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

its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in various pathological conditions.
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit of Indian Provisional Patent Application Nos. IN 201921049157, filed on 29th November 2019 and IN 202021035414, filed on 17th August 2020, the disclosures of which are incorporated herein by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION
Multiple signaling pathways control the initiation, progression, spread, metastasis, immune evasion of cancer. Key signaling pathways include RTK/RAS pathway, PI3K pathway, Wnt pathway, Myc pathway and the cell cycle pathway (Francisco Sanchez-Vega et al., Cell, 2018, 173(2):321-337.e10). RAS-family proteins (KRAS, HRAS and NRAs and their respective
mutants) are small GTPases that exist in cells in either GTP-bound (inactive) or GDP-bound (active) states (Siqi Li et al, Nat. Rev. Cancer, 2018, 18(12):767-777). The activity of RAS proteins is modulated by proteins known as GTPase Activating Proteins (GAPs) or Guanine Nucleotide Exchange Factors (GEFs). The GAP proteins belonging to the RAS family include members such as NF1, TSC2, IQGAP1, etc. which activate the GTPase function of the RAS proteins and thus terminate the signaling by catalyzing the hydrolysis of GTP to GDP. In contrast, the RAS family GEFs include proteins such as SOS1, SOS2, RASGRP, RASGRF2, etc. which activate the RAS proteins by exchanging GTP for GDP (Johannes L. Bos et al, Cell, 2007, 129(5):865-77).
Ras-GTP binds to effector proteins such as Raf and PI3K which in turn leads to activation of the RAF-MEK-ERK (MAPK) and PI3K-mTOR-AKT (PI3K) signaling pathways (Suzanne Schubbert et al., Nat. Rev. Cancer, 2007, 7(4):295-308). Triggering of one or more of these cellular signaling pathways leads to the initiation and maintenance of the oncogenic phenotype involving enhanced cell proliferation, increased cell survival, altered metabolism, angiogenesis, migratory potential and immune evasion eventually leading to establishment and metastasis of cancers (Yousef Ahmed Fouad et al., Am. J. Cancer Res., 2017, 1;7(5):1016-1036; Douglas Hanahan et al., Cell, 2011, 4;144(5):646-74). RAS proteins undergo point mutations at several amino acid residues – the key hot spots being positions G12, G13 and Q61. These mutations render the RAS proteins constitutively active since the proteins are predominantly in the active GTP-bound form (Ian A. Prior et al., Cancer Res.2012, 15; 72(10): 2457–2467; Adrienne D. Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11):828-51). Interaction of RAS proteins with GEFs such as Son of Sevenless 1 (SOS1) plays a crucial role in relaying the signals to downstream effectors. The SOS1 protein harbors several domains such as the Dbl homology domain (DH), a Pleckstrin homology domain (PH), RAS exchanger motif (REM), CDC25 homology domain and a C-terminal proline rich domain (PxxP) (Pradeep Bandaru et al., Cold Spring Harb Perspect Med., 2019, 1;9(2). pii: a031534). SOS1 has been shown to have a catalytic site as well as an allosteric site. The catalytic site is preferentially bound by RAS-GDP whereas RAS-GTP binds with the allosteric site with better affinity than RAS-GDP (S. Mariana Margarit et al., Cell, 2003, 7;112(5):685-95; Hao-Hsuan Jeng et al., Nat. Commun., 2012; 3:1168). Furthermore, binding of oncogenic KRAS to SOS1 promotes
the activation of wild type HRAS and NRAS (Hao-Hsuan Jeng et al., Nat. Commun., 2012;3:1168). The catalytic (guanine nucleotide exchange) function of SOS1 is critical for KRAS oncogenic activity in cancer cells (You X et al., Blood. 2018, 13;132(24):2575-2579; Erin Sheffels et al., Sci Signal.2018, 4;11(546). pii: eaar8371). SOS1 plays a key role in signal transmission following cellular activation by Receptor Tyrosine Kinases (RTKs) (Frank McCormick et al., Nature, 1993, 6;363(6424):45-51; Stephane Pierre et al., Biochem Pharmacol.2011, 1;82(9):1049-56). Additionally, receptors on lymphocytes (B cell and T cell receptor) (Mateusz Poltorak et al., Eur J Immunol.2014, 44(5):1535-40; Stephen R. Brooks et al., J Immunol. 2000, 15;164(6):3123-31) and hematopoietic cells (Mario N. Lioubin et al., Mol Cell Biol., 1994, 14(9):5682-91).
The role of SOS1 in the RAS-mediated signaling pathways make it an attractive target for cancer therapy. Pharmacological intervention with SOS1 inhibitors has been shown to attenuate or eliminate the downstream effector events of the RAS-mediated pathways (Roman C. Hillig et al., Proc. Natl. Acad. Sci. U S A.2019, 12;116(7):2551-2560; Chris R. Evelyn et al., J Biol Chem., 2015, 15; 290(20): 12879-98).
In addition to cancer, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g. Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et a/., Biochem. Pharmacol., 2011,82(9):1049-56).
In addition, the other diseases associated with hSOS1 expression is significantly upregulated in whole blood cell extracts of pediatric patients with acute community-acquired Staphylococcus aureus infection and in patients with Acute Respiratory Distress Syndrome (ARDS)/Acute Lung Injury (ALI) and Sepsis (F.C. Baltanás, et al. BBA - Reviews on Cancer 1874 (2020) 188445).
In addition, several patent applications related to SOS1 are published which are as follows: WO2004003152, WO2014144148, WO2016077793, WO2018115380, WO2018172250, WO2019122129, WO2019201848, WO2020180768, and WO2020180770.
The foregoing shows that there exists an unmet need for SOS1 inhibitory compounds for treating diseases or disorders involving SOS1, particularly cancer that are dependent on the SOS1.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compounds of the general formula (I), their pharmaceutically acceptable salts, tautomeric forms, stereoisomers, polymorphs, solvates, combinations with suitable other medicament or medicaments and pharmaceutical compositions thereof and use thereof in treating various diseases or disorders including cancers,

wherein, ring A, R1 to R5, X, Y, m, and n are described in detail below. The compounds of the present invention are potent inhibitors of SOS1.
According to one aspect of the present invention, there is provided a compound represented by the general formula (I), its tautomeric form, its stereoisomer, its polymorph, its solvate, its pharmaceutically acceptable salt, its combinations with suitable medicament and its pharmaceutical compositions, wherein, ring A, R1 to R5, X, Y, m, and n are described in detail below.
In other aspect the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, and its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder mediated through SOS1.
In another aspect the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric form, its stereoisomer, its polymorph, its solvate, or its pharmaceutically acceptable salt in combination with the usual pharmaceutically employed carriers, diluents, and the like are useful for the treatment of a disease or disorder such as cancer, infectious disease or disorder, or RASopathy disease or disorder.
In yet other aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating disease characterized by excessive or abnormal cell proliferation such as cancer.
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases like pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating diseases such as Neurofibromatosis type 1 (NF1), Noonan Syndrome with Multiple Lentigines (NSML), Noonan-like/multiple giant cell lesion syndrome, Hereditary Gingival Fibromatosis (HGF), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Legius
Syndrome, Acute Staphylococcus aureus infection (Pediatric Patients), Pure mucosal neuroma syndrome, Fibrous Epulis, Acute Respiratory Distress syndrome/Acute Lung injury and Sepsis, Costello Syndrome (CS), and Cardio-Facio-cutaneous Syndrome (CFC Syndrome).
In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in therapeutic regimens in the context of first line, second line, or any further line of treatments. In another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for use in the prevention, short-term or long term treatment of the above-mentioned diseases optionally in combination with radiotherapy and/or surgery.
In yet another aspect the present invention provides the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition for treating various cancers mentioned above which harbor hyperactive or aberrantly activated signaling pathways involving RAS and or SOS1 proteins.
In another aspect the present invention provides use of the compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or its solvate in combination with other agents such as radiation, chemotherapeutic agents and/or targeted agents in multiple cancers and their subtypes as mentioned above. The agents that can be used for combination therapy include targeted agents such as inhibitors of RTKs, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyltransferases (HMTs), DNA methyltransferases (DNMTs), protein arginine methyltransferases (PRMTs), RAS inhibitors, KRAS inhibitors, MEK inhibitors, ERK1/2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
DETAIL DESCRIPTION OF THE INVENTION
The present invention is related to a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable one or more other medicaments, its pharmaceutical composition, method of making of the compound, its use as SOS1 inhibitor, and its therapeutic utility in treating, or ameliorating various pathological conditions. The compound of formula (I) is as shown below:

