HETEROCYCLIC COMPOUNDS USEFUL AS IDO AND/OR TDO MODULATORS

This application claims the benefit of Indian provisional applications IN 201621007541 filed on 03 ^rd March 2016 and IN 201621023307 filed on 07 ^th July 2016 which are hereby incorporated in their entirety.

FIELD OF THE INVENTION

Present invention relates to novel pharmaceutical heterocyclic compounds that are inhibitors of indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO). The invention further relates to preparation of these novel compounds and method of treatment for conditions related to tryptophan degradation using the compounds of the invention.

BACKGROUND OF THE INVENTION

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan degrading enzymes that catalyze the first step in tryptophan catabolism independently in the kynurenine pathway (KP). The catabolism in turn results in depletion of tryptophan levels and formation of KP metabolites which modulates the activity of the mammalian immune, reproductive, and central nervous systems. Tryptophan (Trp) is an essential amino acid in humans as it has to be obtained through diet as body do not biosynthesize it and most of the dietary Trp being metabolized through the kynurenine pathway. Trp is also required for biosynthesis of proteins, neurotransmitters like serotonin, melatonin and Vitamin B3 (Niacin). Excessive activation of the kynurenine pathway not only causes depletion of Trp levels but also give rise to production of kynurenine based metabolites and thereby causing suppression of tumor killing T cells proliferation and also promote differentiation and activation of immune- suppressant regulatory T cells (Tregs), respectively. In addition, the production of metabolites can provide a source of nicotinamide dinucleotide (NAD ⁺ ) and have other biological effects, particularly in the immune, reproductive, and central nervous systems. (Ball HJ et al., Front Immunol. 2014; 5: Article 485)

Though both IDO & TDO catalyze oxidative cleavage of tryptophan to N'- formylkynurenine, they differ from each other in many aspects. IDO is a monomer, which is distributed ubiquitously in extrahepatic tissues particularly in lung, small intestine & placenta. There are two major subtypes of IDO (IDOl & ID02). Sequence analysis indicates that for humans and mice, IDOl and ID02 proteins possess 43% homology and that the residues required for tryptophan catalytic activity are highly conserved (Ball HJ, et al. Gene 2007; 396(1 ):203-213). It's important to note, however, that IDOl possesses a higher affinity for L- tryptophan, when compared to ID02 (Yuasa HJ, et al. Comp Biochem Physiol B. 2009; 153(2):137-144). On the other hand TDO is a tetramer, located extensively in liver & placenta. Structural studies of IDO versus TDO show that conserved Argl 17 and Tyrl 13 are found both in TDO and IDO which presents active site environments, however, His55 in TDO is replaced by Serl67b in IDO. (Thackray, S. et al., Biochem Society Transaction. 2008; pp. 36, 1120-1123). Till date, KP appears to be implicated in a variety of diseases and disorders, including immune system disorders, Cancer, acquired immune deficiency syndrome (AIDS), dementia complex, alzheimer's disease (AD), huntington's disease, amyotrophic lateral sclerosis (ALS), schizophrenia, psychiatric disorders, depressive disorders and neoplasias. Numerous studies have measured the levels of tryptophan and kynurenines under those conditions. Significant imbalances in Trp and its metabolites were frequently observed, which when brought back within normal ranges, often resulted in alleviation of symptoms.

The Trp catabolism is a central pathway maintaining the immunosuppressive microenvironment in many types of cancers. A relationship between cancer and elevated Trp catabolism was recognized in the early 1950s by analyzing the urine of bladder cancer patients (Boyland E. Biochem J. 1995; 60:v. Annual General Meeting). The classic concept proposes that tumor cells or myeloid cells in the tumor microenvironment or draining lymph nodes express high levels of indoleamine 2,3-dioxygenase 1 (IDOl) which leads to tumour escape from immunologically mediated rejection. Recently, it has been found that tumor cells and possibly specialized myeloid cells may express and catabolize Trp via TDO instead of or in addition to IDOl. A survey of cancer cell lines indicates that 16% of tumor cell lines are IDOl positive, while 19% are TDO positive and 15% express both TDO and IDOl (Pilotte L et al. Proc Natl Acad Sci USA., 2012; 109:2497-2502). These observations suggest that targeting TDO may complement IDOl inhibition. Thus, TDO may represent an additional target for cancer immunotherapy. Remarkably, IDOl inhibitors available to date do not cross-inhibit TDO and vice-versa, probably due to low sequence homology of these two enzymes despite similar enzymatic properties (Platten M et al., Front Immunol, 2015; 5: Article 673).

Many small molecules like 1 -methyl-tryptophan & its derivatives, natural product derivatives like epigallocatechin gallate, brassilexin, coumaric acid are used in medicament as IDO inhibitor. WO 2007/054348 describes 'Novel Medicaments' and WO 2010/008427 describes 'Tryptophan Catabolism in Cancer Treatment and Diagnosis'. Both these references talks about use of natural product derivatives in the treatment of disorders related to tryptophan catabolism pathway.

Application number WO 2006/122150 describes 'Modulators Of Indoleamine 2,3-

Dioxygenase And Methods Of Using The Same', WO 2014/150677 describes 'Inhibitors Of Indoleamine 2,3-Dioxygenase (IDO)', WO 2014/186035 describes 'Inhibitors Of The Kynurenine Pathway', WO 2014/159248 describes 'Tricyclic Compounds As Inhibitors Of Immunosuppression Mediated By Tryptophan Metabolization' , WO 2012/142237 describes 'Fused Imidazole Derivatives Useful As IDO Inhibitors', WO 2011/056652 describes 'Imidazole Derivatives As IDO Inhibitors', US 2016/0075711 describes 'Compounds For The Inhibition Of Indoleamine-2,3-Dioxygenase', US 5,428,160 describes 'Substituted imidazo[5-a]pyridine derivatives and other substituted bicyclic derivatives', US 6,420,057 describes 'Organic electroluminescent element' and JPH 0971586 describes 'New Bicyclic Condensed Imidazole Derivative'.

Some other additional references which have disclosed Imidazo-quinazolin derivatives. For example WO2012028578 discloses Substituted Fused pyrimidinones and dihydropyrimidinones; WO 2007/028789 discloses Quinazoline derivatives as antiviral agents; US 4,771,051 discloses 3-substituted-4,5-dihydro-5-oxo imidazoquinazolines, their preparation, and their use in treating benzodiazepin receptor-related ailments; US 5,733,905 discloses tricyclic diazepine vasopressin antagonists and oxytocin antagonists; EP 283162 discloses heterocyclic compounds and their preparation and use; US 5,646,154 discloses pharmaceutical compositions for inhibiting the formation of tumor necrosis factor; WO 2012/142237 discloses fused Imidazole derivatives useful as IDO inhibitors; and JP 2010120893 discloses method for producing Imidazole compounds.

The present invention includes novel compounds that are inhibitors of IDO and/or TDO, methods for preparing the novel compounds, pharmaceutical compositions comprising the novel compounds, methods for using the novel compounds and a novel approach to identify promising compounds that can be potential IDO and/or TDO inhibitors. The compounds of the invention herein will help to meet the need to develop potential inhibitors of IDO and/or TDO. Considering the role of IDO & TDO in many clinical manifestations like cancer, acquired immune deficiency syndrome (AIDS), dementia, Alzheimer's disease (AD), schizophrenia, Huntington's disease, amyotrophic lateral sclerosis (ALS), autoimmune disorders like rheumatoid arthritis etc. compounds of the present invention will prove beneficial for the treatment of these diseases.

SUMMARY OF THE INVENTION

Present invention provides indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3- dioxygenase (TDO) inhibitor compounds of the general Formula (I):

Formula (I)

wherein,

R can be hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl , substituted or unsubstituted arylamino or substituted or unsubstituted heteroarylamino; and R can be preferably further substituted by one or more substituents selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted spiro radical, -OR ^A , -SR ^A , -C(0)OR ^A , -C(0)NR ^A R ^B , -C(0)R ^A , -C(S)R ^A , - OC(0)R ^A , -OC(0)NR ^A R ^B , -NR ^A R ^B , -N(R ^A )C(0)R ^B , -N(R ^A )C(S)R ^B , -NR ^A SOR ^B , -NR ^A S0 ₂ R ^B , - N(R ^A )C(0)OR ^B , -N(R ^A )C(0)NR ^B R ^c , -N(R ^A )C(S)NR ^B R ^C , -S(0)R ^A , -S(0) ₂ R ^A , -S(0)NR ^A R ^B or - S(0) ₂ NR ^A R ^B ;

Xi, X ₂ , X ₃ and X ₄ can be independently selected from CR ¹ , CH ₂ or N;

W can be CR ² R ³ ;

n can be an integer 0-6;

Y can be -CO or -CHR ⁴ ;

Z can be -CO, -CHF or -CHOR ² ;

R ^A , R ^B and R ^c can be independently selected from the group consisting of hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstitued heterocycloalkyl, substituted or unsubstitued heteroaryl or substituted or unsubstitued heteroarylalkyl;

R ¹ can be hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted spiro radical, - OR ^A , -SR ^A , -C(0)OR ^A , -C(0)NR ^A R ^B , -C(0)R ^A , -C(S)R ^A , -OC(0)R ^A , -OC(0)NR ^A R ^B , -NR ^A R ^B , - N(R ^A )C(0)R ^B , -N(R ^A )C(S)R ^B , -NR ^A SOR ^B , -NR ^A S0 ₂ R ^B , -N(R ^A )C(0)OR ^B , -N(R ^A )C(0)NR ^B R ^c , - N(R ^A )C(S)NR ^B R ^C , -S(0)R ^A , -S(0) ₂ R ^A , -S(0)NR ^A R ^B or -S(0) ₂ NR ^A R ^B ;

R ² and R ³ can be independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or haloalkyl;

R ⁴ can be hydrogen, Ci-C ₄ alkyl or halogen. Pharmaceutically acceptable salts of the compounds of the Formula (I) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the Formula (I) are also contemplated.

It should be understood that Formula (I) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof, which may be contemplated from the chemical structure of the genus described herein.

Also contemplated are prodrugs of the compounds of the Formula (I), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (1), wherein Y is -CO and -CHR ⁴ , preferably -C(O)- and -CH ₂ .

According to one embodiment, there is provided a compound of formula (1), wherein Z is -C(O)-, -CHOR ² and CHF, preferably -C(O)-, -CHOH, -CHOMe and -CHF.

According to one embodiment, there is provided a compound of formula (1), wherein n is 0-4, preferably 0, 1, and 2.

According to one embodiment, there is provided a compound of formula (1), wherein Xi is CR ¹ , preferably =CH-.

According to one embodiment, there is provided a compound of formula (1), wherein X ₂ is CR ¹ , preferably =CH-.

According to one embodiment, there is provided a compound of formula (1), wherein X ₃ is CR ¹ , preferably =CH- and =CC1.

According to one embodiment, there is provided a compound of formula (1), wherein X ₄ is CR ¹ , preferably =CH- and =CF.

According to one embodiment, there is provided a compound of formula (1), wherein W is -CH ₂ - and -CH-alkyl, preferably -CH ₂ and -CHMe.

According to one embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylamino, preferably substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridine, substituted or unsubstituted thiophene, substituted or unsubstituted pyrazine, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine and substituted or unsubstituted phenylamine.

According to one embodiment, there is provided a compound of Formula (I), wherein R ¹ is independently hydrogen and halogen, preferably hydrogen, chloro and fluoro.

According to one embodiment, there is provided a compound of Formula (I), wherein R ² is hydrogen and substituted or unsubstituted alkyl, preferably hydrogen and methyl.

According to one embodiment, there is provided a compound of Formula (I), wherein R ³ is hydrogen and substituted or unsubstituted alkyl, preferably hydrogen and methyl.

According to one embodiment, there is provided a compound of Formula (I), wherein R ⁴ is hydrogen.

Another embodiment of the present invention provides indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) inhibitor compounds of the general Formula (IA):

Formula (IA)

wherein,

R can be hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl , substituted or unsubstituted arylamino or substituted or unsubstituted heteroarylamino; and R can be preferably further substituted by one or more substituents selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted spiro radical, -OR ^A , -SR ^A , -C(0)OR ^A , -C(0)NR ^A R ^B , -C(0)R ^A , -C(S)R ^A , - OC(0)R ^A , -OC(0)NR ^A R ^B , -NR ^A R ^B , -N(R ^A )C(0)R ^B , -N(R ^A )C(S)R ^B , -NR ^A SOR ^B , -NR ^A S0 ₂ R ^B , - N(R ^A )C(0)OR ^B , -N(R ^A )C(0)NR ^B R ^c , -N(R ^A )C(S)NR ^B R ^C , -S(0)R ^A , -S(0) ₂ R ^A , -S(0)NR ^A R ^B or - S(0) ₂ NR ^A R ^B ;

Xi, X ₂ , X ₃ and X ₄ can be independently selected from CH ₂ or NH;

W can be CR ² R ³ ;

n can be an integer 0-6;

Y can be -CO or -CHR ⁴ ;

Z can be -CO, -CHF or -CHOR ² ;

R ^A , R ^B and R ^c can be independently selected from the group consisting of hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstitued heterocycloalkyl, substituted or unsubstitued heteroaryl or substituted or unsubstitued heteroarylalkyl;

R ² and R ³ can be independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or haloalkyl;

R ⁴ can be hydrogen, Ci-C ₄ alkyl or halogen.

