DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

NOVEL HETEROCYCLIC COMPOUNDS AS SOS1:KRAS PROTEIN-PROTEIN INTERACTION INHIBITORS

We, SATYARX PHARMA INNOVATIONS Pvt Ltd,
an Indian company having address at 3rd Floor Block B, CDC Towers,
Plot No l0/8, Road No. 5, Nacharam Industrial Area,
Hyderabad 500 076, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF INVENTION
The present invention relates to novel compounds of formula (I) which are inhibitors of SOS1:KRAS protein-protein interaction, their pharmaceutically acceptable salts, solvates, polymorphs, tautomers, optical and geometric isomers thereof.
The present invention also relates to a process for their manufacture , derivatives of formula (I), pharmaceutical compositions containing them, and their use for the treatment or use in the treatment of cancer.

Formula (I)

BACKGROUND OF THE INVENTION
Son of Sevenless 1 (SOS1) is a human homologue of the originally identified Drosophila protein Son of Sevenless (Pierre et al., Biochem. Pharmacol., 201 1 , 82(9): 1049-56; Chardin et al., Cytogenet. Cell. Genet., 1994, 66(1 ):68-9). The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by the Dbl homology domain (DH), a Pleckstrin homology domain (PH), a helical linker (HL), RAS exchanger motif (REM), CDC25 homology domain and a C-terminal proline rich domain (PR). In the native state, the GEF activity of SOS family of proteins is autoinhibited by its own N terminal autoinhibitory domain, and is activated only upon membrane recruitment (Science, 2019, 363, 1098-1103)
SOS1 and SOS2 are the most widely expressed guanidine exchange factors (GEFs) that are responsible for activation of RAS and RAC proteins (BBA Reviews on Cancer, Volume 1874, Issue 2, December 2020, 188445). SOS1 and SOS2 appear to be ubiquitously expressed, as the presence of specific RNAs or proteins for those genes is detectable in practically all human cells, organs and tissues tested. Constitutive KO SOS1 gene in mouse showed that SOS1 is essential for intrauterine and placental development, with constitutive-null-animals dying during mid-gestation due to defects of the embryos (EMBO J 19, 2000, 642-654 ; Genes Dev, 1997, 11, 309-320). In contrast, adult SOS2-constitutive-KO mice were perfectly viable and fertile and did not show any obvious phenotypic abnormalities [Mol. Cell. Biol, 20, 2000, 6410-6413]. SOS1 is the most crucial player in this nucleotide exchange reaction It promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). The mechanism is probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity. SOS-mediated activation of WT RAS is critical for the development of RAS-mutant tumors (Nat. Communications 2012, 3, 1168; Enzym, 2013, 25-39; Cancer Discovery 2013, 3, 113-123)
The initial proof of concept for evaluating SOS1 as a pharmacological target to treat cancer was obtained based on some genetic ablation studies. SOS1 KO / siRNA in mouse resulted in reduction in leukemogenesis (Leukemia, 2018, 32, 820-827; Blood, 2018, 132, 2575-2579), skin cancers (Mol. Cell. Biol. 2018, 38, e00048-18) and gastroesophageal cancers (Nat Med 2018, 24, 968-977). SOS1 is the second most common mutation in Noonan Syndrome (~16.5%), an autosomal dominant disorder and the most predominant RASopathic condition (Mol Syndromol, 2010, 1, 2-26; Eur. J. of Med. Genetics, 2010 53, 322-324).
SOS1 is significantly mutated in lung adenocarcinoma (LUAD) patients who do not present canonical gain of function mutations in receptor tyrosine kinase pathway players like RAS/RAF, etc. (Genes, chromosomes & cancer. 2008;47(3):253–9; Mol Cancer Res. 2019 April ; 17(4): 1002–1012). Somatic SOS1 mutations are reported in rare and sporadic cancers like lung squamous cell carcinoma (Nat. Genetics, 2016, 48, 607-616), uterine corpus endometrial carcinoma (Cell. 2018 April 05; 173(2): 321–337), urothelial bladder cancer ,liver hepatocellular carcinoma, acute myeloid leukemia (Int J Hematol, 88, 460-462, lower grade glioma and cutaneous melanoma (Ophthalmic Genet. 40 (2019) 22–28. ; Genes Chromosoma and Cancer 2008, 47, 253-259). SOS1 mutations are also reported in melanoma patients devoid of NRAS or BRAF mutations (Plos Genetics 2016, 12, e1006081). In vitro studies demonstrated SOS1 overexpression in cell lines derived from renal, bladder or prostate carcinomas (Oncogene, 1996, 12, 1097, 1107 ; IUBMB Life 2000, 49, 317-320 ; J. Urol, 1997, 158, 908-911 ; Int J of Oncol, 2009, 35, 751-760). In contrast, SOS1 deficiency co-relates with loss of metastatic capacity in ovarian cancer (Cancer Res, 2010, 70, 9979-9990). Thus SOS1 can be considered as a promising therapeutic target for anticancer treatment.
Recently, several patent applications are published which disclose / claim SOS1:KRAS protein-protein interaction inhibitors some of which are given below :
WO 2018/115380 A1 by Boehringer Ingelheim discloses benzylamino substituted quinazolines having the following formula :

wherein the groups R1 to R7 have the meanings given therein, their use as inhibitors of SOS1:KRAS protein-protein interaction, pharmaceutical compositions which contain compounds of this kind and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases. However, R7 is specifically limited to the groups C1-4alkyl and C1-4haloalkyl. This specification nowhere enables any other groups in the description of R7.
WO 2018/172250 A1 of Bayer Pharma Aktiengesellschaft disclose specifically different 2-methyl-quinazolines, which inhibits the binding of hSOS1, having the structure

WO 2019/122129 A1 of Boehringer Ingelheim benzylamino substituted pyridopyrimidinones of formula (I)

R3 is selected from the group consisting of hydrogen, C1-4alkyl and C1-4 haloalkyl
Treatment of cancer continues to be a challenge though several drugs that have been approved with different mechanism. In view of this there is unmet need for new drugs that can treat such diseases more effectively. We herein describe novel compounds which are inhibitors of SOS1:KRAS protein-protein interaction, which bind to the SOS1 catalytic site and simultaneously prevent interactions with and activation of RAS-family proteins. None of the prior-art referred neither disclose nor enable 2-ketoquinazolines. The novel compounds of formula (I) presented herein have inhibitory effect on the interaction of SOS1 and KRAS protein.

SUMMARY OF THE INVENTION
The present invention relates to novel compounds of formula (I) which are inhibitors of SOS1:KRAS protein-protein interaction, their pharmaceutically acceptable esters, salts, solvates, isomers thereof.

In one aspect of the present invention relates to novel compounds of formula (I)

Formula (I)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable regioisomer thereof;
wherein,
R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
x, y, z independently represent C or N with a limitation of upto only 2 N atoms in the ring system.

In another aspect the present invention relates to novel compounds of formula (I)

Formula (I)
or a pharmaceutically acceptable salt or a pharmaceutically acceptable regioisomer thereof;
wherein,
R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is substituted by one or more, identical or different substituent selected from R7;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is substituted by one or more, identical or different substituent selected from R7 ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is substituted by one or more, identical or different substituent selected from R7 ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is substituted by one or more, identical or different substituent selected from R7;
R3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituent selected from R7;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituent selected from R7;
R7 is selected from the group consisting of hydrogen atom, halogen, nitro, cyano, hydroxy, hydroxyl alkyl, amino, oxo (=O), thiooxo (=S), carboxy, -C(O)O(C1-C6alkyl), -C(O)(C1-C6alkyl), =N-OH, alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl;
x, y, z independently represent C or N with a limitation of upto only 2 N atoms in the ring system.

In another aspect of the present invention, it relates to process for the preparation of novel compounds of formula (I).

In yet another aspect of the present invention, it relates to pharmaceutical composition comprising novel compounds of the formula (I) and processes for preparing thereof.

In yet further another aspect of the present invention, the invention relates to use of compounds of formula (I) and pharmaceutically acceptable derivatives, salts and regioisomers thereof, including mixtures thereof in all ratios as a medicament, by inhibiting SOS1 in treating diseases such as cancer.

DETAILED DESCRIPTION OF THE INVENTION

According to another embodiment, specifically provided are compounds of formula (I), in which the group

is specifically represented by

According to preceding embodiment the present invention specifically relates to novel quinazolinone compounds wherein all of x, y, z of the compound of formula (I) represent “C” represented by formula (Ia)

Formula (Ia)

R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group are optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group are optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

In another aspect of the present invention relates to novel pyridopyrimidinone compounds wherein x, y of the compound of formula (I) represent “C” and z represent “N” represented by formula (Ib)

Formula (Ib)
R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

In another aspect of the present invention relates to novel pyridopyrimidinone compounds wherein x represent “N” and y, z of the compound of formula (I) represent “C” represented by formula (Ic)

Formula (Ic)
R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

In another aspect of the present invention relates to novel pyrimidopyrimidinone compounds wherein x, z represent “N” and y of the compound of formula (I) represent “C” represented by formula (Id)

Formula (Id)

R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

In another aspect of the present invention relates to novel pyridopyrimidinone compounds wherein x, z represent “C” and y of the compound of formula (I) represent “N” represented by formula (Ie)

Formula (Ie)

R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

In another aspect of the present invention relates to novel pyridopyrimidinone compounds wherein x, z represent “C” and y of the compound of formula (I) represent “N” represented by formula (If)

Formula (If)

R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group are optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, alkyl, or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents.

According to another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen; R4 and R5 are hydrogen, halogen, amino or alkyl.

According to another embodiment, specifically provided are compounds of formula (I), in which the group

is specifically represented by

Without limiting the scope of present invention, the following definitions are provided in order to understand the detailed description of the present invention.
The term “Alkyl” as used herein refers and is not limited to a hydrocarbon chain that may be a linear or branched chain, containing the indicated number of carbon atoms, for example, a C1-C12 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of C1-C12 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups.
The term alkenyl as used herein refers and is not limited to a linear, branched unsaturated C1-C6 hydrocarbyl group containing a double bond, but are not limited to ethenyl, propenyl, butenyl. An alkenyl group can be unsubstituted or substituted with one or more suitable groups.
The term alkynyl as used herein refers and is not limited to a linear, branched unsaturated C1-C6 hydrocarbyl group containing a triple bond, but are not limited to acetylenyl, propynyl, butynyl. An alkynyl group can be unsubstituted or substituted with one or more suitable groups.
The term "Amino" as used herein refers and is not limited to an –N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups. An amino group can be unsubstituted or substituted with one or more of the suitable groups.
The term "Aryl" as used herein refers and is not limited to an optionally substituted monocylic, bicyclic or polycyclic aromatic carbocyclic ring system of about 6 to 14 carbon atoms. Examples of a C6-C14 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl. Aryl group which can be unsubstituted or substituted with one or more suitable groups.
The term "Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.
"Hydroxy" refers to -OH group.
The term “cycloalkyl” as used herein refers and is not limited to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic 3 to 10 member ring system. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. A cycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
The term “Heterocyclyl” as used herein refers and is not limited to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH and C(O). Exemplary heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, azetadine, oxetane, thietane and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
The term “Heteroaryl” as used herein refers and is not limited to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen. Examples of C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
“Optionally substituted or substituted” as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with suitable substitutions as exemplified but not limited to halogen, nitro, cyano, hydroxy, hydroxyl alkyl, amino, oxo (=O), thiooxo (=S), -N(C1-C3alkyl)C(O)(C1-C6alkyl), -NHC(O)(C1-C6alkyl), -NHC(O)(cycloalkyl), -NHC(O)(aryl), -NHC(O)(heterocyclyl), -NHC(O)(heteroaryl), -NHC(O)H, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)NH(cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(heteroaryl), -C(O)N(C1-C6alkyl)(C1-C6alkyl), -S(O)NH(C1-C6alkyl), -S(O)2NH(C1-C6alkyl), -S(O)NH(cycloalkyl), -S(O)2NH(cycloalkyl), carboxy, -C(O)O(C1-C6alkyl), -C(O)(C1-C6alkyl), =N-OH, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl.
The particular compounds of the present invention without departing from the scope of the definitions given under compounds of formula (I) and particular compounds emanated from formula (I) are summarized herein below encompassing the entirety of the scope of compounds within compound of formula (I).
(R)-6,7-dimethoxy-4-((1-(naphthalen-1-yl)ethyl)amino)quinazolin-2(1H)-one
(R)-6,7-dimethoxy-1-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)quinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(3-hydroxypropyl)-6,7-dimethoxyquinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxy-1-(tetrahydro-2H-pyran-4-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxyquinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-1-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-(2-aminothiazol-4-yl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-fluoro-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-isopropylpyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-(2-hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinopyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
(R)-4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-fluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one.
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-isopropylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(3-hydroxypropyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(4-hydroxybutyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(5-hydroxypentyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-methoxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(3-methoxypropyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(4-methoxybutyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(5-methoxypentyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(3-hydroxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(3-fluoroazetidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-cyclobutylpyrido[4,3-d]pyrimidine-2,5(1H,6H)-dione
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-cyclobutylpyrido[4,3-d]pyrimidine-2,7(1H,6H)-dione
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(5-amino-2-fluoro-3-(difluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxyquinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(fluoromethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(methoxymethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(hydroxymethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-morpholinopyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methoxypiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-fluoropiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-isopropylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4,4-difluoropiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-methylpyrrolidin-3-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-isopropylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-methoxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidin-2(1H)-one

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable regioisomer thereof.
Further embodiments of the invention includes use of compounds of formula (I) or pharmaceutically acceptable derivatives, salts and regio-isomers thereof, including mixtures thereof in all ratios as a medicament.
Use of compounds as above and pharmaceutically usable derivatives, salts and regioisomers there¬of, including mixtures thereof in all ratios, for the preparation of a medi-cament for the treatment of cancer and other associated disorders.
Targeting SOS1 appears promising for treating cancer and various other non-cancerous indications like RASopathies including neurofibromatosis (NF1), Costello syndrome (CS), Legius (LGSS), Leopard (LPRD), cardiofaciocutaneous syndrome (CFC), Noonan syndrome (NS) and other NS-like disorders (Mol. Syndromology, 2010, 1, 2-26; Annu. Rev. Genomics. Human. Genetics, 2013, 14, 355-369; Human Mol. Genetics, 2016, 25, R123-R125; Curr. Gen. Med. Rep, 2016, 4, 57-64; BBA - Reviews on Cancer 1874 (2020) 188445). Noonan syndrome is an autosomal dominant disease bearing SOS1 gain of function mutations. SOS1 involvement in hereditary gingival fibromatosis is also reported. HGF is a rare, autosomal dominant condition characterized by benign, uncontrolled gingival overgrowth. The causal mutation in SOS1 gene results in lack of autoinhibitory domain of the protein leading to constitutive activation and uncontrolled growth in the gingival region (J Dent Res, 2007, 86, 25-34; Am. J. Human Genetics, 2002, 70, 943-954).
Unless specifically indicated, the general formula of compound (I) shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.
In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.
The present invention further provides a pharmaceutical composition comprising at least one compound according to formula (I) and/or pharmaceutically usable derivatives, salts, tautomers and regioisomers thereof, including mixtures thereof in all ratios, optional additional second active ingredient, and excipients.
The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
The term “regioisomer” or “regioisomers” refers to the positional isomers, which is a category of structural isomers, wherein the position or the substituent changes position on the parent structure. Herein the term regioisomer without departing from the scope of compound of formula (I) inherently includes all regioisomers either as a pure regioisomer or mixture of two or more regioisomers thereof. Since the pharmaceutical activity of the regioisomers of the compounds of the present invention may differ, it may be desirable to use the regioisomers. In these cases the regioisomers can be separated at any of the possible stage either as an intermediate or as an end product by the process well known to the person skilled in the art or even employed as such in the synthesis.
The term “tautomer” or “tautomers” refers to the compound of formula (I) of the present invention wherein any hydrogen atom is replaced by a hydroxyl group on a carbon with a double bond. The present invention includes all possible tautomeric forms.
Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).
Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
For example, in the case of oral administration as tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.
Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica­ment after the capsule has been taken.
In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl­pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre­specified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for­mulated by dispersion of the compounds in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
The formulations cab be in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like.
Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus­pended in a suitable carrier, in particular an aqueous solvent.
Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurized dispensers with aerosols, nebulisers or inhalers.
Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.
A therapeutically effective amount of a compound of the formula (I) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
In a further aspect, the present invention relates to a process for preparing novel compounds of formula (I).
The novel compounds of formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
In another embodiment of the present invention provides methods useful for preparing the compounds of formula (I) depicted generically in the Schemes given hereunder. One skilled-in-the-art will recognize that any of the Schemes can be adapted to produce the compounds of formula (I) and pharmaceutically accepted salts of compounds of formula (I) according to the present invention. All symbols/variables are as defined hereunder unless otherwise stated.
Compound of Formula (I) can be prepared by a general process of reacting compound of formula (II) with a compound of formula (III) wherein X is a halogen atom or any leaving group as shown in the scheme –1. The reaction is carried out using an organic or inorganic base in a solvent at a temperature in the range of room temperature to reflux temperature of the solvent used. The conversion of compound of formula III to Formula I is done using a basifying agent in a solvent.