Wherein,
Ring A is selected from aryl, heteroaryl, and heterocyclyl;
‘----’ is either a single bond or double bond;
X and Y are independently selected from C, O, and NRc, provided that both X and Y cannot be O at the same time;
R1 is selected from hydrogen and substituted or unsubstituted alkyl;
R2 is selected from hydrogen, halogen, alkyl, and cycloalkyl;
R3 is selected from –OR6, -NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R4 is selected from oxo and substituted or unsubstituted alkyl;
R5 is selected from halo, cyano, –NRcRd, substituted or unsubstituted alkyl, -C(=O) substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; optionally two R5 groups attached to the adjacent carbon atoms forming a substituted or unsubstituted heterocycle;
R6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, and alkyl substituted with substituted heterocyclyl;
Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl;
Rc and Rd 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, it is substituted with 1 to 5 substituents independently selected from oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR7, -C(=O)OH, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and –C(=O)NR8R8a;
when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR7, -C(=O)OH, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and –C(=O)NR8R8a;
when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR7, -NR8R8a, -NR8C(=O)R9, –C(=O)R9, –C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;
when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR7, -NR8R8a, -NR7C(=O)R9, –C(=O)R9, –C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;
when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR7, –C(=O)NR8R8a, -C(=O)OH, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R8, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), –C(=O)R9, and -C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=O) group(s);
R7 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;
R8 and R8a are each independently selected from hydrogen, alkyl, and cycloalkyl; and R9 is selected from alkyl and cycloalkyl.
In accordance with an embodiment of the invention, A is selected from aryl and heteroaryl. In certain embodiments, A is selected from phenyl and pyridyl.
In any of the above embodiments, R1 is substituted or unsubstituted alkyl.
In certain embodiments, R1 is methyl.
In any of the above embodiments, R2 is hydrogen.
In any of the above embodiments, R3 is selected from the group consisting of –OR6, -NRaRb, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl.
In certain embodiments, R3 is selected from the group consisting of

In any of the above embodiments, R4 is selected from oxo and methyl.
In any of the above embodiments, R5 is selected from the group consisting of halogen, cyano, –NRcRd, substituted or unsubstituted alkyl, and -C(=O) substituted or unsubstituted alkyl; two R5 groups adjacent to the carbon atom to which they are attached form substituted or unsubstituted heterocyclyl.
In certain embodiments, R5 is selected from the group consisting of fluorine, -CH3, -CF3, -NH2,

carbon atom to which they are attached form
In any of the above embodiments, R6 is selected from the group consisting of methyl,
tetrahydrofuran-3-yl, a
In any of the above embodiments, Ra and Rb are independently selected from the group
consisting of hydrogen, methyl,
In any of the above embodiments, Rc and Rd are independently selected from hydrogen and methyl.
Whenever a range of the number of atoms in a structure is indicated (e.g., a C1 to C20 alkyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-6 carbon atoms (e.g., C1 to C6), 2-6 carbon atoms (e.g., C2 to C6), 3-6 carbon atoms (e.g., C3 to C6), as used with respect to any chemical group (e.g., alkyl etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, and/or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, as appropriate).
General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.
The term ‘alkyl’, as used herein, means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably, the alkyl chain may contain 1 to 10 carbon atoms. More preferably, alkyl chain may contain up to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term ‘haloalkyl’, as used herein means an alkyl group as defined hereinabove wherein at least one of the hydrogen atoms of the said alkyl group is substituted with halogen. The haloalkyl group is exemplified by chloromethyl, 1-chloroethyl, and the like.
The term ‘perhaloalkyl’, as used herein, means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
The term ‘cycloalkyl’ as used herein, means a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring
containing 3 to 6 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring. Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene, spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2,1'-cyclopentane], hexahydro-2'H-spiro[cyclopropane-1,1'-pentalene]. Tricyclic ring systems are the systems wherein the bicyclic systems as described above are further annulated with third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03.7]nonane, and tricyclo[3.3.1.13.7]decane (adamantane).
The term ‘cycloalkenyl’ as used herein, means a cycloalkyl group as defined above containing at least one double bond.
The term ‘aryl’, as used herein, refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons, e.g. tetrahydro-naphthalene. Aryl group also include bicyclic systems like 2,3-dihydro-indene-5-yl, and 2,3-dihydro-1-indenone-5-yl.
The term ‘heteroaryl’, as used herein, refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated),
wherein at least one ring in the ring system is aromatic. The term ‘heteroaryl’ as used herein, also include partially saturated bicyclic and tricyclic aromatic ring system, e.g. 2,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-1-isobenzofuranone-5-yl, 2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl, and 2,3-dihydro-1-isoindolinone-5-yl. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include, but not limited to, 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, 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] isoxazolyl, 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-isobenzofuranone-5-yl, 2,3-dihydro-1H-indol-5-yl, 2,3-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.
The term ‘heterocycle’ or ‘heterocyclic’ or ‘heterocyclyl’ as used herein, means a ‘cycloalkyl’ or ‘cycloalkenyl’ group wherein one or more of the carbon atoms are replaced by heteroatoms/groups selected from N, S, SO2, and O. The heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include, but are not limited to, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-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 also includes bridged and spiro heterocyclic systems such as azabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 6-oxa-3-azabicyclo[3.1.1]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.
The ‘halogen’ means fluorine, chlorine, bromine, or iodine.
The term ‘oxo’ means a divalent oxygen (=O) attached to the parent group. For example, oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a cyclohexanone, and the like.
The term ‘annulated’ means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
The term ‘bridged’ means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring atoms.
A compound, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, its pharmaceutical
composition thereof as described hereinabove wherein the compound of general formula (I), is selected from the group consisting of:
(R)-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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-N6-(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); N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-((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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-(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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-(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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6-(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]quinazoline-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] quinazoline-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-(methoxy methyl) 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)-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 (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).
According to a feature re of the present invention, the compounds of general formula (I) where
all the symbols are as defined earlier, can be prepared by methods illustrated in the schemes
and examples provided herein below. However, the disclosure should not be construed to limit
the scope of the invention arriving at compound of formula (I) as disclosed herein above.
Scheme - A illustrates the synthesis of compound of formula (A5)