Pharmaceutically acceptable salts of the compounds of the Formula (IA) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the Formula (IA) are contemplated.

It should be understood that Formula (IA) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof, which may be contemplated from the chemical structure of the genus described herein. Also contemplated are prodrugs of the compounds of the Formula (IA), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (1A), wherein Y is -CO and -CHR ⁴ , preferably -C(O)-.

According to one embodiment, there is provided a compound of formula (1A), wherein Z is -C(O)-, and -CHOR ² preferably -C(O)- and -CHOH.

According to one embodiment, there is provided a compound of formula (1A), wherein n is 0-4, preferably 1 and 2.

According to one embodiment, there is provided a compound of formula (1A), wherein Xi is -CH2-.

According to one embodiment, there is provided a compound of formula (1A), wherein X ₂ is -CH2-.

According to one embodiment, there is provided a compound of formula (1A), wherein X ₃ is -CH2-.

According to one embodiment, there is provided a compound of formula (1A), wherein

X ₄ is -CH ₂ - .

According to one embodiment, there is provided a compound of formula (1A), wherein W is -CH ₂ -.

According to one embodiment, there is provided a compound of formula (1A), wherein R is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, preferably substituted or unsubstituted phenyl, and substituted or unsubstituted cyclohexyl.

According to one embodiment, there is provided a compound of Formula (IA), wherein R ² is hydrogen.

In another embodiment, the compounds of the present invention have human IDO IC50 values >500 nM.

In another embodiment, the compounds of the invention have human IDO IC50 values < 500 nM.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from either ChemDraw Professional 15.0 version or ISISDraw 2.4 version): 4-(2-Oxo-2-phenyl-ethyl)-4H-imidazo[l,5-a]quinazolin-5-one (Compound 1);

4-(2-Hydroxy-2-phenyl-ethyl)-4H-imidazo[l,5-a]quinazolin-5-o ne (Compound 2);

2-(5H-Imidazo[l,5-a]quinazolin-4-yl)-l-phenyl-ethanol (Compound 3);

4-(2-Cyclohexyl-2-oxo-ethyl)-4H-imidazo[l,5-a]quinazolin-5-o ne (Compound 4);

4-(2-Cyclohexyl-2-hydroxy-ethyl)-4H-imidazo[l,5-a]quinazolin -5-one (Compound 5);

4-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound 6); 4-[2-(4-Fluoro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one

(Compound 7);

4-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound 8); 4-[2-(4-Chloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a]qui nazolin -5-one

(Compound 9);

4-[2-(5-Oxo-5H-imidazo [l,5-a]quinazolin-4-yl)-acetyl]-enzonitrile (Compound 10); 4-[l-Hydroxy-2-(5-oxo-5H-imidazo[l, 5-a] quinazolin-4-yl)-ethyl]-benzonitrile (Compound 11);

4-[2-(2-Chloro-phenyl)-2-oxo-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound

12);

4- [2-(2-Chloro-phenyl)-2-hydroxy-ethyl] -4H-imidazo [ 1 , 5-a]quinazolin-5 -one

(Compound 13);

4- [2-(4-Bromo-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 ,5 -a] quinazolin-5 -one (Compound 14);

4-[2-(4-Bromo-phenyl)-2-hydroxy-eth yl]-4H-imidazo[l,5-a]quinazolin-5-one (Compound 15);

4-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound

16);

4- [2-Hydroxy-2-(4-methoxy-phenyl)-ethyl] -4H-imidazo[ 1 ,5 -a] quinazolin-5 -one

(Compound 17);

4- [2-(3-Chloro-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 ,5 -a] quinazolin-5 -one (Compound

18);

4-[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one

(Compound 19);

4-(2-Oxo-2-pyridin-3-yl-ethyl)-4H-imidazo[l,5-a]quinazolin-5 -one (Compound 20); 4-(2-Hydroxy-2-pyridin-3-yl-ethyl)-4H-imidazo [l,5-a]quinazolin-5-one (Compound 21); 4- [2-(2- Amino-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 ,5 -a] quinazolin-5 -one (Compound

22);

4-(2-Oxo-2-thiophen-3-yl-ethyl)-4H-imidazo [l,5-a]quinazolin-5-one (Compound 23); 4-(2-Hydroxy-2-thiophen-3-yl-ethyl)-4H-imidazo[l,5-a]quinazo lin-5-one (Compound

24);

4-[2-(3-Chloro-phenyl)-2-methoxy-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one

(Compound 25);

4-[2-(2-Chloro-phenyl)-2-oxo-ethyl]-6-fluoro-4H-imidazo[l,5- a]quinazolin-5-one (Compound 26);

4-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-6-fluoro-4H-imidazo[l,5- a]quinazolin-5-one (Compound 27);

4-[2-(3-Chloro-4-fluoro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5- a] quinazolin-5-one (Compound 28);

4-[2-Oxo-2-(4-phenylacetyl-piperazin-l-yl)-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound 29);

4-(2-Biphenyl-4-yl-2-oxo-ethyl)-4H-imidazo [l,5-a]quinazolin-5-one (Compound 30); 4- [2-(2,5 -Dimethoxy-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 , 5-a]quinazolin-5 -one

(Compound 31);

4-[2-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-ethyl]-4H-imidaz o[l,5-a]quinazolin-5-one (Compound 32);

4-[2-(2,5-Dimethoxy-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5- a] quinazolin-5-one (Compound 33);

4- [2-(3 ,4-Difluoro-phenyl)-2-oxo-ethyl] -4H-imidazo[ 1 ,5 -a] quinazolin-5-one (Compound

34);

4- [2-(3 ,4-Difluoro-phenyl)-2-hydroxy-ethyl] -4H-imidazo[ 1 ,5 -a]quinazolin-5 -one (Compound 35);

4-[2-(2,5-Dichloro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

36);

4-[2-(2,5-Dichloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a ]quinazolin-5-one (Compound 37); 4-[2-(2,5-Difluoro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

38);

4-[2-(2,5-Difluoro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a ]quinazolin-5-one (Compound 39);

4-[2-(2,4-Difluoro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

40);

4- [2-(3-Chloro-4-fluoro-phenyl)-2-hydroxy-ethyl] -4H-imidazo [ 1 , 5-a] quinazolin-5 -one (Compound 41);

4-[2-(2,4-Difluoro-phenyl)-2-hydrox y-ethyl]-4H-imidazo[l,5-a]quinazolin-5-one (Compound 42);

4-(2-Benzo[l,3]dioxol-5-yl-2-hydroxy-ethyl)-4H-imidazo[l,5-a ]quinazolin-5-one (Compound 43);

4-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]quinazo lin-5-one (Compound

44);

4-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one

(Compound 45);

4-(2-Benzo[l,3]dioxol-5-yl-2-oxo-ethyl)-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

46);

4-[2-(2-Benzyloxy-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]quin azolin-5-one (Compound 47);

4-[2-(3-Benzyloxy-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]quin azolin-5-one (Compound

48) ;

4-[2-(3,5-Dichloro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

49) ;

4-[2-(2,3-Dichloro-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]qui nazolin-5-one (Compound

50) ;

4-(2-Naphthalen- 1 -yl-2-oxo-ethyl)-4H-imidazo [l,5-a]quinazolin-5-one (Compound 51); 4-[2-(2,3-Dichloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a ]quinazolin-5-one (Compound 52);

4-[2-(3-Benzyloxy-phenyl)-2-hydroxy-ethyl] -4H-imidazo[l,5-a]quinazolin-5-one

(Compound 53); 4-(2-Hydroxy-2-naphthalen- 1 -yl-ethyl)-4H-imidazo[ 1 ,5-a]quinazolin-5-one (Compound

54);

4-[2-(3,5-Dichloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a ]quinazolin-5-one (Compound 55);

4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin -4-yl)-acetyl] -benzoic acid methyl ester

(Compound 56);

4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethyl]-4H-imidazo[l,5- a]quinazolin-5-one (Compound 57);

4- [2-(4- Amino-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 ,5 -a] quinazolin-5 -one (Compound 58);

l-(2-Chloro-phenyl)-2-(5H-imidazo[l,5-a] quinazolin-4-yl)-ethanol (Compound 59);

4- [2-(2-Bromo-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 ,5 -a] quinazolin-5 -one (Compound

60);

4- [2-(2,6-Dichloro-3 -fluoro-phenyl)-2-oxo-ethyl] -4H-imidazo [ 1 , 5-a] quinazolin-5 -one (Compound 61);

l-(4-Fluoro-phenyl)-2-(5H-imidazo[l,5-a] quinazolin-4-yl)-ethanol (Compound 62); 4-[2-(4-Benzyloxy-phenyl)-2-oxo-ethyl]-4H-imidazo[l,5-a]quin azolin-5-one (Compound

63);

N-Benzyl-4-[2-(5-oxo-5H-imidazo[l,5-a] quinazolin-4-yl)-acetyl]-benzamide (Compound 64);

4-Methyl-N- { 4-[2-(5-oxo-5H-imidazo[ 1 ,5-a]quinazolin-4-yl)-acetyl] -phenyl } - benzenesulfonamide (Compound 65);

4-(2-Naphthalen-2-yl-2-oxo-ethyl)-4H-imidazo [l,5-a]quinazolin-5-one (Compound 66); l-(2-Chloro-phenyl)-2-(5H-imidazo[l,5-a] quinazolin-4-yl)-ethanone (Compound 67); 4-[2-(2,3-Dichloro-4-methoxy-phenyl)-2-oxo-ethyl]-4H-imidazo [l,5-a]quinazolin-5-one (Compound 68);

N-{4-[3-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-propionyl]- phenyljmethanesulfonamide (Compound 69);

N-{4-[3-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-propionyl]- phenyl}-acetamide (Compound 70);

4-(2-morpholino-2-oxoethyl)imidazo[l,5-a]quinazolin-5(4H)-on e (Compound 71); 4-(l-oxo-l-phenylpropan-2-yl)imidazo[l,5-a]quinazolin-5(4H)- one (Compound 72); 4-(l-hydroxy-l-phenylpropan-2-yl)imidazo[l,5-a]quinazolin-5( 4H)-one (Compound 73); 4-(2-oxo-2-(pyrazin-2-yl)ethyl)imidazo[l,5-a]quinazolin-5(4H )-one (Compound 74); (N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)phen yl)benzenesulfonamide) (Compound 75);

N-(3-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)benzenesulfonamide (Compound 76);

N-isobutyl-4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acet yl)benzenesulfonamide (Compound 77);

N-benzyl-4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl )benzenesulfonamide (Compound 78);

4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)-N-(p-to lyl)benzenesulfonamide (Compound 79);

l-(4-Fluoro-phenyl)-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- urea (Compound 80);

l-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-3-phenyl-urea (Compound 81);

l-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-3-p-tolyl-urea (Compound 82);

l-(4-Isopropyl-phenyl)-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quina zolin-4-yl)-acetyl]- phenyl}-urea (Compound 83);

3-butyl- 1 -(butylcarbamoyl)- 1 -(4-(2-(5-oxoimidazo[ 1 ,5-a]quinazolin-4(5H)- yl)acetyl)phenyl)urea (Compound 84);

l-(4-Methoxy-phenyl)-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazo lin-4-yl)-acetyl]- phenyl}-urea (Compound 85);

l-Benzyl-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-ac etyl]-phenyl}-urea (Compound 86);

l-Cyclohexyl-3- { 4-[2-(5-oxo-5H-imidazo[ 1 ,5-a]quinazolin-4-yl)-acetyl] -phenyl } -urea (Compound 87);

l-(2-Fluoro-phenyl)-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- urea (Compound 88); l-(2-Fluoro-phenyl)-3-{3-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- urea (Compound 89);

1- (4-(l-hydroxy-2-(imidazo[l,5-a]quinazolin-4(5H)-yl)ethyl)phe nyl)-3-phenylurea (Compound 90);

l-(3-chloro-4-fluorophenyl)-3-(4-(2-(5-oxoimidazo[l,5-a]quin azolin-4(5H)- yl)acetyl)phenyl)urea (Compound 91);

2- (2,5-Difluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinaz olin-4-yl)-acetyl]- phenyl} -acetamide (Compound 92);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-benzamide

(Compound 93);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-phenyl-acetamide (Compound 94);

N-{4-[l-Hydroxy-2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-e thyl]-phenyl}-2-phenyl- acetamide (Compound 95);

N-{3-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-phenyl-acetamide (Compound 96);

N-{2-Chloro-4-[2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-ac etyl]-phenyl}-2-phenyl- acetamide (Compound 97);

N-{4-[2-(7-Chloro-5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-ac etyl]-phenyl}-2-phenyl- acetamide (Compound 98);

N- { 2-Fluoro-4- [2-(5 -oxo-5H-imidazo [ 1 , 5-a] quinazolin-4-yl)-acetyl] -phenyl } -2-phenyl- acetamide (Compound 99);

N- { 2-Diisobutylamino-5-[2-(5-oxo-5H-imidazo[ 1 ,5-a]quinazolin-4-yl)-acetyl] -phenyl } - 2-phenyl-acetamide (Compound 100);