Scheme-1

The compound of formula (I) when R6 is hydrogen is converted to compound of formula I when R6 is any other group other than hydrogen by using an alkylating agent such as alkyl halide or any suitable alkylating agent in the presence of a hydride base suc a as sodium hydride, potassium hydride or inorganic base such as Na2CO3, K2CO3 and CS2CO3, or an organic base DIPEA and TEA can be used. The general process is shown in the scheme given below :

Scheme-2
The starting materials used in the invention such as compounds of Formulae (II) and (III) may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one skilled in the art of organic chemistry. Some of the starting materials are commercially available and used as such in working of the invention.
If the above set of general synthetic methods is not applicable to obtain all the compounds according to formula (I) and/or necessary intermediates for the synthesis of compounds of formula (I), suitable methods of preparation known by a person skilled in the art should be used.
The compounds of the present invention wherever has an amino group can be obtained by reducing a nitro compound as shown in the scheme given below :

Scheme-3
Suitable reducing agents include those that are known to one of ordinary skill in the art including, for example, Pd/C, Pt/C, Raney Ni, Fe powder, borane, sodium borohydride, sodium cyanoborohydride, lithium borohydride, potassium borohydride, boron trifluoride-etherate complex.
The compounds if obtained with protecting groups, appropriate deprotecting agents have to be used to obtain the respective compounds as shown below :

Scheme-4

wherein n represents an integer in the range of 0 to 4, Pg represents a protecting group such as benzyl, t-Boc, TBDMS, TMS, Ms, Tosyl, etc.
In general, the synthetic pathways used for the preparation of any individual compound of formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compounds of formula (I), which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula (I) with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.

EXAMPLES
Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Example-1: Synthesis of (R)-6,7-dimethoxy-4-((1-(naphthalen-1-yl)ethyl) amino)quinazolin-2(1H)-one (1):

To a solution of (R)-2-chloro-6,7-dimethoxy-N-(1-(naphthalen-1-yl) ethyl) quinazolin-4-amine (20 mg, 0.051 mmol) in AcOH (1 mL) was added sodium acetate (50 mg) and heated at 80 °C for overnight. After completion of reaction, reaction mixture was cooled to room temperature, diluted with cold water and stirred vigorously for 1 h. The precipitated solid was filtered and washed with cold water and n-hexane, then dried under vacuum to afford the titled product (5 mg, 26%) as an off-white solid.
1H NMR (400 MHz, DMSO-d6): d 10.49 (s, 1H), 8.28 (d, J = 6.8 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.66-7.64 (m, 2H), 7.56-7.51 (m, 3H), 6.64 (s, 1H), 6.31–6.28 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H); LC-MS (m/z): 376.0 [M+H]+

Example-2: Synthesis of (R)-6, 7-dimethoxy-1-methyl-4-((1-(naphthalen-1-yl) ethyl) amino) quinazolin-2(1H)-one (2):

To a stirred solution of (R)-6, 7-dimethoxy-4-((1-(naphthalen-1-yl) ethyl) amino) quinazolin-2(1H)-one (100 mg, 0.26 mmol) in DMF (5 mL) was added 60% Sodium hydride (9.6 mg, 0.39 mmol) at 0 °C under nitrogen atmosphere. To this was added a solution of methyl iodide (0.016 mL, 0.26 mmol) in DMF (0.3 mL) drop wise at 0 °C and stirred for 4 h at the same temperature. After completion of reaction, reaction mixture was quenched with ice-water, extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 3% methanol in DCM as an eluent to afford the titled product (15 mg, 14%) as off white solid.
1H NMR (400 MHz, DMSO-d6): d 8.28 (d, J = 8 Hz, 1H), 8.13 (d, J = 8 Hz, 1H), 7.94-7.92 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.55–7.47 (m, 3H), 6.77 (s, 1H), 6.32-6.27 (q, J = 13.6 Hz, 1H) 3.90 (s, 3H), 3.79 (s, 3H), 3.45 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); LC-MS (m/z): 390.2 [M+H]+

Example-3: Synthesis of (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl) amino)-6,7-dimethoxy-quinazolin-2(1H)-one

Step-a: (R)-2-Chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6,7-dimethoxy-quinazolin-4-amine (3a): To a stirred a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (214 mg, 1.13 mmol) in isopropyl alcohol (5 mL), was added (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (351.9 mg, 1.36 mmol) and potassium carbonate (781.08 mg, 5.66 mmol) and the reaction mixture was heated at 60 °C for overnight. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude compound was purified with flash column chromatography and eluted at 40 % ethyl acetate in hexane to afford the titled product as a white solid. Yield: 100 mg (29%); 1H-NMR (300 MHz, CDCl3): d 7.61-7.50 (m, 2H), 7.26-7.21 (m, 1H), 7.14 (s, 1H), 6.91 (t, J = 54.9 Hz, 1H), 6.82 (s, 1H), 5.83-5.74 (m, 2H), 4.11 (s, 3H), 3.97 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); LCMS: m/z 412.2 [M+H]+.
Step-b: (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxy-quinazolin-2(1H)-one (3) : To (R)-2-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6,7-dimethoxyquinazolin-4-amine (50 mg, 0.12 mmol) was added acetic acid (3 mL) and the reaction mixture was stirred at 90 °C overnight. The progress of the reaction was monitored by TLC. Upon completion of the reaction, saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture and it was extracted with ethyl acetate (40 mL), washed with water (15 mL) and brine solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified with flash column chromatography and eluted with 3% methanol in chloroform to afford the titled product as a white solid. Yield: 15 mg (31%); 1H-NMR (300 MHz, DMSO-d6): d 10.50 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.72 (s, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 54.3 Hz, 1H), 6.65 (s, 1H), 5.75 (quin, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H); LCMS: m/z 394 [M+H]+

Example-4: Synthesis of (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(3-hydroxypropyl)-6,7-dimethoxyquinazolin-2(1H)-one

Step-a: (R)-1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-((1-(3-(difluoromethyl)-2-fluoro-phenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one (4a): (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one (70 mg, 0.178 mmol) was dissolved in dimethylformamide (2 mL) and added cesium carbonate (175 mg, 0.534 mmol) followed by (3-bromopropoxy) (tert-butyl)dimethylsilane (120 mg, 0.534 mmol) at room temperature. The reaction mixture was heated to 150 °C for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, it was quenched with ice-cold water and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 3% methanol in chloroform to afford the titled compound. Yield 80 mg, (80%); 1H-NMR (300 MHz, CDCl3): d 7.57 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 6.9 Hz, 1H), 7.17 (t, J = 6.3 Hz, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 6.89 (t, J = 54.9 Hz, 1H), 5.78 (m, 1H)), 4.00 (s, 3H), 3.96 (s, 3H), 3.86-3.74 (m, 4H), 1.95-1.92 (m, 2H), 1.72 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H). [one proton merged with CDCl3 signal].
Step-b: (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(3-hydroxypropyl)-6,7-dimethoxyquinazolin-2(1H)-one (4): A solution of (R)-1-(3-((tert-butyldimethyl-silyl)oxy)propyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl) ethyl)amino)-6,7-dimethoxy-quinazolin-2(1H)-one (80 mg, 0.14 mmol) in dry tetrahydrofuran (3 mL) at 0 °C was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.3 mL) and the reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, it was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine solution (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 2% methanol in chloroform to afford the titled compound. Yield: 10 mg (16%); 1H-NMR (300 MHz, CDCl3): d 7.56-7.48 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.91 (t, J = 54.9 Hz, 1H), 6.85 (s, 1H), 5.78 (bs, 2H), 4.59-4.49 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.69 (t, J = 5.7 Hz, 2H), 2.01-1.95 (m, 2H), 1.70 (d, J = 6.3 Hz, 3H) [one proton merged with CDCl3 signal]; LCMS: m/z 452.2 [M+H]+

Example-5: Synthesis of (R)-4-((1-(2-Fluoro-3-(difluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxy-1-(tetrahydro-2H-pyran-4-yl)quinazolin-2(1H)-one

(R)-4-((1-(2-Fluoro-3-(difluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxy-1-(tetrahydro-2H-pyran-4-yl)quinazolin-2(1H)-one (5): In 25 mL seal tube, (R)-4-((1-(2-fluoro-3-(difluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one (70 mg, 0.178 mmol) was dissolved in dimethylformamide (2 mL) and cesium carbonate (175 mg, 0.54 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (38 mg, 0.21 mmol) were added to this. The reaction mixture was heated at 150 °C for overnight. Reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 2% methanol in chloroform to afford the titled compound. Yield: 10 mg (12%); 1H-NMR (300 MHz, CDCl3): d 7.52-7.46 (m, 2H), 7.17 (t, J = 7.5 Hz, 1 H), 7.04 (s, 1H), 6.95 (s, 1H), 6.91 (t, J = 54.9 Hz, 1H), 6.08-5.82 (bs, 1H), 5.72 (quin, J = 7.2 Hz, 1H), 5.04-4.98 (m, 1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.96-3.86 (m, 2H), 3.62-3.54 (m, 1H), 3.50-3.42 (m, 1H), 2.09-2.04 (m, 1H), 1.90-1.82 (m, 1H), 1.71 (d, J = 6.9 Hz, 3H), 1.67-1.57 (m, 2H); LCMS: m/z 478.5 [M+H]+

Example-6: Synthesis of 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl) amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step-a: (S)-2,4-Dichloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)quinazoline (6a): To a stirred solution of 2,4-dichloro-7-methoxyquinazolin-6-ol (250 mg, 1.02 mmol) and (R)-tetrahydrofuran-3-ol (108.18 mg, 1.23 mmol) in THF (20 mL) at room temperature were added triphenylphosphine (403 mg, 1.54 mmol) and diethyl azadicarboxylate (267.6 mg, 1.54 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. Progress of the reaction was monitored by TLC and after completion of reaction, reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude compound which was purified by flash column chromatography and eluted with 15% ethyl acetate in hexane to afford 490 mg of titled compound with some impurity which was used in the next step without any further purification.
Step-b: 2-Chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (6b): To a solution of (S)-2,4-dichloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)quinazoline (150 mg, 0.48 mmol) in isopropyl alcohol were added (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (128.9 mg, 0.57 mmol), diisopropylethylamine (185 mg, 1.43 mmol) and potassium iodide (5 mg) at room temperature. Reaction mixture was heated at 100 °C for 10 h. After completion of reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and residue was diluted with dichloromethane (50 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide crude compound which was purified by flash column chromatography and eluted with 3% methanol in dichloromethane to afford the titled compound as off white solid. Yield: 125 mg (56%); 1H-NMR (300 MHz, DMSO-d6): d 7.59-7.49 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.94 (s, 1H), 6.90 (t, J = 54.9 Hz, 1H), 5.94 (d, J = 6.0 Hz, 1H), 5.75 (quin, J = 6.6 Hz, 1H), 4.99-4.93 (m, 1H), 4.08-4.00 (m, 4H), 3.93 (s, 3H), 2.25-2.20 (m, 2H), 1.73 (d, J = 6.6 Hz, 3H).
Step-c: 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (6): Titled compound was synthesized following the same experimental procedure utilized for compound 3 using 2-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine as starting material. Yield 65 mg (56%); 1H-NMR (300 MHz, CDCl3): d 12.07 (s, 1H), 7.54-7.46 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.02 (s, 1H), 6.88 (t, J = 54.9 Hz, 1H), 6.75 (s, 1H), 6.13 (d, J = 8.7 Hz, 1H), 5.98-5.91 (m, 1H), 4.97 (m, 1H), 4.07-4.02 (m, 2H), 3.93-3.87 (m, 5H), 2.19-2.14 (m, 2H), 1.65 (d, J = 6.6 Hz, 3H); LCMS: m/z 450.2 [M+H]+;

Example-7: Synthesis of (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxy-quinazolin-2(1H)-one

Step-a: (R)-2-Chloro-6,7-dimethoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl)-quinazolin-4-amine (7a): Title compound was synthesized following the same experimental procedure utilized for 2-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine using 2,4-Dichloro-6,7-dimethoxyquinazoline and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride as starting materials. Yield 250 mg (57%); 1H-NMR (300 MHz, CDCl3): d 8.48 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 5.84 (d, J = 6.6 Hz, 1H), 5.65 (m, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 1.78 (d, J = 6.9 Hz, 3H); LCMS: m/z 457.3 [M+H]+.
Step-b: (R)-6,7-Dimethoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) amino)quinazolin-2(1H)-one (7b): Titled compound was synthesized following the same experimental procedure utilized for compound 3 using (R)-2-Chloro-6,7-dimethoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-quinazolin-4-amine as starting material. Yield: 200 mg (83%); 1H-NMR (300 MHz, DMSO-d6): d 10.53 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 7.66 (s, 1H), 6.66 (s, 1H), 5.69 (quin, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); LCMS: m/z 439.2 [M+H]+.
Step-c: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxy-quinazolin-2(1H)-one (7): To a solution of (R)-6,7-Dimethoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-amino)quinazolin-2(1H)-one (200 mg, 0.45 mmol) in methanol (10 mL) at room temperature was added 10% Pd-C (50% wet, 80 mg) and the reaction mixture was stirred under hydrogen atmosphere for 14 h. Progress of the reaction was monitored by TLC. Reaction mixture was filtered through celite bed, washed with methanol and filtrate was evaporated under reduced pressure to provide crude compound which was purified by flash column chromatography and eluted with 5-10% methanol in dichloromethane to afford the titled compound. Yield: 120 mg (65%); 1H-NMR (300 MHz, DMSO-d6): d 10.45 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 6.81 (s, 2H), 6.71 (s, 1H), 6.66 (s, 1H), 5.57 (s, 2H), 5.51-5.48 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); LCMS: m/z 409.2 [M+H]+.