The compound of formula (A1) undergoes a metal catalyzed cross coupling with alkoxy vinyl stannane, e.g. tributyl(1-ethoxyvinyl)tin in presence of palladium catalysts such as Pd(Ph3P)2Cl2, Pd2(dba)3, and the like; optionally using bases such as triethylamine, N,N-Diisopropylethylamine, and the like, in hydrocarbon solvents like toluene or ether solvents like
1,4-dioxane to furnish the alkoxy vinyl intermediate which in turn provide compound of
formula (A2) in acidic condition by employing aqueous mineral acids such as hydrochloric
acid in ether solvent such as THF, 1,4-dioxane and the like.
The compound of formula (A2) was then reacted with corresponding chirally pure tert-butanesulfinamide in presence of Lewis acid such as titanium alkoxides e.g. titanium tetraethoxide, titanium isopropoxide, and the like, in ether solvents such as 1,4-dioxane, THF,
and the like, to obtain the compound of formula (A3).
The compound of formula (A3) reacted with reducing agent such as metal hydrides e.g. sodium borohydride, L-selectride, and the like in solvents such as THF, 1,4-dioxane, methanol, and the
like, optionally in presence of water to provide compound of formula (A4). Major diastereoisomer in the compound of formula (A4) after reduction was separated or taken ahead
as such.
The compound of formula (A4) under acidic condition undergoes cleavage of sulfinyl derivative to generate amine of formula (A5) as a free base or salt. The acids employed for the transformation may involve mineral acids such as hydrochloric acid or organic acids such as trifluoroacetic acid.
Scheme - B illustrates the synthesis of compound of formula (I) and (I-A)
Compound of formula (B1) was either commercially purchased or prepared by following a procedure reported in Russian Journal of Organic Chemistry, 2002, vol. 38, # 12, p. 1764 –
1768. Halogenation of carboxylic acid (B1) using N-halosuccinimide reagent such as but not
limited to NBS, NIS, and NCS gives corresponding dihalo compound of formula (B2), which
on coupling with different amidines of formula (B3) gives compound of formula (B4) (where
R1 = alkyl).
The compound of formula (B4) could be either directly converted to compound of formula
(B6) using different benzylic amines (A5) and coupling reagents such as but not limited to BOP, etc in polar solvents such as but not limited to ACN, DMF, and DMSO, or compound of
formula (B4) could be further halogenated by using reagents such as but not limited to chlorinating agents like POCl3, POBr3, Oxalyl chloride, or SOCl2 and bases such as but not
limited to DIPEA, TEA, and N,N-dimethyl aniline in solvents such as but not limited to chloroform, dichloroethane, and chlorobenzene to give compound of formula (B5).
Compound of formula (B5) undergoes a nucleophilic substitution reaction with different benzylic amines (A5) leading to compound of formula (B6). The compound of formula (B6)
could be further acylated using Stille reaction condition to compound of formula (B7) which
could be further converted into compound of formula (I-A) through reductive amination using appropriate substituted amine. The compound of formula (B6) could be further functionalized
e.g. transition metal catalyzed C-C coupling, C-N bond formation or C-O bond formation reactions like Suzuki or Buchwald reaction utilizing corresponding counterpart, i.e. substituted
amine or substituted boronate to get compound of formula (I).
Scheme – C illustrates the synthesis of compound of formula (B4)

Compound of formula (C1) was obtained commercially or can be obtained through following
a procedure reported in WO2017139778 and Helvetica Chimica Acta, 1981, vol. 64, # 2, p.
572 - 578.
The compound of formula (C1) was treated with Chloral hydrate and hydroxylamine to afford
the compound of formula (C2) at appropriate temperature.
The compound of formula (C2) which upon treating with inorganic acids like H2SO4 gets
cyclized at appropriate temperature leading to isatin derivative as compound of formula (C3) which on coupling with different amidines (B3) by using bases such as K3PO4, K2CO3, Na2CO3, Cs2CO3 etc in polar aprotic solvents like DMF, DMSO etc at appropriate temperature leading
to compound of formula (B4) (where R1 = alkyl).
Scheme – D illustrates the synthesis of compound of formula (I-B)
The compound of formula (D1) can be synthesized via acetylation of corresponding aniline compound of formula (B6) as mentioned in above Scheme - B.
The compound of formula (D1) was converted to corresponding carbamate compound of
formula (D2) using transition metal catalyzed cross coupling such as via Buchwald Hartwig coupling, which further upon deprotection lead to intermediate compound of formula (D3).
The compound of formula (D3) could be further functionalized to urea compound of formula
(D4) by treating with corresponding isocyanates (where Rh = Ri = H, CH3).
The compound of formula (D4) could be further cyclized leading to final compound of formula (I-B) using bases such as KOtBu, NaH etc in a polar aprotic solvent like DMF, DMSO etc at appropriate temperature.
Scheme – E illustrates the synthesis of compound of formula (I-C)
The compound of formula (B6) as prepared following Scheme - B, could be converted to corresponding hydroxy derivative of compound of formula (E1) via e.g. transition metal catalyzed cross coupling.
Compound of formula (E1) could be further alkylated by using bases such as K2CO3, Na2CO3, to the compound of formula (I-C).
Scheme – F illustrates formation of compound of formula (I-D) starting from commercially available compound of formula (F1)
Compound of formula (F1) upon alkylation using propargyl bromide affords corresponding compound of formula (F2).
Nitration of compound of formula (F2) with nitrating reagents such as, although not limited to
nitric acid, potassium nitrate, and the like, in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid, and the like, anhydrides like acetic anhydride, trifluroacetic anhydride, and the like, or mixture(s) thereof to provides compound
of formula (F3), which upon Claisen rearrangement and in situ cyclization at appropriate temperature, to affords compound of formula (F4). Such reactions can be carried out in either
neat or in presence of high boiling solvents such as, although not limited to NMP, diphenyl
ether, xylene, N,N-diethyl aniline, and the like or mixtures thereof and also in combination
with bases such as, although not limited to cesium fluoride and high boiling solvents such as, although not limited to N,N-diethyl aniline, NMP, diphenyl ether, xylene, and the like or mixtures thereof.
Compound of formula (F4) was converted to corresponding aniline derivative of compound of formula (F5) through selective reduction of nitro group by using reducing agents, although not limited to, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride and the like. Such reduction could be carried out in one or more solvents, e.g., ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol and, the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, and the like or mixtures thereof.
Compound of formula (F5) could be further cyclized to give compound of formula (F6) as tricyclic building block. Such reaction can be carried out in polar solvent like acetonitrile using acids such as, but not limited to methane sulfonic acid or hydrochloric acid at appropriate temperature.
The compound of formula (F6) is treated with tri-isopropyl benzene sulfonyl chloride to afford corresponding sulfonate derivative of compound of formula (F7) in solvents such as ethers like THF or 1,4-Dioxane at appropriate temperature.
Compound of formula (F7) undergoes a nucleophilic substitution reaction with appropriate chiral benzylic amines leading to the compound of formula (F8) using organic basic reagents such as, but not limited to DIPEA or TEA in a polar aprotic solvent like dioxane or THF at appropriate temperature.
The compound of formula (F8) demethylated to corresponding hydroxy derivative of compound of formula (F9) by using reagents like Lewis acids such as, but not limited to BBr3, AlCl3, etc and basic reagents such as, but not limited to NaSEt, etc in polar solvents such as, although not limited to DMF, can, and the like or mixtures thereof, and halogenated solvents such as, although not limited chloroform, dichloromethane, and the like or mixtures thereof. The compound of formula (F9) can be further alkylated by using inorganic bases such as, but not limited to K2CO3, Na2CO3, and Cs2CO3 etc in polar aprotic solvents like DMF, DMSO etc at appropriate temperature leading to final compound of formula (I-D).
Scheme - G illustrates formation of compound of formula (I-E) starting from compound of
formula (G1) (Reference: CN105884699)