2-(2-Fluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- acetamide (Compound 101);

N- { 4- [2-(6-Fluoro-5 -oxo-5H-imidazo [ 1 , 5-a] quinazolin-4-yl)-acetyl] -phenyl } -2-phenyl- acetamide (Compound 102);

N-{3-Chloro-4-[2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-ac etyl]-phenyl}-2-phenyl- acetamide (Compound 103); N- { 2-Isobutoxy-5-[2-(5-oxo-5H-imidazo[ 1 ,5-a]quinazolin-4-yl)-acetyl] -phenyl } -2- phenyl-acetamide (Compound 104);

N-{3-Chloro-4-[2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-ac etyl]-phenyl}-2-(2- fluoro-phenyl)-acetamide (Compound 105);

N- { 2-Fluoro-4- [2-(5 -oxo-5H-imidazo [ 1 , 5-a] quinazolin-4-yl)-acetyl] -phenyl } -2-(2- fluoro-phenyl)-acetamide (Compound 106);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-m-tolyl-acetamide (Compound 107);

2-(3-Chloro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- acetamide (Compound 108);

2-(2,4-Dichloro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quin azolin-4-yl)-acetyl]- phenyl} -acetamide (Compound 109);

N-{4-[3-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-propionyl]- phenyl}-2-phenyl- acetamide (Compound 110);

N-{4-[3-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-propionyl]- phenyl}-benzamide (Compound 111);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-o-tolyl-acetamide (Compound 112);

2-({4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-ph enylcarbamoyl}-methyl)- benzoicacidmethylester (Compound 113);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-(tetrahydro-pyran- 4-yl)-acetamide (Compound 114);

2-(2-Chloro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- acetamide (Compound 115);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-p-tolyl-acetamide (Compound 116);

2-Propyl-pentanoicacid { 4- [2-(5-oxo-5H-imidazo [ 1 ,5 -a] quinazolin-4-yl)-acetyl] -phenyl } - amide (Compound 117);

2-(4-Chloro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- acetamide (Compound 118); 2-(3-Fluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)-acetyl]-phenyl}- acetamide (Compound 119);

5-Methyl-isoxazole-4-carboxylicacid{4-[2-(5-oxo-5H-imidazo[l ,5-a]quinazolin-4-yl)- acetyl] -phenyl} -amide (Compound 120);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-(3- trifluoromethyl-phenyl)-acetamide (Compound 121);

2-(3,4-Dichloro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quin azolin-4-yl)-acetyl]- phenylj-acetamide (Compound 122);

2-(3-Chloro-4-fluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a ]quinazolin-4-yl)-acetyl]- phenyl }-acetamide (Compound 123);

2-Cyclopropyl-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazolin-4-y l)-acetyl]-phenyl}- acetamide (Compound 124);

N-Methyl-N- { 4- [2-(5 -oxo-5H-imidazo [ 1 ,5 -a] quinazolin-4-yl)-acetyl] -phenyl } -2-phenyl- acetamide (Compound 125);

N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin-4-yl)-acetyl]-phe nyl}-2-pyridin-3-yl- acetamide (Compound 126);

2-Cyclohexyl-N- { 4- [2-(5 -oxo-5H-imidazo[ 1 ,5 -a] quinazolin-4-yl)-acetyl] -phenyl } - acetamide (Compound 127);

4-(2-(4-(dimethylamino)phenyl)-2-oxoethyl)imidazo[l,5-a]quin azolin-5(4H)-one (Compound 128);

2-fluoro-N-(3-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)ace tyl)phenyl)benzamide (Compound 129);

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)nicotinamide

(Compound 130);

2-(2-fluorophenyl)-N-(3-(2-(5-oxoimidazo[l,5-a]quinazolin-4( 5H)- yl)acetyl)phenyl)acetamide (Compound 131);

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)-2-(2- (trifluoromethyl)phenyl)acetamide (Compound 132);

N-(3-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)nicotinamide

(Compound 133); 2-cyclohexyl-N-(3-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl )acetyl)phenyl)acetamide (Compound 134);

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)propionamide

(Compound 135);

4-(2-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)imidazo[ l,5-a]quinazolin-5(4H)-one (Compound 136);

4-(2-oxo-2-(4-(piperidin-l-yl)phenyl)ethyl)imidazo[l,5-a]qui nazolin-5(4H)-one

(Compound 137);

2-fluoro-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)ace tyl)phenyl)benzamide (Compound 138);

4-(2-oxo-2-phenylethyl)-6,7,8,9-tetrahydroimidazo[l,5-a]quin azolin-5(4H)-one

(Compound 139);

N-(4-(2-(5-oxo-6,7,8,9-tetrahydroimidazo[l,5-a]quinazolin-4( 5H)-yl)acetyl)phenyl)-2- phenylacetamide (Compound 140);

4-(2-(l-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-2-oxoethyl )imidazo[l,5-a]quinazolin- 5(4H)-one (Compound 141);

4-(2-oxo-2-(l-(2-phenylacetyl)piperidin-4-yl)ethyl)imidazo[l ,5-a]quinazolin-5(4H)-one (Compound 142);

4-(2-hydroxy-2-(l-(2-phenylacetyl)piperidin-4-yl)ethyl)imida zo[l,5-a]quinazolin-5(4H)- one (Compound 143);

N-benzyl-4-methyl-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5 H)- yl)acetyl)phenyl)benzenesulfonamide (Compound 144);

4-(2-(4-(benzylamino)phenyl)-2-oxoethyl)imidazo[l,5-a]quinaz olin-5(4H)-one

(Compound 145);

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)benzy l)benzamide (Compound

146);

4-(2-oxo-2-(piperidin-l-yl)ethyl)imidazo[l,5-a]quinazolin-5( 4H)-one (Compound 147); 2-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)isoindoline-l,3-dione (Compound 148);

2-((4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)phen yl)carbamoyl)benzoicacid (Compound 149); 2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)-N-phenylacetamide (Compound 150);

2-(2-fluorophenyl)-N-(4-(2-(imidazo[l,5-a]quinazolin-4(5H)-y l)-2- oxoethyl)phenyl)acetamide (Compound 151);

1- (imidazo[l,5-a]quinazolin-4(5H)-yl)-2-phenylethan-l-one (Compound 152);

N-(4-(l-fluoro-2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)eth yl)phenyl)-2- phenylacetamide (Compound 153);

4-(2-(3 -chlorophenyl)-2-fluoroethyl)imidazo [ 1 ,5 -a] quinazolin-5 (4H)-one (Compound

154);

2- (2-fluorophenyl)-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H )- yl)acetyl)phenyl)acetamide hydrochloride (Compound 155);

2-(2-fluorophenyl)-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4( 5H)- yl)acetyl)phenyl)acetamide methaneslfonate (Compound 156); or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including hydrates and prodrugs of compounds are also contemplated.

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

The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO).

The present invention further provides a method of treating a disease, condition and/or disorder mediated by an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to treat that condition.

Also provided herein are processes for preparing compounds described herein.

The invention provides a method for preventing, ameliorating or treating a cancer mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) mediated disease, disorder or syndrome is cancer for example but are not limited to a solid or liquid tumour including cancer of the eye, brain (such as gliomas, glioblastomas, medullablastomas, craniopharyngioma, ependymoma, and astrocytoma), colon, parathyroid gland, gall bladder, head and neck, breast, bone, hypopharyngeal gland, lung, bronchus, liver, skin (melanomas), ureter, urethra, urothelium, testicles, vaginal, anus, mouth, lip, throat, oral cavity, nasal cavity, Gastro-intestinal, Gastric stomach, Gastro-intestinal stromal cells, small intestine, laryngeal gland, ovary, thyroid, bile duct, cervix, heart, spinal cord, kidney, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, penile tissue, pancreas, adrenal glands; an epithelial and squamous cell cancers of various tissue types, an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte- Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma (ATLL), juvenile myelomonocytic leukaemia, Hodgkin's lymphoma, classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, and cutaneous T-cell lymphoma),

Barret's adenocarcinoma, cervical cancer, esophageal cancer, ovarian cancer, colo- rectal cancer, prostate cancer, hematologic cancers, cancer of Biliary Tract, blood cancer, large in testinal colon carcinoma, histiocytic lymphoma, lung adenocarcinoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, diffuse large B-cell lymphoma (DLBCL), gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, metastatic carcinomas and plasmocytoma, an inflammatory condition, an infectious disease, Chagas disease, a central nervous system disease or disorder, depression, psychosis, psychiatric disorders, bipolar disorders, anxiety, insomnia, a neurodegenerative disorder, Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, dementia, cognitive disorders, psychotic disorders / cognitive disorder / dementia associated with various neurodegenerative diseases, trauma, age-related cataracts, organ transplant rejection, viral infection, anti -retro viral therapy, treating or preventing HIV/AIDS, chronic HBV, malaria, schizophrenia, HCV, inflammation-associated arthritis or autoimmune arthritis, allergic airways disease, joint inflammation, multiple sclerosis, allergic encephalomyelitis, atherosclerosis, coronary artery disease, kidney disease, sepsis-induced hypotension, pain, chronic pain of inflammatory and neuropathic nature, chemotherapy induced neuropathies, musculo-skeletal pain, General anaesthesia, Cataracts, Endometriosis, Contraception and abortion, coronary heart disease, chronic renal failure, or post anaesthesia cognitive dysfunction, and the like.

An indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in BPS Bioscience, San Diego, CA, USA and some other literature.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel pharmaceutical heterocyclic compounds and related derivatives, which may be used as indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3- dioxygenase (TDO) as anti-cancer compounds and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO), are also provided.

The following definitions apply to the terms as used herein:

The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, examples include but are not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, 1,1- dimethylethyl and the like. The term "alkenyl" refers to aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain radical having 2 to 10 carbon atoms which is attached to the rest of the molecule by a single bond. Examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2- butenyl and the like.

The term "alkynyl" refers to straight or branched chain hydrocarbon radicals having at least one carbon-carbon triple bond, having 2 to 12 carbon which is attached to the rest of the molecule by a single bond. Examples include but are not limited to ethynyl, propynyl and butnyl.

The term "alkoxy" as used herein denotes alkyl group as defined above attached through an oxygen linkage with the main molecule. Examples of alkoxy substituents include but not limited to methoxy, ethoxy, propoxy and the like

The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms. Examples include but are not limited to phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl.

The term "arylalkyl" refers to an aryl ring as defined above directly bonded to an alkyl group as defined above. Examples include but are not limited to -CH2C6H5, and -C2H5C6H5.

The term "aryloxy" as used herein denotes aryl group as defined above attached through an oxygen linkage with the main molecule. Examples of aryloxy substituents include but not limited to phenoxy, biphenyloxy, naphthyloxy and the like.

The term "heteroaryl" as used herein refers to a stable 3 to 15 membered aromatic ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purpose of this invention, the heteroaryl ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heteroaryl ring may be optionally oxidized to various oxidation states. Non-limiting examples include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, lH-indazolyl, 2H- indazolyl, indolizinyl, isobenzofuryl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl groups and the like.

The term "heteroarylalkyl" refers to heteroaryl ring radical as defined above directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.

The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, attached to the main molecule through an oxygen atom. Representative examples of heteroaryloxy include, but are not limited to, fur-3-yloxy, lH-imidazol-2-yloxy, lH-imidazol-4- yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, (6-(trifluoromethyl)pyridin-3- yl)oxy, (6-(cyano)pyridin-3-yl)oxy, (2-(cyano)pyridin-4-yl)oxy, (5-(cyano)pyridin-2-yl)oxy, (2- (chloro)pyridin-4-yl)oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy, and thien-3- yloxy.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 14 carbon atoms attached via a single bond to the rest of the molecule. Examples of monocyclic ring system include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and, cyclohexyl. Examples of multicyclic ring system include but are not limited to perhydronapthtliyl, adamantyl and norbornyl groups bridged cyclic group or spirobicyclic groups e.g. spiro (4,4) non-2 -yl.

The term "cycloalkenyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with at least one carbon- carbon double bond. Examples include but are not limited to cyclopropenyl, cyclobutenyl and cyclopentenyl.

The term "cycloalkylalkyl" refers to cyclic ring-containing radical containing 3 to about 8 carbon atoms directly attached to alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure. Examples include but are not limited to cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl.

The term "heterocycloalkyl" as used herein refers to a stable 3- to 15 membered saturated non-aromatic ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purpose of this invention, the heterocycloalkyl ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocycloalkyl ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized. Examples of heterocycloalkyl ring systems include but not limited to oxetan, tetrahydrofuran, tetrahydropyran or oxepane, dioxane, azetidine, pyrrolidine, piperidine, hexahydroazepine, hexahydrodiazepine, tetrahydrothiophene, thietan, tetrahydrothiopyran, thiepan, morpholine as well as bridged heterocycloalkyl systems such as oxabicyclo[4.4.0]decane and azabicyclo[2,2, l]undecane.

The term "heterocyclolalkylalkyl" as used herein refers to a heterocyloalkyl ring as defined above attached to alkyl group. The heterocyclolalkylalkyl radical may be bonded to the main structure at any carbon atom in the alkyl group.