Example-8: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step a: 2-Chloro-7-methoxy-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (8a): Titled compound was synthesized following the same experimental procedure utilized for 2-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine using (S)-2,4-Dichloro-7-methoxy-6-((tetrahydro-furan-3-yl)oxy)quinazoline and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride as starting materials. Yield: 200 mg (35%); 1H-NMR (300 MHz, CDCl3): d 8.50 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 5.71-5.61 (m, 2H), 5.13-5.11 (m, 1H), 4.12-3.92 (m, 4H), 3.79 (s, 3H), 2.29-2.24 (m, 2H), 1.78 (d, J = 1.8 Hz, 3H); LCMS: m/z 513.2 [M+H]+.
Step b: 7-Methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (8b): Titled compound was synthesized following the same experimental procedure utilized for compound 3 using 2-Chloro-7-methoxy-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine as starting material. Yield 150 mg (78%); 1H-NMR (300 MHz, DMSO-d6): d 10.56 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.30-8.26 (m, 2H), 7.70 (s, 1H), 6.68 (s, 1H), 5.74-5.67 (m, 1H), 5.03 (m, 1H), 3.90-3.81 (m, 4H), 3.78 (s, 3H), 2.22-2.18 (m, 1H), 2.03-1.98 (m, 1H), 1.61 (d, J = 6.9 Hz, 3H).
Step-c: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (8): Titled compound was synthesized following the same experimental procedure utilized for compound 7 using 7-Methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one as starting material. Yield 100 mg (71%); 1H NMR (300 MHz, CD3OD): d 7.66 (s, 1H), 6.96-6.95 (m, 2H), 6.79 (s, 1H), 6.76 (s, 1H), 5.65 (q, J = 6.9 Hz, 1H), 5.07-5.04 (m, 1H), 4.04-3.88 (m, 4H), 3.87 (s, 3H), 2.20-2.15 (m, 2H), 1.61 (d, J = 6.9 Hz, 3H) [Exchangeable protons are not visible]; LCMS: m/z 465.2 [M+H]+

Example-9: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-7-methoxy-1-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step-a: 7-Methoxy-1-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (9a) : In a sealed tube to a solution of 7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)-quinazolin-2(1H)-one (135 mg, 0.26 mmol) in dry dimethylformamide (10 mL) were added cesium carbonate (90 mg, 0.27 mmol) and methyl iodide (130 mg , 0.91 mmol), then the sealed tube was capped and heated at 150 °C for 14 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with ice-cold water (3 X 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide. crude compound which was purified by flash column chromatography using 2% methanol in dichloromethane to afford the titled compound as white solid. Yield: 52 mg (38%); 1H-NMR (300 MHz, CDCl3): d 8.36 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.26 (s, 1H) [proton is embedded with CDCl3 signal], 6.61 (s, 1H), 6.27 (d, J = 7.2 Hz, 1H), 5.86-5.76 (m, 1H), 4.99-4.95 (m, 1H), 4.05-4.00 (m, 2H), 4.00 (s, 3H), 3.99-3.83 (m, 2H), 3.59 (s, 3H), 2.17-2.04 (m, 2H), 1.65 (d, J = 7.2 Hz, 3H); LCMS: m/z 509.3 [M+H]+.
Step-b: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-1-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (9): Titled compound was synthesized following the same experimental procedure utilized for compound 7 using 7-methoxy-1-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled product as white solid; Yield 25 mg (45%); 1H-NMR (300 MHz, CD3OD): d 7.71 (s, 1H), 6.97-6.96 (m, 2H), 6.90 (s, 1H), 6.79 (s, 1H), 5.64 (q, J = 7.2 Hz, 1H), 5.13-5.08 (m, 1H), 4.06-3.87 (m, 7H), 3.61 (s, 3H), 2.25-2.16 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H); [exchangeable protons are not visible] LCMS: m/z 479.3 [M+H]+.

Example-10: Synthesis of (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-2(1H)-one

Step-a: 2,4-Dichloro-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (10a) : 2,4-Dichloro-7-methoxyquinazolin-6-ol (500 mg, 2.06 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature and stirred for 5 minutes. To this reaction mixture were slowly added tetrahydro-2H-pyran-4-ol (252.1 mg, 2.47 mmol), diethyl azadicarboxylate (624 mg, 3.09 mmol) and triphenylphosphine (809.5 mg, 3.09 mmol) and the mixture was stirred for 16 h at room temperature. Reaction progress was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15% ethyl acetate: hexane to afford 900 mg of semi-pure compound which was directly used for the next step without further purification.
Step-b: (R)-2-Chloro-7-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) -6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine (10b): To a solution of 2,4-dichloro-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (250 mg, 0.762 moles) in dry tertrahydrofuran (10 mL) were added (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (210 mg, 0.762 mmol) followed by diisopropylethylamine (0.272 mL, 1.55 mmol) and the reaction mixture was stirred at room temperature for 16 h. Reaction progress was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 25-30% ethyl acetate in hexane to afford the titled compound as white solid. Yield 180 mg (23%); 1H-NMR (CDCl3): d 8.49 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 5.71-5.60 (m, 2H) 4.62-4.57 (m, 1H), 4.07-4.00 (m, 2H), 3.94 (s, 3H), 3.62-3.54 (m, 2H), 2.07-2.03 (m, 2H), 1.94-1.83 (m, 2H), 1.78 (d, J = 6.6 Hz, 3H); LCMS: m/z 527 3 [M+H]+.
Step-c: (R)-7-Methoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-2(1H)-one (10c): Titled compound was synthesized following the same experimental procedure utilized for compound 3 using (R)-2-Chloro-7-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine as starting material. Yield 140 mg (80%); 1H-NMR (DMSO-d6): d 10.56 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.26 (s, 2H), 7.80 (s, 1H), 6.68 (s, 1H), 5.70-5.65 (m, 1H) 4.46-4.40 (m, 1H), 3.91-3.85 (m, 2H), 3.81 (s, 3H), 3.49-3.41 (m, 2H), 1.98-1.90 (m, 2H), 1.66-1.64 (m, 2H), 1.61 (d, J = 6.9 Hz, 3H); LCMS: m/z 509 3 [M+H]+.
Step-d: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-2(1H)-one (10): Titled compound was synthesized following the same experimental procedure utilized for compound 7 using (R)-7-Methoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((tetrahydro-2H-pyran-4-yl)oxy)-quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled product as a white solid; Yield: 60 mg (46%); 1H-NMR (DMSO-d6): d 10.48 (s, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 6.80 (d, J = 7.5 Hz, 2H), 6.70 (s, 1H), 6.68 (s, 1H), 5.57 (s, 2H), 5.46 (t, J = 7.2 Hz, 1H) 4.47-4.40 (m, 1H), 3.89-3.85 (m, 2H), 3.81 (s, 3H), 3.47-3.40 (m, 2H), 1.94-1.90 (m, 2H), 1.64-1.56 (m, 2H), 1.51 (d, J = 6.9 Hz, 3H); LCMS: m/z 479 [M+H]+.

Example-11: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl) ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step-a: 2,4-Dichloro-7-methylquinazolin-6-ol (11a): To a solution of 2,4-dichloro-6-methoxy-7-methylquinazoline (500 mg, 2.07 mmol) in dry dichloromethane (15 mL) was added BBr3 (1.0 M in dichloromethane, 1.0 mL, 8.264 mmol) at 0 °C. Reaction mixture was allowed to warm to room temperature and stirred for 15 h. Reaction progress was monitored by TLC. Reaction mixture was quenched with 5% aqueous sodium bicarbonate at -5 °C, diluted with dichloromethane (50 mL). Organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 10% ethyl acetate in hexane to afford the titled compound as an off-white solid. Yield: 350 mg (81%); 1H-NMR (300 MHz, DMSO-d6): d 11.18 (bs, 1H), 7.82 (s, 1H), 7.43 (s, 1H), 2.39 (s, 3H).
Step-b: (S)-2,4-Dichloro-7-methyl-6-((tetrahydrofuran-3-yl)oxy)quinazoline (11b): To a stirred solution of 2,4-dichloro-7-methylquinazolin-6-ol (100 mg, 4.36 mmol) in tetrahydrofuran (5 mL) were added (R)-tetrahydrofuran-3-ol (46 mg, 5.22 mmol) and triphenylphosphine (200 mg, 0.66 mmol). To above solution was slowly added diethyl azadicarboxylate (114 mg, 0.66 mmol) and stirred for 12 h. After consumption of starting material, reaction mixture was quenched with water and extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15% ethyl acetate in hexane to afford the titled compound as an off-white solid. Yield: 40 mg (31%); 1H-NMR (300 MHz, CDCl3): d 7.77 (s, 1H), 7.26 (s, 1H), 5.13-5.16 (m, 1H), 3.93-4.17 (m, 4H), 2.45 (s, 3H), 2.44-2.33 (m, 1H), 2.25-2.27 (m, 1H). [Note: one aromatic proton is merged with CDCl3 signal]; LCMS: m/z 299.1 [M+H]+.
Step-c: 2-Chloro-7-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (11c): (S)-2,4-Dichloro-7-methyl-6-((tetrahydro-furan-3-yl)oxy)quinazoline (130 mg, 0.43 mmol) was dissolved in dimethylsulfoxide (6 mL), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (148 mg, 0.52 mmol) and diisopropylethylamine (0.227 mL, 1.29 mmol) were added and the reaction mixture was heated at 150 °C in microwave for 30 minutes. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2 x 20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 20-30 % ethyl acetate in hexane to afford the titled compound as an off-white solid. Yield: 80 mg (38%); 1H-NMR (300 MHz, CDCl3): d 8.45 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.53 (d, J = 0.9 Hz, 1H), 6.03 (d, J = 6.3 Hz, 1H), 5.71-5.61 (m, 1H), 5.12-5.08 (m, 1H), 4.11-3.90 (m, 4H), 2.33-2.35 (m, 2H), 2.26 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H);
Step-d: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (11d): The titled compound was synthesized following the same experimental procedure utilized for compound 3 using 2-chloro-7-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine as starting material. Yield: 53 mg (69%); 1H-NMR (300 MHz, CDCl3): d 10.57 (bs, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 6.92 (d, J = 5.1 Hz, 1H), 5.92 (m, 1H), 5.04 (m, 1H), 4.05-3.93 (m, 4H), 2.27 (s, 3H), 2.21-2.17 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H) [one proton merged with CDCl3 signal]; LCMS: m/z 479.3 [M+H]+.
Step-e: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (11): The titled compound was synthesized following the same experimental procedure utilized for compound 7 using 4-(((R)-1-(3-Nitro-5-(trifluoromethyl)-phenyl)ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one as starting material, the residue was purified by prep-HPLC to afford the titled product as a white solid; Yield: 21 mg (43%); 1H-NMR (300 MHz, CD3OD): d 7.56 (s, 1H), 7.07 (s, 1H), 6.98-6.96 (m, 2H), 6.81 (bs, 1H), 5.69 (q, J = 7.2 Hz, 1H), 5.17-5.65 (m, 1H), 4.04-3.92 (m, 4H), 2.33-2.24 (m, 1H), 2.29 (s, 3H), 2.19-2.16 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 449.3 [M+H]+.

Example-12: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step-a: (R)-2-Chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) quinazolin-6-ol (12a): 2,4-Dichloroquinazolin-6-ol (0.20 g, 0.93 mmol) was dissolved in isopropyl alcohol (10 mL) and sequentially added (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (0.264 g, 0.93 mmol) and diisopropylethylamine (0.5 mL, 2.8 mmol) followed by catalytic amount of potassium iodide. The resultant reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure and residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), brine solution (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude compound which was purified with flash column chromatography using 20-30% ethyl acetate in hexane to afford the titled compound as an off-white solid. Yield: 320 mg (83%); 1H-NMR (CD3OD): d 8.59 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 7.80-7.72 (m, 1H), 7.59-7.52 (m, 1H), 7.48-7.30 (m, 1H), 5.66-5.59 (m, 1H), 1.75 (d, J = 7.2 Hz, 3H) [exchangeable protons are not visible]; MS: m/z 413.2 [M+H]+.
Step-b: 2-Chloro-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-4-amine (12b): To a stirred solution of (R)-2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-ol (0.34 g, 0.82 mmol) in dimethylformamide (15 mL) was added (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (0.6 g, 2.40 mmol) and cesium carbonate (0.322 g, 0.98 mmol). The resultant reaction mixture was stirred at 100 °C for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water and then extracted with ethyl acetate (50 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified with flash column chromatography and eluted with 30-50% ethyl acetate in hexane to afford the titled compound. Yield: 0.3 g (75%); 1H-NMR (CD3OD): d 8.06 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 2.7 & 9.0 Hz, 1H), 5.69-5.62 (m, 1H), 5.22-5.12 (m, 1H), 4.08-3.88 (m, 4H), 2.41-2.15 (m 2H), 1.78 (d, J = 7.2 Hz, 3H). [exchangeable protons are not visible]
Step-c: 4-(((R)-1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (12c): To a solution of 2-chloro-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (0.3 g, 0.62 mmol) in acetic acid (30 mL) was added water (3 mL) and the reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, acetic acid was evaporated under reduced pressure and the residue was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (2 x 10 mL) and water (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 1-2% methanol in dichloromethane to afford the titled compound as an off-white solid. Yield: (0.2 g, 69%); 1H-NMR (DMSO-d6): d 10.62 (s, 1H), 8.56 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.31-7.25 (m, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.72-5.67 (m, 1H), 5.10 (s, 1H), 3.95-3.75 (m, 4H), 2.28-2.22 (m, 1H), 2.00-1.96 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H); LCMS: m/z 465.0 [M+H]+.
Step-d: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one (12): The titled compound was synthesized following the same experimental procedure utilized for compound 7 using 4-(((R)-1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as a white solid. Yield: 35 mg (19%); 1H-NMR (300 MHz, CD3OD): d 7.67 (d, J = 2.7 Hz, 1H), 7.29 (dd, J = 2.4 & 9.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.97 (s, 2H), 6.80 (s, 1H), 5.67 (q, J = 7.2 Hz, 1H), 5.13-5.09 (m, 1H), 4.01-3.86 (m, 4H), 2.33-2.09 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H) [exchangeable protons were not observed]; LCMS: m/z 435 [M+H]+.

Example-13: Synthesis of 4-(((R)-1-(3-(2-Aminothiazol-4yl)phenyl)ethyl)amino) -7-methoxy-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one