Compound of formula (G1) upon alkylation using 3-chloro-2-methylprop-1-ene afford compound of formula (G2). Such reaction could be carried out by using inorganic bases such
as, although not limited to K2CO3, Cs3CO3, Na2CO3 and organic bases such as, although not
limited to DIPEA, TEA, diisopropyl amine, and the like etc., and the polar aprotic solvents
such as, although not limited to acetone, acetonitrile, and DMF or mixture(s) thereof.
The compound of formula (G2) upon Claisen rearrangement at appropriate temperature to
affords hydroxyl derivative of compound of formula (G3). Such reactions can be carried out in
either neat or in presence of high boiling solvents such as, but not limited to NMP, diphenyl
Ether, xylene, N,N-diethyl aniline, and the like or mixtures thereof.
Compound of formula (G3) upon cyclization in solvents such as, although not limited to THF, Diethyl ether, dioxane, and ACN under acidic conditions such as, but not limited to formic acid, acetic acid, hydrochloric acid, and the like mixture(s) thereof at appropriate temperature to afford compound of formula (G4).
The compound of formula (G4) further converted to corresponding aniline derivatives of compound of formula (G5) through selective reduction of nitro group by using reducing agents such as, although not limited to, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride, and the like. Such reduction reaction can be carried out in one or more solvents, e.g. ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol, and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, and the like or mixture(s) thereof.
The compound of formula (G5) could be further cyclized to give compound of formula (G6) as tricyclic building block. Such reaction can be carried out in polar solvent like acetonitrile using acids such as, but not limited to methane sulphonic acid, hydrochloric acid etc at appropriate temperature.
The compound of formula (G6) could be halogenated by using reagents such as, although not limited to, POCl3 or POBr3 in combination with organic bases such as, although not limited to DIPEA, TEA in halogenated solvents such as, although not limited to chlorobenzene, chloroform, DCM etc at appropriate temperature to give compound of formula (G7).
The compound of formula (G7) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the compound of formula (G8) using organic basic reagents such as, but not limited to DIPEA, TEA etc in a polar aprotic solvents like dioxane, THF etc at appropriate temperature.
The compound of formula (G8) demethylated to corresponding hydroxy derivative of compound of formula (G9) by using reagent such as, but not limited to BBr3, NaSEt etc in polar solvents such as DMF, ACN, and the like; halogenated solvents such as chloroform, dichloromethane, etc.
The compound of formula (G9) can be further alkylated to form ether compound of general formula (I-E) by using organic bases such as, but not limited, DIPEA, TEA at appropriate temperature or the said alkylation can be carried out by using bases such as K2CO3, Na2CO3, Cs2CO3, etc in polar aprotic solvents like DMF, DMSO etc at appropriate temperature. The compound of formula (G9) could be converted to ether compound of general formula (I-E) via Mitsunobu reaction also.
However, the compound of formula (G9) could also be converted to corresponding triflate with triflic anhydride in halogenated solvents such as, but not limited to DCM, CHCl3, etc and further reacting this triflate intermediate with appropriate aliphatic amines or boronic acid to afford compound of general formula (I-E). This reaction could be mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof; a suitable ligand such as, although not limited to Xanthophos, BINAP, Ru-Phos, or mixture(s) thereof; in the presence of suitable base, preferably inorganic bases such as, although not limited to e.g., K2CO3, Na2CO3, Cs2CO3, NaOtBu, Potassium phosphate, or mixture(s) thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, dioxane, and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA, or mixture(s) thereof.
Scheme - H illustrates formation of compound of formula (I-F) starting from compound of formula (F4)

The compound of formula (F4) can be reduced to corresponding aniline derivative (H1) through selective reduction of nitro group and aromatic double bond by using reducing agents,
such as, although not limited to, such reducing agents include hydrogenation with palladium
on carbon, metal reductions like iron, tin or tin chloride, and the like. Such reduction reaction
can be carried out in one or more solvents, although not limited to, e.g., ethers such as THF,
1,4-dioxane, and the like; alcohol such as methanol, ethanol, and the like; under either neutral
or acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, and the like,
or mixture(s) thereof.
The compound of formula (H1) can be further cyclized to give compound of formula (H2) as tricyclic building block. Such reaction can be carried out in polar solvent like acetonitrile using
acids such as, but not limited to methane sulphonic acid, hydrochloric acid etc at appropriate temperature.
The compound of formula (H2) can be halogenated by using reagents such as, although not limited, POCl3 or POBr3 in combination with organic bases such as, although not limited to, DIPEA, TEA in halogenated solvents such as chlorobenzene, chloroform, DCM etc at appropriate temperature to give the compound of formula (H3).
The compound of formula (H3) undergoes a nucleophilic substitution reaction with different chiral benzylic amines of compound of formula (A5) leading to the compound of formula (H4) using organic basic reagents such as, but not limited to DIPEA, TEA etc in a polar aprotic solvents like dioxane, THF etc at appropriate temperature.
The compound of formula (H4) demethylated to corresponding hydroxy derivative of compound of formula (H5) by using Lewis Acids reagent such as, but not limited to BBr3, AlCl3 etc and basic reagents such as, but not limited to NaSEt, etc in polar solvents such as, although not limited to DMF, can, and the like; halogenated solvents such as, although not limited to chloroform, dichloromethane, etc.
The compound of formula (H5) could be further alkylated to form ether compound of general formula (I-F) by using organic bases such as, but not limited to DIPEA, TEA etc at appropriate temperature, the said alkylation can be carried out by using bases such as K2CO3, Na2CO3, Cs2CO3, etc in polar aprotic solvents like DMF, DMSO etc at appropriate temperature. The compound of formula (H5) could be converted to ether compound of general formula (I-F) via Mitsunobu reaction also.
However, the compound of formula (H5) could also be converted to corresponding triflate with triflic anhydride in halogenated solvents such as, but not limited to, DCM, CHCl3, etc and further reacting this triflate intermediate with appropriate aliphatic amines or boronic acid to afford compound of general formula (I-F). This reaction could be mediated by a suitable catalyst such as, e.g., Pd(PPh3)2Cl2, Pd2dba3, Pd(PPh3)4, Pd(OAc)2, or mixture(s) thereof; a suitable ligand such as, although not limited to Xanthophos, BINAP, Ru-Phos or mixture(s) thereof; in the presence of suitable base, preferably inorganic bases such as, although not limited to e.g. K2CO3, Na2CO3, Cs2CO3, NaOtBu, Potassium phosphate, or mixture(s) thereof. Such reactions can be carried out in solvents like ethers such as THF, dioxane, and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA, or mixture(s) thereof.
Scheme - I illustrates the synthesis of compounds of formula (I-G) and (I-H)
The compound of formula (B5) undergoes a nucleophilic substitution reaction with compound
of formula (A5) in the presence of organic base such as, although not limited to TEA, pyridine, DIPEA, or DMAP leading to compound of formula (I1). Such reactions can be carried out in
polar protic solvents such as MeOH, EtOH, IPA, and the like; amides such as DMF, DMA,
and the like; ethers such as THF or 1,4-Dioxane and the like; halogenated solvents such as
CHCl3, DCE, chlorobenzene, and the like; polar aprotic solvents such as DMSO, can, and the
like.
The compound of formula (I1) subjected to a controlled oxidation by using reagents such as,
but not limited to, the said reagent is the combination oxalyl chloride and DMSO in organic
solvents such as DCM, CHCl3, DCE, and the like; in presence of organic base such as, but not
limited to, triethylamine, N,N-diisopropylethylamine to give aldehyde compound of formula
(I2).
The compound of formula (I2) was then subjected to the olefination reaction by using reagents such as, but not limited to, alkyltriphenyl phosphonium halide in presence of base such as, but not limited to, KHMDS, LDA in presence of ether solvent such as, but not limited to, THF, 1,4-dioxane, and like to obtain the compound of formula (I3).
The compound of formula (I3) undergoes hydroboration reaction by using a regents such as, but not limited to, Borane-THF complex, Borane-DMS complex or Per-acids like hydrogen peroxide in ether solvents such as, but not limited to, THF, 1,4-dioxane to gives the two regioisomers of compound of formula (I4) and racemic mixture (I5).
The compound of formula (I-G) and racemic mixture (I-H) could be prepared by the Buchwald coupling of compound of formula (I4) and racemic mixture (I5) respectively with appropriate aliphatic amines. This reaction could 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, xanthophos, BINAP, Ru-Phos, or mixture(s) thereof; in the presence of suitable base, preferably inorganic bases such as, but not limited to, alkali metal carbonates, e.g., Na2CO3, K2CO3, Cs2CO3, sodium tert-butoxide, potassium phosphate, or mixture(s) thereof. Such reactions could be carried out in solvents like ethers such as THF, dioxane, and the like; hydrocarbons, e.g., toluene and the like; amides such as DMF, DMA, and the like or mixture(s) thereof. The final separation through chiral chromatography would provide pure diastereomers of compound of formula (I-G).
Scheme - J illustrates formation of compound of formula (I-I) starting from compound of formula (L1) (Reference: CN105884699)