The term "arylamino" refers to an aryl ring as defined above attached via amino group to the rest of the molecule. Examples include but are not limited to -NHC ₆ H5. For the purpose of this invention only one or both the hydrogen atoms of amino group can be substituted by aryl group.

The term "heteroarylamino" refers to heteroaryl ring as defined above attached via amino group to the rest of the molecule. Examples include but are not limited to -NH-furan, -NH- lH-imidazole, -NH-pyridine. For the purpose of this invention only one or both the hydrogen atoms of amino group can be substituted by heteroaryl group.

The term "halogen" as used herein refers to fluorine, chlorine, bromine, iodine.

The term "haloalkyl" as used herein refers to alkyl radical having one or more hydrogen atoms replaced by a halogen atom. Non-limiting examples include chloromethyl, fluoroethyl, chloroethyl, difluoromethyl, dichloromethyl, trifluoromethyl and the like.

The substituents in the 'substituted alkyl', 'substituted alkenyl', 'substituted alkynyl', 'substituted cycloalkyl', 'substituted cycloalkylalkyl', 'substituted cyclocalkenyl', 'substituted arylalkyl', 'substituted aryl', 'substituted aryloxy', 'substituted heteroaryl', 'substituted heteroaryloxy', 'substituted heteroarylalkyl', 'substituted heterocycloalkyl', 'substituted heterocycloalkylalkyl', 'substituted spiro' may be the same or different which one or more selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=0), thio (=S), or optionally substituted groups selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclic ring, -COOR ^A , - C(0)R ^A , -C(S)R ^A , -C(0)NR ^A R ^B , -NR ^A CONR ^B R ^c , -N(R ^A )SOR ^B , -N(R ^A )S02R ^B , -(=N- N(R ^A )R ^B ), - NR ^A C(0)OR ^B , -NR ^A R ^B , -NR ^A C(0)R ^B , -NR ^A C(S)R ^B , -NR ^A C(S)NR ^B R ^C , - SONR ^A R ^B -, -S02NR ^A R ^B , -OR ^A , - OR ^A C(0)NR ^B R ^c , -OR ^A C(0)OR ^B -, -OC(0)R ^A , - OC(0)NR ^A R ^B , -R ^A NR ^B R ^C , -R ^A R ^B R ^C , -R ^A CF ₃ , -R ^A NR ^B C(0)R ^c , -R ^A OR ^B , -R ^A C(0)OR ^B , - R ^A C(0)NR ^B R ^c , -R ^A C(0)R ^A , - R ^A OC(0)R ^B , -SR ^A , -SOR ^A , -S0 ₂ R ^A , -ONO2, (wherein R ^A , R ^B and R ^c in each of the above groups can be hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstitued heterocyclic ring, substituted or unsubstitued heterocyclylalkyl, substituted or unsubstitued heteroaryl or substituted or unsubstitued heteroarylalkyl ).

"Pharmaceutically acceptable salts" as used herein refers to acid addition salts and salts derived from inorganic or organic bases. Non-limiting examples of acid addition salts include acetates, ascorbates, benzenesulfonates, benzoates, borates, citrates, glycerophosphates, hydrohalides, ketoglutarates, maleates, methanesulphonates, nitrates, palmoates, perchlorates, phosphates, salicylates, succinates, sulphates, tartrates, trifluroacetate and the like. Examples of inorganic base salt include salts derived from Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn etc. Examples of organic base salt includes salts derived from benzyl amine, choline, choline hydroxide, dicyclohexyl amine, glucamine, metformin, Ν,Ν'-diacetylethylenediamine, spermidine, thiamine, trialkyl amine, triethyl amine and the like; chiral bases like alkylphenyl amine, glycinol, phenyl glycinol and the like; alkyl halides such as methyl halide, ethyl halide and the like. Aryl alkyl halide such as benzyl halide and the like; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, histidine, lysine, arginine, serine and the like; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts.

The term "prodrug" means a compound that is transformed in vivo to yield a compound of Formula (I), (IA) or a pharmaceutically acceptable salt, hydrate or solvate, or metabolite of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "treating" or "treatment" of a state, disease, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;

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

(3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.

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

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

The compounds of the present invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (I) and (IA), the present invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present invention may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

PHARMACEUTICAL COMPOSITIONS

The present invention provides pharmaceutical compositions which includes at least one compound described herein and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient for the purpose of this invention includes but not limited to diluents or carrier, binder, bulking agent. Preferably, the contemplated pharmaceutical compositions include a compound(s) described herein in therapeutically effective amount sufficient to treat conditions related to an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) in a subject. The subjects contemplated include, for example, a living cell and a mammal, including human.

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

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

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

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

The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions, liquids, gels, or products for topical application.

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

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

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

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

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

METHODS OF TREATMENT

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO).

The present invention further provides a method of treating a disease, condition and/or disorder mediated by an indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. Diseases, conditions, and/or disorders that are mediated by an indoleamine 2,3- dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) are believed to include, but are not limited to a solid or liquid tumour including cancer of the eye, brain (such as gliomas, glioblastomas, medullablastomas, craniopharyngioma, ependymoma, and astrocytoma), colon, parathyroid gland, gall bladder, head and neck, breast, bone, hypopharyngeal gland, lung, bronchus, liver, skin (melanomas), ureter, urethra, urothelium, testicles, vaginal, anus, mouth, lip, throat, oral cavity, nasal cavity, Gastro-intestinal, Gastric stomach, Gastro-intestinal stromal cells, small intestine, laryngeal gland, ovary, thyroid, bile duct, cervix, heart, spinal cord, kidney, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, penile tissue, pancreas, adrenal glands; an epithelial and squamous cell cancers of various tissue types, an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte- Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma (ATLL), juvenile myelomonocytic leukaemia, Hodgkin's lymphoma, classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, and cutaneous T-cell lymphoma),

Barret's adenocarcinoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, hematologic cancers, cancer of Biliary Tract, blood cancer, large in testinal colon carcinoma, histiocytic lymphoma, lung adenocarcinoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, diffuse large B-cell lymphoma (DLBCL), gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, metastatic carcinomas and plasmocytoma, an inflammatory condition, an infectious disease, Chagas disease, a central nervous system disease or disorder, depression, psychosis, psychiatric disorders, bipolar disorders, a neurodegenerative disorder, Parkinson's disease (PD), Alzheimer's disease, stroke, amyotrophic lateral sclerosis, dementia, cognitive disorders, psychotic disorders / cognitive disorder / dementia associated with various neurodegenerative diseases, insomnia, trauma, age-related cataracts, organ transplant rejection, viral infection, anti -retroviral therapy, treating or preventing HIV/ AIDS, chronic HBV, malaria, schizophrenia, HCV, inflammation- associated arthritis or autoimmune arthritis, allergic airways disease, joint inflammation, multiple sclerosis, allergic encephalomyelitis, atherosclerosis, coronary artery disease, kidney disease, sepsis-induced hypotension, Psychiatric disorders and pain, chronic pain, General anaesthesia, Cataracts, Endometriosis, Contraception and abortion, coronary heart disease, chronic renal failure, or post anaesthesia cognitive dysfunction and the like.

The compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when used suitably in combination with the available further agent/drugs. The further agent/drugs for treating cancer is not especially limited, provided that it affords some utility for cancer treatment. However, typically the further agent for treating cancer is selected from anti-hyperproliferative, anticancer, chemotherapeutic agents, radiation therapy, anti-microtubule agents, cell-cycle checkpoint inhibitors, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors or anti-angiogenic agents (VEGF (R), PDGF (R), FGF (R), TGF-beta 1), immunotherapeutic agents, immune check-point inhibitors, proapoptotic agents and cell cycle signaling inhibitors. An immunotherapeutic agent may consist of but is not limited to an anti-tumor vaccine, an oncolytic virus, an immune stimulatory agonist antibodies such as anti-OX40, anti-41BB, anti-CD27, anti-CD28, anti-CD137, anti-GITR (or TNFRSF18), anti-HVEM (or TNFRSF14) and immune inhibitory antagonist antibodies such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-CD40, anti-LAG3, anti-TIM3, anti-BTLA and anti- VISTA, a peptide, a dinucleotide, a cyclic dinucleotide, STING (stimulator of interferon genes) activators/modulators, a novel adjuvant, a cancer vaccine, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, tumor microenvironment modulators, a tumor immunosuppression inhibitor/modulator. Also, any novel combination (synergistic/antagonistic), orthosteric and allosteric modulators wherein the administration dose can be decreased in comparison with administration of either drug alone to improve/synergize therapeutic efficacy or minimize/reduce adverse effects/events of co-administrated anti-cancer drugs.

METHODS OF PREPARATION

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 4. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. Compounds of the present invention can be synthesized from naturally occurring sources too. Key intermediates required for synthesizing analogues are either commercially available or can be prepared by the methods published in the literature.

Scheme 1

Formula (I) The compounds of Formula (I) (W, Xi, X ₂ , X3, ¾, Y, Z, n and R can be same as defined above and PG can be suitable protecting group and LG can be suitable leaving group) can be synthesized as described in the above scheme 1. The amine compounds of formula (1) can be coupled with the NH protected acid of formula (2) in the presence of amide coupling reagent, suitable base & solvent to get amide compounds of formula (3). The amide coupling reagent used herein include but are not limited to Dicyclohexylcarbodiimide (DCC), (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 0-(7-Azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), isobutyl chloroformate, isopropyl chloroformate or the like. The base used for coupling can be organic or inorganic base known in the art. Preferebelly amine bases are used which include but are not limited to triethylamine, diisopropylethylamine, N-methylmorpholine (NMM) or the like. Solvents used herein include but are not limited to polar solvents like DMF, NMP or the like; non-polar solvents like DCM, toluene or the like; or other solvents such as THF, ethyl acetate or the like. The protecting agents used for protection of amine group in compounds (2) can include but are not is not limited to feri-butyloxycarbonyl protecting group (BOC), Fluorenylmethyloxycarbonyl (Fmoc), Carbobenzyloxy (Cbz), Benzoyl (Bz), Benzyl (Bn) or the like. Compounds of formula (4) can be obtained by the cyclization of amide of formula (3) in the presence of suitable base & solvent. The base used herein includes both organic and inorganic bases known in the art. Examples of organic bases include but not limited to Organolithiums such as n-BuLi, tert-BuLi etc, Amines such as Dabco, Triethylamine, DIPEA or the like, Metal alkoxides such as Sodium tert-butoxide, Lithium tert-butoxide or the like. Examples of inorganic bases include but not limited to Potassium hydroxide, Sodium hydroxide, Calcium carbonate, Cesium hydroxide or the like. Solvent used herein include solvents of different categories like polar protic, polar aprotic or non-polar. Examples include but not limited to ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF or the like. Compounds of formula (4) can be converted to formamide compounds of formula (5) using ethyl formate in the presence of reagents such as trifluoroacetic acid, hydrochloric acid or the like using suitable base & solvent. The base used herein includes both organic and inorganic bases known in the art. Examples of organic bases include but not limited to Organolithiums such as n-BuLi, tert-BuLi etc, Amines such as Dabco, Triethylamine, DIPEA etc., Metal alkoxides such as Sodium teri-butoxide, Lithium tert-butoxide etc. Examples of inorganic bases include but not limited to Potassium hydroxide, Sodium hydroxide, Calcium carbonate, Cesium hydroxide etc. Preferebelly amine bases are used which include but are not limited to triethylamine, diisopropylethylamine, N- methylmorpholine (NMM) or the like. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar. Preferebelly halogenated solvents are used which include but are not limited to chloroform, chlorobenzene , trichloroethylene, carbon tetrachloride, dichloromethane or the like. The formamide compounds of formula (5) can be further cyclized to fuzed imidazole compounds of formula (6) in presence of cyclization reagent such as phosphoric acid, Eaton's reagent (7.7 wt% phosphorus pentoxide solution in methanesulfonic acid) or the like in a suitable solvent. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The final compounds of the formula (8) can be prepared through couling of fuzed imidazole compounds of formula (6) with compounds of formula (7) in presence of suitable base and solvent. The base used herein includes both organic and inorganic bases known in the art. Examples of organic bases include but not limited to Organolithiums such as n-BuLi, tert-BuLi etc, Amines such as Dabco, Triethylamine, DIPEA etc., Metal alkoxides such as Sodium feri-butoxide, Lithium tert- butoxide etc. Examples of inorganic bases include but not limited to Potassium hydroxide, Sodium hydroxide, Calcium carbonate, Cesium hydroxide etc. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The other final compounds of Formula (I) of the invention can be prepared by subsequent reduction of compound of formula (8) with suitable reducing agent. Examples of suitable reducing agent includes but are not limited to NaBH ₄ , Lithium Aluminium Hydride (LAH), DIBAL-H or the like. Scheme 2

(9) (10) (11)

wherein R =

^■ "N ^A NR ¹

The intermediate compounds of urea-Formula (7) (wherein, R ^A , R ^B , LG, W and n are same as defined above and Ring A can be substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl) can be synthesized as described in the above scheme 2. The amine compound of formula (9) can be coupled with isocynate of formula (10) in suitable solvent to get urea of formula (11). Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The terminal alkyl hydrogen of urea (11) can be replaced with suitable leaving group such as bromide, chloride or the like using reagent such as bromine in acetic acid, chlorine in acetic acid or the like to get intermediate compounds of urea-Formula (7).

