5.59(m,1H),4.76(s,4H),4.16(s,4H),3.10-2.99(m,2H),2.98-2.88(m,2H),2.31(s,3H),2.13-2.01(m,2H),1.67(d,J=7.1Hz,3H)

[0787] Step-3: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0788] The title compound was synthesized by using (R / S)-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine and following a similar reaction protocol as described in step 7 of Intermediate-12.

[0789] MS(ES+)m / z=466.23(M+1) 1H NMR(400MHz,DMSO-d6)δ7.90(d,J=8.2Hz,1H),6.98(s,1H),6.82( t,J=54Hz,1H),6.77-6.75(m,1H),6.74-6.73(m,1H),6.58-6.56(m,1H),5.63-5.53(m,1H),5.34(s,2H),4.75(s,4 H),4.13(s,4H),3.05(t,J=7.7Hz,2H),2.94(t,J=7.6Hz,2H),2.35(s,3H),2.13-2.02(m,2H),1.54(d,J=7.0Hz,3H)

[0790] The examples disclosed in Table 5 were synthesized by using 2-methyl-6-morpholino-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one and the appropriate amine and following a reaction protocol similar to that described in step 2 of Intermediate-42.

[0791] [Table 5] TIFF0007629922000103.tif197155

[0792] Example 82: (R / S)-3,3-difluoro-3-(2-fluoro-3-((R / S)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound 82a) and (S / R)-3,3-difluoro-3-(2-fluoro-3-((S / R)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound 82b)

[0793] [ka]

[0794] The title compound was prepared following similar reaction conditions as described in Example 1 by using morpholine and Intermediate-39a and 39b, respectively.

[0795] (R / S)-3,3-Difluoro-3-(2-fluoro-3-((R / S)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound-82a)

[0796] MS m / z=531.44(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.19(bs,1H),7.65-7.55(m,2H),7.34-7.25(m,1H),7 .23-7.16(m,1H),5.89-5.78(m,1H),5.23(s,1H),4.69(t,J=6.1Hz,1H),3.83- 3.77(m,4H),3.52-3.43(m,2H),3.14-3.07(m,2H),3.08-3.01(m,4H),3.00-2 .94(m,2H),2.32(s,3H),2.12-2.01(m,2H),1.59(d,J=7.1Hz,3H),1.20(s,3H)

[0797] (S / R)-3,3-Difluoro-3-(2-fluoro-3-((S / R)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound-82b)

[0798] MS m / z=531.43(M+1) 1H NMR(400MHz,DMSO-d6)δ8.19(bs,1H),7.65-7.55(m,2H),7.34-7.25(m,1H),7.23- 7.16(m,1H),5.89-5.78(m,1H),5.23(s,1H),4.69(t,J=6.1Hz,1H),3.83-3.77(m,4 H),3.52-3.43(m,1H),3.41-3.36(m,1H),3.14-3.07(m,2H),3.08-3.01(m,4H),3. 00-2.94(m,2H),2.32(s,3H),2.12-2.01(m,2H),1.59(d,J=7.1Hz,3H),1.22(s,3H)

[0799] Example 83: (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (Compound 83)

[0800] [ka]

[0801] The title compound was synthesized by using Intermediate-25 and following a similar reaction protocol as described in Step-7 of Intermediate-12.

[0802] MS(ES+)m / z=486.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.21-8.17(m,2H),6.90-6.87(m,1H),6.86-6.83(m,1H),6.72-6.69(m,1H),5.60-5.50(m,3H),4.25(s,2H) ,4.09-3.96(m,3H),3.80-3.65(m,1H),3.21-3.13(m,2H),2.91-2.86(m,2H),2.42(s,3H),2.18-2.06(m,2H),1.54(d,J=7.0Hz,3H)

[0803] Example 84: (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (Compound 84)

[0804] [ka]

[0805] To a solution of ((R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol) (100 mg, 0.189 mmol) in dichloromethane (5 ml) cooled in an ice-water bath, a 1 M solution of boron tribromide (0.283 ml, 0.283 mmol) in dichloromethane was slowly added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-water and extracted with dichloromethane (50 ml × 2). The separated organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (72 mg). The crude residue was purified by preparative HPLC purification to afford (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (27 mg, 27.7% yield) as a white solid.

[0806] MS m / z=515.57(M+) 1H NMR(400MHz,DMSO-d6)δ8.10(d,J=8.0Hz,1H),7.56(s,1H),6.92-6.83(m,2H),6.69(s,1H),5.62-5.55(m,1H),5.53(s,2H),4.66-4.57(m, 1H),4.16(s,1H),3.28(s,2H),3.14-2.98(m,6H),2.97-2.91(m,2H), 2.37(s,3H),2.12-2.02(m,2H),1.83-1.72(m,2H),1.60-1.48(m,5H)

[0807] The following compounds were made by using the above procedures shown in Example-63 and Example-35, respectively.

[0808] [Table 6]

[0809] Example 87: (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound 87)

[0810] [ka]

[0811] Step-1: 2-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

[0812] To a stirred solution of 6-bromo-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (1.0 g, 3.58 mmol) (Intermediate-18) in 1,4-dioxane (10 mL) and water (2 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.263 g, 5.37 mmol) (commercially available), cesium carbonate (3.50 g, 10.75 mmol), and PdCl(dppf).DCM adduct (0.146 g, 0.179 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 15 minutes and heated in a sealed vial at 80 °C for 3 hours. After completion of the reaction, the reaction mixture was evaporated to give a crude (1.9 g), which was purified by flash column chromatography using a gradient elution with 0 to 1% MeOH in DCM to give 2-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (0.780 g, 70.8% yield) as a pale yellow solid.

[0813] MS(ES+)m / z=308.09(M+1) 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),7.94(d,J=2.7Hz,1H),7.84(s,1H),7.70-7.63(m,1H),6.50-6 .44(m,1H),3.51(s,3H),3.14(t,J=7.5Hz,2H),3.06(t,J=7.4Hz,2H),2.37(s,3H),2.16-2.02(m,2H)

[0814] Step-2: (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one

[0815] To a solution of 2-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one (150 mg, 0.488 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (149 mg, 0.732 mmol) (Intermediate-10) in ACN (15 ml) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (324 mg, 0.732 mmol) and DBU (0.368 ml, 2.440 mmol) at 0° C. and stirred at 100° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated and purified by flash column chromatography using a gradient elution with 0 to 5% MeOH in DCM to give (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (10 mg, yield 4.15%).

[0816] MS(ES+)m / z=494.17(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.26(d,J=8.0Hz,1H),8.16(s,1H),7.94-7.90(m, 1H),7.74-7.69(m,1H),6.91-6.88(m,1H),6.87-6.84(m,1H),6.71-6.68(m ,1H),6.55-6.50(m,1H),5.64-5.48(m,3H),3.54(s,3H),3.20-3.13(m,2H ),3.12-3.01(m,2H),2.42(s,3H),2.18-2.03(m,2H),1.55(d,J=7.0Hz,3H)

[0817] Using a procedure similar to that described in Example 87, the examples disclosed in Table 7 were prepared using 2-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one and the appropriate amine.

[0818] [Table 7]

[0819] Example 90: (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound 90)

[0820] [ka]

[0821] Step-1: 6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one

[0822] The title compound was synthesized according to the similar reaction protocol as described in Step-1 of Example-87 by using Intermediate-18 and (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid. MS(ES+)m / z=324.15(M+1)

[0823] Step-2: (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one

[0824] The title compound was synthesized by using 6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-3,7,8,9-tetrahydro-4H-cyclopenta[h]quinazolin-4-one and Intermediate-10 and following the same reaction protocol as described in Step-2 of Example-87.

[0825] MS(ES+)m / z=510.5(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),8.06-8.01(m,1H),6.90-6.88(m,1H),6.86-6.83(m,1H),6.71-6.68(m,1H),5.91-6.84(m ,1H),5.61-5.50(m,3H),4.21-4.08(m,2H),3.76-3.61(m,2H),3.17-2.96(m,4H),2.40(s,3H),2.13-2.03(m,5H),1.55(d,J=7.1Hz,3H)

[0826] Example 91: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 91)

[0827] [ka]

[0828] To a solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (100 mg, 0.215 mmol) (Intermediate-22) in 1,4-dioxane (50 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (57.5 mg, 0.258 mmol), cesium carbonate (210 mg, 0.645 mmol), and PdCl(dppf).DCM (8.77 mg, 10.75 μmol) were added at room temperature. The resulting reaction mixture was heated at 80 °C for 3 hours in a sealed vial. After completion of the reaction, the reaction mixture was filtered and evaporated to give the crude product (195 mg), which was purified by flash column chromatography using 22 to 40% ethyl acetate in hexane as an eluent to give the desired (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (10 mg, 9.66% yield) as a white solid.

[0829] MS(ES+)m / z=481.3(M+) 1 H NMR(400MHz,DMSO-d6)δ8.23(d,J=7.9Hz,1H),8.03(s,1H),6.92-6.87(m, 1H),6.86-6.82(m,1H),6.73-6.67(m,1H),5.84-5.78(m,1H),5.64-5.50(m ,3H),3.15-3.08(m,2H),3.07-3.00(m,3H),2.63-2.58(m,2H),2.57-2.54 (m,3H),2.39(s,3H),2.31(s,3H),2.00-2.12(m,2H),1.55(d,J=7.1Hz,3H)

[0830] Using procedures similar to those described above, the examples disclosed in Table 8 were prepared using the appropriate starting materials and intermediates.

[0831] [Table 8] TIFF0007629922000113.tif255158TIFF0007629922000114.tif255151TIFF0007629922000115.tif116165

[0832] Example 100: (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)(cyclopropyl)methanone (Compound 100)

[0833] [ka]

[0834] Step-1: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine hydrochloride

[0835] To a stirred solution of tert-butyl (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 1.938 mmol) (Compound-99) in 1,4-dioxane (10 ml) was added 4 M HCl in dioxane (24.22 ml, 97 mmol) at 25° C., and then the reaction mixture was stirred at 25° C. for 1.5 hours under N atmosphere. After completion of the reaction, the reaction mixture was evaporated to give crude product (1.56 g). The crude was stirred in ethyl acetate and filtered to give the desired compound (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine hydrochloride (700 mg, 77% yield) as a white solid. MS(ES+)m / z=468.3(M+1)

[0836] Step-2: (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)(cyclopropyl)methanone

[0837] To a stirred solution of cyclopropanecarboxylic acid (0.025 g, 0.286 mmol) in DMF (5 ml), HATU (0.109 g, 0.286 mmol) and DIPEA (0.055 ml, 0.317 mmol) were added at room temperature, and the resulting mixture was stirred for 15 minutes. Meanwhile, in a separate RB, to a solution of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine hydrochloride (0.16 g, 0.317 mmol) (the product of Step 1 of Example 100) in DMF (5 ml), DIPEA (0.055 ml, 0.317 mmol) was added at room temperature and cooled to 0 °C. The above prepared solution of cyclopropylcarboxylic acid activated ester was added dropwise at 0°C and stirred for 2 hours at 0°C. After completion of the reaction, ice-cold water was added, and the solid precipitated product was filtered off and dried. The residue was purified by flash column chromatography using gradient elution with ethyl acetate in hexane (0 to 80%) to give (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)(cyclopropyl)methanone (0.1 g, 58.8% yield). MS(ES+)m / z=536.20(M+1)

[0838] Step-3: (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)(cyclopropyl)methanone

[0839] A mixture of (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)(cyclopropyl)methanone (0.1 g, 0.187 mmol), ammonium formate (0.082 g, 1.307 mmol) and palladium hydroxide on carbon (0.026 g, 0.187 mmol) in ethanol (10 ml) and water (1 ml) was stirred at 80° C. for 1 hour. The reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (50 ml×2) and the combined filtrates were concentrated in vacuo. The crude mass (90 mg) was purified by reverse phase prep to give (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)(cyclopropyl)methanone (0.012 g, 0.022 mmol, 11.96% yield) as an off-white solid.