The compound of formula (J1) upon esterification using chlorinating reagents such as, but not
limited to, thionyl chloride, oxalyl chloride in methanol affords the compound of formula (J2).
Nitration of compound of formula (J2) with nitrating reagents such as, although not limited to
nitric acid, potassium nitrate, and the like in acids such as, although not limited to tin (IV) chloride, sulphuric acid, trifluroacetic acid, acetic acid, and the like, anhydrides like acetic anhydride, trifluroacetic anhydride, and the like, or mixture(s) thereof to provides the compound of formula (J3).
The compound of formula (J3) selectively demethylated to corresponding hydroxy derivative
of compound of formula (J4) by using reagent such as, but not limited to AlCl3, BBr3, NaSEt,
etc in polar solvents such as DMF, can, and the like; halogenated solvents such as chloroform, dichloromethane, etc.
Compound of formula (J4) upon ether formation using protected amino alcohols like tert-butyl(2-hydroxyethyl)carbamate affords the compound of formula (J5). Such reaction could be carried out by using regents such as, although not limited to DIAD, DEAD, Triphenyl phosphine etc and solvents such as, but not limited to, ethers such as THF, dioxane, and the like; hydrocarbons, e.g., toluene or mixtures(s) thereof.
The compound of formula (J5) upon cyclization afford compound of formula (J6). This reaction could 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, although not limited to Xanthophos, BINAP, Ru-Phos, or mixture(s) thereof; in the presence of suitable base, preferably inorganic bases such as, although not limited to e.g., K2CO3, Na2CO3, Cs2CO3, NaOtBu, Potassium phosphate, or mixture(s) thereof. Such reactions can be carried out in solvents like, e.g., ethers such as THF, Dioxane, and the like; hydrocarbons, e.g., toluene; amides such as DMF, DMA, or mixture(s) thereof.
The compound of formula (J6) under acidic condition undergoes deprotection to generate compound of formula (J7). The acids employed for the transformation may involve mineral acids such as hydrochloric acid or organic acids like trifluoroacetic acid.
The compound of formula (J7) upon alkylation or reductive amination using alkyl halides or aldehydes respectively afford compound of formula (J8). Such reaction could be carried out by using inorganic bases such as, although not limited to K2CO3, Cs2CO3, and Na2CO3, and the polar aprotic solvents such as, although not limited to acetone, acetonitrile, and DMF, or mixture(s) thereof, for alkylation and reducing agents like NaCNBH4, Na(CH3COO)3BH etc in solvents like polar protic solvents such as but not limited to methanol, ethanol, acetic acid, and DME.
The compound of formula (J8) further converted to corresponding aniline derivatives of compound of formula (J9) through selective reduction of nitro group by using reducing agents, although not limited to, such reducing agents include hydrogenation with palladium on carbon, metal reductions like iron, tin or tin chloride, and the like. Such reduction reaction can be carried out in one or more solvents, e.g. ethers such as THF, 1,4-dioxane, and the like; alcohol such as methanol, ethanol, and the like; under acidic conditions involving ammonium chloride, acetic acid, hydrochloric acid, and the like, or mixture(s) thereof.
The compound of formula (J9) which on coupling with different amidines of compound of formula (B3) gives the compound of formula (J10) as tricyclic building block.
The compound of formula (J10) could be halogenated by using reagents such as, although not limited to, POCl3 and POBr3 or combination with organic bases such as, although not limited to DIPEA and TEA in halogenated solvents such as, although not limited to chlorobenzene, chloroform, and DCM at appropriate temperature to give the compound of formula (J11). The compound of formula (J11) undergoes a nucleophilic substitution reaction with different chiral benzylic amines of compound of formula (A5) leading to the compound of formula (I-I) using organic basic reagents such as but not limited to DIPEA and TEA in a polar aprotic solvents like dioxane and THF at appropriate temperature.
Scheme – K illustrates formation of compound of formula (I-J) starting from compound of formula (M1) (Reference: CN105884699)
The compound of formula (K1) upon alkylation using ethyl 2-bromo-2-methylpropanoate
afford the compound of formula (K2). Such reaction could be carried out by using inorganic
bases such as, although not limited to K2CO3, Cs3CO3, and Na2CO3 and organic bases such as, although not limited to DIPEA, TEA, diisopropyl amine, and the like, and the polar aprotic
solvents such as, although not limited to acetone, acetonitrile, and DMF, or mixture(s) thereof.
The compound of formula (K2) further converted to corresponding cyclized derivatives of compound of formula (K3) through selective reduction of nitro group by using reducing agents, although not limited to, such reducing agents include hydrogenation with palladium on carbon,
metal reductions like iron, tin or tin chloride, and the like. Such reduction reaction can be
carried out in one or more solvents, e.g. ethers such as THF, 1,4-dioxane, and the like; alcohol
such as methanol, ethanol, and the like; under acidic conditions involving ammonium chloride,
acetic acid, hydrochloric acid, and the like, or mixture(s) thereof.
The compound of formula (K3) undergoes halogenation using N-halosuccinimide reagent such as, but not limited to NBS, NIS, and NCS gives corresponding dihalo compound of formula (K4), which on alkylation using alkyl halides afford compound of formula (K5). Such reaction could be carried out by using inorganic bases such as, although not limited to K2CO3, Cs2CO3, and Na2CO3, and the polar aprotic solvents such as, although not limited to acetone, acetonitrile, and DMF, or mixture(s) thereof.
The compound of formula (K5), which on coupling with different amidines of compound of formula (B3) gives compound of formula (K6) (where R1 = alkyl) which could be halogenated by using reagents such as, although not limited to POCl3 and POBr3 in combination with organic bases such as, although not limited to DIPEA and TEA in halogenated solvents such as, although not limited to chlorobenzene, chloroform, and DCM at appropriate temperature to give compound of formula (K7).
The compound of formula (K7) undergoes a nucleophilic substitution reaction with different chiral benzylic amines (A5) leading to the compound of formula (K8) using organic basic reagents such as but not limited to DIPEA and TEA in a polar aprotic solvents like dioxane and THF at appropriate temperature.
The compound of formula (K8) could be further functionalized e.g. transition metal catalyzed C-C or C-N coupling reactions like Suzuki or Buchwald reaction utilizing corresponding counterpart, i.e. substituted amine or substituted boronate to gives the compound of formula (I-J).
All intermediates used for the preparation of the compounds of the present invention, were prepared by approaches reported in the literature or by methods known to people skilled in the art of organic synthesis. Detailed experimental procedures for the synthesis of intermediates are given below.
The intermediates and the compounds of the present invention can be obtained in a pure form by any suitable method, for example, by distilling off the solvent in vacuum and/or re-crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g., flash chromatography) on a suitable support material such as alumina or silica gel using an eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and/or their combinations. Preparative LC-MS method can also be used for the purification of the molecules described herein.
Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of the layers and drying of the organic layer over sodium sulphate, filtration, and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally by using a mobile phase with suitable polarity, and purification using selective crystallization.
Salts of compound of formula (I) can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which is then treated with the desired acid or base as described in Berge S. M. et al., “Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1-19 (1977)” and in “Handbook of Pharmaceutical Salts - Properties, Selection, and Use,” by P. Heinrich Stahland Camille G. Wermuth, 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 of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium.
The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with an inorganic acid, 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 an inorganic base, such as sodium hydroxide or potassium hydroxide. The conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent. The mixture is maintained at a suitable temperature (e.g., between 0 ^C and 50 ^C). The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent. The stereoisomers of the compounds of formula (I) of the present invention can be prepared by stereospecific synthesis or resolution of racemic compound mixture by using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
Prodrugs of the compounds of the invention can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted to ester groups via 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, e.g., ethyl esters, lower alkenyl esters, di-lower alkylamino lower-alkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. The compounds of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomeric forms are contemplated as an aspect of the present invention and such tautomers may be in equilibrium or predominant in one of the forms. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in abundance in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl, and 123I respectively.
Thus the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric form, its stereoisomer, its polymorph, its solvate, its pharmaceutically acceptable salts in combination with pharmaceutically acceptable carriers, diluents, excipients, and the like.
The pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers or excipients include saline (e.g., 0.9% saline), Cremophor EL® (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). A preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
Formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal, and vaginal administration can be developed for the compound of formula (I), its tautomeric form, its stereoisomer, its polymorph, its solvate, and its pharmaceutically acceptable salt.
The pharmaceutical compositions can be administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. Thus, the invention provides compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for
parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill 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 anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids 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.
Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
Topical formulations, including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include 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, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
A compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. A compound of the invention is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compounds of the 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 the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides can be employed. The surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%. The balance of the composition is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin, for intranasal delivery. These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
Additionally, the compound of the 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 formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
The concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