Scheme 3

The intermediate compounds of reverse amide-Formula (7) (wherein, R ^A , LG, W, n and Ring A are same as defined above) can be synthesized as described in the above scheme 3. The amine compound of formula (12) can be coupled with acid of formula (13) using coupling reagent such as T ₃ P (Propylphosphonic Anhydride) or the like in presence of suitable base & solvent to get amide of formula (14). The base used herein includes both organic and inorganic bases known in the art. Examples of organic bases include but not limited to Organolithiums such as n-BuLi, tert-BuLi etc, Amines such as Dabco, Triethylamine, DIPEA etc., Metal alkoxides such as Sodium tert-butoxide, Lithium tert-butoxide etc. Examples of inorganic bases include but not limited to Potassium hydroxide, Sodium hydroxide, Calcium carbonate, Cesium hydroxide etc. Preferebelly amine bases are used which include but are not limited to triethylamine, diisopropylethylamine, N-methylmorpholine (NMM) or the like. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The terminal alkyl hydrogen of amide (14) can be replaced with suitable leaving group such as bromide, chloride or the like with using reagent such as bromine in acetic acid, chlorine in acetic acid or the the like to get intermediate compounds of reverse amide-formula (7).

Scheme 4

Formula (IA) < ^1B > The compounds of Formula (IA) (W, Xi, X ₂ , X ₃ , X4, Y, Z, n and R can be same as defined above and LG can be suitable leaving group) can be synthesized as described in the above scheme 4. The amine compounds of formula (15) can be converted to the formamide compounds of formula (16) using suitable formylating agents such as chloral, formic acid, formaldehyde or the like in suitable solvent. Solvents used herein include but are not limited to non-polar solvents like DCM, toluene, chloroform or the like; polar solvents like Acetonitrile, DMF, NMP or the like; or other solvents such as THF, ethyl acetate or the like. The formamide compounds of formula (16) can be cyclized to fuzed imidazole compounds of formula (17) in presence of cyclization reagent such as phosphoric acid, Eaton's reagent (7.7 wt% phosphorus pentoxide solution in methanesulfonic acid) or the like in a suitable solvent. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The final compounds of the formula (18) can be prepared through couling of fuzed imidazole compounds of formula (17) with compounds of formula (7) in presence of suitable base and solvent. The base used herein includes both organic and inorganic bases known in the art. Examples of organic bases include but not limited to Organolithiums such as n-BuLi, tert-BuLi etc, Amines such as Dabco, Triethylamine, DIPEA etc., Metal alkoxides such as Sodium tert- butoxide, Lithium tert-butoxide etc. Examples of inorganic bases include but not limited to Potassium hydroxide, Sodium hydroxide, Calcium carbonate, Cesium hydroxide etc. Suitable solvents used herein include solvents of different categories like polar protic, polar aprotic or non-polar such as ethanol, methanol, DMF, DMSO, 1,4-dioxane, chloroform, diethyl ether, acetone, acetonitrile, THF, xylene, toluene, chloroform, carbon tetrachloride, dichloromethane or the like. The other final compounds of Formula (IA) of the invention can be prepared by subsequent reduction of compounds of formula (18) with suitable reducing agent. Examples of suitable reducing agent include but are not limited to NaBH ₄ , Lithium Aluminium Hydride (LAH), DIBAL-H or the like.

The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Abbreviations as used herein, are defined as follows:

AcOH : Acetic Acid

AD : Alzheimer's Disease

AIDS : Acquired Immune Deficiency Syndrome

ALL : Acute Lymphatic Leukemia

ALS : Amyotrophic Lateral Sclerosis

AML : Acute Myeloid Leukemia

BOC: tert-butyloxycarbonyl BOP: (Benzotriazol - 1 -yloxy) tri s( dimethylamino)phosphonium hex afluorophosphate

Cbz: Carbobenzyloxy

CC14 : Carbon Tetrachloride

CHC13 : Trichloromethane or Chloroform

CLL : Chronic Lymphatic Leukemia

CML : Chronic Myeloid Leukemia

DCC: Dicyclohexylcarbodiimide

DCM/MDC : Dichloromethane

DIBAL-H : Diisobutylaluminium Hydride

DIPEA : N,N-Diisopropylethylamine

DLBCL : Diffuse Large B-Cell Lymphoma

DM : Demineralised

DMF : Dimethylformamide

DMP : Dess-Martin Periodinane

DMSO: Dimethyl sulfoxide

EtOAc : Ethyl Acetate

EtOH : Ethanol

Fmoc: Fluorenylmethyloxycarbonyl

HATU: 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: 0-(Benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate HC1 : Hydrochloric Acid

HPLC : High Performance Liquid Chromatography

IDO : Indoleamine 2,3-dioxygenase

K2C03 : Potassium Carbonate

KMn04 : Potassium Permanganate

KOAc : Potassium Acetate

KP : Kynurenine Pathway

LAH : Lithium Aluminium Hydride

LCMS : Liquid Chromatography-Mass Spectrometry

MeOH : Methanol

MTBE: Methyl tert-butyl ether Na2C03 : Sodium Carbonate

Na2S04 : Sodium Sulphate

NaBH4 : Sodium Borohydride

NADC : Nicotinamide Dinucleotide

NaH : Sodium Hydride

NaHC03 : Sodium Bicarbonate

n-BuLi : n-Butyllithium

NFK : N-formylkynurenine

NMM: N-methylmorpholine

NMP: N-Methyl-2-pyrrolidone

NMR: Nuclear Magnetic Resonance

NSCLC : Non-Samll-Cell-Lung Cancer

PBr3 : Phosphorus Tribromide

PIP : Piperidine

T3P: Propylphosphonic Anhydride

TBDMSC1 : tert-Butyldimethylsilyl Chloride

TBTU: O-(Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate

TDO : Tryptophan 2,3-dioxygenase

THF : Tetrahydrofuran

TLC : Thin-Layer Chromatography

EXPERIMENTAL

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

EXAMPLES Example 1; Preparation of 4-(2-Oxo-2- henyl-ethyl)-4H-imidazori,5-alquinazolin-5-one:

Step 1: Synthesis of [(2-Carbamoyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester:

N-Boc glycine (15.0 g, 85 mmol) was added to THF (300 ml) and cooled to 0-10 °C, triethyl amine (10.83 g, 0.107 mol) was added and reaction mass was stirred for around 10 to 15 minutes at the same temperature. Isobutyl chloroformate (11.67 g, 0.085 mol) was added and reaction mass was stirred for around 30 to 40 minutes at 0-10 °C. 2-Amino benzamide (17.5 g,.0128 mol) was added and reaction mass was stirred at around 25-35°C for around 16 hours. Reaction mass was quenched with 2N HC1 and extracted with ethyl acetate. Organic layer was washed with water followed by brine and concentrated under reduced pressure. Concentrated mass was triturated to yield [(2-Carbamoyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (12.0 g, 48%).

^X HNMR (DMSO-d6) δ: 11.98 (s, 1H), 8.53 (d, 1H, 8.4 Hz), 8.19 (s, 1H), 7.78 (dd, 1H, = 1.2, 7.6 Hz), 7.59 (br. s, 1H), 7.50-7.42 (m, 2H), 7.13-7.09 (m, 1H), 3.64 (d, 2H, / = 6 Hz), 1.42 (s, 9H).

Step 2: Synthesis of (4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-carbamic acid tert-butyl ester:

[(2-Carbamoyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (step 1, 12 g, 40 mmol) was dissolved in ethanol (60 ml) at room temperature. Aqueous sodium hydroxide solution (11.52 g, 288 mmol) was added and the reaction mixture was stirred at room temperature for around 16 hours. Reaction mixture was quenched with hydrochloric acid and filtered to give crude product, which was washed with water and dried to give (4-Oxo-3,4- dihydro-quinazolin-2-ylmethyl)-carbamic acid tert-butyl ester (10.5 g, 93%).

¾NMR (DMSO-d6) δ: 12.14 (br. s, 1H), 8.09 (d, 1H, = 7.6 Hz), 7.79 (dt, 1H, = 1.2, 8.4 Hz), 7.61 (d, 1H, = 8 Hz), 7.49 (t, 1H, = 7.6 Hz), 7.17 (s, 1H), 4.1 (d, 2H, = 5.6 Hz), 1.40 (s, 9H).

Step 3: Synthesis of N-(4-Oxo-3,4-dihydro- uinazolin-2-ylmethyl)-formamide:

(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-carbamic acid tert-butyl ester (step 2, 11 g, 40 mmol) was suspended in dichloromethane (550 ml) at room temperature. Trifluoroacetic acid (99 ml) was added and the reaction mixture was refluxed for around 5 hours. After completion of reaction, solvents were evaporated under reduced pressure and the residue was cooled to 0-5 °C. To the crude residue was added ethyl formate (396 ml), triethyl amine (82.5 ml) and reaction mixture was refluxed for around 14 hours. Solvents were evaporated under reduced pressure and water was added to crude residue and reaction mixture was filtered. Crude product was purified using MeOH and MTBE to give N-(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-formamide (6 g, 74%).

^X HNMR (DMSO-d6) δ: 11.89 (br. s, 1H), 8.50 (br. s, 1H), 8.17 (s, 1H), 8.09 (d, 1H, = 7.2 Hz), 7.79 (t, 1H, = 7.2 Hz), 7.62 (d, 1H, = 8 Hz), 7.49 (t, 1H, = 7.6 Hz), 4.29 (d, 2H, = 5.6 Hz).

Step 4: Synthesis of 4H-Imidazo[l,5-a]quinazolin-5-one:

To a suspension of N-(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-formamide (step 3, 4 g, 19.7 mmol) in xylene (100 ml) was added polyphospohoric acid (100 g) and the reaction mixture was heated at around 140 °C for around 6 hours. Reaction mixture was cooled to room temperature and xylene layer was decanted. The residue was washed with ethyl acetate, dissolved in water and basified with aqueous sodium hydroxide solution. Precipitated solid was filtered, washed with water and dried to give 4H-Imidazo[l,5-a]quinazolin-5-one (3g, 82%). ¾NMR (DMSO-d6) δ: 11.75 (br. s, 1H), 8.52 (s, 1H), 8.17 (d, 1H, = 8 Hz), 8.12 (dd, 1H, = 1.2, 8 Hz), 7.84 (dt, 1H, = 1.6, 8.8 Hz), 7.49 (dt, 1H, = 0.8, 8 Hz), 6.53 (s, 1H).

Step 5: Synthesis of 4-(2-Oxo-2-phen l-ethyl)-4H-imidazo[l,5-a]quinazolin-5-one:

To a stirred solution of 4H-Imidazo[l,5-a]quinazolin-5-one (step 4, 500 mg, 2.7 mmol) in DMF (10 ml) was added cesium carbonate (1.33 g, 4.05 mmol) and phenacyl chloride (501 mg, 3.24 mmol) at room temperature. Reaction mixture was heated at around 70 °C for around 1 hour. Reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. Organic layer was concentrated under reduced pressure to give crude product which was purified by crystallization in ethyl acetate -hexane to give desired compound (251 mg, 31%).

^NMR (DMSO-d6) δ: 8.66 (s, 1H), 8.27 (d, 1H, = 8 Hz), 8.18-8.11 (m, 3H), 7.95-7.88 (m, 1H), 7.75 (t, 1H, = 8 Hz), 7.62 (t, 2H, = 8 Hz), 7.55 (t, 1 H, = 7.6 Hz), 6.86 (s, 1H), 5.61 (s, 2H); Mass (LCMS): 304.1 (M + 1); Purity: 94.88%.

Example 2: Preparation of 4-(2-Hvdroxy-2-phenyl-ethyl)-4H-imidazo[l,5-alquinazolin-5-o ne:

To a stirred solution of 4-(2-Oxo-2-phenyl-ethyl)-4H-imidazo[l,5-a]quinazolin-5-one (Example 1, 100 mg, 0.33 mmol) in methanol (10 ml) was added sodium borohydride (63 mg, 1.64 mmol) at room temperature. Reaction mixture was stirred at 25-35°C for around 30 minutes and diluted with water. The precipitated solid was filtered, washed with water and triturated to give desired compound. ^X HNMR (DMSO-d6) δ: 8.60 (s, 1H), 8.21-8.16 (m, 2H), 7.89-7.84 (m, 1H), 7.54-7.5 (m, 1H), 7.46 (d, 2H, = 7.2 Hz), 7.35 (t, 2H, = 7.2 Hz), 7.28-7.25 (m, 1H), 6.85 (s, 1H), 5.56 (d, 1H, = 4.6 Hz), 5.11-5.07 (m, 1H), 4.15-4.10 (m, 1H), 4.06-4.01 (m, 1H) ; Mass (LCMS): 306.1 (M + 1); Purity: 95.01%.

Example 3: Preparation of 2-(5H-Imidazo|T,5-al uinazolin-4-yl)-l-phenyl-ethanol:

To a suspension of lithium aluminum hydride (150 mg, 4 mmol) in THF (5 ml) was added solution of 4-(2-Hydroxy-2-phenyl-ethyl)-4H-imidazo[l,5-a]quinazolin-5-o ne (Example 2, 100 mg, 033 mmol) and reaction mixture was refluxed for around 5 hours. Reaction mixture was quenched with sodium sulfate decahydrate, filtered, and filtrate was concentrated to give crude product. Crude product was purified using trituration to give desired compound.