[0840] MS(ES+)m / z=538.20(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.99(s,1H),6.87(s,1H),6.84(s,1H),6.70(s,1H),5.63- 5.54(m,1H),5.55(s,2H),4.66-4.62(m,1H),4.47-4.43(m,1H),3.26-3.20(m,1H),3.19-3.11(m ,2H),3.10-3.06(m,2H),3.02-2.84(m,1H),2.75-2.63(m,1H),2.39(s,3H),2.18-2.01(m,3H),1 .94-1.86(m,1H),1.79-1.76(m,1H),1.74-1.66(m,2H),1.56(d,J=7.1Hz,3H),0.78-0.70(m,4H)

[0841] Using procedures similar to those described above, the examples disclosed in Table 9 were prepared using the appropriate starting materials.

[0842] [Table 9] TIFF0007629922000118.tif253156TIFF0007629922000119.tif115155

[0843] Example 106: (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(4,5-Dihydrooxazol-2-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-106)

[0844] [ka]

[0845] Step-1: (R)—N-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0846] To a stirred solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (0.3 g, 0.645 mmol) (Intermediate-22) in CHCl (15 ml), DIPEA (0.338 ml, 1.934 mmol) was added, followed by acetyl chloride (0.055 ml, 0.774 mmol) at 0° C. under nitrogen atmosphere, and stirring was continued for 3 hours at 0° C. After completion of the reaction, the reaction mass was poured into water (10 ml) and extracted with CHCl (3×50 ml), the organic layer was washed with water (20 ml), brine (15 ml) and dried over anhydrous NaSO. The solvent was concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography using a gradient elution with 0 to 40% ethyl acetate in hexanes to afford the title compound (R)—N-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.279 g, 85% yield) as a white solid.

[0847] MS(ES+)m / z=507.2(M+1) 1 H NMR (400 MHz, chloroform-d): δ 8.28 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.45 (s, 1H), 5.88-5.63 (m, 2H), 3.36-3.21 (m, 2H), 3.13-3.04 (m, 2H), 2.53 (s, 3H), 2.19 (m, 2H), 2.10 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H).

[0848] Step-2: tert-butyl (R)-(4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)carbamate

[0849] To a sealed tube were added tert-butyl carbamate (4.39 g, 37.4 mmol), Pd2(dba)3 (0.686 g, 0.749 mmol), cesium carbonate (6.10 g, 18.72 mmol), Xantphos (0.867 g, 1.498 mmol), (R)-N-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (1.9 g, 3.74 mmol) and toluene (30 ml). After sealing the tube, the reaction mixture was stirred at 110° C. for 5 hours. After cooling the reaction mass to room temperature, ethyl acetate (100 ml) and water (50 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (100 ml), brine (50 ml), dried over anhydrous NaSO, filtered, and concentrated to give the crude compound (3.4 g), which was purified by flash column chromatography using a gradient elution with 0 to 7% MeOH in CHCl to give tert-butyl (R)-(4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)carbamate (2.01 g, 99% yield) as a white solid.

[0850] MS(ES+)m / z=544.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.84(s,1H),8.29(s,1H),8.08(s,1H),7.97(s,1H),7.76(s,1H),7.56-7.33(m,1H),5 .59(t,J=7.3Hz,1H),3.13(t,J=9.5Hz,2H),2.98(m,2H),2.37(s,3H),2.14-2.02(m,5H),1.60(d,J=7.1Hz,3H),1.49(s,9H)

[0851] Step-3: (R)—N-(3-(1-((6-amino-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0852] To a stirred solution of tert-butyl (R)-(4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)carbamate (0.04 g, 0.074 mmol) in CHCl (2.00 ml) was added TFA (1.5 ml) dropwise at 0° C. under N atmosphere. The reaction mass was stirred overnight at room temperature. After completion of the reaction, the reaction mass was distilled under reduced pressure to obtain the crude product, which was diluted with 10% aqueous NaHCO and extracted with ethyl acetate (25 ml×3). The organic layer was dried over anhydrous NaSO, filtered and concentrated under reduced pressure to obtain the crude compound. The crude compound was precipitated in ethyl acetate (20%) in pentane to give (R)-N-(3-(1-((6-amino-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.03 g, 92% yield) as a white solid.

[0853] MS(ES+)m / z=444.29(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.94(s,1H),7.80(s,1H),7.49(s,1H),7.39(s,1H),7.17(s,1H),5.61(s,1 H),5.31(s,2H),3.09(s,2H),2.85(t,J=7.8Hz,2H),2.40(s,3H),2.11(m,2H),2.04(s,3H),1.60(d,J=7.0Hz,3H)

[0854] Step-4: (R)—N-(3-(1-((6-(3-(2-chloroethyl)ureido)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0855] To a stirred solution of (R)-N-(3-(1-((6-amino-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.05 g, 0.113 mmol) in THF (10 ml) was added 1-chloro-2-isocyanatoethane (0.029 g, 0.271 mmol) dropwise at room temperature under N atmosphere. Subsequently, the reaction mass was stirred at 50° C. for 5 hours. The reaction mass was distilled under reduced pressure to give crude compound (86 mg). The crude compound was purified by flash column chromatography using a gradient elution with 0→6% MeOH in DCM to afford the title compound (R)—N-(3-(1-((6-(3-(2-chloroethyl)ureido)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.055 g, 89% yield) as a brown solid.

[0856] MS(ES+)m / z=549.07(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.45(s,1H),8.23(s,1H),7.96(s,1H ),7.80(s,1H),7.53(s,1H),7.39(s,1H),6.95(s,1H),5.63(t,J=7.3Hz,1H) ,3.70(t,J=6.1Hz,2H),3.52-3.46(m,2H),3.18-3.11(m,2H),2.96(t,J=7. 5Hz,2H),2.43(s,3H),2.20-2.10(m,2H),2.04(s,3H),1.62(d,J=7.2Hz,3H)

[0857] Step-5: (R)—N-(3-(1-((6-((4,5-dihydrooxazol-2-yl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0858] To a stirred solution of (R)-N-(3-(1-((6-(3-(2-chloroethyl)ureido)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.025 g, 0.046 mmol) in DMF (2.0 ml) was added potassium tert-butoxide (0.015 g, 0.137 mmol) in portions at room temperature under N atmosphere. Subsequently, the reaction mass was heated at 70° C. for 7 hours. After completion of the reaction, the reaction mixture was allowed to reach room temperature and then poured into water (5 ml) and extracted with ethyl acetate (15 ml), the organic layer was washed with water (15 ml), brine (10 ml), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using a gradient elution with 0→6% MeOH in DCM to afford the title compound (R)—N-(3-(1-((6-((4,5-dihydrooxazol-2-yl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.019 g, 81% yield) as a white solid.

[0859] MS(ES+)m / z=513.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.07(s,1H),8.00(s,1H),7.74(s,1H ),7.49(d,J=4.5Hz,1H),7.40(d,J=4.3Hz,1H),6.83(s,1H),5.66-5.56(m, 1H),3.96-3.82(m,2H),3.47(t,J=7.8Hz,2H),3.19-3.08(m,2H),3.05-2.9 5(m,2H),2.39(s,3H),2.14-2.04(m,2H),2.03(s,3H),1.60(d,J=7.1Hz,3H)

[0860] Process-6:(R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6-(4,5-Dihydrooxazol-2-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine

[0861] To the compound of (R)—N-(3-(1-((6-((4,5-dihydrooxazol-2-yl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.035 g, 0.068 mmol) was added 4M HCl (0.341 ml, 1.366 mmol) in MeOH (1 ml) and the reaction mass was heated to 60° C. for 7 hours. After completion of the reaction, the reaction mass was distilled under reduced pressure to obtain a crude residue. The residue was neutralized with 10% aqueous NaHCO solution and extracted with ethyl acetate (15 ml). The organic layer was washed with water (30 ml), brine (10 ml), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to obtain crude compound (0.057 g). The crude compound was purified by flash column chromatography using a gradient elution with 0→7% MeOH in DCM to give the title compound (R)—N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6-(4,5-dihydrooxazol-2-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (0.027 g, 84% yield) as a white solid.

[0862] MS(ES+)m / z=471.1(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.42-7.35(m,1H),6.89-6.87(m,1H),6.85-6.83(m,1H),6.82-6.80(s,1H),6.71-6.68(m,1H),5.60-5.5 0(m,3H),3.96-3.82(m,2H),3.46(t,J=7.8Hz,2H),3.19-3.10(m,2H),3 .05-2.98(m,2H),2.41(s,3H),2.12-2.04(m,2H),1.55(d,J=7.1Hz,3H)

[0863] Example 107: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((3-methyloxetan-3-yl)methoxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 107)

[0864] [ka]

[0865] Step-1: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol

[0866] To a solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (0.220 g, 0.473 mmol) (Intermediate-22) in 1,4-dioxane (2 mL) and water (0.5 mL) was added KOH (0.080 g, 1.418 mmol). The mixture was thoroughly deoxygenated by purging with nitrogen for 15 minutes before adding Pd(dba) (0.043 g, 0.047 mmol) and di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (0.020 g, 0.047 mmol). The resulting mixture was heated to 80 °C in a sealed tube for 17 hours. After completion of the reaction, the reaction mass was cooled to room temperature and concentrated under vacuum to give an oily residue (0.37 g), which was dissolved in water (20 ml) and neutralized by using 2N HCl solution. The aqueous layer was extracted with ethyl acetate (30 ml). The organic layer was washed with water (20 ml), brine (10 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound (0.150 g). The crude compound was purified by flash column chromatography using a gradient elution of 0 to 30% ethyl acetate in hexane to give the title compound (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol (0.070 g, 36.80% yield) as a white solid. MS(ES+)m / z=403.16(M+1)

[0867] Step-2: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((3-methyloxetan-3-yl)methoxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine

[0868] To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol (70 mg, 0.174 mmol) in DMF (2 ml), 3-(bromomethyl)-3-methyloxetane (37.3 mg, 0.226 mmol) was added followed by K2CO3 (48.1 mg, 0.348 mmol). Subsequently, the reaction mixture was stirred at 80°C for 17 hours. After completion of the reaction, the reaction mass was cooled to room temperature and quenched with water (15 ml), the aqueous layer was extracted with ethyl acetate (20 ml), and the combined organic layer was washed with water (30 ml), brine (10 ml), dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated to give the crude compound (65 mg). The crude compound was purified by flash column chromatography using a gradient elution with 0 to 60% ethyl acetate in hexanes to afford the title compound (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((3-methyloxetan-3-yl)methoxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (0.015 g, 17.72% yield) as a white solid.