Step-a: 4-(3-Bromophenyl)thiazol-2-amine (13a) : To a stirred solution of 2-bromo-1-(3-bromophenyl)ethan-1-one (3.0 g, 8.41 mmol) in methanol (30 mL) at room temperature was added thiourea (1.54 g, 9.25 mmol) and the reaction mixture was stirred at 70 °C for 2 h. Reaction progress was monitored by TLC. Reaction mixture was evaporated under reduced pressure and crude compound was diluted with ethyl acetate (20 mL), washed with water (20 mL), brine solution (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under pressure. The crude product was purified with flash column chromatography and eluted with 15% ethyl acetate in hexane to afford the titled compound as off white solid. Yield: 1.3 g (61%); 1H-NMR (300 MHz, CDCl3): d 7.94 (t, J = 6.0 Hz, 1H), 7.70-7.66 (dt, J = 9.0 & 4.2 Hz, 1H), 7.43-3.39 (dt, J = 9.0 & 3.0 Hz, 1H), 7.24 (t, J = 9.0 Hz, 1H), 6.74 (s, 1H) (Exchangeable protons are not visible); LCMS: m/z 256.9 [M+H]+.
Step-b: 1-(3-(2-Aminothiazol-4-yl)phenyl)ethan-1-one (13b): To a stirred solution of 5-(3-bromophenyl)thiazol-2-amine (1.65 g, 6.52 mmol) in 1,4-dioxane (20 mL) at room temperature was added tributyl(1-ethoxyvinyl)stannane (3.0 g, 8.54 mmol) and triethylamine (1.32 g, 13.14 mmol) and argon gas was purged to the reaction mixture for 30 minutes. Then tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.066 mmol) was added followed by purging with argon gas for 5 minutes. The reaction mixture was heated at 100 °C for 16 h. After completion of reaction, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine solution (30 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified with flash column chromatography and eluted with 15% ethyl acetate in hexane to afford the titled compound as pale-yellow liquid. Yield 365 mg (26%); 1H-NMR (300 MHz, CDCl3): d 8.36 (t, J = 6.0 Hz, 1H), 7.99-7.86 (dt, J = 1.5 & 2.7 Hz, 2H), 7.47 (t, J = 8.1 Hz, 1H), 6.82 (s, 1H), 5.15 (bs, 2H), 2.65 (s, 3H).
Step-c: (R,Z)-N-(1-(3-(2-Aminothiazol-4-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (13c) : To a stirred solution of 1-(3-(2-aminothiazol-4-yl)phenyl)ethan-1-one (350 mg, 1.59 mmol), (R)-2-methylpropane-2-sulfinamide (233.7 mg, 1.91 mmol) in dry tetrahydrofuran (20 mL) at room temperature was added titanium(IV) isopropoxide (545 mg, 1.91 mmol). Reaction mixture was heated to 70 °C for 16 h. The reaction mixture was quenched with water (5 mL) and stirred for 30 minutes and. The filtrate was extracted with ethyl acetate (30 mL), washed with water (20 mL), brine solution (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified with flash column chromatography and eluted with 20% ethyl acetate in hexane to afford the titled compound as pale yellow gummy liquid. Yield: 300 mg (58%); 1H-NMR (300 MHz, CDCl3): d 8.28 (bs, 1H), 7.89-7.80 (m, 2H), 7.42 (t, J = 15.0 Hz, 1H), 6.77 (s, 1H), 5.23 (bs, 2H), 2.80 (s, 3H), 1.28 (s, 9H). LCMS: m/z 322.2 [M+H]+.
Step-d: (R)-N-((R)-1-(3-(2-Aminothiazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (13d): To a stirred solution of (R,Z)-N-(1-(3-(2-aminothiazol-4-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (300 mg, 0.93 mmol) in tetrahydrofuran:water (16 mL; 15:1) at -78 °C was added sodium borohydride (70.56. mg, 1.86 mmol) and stirred for 30 minutes. Then temperature of the reaction was raised to -20 °C and stirred for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). Combined organic layer was washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified with flash column chromatography and eluted with 20% ethyl acetate in hexane to afford the titled compound as off-white solid. Yield: 300 mg. The ratio of both diastereomer was determined by LCMS; 4.39 (81.1%), m/z 324.1 [M+H]+ and 4.22 (9.6%), m/z 324.1 [M+H]+.
Step-e: (R)-4-(3-(1-Aminoethyl)phenyl)thiazol-2-amine dihydrochloride (13e): To a stirred solution of (R)-N-((R)-1-(3-(2-aminothiazol-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (350 mg, 1.08 mmol) in diethyl ether (5 mL) was added hydrochloric acid in ether (2.0 M, 2 mL) at room temperature and stirred for 3 h. Progress of the reaction was monitored by TLC. Reaction mixture was evaporated under reduced pressure to provide the crude compound which was co-distilled with toluene (2 x 10 mL) to afford the titled product as dihydrochloride salt as off white solid. Yield: 310 mg; 1H-NMR (300 MHz, DMSO-d6): d 8.67 (bs, 3H), 8.07 (bs, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.58-7.48 (m, 3H), 7.30-7.14 (m, 2H), 5.50 (bs, 1H), 4.41 (t, J = 11.7 Hz, 1H), 1.57 (d, J = 6.0 Hz, 3H).
Step-f: 4-(3-((R)-1-((2-Chloro-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)phenyl)thiazol-2-amine (13f): To a stirred solution of (R)-5-(3-(1-aminoethyl)phenyl)thiazol-2-amine dihydrochloride (200 mg, 0.69 mmol) in dimethyl sulfoxide (20 mL) at room temperature was added (S)-2,4-dichloro-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)quinazoline (321.1 mg, 1.01 mmol) and cesium carbonate (766.5 mg, 2.35 mmol) and the reaction mixture was heated at 150 °C with stirring for 16 h. Reaction progress was monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL) and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified with flash column chromatography and eluted with 3% methanol in dichloromethane to afford the titled compound as off white solid. Yield: 80 mg, (21%); 1H-NMR (300 MHz, CDCl3): d 7.90 (s, 1H), 7.61 (dt, J = 6.9 & 2.1 Hz, 1H), 7.42-7.28 (m, 3H), 7.11 (s, 1H), 6.70 (s, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.71-5.66 (m, 1H), 5.26 (bs, 2H), 5.06-5.03 (s, 1H), 4.03-3.99 (m, 4H), 3.89 (s, 3H), 2.23-2.17 (m, 2H), 1.69 (d, J = 6.9 Hz, 3H); LCMS: m/z 498.3 [M+H]+.
Step-g: 4-(((R)-1-(3-(2-Aminothiazol-4-yl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-tetra-hydrofuran-3-yl)oxy)quinazolin-2(1H)-one (13): The titled compound was synthesized following the same experimental procedure utilized for compound 3 using 4-(3-((R)-1-((2-Chloro-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)phenyl)thiazol-2-amine as starting material. Yield: 7 mg (9%); 1H-NMR (300 MHz, CD3OD): d 7.84 (s, 1 H), 7.67 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.39-7.29 (m, 2H), 6.81 (s, 1H), 6.75 (s, 1H), 5.75 (q, J = 6.9 Hz, 1H), 5.07 (bs, 1H), 4.01-3.87 (m, 4H), 3.90 (s, 3H), 2.32-2.15 (m, 2H), 1.66 (d, J = 7.2 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 480.3 [M+H]+.

Example-14: Synthesis of (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one

Step-a: Methyl 4-methoxy-2-nitro-5-(pyrrolidin-1-yl)benzoate (14a): To a solution of methyl 5-fluoro-4-methoxy-2-nitrobenzoate (500 mg, 2.18 mmol) in dimethylformamide (10 mL) were added cesium carbonate (1.42 g, 4.36 mmol) and pyrrolidine (0.3 mL, 3.27 mmol) at room temperature. Reaction mixture was heated at 90oC for 1.5 h. Reaction progress was monitored by TLC. Upon consumption of starting material, the reaction mixture was evaporated under reduced pressure. The crude compound was diluted with ethyl acetate (50 mL), washed with water (2 x 20 mL) and brine solution (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash column chromatography and eluted with 20-30% ethyl acetate in hexane to afford the titled compound as a brown solid. Yield: 250 mg (40%); 1H-NMR (300 MHz, CDCl3): d 7.51 (s, 1H), 6.50 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.59-3.55 (m, 4H), 1.97-1.92 (m, 4H).
Step-b: Methyl 2-amino-4-methoxy-5-(pyrrolidin-1-yl)benzoate (14b) : To a stirred solution of methyl 4-methoxy-2-nitro-5-(pyrrolidin-1-yl)benzoate (250 mg, 1.00 mmol) in methanol (40 mL) at room temperature was added 10% Pd-C (50% wet, 380 mg) and the reaction mixture was stirred under hydrogen atmosphere for 8 h. Reaction progress was monitored by TLC. Upon completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (20 mL). The filtrate was evaporated under reduced pressure to afford the titled compound as a pinkish sticky solid. Yield: 225 mg (100%); 1H-NMR (300 MHz, CDCl3): d 7.39 (s, 1H), 6.11 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.10 (bs, 4H), 1.95-1.90 (m, 4H) (Exchangeable protons are not visible).
Step-c: 7-Methoxy-6-(pyrrolidin-1-yl)quinazolin-2,4(1H,3H)-dione (14c): To preheated urea (1.5 g, 25.0 mmol) at 150 °C was added methyl 2-amino-4-methoxy-5-(pyrrolidin-1-yl)benzoate (500 mg, 1.91 mmol) and reaction mixture was heated for 16 h. Reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was cooled to 100 °C and quenched with water (5 mL) and stirred for 1 h. The reaction mixture was filtered to obtain solid which was washed with water (10 mL) and dried under vacuum to afford the titled compound as a brown solid. Yield: 100 mg (19%); 1H-NMR (300 MHz, CDCl3): d 10.97 (s, 1H), 10.80 (s, 1H), 7.04 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 3.16 (m, 4H), 1.84 (m, 4H); LCMS: m/z 261.2 [M+H]+.
Step-d: 2,4-Dichloro-7-methoxy-6-(pyrrolidin-1-yl)quinazoline (14d) : To a solution of 7-methoxy-6-(pyrrolidin-1-yl)quinazoline-2,4(1H,3H)-dione (100 mg, 0.38 mmol) in phosphorus(V) oxychloride (1 mL) was added N,N-diethylaniline (0.2 mL) at room temperature. Reaction mixture was heated to 100 °C for 6 h. The reaction progress was monitored by TLC. Upon completion of reaction, phosphorus(V)oxychloride was distilled off under reduced pressure and residue was poured onto ice water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the titled compound as a greenish solid. Yield: 115 mg (99%); 1H-NMR (300 MHz, CDCl3): d 7.16 (s, 1H), 6.93 (s, 1H), 3.98 (s, 3H), 3.57-3.53 (m, 4H), 2.02-1.98 (m, 4H).
Step-e: (R)-2-Chloro-7-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) -6-(pyrrolidin-1-yl)quinazolin-4-amine (14e): To a solution of 2,4-dichloro-7-methoxy-6-(pyrrolidin-1-yl)quinazoline (100 mg, 0.34 mmol) in dimethyl sulfoxide (2 mL) were added cesium carbonate (273 mg, 0.84 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (108.67 mg, 0.40 mmol). The reaction mixture was heated at 150 °C for 1 h in microwave. Reaction progress was monitored by TLC. Reaction mixture was diluted with ethyl acetate (25 mL), water (10 mL) and extracted. Organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound as purified by flash column chromatography and eluted with 25% ethyl acetate in hexane to afford the titled compound as a brown sticky solid. Yield: 50 mg (30%). 1H-NMR (300 MHz, CDCl3): d 8.45 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.0 (s, 1H), 6.74 (s, 1H), 6.19 (bs, 1H), 5.67-5.63 (m, 1H), 3.85 (s, 3H), 3.44-3.42 (m, 4H), 2.0-1.94 (m, 4H), 1.65 (d, J = 6.9 Hz, 3H).
Step-f: (R)-7-Methoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one (14f) : The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using (R)-2-chloro-7-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidin-1-yl)quinazolin-4-amine as starting material. Yield 25 mg (52%); 1H-NMR (300 MHz, CDCl3): d 10.40 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H merged with CDCl3 peak), 6.62 (s, 1H), 5.73-5.68 (m, 1H), 3.80 (s, 3H), 3.24-3.23 (m, 4H), 1.90-1.86 (m, 4H), 1.63 (d, J = 6 Hz, 3H).
Step-g: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one (14): To a solution of (R)-7-methoxy-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one (25 mg, 0.05 mmol) in methanol (3 mL) was added 10% Pd-C (50% wet, 2 mg) and reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 h. Reaction progress was monitored by TLC. The reaction mixture was filtered through celite bed, washed with methanol (5 mL) and evaporated under reduce pressure. The yellow solid formed was purified with flash column chromatography and eluted with 5% methanol in dichloromethane to afford the titled compound as an off-white solid. Yield 3.5 mg (15%); 1H-NMR (300 MHz, CD3OD): d 7.41 (s, 1H), 6.97 (s, 2H), 6.80 (s, 1H), 6.73 (s, 1H), 5.66 (q, J = 6.3 Hz, 1H), 3.94 (s, 3H), 3.32 (bs, 4H), 1.96 (bs, 4H), 1.62 (d, J = 6.3 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 448.0 [M+H]+.

Example-15: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl) ethyl)amino)-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazolin-2(1H)-one

Step-a: Methyl 4-methoxy-5-(3-methoxypyrrolidin-1-yl)-2-nitrobenzoate (15a): To a solution of methyl 5-fluoro-4-methoxy-2-nitrobenzoate (680 mg, 2.97 mmol) in dimethylformamide (10 mL) was added cesium carbonate (2.8 g, 8.90 mmol) and 3-methoxypyrrolidine (300 mg, 2.97 mmol). The reaction mixture was heated to 90 °C for 5 h. Reaction progress was monitored by TLC. Upon completion of reaction, the reaction mixture was cooled to 20 °C, ethyl acetate (50 mL) was added. The organic phase was washed with water (2 x 20 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15-20% ethyl acetate in hexane to afford the titled compound as an orange solid. Yield: 630 mg (68%); 1H-NMR (300 MHz, CDCl3): d 7.51 (s, 1H), 6.51 (s, 1H), 4.04-4.00 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.80-3.75 (m, 1H), 3.72-3.66 (m, 2H), 3.58-3.51 (m, 1H), 3.34 (s, 3H), 2.14-2.10 (m, 1H), 2.04-1.97 (m, 1H); LCMS: m/z 311.0 [M+H]+.
Step-b: Methyl 2-amino-4-methoxy-5-(3-methoxypyrrolidin-1-yl)benzoate (15b) : To a stirred solution of methyl 4-methoxy-5-(3-methoxypyrrolidin-1-yl)-2-nitrobenzoate (630 mg, 2.03 mmol) in methanol (30 mL) and water (10 mL) was added iron powder (750 mg, 12.18 mmol) and ammonium chloride (680 mg, 12.18 mmol) and the reaction mixture was heated to 90 °C and stirred for 5 h. Reaction progress was monitored by TLC. The reaction mass was filtered, washed with methanol, and combined filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (50 mL), organic layer was washed with water (30 mL), brine solution (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound as a brown liquid. Yield: 550 mg (96%); 1H-NMR (300 MHz, CDCl3:) d 7.29 (s, 1H), 6.11 (s, 1H), 5.54 (bs, 2H), 4.07-4.01 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.37 (s, 3H), 3.26-3.10 (m, 4H), 2.22-2.10 (m, 1H), 1.97-1.92 (m, 1H); LCMS: m/z 281.0 [M+H]+.
Step-c: 7-Methoxy-6-(3-methoxypyrrolidin-1-yl)quinazoline-2,4(1H,3H)-dione (15c) : The titled compound was synthesized following the same experimental procedure utilized for 7-methoxy-6-(pyrrolidin-1-yl)quinazolin-2,4(1H,3H)-dione using Methyl 2-amino-4-methoxy-5-(3-methoxypyrrolidin-1-yl)benzoate and urea as starting materials. Yield: 350 mg (61%); 1H-NMR (300 MHz, DMSO-d6): d 10.99 (s, 1H), 10.82 (s, 1H), 7.02 (s, 1H), 6.63 (s, 1H), 4.02-3.97 (m, 1H), 3.83 (s, 3H), 3.47-3.42 (m, 1H), 3.32-3.27 (m, 1H), 3.22 (s, 3H), 3.15-3.06 (m, 2H), 2.05-1.96 (m, 1H), 1.92-1.87 (m, 1H); LCMS: m/z 292.0 [M+H]+.
Step-d: 2,4-Dichloro-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazoline (15d) : A solution 7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazolin-2,4(1H,3H)-dione (350 mg, 1.20 mmol) in phosphorus(V) oxychloride (10 mL) was cooled to 0 °C and diisopropylethylamine (1.0 mL) was added. The reaction mixture was heated at 110 °C for 8 h. Reaction progress was monitored by TLC. Upon consumption of starting material, phosphorus(V) oxychloride was distilled off under reduced pressure. The residue was quenched with ice and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15% ethyl acetate in hexane to afford the titled compound as a yellow solid. Yield: 250 mg (65%); 1H-NMR (300 MHz, CDCl3) d 7.16 (s, 1H), 6.95 (s, 1H), 4.09-4.06 (m, 1H), 3.98 (s, 3H), 3.82-3.76 (m, 1H), 3.74-3.65 (m, 1H), 3.61-3.54 (m, 1H), 3.53-3.476 (m, 1H), 3.37 (s, 3H), 2.21-2.15 (m, 2H); LCMS: m/z 327.9 [M+H]+.
Step-e: 2-Chloro-7-methoxy-6-(3-methoxypyrrolidin-1-yl)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (15e) : To a solution of 2,4-dichloro-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazoline (250 mg, 0.86 mmol) in dimethyl sulfoxide (20 mL) were added cesium carbonate (1.7 g, 5.13 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (230 mg, 0.86 mmol) and heated at 100 °C for 12 h. Reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was diluted with ethyl acetate (50 mL) and subsequently washed with water (2 x 20 mL) and brine (20 mL) solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude compound which was purified with flash column chromatography and eluted with 50% ethyl acetate in hexane to afford the titled compound as an orange solid; Yield: 250 mg (62%); 1H-NMR (300 MHz, CDCl3): d 8.49 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.06 (s, 1H), 6.57 (d, J = 3Hz, 1H), 5.64-5.63 (m, 2H), 4.08 (bs, 1H), 3.91 (s, 3H), 3.79-3.72 (m, 1H), 3.62-3.54 (m, 1H), 3.49-3.37 (m, 2H), 3.36 (s, 3H), 2.14-2.09 (m, 2H), 1.77 (d, J = 6.6 Hz, 3H); LCMS: m/z 525.9 [M+H]+.
Step-f: 7-Methoxy-6-(3-methoxypyrrolidin-1-yl)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)-phenyl)ethyl)amino)quinazolin-2(1H)-one (15f): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using 2-Chloro-7-methoxy-6-(3-methoxypyrrolidin-1-yl)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) quinazolin-4-amine as starting material. Yield: 150 mg (62%); 1H-NMR (300 MHz, DMSO-d6): d 10.42 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.26 (bs, 2H), 7.31 (s, 1H), 6.62 (s, 1H), 5-74-5.67 (m, 1H), 4.04-4.03 (m, 1H), 3.81 (s, 3H), 3.56-3.49 (m, 1H), 3.41-3.31 (m, 1H), 3.25 (s, 3H), 3.22-3.13 (m, 2H), 2.05-1.90 (m, 2H), 1.63 (d, J = 6.0 Hz, 3H); LCMS: m/z 508.0 [M+H]+.
Step-g: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazolin-2(1H)-one (15): To a solution of 7-methoxy-6-(3-methoxypyrrolidin-1-yl)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one (150 mg, 0.30 mmol) in methanol (40 mL) were added water (10 mL), iron powder (136 mg, 2.35 mmol) and ammonium chloride (150 mg, 2.35 mmol) and reaction mixture was heated at 80 °C for 2 h. Reaction progress was monitored by TLC. Upon consumption of starting material, the reaction mixture was filtered, and washed with methanol. The filtrate was concentrated under reduce pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude product which was purified by prep-HPLC to afford the titled compound as a pale-yellow solid. Yield 70 mg (50%); 1H-NMR (300 MHz, DMSO-d6): d 10.35 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.80 (s, 2H), 6.70 (s, 1H), 6.62 (s, 1H), 5-56-5.48 (m, 3H), 4.02 (bs, 1H), 3.81 (s, 3H), 3.54-3.45 (m, 1H), 3.24 (s, 3H), 3.17-3.12 (m, 2H), 2.06-1.89 (m, 2H), 1.51 (d, J = 6.9 Hz, 3H) [one proton merged with DMSO-d6 moisture peak]; LCMS: m/z 478.2 [M+H]+.