¾NMR (DMSO-d6) δ: 8.04 (s, 1H), 7.58 (br. d, 1H, = 6.8 Hz), 7.47-7.21 (br. m, 8H), 6.2 (s, 1H), 5.49 (s, 1H), 4.97 (br. s, 1H), 4.8 (br. d, 1H, = 12.8 Hz), 4.46 (br. d, 1H, = 12.8 Hz). 3.31-3.20 (m, 2H); Mass (LCMS): 292.1 (M + 1); Purity (TIC in mass): 92.98.%.

Following Example 4-74 & 147 have been synthesized by the above procedures described in Example 1, 2 and 3 with their corresponding intermediates in similar reaction consitions:

^X HNMR (DMSO-d6) δ: 8.59 (s, IH), 8.19 (d,

4-(2-Cyclohexyl-2-hydroxy- IH, = 8.4 Hz), 8.16 (d, 1Η, = 8 Hz), ethyl)-4H-imidazo[l,5- 7.85 (t, IH, = 8 Hz), 7.51 (t, IH, = 7.6 a]quinazolin-5-one Hz), 6.74 (s, IH), 4.69 (br. s, IH), 4.05 (dd,

IH, = 3.2, 13.6 Hz), 3.85 (dd, IH, = °OH 9.2, 13.6 Hz), 3.76-3.71 (m, IH), 1.89-1.86

(m, IH), 1.71-1.61 (m, 4H), 1.39-1.37 (m, IH), 1.24-1.07 (m, 5H); Mass (LCMS): 312.2 (M + 1); Purity : 99.08%.

4-[2-(4-Fluoro-phenyl)-2- oxo-ethyl]-4H-imidazo [1,5- ^X HNMR (DMSO-d6) δ: 8.66 (s, IH), 8.27- a]quinazolin-5-one 8.15 (m, 4H), 7.94-7.90 (m, IH), 7.55 (t, IH,

= 7.6 Hz), 7.46 (t, 2H, = 8.8 Hz), 6.85 (s, IH), 5.60 (s, 2H); Mass (LCMS): 322.1 (M + 1); Purity: 94.30%.

4-[2-(4-Fluoro-phenyl)-2- hydroxy-ethyl]-4H- ^X HNMR (DMSO-d6) δ: 8.6 (s, IH), 8.21- imidazo[l,5-a] quinazolin-5- 8.15 (m, 2H), 7.87 (dt, IH, = 1.2, 8 Hz),

7.54-7.46 (m, 3H), 7.16 (t, 2H, = 8.8 Hz), one

6.84 (s, IH), 5.63 (d, IH, = 4.4 Hz), 5.09 (dt, lH, = 4.4, 8.4 Hz), 4.16-4.10 (m, IH), 4.04-3.99 (m, IH); Mass (LCMS): 324.1 (M + 1); Purity: 94.78%.

4-[2-(4-Chloro-phenyl)-2- oxo-ethyl]-4H-imidazo [1,5- ^X HNMR (DMSO-d6) δ: 8.66 (s, IH), 8.26 (d, a]quinazolin-5-one IH, = 8.2 Hz), 8.17-8.12 (m, 3H), 7.94- 7.90 (m, IH), 7.71-7.68 (m, 2H), 7.55 (t, IH, = 7.2 Hz), 6.86 (s, IH), 5.60 (s, 2H); Mass (LCMS): 338 (M + 1); Purity: 91.94%.

^X HNMR (DMSO-d6) δ: 8.60 (s, IH), 8.21- 8.15 (m, 2H), 7.89-7.84 (m, IH), 7.52 (t, IH,

4-[2-(4-Chloro-phenyl)-2- = 7.2 Hz), 7.48 (d, 2H, = 8.2 Hz), 7.39 hydroxy-ethyl]-4H- (d, 2H, = 8.2 Hz), 6.85 (s, IH), 5.68 (d, imidazo[l,5-a]quinazolin -5- IH, = 4.4 Hz), 5.11-5.07 (m, IH), 4.12 one

(dd, IH, = 8.4, 14 Hz), 4.03 (dd, IH, = 4.4, 14 Hz); Mass (LCMS): 340.1 (M+l); Purity: 93.40%.

4-[2-(5-Oxo-5H-imidazo [1,5- a]quinazolin-4-yl)-acetyl]- ^X HNMR (DMSO-d6) δ: 8.67 (s, IH), 8.28- enzonitrile 8.26 (m, 3H), 8.16 (dd, IH, = 1.6, 7.2 Hz), ς 8.14-8.10 (m, 2H), 7.94-7.90 (m, IH), 7.57- · ο 7.53 (m, IH), 6.88 (s, IH), 5.66 (s, 2H);

Mass (LCMS): 329.1 (M+1); Purity: 96.02%.

4-[ 1 -Hydroxy-2-(5-oxo-5H- ^X HNMR (DMSO-d6) δ: 8.60 (s, IH), 8.20 (d, imidazo[l, 5-a] quinazolin-4- IH, = 7.6 Hz), 8.16 (d, 1Η, = 8.8 Hz), yl)-ethyl] -benzonitrile 7.87-7.80 (m, 3H), 7.65 (d, 2H, = 7.2 Hz),

7.54-750 (m, IH), 6.86 (s, IH), 5.86 (br. s, IH), 5.18-5.15 (m, IH), 4.18-4.00 (m, 2H); Mass (LCMS): 331.1 (M+1); Purity:

^< r ^N XK 92.88%..

4-[2-(2-Chloro-phenyl)-2-

^X HNMR (DMSO-d6) δ: 8.67 (s, IH), 8.26 (d, oxo-ethyl]-4H-imidazo [1,5- IH, = 8.4 Hz), 8.18 (d, 1Η, = 7.6 Hz), a]quinazolin-5-one

7.99 (d, IH, = 7.2 Hz), 7.92 (t, IH, = 7.6 Hz), 7.63 (d, 2H, = 3.6 Hz), 7.57-7.54

Q _Y °O CI (m, 2H), 6.89 (s, IH), 5.46 (s, 2H); Mass

(LCMS): 338 (M+1); Purity: 92.83%.

^X HNMR (DMSO-d6) δ: 8.59 (s, IH), 8.20

4-[2-(2-Chloro-phenyl)-2- (d, lH, = 8.4 Hz), 8.17 (d, 1Η, = 8.4 hydroxy-ethyl]-4H- Hz), 7.86 (t, IH, = 7.6 Hz), 7.78 (d, IH, imidazo[l,5-a]quinazolin -5- = 7.6 Hz), 7.51 (t, IH, = 7.6 Hz), 7.42 (t, one IH, = 7.2 Hz), 7.36 (d, 1Η, = 7.6 Hz),

7.30 (t, IH, = 7.2 Hz), 6.74 (s, IH), 5.78

Q °OH CI (br. s, IH), 5.47 (br. s, IH), 4.22 (dd, IH, =

8.8, 13.6 Hz), 4.02 (dd, IH, = 4.4, 13.6 Hz); Mass (LCMS): 340 (M +1); Purity : 96.5%.

4-[2-(4-Bromo-phenyl)-2- ^X HNMR (DMSO-d6) δ: 8.66 (s, IH), 8.26 (d, oxo-ethyl]-4H-imidazo [1,5- IH, = 8.4 Hz), 8.16 (d, 1Η, = 8 Hz), a]quinazolin-5-one 8.05 (d, 2H, = 8.4 Hz), 7.92 (t, 1H, = 7.2 Hz), 7.84 (d, 2H, = 8.4 Hz), 7.54 (t, 1H, = 7.6 Hz), 6.85 (s, 1H), 5.60 (s, 2H); Mass (LCMS): 383 (M+1); Purity: 96.8%.

4-[2-(4-Bromo-phenyl)-2- hydroxy-eth yl]-4H-

^X HNMR (DMSO-d6) δ: 8.60 (s, 1H), 8.183- imidazo[l,5-a]quinazolin -5- one 8.181 (m, 2H), 7.86 (br. s, 1H), 7.53-7.42 (m,

5H), 6.85 (s, 1H), 5.68 (br. s, 1H), 5.08 (br. s, 1H), 4.11-4.05 (m, 2H); Mass (LCMS): 385.1 (M+1); Purity: 96.38%.

4-[2-(4-Methoxy-phenyl)-2- ^X HNMR (DMSO-d6) δ: 8.65 (s, 1H), 8.26 (d, oxo-ethyl]-4H-imidazo [1,5- 1H, = 8.4 Hz), 8.17 (dd, 1H, = 1.2, 8.0 a]quinazolin -5-one Hz), 8.09 (d, 2H, = 8.8 Hz), 7.92 (dt, 1H,

= 1.2 Hz, 8.4 Hz), 7.57-7.53 (m, 1H), 7.13 (d, 2H, = 8.8 Hz), 6.8 (s, 1H), 5.54 (s, 2H), 3.88 (s, 3H); Mass (LCMS): 334.1 (M+1); Purity: 95.55%.

4-[2-Hydroxy-2-(4-methoxy- ^X HNMR (DMSO-d6) δ: 8.60 (s, 1H), 8.21- phenyl)-ethyl]-4H- 8.16 (m, 2H), 7.86 (t, 1H, = 6.8 Hz), 7.52 imidazo[l,5-a] quinazolin-5- (t, 1H, = 7.6 Hz), 7.37 (d, 2H, = 8.4 one Hz), 6.9 (d, 2H, = 8.4 Hz), 6.84 (s, 1H),

5.46 (d, 1H, = 4.4 Hz), 5.05-501 (m, 1H), 4.11 (dd, 1H, = 8.4, 13.6 Hz), 4.0 (dd, 1H, = 4.4, 13.6 Hz), 3.73 (s, 3H); Mass (LCMS): 336.1 (M+1); Purity: 97.15%.

4-[2-(3-Chloro-phenyl)-2-

^X HNMR (DMSO-d6) δ: 8.66 (s, 1H), 8.26 (d, oxo-ethyl]-4H-imidazo [1,5- 1H, = 8.4 Hz), 8.17-8.15 (m, 2H), 8.06 (d, a]quinazolin-5-one

1H, = 8.0 Hz), 7.92 (dt, 1H, = 1.2, 8.4 Hz), 7.82 (dd, 1H, = 1.2, 8.0 Hz), 7.65 (t, 1H, = 7.6 Hz), 7.55 (t, 1H, = 7.6 Hz), 6.87 (s, 1H), 5.63 (s, 2H); Mass (LCMS): 338 (M+1); Purity: 92.49%.

4-[2-(3-Chloro-phenyl)-2- ^X HNMR (DMSO-d6) δ: 8.60 (s, 1H), 8.21 (d, hydroxy-ethyl]-4H- IH, J = 8 Hz), 8.17 (dd, 1Η, = 1.6, 8.0 imidazo[l,5-a]quinazolin -5- Hz), 7.89-7.85 (m, IH), 7.87 (dt, IH, = one 1.6, 8.0 Hz), 7.54-7.50 (m, 2H), 7.41-7.31

(m, 3H), 5.71 (d, IH, = 4.4 Hz), 5.1 (dt, IH, = 4.4, 8.8 Hz), 4.14 (dd, IH, = 8.8, 14 Hz), 4.05 (dd, IH, = 4.4, 14 Hz); Mass (LCMS): 340.1 (M+l); Purity: 92.73%.

CI

4-(2-Oxo-2-pyridin-3-yl- ^X HNMR (DMSO-d6) δ: 9.30 (s, IH), 8.89 ethyl)-4H-imidazo[l,5- (dd, IH, = 1.6, 4.8 Hz), 8.66 (s, IH), 8.44 a]quinazolin-5-one (dt, IH, = 2, 8 Hz), 8.26 (d, IH, = 8

Hz), 8.16 (d, IH, = 8 Hz), 7.95-7.90 (m, IH), 7.65 (dd, IH, = 4.8, 8 Hz), 7.57-7.53 (m, IH), 6.88 (s, IH), 5.66 (s, 2H); Mass (LCMS): 305 (M+l); Purity : 91.71%.

^X HNMR (DMSO-d6) δ: 8.60 (s, 2H), 8.47 (d,

4-(2-Hydroxy-2-pyridin-3-yl- IH, = 3.2 Hz), 8.19 (d, 1Η, = 8.4 Hz), ethyl)-4H-imidazo [1,5- 8.15 (d, IH, = 8.4 Hz), 7.88-7.84 (m, 2H), a]quinazolin-5-one 7.51 (t, IH, = 7.6 Hz), 7.37 (dd, IH, =

4.8, 7.6 Hz), 6.88 (s, IH), 5.77 (br. d, IH,

OH = 4.8 Hz), 5.16-5.14 (m, IH), 4.21 (dd, IH,

= 8.4, 13.6 Hz), 4.08 (dd, IH, = 4.8, 13.6 Hz); Mass (LCMS): 307.1 (M+l); Purity : 94.07%.