For example, a typical pharmaceutical composition for intravenous infusion could 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 parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington’s Pharmaceutical Science (17th ed., Mack Publishing Company, Easton, PA, 1985).
It will be appreciated by one of ordinary skill in the art that, in addition to the aforesaid described pharmaceutical compositions, the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents no.4235871, 4501728, 4837028, and 5019369.
The compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder. Such doses are known in the art (see, for example, the Physicians’ Desk Reference (2004)). The compounds 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).
Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present method can involve the administration of about 0.1 μg to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 μg to about 200 mg of the compound of the invention would be more commonly used, depending on a patient’s physiological response. By way of example and not intending to limit the invention, the dose of the pharmaceutically active agent(s) described herein for methods of treating a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject 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/kg body weight per day. The dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg 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/kg body weight per day.
The terms “treat,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, amelioration, or inhibition. Rather, there are varying degrees of treatment, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. Furthermore, the treatment, amelioration, or inhibition provided by the inventive method can include treatment, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer. Also, for purposes herein, “treatment,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
In accordance with the invention, the term subject includes an “animal” which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. In one aspect, the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). In another aspect, the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla,
including Equines (horses). In a further aspect, the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). In yet another aspect, the mammal is human.
Compounds belonging to this invention can be used for the treatment of the various cancers mentioned below which harbor hyperactive or aberrantly activated signaling pathways involving SOS1 proteins.
Compounds belonging to this invention can be used for the treatment of the various cancers mentioned below which harbor hyperactive or aberrantly activated signaling pathways involving RAS and or SOS1 proteins.
The compounds, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or its solvate its combination with suitable medicament, its pharmaceutical composition thereof as described hereinbelow can be suitable for treating diseases characterized by excessive or abnormal cell proliferation such as cancer.
The cancer, tumor, and other proliferative diseases can be treated with the compounds of the present invention is but not limited to:
1. Cancers of the head and neck, e.g. cancers of nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pillar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords, hypopharynx, salivary glands (including minor salivary glands).
2. Cancers of the lung, e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer), class 3 BRAF-mutant lung cancer.
3. Neoplasms of the mediastinum, e.g. neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma,
ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma).
4. Cancers of the gastrointestinal (GI) tract, e.g. cancers of the esophagus, stomach (gastric cancer), esophagiogastric adenocarcinoma pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma.
5. Cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis).
6. Cancers of the testis, e.g. seminomas, non-seminomas.
7. Gynecologic cancers e.g. cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus).
8. Cancers of the breast, e.g. mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), 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.
9. Cancers of the endocrine system, e.g. cancers of the endocrine glands, thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors.
10. Sarcomas of the soft tissues, e.g. 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 pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor.
11. Sarcomas of the bone, e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, 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, chondroblastoma;
12. Mesothelioma, e.g. pleural mesothelioma, peritoneal mesothelioma.
13. Cancers of the skin, e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer, class 3 BRAF-mutant melanoma.
14. Neoplasms of the central nervous system and brain, e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axis tumors.
15. Lymphomas and Leukemias, e.g. B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult 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 predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous/myeloid leukemia (AML), acute lymphatic/lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic/lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous/myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML).
16. Cancers of unknown primary site (CUP).
17. Epithelial cancers, e.g. squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous,
papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid), oncocytic carcinoma. and
18. Nonepithelial cancers, e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.
All cancers mentioned above which are characterized by their specific location or origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.
All cancers mentioned above may be further differentiated by their histopathological classification.
The compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition as described herein above can 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, Fibrous Epulis, Acute Respiratory Distress syndrome/Acute Lung injury and Sepsis, Costello Syndrome (CS), and Cardio-Facio-cutaneous Syndrome (CFC Syndrome).
The compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition as described hereinabove may be used in therapeutic regimens in the context of first line, second line, or any further line of treatments.
The compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, its combination with suitable medicament, or its pharmaceutical composition as described hereinabove may be used for the prevention, short-term or long term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy and/or surgery.
The compound of formula I, its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, its solvate, belonging to the present invention can be combined with other agents such as radiation, chemotherapeutic agents and/or targeted agents in multiple cancers and their subtypes as mentioned above. The agents that can be used for combination therapy include targeted agents such as inhibitors of RTKs, cyclin-dependent kinase (CDK) inhibitors, Ser-Thr kinase inhibitors, non-receptor tyrosine kinase inhibitors, inhibitors of epigenetic mechanism such as histone methyl transferases (HMTs), DNA methyl transferases (DNMTs), protein arginine methyl transferases (PRMTs), RAS inhibitors, KRAS inhibitors, MEK inhibitors, ERK1/2 inhibitors, Focal Adhesion Kinase (FAK) inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
The following examples are provided to further illustrate the present invention and should not be constructed in any way to limit the scope of the present invention.
All 1HNHR spectra were determined in the solvent indicated and chemical shifts are reported in δ units downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz).
Some of the representative examples of the present invention were prepared by following one or more reaction schemes as described above.
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the relative 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 invention. The patents and patent applications mentioned in the description are incorporated herein by reference.
The notation “or1” “or2” and “or3” in structural formulae denote that chiral center is ascertained to be either R or S, herein absolute configuration is not determined.
Intermediate synthesis:
Intermediate - 1: (R/S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one
hydrochloride
Step - 1: 4'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one
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 min, followed by addition of MeI (3.94 ml, 63.0 mmol) at 0°C, reaction mixture was stirred at room temperature for 3 h. After completion of reaction, the reaction mixture was quenched with ice water solution. The formed solid filtered and dried under vacuo
to afford 4'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (9.0 g, 85% yield) as brown solid.
MS (ES+) m/z = 254.21 (M+2).
1H NMR (400 MHz, DMSO-d6) δ 7.25 – 7.10 (m, 3H), 3.21 (s, 3H), 2.17 (q, J = 3.9 Hz, 2H),
1.40 (q, J = 3.9 Hz, 2H).
Step - 2: 4'-acetyl-1'-methyl spiro[cyclopropane-1,3'-indolin]-2'-one
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), PdCl2(PPh3)2 (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 reaction, mixture was cooled to room temperature and filtered through celite bed. Filtrate was concentrated and the residue was suspended in 2N HCl (20 ml) and THF (50 ml) and stirred for 30 min and then extracted with ethyl acetate (500 ml x 2). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to get crude (7.3 g). The crude residue was purified by column chromatography using eluent (0 - 30%) ethyl acetate in hexane to obtain 4'-acetyl-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (5.1 g, 66.4% yield) as light brown solid. MS (ES+) m/z = 216.45 (M+).
1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.8, 1.1 Hz, 1H), 3.23 (s, 3H), 2.56 (s, 3H), 2.17 - 2.05 (m, 2H), 1.35 - 1.38 (m, 2H). Step - 3: (R)-2-methyl-N-((R/S)-1-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-4'-yl)ethyl)propane-2-sulfinamide
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 nitrogen atmosphere. The resulting reaction mass was heated to 80°C for 16 h. After completion of reaction, reaction mixture was allowed to cooled -78°C, followed by addition of sodium borohydride (3.08 g, 81 mmol) then temperature of the mixture was gradually raised to room temperature and stirred for 2 h. Then reaction mass was poured into ice cold water (50 ml), then added ethyl acetate (500 ml) and stirred for 30 min. Filtered the residue and washed with ethyl acetate, organic layer was separated and dried with anhydrous Na2SO4 and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography by using eluent 60% ethyl acetate in hexane to obtain (R)-2-methyl-N-((R/S)-1-(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-4'-yl)ethyl)propane-2-sulfinamide (1.9 g, 25.5% yield) as sticky liquid.
MS (ES+) m/z = 320.53 (M+).
1H NMR (400 MHz, DMSO-d6) δ 7.31 - 7.26 (m, 1H), 7.20 (dd, J = 8.1, 1.1 Hz, 1H), 6.97 (dd, J = 7.6, 1.1 Hz, 1H), 5.53 (d, J = 5.9 Hz, 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 = 6.7 Hz, 3H), 1.09 (s, 9H). Step - 4: (R/S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride
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 a dropwise solution of 4M HCl in Dioxane (7.41 ml, 29.6 mmol) at 0°C, under nitrogen atm and continued the stirring for 3h. After completion of reaction distilled the solvent under reduced pressure at 35°C, resulting residue was triturated with diethyl ether (15 ml), filtered and solid was dried in vacuo to obtain (R/S)-4'-(1-aminoethyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride (0.5 g, 33.4% yield) as yellow solid.
1H NMR (400 MHz, DMSO - d6) δ 8.54 (s, 2H), 7.39 (d, J = 1.8 Hz, 1H), 7.38 (s, 1H), 7.13 – 7.08 (m, 1H), 3.84 - 3.88 (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 = 6.7 Hz, 3H).
Intermediate - 2: (R/S)-2-(3-(1-aminoethyl)-2-fluorophenyl) propan-2-ol hydrochloride