Example-16: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-fluoro-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one

Step-a: 2-Bromo-5-fluoro-4-methoxyaniline (16a): To a solution of 3-fluoro-4-methoxyaniline (5 g, 35.42 mmol) in dry dichloromethane (160 mL) at -15 °C was added bromine (1.85 mL) in dichloromethane (20 mL) drop-wise and stirred for 30 min. The progress of the reaction was monitored by TLC. Upon consumption of starting material, the reaction mixture was quenched with water, diluted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Product was purified by flash column chromatography and eluted with 2% ethyl acetate in hexane to afford the titled compound as a brown solid. Yield 5 g (64%); 1H-NMR (300 MHz, CDCl3) d 7.03 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 12.3 Hz, 1H), 3.80 (s, 3H), 3.74 (bs, 2H); LCMS: m/z 221.9 [M+H]+.
Step-b: 2-Amino-4-fluoro-5-methoxybenzonitrile (16b): To a solution of 2-bromo-5-fluoro-4-methoxyaniline (1.0 g, 4.54 mmol) in N-methyl-2-pyrrolidone (15 mL) was added copper(I) cyanide (1.22 g, mmol) and reaction mixture was heated at 180 °C for 1 h in microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (30 mL) then extracted. The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure and the residue obtained was purified by flash column chromatography and eluted with 8-10% ethyl acetate in hexane to afford the titled compound as a yellow solid. Yield 663 mg (72%); 1H-NMR (300 MHz, CDCl3): d 6.94 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 12.3 Hz, 1H), 4.23 (bs, 2H), 3.82 (s, 3H).
Step-c: Methyl (2-cyano-5-fluoro-4-methoxyphenyl)carbamate (16c) : To a solution of 2-amino-4-fluoro-5-methoxybenzonitrile (1.0 g, 6.02 mmol) in dichloromethane (24 mL) and dimethylformamide (2 mL) was added diisopropylethylamine (1.8 mL). The reaction mixture was cooled to 0 °C and ethyl chloroformate (0.98 g, 9.03 mmol) was added to it and stirred for 2 h. The reaction mixture was allowed to come to room temperature and stirred for 48 h. The progress of the reaction was monitored by TLC. Upon consumption of starting material, the reaction mixture was poured into ice- water and extracted with dichloromethane (100 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 3-4% ethyl acetate in hexane to afford the titled compound as a white solid. Yield 0.60 g (42%); 1H-NMR (300 MHz, CDCl3): d 8.05 (d, J = 13.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.02 (bs, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).
Step-d: 7-Fluoro-6-methoxyquinazoline-2,4(1H,3H)-dione (16d): To a solution of methyl (2-cyano-5-fluoro-4-methoxyphenyl)carbamate (0.6 g, 2.52 mmol) in ethanol (40 mL) at room temperature were added sodium hydroxide (0.28 g, 6.95 mmol) and hydrogen peroxide (35 mL) and the reaction mixture was stirred at 100 °C for 4 h. The progress of the reaction was monitored by TLC. Upon consumption of starting material, reaction mixture was cooled to room temperature and volatiles were evaporated under reduced pressure. The residue was stirred in ethyl acetate and solid obtained was filtered and dried under vacuum to afford the titled compound as a yellow solid. Yield 0.52 g (99%); 1H-NMR (300 MHz, DMSO-d6): d 8.50 (s, 2H), 7.39 (d, J = 10.2 Hz, 1H), 6.66 (d, J = 13.8 Hz, 1H), 3.75 (s, 3H); LCMS: m/z 211.9 [M+H]+.
Step-e: 2,4-Dichloro-7-fluoro-6-methoxyquinazoline (16e): To a solution of 7-fluoro-6-methoxyquinazoline-2,4(1H,3H)-dione (0.52 g, 2.48 mmol) in phosphorous(V)oxychloride (20 mL) was added N,N-diethylaniline (3 mL) dropwise at 10 °C. The reaction mixture was then heated at 120 °C for 4 h. The progress of the reaction was monitored by TLC. Upon consumption of starting material, phosphorous(V) oxychloride was distilled off under reduced pressure. The residue was poured over crushed ice and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated sodium bicarbonate (2 X 25 mL), water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 2-5% ethyl acetate in hexane to afford the titled compound as a yellow solid. Yield 0.3 g (49%); 1H-NMR (300 MHz, CDCl3): d 7.65 (d, J = 10.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 4.09 (s, 3H).
Step-f: (R)-2-Chloro-7-fluoro-6-methoxy-N-(1-(3-nitro-5-(trifluoromethyl) phenyl)ethyl)-quinazolin-4-amine (16f): To a solution of 2,4-dichloro-7-fluoro-6-methoxyquinazoline (0.3 g, 1.21 mmol) in dimethyl sulfoxide (15 mL) were added (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (0.33 g, 1.21 mmol) and N,N-diisopropylethylamine (0.8 mL). The reaction mixture was heated at 150 °C in microwave for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and poured over crushed ice. The organic layer was separated and washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude was purified by flash column chromatography and eluted with 15-17% ethyl acetate: hexane to afford the titled compound as a yellow solid. Yield 0.51 g (96%); 1H-NMR (300 MHz, CDCl3): d 8.51 (s, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.46 (d, J = 11.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.6 Hz, 1H), 5.64 (quin, J = 6.9 Hz, 1H), 4.07 (s, 3H), 1.81 (d, J = 6.9 Hz, 3H); LCMS: m/z 444.9 [M+H]+;
Step-g: (R)-2-Chloro-7-fluoro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl)amino)-quinazolin-6-ol (16g): To a solution of (R)-2-chloro-7-fluoro-6-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (0.51 g, 1.15 mmol) in dry dichloromethane (30 mL) at -78 °C was added boron tribromide (1.0 M in dichloromethane, 15 mL) under inert atmosphere. The reaction mixture was then warmed to room temperature and stirred for 5 h. The progress of the reaction was monitored by TLC. Upon consumption of starting material, the reaction mixture was diluted with dichloromethane (50 mL), quenched with sodium bicarbonate (30 mL) solution, and extracted. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15-20% ethyl acetate in hexane to afford the titled compound as a yellow solid. Yield 0.45 g (91%); LCMS: m/z 431.3 [M+H]+.
Step-h: 2-Chloro-7-fluoro-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (16h): To a solution of (R)-2-chloro-7-fluoro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-ol (32 mg, 0.07 mmol) in dry dimethylformamide (3 mL) were added (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (53.1 mg, 0.22 mmol), cesium carbonate (29.9 mg, 0.09 mmol) and heated to 100 °C for 4 h. The progress of the reaction was monitored by TLC. Upon consumption of starting material, the reaction mixture was poured over ice-water and extracted the product with ethyl acetate (20 mL). The organic layer was washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 25-30% ethyl acetate in hexane to afford the titled compound as a yellow oil. Yield 14 mg (38%); 1H-NMR (300 MHz, CDCl3): d 8.49 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.45 (d, J = 11.4 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 6.3 Hz, 1H), 5.64 (quin, J = 6.9 Hz, 1H), 5.10-5.17 (m, 1H), 4.09-3.93 (m, 4H), 2.30-2.23 (m, 2H), 1.79 (d, J = 6.9 Hz, 3H); LCMS: m/z 500.9 [M+H]+.
Step-i: 7-Fluoro-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (16i): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using 2-chloro-7-fluoro-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine as starting material. Yield 0.3 g (76%); 1H-NMR (300 MHz, DMSO-d6): d 10.72 (s, 1H), 8.54 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 11.7 Hz, 1H), 5.70 (quin, J = 6.9 Hz, 1H), 5.13-5.10 (m, 1H), 3.95-3.78 (m, 4H), 2.31-2.23 (m, 1H), 2.09-1.99 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H); LCMS: m/z 482.90 [M+H]+.
Step-j: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-fluoro-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (16): To a solution of fluoro-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one (0.2 g, 0.41 mmol) in methanol (15 mL) and water (8 mL) were added ammonium chloride (0.2 g, 3.73 mmol) and iron powder (0.2 g, 3.58 mmol). The reaction mixture was heated at 100 °C for 1.5 h. The progress of the reaction was monitored by TLC, the reaction mixture was cooled to room temperature and filtered through celite bed. The filtrate was extracted with 20% methanol in chloroform (2 x 50 mL) and then washed with sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the titled compound as a white solid. Yield 0.14 g (75%).
1H-NMR (300 MHz, DMSO-d6): d 10.65 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 11.7 Hz, 1H), 6.81-6.80 (m 2H), 6.72 (s, 1H), 5.58 (s, 2H), 5.49 (quin, J = 7.2 Hz, 1H), 5.10 (bs, 1H), 3.94-3.76 (m, 4H), 2.29-2.21 (m, 1H), 2.07-2.01 (m, 1H), 1.52 (d, J = 6.9 Hz, 3H); LCMS: m/z 453.0 [M+H]+.

Example-17: Synthesis of 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl) ethyl)amino)-7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)quinazolin-2(1H)-one

Step-a: tert-Butyl (S)-3-((2,4-dichloro-7-methoxyquinazolin-6-yl)oxy) pyrrolidine-1-carboxylate) (17a): To a solution of 2,4-dichloro-7-methoxyquinazolin-6-ol (2 g, 8.16 mmol) in tetrahydrofuran at room temperature were sequentially added diisopropyl azadicarboxylate (2.49 g, 12.24 mmol), triphenylphosphine (3.23 g, 12.24 mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.84 g, 9.83 mmol) and the reaction mixture was stirred for 16 h. Reaction progress was monitored by TLC. Upon consumption of starting material, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 ml) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 5% methanol in dichloromethane to afford the titled compound (3.5 g). The product was contaminated with reduced product diisopropyl azadicarboxylate and directly used for next step.
Step-b: tert-Butyl (S)-3-((2-chloro-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)-ethyl)amino)quinazolin-6-yl)oxy)pyrrolidine-1-carboxylate (17b) : To a solution of tert-butyl (S)-3-((2,4-dichloro-7-methoxyquinazolin-6-yl)oxy)pyrrolidine-1-carboxylate (0.75 g, 1.81 mmol) in dimethyl sulfoxide was added cesium carbonate (1.46 g, 4.52 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (0.49 g, 1.81 mmol) and the reaction mixture was heated at 80 °C for 8 h. Reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was diluted with ethyl acetate (75 mL), water (50 mL) and extracted. Organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 30% ethyl acetate in hexane to afford the titled compound as yellow solid. Yield: 0.42 g, (38%); 1H-NMR (300 MHz, CDCl3): d 8.49 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.55 (d, J = 6.3 Hz, 1H), 5,65 (quin, J = 6.9 Hz, 1H), 5.00-4.98 (m, 1H), 3.88 (s, 3H), 3.64-3.55 (m, 4H), 2.27-2.04 (m, 2H), 1.89 (s, 9H), 1.71 (d, J = 7.2 Hz, 3H); LCMS: m/z 612.6 [M+H]+.
Step-c: 7-Methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-pyrrolidin-3-yl)oxy)quinazolin-2(1H)-one (17c): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using tert-Butyl (S)-3-((2-chloro-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)-ethyl)amino)quinazolin-6-yl)oxy)pyrrolidine-1-carboxylate as starting material and stirred for 2 h. Yield: 80 mg (100%); 1H-NMR (300 MHz, CD3OD): d 8.57 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 6.75 (s, 1H), 5,76 (q, J = 6.9 Hz, 1H), 5.00-4.98 (m, 1H), 3.91 (s, 3H), 3.62-3.52 (m, 1H), 3.18-2.86 (m, 3H), 2.17-2.08 (m, 2H), 1.71 (d, J = 7.2 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 494.0 [M+H]+.
Step-d: 7-Methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one (17d): To a solution of 7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-pyrrolidin-3-yl)oxy)quinazolin-2(1H)-one (0.1 g, 0.20 mmol) in methanol (1.5 mL) was added acetic acid (0.012 mL) and the reaction mixture was cooled to 0 °C. To the reaction mixture was added aqueous formaldehyde (37%, 0.045 mL, 0.67 mmol) and followed by the addition of sodium cyanoborohydride (20 mg) and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 mL), water (10 mL) and extracted. Organic layer was washed with brine (10 mL) dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 12-15% methanol in dichloromethane to afford the titled compound as off-white solid. Yield: 70 mg (98%); 1H-NMR (300 MHz, CD3OD): d 8.55 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5,71 (q, J = 7.2 Hz, 1H), 5.18-5.15 (m, 1H), 3.91 (s, 3H), 3.58-3.45 (m, 2H), 3.32-3.24 (m, 2H), 2.90 (s, 3H), 2.55-2.42 (m, 1H), 2.33-2.24 (m, 1H), 1.71 (d, J = 7.2 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 508.0 [M+H]+.
Step-e: 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)quinazolin-2(1H)-one (17): The titled compound was synthesized following the same experimental procedure utilized for compound 7 using 7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as white solid. Yield: 21 mg (28%);
1H-NMR (300 MHz, CD3OD): d 7.61 (s, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.80 (s, 2H), 5.64 (q, J = 6.6 Hz, 1H), 5.00 (bs, 1H), 3.91 (s, 3H), 3.06-2.96 (m, 3H), 2.71-2.65 (m, 1H), 2.50 (s, 3H), 2.40-2.33 (m, 1H), 2.13-2.04 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H) [exchangeable protons are not visible]; LCMS: m/z 478.2 [M+H]+

Example-18: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(((S)-1-isopropylpyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one

Step-1: 6-(((S)-1-Isopropylpyrrolidin-3-yl)oxy)-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one (18a) : The titled compound was synthesized following the same experimental procedure utilized for 7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one using 7-Methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-pyrrolidin-3-yl)oxy)quinazolin-2(1H)-one and acetone as starting materials. Yield: 80 mg (80%); 1H-NMR (300 MHz, CD3OD): d 8.56 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.71 (s, 1H), 6.78 (s, 1H), 5.75 (q, J = 6.9 Hz, 1H), 5.08-5.04 (m, 1H), 3.93 (s, 3H), 3.63 (bs, 2H), 3.13-3.02 (m, 2H), 2.39-2.33 (m, 1H), 2.26-2.20 (m, 1H), 1.71 (d, J = 7.2 Hz, 3H), 1.30 (d, J = 6.3 Hz, 6H) [exchangeable protons are not visible and one proton merged with CD3OD signal]; LCMS: m/z 536.2 [M+H]+.
Step-b: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-isopropylpyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one (18): The titled compound was synthesized following the same experimental procedure utilized for compound 7 using 6-(((S)-1-Isopropylpyrrolidin-3-yl)oxy)-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound; Yield: 10.6 mg (14%).
1H-NMR (300 MHz, CD3OD): d 7.60 (s, 1H), 7.00 (s, 1H), 6.95 (s, 1H), 6.80 (s, 2H), 5.64 (q, J = 7.2 Hz, 1H), 5.00-4.95 (m, 1H), 3.91 (s, 3H), 3.13-3.07 (m, 1H), 2.99-2.95 (m, 2H), 2.76-2.70 (m, 1H), 2.62-2.56 (m, 1H), 2.34-2.27 (m ,1H), 2.09-2.02 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.3 Hz, 6H) [exchangeable protons are not visible]; LCMS: m/z 506.0 [M+H]+.