[0869] MS(ES+)m / z=487.24(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.63(s,1H),7.01-6.83(m,2H),6.74-7.69(m,1H),5.70-5.44(m,3H),4.59-4.51(m,2H),4.39-4.34( m,2H),4.30-4.12(m,2H),3.14(t,J=7.7Hz,2H),2.96(t,J=7.5Hz,2H),2.40(s,3H),2.16-2.10(m,2H),1.58(d,J=7.0Hz,3H),1.43(s,3H)

[0870] Example 108: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 108)

[0871] [ka]

[0872] To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol (250 mg, 0.621 mmol) in DMF (10 ml) was added iodomethane (106 mg, 0.745 mmol) and CsCO (304 mg, 0.932 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 1 h in a sealed vial. The reaction mixture was brought to room temperature, diluted with ethyl acetate (50 ml), and washed with water (30 ml × 2). The separated organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography using 0→90% ethyl acetate in hexanes as eluent, followed by reverse-phase preparative purification to give (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (14 mg, 5.41% yield).

[0873] MS(ES+)m / z=416.41(M+) 1 H NMR(400MHz,DMSO-d6)δ8.04(d,J=8.0Hz,1H),7.55(s,1H),6.90-6.84(m,2H),6.70(s,1H),5.66-5.45(m,3H), 3.92(s,3H),3.12(t,J=7.6Hz,2H),2.93(t,J=7.4Hz,2H),2.38(s,3H),2.16-2.04(m,2H),1.57(d,J=7.0Hz,3H)

[0874] Example 109: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound 109)

[0875] [ka]

[0876] To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol (170 mg, 0.422 mmol) in DMF (10 ml) was added (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (123 mg, 0.507 mmol) and CsCO (206 mg, 0.634 mmol) at room temperature, and then the reaction mixture was heated at 80 °C for 1 h in a sealed vial. After completion of the reaction, the reaction mixture was brought to room temperature and diluted with ethyl acetate (50 ml). The organic layer was washed with water (20 ml × 2) and brine (20 ml). The separated organic layer was dried over NaSO, filtered, and concentrated. The crude mass was purified by flash column chromatography using 80→90% ethyl acetate in hexane as eluent to give N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (10 mg, 5.01% yield).

[0877] MS(ES+)m / z=473.23(M+1) 1H NMR(400MHz,DMSO-d6)δ8.03-7.98(m,1H),7.53(s,1H),6.88(s,1H),6.86-6.84( m,1H),6.71-6.68(m,1H),5.64-5.57(m,1H),5.55(s,2H),5.25-5.20(m,1H),4.05 -4.00(m,1H),3.93-3.86(m,1H),3.85-3.78(m,2H),3.16-3.09(m,2H),2.95-2.8 8(m,2H),2.38(s,3H),2.35-2.28(m,1H),2.15-1.98(m,3H),1.57(d,J=7.0Hz,3H)

[0878] Example 110: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine (Compound 110)

[0879] [ka]

[0880] Step-1: Methyl 3-methoxy-4-(prop-2-en-1-yloxy)benzoate

[0881] To a stirred solution of methyl 4-hydroxy-3-methoxybenzoate (70 g, 384 mmol) (commercially available) in DMF (500 ml), K2CO3 (80 g, 576 mmol) was added and stirred for 30 minutes, after which 80% 3-bromoprop-1-ene in toluene (43.6 ml, 384 mmol) was added dropwise at ambient temperature. The resulting mixture was stirred for 2 hours at 25 °C. After completion of the reaction, the reaction mass was cooled to 0 °C and ice-cold water (1000 ml) was slowly added to precipitate the solid compound, which was filtered, and the residue was washed with water (500 ml × 2) and dried under vacuum to give methyl 3-methoxy-4-(prop-2-en-1-yloxy)benzoate (80 g, 95% yield) as an off-white solid.

[0882] 1H NMR(400MHz,DMSO-d6)δ7.59(dd,J=8.4,2.0Hz,1H),7.48(d,J=2.0Hz,1H),7. 14(d,J=8.4Hz,1H),4.90(d,J=2.4Hz,2H),3.83(s,6H),3.62(t,J=2.4Hz,1H)

[0883] Step-2: Methyl 5-methoxy-2-nitro-4-(prop-2-en-1-yloxy)benzoate

[0884] To a stirred solution of methyl 3-methoxy-4-(prop-2-en-1-yloxy)benzoate (79 g, 359 mmol) in DCM (1000 ml) at −15° C., tin(IV) chloride (63.1 ml, 538 mmol) and fuming nitric acid (16.03 ml, 359 mmol) were added dropwise simultaneously. After 10 minutes, the solution was allowed to warm to room temperature and stirred for 2 hours. The mixture was slowly poured into cold water (1000 ml) and diluted with dichloromethane (1000 ml). The organic phase was separated and washed with brine (300 ml × 2), dried over sodium sulfate, and filtered. The solvent was removed under vacuum. The crude mass (98 g) was recrystallized from methanol (500 ml) to give methyl 5-methoxy-2-nitro-4-(prop-2-en-1-yloxy)benzoate (90 g, 95% yield) as a pale yellow solid.

[0885] 1 H NMR(400MHz,DMSO-d6)δ7.76(s,1H),7.36(s,1H),5.02(d,J=2.4Hz,2H),3.94(s,3H),3.84(s,3H),3.70(t,J=2.4Hz,1H)

[0886] Step-3: Methyl 7-methoxy-2-methyl-4-nitrobenzofuran-5-carboxylate

[0887] A mixture of methyl 5-methoxy-2-nitro-4-(prop-2-en-1-yloxy)benzoate (20 g, 75 mmol), cesium fluoride (11.45 g, 75 mmol), and N,N-diethylaniline (320 mL) was heated at 210 °C for 6 h. Upon completion, the reaction mixture was brought to room temperature, diluted with ethyl acetate (1000 mL), and filtered through Celite. The filtrate was washed with 6 M HCl (5 × 300 mL) and brine (300 mL). The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue (18 g) was purified by flash column chromatography using a gradient elution with ethyl acetate (0 to 30%) to give methyl 7-methoxy-2-methyl-4-nitrobenzofuran-5-carboxylate (9 g, 45.0% yield).

[0888] 1 H NMR(400MHz,DMSO-d6)δ7.21(s,1H),7.02(d,J=1.0Hz,1H),4.08(s,3H),3.87(s,3H),2.54(d,J=1.0Hz,3H)

[0889] Step-4: Methyl 4-amino-7-methoxy-2-methylbenzofuran-5-carboxylate

[0890] To a stirred solution of methyl 7-methoxy-2-methyl-4-nitrobenzofuran-5-carboxylate (24 g, 90 mmol) in EtOH (250 mL):water (30 mL) was added iron (25.3 g, 452 mmol) and ammonium chloride (24.20 g, 452 mmol) at room temperature. The resulting mixture was stirred at 85°C for 1 hour. The reaction mass was concentrated and diluted with ethyl acetate (1000 mL). The formed suspension was filtered through a bed of Celite, and the filtrate was washed with water (500 mL) and brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (24 g) was crystallized in diethyl ether (200 mL) to give methyl 4-amino-7-methoxy-2-methylbenzofuran-5-carboxylate (20 g, 94% yield) as an off-white solid.

[0891] 1 H NMR(400MHz,DMSO-d6)δ7.09(s,1H),6.86(d,J=1.1Hz,1H),6.81(s,2H,D2O exchangeable),3.81(s,3H),3.79(s,3H),2.42(d,J=1.1Hz,3H)

[0892] Step-5: 6-Methoxy-2,8-dimethylfluoro[2,3-h]quinazolin-4(3H)-one

[0893] To a stirred solution of methyl 4-amino-7-methoxy-2-methylbenzofuran-5-carboxylate (20 g, 85 mmol) in acetonitrile (200 ml) was added methanesulfonic acid (33.1 ml, 510 mmol) at 25°C. The resulting reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, acetonitrile was evaporated, and the residue was diluted with water (200 ml) and neutralized with saturated 20% aqueous sodium hydroxide solution. The formed precipitate was filtered off, and the residue was washed with water (30 ml × 2) and dried under vacuum to give 6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4(3H)-one (15 g, 72.2% yield).

[0894] MS(ES+)m / z=245.1(M+1) 1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H,D2O exchangeable),7.36(s,1H),6.94(d,J=1.2Hz,1H),4.00(s,3H),2.50(s,3H),2.39(s,3H)

[0895] Step-6: 6-Methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate

[0896] To a stirred suspension of 6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4(3H)-one (2 g, 8.19 mmol) in THF (250 mL) were added potassium carbonate (3.39 g, 24.56 mmol), DMAP (1.100 g, 9.01 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (3.72 g, 12.28 mmol) in that order at 25°C. The resulting reaction mixture was stirred at 75°C for 6 hours. After complete consumption of the starting material, the reaction mixture was brought to room temperature and diluted with ethyl acetate (500 mL). The suspended solid salts were filtered off, and the filtrate was concentrated under reduced pressure. The residue (6.5 g) was purified by column chromatography using a gradient elution with ethyl acetate in hexane (0 to 20%) to give 6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate (2.7 g, 64.6% yield). MS(ES+)m / z:511.06(M+1)

[0897] Step-7: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine

[0898] To a stirred solution of 6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (2.7 g, 5.29 mmol) in DMSO (25 mL), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (1.080 g, 5.29 mmol) and TEA (7.37 mL, 52.9 mmol) were added sequentially at room temperature. The resulting mixture was stirred at 90 °C for 16 hours. After completion of the reaction, the reaction mixture was brought to room temperature, diluted with ethyl acetate (200 mL), and washed with water (100 mL × 2) and brine (100 mL). The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue (5.2 g). The residue was purified by flash column chromatography using gradient elution with ethyl acetate in hexanes (0 to 20%) to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine (1.2 g, 52.7% yield).

[0899] MS(ES+)m / z:431.08(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.07(d,J=7.9Hz,1H,D2O exchangeable),7.62(s,1H),6.98(d,J=1.2Hz,1H),6.91(s,1H),6.88(d,J=1.9Hz,1H), 6.71(d,J=1.9Hz,1H),5.62(p,J=7.1Hz,1H),5.55(s,2H,D2O exchangeable),4.05(s,3H),2.55(s,3H),2.44(s,3H),1.58(d,J=7.1Hz,3H)

[0900] Example 111: N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine (Compound 111)

[0901] [ka]

[0902] Step-1: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethylfuro[2,3-h]quinazolin-6-ol

[0903] To a stirred solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine (1.2 g, 2.79 mmol) in DMF (50 ml) was added sodium ethanethiolate (2.345 g, 27.9 mmol) at 25° C. The resulting reaction mixture was stirred at 100° C. for 16 hours. After completion of the reaction, the reaction mixture was brought to room temperature, diluted with water (10 ml), and neutralized with 10% HCl (pH: 7) solution at 0° C. The product was extracted with ethyl acetate (120 ml), and the organic layer was washed with water (20 ml × 2) and brine (20 ml). The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue (1.5 g) was purified by flash column chromatography using a gradient elution with methanol in dichloromethane (0 to 15%) to give (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethylfuro[2,3-h]quinazolin-6-ol (1 g, 86% yield).