Step - 1: 2-(3-bromo-2-fluorophenyl)propan-2-ol
Taken methyl 3-bromo-2-fluorobenzoate (9.5 g, 40.8 mmol) (commercially available) in THF (40 ml) cooled in ice bath and methyl magnesium chloride (40.8 ml, 122 mmol) in diethyl ether was added dropwise into it. After stirring for 1.5 h at room temperature, a saturated aqueous solution of ammonium chloride (5 ml) and water (20 ml) was added sequentially to the reaction mixture and extracted with ethyl acetate (40 ml), the organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mass was purified by flash column chromatography by using eluent 0 - 10% ethyl acetate in hexane to get 2-(3-bromo-2-fluorophenyl)propan-2-ol (7.0 g, 73.7% yield) as a colorless liquid.
1H NMR (400 MHz, DMSO-d6) δ 7.65-7.60 (m, 1H), 7.59-7.54 (m, 1H), 5.42 (s, 1H), 1.48 (d, J = 1.4 Hz, 6H).
Step - 2: 1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethan-1-one
The title compound was synthesized by using 2-(3-bromo-2-fluorophenyl)propan-2-ol and following analogous reaction protocol as described in Step - 2 of intermediate - 1.
1H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.83 (m, 1H), 7.70 - 7.61 (m, 1H), 7.27 (t, J = 7.7 Hz, 1H), 5.41 (s, 1H), 2.58 (s, 3H), 1.52 (d, J = 1.4 Hz, 6H).
Step – 3: (R)-N-(1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide
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 nitrogen atmosphere. The resulting reaction mixture was heated at 80°C for 16 h. After complete consumption of starting material, the reaction mixture was allowed to room temperature and diluted with ethyl acetate (100 ml). Water (10 ml) was added dropwise, resulted white precipitate was filtered through celite, washed residue with ethyl acetate (30 ml X 2). The filtrate was washed with water (50 ml), dried over anhydrous sodium sulphate, filtered and concentrated. The crude mass was purified by flash column chromatography by using 0 to 30% ethyl acetate in hexane to afford (R)-N-(1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 84%) as colorless liquid.
Step - 4: (R)-N-((R/S)-1-(2-fluoro-3-(2-hydroxypropan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
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 NaBH4 (0.634 g.16.70 mmol) at 0°C and stirred at 27°C for 1 hr. The reaction mixture was poured in ice cold water and extracted with ethyl acetate (50 x 2 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated. The obtained crude product was purified by flash column chromatography (0 – 40% ethyl acetate in Hexane) to afford (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 sticky solid.
MS (ES+) m/z = 324.15 (M+Na).
1H NMR (400 MHz, DMSO-d6) δ 7.54 - 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 = 6.8 Hz, 3H), 1.09 (s, 9H).
Step - 5: (R/S)-2-(3-(1-aminoethyl)-2-fluorophenyl) propan-2-ol hydrochloride
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 analogous reaction protocol as described in Step - 4 of Intermediate - 1.
1H NMR (400 MHz, DMSO - d6) δ 8.36 (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).
Intermediate - 3: (R/S)-3-(1-aminoethyl)-5-methylaniline
Step - 1: (R)-2-methyl-N-((R/S)-1-(3-methyl-5-nitrophenyl)ethyl)propane-2-sulfinamide The title compound was synthesized by using 1-(3-methyl-5-nitrophenyl)ethan-1-one (commercially available) and following analogous reaction protocol as described in Step - 3 of Intermediate - 1.
1H 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).
CLAIMS
1. A compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof,
Wherein
Ring A is selected from aryl, heteroaryl, and heterocyclyl;
‘----’ is either a single bond or double bond;
X and Y are independently selected from C, O, and NRc, provided that both X and Y cannot be O at the same time;
R1 is selected from hydrogen and substituted or unsubstituted alkyl;
R2 is selected from hydrogen, halogen, alkyl, and cycloalkyl;
R3 is selected from –OR6, -NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
R4 is selected from oxo and substituted or unsubstituted alkyl;
R5 is selected from halogen, cyano, –NRcRd, substituted or unsubstituted alkyl, -C(=O) substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; optionally two R5 groups attached to the adjacent carbon atoms forming substituted or unsubstituted heterocycle; R6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, and alkyl substituted with substituted heterocyclyl;
Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl;
Rc and Rd 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, it is substituted with 1 to 5 substituents independently selected from oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR7, -C(=O)OH, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and –C(=O)NR8R8a;
when an cycloalkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, alkyl, hydroxyalkyl, cyano, aryl, heteroaryl, heterocyclyl, -OR7, -C(=O)OH, -C(=O)O(alkyl), -NR8R8a, -NR8C(=O)R9, and –C(=O)NR8R8a;
when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, heteroaryl, -OR7, -NR8R8a, -NR8C(=O)R9, –C(=O)R9, –C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;
when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR7, -NR8R8a, -NR7C(=O)R9, –C(=O)R9, –C(=O)NR8R8a, -SO2-alkyl, -C(=O)OH, and -C(=O)O-alkyl;
when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, perhaloalkyl, -OR7, –C(=O)NR8R8a, -C(=O)OH, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R8, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), –C(=O)R9, and -C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=O) group(s);
R7 is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl;
R8 and R8a are each independently selected from hydrogen, alkyl, and cycloalkyl; and R9 is selected from alkyl and cycloalkyl.
2. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in claim 1, wherein A is selected from aryl and heteroaryl.
3. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in claim 1 or 2, wherein A is selected from phenyl and pyridyl.
4. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 3, wherein R1 is substituted or unsubstituted alkyl.
5. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 4, wherein R1 is methyl.
6. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 5, wherein R2 is hydrogen.
7. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 6, wherein R3 is selected from –OR6, -NRaRb, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl.
8. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 7, wherein R3 is selected from
-OC

9. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 8, wherein R4 is selected from oxo and methyl.
10. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 9, wherein R5 is selected from the group consisting of halogen, cyano, –NRcRd, substituted or unsubstituted alkyl, and -C(=O) substituted or unsubstituted alkyl; optionally two R5 groups attached to the adjacent carbon atoms forming substituted or unsubstituted heterocycle.
11. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 10, wherein R5 is selected from fluorine, -CH3, -CF3, -NH2, -CHF2, -CN, -COCF3,


nally two R5 groups attached to the
adjacent carbon atoms forming and .
12. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims
from 1 to 11, wherein R6 is selected from methyl, tetrahydrofuran-3-yl, and
.
13. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims
1 to 12, wherein Ra and Rb are independently selected from hydrogen, methyl,
,

14. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 13, wherein Rc and Rd are independently selected from hydrogen and methyl.
15. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 14, wherein A is selected from aryl and heteroaryl; ‘----’ is either a single bond or double bond; X and Y are independently selected from C, O, and NRc, provided that both X and Y cannot be O at the same time; R1 is substituted or unsubstituted alkyl; R2 is hydrogen; R3 is selected from–OR6, -NRaRb, substituted or unsubstituted cycloalkyl, alkyl substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R4 is selected from oxo and substituted or unsubstituted alkyl; R5 is selected from halogen, cyano, –NRcRd, substituted or unsubstituted alkyl, and -C(=O)substituted or unsubstituted alkyl; optionally two R5 groups attached to the adjacent carbon atoms forming substituted or unsubstituted heterocycle; R6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, and alkyl substituted with substituted heterocyclyl; Ra and Rb are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl; Rc and Rd 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.
16. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in one of claims from 1 to 15, wherein A is selected from phenyl and pyridyl; ‘----’ is either a single bond or double bond; X and Y are independently selected from C, O, and NRc, provided that both X and Y cannot be O at the same time; R1 is methyl; R2 is hydrogen; R3 is selected from
-OC

R4 is
CH3
R5 groups attached to the adjacent carbon atoms forming and
selected
from methyl, tetrahydrofuran-3-yl, and ; Ra and Rb are independently selected
from hydrogen, methyl,
, , , , d Rd are independently selected from hydrogen and methyl; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, and 4.
17. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 16, wherein the compound is selected from:
(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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-N6-(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); N4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-((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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-(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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-N6-(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)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6-(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]quinazoline-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] quinazoline-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-(methoxy methyl) 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)-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 (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).
18. A pharmaceutical composition comprising a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims form 1 to 17 and a pharmaceutically acceptable carrier.
19. A method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof as claimed in any one of claims from 1 to 17.
20. A method for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting the interaction of SOS1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof as claimed in any one of claims from 1 to 17.
21. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 19 or 20, wherein the said disease, disorder, and/or condition is a cancer.
22. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 21, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
23. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 19 or 20, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/Acute Lung injury, and Sepsis.
24. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 19 or 20, wherein the said disease, disorder, and/or condition is a RASopathy.
25. A method for the treatment and/or prevention of a disease, disorder, and/or a condition as claimed in claim 24, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius
Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary Gingival Fibromatosis (HGF).
26. The method as claimed in claims 18 to 25, wherein the compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, is administered before, after, or together with at least one or more pharmacologically active substance.
27. Use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 17, for the treatment and/or prevention of a disease, disorder, and/or a condition by inhibiting SOS1 in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
28. Use of a compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 17, for the treatment and/or prevention of a disease, disorder, and/or condition by inhibiting the interaction of SOS1 and RAS family protein in a subject, comprising administering to the subject a therapeutically effective amount of a said compound.
29. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 27 or 28, wherein the said disease, disorder, and/or condition is cancer.
30. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 29, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, class 3 BRAF-mutant cancers, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast
cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, Pure mucosal neuroma syndrome, Fibrous Epulis, and sarcomas.
31. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 27 or 28, wherein the said disease is Acute Staphylococcus aureus infection (Pediatric Patients), Acute Respiratory Distress syndrome/Acute Lung injury, and Sepsis.
32. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 27 or 28, wherein the said the disease is a RASopathy.
33. The use of a compound for the treatment and/or prevention of a disease, disorder, and/or condition as claimed in claim 32, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, Noonan-like/multiple giant cell lesion syndrome and Hereditary gingival fibromatosis (HGF).
34. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 17, for treatment and/or prevention of cancer, wherein said compound is administered in combination with at least one more pharmacologically active substance.
35. The compound of the general formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its polymorph, or solvate thereof, as claimed in any one of claims from 1 to 17, for treatment and/or prevention of cancer, wherein the compound is administered before, after, or together with at least one other pharmacologically active substance.