Example-19: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-(2-hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one

Step-a: 6-(((S)-1-(2-Hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one (19a): To a solution of 7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-pyrrolidin-3-yl)oxy)quinazolin-2(1H)-one (0.19 g, 0.38 mmol) in acetonitrile (5 mL) were added cesium carbonate (0.37 g, 1.13 mmol) and 2-bromoethan-1-ol (0.05 mL, 0.70 mmol) and reaction mixture was heated at 60 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (15 mL), extracted with 20% methanol in dichloromethane (2 X 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified with flash column chromatography and eluted with 16% methanol in dichloromethane to afford the titled compound as a pale yellow solid. Yield 120 mg (60%); 1H-NMR (300 MHz, CD3OD): d 8.58 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 6.79 (s, 1H), 5.75 (q, J = 6.9 Hz, 1H), 5.20 (bs, 1H), 3.94 (s, 3H), 3.88 (t, J = 5.1, 2H), 3.70-3.60 (m, 3H), 3.55-3.49 (m, 1H), 3.40-3.35 (m, 2H), 2.45-2.29 (m, 2H), 1.72 (d, J = 7.2 Hz, 3H) (Exchangeable protons are not visible); LCMS: m/z 538.0 [M+H]+.
Step-b: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-(2-hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one (19): The titled compound was synthesized following the same experimental procedure utilized for compound 16 using 6-(((S)-1-(2-Hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxy-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as off-white solid; Yield 25 mg (18%); 1H-NMR (300 MHz, DMSO-d6): d 10.48 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.74 (s, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.69 (s, 1H), 5.57 (s, 2H), 5.49 (quin, J = 7.2 Hz, 1H), 5.06-4.82 (m, 2H), 3.81 (s, 3H), 3.67-3.58 (m, 2H), 3.25-2.72 (m, 6H), 2.39-2.26 (m, 1H), 2.05-1.92 (m, 1H), 1.52 (d, J = 7.2 Hz, 3H); LCMS: m/z 508.0 [M+H]+.

Example-20: Synthesis of (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(pyrrolidin-1-yl)pyrido-[3,4-d]pyrimidin-2(1H)-one

Step-a: 5-Nitro-2-(pyrrolidin-1-yl)isonicotinamide (20a): To a solution of 2-chloro-5-nitroisonicotinamide (3.5 g, 17.36 mmol) in 1,4-dioxane (140 mL) were added diisopropylethylamine (10.5 mL, 52.09 mmol) and pyrrolidine (7 mL, 86.81 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was heated at 90 °C and stirred for 16 h. Reaction progress was monitored by TLC. After completion of reaction, 1,4-dioxane was distilled off under reduced pressure. The solid obtained was filtered, washed with water and dried under vacuum to afford the titled compound as a yellow solid. Yield: 3.3 g (80%); 1H-NMR (300 MHz, DMSO-d6): d 8.88 (s, 1H), 7.94 (bs, 1H), 7.67 (bs, 1H), 6.43 (s, 1H), 3.47 (bs, 4H), 1.97 (bs, 4H); LCMS: m/z 237.2 [M+H]+.
Step-b: 5-Amino-2-(pyrrolidin-1-yl)isonicotinamide (20b): To a solution of 5-nitro-2-(pyrrolidin-1-yl)isonicotinamide (230 mg, 0.97 mmol) in methanol (10 mL) was added 10% Pd-C (50% wet, 90 mg) and the reaction mixture was stirred under hydrogen atmosphere for 4 h. Reaction progress was monitored by TLC, the reaction mixture was filtered through celite bed, washed with methanol (10 mL) and evaporated under reduced pressure to afford the titled compound as an orange semi-solid. Yield: 180 mg (90%); 1H-NMR (300 MHz, DMSO-d6): d 7.99 (bs, 1H), 7.74 (s, 1H), 7.40 (bs, 1H), 7.03 (bs, 1H), 6.53 (s, 1H), 6.41 (bs, 1H), 3.32-3.26 (m, 4H), 1.92-1.88 (m, 4H); LCMS: m/z 207.1 [M+H]+.
Step-c: 6-(Pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (20c): 5-Amino-2-(pyrrolidin-1-yl)isonicotinamide (180 mg, 0.87 mmol) was dissolved in 1,4-dioxane (10 mL) by sonication. To the above solution at room temperature was added triphosgene (600 mg, 1.74 mmol) in portions, then the reaction mixture was stirred at 80 °C for 1 h. Reaction progress was monitored by TLC. Upon consumption of starting material, 1,4-dioxane was distilled off under reduced pressure and the residue was triturated with ethyl acetate. The resulting solid was filtered, washed with ethyl acetate and dried under vacuum to afford the titled compound as yellow solid. Yield: 130 mg (65%); 1H-NMR (300 MHz, DMSO-d6): d 11.40 (s, 1H), 10.92 (s, 1H), 8.10 (s, 1H), 6.84 (s, 1H), 3.41 (bs, 4H), 1.96 (bs, 4H); LCMS: m/z 233.1 [M+H]+.
Step-d: 2,4-Dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine (20d): To a solution of 6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (1.6 g, 6.89 mmol) in phosphorus(V)oxychloride (54 mL) was added diisopropylethylamine (5.5 mL) at room temperature and the reaction mixture was stirred at 120 °C for 3 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, phosphorus(V)oxychloride was distilled off under reduced pressure. The residue was poured onto ice and the compound was extracted with ethyl acetate (2 X 100 mL). Combined organic layer was washed with saturated sodium bicarbonate (50 mL), water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the titled compound as orange solid. Yield: 900 mg (49%); 1H-NMR (300 MHz, CDCl3): d 9.06 (s, 1H), 6.51 (s, 1H), 3.58 (t, J = 6.3 Hz, 4H), 2.13-2.08 (m, 4H); LCMS: m/z 269.2 [M+H]+.
Step-e: (R)-2-Chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-4-amine (20e): To a solution of 2,4-dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine (250 mg, 0.83 mmol) in tetrahydrofuran (20 mL) were added cesium carbonate (0.7 g, 2.16 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (150 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 16 h. Reaction progress was monitored by TLC. After completion of reaction, reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 20-25% ethyl acetate in hexane to afford the titled compound as brown solid. Yield 466 mg (53%); 1H-NMR (300 MHz, CDCl3): d 8.84 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.10 (s, 1H), 6.12 (s, 1H), 5.99 (d, J = 5.7 Hz, 1H), 5.64 (quin, J = 6.9 Hz, 1H), 3.55 (t, J = 6.6 Hz, 4H), 2.11-2.06 (m, 4H), 1.80 (d, J = 7.2 Hz, 3H); LCMS: m/z 467 [M+H]+.
Step-f: (R)-4-((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (20f): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using (R)-2-chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-4-amine as starting material and reaction mixture was stirred for 1 h. Yield: 180 mg (56%); 1H-NMR (300 MHz, DMSO-d6): d 10.46 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.09 (s, 1H), 5.69 (quin, J = 6.9 Hz, 1H), 3.42 (bs, 4H), 1.98 (t, J = 6.3 Hz, 4H), 1.64 (d, J = 7.2 Hz, 3H); LCMS: m/z 449.2 [M+H]+.
Step-g: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido-[3,4-d]pyrimidin-2(1H)-one (20): The titled compound was synthesized following the same experimental procedure utilized for compound 7 using (R)-4-((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as yellow solid. Yield: 70 mg (42%).
1H-NMR (300 MHz, DMSO-d6): d 10.39 (s, 1H), 8.52 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 7.12 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 5.58 (s, 2H), 5.47 (quin, J = 7.2 Hz, 1H), 3.39 (bs, 4H), 1.99-1.95 (m, 4H), 1.53 (d, J = 7.2 Hz, 3H); LCMS: m/z 419.30 [M+H]+

Example-21: Synthesis of 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one

Step-a: 2-(3-Methoxypyrrolidin-1-yl)-5-nitroisonicotinamide (21a): The titled compound was synthesized following the same experimental procedure utilized for 5-nitro-2-(pyrrolidin-1-yl)isonicotinamide using 2-chloro-5-nitroisonicotinamide and 3-methoxypyrrolidine as starting materials. Yield: 350 mg (90%); 1H-NMR (300 MHz, DMSO-d6): d 8.88 (s, 1H), 7.94 (bs, 1H), 7.68 (bs, 1H), 6.47 (s, 1H), 4.10 (bs, 1H), 3.77-3.50 (m, 4H), 3.27 (s, 3H), 2.16-2.04 (m, 2H).
Step-b: 5-Amino-2-(3-methoxypyrrolidin-1-yl)isonicotinamide (21b): The titled compound was synthesized following the same experimental procedure utilized for 5-amino-2-(pyrrolidin-1-yl)isonicotinamide using 2-(3-Methoxypyrrolidin-1-yl)-5-nitroisonicotinamide as starting material. Yield: 300 mg (96%); 1H-NMR (300 MHz, DMSO-d6): d 7.99 (bs, 1H), 7.74 (s, 1H), 7.40 (bs, 1H), 7.11 (bs, 1H), 6.54 (s, 1H), 6.49 (bs, 1H), 4.03-3.99 (m, 1H), 3.45-3.35 (m, 4H), 3.25 (s, 3H), 2.05-1.96 (m, 2H); LCMS: m/z 237 [M+H]+.
Step-c: 6-(3-Methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2,4(1H,3H)-dione (21c): The titled compound was synthesized following the same experimental procedure utilized for 6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione using 5-Amino-2-(3-methoxypyrrolidin-1-yl)isonicotinamide as starting material. Yield: 300 mg (90%); LCMS: m/z 263 [M+H]+.
Step-d: 2,4-Dichloro-6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidine (21d) : The titled compound was synthesized following the same experimental procedure utilized for 2,4-dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine using 6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2,4(1H,3H)-dione as starting material. Yield: 120 mg (42%); 1H-NMR (300 MHz, CDCl3): d 9.06 (d, J = 0.9 Hz, 1H), 6.53 (d, J = 0.6 Hz, 1H), 4.19-4.14 (m, 1H), 3.77-3.62 (m, 4H), 3.40 (s, 3H), 2.32-2.14 (m, 2H); LCMS: m/z 299.1 [M+H]+.
Step-e: 2-Chloro-6-(3-methoxypyrrolidin-1-yl)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4-amine (21e): To a solution of 2,4-dichloro-6-(3-methoxypyrrolidin-1-yl)-1,2-dihydropyrido[3,4-d]pyrimidine (120 mg, 0.44 mmol) in tetrahydrofuran (20 mL) were added cesium carbonate (650 mg, 2.2 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)-phenyl)ethan-1-amine hydrochloride (100 mg, 0.35 mmol) at room temperature. Reaction mixture was stirred at 80 °C for 16 h. Reaction progress was monitored by TLC. Upon consumption of starting material, the reaction mixture was filtered, washed with ethyl acetate (50 mL). The combined filtrate was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography and eluted with 20-25% ethyl acetate in hexane to afford the titled compound as yellow solid. Yield: 200 mg (100%); 1H-NMR (300 MHz, CDCl3): d 8.85 (s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 6.11 (s, 1H), 5.94 (d, J = 6.6 Hz, 1H), 5.64 (quin, J = 6.6 Hz, 1H), 4.16-4.09 (m, 1H), 3.67-3.58 (m, 4H), 3.39 (s, 3H), 2.28-2.13 (m, 2H), 1.80 (d, J = 6.9 Hz, 3H); LCMS: m/z 496.9 [M+H]+.
Step-f: 6-(3-methoxypyrrolidin-1-yl)-4-(((R)-1-(3-nitro-5-(trifluoromethyl) phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (21f) : The titled compound was synthesized following the same experimental procedure utilized for -(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using 2-Chloro-6-(3-methoxypyrrolidin-1-yl)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4-amine as starting material and reaction mixture was stirred for 1 h. Yield: 90 mg (49%); 1H-NMR (300 MHz, DMSO-d6): d 10.48 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.11 (s, 1H), 5.69 (quin, J = 6.9 Hz, 1H), 4.12 (bs, 1H), 3.55-3.41 (m, 4H), 3.29 (s, 3H), 2.11-2.07 (m, 2H), 1.64 (d, J = 7.2 Hz, 3H); LCMS: m/z 478.9 [M+H]+.
Step-g: 4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (21): The titled compound was synthesized following the same experimental procedure utilized for compound 16 using 6-(3-methoxypyrrolidin-1-yl)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as yellow solid. Yield: 55 mg (65%).
1H-NMR (300 MHz, DMSO-d6): d 10.41 (s, 1H), 8.51 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.13 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 5.58 (s, 2H), 5.47 (quin, J = 6.9 Hz, 1H), 4.11 (bs, 1H), 3.51-3.37 (m, 4H), 3.28 (s, 3H), 2.09-2.06 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H); LCMS: m/z 449.0 [M+H]+.