[0904] MS(ES+)m / z:416.41(M+) 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H,D2O exchangeable),8.20(s,1H,D2O exchangeable),7.52(s,1H),7.03(s,1H),6.93(s,1H),6.87(s,1 H),6.70(s,1H),5.59(p,J=7.1Hz,1H),5.54(bs,2H,D2O exchangeable),2.54(d,J=1.1Hz,3H),2.46(s,3H),1.56(d,J=7.1Hz,3H)

[0905] Step-2: N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine

[0906] To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethylfuro[2,3-h]quinolin-6-ol (0.2 g, 0.481 mmol) in DMF (10 ml), CsCO (0.173 g, 0.530 mmol) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (0.128 g, 0.530 mmol) were added at room temperature and heated at 90 °C for 1 h. After completion of the reaction, the reaction mass was brought to room temperature, diluted with ethyl acetate (60 ml), and washed with water (30 ml × 2) and brine (30 ml). The separated organic layer was dried over NaSO, filtered, and concentrated. The residue (200 mg) was purified by flash column chromatography using gradient elution with methanol in dichloromethane (0 to 5%) to give N-((R)1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine (0.15 g, 64.0% yield) as an off-white solid.

[0907] MS(ES+)m / z:487.17(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.59(s,1H),6.99(d,J=1.3Hz,1H),6.89(s ,1H),6.87(s,1H),6.71(d,J=1.9Hz,1H),5.64(p,J=7.3Hz,1H),5.56(s,2H),5. 42-5.38(m,1H),4.06-4.02(m,1H),3.99-3.89(m,2H),3.87-3.82(m,1H),2.50( s,3H),2.44(s,3H),2.41-2.32(m,1H),2.18-2.09(m,1H),1.58(d,J=7.1Hz,3H)

[0908] Example 112: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 112)

[0909] [ka]

[0910] Step-1: Methyl 5-methoxy-4-((2-methylallyl)oxy)-2-nitrobenzoate

[0911] To a stirred solution of commercially available methyl 4-hydroxy-5-methoxy-2-nitrobenzoate (26 g, 114 mmol) in DMF (200 ml) was added KCO (23.73 g, 172 mmol) and 3-chloro-2-methylprop-1-ene (13.47 g, 149 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 3 hours. The reaction mass was brought to room temperature, diluted with ethyl acetate (500 ml), and washed with water (300 ml × 3) and brine (300 ml). The separated organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography using a gradient elution of 10 to 20% ethyl acetate in hexane to give methyl 5-methoxy-4-((2-methylallyl)oxy)-2-nitrobenzoate (30 g, 93% yield) as a brown oil, which was allowed to stand for an extended period until it solidified.

[0912] MS(ES+)m / z=281.59(M+) 1 H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.34(s,1H),5.09(t,J=1.8Hz,1H),5.01(t,J=1.8Hz,1H),4.66(s,2H),3.94(s,3H),3.83(s,3H),1.77(s,3H)

[0913] Step-2: Methyl 4-hydroxy-5-methoxy-3-(2-methylallyl)-2-nitrobenzoate

[0914] A mixture of methyl 5-methoxy-4-((2-methylallyl)oxy)-2-nitrobenzoate (30 g, 107 mmol) and NMP (300 ml) was heated at 210° C. for 3 hours. After completion of the reaction, the reaction mixture was brought to room temperature, diluted with ethyl acetate (1000 ml), and the organic matter was washed with water (500 ml × 5) and brine (500 ml). The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient elution with ethyl acetate in hexane (20 to 30%) to give methyl 4-hydroxy-5-methoxy-3-(2-methylallyl)-2-nitrobenzoate (8.5 g, 28.3% yield).

[0915] MS(ES+)m / z=282.1(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H,D2O exchangeable),7.40(s,1H),4.70-4.66(m, 1H),4.35-4.26(m,1H),3.94(s,3H),3.79(s,3H),3.23(s,2H),1.67(s,3H)

[0916] Step-3: Methyl 7-methoxy-2,2-dimethyl-4-nitro-2,3-dihydrobenzofuran-5-carboxylate

[0917] A mixture of methyl 4-hydroxy-5-methoxy-3-(2-methylallyl)-2-nitrobenzoate (8.5 g, 30.2 mmol) in formic acid (100 ml) was heated to 110° C. for 2 hours. After completion of the reaction, the reaction mass was brought to room temperature and concentrated under reduced pressure. The crude mass was diluted with ethyl acetate (500 ml) and washed with a saturated solution of sodium bicarbonate (200 ml × 2), water (200 ml), and brine (200 ml). The separated organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography using a gradient elution with ethyl acetate in hexane (0 to 30%) to give methyl 7-methoxy-2,2-dimethyl-4-nitro-2,3-dihydrobenzofuran-5-carboxylate (6.2 g, 72.9% yield) as a white solid.

[0918] MS(ES+)m / z=282.09(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.26(s,1H),3.90(s,3H),3.80(s,3H),3.31(s,2H),1.47(s,6H)

[0919] Step-4: Methyl 4-amino-7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate

[0920] The title compound was synthesized by using methyl 7-methoxy-2,2-dimethyl-4-nitro-2,3-dihydrobenzofuran-5-carboxylate and following the same reaction protocol as described in step 4 of Example 110.

[0921] MS(ES+)m / z=252.21(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.14(s,1H),6.21(s,2H,D2O exchangeable),3.75(s,3H),3.65(s,3H),2.84(s,2H),1.43(s,6H)

[0922] Step-5: 6-Methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-(3H)-one

[0923] The title compound was synthesized by using methyl 4-amino-7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate and following the same reaction protocol as described in step-5 of Example-110.

[0924] 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H,D2O exchangeable),7.36(s,1H),3.84(s,3H),3.18(s,2H),2.30(s,3H),1.47(s,6H) MS(ES+)m / z=261.02(M+1)

[0925] Step-6: 4-chloro-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazoline

[0926] To a stirred solution of 6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4(3H)-one (4.5 g, 17.29 mmol) in chlorobenzene (100 ml), DIPEA (7.85 ml, 44.9 mmol) was added, followed by dropwise addition of POCl (3.54 ml, 38.0 mmol) at room temperature. The resulting reaction mixture was heated at 90 °C for 16 hours. After completion of the reaction, the reaction mass was brought to room temperature and concentrated under vacuum. The crude mass was diluted with ethyl acetate (500 ml) and washed with water (100 ml × 2) and brine (100 ml). The separated organic layer was dried over Na SO , filtered, and concentrated. The crude product was purified by flash column chromatography using a gradient elution with 0 to 40% ethyl acetate in hexanes to give 4-chloro-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazoline (4 g, 83% yield) as a brown solid.

[0927] MS(ES+)m / z=279.27(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.33(s,1H),3.97(s,3H),3.35(s,2H),2.66(s,3H),1.54(s,6H)

[0928] Step-7: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0929] To a stirred solution of 4-chloro-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazoline (3 g, 10.76 mmol) in EtOH (50 ml), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (1.978 g, 9.69 mmol) (Intermediate-10) and TEA (15.00 ml, 108 mmol) were added at room temperature. The resulting reaction mixture was heated at 100° C. for 64 hours. After completion of the reaction, it was brought to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution with 0 to 5% MeOH in DCM to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (3.5 g, 72.8% yield) as a light brown solid.

[0930] MS(ES+)m / z=447.17(M+1) 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.94(s,1H),6.91-6.89(m,1H),6.88-6.85(m,1H),6.75-6.71(m,1H),5.68(p ,J=7.2Hz,1H),5.60(s,2H),3.95(s,3H),3.28(s,2H),2.52(s,3H),1.62(d,J=7.0Hz,3H),1.52(s,3H),1.50(s,3H)

[0931] Step-8: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-ol

[0932] The title compound was synthesized by using (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine and following the same reaction protocol as described in Step 1 of Example 111.

[0933] MS(ES+)m / z=433.17(M+1) 1 H NMR (400MHz, DMSO-d6) δ9.54 (s, 1H, D2O exchangeable), 7.92 (s, 1H, D2O exchangeable), 7.54 (s, 1H), 6.90-6.88 (m, 1H), 6.84-6.82(m,1H),6.69-6.67(m,1H),5.56-5.47(m,3H),3.20(s,2H),2.34(s,3H),1.54-1.47(m,9H)

[0934] Step-9: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0935] The title compound was synthesized by using (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-ol and following a similar reaction protocol as described in step 2 of Example 111.

[0936] MS(ES+)m / z=503.30(M+1) 1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.65(s,1H),6.88-6.86(m,1H),6.85-6.83(m,1H),6.71-6.68(m,1H),5.62-5.55(m,1H),5.54(s,2H),5.22 -5.17(m,1H),3.99-3.76(m,4H),3.19(s,2H),2.35(s,3H),2.32-2.23(m ,1H),2.09-1.98(m,1H),1.55(d,J=7.0Hz,3H),1.50(s,3H),1.47(s,3H)

[0937] Example 113: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 113)

[0938] [ka]

[0939] Step-1: (R)—N-(3-(1-((6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0940] To a stirred solution of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (1.34 g, 3.00 mmol) in dichloromethane (20 ml), DIPEA (2.097 ml, 12.01 mmol) and DMAP (0.037 g, 0.300 mmol) were added at room temperature. The resulting mixture was cooled to 0 °C, and then acetyl chloride (0.256 ml, 3.60 mmol) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, it was diluted with dichloromethane (100 ml) and washed with water (50 ml) and brine (50 ml). The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient elution with 1→5% MeOH in DCM to give (R)—N-(3-(1-((6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (1.4 g, 95% yield) as a brown solid. MS(ES+)m / z=489.17(M+1)

[0941] Step-2: (R)—N-(3-(1-((6-hydroxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0942] The title compound was synthesized using (R)-N-(3-(1-((6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide according to the same reaction protocol as described in Step 1 of Example 111. MS(ES+)m / z=475.17(M+1)

[0943] Step-3: (R)-4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate

[0944] A mixture of (R)-N-(3-(1-((6-hydroxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (0.271 g, 0.571 mmol) and DIPEA (0.120 ml, 0.685 mmol) in dichloromethane (10 ml) was cooled to −15° C., and to this was slowly added trifluoromethanesulfonic anhydride (0.115 ml, 0.685 mmol) under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at −15° C. After completion of the reaction, the reaction mixture was quenched with methanol (1.0 ml), stirred for 5 minutes at room temperature, diluted with dichloromethane (100 ml), and washed with a saturated solution of NaHCO (50 ml) and brine (50 ml). The organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography using a gradient elution with MeOH in dichloromethane (1 to 5%) to give (R)-4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate (0.33 g, 95%) as a light brown oil. MS(ES+)m / z=606.83(M+1)

[0945] Step-4: (R)—N-(3-(trifluoromethyl)-5-(1-((2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0946] To a sealed tube containing a solution of (R)-4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate (0.32 g, 0.528 mmol) and CsCO (0.516 g, 1.583 mmol) in toluene (14 mL) was added morpholine (0.460 g, 5.28 mmol). The mixture was thoroughly deoxygenated by purging with nitrogen for 15 minutes before the addition of palladium(II) acetate (0.012 g, 0.053 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl (X-Phos) (0.050 g, 0.106 mmol). The resulting reaction mixture was stirred at 120°C for 8 hours. After completion of the reaction, the reaction mass was brought to room temperature, diluted with ethyl acetate (50 ml), and filtered through Celite. The cake was washed with ethyl acetate (20 ml x 2). The combined organic layers were concentrated under vacuum. The residue (0.32 g) was purified by flash column chromatography using gradient elution with MeOH in DCM (1 to 5%) to give (R)-N-(3-(trifluoromethyl)-5-(1-((2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide (0.1 g, 34.9%) as an off-white solid. MS(ES+)m / z=543.87(M+1)

[0947] Step-5: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0948] To a stirred solution of (R)-N-(3-(trifluoromethyl)-5-(1-((2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide (0.1 g, 0.184 mmol) in methanol (5 ml), concentrated HCl (0.153 ml, 1.840 mmol) was added at room temperature. The resulting reaction mixture was heated at 60° C. for 6 hours. After completion of the reaction, the reaction mass was concentrated under vacuum. The obtained solid was washed with diethyl ether (10 ml×3). The solid compound was added to a saturated solution of sodium bicarbonate (10 ml) and the product was extracted in ethyl acetate (30 ml×3). The combined organic layer was washed with water (10 ml) and brine (20 ml). The separated organic layer was dried over Na2SO4, filtered and evaporated to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (0.030 g, 32.5%) as a light brown solid.