4- [2-(2- Amino-phenyl)-2- ^X HNMR (DMSO-d6) δ: 9.0 (s, IH), 8.29 (d, oxo-ethyl]-4H-imidazo [1,5- IH, = 8 Hz), 8.20 (d, IH, = 8.0 Hz), a]quinazolin-5-one 7.97-7.94 (m, 2H), 7.62-7.59 (m, IH), 7.36- 7.32 (m, IH), 7.04 (br. s, IH), 6.81 (d, IH, = 8.4 Hz), 6.64 (t, IH, = 7.6 Hz), 5.51 (s, 2H); Mass (LCMS): 319.1 (M+l); Purity : 91.05%.

4-(2-Oxo-2-thiophen-3-yl-

^X HNMR (DMSO-d6) δ: 8.79 (s, IH), 8.78 (s, ethyl)-4H-imidazo [1,5- IH), 8.25 (d, IH, = 8.0 Hz), 8.16 (d, IH, a]quinazolin-5-one

= 7.2 Hz), 7.93-7.89 (m, IH), 7.74-7.72 (m, IH), 7.61 -7.60 (m, IH), 7.55 (t, IH, = 7.6 Hz), 6.83 (s, IH), 5.49 (s, 2H) ; Mass (LCMS): 310.1 (M+l); Purity : 92.17%.

one 1H, = 7.6 Hz), 7.68 (t, 1H, = 8.4 Hz), ςν° 7.55 (t, IH, = 7.6 Hz), 6.86 (s, IH), 5.64 (s, 2H); Mass (LCMS): 356.1 (M+1); Purity : 99.01%.

4-[2-Oxo-2-(4-phenylacetyl-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.63 (s, piperazin- 1 -yl)-ethyl] -4H- IH), 8.23 (d, IH, = 8.4 Hz), 8.15 (d, IH, imidazo [l,5-a]quinazolin-5- = 7.6 Hz), 7.89 (t, IH, = 7.6 Hz), 7.53 (t, one

IH, = 7.6 Hz), 7.31 (t, 2H, = 7.2 Hz), 7.26-7.21 (m, 3H), 6.78 (s, IH), 4.91 (s, 2H), 3.8-3.72 (m, 3H), 3.62-3.59 (m, 3H), 3.44- 3.39 (m, 4H); Mass (LCMS): 430.2 (M+1); Purity : 94.78%.

0

4-(2-Biphenyl-4-yl-2-oxo- ethyl)-4H-imidazo [1,5-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, a]quinazolin-5-one

IH), 8.28-8.19 (m, 3H), 7.93-7.92 (m, 3H), 7.80-7.78 (m, 3H), 7.55-7.45 (m, 4H), 6.86 (s, IH), 5.64 (s, 2H); Mass (LCMS): 380.2 (M+1); Purity: 92.71%.

4-[2-(2,5-Dimethoxy-phenyl)-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.66 (s, 2-oxo-ethyl] -4H-imidazo [ 1 , 5 - IH), 8.26 (d, IH, = 8 Hz), 8.16 (d, IH, = a]quinazolin -5-one

7.6 Hz), 7.92 (t, IH, = 8.4 Hz), 7.55 (t, IH, = 7.6 Hz), 7.26-7.25 (m, 3H), 6.77 (s, IH), 5.37 (s, 2H), 3.98 (s, 3H), 3.74 (s, 3H); Mass (LCMS): 364.1 (M+1); Purity : 91.55%.

4-[2-(3,5-Bis-trifluoromethyl- phenyl)-2-oxo-ethyl]-4H-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.69 (s, imidazo [1,5-a] quinazolin-5- 2H), 8.67 (s, IH), 8.53 (s, IH), 8.27 (d, IH, one

= 8 Hz), 8.17 (d, IH, = 7.6 Hz), 7.93 (t, IH, = 8 Hz), 7.55 (t, IH, = 7.6 Hz), 6.89 (s, IH), 5.81 (s, 2H); Mass (LCMS): 440.1 (M+1); Purity : 94.14%.

4-[2-(2,5-Dimethoxy-phenyl)- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.62 (s, 2-hydroxy-ethyl] -4H- IH), 8.21 (d, IH, = 8.4 Hz), 8.17 (d, IH, imidazo[l,5-a] quinazolin-5- = 1.2 Hz), 7.87 (dt, IH, = 1.2, 8.4 Hz), one 7.52 (t, IH, = 7.6 Hz), 7.15-7.14 (m, IH),

6.88 (d, IH, = 8.8 Hz), 6.82-6.79 (m, 2H),

Q °OH 5.45 (d, IH, = 4.8 Hz), 5.40-5.37 (m, IH),

4.34 (dd, IH, = 9.2, 13.6 Hz), 3.77(dd, IH, = 3.6, 13.6 Hz), 3.73 (s, 3H), 3.70 (s, 3H); Mass (LCMS): 423.1 (M+1); Purity :

96.88%.

4-[2-(3,4-Difluoro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, oxo-ethyl] -4H-imidazo [ 1 , 5 -a] IH), 8.27 (d, IH, = 8.0 Hz), 8.24-8.19 (m, quinazolin-5 -one IH), 8.16 (d, IH), J= 8.0 Hz), 8.04-8.02 (m,

IH), 7.95-7.91 (m, IH), 7.73-7.71 (m, IH), 7.56 (t, IH, = 8 Hz), 6.86 (s, IH), 5.62 (s, 2H); Mass (LCMS): 340.1 (M+1); Purity : 95.21%.

4-[2-(3,4-Difluoro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.61 (s, hydroxy-ethyl]-4H- IH), 8.22-8.15 (m, 2H), 7.87 (t, IH, = 7.6 imidazo[l,5-a] quinazolin-5- Hz), 7.55-7.50 (m, 2H), 7.42-7.35 (m, IH), one 7.26-7.24 (m, IH), 6.89 (s, IH), 5.78 (d, IH,

= 4.0 Hz), 5.10-5.06 (m, IH), 4.15 (dd, IH, = 8.8, 13.6 Hz), 4.02 (dd, IH, = 4.4, 13.6 Hz), Mass (LCMS): 342.1 (M+1); Purity :97.49 %.

4- [2-(2,5 -Dichloro-phenyl)-2- oxo-ethyl] -4H-imidazo [ 1 , 5 -a] ^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, quinazolin-5 -one IH), 8.26 (d, IH, = 8.4 Hz), 8.18 (d, IH,

= 8 Hz), 8.14 (d, lH, = 1.2 Hz), 7.92 (t, IH, = 7.6 Hz), 7.73-7.65 (m, 2H), 7.54 (t, IH, = 7.6 Hz), 6.93 (s, IH), 5.49 (s, 2H); Mass (LCMS): 372; Purity :94.22 %.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s,

4- [2-(2,5 -Dichloro-phenyl)-2- IH), 8.21-8.12 (m, 2H), 7.87 (t, IH, = 6.8 hydroxy-ethyl]-4H- Hz), 7.75 (br.s, IH), 7.51 (t, IH, = 7.2 imidazo[l,5-a] quinazolin-5- Hz), 7.39 (br.s, 2H), 6.79 (s, IH), 5.98-5.97 one

(m, IH), 5.42 (br.s, IH), 4.21-4.16 (m, IH), 4.09-4.06 (m, IH); Mass (LCMS): 374; Purity : 96.05%.

4- [2-(2,5 -Difluoro-phenyl)-2- oxo-et hyl]-4H-imidazo[l,5- ^X HNMR (DMSO-d6, 400 MHz) 5:8.67 (s, a] quinazolin-5-one IH), 8.26 (d, IH, = 8Hz), 8.16 (d, IH, =

8 Hz), 7.94-7.91 (m, IH), 7.78-7.74 (m, IH), V°0 F 7.70-7.64 (m, IH), 7.60-7.53 (m, 2H), 6.91

(s, IH), 5.45 (s, 2H, = 2.4 Hz); Mass (LCMS): 340.1 (M+l); Purity : 91.84%.

F

4- [2-(2,5 -Difluoro-phenyl)-2-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.59 (s, hydroxy-ethyl]-4H- IH), 8.21-8.15 (m, 2H), 7.87 (t, IH, = 7.6 imidazo[l,5-a] quinazolin-5- Hz), 7.52 (t, IH, = 7.6 Hz), 7.46-7.42 (m, one

IH), 7.17-7.14 (m, 2H), 6.75 (s, IH), 5.89 (d, IH, = 4.8 Hz), 5.39-5.34 (m, IH), 4.22

Q _Y °OH F (dd, IH, = 834, 13.2 Hz), 4.04 (dd, IH,

= 4.4, 13.2 Hz); Mass (LCMS): 342.1 (M+l); Purity : 94.92%.

F

4-[2-(2,4-Difluoro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.66 (s, oxo-ethyl] -4H-imidazo [ 1 , 5 -a] IH), 8.26 (d, IH, = 8.0 Hz), 8.16 (d, IH, quinazolin-5- one = 8.0 Hz), 8.10-8.04 (m, IH), 7.92 (t, IH,

= 7.6 Hz), 7.60-7.53 (m, 2H), 7.33 (t, IH,

P _Y °O F = 8 Hz), 6.90 (s, IH), 5.41 (d, 2H, = 2.4

Hz); Mass (LCMS): 340.1 (M+l); Purity : 97.60%.

4-[2-(3-Chloro-4-fluoro- phenyl)-2-hydroxy-ethyl] - ^X HNMR (DMSO-d6, 400 MHz) δ: 8.61 (s, 4H-imidazo[ 1 ,5-a] IH), 8.21-8.15 (m, 2H), 7.86 (t, IH, = 7.6 quinazolin-5 -one Hz), 7.65 (d, IH, = 6.8 Hz), 7.51 (t, IH,

= 7.6 Hz), 7.43-7.35 (m, 2H), 6.9 (s, IH), 5.77 (d, IH, = 4 Hz), 5.08 (br.s, IH), 4.18- 4.15 (m, IH), 4.04-4.0 (m, IH); Mass (LCMS): 358.1 (M+l); Purity : 97.79%.

4-[2-(2,4-Difluoro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s, hydrox y-ethyl]-4H- IH), 8.20 (d, IH, = 8.4 Hz), 8.15 (d, IH, imidazo[l ,5-a] quinazolin-5- = 7.6 Hz), 7.86 (t, IH, = 7.6 Hz), 7.72- one 7.65 (m, IH), 7.51 (t, IH, = 7.6 Hz), 7.16- 7.1 (m, 2H), 6.71 (s, IH), 5.81 (d, IH, =

Q _Y °OH F 4.4 Hz), 5.35-5.34 (m, IH), 4.25-4.2 (m,

IH), 4.03-3.99 (m, IH); Mass (LCMS): 342.1 (M+1); Purity : 97.24%.

4-(2-Benzo[l,3]dioxol-5-yl-2- hydroxy-ethyl)-4H- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s, imidazo[l ,5-a] quinazolin-5- IH), 8.19 (t, 2H, = 8.4 Hz), 7.86 (t, IH, one = 7.6 Hz), 7.52 (t, IH, = 7.6 Hz), 7.05 (s,

IH), 6.88-6.83 (m, 3H), 5.99 (s, 2H), 5.51 (d, IH, = 4.4 Hz), 5.02-4.98 (m, IH), 4.13- 4.07 (m, IH), 4.00-3.96 (m, IH); Mass (LCMS): 350.1 (M+1); Purity : 95.71%.

4-[2-(3-Fluoro-phenyl)-2- oxo-ethyl] -4H-imidazo [ 1 , 5 -a] ^X HNMR (DMSO-d6, 400 MHz) δ: 8.68 (s, quinazolin-5 -one IH), 8.26 (d, IH, = 8 Hz), 8.17 (dd, IH,

= 0.8, 8 Hz), 7.98-7.90 (m, 3H), 7.69-7.53

Q > o (m, 3H), 6.87 (s, IH), 5.62 (s, 2H); Mass

(LCMS): 322.1 (M+1); Purity : 95.77%.

4-[2-(3-Fluoro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s, hydroxy-ethyl]-4H- IH), 8.20 (d, IH, = 7.6 Hz), 8.17 (d, IH, imidazo[l ,5-a]quinazolin -5- = 7.6 Hz), 7.87 (t, IH, = 8 Hz), 7.52 (t, one IH, = 7.6 Hz), 7.40-7.35 (m, IH), 7.31- 7.25 (m, 2H), 7.11-7.07 (m, IH), 6.88 (s, IH), 5.71 (d, IH, = 4.8 Hz), 5.13-5.09 (m, IH), 4.17-4.1 1 (m, IH), 4.07-4.02 (m, IH); Mass (LCMS): 324.1 (M+1); Purity :95.07

F %.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, IH), 8.26 (d, IH, = 8 Hz), 8.16 (dd, IH,

4-(2-Benzo[l,3]dioxol-5-yl-2- = 1.2, 8 Hz), 7.94-7.90 (m, IH), 7.78 (dd, oxo-ethyl)-4H-imidazo[ l,5- IH, = 1.2, 8 Hz), 7.58-7.53 (m, 2H), 7.13 a]quinazolin -5-one

(d, IH, = 7.6 Hz), 6.81 (s, IH), 6.18 (s, 2H), 5.52 (s, 2H); Mass (LCMS): 348.1 (M+l); Purity: 95.54%.