Example-22: Synthesis of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-morpholinopyrido[3,4-d]pyrimidin-2(1H)-one

Step-a: 2-Morpholino-5-nitroisonicotinamide (22a): The titled compound was synthesized following the same experimental procedure utilized for 5-nitro-2-(pyrrolidin-1-yl)isonicotinamide using 2-chloro-5-nitroisonicotinamide and morpholine as starting materials. Yield: 550 mg (87%); 1H-NMR (300 MHz, DMSO-d6): d 8.88 (s, 1H), 7.98 (bs, 1H), 7.71 (bs, 1H), 6.85 (s, 1H), 3.69-3.66 (m, 4H), 3.09-3.06 (m, 4H).
Step-b: 5-Amino-2-morpholinoisonicotinamide (22b): The titled compound was synthesized following the same experimental procedure utilized for 5-amino-2-(pyrrolidin-1-yl)isonicotinamide using 2-morpholino-5-nitroisonicotinamide as starting material. Yield: 490 mg (98%); 1H-NMR (300 MHz, DMSO-d6): d 8.04 (bs, 1H), 7.82 (s, 1H), 7.41 (bs, 1H), 6.90 (s, 1H), 5.75 (bs, 2H), 3.71-3.68 (m, 4H), 3.23-3.20 (m, 4H); LCMS: m/z 222.9 [M+H]+.
Step-c: 6-Morpholinopyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (22c) : The titled compound was synthesized following the same experimental procedure utilized for 6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione using 5-Amino-2-morpholinoisonicotinamide as starting material. Yield: 320 mg (58%); 1H-NMR (300 MHz, DMSO-d6): d 11.40 (s, 1H), 11.03 (s, 1H), 8.22 (s, 1H), 7.10 (s, 1H), 3.73-3.69 (m, 4H), 3.40-3.36 (m, 4H); LCMS: m/z 248.9 [M+H]+.
Step-d: 4-(2,4-Dichloropyrido[3,4-d]pyrimidin-6-yl)morpholine (22d) : The titled compound was synthesized following the same experimental procedure utilized for 2,4-dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine using 6-morpholinopyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione as starting material. Yield: 250 mg (68%); 1H-NMR (300 MHz, CDCl3): d 9.09 (d, J = 0.6 Hz, 1H), 6.85 (d, J = 0.6 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.70-3.67 (m, 4H); LCMS: m/z 284.9 [M+H]+.
Step-e: (R)-2-chloro-6-morpholino-N-(1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl)pyrido[3,4-d]pyrimidin-4-amine (22e) : To a solution of 4-(2,4-dichloropyrido[3,4-d]pyrimidin-6-yl)morpholine (250 mg, 0.83 mmol) in dimethyl sulfoxide (25 mL) were added cesium carbonate (2.0 g, 6.19 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (280 mg, 1.04 mmol) and reaction mixture was heated at 100 °C for 12 h. Reaction progress was monitored by TLC. After completion of reaction, reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 20-25% ethyl acetate in hexane to afford the titled compound as yellow solid. Yield 300 mg (71%); 1H-NMR (300 MHz, CDCl3): d 8.84 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 6.55 (s, 1H), 6.30 (d, J = 6.3 Hz, 1H), 5.65 (quin, J = 6.9 Hz, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.59 (t, J = 5.1 Hz, 4H), 1.78 (d, J = 6.9 Hz, 3H);
Step-f: (R)-6-Morpholino-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) pyrido[3,4-d]pyrimidin-2(1H)-one (22f) : The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using (R)-2-chloro-6-morpholino-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-pyrido[3,4-d]pyrimidin-4-amine as starting material and reaction mixture was stirred for 4 h. Yield: 160 mg (56%); 1H-NMR (300 MHz, DMSO-d6): d 10.62 (s, 1H), 8.71 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.68 (quin, J = 7.2 Hz, 1H), 3.77 (bs, 4H), 3.42 (bs, 4H), 1.63 (d, J = 6.9 Hz, 3H); LCMS: m/z 464.9 [M+H]+.
Step-g: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholino-pyrido[3,4-d]pyrimidin-2(1H)-one (22): The titled compound was synthesized following the same experimental procedure utilized for compound 16 using (R)-6-morpholino-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) pyrido[3,4-d]pyrimidin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as yellow solid. Yield: 100 mg (66%).
1H-NMR (300 MHz, DMSO-d6): d 10.55 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 7.49 (s, 1H), 6.80 (s, 2H), 6.72 (s, 1H), 5.58 (s, 2H), 5.46 (quin, J = 7.2 Hz, 1H), 3.77-3.74 (m, 4H), 3.42-3.38 (m, 4H), 1.53 (d, J = 6.9 Hz, 3H); LCMS: m/z 435.0 [M+H]+.

Example-23: Synthesis of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one

Step-a: 2-(4-Methoxypiperidin-1-yl)-5-nitroisonicotinamide (23a) : The titled compound was synthesized following the same experimental procedure utilized for 5-nitro-2-(pyrrolidin-1-yl)isonicotinamide using 2-chloro-5-nitroisonicotinamide and 4-methoxypiperidine as starting materials. Yield: 610 mg (87%); 1H-NMR (300 MHz, DMSO-d6): d 8.86 (s, 1H), 7.95 (bs, 1H), 7.68 (bs, 1H), 6.84 (s, 1H), 4.09-4.05 (m, 2H), 3.51-3.37 (m, 3H), 3.28 (s, 3H), 1.91-1.86 (m, 2H), 1.51-1.40 (m, 2H); LCMS: m/z 281.0 [M+H]+.
Step-b: 5-Amino-2-(4-methoxypiperidin-1-yl)isonicotinamide (23b) : The titled compound was synthesized following the same experimental procedure utilized for 5-amino-2-(pyrrolidin-1-yl)isonicotinamide using 2-(4-Methoxypiperidin-1-yl)-5-nitroisonicotinamide as starting material. Yield: 520 mg (95%); 1H-NMR (300 MHz, DMSO-d6): d 8.02 (bs, 1H), 7.78 (s, 1H), 7.38 (bs, 1H), 6.89 (s, 1H), 5.66 (bs, 2H), 3.75-3.71 (m, 2H), 3.46-3.42 (m, 1H), 3.26 (s, 3H), 2.93-2.85 (m, 2H), 1.90-1.87 (m, 2H), 1.48-1.41 (m, 2H); LCMS: m/z 251.0 [M+H]+.
Step-c: 6-(4-Methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (23c) : The titled compound was synthesized following the same experimental procedure utilized for 6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione using 5-Amino-2-(4-methoxypiperidin-1-yl)isonicotinamide as starting material. Yield: 400 mg (69%); 1H-NMR (300 MHz, DMSO-d6): d 11.37 (s, 1H), 11.0 (s, 1H), 8.19 (s, 1H), 7.12 (s, 1H), 3.88-3.82 (m, 2H), 3.43-3.37 (m, 1H), 3.27 (s, 3H), 3.18-3.11 (m, 2H), 1.91-1.88 (m, 2H), 1.46-1.42 (m, 2H); LCMS: m/z 276.9 [M+H]+.
Step-d: 2,4-Dichloro-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidine (23d) : The titled compound was synthesized following the same experimental procedure utilized for 2,4-dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine using 6-(4-Methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione as starting material. Yield: 305 mg (67%); 1H-NMR (300 MHz, CDCl3): d 9.06 (d, J = 0.9 Hz, 1H), 6.84 (s, J = 0.6 Hz, 1H), 4.09-4.01 (m, 2H), 3.55-3.44 (m, 3H), 3.41 (s, 3H), 2.04-1.96 (m, 2H), 1.77-1.67 (m, 2H); LCMS: m/z 314.9 [M+H]+.
Step-e: ((R)-2-Chloro-6-(4-methoxypiperidin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)-phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (23e) : The titled compound was synthesized following the same experimental procedure utilized for (R)-2-chloro-6-morpholino-N-(1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl)pyrido[3,4-d]pyrimidin-4-amine using 2,4-Dichloro-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidine as starting material. Yield: 300 mg (61%); 1H-NMR (300 MHz, CDCl3): d 8.82 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 6.49 (s, 1H), 6.05 (d, J = 6.6 Hz, 1H), 5.63 (quin, J = 6.9 Hz, 1H), 4.06-3.97 (m, 2H), 3.52-3.47 (m, 1H), 3.44-3.36 (m, 5H), 2.03-1.96 (m, 2H), 1.79 (d, J = 7.2 Hz, 3H), 1.75-1.65 (m, 2H).
Step-f: (R)-6-(4-Methoxypiperidin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl) phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (23f): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using ((R)-2-Chloro-6-(4-methoxypiperidin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)-phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine as starting material and reaction mixture was stirred for 1 h. Yield: 160 mg (55%); 1H-NMR (300 MHz, DMSO-d6): d 10.57 (s, 1H), 8.69 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.68 (quin, J = 7.2 Hz, 1H), 3.94-3.89 (m, 2H), 3.45-3.39 (m, 1H), 3.29 (s, 3H), 3.17-3.10 (m, 2H), 1.99-1.91 (m, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.53-1.43 (m, 2H); LCMS: m/z 492.9 [M+H]+.
Step-g: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (23): The titled compound was synthesized following the same experimental procedure utilized for compound 16 using (R)-6-(4-Methoxypiperidin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-amino)pyrido[3,4-d]pyrimidin-2(1H)-one as starting material. Product was purified by prep.HPLC to afford the titled compound as yellow solid. Yield: 70 mg (46%).
1H-NMR (300 MHz, DMSO-d6) d 10.49 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 7.49 (s, 1H), 6.79 (s, 2H), 6.72 (s, 1H), 5.58 (s, 2H), 5.46 (quin, J = 6.9 Hz, 1H), 3.93-3.88 (m, 2H), 3.43-3.37 (m, 1H), 3.29 (s, 3H), 3.14-3.07 (m, 2H), 1.96-1.92 (m, 2H), 1.53 (d, J = 6.9 Hz, 3H), 1.49-1.44 (m, 2H); LCMS: m/z 463.0 [M+H]+.

Example-24: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one

Step-a: 3-Nitro-6-(pyrrolidin-1-yl)picolinonitrile (24a): To a stirred solution of 6-chloro-3-nitropicolinonitrile (500 mg, 2.74 mmol) in tetrahydrofuran (15 mL) at room temperature was added cesium carbonate (2.6 g, 8.20 mmol) and the reaction mixture was stirred at 80 °C for 12 h. Reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 35% ethyl acetate in hexane to afford the titled compound as yellow solid. Yield: 450 mg (76%); 1H NMR (300 MHz, CDCl3): d 8.30 (d, J = 9.6 Hz, 1H), 6.85 (d, J = 9.6 Hz, 1H), 3.60 (t, J = 6.3 Hz, 2H), 3.48 (t, J = 6.3 Hz, 2H), 2.04-1.93 (m, 4H).
Step-b: 3-Amino-6-(pyrrolidin-1-yl)picolinamide (24b): To a stirred solution of 3-nitro-6-(pyrrolidin-1-yl)picolinonitrile. (1.7 g, 7.7.0 mmol) in ethanol (60 mL) was added stannous chloride (5.9 g, 31.11 mmol) at room temperature. Reaction mixture was heated to 80 °C for 16 h. Reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was evaporated under reduced pressure. The crude compound was diluted with 10% methanol in DCM (100 mL), washed with water (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to the titled compound as pale-yellow solid which was used in the next step without any further purification. Yield: 3.6 g (crude); LCMS: m/z 207.0 [M+H]+.
Step-c: 6-(Pyrrolidin-1-yl)pyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione (24c): To a solution of 3-amino-6-(pyrrolidin-1-yl)picolinamide (3.6 g, 17.31 mmol) in 1,4-dioxane (50 mL) was added triphosgene (10 g, 34.70 mmol) at room temperature. Reaction mixture heated at 80 °C for 6 h. The reaction progress was monitored by TLC. Upon consumption of starting material, reaction mixture was evaporated under reduced pressure. The crude compound was washed with n-pentane (2 x 30 mL) and diethyl ether (2 X 20 mL) to afford the titled compound as yellow solid. Yield: 1.5 g (83% in 2 steps); 1H NMR (300 MHz, DMSO-d6): d 11.36 (bs, 1H), 10.96 (bs, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 3.47-3.41 (m, 4H), 1.98-1.92 (m, 4H); LCMS: m/z 233.0 [M+H]+.
Step-d: 2,4-Dichloro-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidine (24d): The titled compound was synthesized following the same experimental procedure utilized for 2,4-Dichloro-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine using 6-(Pyrrolidin-1-yl)pyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione as starting material. Yield: 350 mg (20%); 1H NMR (300 MHz, CDCl3): d 7.89 (d, J = 9.3 Hz, 1H), 7.12 (d, J = 9.3 Hz, 1H), 3.65 (bs, 4H), 2.10 (bs, 4H); LCMS: m/z 268.9 [M+H]+.
Step-e: (R)-2-Chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-amine (24e): The titled compound was synthesized following the same experimental procedure utilized for 2-Chloro-6-(3-methoxypyrrolidin-1-yl)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)-ethyl)pyrido[3,4-d]pyrimidin-4-amine using 2,4-Dichloro-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidine and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride as starting materials. Yield 410 mg (68%); 1H NMR (300 MHz, CDCl3): d 8.49 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 6.6 Hz, 1H), 6.94 (d, J = 9.3 Hz, 1H), 5.58 (quin, J = 6.9 Hz, 1H), 3.63-3.55 (m, 4H), 2.11-2.06 (m, 4H), 1.76 (d, J = 6.9 Hz, 3H); LCMS: m/z 466.9 [M+H]+.
Step-f: (R)-4-((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one (24f): The titled compound was synthesized following the same experimental procedure utilized for 4-(((R)-1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydro-furan-3-yl)oxy)quinazolin-2(1H)-one using (R)-2-Chloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-4-amine as starting material. Yield: 185 mg (77%); 1H NMR (300 MHz, CDCl3): d 12.30 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.55 (d, J = 9.3 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 9.3 Hz, 1H), 5.83 (quin, J = 7.5 Hz, 1H), 3.53-3.48 (m, 4H), 2.08-2.03 (m, 4H), 1.72 (d, J = 6.9 Hz, 3H); LCMS: m/z 449.0[M+H]+.
Step-g: (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one (24): The titled compound was synthesized following the same experimental procedure utilized for compound 16 using (R)-4-((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one as starting material. The residue was purified by prep-HPLC to afford the titled compound as pale-yellow solid. Yield: 50 mg (30%);
1H NMR (300 MHz, DMSO-d6): d 10.36 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.72 (s, 1H), 5.57 (s, 2H), 5.33 (quin, J = 7.2 Hz, 1H), 3.49-3.44 (m, 4H), 1.98-1.93 (m, 4H), 1.54 (d, J = 6.9 Hz, 3H); LCMS: m/z 419.0 [M+H]+.

Examples in Table 1 were prepared in a similar manner to example 20
Table 1
Example No Structure 1H NMR (400 MHz, DMSO-d6): d ppm LC-MS:
m/z
25
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.49 (s, 1H), 8.55 (d, J=7.7Hz, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 6.80 (d, J = 6.8 Hz, 2H), 6.78 (s, 1H), 5.59 (bs, 2H), 5.46 (t, J = 7.6 Hz, 1H), 3.46 (bs, 4H), 1.59 (bs, 6H), 1.54 (d, J = 7.2 Hz, 3H) 433.20 [M+H]+
26
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-hydroxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.5 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.47 (s, 1H), 6.79 (d, J = 7.2 Hz, 2H), 6.71 (s, 1H), 5.59 (bs, 2H), 5.46 (t, 8.0 Hz, 1H), 4.72 (d, J = 4.4 Hz, 1H), 3.98-3.95 (m, 2H), 3.70-3.68 (m, 1H), 3.06-3.01 (m, 2H), 1.83-1.80 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H), 1.49- 1.39 (m, 2H) 449.10 [M+H]+
27

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-fluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.5 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.59 (s, 1H), 6.79 (d, J = 6.4 Hz, 2H), 6.72 (s, 1H), 5.55 (bs, 2H), 5.46 (t, J = 7.2 Hz, 1H), 4.84-4.63 (m, 1H), 3.70-3.68 (m, 2H), 3.46-3.42 (m, 2H), 1.97-1.93 (m, 2H), 1.75-1.73 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H) 451.20 [M+H]+
28

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.48 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.46 (s, 1H), 6.78 (d, J = 6.8 Hz, 2H), 6.71 (s, 1H), 5.99 (s, 2H), 5.46 (t, J = 7.2 Hz, 1H), 4.22-4.20 (m, 2H), 2.77-22.71 (m, 2H), 1.72-1.70 (m, 2H), 1.60-1.58 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.17-1.11 (m, 2H), 0.94 (d, J = 6.8 Hz, 3H) 447.2 [M+H]+
29

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one hydrochloride 11.30 (bs, 1H), 10.05 (bs, 1H), 9.30 (bs, 2H), 8.30 (s, 1H), 8.06 (s, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 5.50 (t, J = 6.4 Hz, 1H), 3.76 (bs, 4H), 3.56 (s, 1H), 3.21 (bs, 4H), 1.65 (d, J = 6.8 Hz, 3H) 434.10 [M+H]+
30

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-isopropylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.51 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 6.79 (d, J = 6.4 Hz, 2H), 5.59 (bs, 2H), 5.46 (quin, J = 7.6 Hz, 1H), 3.42 (bs, 4H), 2.73-2.69 (m, 1H), 2.57 (bs, 4H), 1.53 (d, J = 7.2 Hz, 3H), 1.01 (d, J = 6.8 Hz, 6H) 476.3 [M+H]+
31

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one 10.5 (s, 1H), 8.56 (d, J = 8.0, Hz, 1H), 8.19 (s, 1H), 7.59 (s, 1H), 6.79 (d, J = 6.4 Hz, 2H), 6.72 (s, 1H), 5.60 (bs, 2H), 5.48-5.44 (m, 1H), 3.67-3.65 (m, 4H), 2.07-2.00 (m, 4H), 1.53 (t, J = 6.8 Hz, 3H) 469.2 [M+H]+

Example-32: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-isopropylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one