[0949] 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J=8.0Hz,1H),7.45(s,1H),6.87(s,1H),6.86-6.84(m,1H),6.70-6.68(m,1H),5.64-5.55(m,1H) ),5.54(s,2H),3.81-3.76(m,4H),3.17(s,2H),3.16-3.12(m,4H),2.34(s,3H),1.55(d,J=7.1Hz,3H),1.49(s,3H),1.47(s,3H) MS(ES+)m / z=502.24(M+1)

[0950] Example 114: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 114)

[0951] [ka]

[0952] Step-1: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate

[0953] The title compound was synthesized by using (R)-4-((1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate and following a similar reaction protocol as described in step 5 of Example 113. MS(ES+)m / z=565.10(M+1)

[0954] Step-2: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0955] The title compound was synthesized using (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate according to the same reaction protocol as that described in Step 4 of Example 113.

[0956] MS(ES+)m / z=513.24(M+) 1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.07(s,1H),6.87(s,1H),6.85-6.83(m,1H),6.67-6.68(m,1H),5.61-5.55(m,1 H),5.54(s,2H),4.74(s,4H),4.09(s,4H),3.13(s,2H),2.34(s,3H),1.54(d,J=7.0Hz,3H),1.47(s,3H),1.45(s,3H)

[0957] Example 115: (R)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 115)

[0958] [ka]

[0959] Step-1: (R / S)—N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0960] The title compound was synthesized by using 4-chloro-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazoline and following a similar reaction protocol as described in step 7 of Example 112. MS(ES+)m / z=459.17(M+1)

[0961] Step-2: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0962] The title compound was synthesized by using (R / S)-N-(1-(3-(difluoromethyl)-5-nitrophenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine and following a similar reaction protocol as described in step 4 of Example 110. MS(ES+)m / z=429.17(M+1)

[0963] Step-3: (R / S)—N-(3-(difluoromethyl)-5-(1-((6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0964] The title compound was synthesized using (R / S)-N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine according to the same reaction protocol as that described in Step 1 of Example 113. MS(ES+)m / z=471.17(M+1)

[0965] Step-4: (R / S)—N-(3-(difluoromethyl)-5-(1-((6-hydroxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0966] The title compound was synthesized using (R / S)-N-(3-(difluoromethyl)-5-(1-((6-methoxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide according to the same reaction protocol as described in Step 1 of Example 111. MS(ES+)m / z=457.17(M+1)

[0967] Step-5: (R / S)-4-((1-(3-acetamido-5-(difluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate

[0968] The title compound was synthesized using (R / S)-N-(3-(difluoromethyl)-5-(1-((6-hydroxy-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide and following a similar reaction protocol as described in step 3 of Example 113. MS(ES+)m / z=589.13(M+1)

[0969] Step-6: (R / S)—N-(3-(difluoromethyl)-5-(1-((2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide

[0970] The title compound was synthesized using (R / S)-4-((1-(3-acetamido-5-(difluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate and following a similar reaction protocol as described in Step 4 of Example 113. MS(ES+)m / z=526.24(M+1)

[0971] Step-7: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0972] The title compound was synthesized using (R / S)-N-(3-(difluoromethyl)-5-(1-((2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)phenyl)acetamide and following a similar reaction protocol as described in step 5 of Example 113.

[0973] MS(ES+)m / z=483.99(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.50(d,J=8.1Hz,1H),6.83(s,1H)6.82(t,J=54Hz,1H),6.77-6.72(m,2H),6.59(s,1H),5.71-5.57(m,1 H),5.36(s,2H),3.81-3.75(m,4H),3.18(s,2H),3.17-3.11(m,4H),2.40(s,3H),1.55(d,J=7.1Hz,3H),1.51(s,3H),1.49(s,3H)

[0974] Example 116: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 116)

[0975] [ka]

[0976] Step-1: (R / S)-4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate

[0977] The title compound was synthesized using (R / S)-4-((1-(3-acetamido-5-(difluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate and following a similar reaction protocol as described in Step 5 of Example 113. MS(ES+)m / z=547.2(M+1)

[0978] Step-2: (R / S)—N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0979] The title compound was synthesized using (R / S)-4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2,8,8-trimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate and following a similar reaction protocol as described in Step 4 of Example 113.

[0980] MS(ES+)m / z=496.3(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.08(s,1H),6.82(t,J=56Hz,1H),6.74(s,1H),6.73(s,1H),6.57(s,1H),5.58(p,J=7 .2Hz,1H),5.34(s,2H),4.73(s,4H),4.08(s,4H),3.13(s,2H),2.33(s,3H),1.53(d,J=7.2Hz,3H),1.47(s,3H),1.45(s,3H)

[0981] Example 117: (R / S)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 117a) and (S / R)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 117b)

[0982] [ka]

[0983] Step-1: Methyl 4-amino-7-methoxy-2-methyl-2,3-dihydrobenzofuran-5-carboxylate

[0984] To a stirred solution of methyl 7-methoxy-2-methyl-4-nitrobenzofuran-5-carboxylate (5 g, 18.85 mmol) in EtOH (50 ml) was added 10% wet Pd—C (2.006 g, 1.885 mmol) at room temperature. The reaction mixture was stirred for 64 hours under an H atmosphere (64 psi). After completion of the reaction, the reaction mixture was diluted with MeOH (100 ml), filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give a crude residue (2.3 g). The crude residue was purified by flash column chromatography using a gradient elution with ethyl acetate in hexane (0 to 30%) to give methyl 4-amino-7-methoxy-2-methyl-2,3-dihydrobenzofuran-5-carboxylate (1.3 g, 29.1% yield).

[0985] 1 H NMR(400MHz,DMSO-d6)δ7.15(s,1H),6.23(s,2H),5.07-4.98(m,1H),3.75(s, 3H),3.66(s,3H),3.28-3.06(m,1H),2.64-2.53(m,1H),1.39(d,J=6.3Hz,3H)

[0986] Step-2: 6-Methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4(3H)-one

[0987] The title compound was synthesized using methyl 4-amino-7-methoxy-2-methyl-2,3-dihydrobenzofuran-5-carboxylate and following the same reaction protocol as described in Step 5 of Example 110. MS(ES+)m / z=247.33(M+1)

[0988] Step-3: 4-chloro-6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazoline

[0989] The title compound was synthesized using 6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4(3H)-one and following a similar reaction protocol as described in Step 6 of Example 112. MS(ES+)m / z=265.1(M+1)

[0990] Step-4: 6-Methoxy-2,8-dimethyl-N-((R)1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0991] The title compound was synthesized using 4-chloro-6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazoline and following a similar reaction protocol as described in Step-7 of Example-112. MS(ES+)m / z=463.17(M+1)

[0992] Step-5: N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine

[0993] The title compound was synthesized using 6-methoxy-2,8-dimethyl-N-((R)1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine according to the same reaction protocol as that described in Step 2 of Example 115. MS(ES+)m / z=433.2(M+1)

[0994] Step-6: N-(3-((R)-1-((6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0995] The title compound was synthesized using N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine according to the same reaction protocol as described in Step 1 of Example 113. MS(ES+)m / z=475.17(M+1)

[0996] Step-7: N-(3-((R)-1-((6-hydroxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0997] The title compound was synthesized using N-(3-((R)-1-((6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide according to the same reaction protocol as described in Step 1 of Example 111. MS(ES+)m / z=461.17(M+1)

[0998] Step-8: 4-(((R)1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate

[0999] The title compound was synthesized using N-(3-((R)-1-((6-hydroxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide according to the same reaction protocol as described in step 3 of Example 113. MS(ES+)m / z=593.83(M+1)

[1000] Step-9: N-(3-((R)-1-(((R / S)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (Peak-1) and N-(3-((R)-1-(((S / R)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (Peak-2)

[1001] The title compound was synthesized using 4-(((R)1-(3-acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-yl trifluoromethanesulfonate and following a similar reaction protocol as described in Step 4 of Example 113. Peak-1: Chiral RT: 8.02 min, Purity: 100%. MS (ES+) m / z = 530.2 (M+1) Peak-2: Chiral RT: 8.89 min, Purity: 98.72%. MS (ES+) m / z = 530.2 (M+1)

[1002] Step-10: (R / S)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-117a) and (S / R)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-117b)

[1003] The title compound was synthesized using N-(3-((R)-1-(((R / S)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (Peak-1) and N-(3-((R)-1-(((S / R)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide (Peak-2) according to a similar reaction protocol as described in Step-5 of Example-113.

[1004] Peak-1 (Compound-117a): MS(ES+)m / z=488.3(M+1) 1 H NMR(400MHz,DMSO-d6)δ13.71(s,1H),9.88(d,J=7.8Hz,1H),7.78(s,1H),7.04(s,1H),7.00(s,1H),6.88(s,1H),5.76(p,J=7.2Hz,1H),5.35-5. 28(m,1H),3.82-3.74(m,4H),3.70-3.56(m,1H),3.27-3.18(m,4H),3.1 3-3.02(m,1H),2.63(s,3H),1.66(d,J=7.0Hz,3H),1.49(d,J=6.2Hz,3H)

[1005] Peak-2 (Compound-117b): MS(ES+)m / z=488.3(M+1) 1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),9.88(d,J=7.8Hz,1H),7.78(s,1H),7.04(s,1H),7.00(s,1H),6.88(s,1H),5.76(p,J=7.2Hz,1H),5.35-5. 28(m,1H),3.82-3.74(m,4H),3.70-3.56(m,1H),3.27-3.18(m,4H),3.1 3-3.02(m,1H),2.63(s,3H),1.66(d,J=7.0Hz,3H),1.49(d,J=6.2Hz,3H)

[1006] Example 118: (R / S)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 118a) and (S / R)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound 118b)

[1007] [ka]

[1008] Step-1: (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-ol

[1009] The title compound was synthesized using N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-4-amine according to the same reaction protocol as described in Step 1 of Example 111. MS(ES+)m / z=418.35(M+1)

[1010] Step-2: (R / S)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Peak-1) (Compound-118a) and (S / R)—N—((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Peak-2) (Compound-118b)

[1011] The title compound was synthesized using (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinazolin-6-ol and following a similar reaction protocol as described in step 2 of Example 111.

[1012] Peak-1: (Compound 118a): Chiral RT: 3.86 min, Purity: 99.56% MS(ES+)m / z=489.24(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.68(s,1H),6.88(s,1H),6.84(s,1H),6 .70(s,1H),5.62-5.57(m,1H),5.56(s,2H),5.24-5.17(m,1H),5.18-5.08(m,1 H),3.99-3.76(m,4H),3.55-3.48(m,1H),3.03-2.89(m,1H),2.38(s,3H),2.2 5-2.70(m,1H),2.06-1.96(m,1H),1.56(d,J=7.1Hz,3H),1.45(d,J=6.3Hz,3H)

[1013] Peak-2: (Compound-118b): Chiral RT: 4.98 min, Purity: 97.63%. MS(ES+)m / z=489.24(M+1) 1H NMR(400MHz,DMSO-d6)d8.00(s,1H),7.68(s,1H),6.88(s,1H),6.84(s,1H),6 .70(s,1H),5.62-5.57(m,1H),5.56(s,2H),5.24-5.17(m,1H),5.18-5.08(m,1 H),3.99-3.76(m,4H),3.55-3.48(m,1H),3.03-2.89(m,1H),2.38(s,3H),2.2 5-2.70(m,1H),2.06-1.96(m,1H),1.56(d,J=7.1Hz,3H),1.45(d,J=6.3Hz,3H)

[1014] Example 119: (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)tetrahydro-2H-pyran-4-ol (Compound 119)

[1015] [ka]

[1016] To a solution of (R)-1-(3-(1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (Intermediate-30) (200 mg, 0.393 mmol) in THF (2 ml) was added n-butyllithium (0.787 ml, 1.967 mmol) at −78° C. The resulting solution was stirred for 30 minutes at −78° C. Subsequently, a solution of tetrahydro-4H-pyran-4-one (commercially available) (47.3 mg, 0.472 mmol) in THF (0.5 mL) was added at −78° C., and the resulting solution was allowed to stir for 3 hours at room temperature. Subsequently, the reaction was quenched with aqueous ammonium chloride (3 ml) and extracted with ethyl acetate (2×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography using an eluent of 0 to 50% ethyl acetate in hexanes, followed by preparative HPLC to give (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)tetrahydro-2H-pyran-4-ol (20 mg, yield 9.60%) as an off-white solid.

[1017] MS(ES+)m / z=530.19(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.47(d,J=7.5Hz,1H),8.14(s,1H),7.68-7.56(m,1H),7.36-7 .24(m,1H),7.24-7.08(m,1H),5.89-5.77(m,1H),5.12(bs,1H),3.93-3.82(m,2H),3. 81-3.72(m,2H),3.34-3.24(m,2H),3.11-2.99(m,2H),2.32(s,3H),2.26-2.13(m,2H) ,2.07-1.97(m,2H),1.80-1.70(m,2H),1.60(d,J=7.0Hz,3H),1.24(s,3H),1.21(s,3H)

[1018] Example 120: (R / S)-2,2,2-trifluoro-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-one (Compound 120)

[1019] [ka]

[1020] Step-1: 1-(3-((R / S)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2,2,2-trifluoroethan-1-ol

[1021] The title compound was synthesized by using Intermediate-19 and Intermediate-44 and following a similar reaction protocol as described in Intermediate-21.

[1022] MS(ES+)m / z=481.24(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.42-8.35(m,1H),7.59(d,J=11.9Hz,1H),7.50-7.41(m,1H),7.39-7.25(m,2H),6.85-6.73(m,1 H),5.66-5.49(m,1H),5.22-5.02(m,1H),3.27-3.19(m,2H),3.11-2.93(m,2H),2.38(s,3H),2.20-2.07(m,2H),1.57(d,J=7.0Hz,3H)

[1023] Step-2: 2,2,2-trifluoro-1-(3-((R / S)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol

[1024] The title compound was synthesized by using 1-(3-((R / S)-1-((6-bromo-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2,2,2-trifluoroethan-1-ol and morpholine and following the same reaction protocol as described in Example-1.

[1025] MS(ES+)m / z=487.36(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.18-8.10(m,1H),7.60(d,J=11.7Hz,1H),7.53(s,1 H),7.50-7.44(m,1H),7.38-7.30(m,2H),6.80(d,J=5.5Hz,1H),5.72-5.62(m ,1H),5.18-5.03(m,1H),3.87-3.72(m,4H),3.13-3.06(m,2H),3.06-3.00(m, 4H),2.99-2.93(m,2H),2.36(s,3H),2.13-2.03(m,2H),1.60(d,J=7.1Hz,3H)

[1026] Step-3: (R / S)-2,2,2-trifluoro-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-one

[1027] To a stirred solution of 2,2,2-trifluoro-1-(3-((R / S)-1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (350 mg, 0.719 mmol) in DCM (5 ml), Dess-Martin periodinane (610 mg, 1.439 mmol) was added at 0 °C and stirred at 25 °C for 3 h. Upon completion, the reaction mixture was filtered through a bed of Celite, and the filtrate was diluted with DCM (70 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by reverse-phase preparative HPLC to give (R / S)-2,2,2-trifluoro-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-one (14 mg, 4.02% yield) as a light brown solid.

[1028] MS(ES+)m / z=485.36(M+1) 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.17(s,1H),8.03-7.93(m,1H),7.93-7.87(m,1H),7.71-7.58(m,1H),7.57-7.51(m,1H),5.71-5.68 (m,1H),3.83-3.75(m,4H),3.18-3.07(m,2H),3.06-3.00(m,4H),3.00-2.91(m,2H),2.36(s,3H),2.17-1.98(m,2H),1.65(d,J=7.1Hz,3H)

[1029] Example 121: (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 121)

[1030] [ka]

[1031] Step-1: Methyl 4-bromo-3,5-dimethoxybenzoate

[1032] To a stirred solution of 4-bromo-3,5-dimethoxybenzoic acid (125 g, 479 mmol) in methanol (600 ml), thionyl chloride (41.9 ml, 575 mmol) was added dropwise at 0-5°C. The mixture was then heated to 65°C for 6 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate (1000 ml), and the organic layer was washed with bicarbonate solution (300 ml x 2). The separated organic layer was washed with brine (300 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-bromo-3,5-dimethoxybenzoate (130 g, 99% yield) as a colorless oil.

[1033] 1 H NMR(400MHz,DMSO-d6)δ7.23(s,2H),3.91(s,6H),3.88(s,3H)

[1034] Step-2: Methyl 4-bromo-3,5-dimethoxy-2-nitrobenzoate

[1035] A solution of methyl 4-bromo-3,5-dimethoxybenzoate (130 g, 473 mmol) in acetic anhydride (2000 ml) was cooled to 0°C. 70% nitric acid (45.3 ml, 709 mmol) was added dropwise, and the mixture was then warmed to room temperature. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate (2 L), and washed with water (500 ml × 2) and brine (500 ml). The separated organic layer was dried over Na2SO4, filtered, and concentrated to give methyl 4-bromo-3,5-dimethoxy-2-nitrobenzoate (151 g, 100% yield) as a yellow solid.

[1036] 1H NMR (400 MHz, chloroform-d) δ 7.29 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.93 (s, 3H)

[1037] Step-3: Methyl 4-bromo-3-hydroxy-5-methoxy-2-nitrobenzoate

[1038] To a stirred solution of methyl 4-bromo-3,5-dimethoxy-2-nitrobenzoate (25.00 g, 78 mmol) in dichloromethane (200 mL) was added aluminum chloride (41.7 g, 312 mmol) in portions over 20 min at 0 °C. The resulting bright red solution was allowed to warm to room temperature and stirred at 25 °C for 1 h. The reaction mixture was poured into a slurry of 1 N HCl (1000 mL) and ice (1000 g), and the aqueous phase was extracted with DCM (3 × 300 mL). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mass was purified by flash column chromatography using 0 → 20% ethyl acetate in petroleum ether as eluent to give methyl 4-bromo-3-hydroxy-5-methoxy-2-nitrobenzoate (14.2 g, 59% yield) as a brown solid.

[1039] 1 H NMR (400 MHz, chloroform-d) δ 11.13 (s, 1H), 6.68 (s, 1H), 4.05 (s, 3H), 3.97 (s, 3H)

[1040] Step-4: Methyl 4-bromo-3-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-methoxy-2-nitrobenzoate

[1041] To a stirred solution of methyl 4-bromo-3-hydroxy-5-methoxy-2-nitrobenzoate (14 g, 45.7 mmol) in THF (140 ml) was added tert-butyl(2-hydroxyethyl)carbamate (14.75 g, 91 mmol) and triphenylphosphine (18.00 g, 68.6 mmol), followed by DIAD (13.34 ml, 68.6 mmol) at room temperature. The resulting mass was stirred for 1 hour at room temperature. Upon completion, the reaction mixture was concentrated, and the resulting crude product was purified by column chromatography using an eluent of 0 to 40% ethyl acetate in hexane to give methyl 4-bromo-3-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-methoxy-2-nitrobenzoate (14.3 g, 69.6% yield) as a white solid.

[1042] 1 H NMR (400 MHz, chloroform-d) δ 7.29 (s, 1H), 4.28-4.11 (m, 2H), 4.02 (s, 3H), 3.92 (s, 3H), 3.56-3.46 (m, 2H), 1.48 (s, 9H)

[1043] Step-5: 4-(tert-butyl)7-methyl-5-methoxy-8-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,7-dicarboxylate

[1044] To a sealed tube containing a solution of methyl 4-bromo-3-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-methoxy-2-nitrobenzoate (14 g, 31.2 mmol) and CsCO (20.31 g, 62.3 mmol) in toluene (160 ml) was added Xantphos (3.61 g, 6.23 mmol). The mixture was thoroughly deoxygenated by purging with nitrogen for 15 minutes before adding palladium(II) acetate (0.700 g, 3.12 mmol). The resulting mixture was stirred at 120°C for 1 hour. The reaction mass was cooled to room temperature, diluted with ethyl acetate (200 ml) and filtered through Celite. The filtrate was concentrated under vacuum to give the crude product.

[1045] The residue was purified by flash column chromatography with gradient elution from 0 to 40% ethyl acetate in petroleum ether to give 4-(tert-butyl) 7-methyl-5-methoxy-8-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,7-dicarboxylate (5.6 g, 48.8% yield) as a pale yellow solid.

[1046] 1 H NMR (400 MHz, chloroform-d) δ 7.06 (s, 1H), 4.39-4.35 (m, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.86-3.73 (m, 2H), 1.46 (s, 9H)

[1047] Step-6: Methyl 5-methoxy-8-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[1048] To a stirred solution of 4-(tert-butyl) 7-methyl 5-methoxy-8-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazine-4,7-dicarboxylate (5.0 g, 13.57 mmol) in DCM (100 ml) was added TFA (10.46 ml, 136 mmol) at room temperature and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. The crude residue was washed with pentane (30 ml × 2), then with diethyl ether (30 ml × 2) and decanted. The solid was filtered and dried to give methyl 5-methoxy-8-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (3.1 g, 85% yield) as a pale yellow solid.

[1049] MS(ES+)m / z=269.2(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.02(s,1H),4.26-4.12(m,2H),3.88(s,3H),3.75(s,3H),3.45-3.35(m,2H)

[1050] Step-7: Methyl 5-methoxy-4-methyl-8-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[1051] To a stirred suspension of methyl 5-methoxy-8-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (2.9 g, 10.81 mmol) in acetic acid (90 ml) was added paraformaldehyde (3.25 g, 108 mmol) at 25 °C under a N atmosphere. After stirring for 1 hour at 25 °C, sodium cyanoborohydride (3.26 g, 51.9 mmol) was added portionwise over 10 minutes, and the resulting mixture was stirred at 25 °C for 14 hours. The reaction mixture was quenched with ice water, neutralized to pH 7 with 6N NaOH solution, and extracted with ethyl acetate (100 ml × 2). The layers were separated, and the combined organic layer was washed with brine (50 ml), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 3.5 g of crude compound. The residue was purified by flash column chromatography with gradient elution from 50 to 60% ethyl acetate in petroleum ether to give methyl 5-methoxy-4-methyl-8-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (2.7 g, 88% yield).