Step-a: 5-amino-2-chloroisonicotinamide (32a): To the stirred solution of 2-chloro-5-nitroisonicotinamide (2.0 g, 9.95 mmol) in Ethanol (22 mL) and water (8 mL) at room temperature was added ammonium chloride (5.3 g, 99.95 mmol) and Iron powder (2.73 g, 49.7 mmol). The reaction mixture was heated at 90°C for 3 h. Progress of the reaction was monitored by TLC. Upon consumption of the starting material, reaction mixture was cooled to rt and diluted with EtOAc (20 mL). Solids were filtered off and filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 5-amino-2-chloroisonicotinamide as pale brown solid. Yield 1.5 g (88%); LCMS: m/z 171.9 [M+H]+.
Step-b: 6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (32b): To the stirred solution of 5-amino-2-chloroisonicotinamide (1.5 g, 8.7 mmol) in 1,4-dioxane (17 mL) was added triphosgene (3.8 g, 13.1 mmol) by portions, reaction mixture stirred at 80°C for 2 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, concentrated under vacuum. The residue obtained was triturated with EtOAc (2 x 25 mL) and decanted. The solid obtained was dried under vacuo to afford 6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione as yellow solid. Yield 1.5 g (87%); LCMS: m/z 198.0[M+H]+.
Step-c: 2,4,6-trichloropyrido[3,4-d]pyrimidine (32c): To the stirred solution of 6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (1.0 g, 5.0 mmol) in POCl3 (10 mL) was added DIPEA (2.7 mL, 15.1 mmol) and heated at 120°C for 3 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, excess POCl3 was evaporated under vacuum resultant residue was triturated with diethyl ether (3 x 30 mL) and decanted. The combined organic layer was washed with NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4 and concentrated under vacuo to afford 2,4,6-trichloropyrido[3,4-d]pyrimidine as pale brown solid. Yield 900 mg (76%); 1H-NMR (400 MHz, CDCl3) d 9.30 (s, 1H), 8.07 (s, 1H).
Step-d: (R)-2,6-dichloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (32d): To the stirred solution of 2,4,6-trichloropyrido[3,4-d]pyrimidine (900 mg, 3.83 mmol) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (1.03 g, 3.83 mmol) in THF (25 mL) at RT was added Cs2CO3 (3.1 g, 9.59 mmol) and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue obtained was purified with flash column chromatography and eluted with 30% ethyl acetate in hexane as an eluent to afford (R)-2,6-dichloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine as a yellow solid. Yield 1.0 g (55%); 1H-NMR (400 MHz, CDCl3) d 8.99 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 6.68 (d, J = 5.2 Hz, 1H), 5.67-5.63 (m, 1H), 1.82 (d, J = 7.2 Hz, 3H).
Step-e: (R)-6-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (32e): (R)-2,6-dichloro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) pyrido[3,4-d]pyrimidin-4-amine (1.0 g, 2.3 mmol) in acetic acid (10 mL) was heated to 80°C and stirred for 4 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to rt, acetic acid was evaporated under vacuum. The resultant residue was diluted Aq.NaHCO3 (30 mL), and extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford (R)-6-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one as a pale yellow solid. Yield 900 mg (94%); 1H-NMR (400 MHz, DMSO-d6) d 11.10 (s, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 8.33-8.30 (m, 3H), 5.66-5.63 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H); LCMS: m/z 414.2 [M+H]+.
Step-f: tert-butyl (R)-4-(4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32f): To a stirred solution of (R)-6-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (350 mg, 0.84 mmol) in 1,4-dioxane (15 mL) at room temperature were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (313 mg, 1.01 mmol) and potassium carbonate (350 mg, 2.53 mmol in water(5 mL)). The reaction mixture was degassed with nitrogen for 2 min, Tetrakis(triphenylphosphine)palladium(0) (97.7 mg, 0.08 mmol) was added and the reaction vial was placed in microwave at 120°C for 1 h. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 30% ethyl acetate in hexane as an eluent to afford tert-butyl (R)-4-(4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale brown solid. Yield mg (641 mg, 74%); LCMS: m/z 561.3[M+H]+.
Step-g: (R)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one hydrochloride (32g): To a stirred solution of tert-butyl (R)-4-(4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 1.78 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (5 mL) and the reaction was stirred at RT for 4 h. Upon completion of the starting material, the reaction mixture was evaporated under reduced pressure. The resultant solid was washed with diethy ether (2 x 3 mL), dried under vacuum to afford (R)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one hydrochloride as a pale brown solid. Yield (520 mg, 59%); LCMS: m/z 461.2[M+H]+.
Step-h: (R)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (32h): To a stirred solution of (R)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one hydrochloride (250 mg, 0.50 mmol) in methanol (10 mL) at room temperature was added sodium bicarbonate (211 mg, 2.51 mmol) by portions. To the above reaction mixture was added sodium cyanoborohydride (158 mg, 2.51 mmol) and acetone (0.5 mL) and stirred for 6 h at rt. The progress of the reaction was monitored by TLC. Upon complete consumption of the starting material the reaction mixture was evaporated under reduced pressure and then diluted with water (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography and eluted with 5% methanol in dichloromethane to afford (R)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one as yellow solid. Yield (100 mg, 40%); 1H-NMR (400 MHz, DMSO-d6) d 10.98 (s, 1H), 8.93 (d, J = 6.4 Hz, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.22 (bs, 1H), 6.69 (bs, 1H), 5.71-5.67 (m, 1H), 3.25 (bs, 1H), 2.85-2.8 (m, 2H), 2.65-2.60 (m, 2H), 1.65 (d, J = 7.2 Hz, 3H), 1.18-1.08 (m, 6H); LCMS: m/z 503.2 [M+H]+.
Step-i: (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-isopropylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (32): To a solution of (R)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2(1H)-one (100 mg, 0.19 mmol) in methanol (10 mL) was added 10% Pd/C (20 mg, slurry in methanol) and stirred under hydrogen gas for 16 h. The progress of the reaction was monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through celite pad and filtrate was evaporated under reduced pressure. The residue obtained was purified by Prep-HPLC to afford (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-isopropylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one as yellow solid. Yield (10 mg, 11%); 1H-NMR (400 MHz, DMSO-d6) d 10.81 (s, 1H), 8.69 (d, J = 3.8 Hz, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 6.82 (d, J = 6.2 Hz, 2H), 6.73 (s, 1H), 5.60 (s, 2H), 5.43 (quin, J = 3.6 Hz, 1H), 2.92-2.89 (m, 2H), 2.75-2.70 (m, 1H), 2.21-2.18 (m, 2H), 1.88-1.59 (m, 7H), 1.52 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 6.8 Hz, 6H); LCMS: m/z 475.3 [M+H]+.

Examples in Table 2 were prepared in a similar manner to example 32
Table 2
Example No Structure 1H NMR (400 MHz): d ppm LC-MS:
m/z
33
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylpyrrolidin-3-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (CD3OD): 8.6 (s, 1H), 8.0 (s, 1H), 6.96 (d, J = 5.2 Hz, 2H), 6.80 (s, 1H), 5.60 (quin, J = 3.6 Hz, 1H), 3.93-3.85 (m, 4H), 3.51-3.46 (m, 1H), 3.02 (bs, 3H), 2.75-2.51 (m, 1H), 2.35-2.18 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H) 433.2
[M+H]+
34
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one (DMSO-d6): 10.86 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 8.05 (s, 1H), 6.81 (d, J = 11.2 Hz, 2H), 6.72 (s, 1H), 5.58 (s, 2H), 5.44 (quin, J = 7.2 Hz, 1H), 3.99-3.96 (m, 2H), 3.49-3.43 (m, 2H), 2.94-2.92 (m, 1H), 1.81-1.76 (m, 4H), 1.53 (d, J = 7.2 Hz, 3H) 434.2 [M+H]+

List of Abbreviations used in the present invention are given below:

ACN Acetonitrile
AC2O Acetic anhydride
AcOH Acetic acid
Aq Aqueous
brs broad singlet
BSA Bovine serum albumin
°C degree Celsius
CDI 1,1'-Carbonyldiimidazole
d doublet
DCM Dichloromethane
DCE Dichloroethane
dd doublet of doublets
DEA Diethyl amine
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DIPEA N, N-Diisopropylethylamine
DMA Dimethylacetamide
DMF Dimethylformamide
DMS Dimethyl sulfate
DMSO Dimethyl sulfoxide
DTT Dithiothreitol
EDTA Ethylene diamine tetraacetic acid
EtOAc Ethyl acetate
EtOH Ethanol
FRET Fluorescence Resonance Energy Transfer
g gram
GST-Tb Glutathione-S-Transferase – Terbium
h hour
HEPES N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)
HIS Histidine
HPLC High-performance liquid chromatography
HTRF Homogenous Time Resolved Fluorescence
IPA Isopropanol
KRAS Kirsten Rat Sarcoma
LC Liquid chromatography
m multiplet
m-CPBA meta-Chloroperoxybenzoic acid
MeI Methyl Iodide
MeMgBr Methyl magnesium bromide
MeOH Methanol
MeONa Sodium methoxide
mg milligram
MHz Megahertz
min minutes
mL milliliter
mmol Millimoles
MS Mass spectrometry
Ms-Cl Methanesulfonyl chloride
MW Microwave
NaOAc Sodium acetate
NMP N-Methyl-2-pyrrolidone
NMR Nuclear magnetic resonance spectroscopy
O/N Over night
Pd-C Palladium on carbon
prep Preparative
RT Room temperature
SOS1 Son of sevenless 1
t triplet
TBAF Tetra-n-butylammonium fluoride
TBS-Cl tert-Butyldimethylsilyl chloride
TEA Triethylamine
THF Tetrahydrofuran
TLC Thin-layer chromatography
TPP Triphenylphosphine
Ts-Cl 4-Toluenesulfonyl chloride

PHARMACOLOGICAL ACTIVITY:

Biochemical assay : Measurement of SOS1-KRAS G12C interaction
This assay quantifies the extent of biochemical interaction of SOS1 and KRAS G12C using a HTRF based energy transfer from GST-Tb tagged KRAS G12C (FRET donor) to HIS-XL665 tagged SOS1 (FRET acceptor). The assay buffer composition is as follows : 5 mM HEPES, 150 mM NaCl, 1 mM DTT, 10 mM EDTA, 0.05% BSA, 0.0025% Igepal and 100 mM FK.
200 nL of compounds or DMSO stock was added to 384 well Proxiplate plus (Perkin Elmer) with Echo system. 5 µL of a premix of GST KRAS G12C (20 nM) and Anti GST-Tb donor (4 nM) was added to the compound/DMSO containing plate using a multichannel pipette, and the components were pre-incubated for 2 min at 23?C. 5 µL of acceptor solution mix containing 40 nM HIS-SOS1cat and 20 nM of anti-6XHIS XL665 was added to the same plate and the complete reaction mixture was further incubated for 30 min at 23?C, before HTRF measurement at Envision (read at 665 and 615 nm). The FRET ratio of DMSO control wells was considered to have 0% inhibition and the % inhibition of individual treatments were calculated accordingly. 3fold serial dilution of compounds were performed starting from 10 µM highest concentration. IC50 curves were generated from % inhibition using XLfit software.
The compounds when tested for their potential to disrupt SOS1-KRAS protein-protein interaction (PPI) in the above-mentioned assay exhibited inhibition. The values of inhibition of this protein-protein interaction for some of the exemplary compounds are given in the below table :

S. No. Compound No: SOS1-KRAS G12C PPI disruption assay: % inhibition @ 1µM
1. 1 56.59
2. 2 35.59
3. 3 72.88
4. 6 92
5. 7 85.93
6. 8 98.43
7. 9 97.03
8. 10 96
9. 12 99.33
10. 14 93.3
11. 15 96.18
12. 16 97.71
13. 17 98.79
14. 18 96.74
15. 19 97.35
16. 20 98.39
17. 21 98.52
18. 22 100
19. 23 97.54
20. 25 94.70
21. 26 92.03
22. 27 97.86
23. 28 95.05
24. 29 93.05
25. 31 87.33

,CLAIMS:WE CLAIM:

1. Novel compounds of formula (I):

Formula (I)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable regioisomer thereof; wherein,
R1 and R2 are same or different and each individually is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, –C(O)alkyl, -C(=O), cycloalkyl, heterocyclyl, aryl, heteroaryl, OR1a, NR1aR1b wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1a is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
R1b is selected from the group consisting of hydrogen, alkyl, –C(O)alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents ;
or R1a and R1b when present on a nitrogen taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N which is optionally substituted by one or more, identical or different substituents;
R3 is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
R4 and R5 are same or different and each individually is selected from the group consisting of hydrogen, halogen, amino, nitro, alkyl or taken together when present on adjacent carbon atoms form an optionally substituted 4-6 membered aryl ring system containing optionally 1-2 heteroatoms independently selected from O and N;
R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein any of the group is optionally substituted by one or more, identical or different substituents;
x, y, z independently represent C or N with a limitation of upto only 2 N atoms in the ring system.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, in which the group

is specifically represented by

wherein the groups R1, R2, and R6 are as defined in claim 1.
3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, in which the group

is specifically represented by

4. The compound of formula (I) according to claim 1, is novel quinazolinone compounds represented by formula (Ia)

Formula (Ia)

wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

5. The compound of formula (I) according to claim 1, is novel pyridopyrimidinone compounds represented by formula (Ib)

Formula (Ib)
wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

6. The compound of formula (I) according to claim 1, is novel pyridopyrimidinone compounds represented by formula (Ic)

Formula (Ic)
wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

7. The compound of formula (I) according to claim 1, is novel pyrimidopyrimidinone compounds represented by formula (Id)

Formula (Id)
wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

8. The compound of formula (I) according to claim 1, is novel pyridopyrimidinone compounds represented by formula (Ie)

Formula (Ie)
wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

9. The compound of formula (I) according to claim 1, is novel pyridopyrimidinone compounds represented by formula (If)

Formula (If)
wherein the groups R1, R2, R3, R4, R5, and R6 are as defined in claim 1.

10. A compound is selected from the group consisting of:

(R)-6,7-dimethoxy-4-((1-(naphthalen-1-yl)ethyl)amino)quinazolin-2(1H)-one
(R)-6,7-dimethoxy-1-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)quinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-(3-hydroxypropyl)-6,7-dimethoxyquinazolin-2(1H)-one
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6,7-dimethoxy-1-(tetrahydro-2H-pyran-4-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6,7-dimethoxyquinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxyquinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-1-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-(2-aminothiazol-4-yl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(pyrrolidin-1-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(3-methoxypyrrolidin-1-yl)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-fluoro-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-6-(((S)-1-methylpyrrolidin-3-yl)oxy)quinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-isopropylpyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(((S)-1-(2-hydroxyethyl)pyrrolidin-3-yl)oxy)-7-methoxyquinazolin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinopyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(pyrrolidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
(R)-4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
(R)-4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-fluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one.
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-isopropylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(3-hydroxypropyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(4-hydroxybutyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(5-hydroxypentyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-methoxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(3-methoxypropyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(4-methoxybutyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(5-methoxypentyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4,4-difluoropiperidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(3-hydroxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(3-fluoroazetidin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-cyclobutylpyrido[4,3-d]pyrimidine-2,5(1H,6H)-dione
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-cyclobutylpyrido[4,3-d]pyrimidine-2,7(1H,6H)-dione
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(5-amino-2-fluoro-3-(difluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxyquinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(fluoromethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(methoxymethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-((S)-tetrahydrofuran-3-yloxy)-7-(hydroxymethyl)quinazolin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-morpholinopyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methoxypiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(piperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-fluoropiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-methylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-isopropylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4,4-difluoropiperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-methylpyrrolidin-3-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(1-isopropylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(4-(2-methoxyethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2(1H)-one
4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-6-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidin-2(1H)-one

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable regioisomer thereof.

11. The pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

13. The method of inhibiting SOS1:KRAS protein-protein interaction comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 10.

14. The method as claimed in claim 13 for the treatment diseases or disorder associated with SOS1:KRAS protein-protein interaction.

Date this fourth (4th) day of June, 2022.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883