[1052] MS(ES+)m / z=283.34(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.06(s,1H),4.23-4.15(m,2H),3.90(s,3H),3.79(s,3H),3.26-3.19(m,2H),2.96(s,3H)

[1053] Step-8: Methyl 8-amino-5-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[1054] The title compound was synthesized by following the similar reaction protocol as described in step-7 of Intermediate-12 using appropriate reagents.

[1055] 1 H NMR(400MHz,DMSO-d6)δ6.81(s,1H),5.93(s,2H),4.15-4.07(m,2H),3.76(s,3H),3.69(s,3H),3.13-3.06(m,2H),2.85(s,3H)

[1056] Step-9: 6-Methoxy-2,7-dimethyl-8,9-dihydro-3H-[1,4]oxazino[3,2-h]quinazolin-4(7H)-one

[1057] The title compound was synthesized by following the similar reaction protocol as described in Step-5 of Example-110 using appropriate reagents.

[1058] MS(ES+)m / z=262.15(M+1) 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),7.03(s,1H),4.19-4.10(m,2H),3.87(s,3H),3.14-3.06(m,2H),2.84(s,3H),2.30(s,3H)

[1059] Step-10: 4-chloro-6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazoline

[1060] The title compound was synthesized by following a similar reaction protocol as described in Intermediate-19, using appropriate reagents.

[1061] MS(ES+)m / z=280.27(M+) 1 H NMR(400MHz,DMSO-d6)δ6.97(s,1H),4.28-4.20(m,2H),3.98(s,3H),3.23-3.16(m,2H),2.94(s,3H),2.65(s,3H)

[1062] Step-11: (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol

[1063] The title compound was synthesized by using 4-chloro-6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazoline and Intermediate-8 and following a similar reaction protocol as described in Intermediate-21.

[1064] MS(ES+)m / z=463.18(M+1) 1 H NMR(400MHz,DMSO-d6)δ7.98(d,J=7.5Hz,1H),7.65-7.58(m,1H),7.44-7.36(m,1H),7.30(s,1H),7.27-7.20(m,1H),5.81(p,J=7.1Hz,1H) ,5.75-5.68(m,1H),4.23-4.08(m,2H),3.96(s,3H),3.93-3.90(m,2H),3.12-3.01(m,2H),2.82(s,3H),2.30(s,3H),1.59(d,J=7.1Hz,3H)

[1065] Example-122: (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one (Compound-122)

[1066] [ka]

[1067] Step-1: Methyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-3-nitrobenzoate

[1068] To a solution of methyl 4-hydroxy-3-nitrobenzoate (20 g, 101 mmol) in DMF was added KCO (29.4 g, 213 mmol), KI (0.337 g, 2.029 mmol), and then ethyl 2-bromo-2-methylpropanoate (commercially available) (21.77 g, 112 mmol) under an inert atmosphere, and heating was continued at 80 °C for 16 h. Upon completion, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using an eluent of 0 to 30% ethyl acetate in hexane to give methyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-3-nitrobenzoate (22 g, 70.7 mmol, 69.7% yield) as a white solid.

[1069] 1 H NMR(400MHz,DMSO-d6)δ8.36(d,J=2.2Hz,1H),8.16-8.10(m,1H),7.12(d,J=8 .9Hz,1H),4.23-4.16(m,2H),3.87(s,3H),1.63(s,6H),1.15(t,J=7.1Hz,3H)

[1070] Step-2: Methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

[1071] To a stirred solution of methyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-3-nitrobenzoate (14 g, 45.0 mmol) in acetic acid, iron (12.56 g, 225 mmol) was added and the reaction mass was heated at 90 °C for 1 hour. After completion, the reaction mixture was cooled to room temperature, filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (200 ml) and basified with saturated aqueous NaHCO. The aqueous layer was extracted with ethyl acetate (500 ml), washed with brine, and dried over anhydrous NaSO. The resulting compound was purified by column chromatography using an eluent of 0 → 70% ethyl acetate in hexane to give methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (9 g, 85% yield) as an off-white solid.

[1072] MS(ES+)m / z=236.14(M+1) 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),7.61-7.44(m,2H),7.04(d,J=8.4Hz,1H),3.82(s,3H),1.43(s,6H)

[1073] Step-3: Methyl 5,8-dibromo-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

[1074] To a stirred solution of methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (6.5 g, 27.6 mmol) in HSO was added NBS (10.82 g, 60.8 mmol) in portions over a period of 15 minutes at room temperature, and stirring was continued for 24 hours. The reaction mixture was slowly poured into ice-cold water, and the precipitated solid was filtered and dried in vacuo. The resulting residue was stirred in ethyl acetate (60 ml) for 15 minutes. The separated solid was filtered and dried under vacuum to give methyl 5,8-dibromo-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (3.7 g, 9.41 mmol, 34.1% yield).

[1075] MS(ES+)m / z=393.97(M+1) 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),7.30(s,1H),3.85(s,3H),1.47(s,6H)

[1076] Step-4: Methyl 5,8-dibromo-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

[1077] To a stirred solution of methyl 5,8-dibromo-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (2.0 g, 5.09 mmol), KI (0.084 g, 0.509 mmol), and KCO (1.407 g, 10.18 mmol) in DMF, MeI (0.477 mL, 7.63 mmol) was added dropwise at room temperature, and stirring was continued for 16 h. After completion, the reaction mixture was slowly poured into ice-cold water, and the precipitated solid was filtered and dried in vacuo to give methyl 5,8-dibromo-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (2 g, 4.91 mmol, 97% yield).

[1078] 1H NMR(400MHz,DMSO-d6)δ7.51(s,1H),3.88(s,3H),3.31(s,3H),1.47(s,6H)

[1079] Step-5: 6-Bromo-2,8,8,10-tetramethyl-3,10-dihydro-4H-[1,4]oxazino[2,3-h]quinazoline-4,9(8H)-dione

[1080] A mixture of methyl 5,8-dibromo-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (700 mg, 1.720 mmol), acetimidamide hydrochloride (244 mg, 2.58 mmol), copper(I) iodide (65.5 mg, 0.344 mmol), and cesium carbonate (1121 mg, 3.44 mmol) in DMF was heated at 120 °C for 12 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using an eluent of 0→70% ethyl acetate in hexane to give 6-bromo-2,8,8,10-tetramethyl-3,10-dihydro-4H-[1,4]oxazino[2,3-h]quinazoline-4,9(8H)-dione (270 mg, 0.767 mmol, 44.6% yield) as a yellow solid. MS(ES+)m / z=354.22(M+2)

[1081] Step-6: 6-Bromo-4-chloro-2,8,8,10-tetramethyl-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one

[1082] The title compound was synthesized according to the same reaction protocol as described in Intermediate-19 by using 6-bromo-2,8,8,10-tetramethyl-3,10-dihydro-4H-[1,4]oxazino[2,3-h]quinazoline-4,9(8H)-dione and appropriate reagents. MS(ES+)m / z=372.16(M+2)

[1083] Step-7: (R)-6-bromo-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one

[1084] The title compound was synthesized by using 6-bromo-4-chloro-2,8,8,10-tetramethyl-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one and Intermediate-6 according to the same reaction protocol as that described in Intermediate-21. MS(ES+)m / z=583.08(M+2)

[1085] Step-8: (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one

[1086] The title compound was synthesized according to the same reaction protocol as that described in step 1 of Example 87 by using (R)-6-bromo-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (commercially available).

[1087] MS(ES+)m / z=610.34(M+1) 1H NMR(400MHz,DMSO-d6)δ8.48-8.37(m,1H),8.00(s,1H),7.73-7.65(m,1H) ,7.65-7.54(m,1H),7.49-7.40(m,1H),7.35-7.27(m,1H),7.27-7.12(m,1 H),6.49-6.35(m,1H),5.90-5.74(m,1H),3.51-3.47(m,6H),2.25(s,3H), 1.61(d,J=7.0Hz,3H),1.45(s,3H),1.42(s,3H),1.24(s,3H),1.20(s,3H)

[1088] Example 123: (R)-4-(4-((1-(3-(...

Claims

1. A compound of the following general formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 96】 (In the formula, Ring A is selected from phenyl and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O, or S; "----" is either a single bond or a double bond, X and Y are independently C, O, and NR ｃ with the proviso that X and Y cannot both be O at the same time; R １ is C1-C6 alkyl, R ２ is hydrogen, R ３ is -OR ６ ;-NR ａ R ｂ substituted or unsubstituted C3-C6 cycloalkyl; C1-C6 alkyl substituted with 3-14 membered substituted or unsubstituted heterocyclyl containing 1-3 heteroatoms selected from N, O, or S; 5-14 membered substituted or unsubstituted heteroaryl containing 1-4 heteroatoms selected from N, O, or S; and 3-14 membered substituted or unsubstituted heterocyclyl containing 1-3 heteroatoms selected from N, O, or S, R ４ is selected from oxo and C 1 -C 6 alkyl; R ５ is halogen, cyano, -NR ｃ R ｄ , substituted or unsubstituted C 1 -C 6 alkyl, —C(═O)(substituted or unsubstituted C 1 -C 6 alkyl), and optionally two R ５ the groups form a 3-14 membered substituted or unsubstituted heterocyclic ring containing 1-3 heteroatoms selected from N, O, or S; R ６ is selected from C 1 -C 6 alkyl; 3-14 membered substituted or unsubstituted heterocyclyl containing 1-3 heteroatoms selected from N, O, or S; and C 1 -C 6 alkyl substituted with 3-14 membered substituted heterocyclyl containing 1-3 heteroatoms selected from N, O, or S; R ａ and R ｂ are independently selected from hydrogen; substituted or unsubstituted C 1 -C 6 alkyl; and 3-14 membered substituted or unsubstituted heterocyclyl containing 1 to 3 heteroatoms selected from N, O, or S; R ｃ and R ｄ are independently selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, and 4; When a C 1 -C 6 alkyl group is substituted, the alkyl group can be selected from the group consisting of oxo (═O), halogen, cyano, C 3 -C 6 cycloalkyl, phenyl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, —OR ７ , -C(=O)OH, -C(=O)O(C 1 -C 6 alkyl), -NR ８ R ８ａ , -NR ８ C(=O)R ９ and -C(=O)NR ８ R ８ａ and is substituted with 1 to 5 substituents independently selected from When a C 3 -C 6 cycloalkyl group is substituted, the cycloalkyl group can be selected from the group consisting of oxo (═O), halogen, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, cyano, phenyl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, —OR ７ , -C(=O)OH, -C(=O)O(C 1 -C 6 alkyl), -NR ８ R ８ａ , -NR ８ C(=O)R ９ and -C(=O)NR ８ R ８ａ and is substituted with 1 to 4 substituents independently selected from When a 5-14 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, or S is substituted, the heteroaryl group is selected from halogen, nitro, cyano, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, perhalo C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, 3-14 membered heterocyclyl, phenyl, 5-14 membered heteroaryl, -OR ７ , -NR ８ R ８ａ , -NR ７ C(=O)R ９ , -C(=O)R ９ , -C(=O)NR ８ R ８ａ , -SO ２ substituted with 1 to 4 substituents independently selected from -C1-C6 alkyl, -C(=O)OH and -C(=O)O-C1-C6 alkyl; When a 3-14 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, or S is substituted, the heterocyclic group is substituted either on a ring carbon atom or on a ring heteroatom, and when the heterocyclic group is substituted on a ring carbon atom, the heterocyclic group is selected from the group consisting of oxo (=O), halogen, cyano, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl, perhaloC1-C6 alkyl, -OR ７ , -C(=O)NR ８ R ８ａ , -C(=O)OH, -C(=O)O-C ​​1 -C 6 alkyl, -N(H)C(=O)(C 1 -C 6 alkyl), -N(H)R ８ and -N(C1-C6 alkyl) ２ and when the heterocyclic group is substituted on a ring nitrogen, the heterocyclic group is substituted with 1 to 4 substituents independently selected from C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, —SO ２ (C 1 -C 6 alkyl), -C(=O)R ９ and -C(=O)O(C1-C6 alkyl), and when the heterocyclic group is substituted on the ring sulfur, the heterocyclic group is substituted with one or two oxo (=O) groups; R ７ is selected from hydrogen, C 1 -C 6 alkyl, perhaloC 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; R ８ and R ８ａ are each independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; R ９ is selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl.

2. 2. A compound of general formula (I) according to claim 1, wherein A is selected from phenyl and pyridyl, or a pharma- ceutically acceptable salt thereof.

3. In the formula, R １ A compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

4. In the formula, R ３ but, -OCH ３、 【Chemistry 97】 and 【Chemistry 98】 2. The compound of claim 1 having general formula (I), or a pharma- ceutically acceptable salt thereof, selected from:

5. In the formula, R ４ A compound of general formula (I) according to claim 1, wherein is selected from oxo and methyl, or a pharma- ceutically acceptable salt thereof.

6. In the formula, R ５ Fluorine, -CH ３ , -CF ３ , -NH ２ , -CHF ２ , -CN, -COCF ３ , 【Chemistry 99】 and 【Chemistry 100】 It is selected from Optionally, two R bonded to adjacent carbon atoms ５ The base is 【Chemistry 101】 and 【Chemistry 102】 2. The compound of claim 1 having the general formula (I), or a pharma- ceutically acceptable salt thereof, which is formed as follows:

7. In the formula, R ６ Methyl, tetrahydrofuran-3-yl and 【Chemistry 103】 2. The compound of claim 1 having general formula (I), or a pharma- ceutically acceptable salt thereof, selected from:

8. In the formula, R ａ and R ｂ are independently hydrogen, methyl, 【Chemistry 104】 and 【Chemistry 105】 2. The compound of claim 1 having general formula (I), or a pharma- ceutically acceptable salt thereof, selected from:

9. In the formula, R ｃ and R ｄ A compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from hydrogen and methyl.

10. wherein A is selected from phenyl and pyridyl, "---" is either a single or double bond, and X and Y are independently selected from C, O and NR ｃ where X and Y cannot both be O at the same time, and R １ is methyl, R ２ is hydrogen, R ３ but, -OCH ３ 、 【Chemistry 106】 and 【Chemistry 107】 It is selected from R ４ is selected from oxo and methyl; R ５ Fluorine, -CH ３ , -CF ３ , -NH ２ , -CHF ２ , -CN, -COCF ３ , 【Chemistry 108】 and 【Chemistry 109】 is selected from the group consisting of Optionally, two R bonded to adjacent carbon atoms ５ The base is 【Chemistry 110】 and 【Chemistry 111】 It is formed, R ６ Methyl, tetrahydrofuran-3-yl and 【Chemistry 112】 It is selected from R ａ and R ｂ are independently hydrogen, methyl, 【Chemistry 113】 and 【Chemistry 114】 It is selected from R ｃ and R ｄ is independently selected from hydrogen and methyl; m is an integer selected from 0, 1, 2 and 3; and n is an integer selected from 0, 1, 2, 3 and 4. The compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof.

11. The compound is (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-methoxypiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-1), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-2), 2-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-3), 2-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-4), N-(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-5), 2-methyl-2-(3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-1-ol (Compound-6), 1,1-difluoro-2-methyl-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-7), N-(1-(2-amino-6-(trifluoromethyl)pyridin-4-yl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-8), (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-(3-(methoxymethyl)azetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-9), (R)-1,1-difluoro-1-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-10), 2,2-difluoro-2-(2-fluoro-3-((R)-1-((2-methyl-6-(((S)-tetrahydrofuran-3-yl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-11), (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N ６ , 2-Dimethyl-N ６ -(oxetan-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-12), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-oxa-8-azaspiro[4.5]decan-8-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-13), N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-14), (S)-1-(4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-15), (R)-1-(4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-16), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-17), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-18), N ４ -((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N ６ -((S)-tetrahydrofuran-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-19), N-(1-(3-amino-5-methylphenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-20), (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N ６ -(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-21), (S)-1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-22), (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-23), (R)-N-(1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-24), (S)-1-(4-(((R)-1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-25), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3-(methoxymethyl)azetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-26), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-27), (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N ６ -(oxetan-3-yl)-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-28), (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-(oxetan-3-ylamino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-29), (R)-1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-30), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-isopropylpiperazin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-31), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-((S)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-32), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-33), N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-34), 2,2-difluoro-2-(2-fluoro-3-((R)-1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-35), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3-methoxyazetidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-36), 1'-methyl-4'-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)spiro[cyclopropane-1,3'-indolin]-2'-one (Compound-37), N-(1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-38), N-((S / R)1-(3-(difluoro((S / R)-tetrahydrofuran-2-yl)methyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-39), 2,2-difluoro-2-(2-fluoro-5-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-40), 2,2-difluoro-2-(2-methyl-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-41), 2,2-difluoro-2-(3-(1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)-2-methylphenyl)ethan-1-ol (Compound-42), (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N ６ -(2-methoxyethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-43), (R)-1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyrrolidin-3-ol (Compound-44), 2,2-difluoro-2-(2-methyl-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-45), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-46), (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-47), (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-ol (Compound-48), (R)-(1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-yl)methanol (Compound-49), (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-methylpiperidin-4-ol (Compound-50), (R)-2-(1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-yl)propan-2-ol (Compound-51), (R)-2-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-2-azaspiro[3.3]heptan-6-ol (Compound-52), (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperazin-2-one (Compound-53), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-(methoxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-54), 1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-55), (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpiperazin-2-one (Compound-56), (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(methoxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-57), 1,1-difluoro-1-(2-fluoro-3-((R)-1-((6-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-58), (R)-1,1-difluoro-1-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-59), (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-60), 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-61), 1,1-difluoro-1-(2-fluoro-3-((R)-1-((6-((R)-2-(methoxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-62), (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-63), (R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (Compound-64), (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-4-ol (Compound-65), (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperazin-2-one (Compound-66), 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3-methylpyrrolidin-3-ol (Compound-67), (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-68), (R)-1-(4-((1-(3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-69), (R)-3,3-difluoro-3-(2-fluoro-3-(1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-1-ol (Compound-70), (R)-1-(4-((1-(3-(1,1-difluoro-3-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-71), 1-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(methoxymethyl)piperidin-4-ol (Compound-72), 1,1-difluoro-1-(2-fluoro-3-((R)-1-((2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)propan-2-ol (Compound-73), 1-(1-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)ethyl)azetidine-3-carbonitrile (Compound-74), (R)-2,2-difluoro-2-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-75), N-(1-(3-amino-5-fluorophenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-76), N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-77), N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-78), 3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)benzonitrile (Compound-79), N-(1-(3-amino-5-methylphenyl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-80), N-(1-(indolin-4-yl)ethyl)-2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-81), 3,3-difluoro-3-(2-fluoro-3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropane-1,2-diol (Compound-82), (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (Compound-83), (R)-1-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (Compound-84), (R)-1-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-4-(hydroxymethyl)piperidin-4-ol (Compound-85), 2,2-difluoro-2-(2-fluoro-3-((R)-1-((6-((R)-2-(hydroxymethyl)morpholino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-86), (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-87), (R)-5-(4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-88), 1-methyl-5-(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-89), (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-90), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-91), 1-(4-(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-92), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-93), (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-94), (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)pyridin-2(1H)-one (Compound-95), (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (Compound-96), (R)-5-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Compound-97), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-98), tert-Butyl-(R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound-99), (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)(cyclopropyl)methanone (Compound-100), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methylpiperidin-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-101), (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)piperidin-1-yl)ethan-1-one (Compound-102), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(1-isopropylpiperidin-4-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-103), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-104), (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinazolin-6-yl)piperidin-1-yl)ethan-1-one (Compound-105), (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N ６ -(4,5-dihydrooxazol-2-yl)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazoline-4,6-diamine (Compound-106), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((3-methyloxetan-3-yl)methoxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-107), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-108), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound-109), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2,8-dimethylfuro[2,3-h]quinazolin-4-amine (Compound-110), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine (Compound-111), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-112), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-113), (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-114), (R)-N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-115), N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-2,8,8-trimethyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-116), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-morpholino-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-117), N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydrofuro[2,3-h]quinazolin-4-amine (Compound-118), (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)tetrahydro-2H-pyran-4-ol (Compound-119), 2,2,2-trifluoro-1-(3-(1-((2-methyl-6-morpholino-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-one (Compound-120), (R)-2,2-difluoro-2-(2-fluoro-3-(1-((6-methoxy-2,7-dimethyl-8,9-dihydro-7H-[1,4]oxazino[3,2-h]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol (Compound-121), (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2,8,8,10-tetramethyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8H-[1,4]oxazino[2,3-h]quinazolin-9(10H)-one (Compound-122), (R)-4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)morpholin-3-one (Compound-123), (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)cyclohexan-1-one (Compound-124) and (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-8,9-dihydro-7H-cyclopenta[h]quinazolin-6-yl)cyclohexan-1-ol (Compound-125), 2. The compound of formula (I) according to claim 1, selected from the group consisting of:

12. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

13. A compound of general formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt thereof, for treating and / or preventing a disease, disorder and / or condition in a subject to which an effective amount is administered, by inhibiting SOS1.

14. A compound of general formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt thereof, for treating and / or preventing a disease, disorder and / or condition in a subject to which an effective amount is administered, by inhibiting the interaction between SOS1 and a protein of the RAS family.

15. 15. A compound for treating and / or preventing a disease, disorder and / or condition according to claim 13 or 14, wherein said disease, disorder and / or condition is cancer.

16. 16. The compound for treating and / or preventing a disease, disorder and / or condition according to claim 15, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF mutant cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, pure mucosal neuroma syndrome, fibrous epulis and sarcoma.

17. 15. A compound for the treatment and / or prevention of diseases, disorders and / or conditions according to claim 13 or 14, wherein said diseases are acute Staphylococcus aureus infection (pediatric patients), acute respiratory distress syndrome / acute lung injury and sepsis.

18. 15. A compound for the treatment and / or prevention of a disease, disorder and / or condition according to claim 13 or 14, wherein said disease is rasopathy.

19. 19. A compound for treating and / or preventing a disease, disorder and / or condition according to claim 18, wherein said lasopathy is selected from the group consisting of Neurofibromatosis Type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigo (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Regius Syndrome, Noonan-like / Multiple Giant Cell Lesion Syndrome and Hereditary Gingival Fibromatosis (HGF).

20. 2. A compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, for treating and / or preventing cancer, wherein said compound is administered in combination with at least one or more pharmacologically active substances.

21. 2. A compound of general formula (I) as claimed in claim 1, or a pharma- ceutically acceptable salt thereof, for treating and / or preventing cancer, said compound being administered before, after or together with at least one other pharmacologically active substance.

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