4-[2-(2-Benzyloxy-phenyl)-2-

^X HNMR (DMS0-d6, 400 MHz) δ: 8.67 (s, oxo-ethyl] -4H-imidazo [1,5- IH), 8.25-8.15 (m, IH), 8.15-8.14 (m, IH), a]quinazolin -5-one

7.92-7.77 (m, IH), 7.75-7.63 (m, IH), 7.62- 7.58 (m, 3H), 7.56-7.47 (m, IH), 7.42-7.13 (m, 4H), 7.13-7.12 (m, IH), 6.65 (s, IH), 5.37 (s, 2H); 5.36 (s, 2H); Mass (LCMS): 410.2 (M+l); Purity : 95.94%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s,

4-[2-(3-Benzyloxy-phenyl)-2- IH), 8.26 (d, IH, = 8 Hz), 8.17 (d, IH, = oxo-ethyl] -4H-imidazo [1,5- 8.8 Hz), 7.92 (t, IH, = 7.8 Hz), 7.72 (d, a]quinazolin -5-one

IH, = 7.6 Hz), 7.70 (d, 1Η, = 2 Hz), 7.56-7.52 (m, 2H), 7.48 (d, 2H, = 7.2 Hz), 7.42-7.38 (m, 3H), 7.35 (d, IH, = 6.8 Hz), 6.85 (s, IH), 5.60 (s, 2H), 5.22 (s, 2H); Mass (LCMS): 410.2 (M+l); Purity : 93.76%.

4- [2-(3 ,5 -Dichloro-phenyl)-2- oxo-ethyl] -4H-imidazo [1,5- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, a]quinazolin -5-one IH), 8.26 (d, IH, = 8 Hz), 8.16 (d, IH, =

8 Hz), 8.12 (d, 2H, = 1.6 Hz), 8.04 (t, IH, 1.6 Hz), 7.92 (t, IH, = 8 Hz), 7.56 (t, IH, = 8 Hz), 6.87 (s, IH), 5.65 (s, 2H); Mass (LCMS):372 (M+l); Purity : 93.96%.

4- [2-(2,3 -Dichloro-phenyl)-2-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.57 (s, oxo-ethyl] -4H-imidazo [1,5- a]quinazolin -5-one IH), 8.26 (d, IH, = 8.4 Hz), 8.18 (d, IH,

= 8 Hz), 7.93-7.88 (m, 3H), 7.58 (d, IH, = Y°O CI 8 Hz), 7.56 (d, IH, = 8 Hz), 6.91 (s, IH),

5.45 (s, 2H); Mass (LCMS): 372; Purity : 96.35%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s,

4-(2-Naphthalen- 1 -yl-2-oxo- IH), 8.51 (d, IH, = 7.6 Hz), 8.43 (d, IH, ethyl)-4H-imidazo [1,5- = 7.2 Hz), 8.28 (d, IH, = 8.4 Hz), 8.24 (d, a]quinazolin-5-one IH, = 8 Hz), 8.20 (dd, IH, = 0.8, 7.6 Hz), 8.06 (dd, IH, = 2.8, 7.2 Hz), 7.93 (t, IH, = 7.8 Hz), 7.72 (t, IH, = 7.6 Hz), 7.64-7.61 (m, 2H), 7.56 (t, IH, = 7.6 Hz), 6.97 (s, IH), 5.63 (s, 2H); Mass (LCMS): 354.1 (M+l); Purity : 94.00%.

4- [2-(2,3 -Dichloro-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s, hydroxy-ethyl]-4H- IH), 8.20 (d, IH, = 8.4 Hz), 8.16 (d, IH, imidazo[l,5-a] quinazolin-5- = 8 Hz), 7.87 (t, IH, = 8.4 Hz), 7.73 (d, one IH, = 7.6 Hz), 7.57 (d, 1Η, = 8 Hz),

7.52 (t, IH, = 7.6 Hz), 7.44 (t, IH, = 7.6 Hz), 6.70 (s, IH), 5.91 (d, IH, = 4.4 Hz), 5.52-5.48 (m, IH), 4.19 (dd, IH, = 8.4, 13.6 Hz), 4.04 (dd, IH, = 4.8, 13.6 Hz); Mass (LCMS): 374; Purity : 97.02%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s,

4-[2-(3-Benzyloxy-phenyl)-2- IH), 8.19 (t, 2H, = 8.8 Hz), 7.87 (t, IH, hydroxy-ethyl] -4H- = 8.4 Hz)7.52 (t, IH, = 8 Hz), 7.45-7.32 imidazo[l,5-a] quinazolin-5- (m, 5H), 7.26 (t, IH, = 8 Hz), 7.12 (s, IH), one

7.03 (d, IH, = 7.2 Hz), 6.90 (d, IH, = 7.6 Hz), 6.86 (s, IH), 5.56 d, IH, = 4.4 Hz), 5.08-5.05 (m, 3H), 4.15-4.09 (m, IH), 4.09 (d, IH, = 2.8 Hz); Mass (LCMS): 412.2 (M+l); Purity : 95.82%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.60 (s,

4-(2-Hydroxy-2-naphthalen- IH), 8.56 (d, IH, = 8.4 Hz), 8.26 (d, IH, l-yl-ethyl)-4H-imidazo[l,5-a] = 7.6 Hz), 8.21 (d, IH, = 8.4 Hz), 7.95 (d, quinazolin-5 -one IH, = 8.0 Hz), 7.90-7.85 (m, 3H), 7.62- 7.51 (m, 4H), 6.85 (s, IH), 5.88-5.86 (m,

Q _Y °OH IH), 5.75 (d,lH, = 4.4 Hz), 4.41 (dd, IH,

= 1.6, 13.4 Hz), 3.93 (dd, IH, = 9.7, 13.4 Hz); Mass (LCMS): 356.1 (M+l); Purity : 95.34%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.61 (s,

4- [2-(3 ,5 -Dichloro-phenyl)-2- IH), 8.23-8.15 (m, 2H), 7.88-7.85 (m, IH), hydroxy-ethyl]-4H- 7.56-7.50 (m, 4H), 6.95 (s, IH), 5.87-5.84 imidazo[l,5-a] quinazolin-5- (m, IH), 5.12-5.07 (m, IH), 4.17-4.16 (m, one

IH), 4.08-4.05 (m, IH) ); Mass (LCMS): 374.1; Purity : 93.74%.

a

4-[2-(5-Oxo-5H-imidazo[l,5- a]quinazolin -4-yl)-acetyl]- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.74 (s, benzoic acid methyl ester IH), 8.28 (d, IH, = 8.4 Hz), 8.25 (d, 2H,

= 8.4 Hz), 8.18-8.15 (m, 3H), 7.95-7.91 (m, IH), 7.56 (t, IH, = 7.6 Hz), 6.93 (s, IH), 5.66 (s, 2H), 3.92 (s, 3H); Mass (LCMS): 362.1 (M+l); Purity : 90.19%.

0

4-[2-Oxo-2-(3- trifluoromethyl-phenyl)- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, ethyl]-4H-imidazo[l,5- IH), 8.40 (s, IH), 8.27 (d, IH, = 8.0 Hz), a]quinazol in-5-one 8.17-8.12 (m, 2H), 7.94-7.85 (m, 3H), 7.55

(t, IH, = 7.6 Hz), 6.89 (s, IH), 5.71 (s, 2H); Mass (LCMS): 372.1 (M+l); Purity : 90.84%.

4- [2-(4- Amino-phenyl)-2- oxo-ethyl]-4H-imidazo [1,5- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.64 (s, a]quinazolin-5-one IH), 8.25 (d, IH, = 8.4 Hz), 8.16 (dd, IH,

= 1.2, 8 Hz), 7.93-7.79 (m, 3H), 7.54 (t, IH, = 7.6 Hz), 6.74 (s, IH), 6.63 (d, 2H, = 8.8 Hz), 6.23 (s, 2H), 5.39 (s, 2H); Mass (LCMS): 319.1 (M+l); Purity : 91.25%. l-(2-Chloro-phenyl)-2-(5H- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.02 (s, imidazo[l,5-a] quinazolin-4- IH), 7.69-7.65 (m, 2H), 7.42-7.30 (m, 5H), yl)-ethanol 7.2 (t, IH, = 7.3 Hz), 6.2 (s, IH), 5.71 (d,

IH, = 4.8 Hz), 5.35-5.33 (m, IH), 4.43 (d, IH, = 14 Hz), 4.33 (d, IH, = 14 Hz), 3.24-3.23 (m, IH), 3.17-3.15 (m, IH); Mass (LCMS): 326.2 (M+l); Purity : 93.55%.

4-[2-(2-Bromo-phenyl)-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.67 (s, oxo-ethyl]-4H-imidazo [1,5- IH), 8.26 (d, IH, = 8 Hz), 8.18 (d, IH, = a]quinazolin-5-one 7.2 Hz), 7.98-7.96 (m, 2H), 7.8 (d, IH, = 6.4 Hz), 7.59-7.54 (m, 3H), 6.89 (s, IH), 5.47 (s, 2H); Mass (LCMS): 382; Purity : 90.31 %.

4- [2-(2,6-Dichloro-3 -fluoro- phenyl)-2-oxo-ethyl]-4H- ^X HNMR (DMSO-d6, 400 MHz) δ: 8.7 (s, imidazo[l,5-a] quinazolin-5- IH), 8.27 (d, IH, = 8 Hz), 8.20 (d, IH, = one 7.6 Hz), 7.94 (t, IH, = 7.2 Hz), 7.75-7.67

(m, 2H), 7.56 (t, IH, = 7.6 Hz), 6.78 (s, IH), 5.44 (s, 2H); Mass (LCMS): 390.1; Purity : 96.61%. l-(4-Fluoro-phenyl)-2-(5H- ^X HNMR (DMSO-d6, 400 MHz) δ: ^X HNMR imidazo[l,5-a] quinazolin-4- (DMSO-d6, 400 MHz) δ: 8.0 (s, IH), 7.63 yl)-ethanol (d, IH, = 8 Hz), 7.46-7.43 (m, 2H), 7.36- 7.13 (m, 5H), 6.20 (s, IH), 5.55 (br. s, IH), 4.96-4.94 (m, IH), 4.34 (d, IH, = 13.6 Hz), 4.21 (d, IH, = 13.6 Hz), 3.24-3.13 (m, 2H); Mass (LCMS): 310.2 (M+1); Purity : 93.39%.

^X HNMR (DMSO-d6, 400 MHz) δ: 8.64 (s,

4-[2-(4-Benzyloxy-phenyl)-2- IH), 8.24 (d, IH, = 8.4 Hz), 8.16 (d, IH, oxo-ethyl] -4H-imidazo [1,5- = 7.6 Hz), 8.07 (d, 2H, = 8.2 Hz), 7.91 (t, a]quinazolin -5-one

IH, = 7.2 Hz), 7.55 (t, IH, = 7.6 Hz), 7.47 (d, 2H, = 7.2 Hz), 7.41 (t, 2H, = 7.2 Hz), 7.35 (t, IH, = 6.8 Hz), 7.20 (d, 2H, = 8.8 Hz), 6.79 (s, IH), 5.53 (s, 2H), 5.25 (s, 2H); Mass (LCMS): 410.1 (M+1); Purity : 98.91%.

N-Benzyl-4-[2-(5-oxo-5H- ^X HNMR (DMSO-d6, 400 MHz) δ: 9.28 (t, imidazo[l,5-a] quinazolin-4- IH, = 8 Hz), 8.67 (s, IH), 8.27 (d, IH, = yl)-acetyl] -benzamide 8 Hz), 8.20 (d, 2H, = 8.4 Hz), 8.17 (dd,

IH, = 0.8, 7.6 Hz), 8.10-8.07 (m, 2H), 7.94-7.90 (m, IH), 7.55 (t, IH, = 8 Hz), 7.35-7.30 (m, 4H), 7.27-7.24 (m, IH), 6.87 (s, IH), 5.64 (s, 2H), 4.50 (d, 2H, = 6.4

0 Hz); Mass (LCMS): 437.2 (M+1; Purity

(M+l); Purity: 94.69%.

N-{4-[3-(5-Oxo-5H- ^X HNMR (DMSO-d6, 400 MHz) 5: 10.32 (s, imidazo[l,5-a]quinazolin -4- IH), 8.64 (s, IH), 8.21 (d, IH, = 8.4 Hz), yl)-propionyl] -phenyl }- 8.17 (dd, IH, = 1.6, 8 Hz), 7.93 (d, 2H, methanesulfonamide = 8.8 Hz), 7.87 (dt, IH, = 1.6, 8 Hz), 7.52

(t, IH, = 8 Hz), 7.25 (d, 2H, = 8.8 Hz), 6.91 (s, IH), 4.32 (t, 2H, = 7.6 Hz), 3.43 (t, 2H, = 7.6 Hz), 3.08 (s, 3H); Mass

0 (LCMS): 411.1 (M+l); Purity: 90.82%.

N-{4-[3-(5-Oxo-5H- ^X HNMR (DMSO-d6, 400 MHz) 5: 10.25 (s, imidazo[l,5-a]quinazolin -4- IH), 8.64 (s, IH), 8.21 (d, IH, = 8.4 Hz), yl)-propionyl] -phenyl } - 8.17 (dd, IH, = 1.6, 8 Hz), 7.91 (d, 2H, acetamide = 8.8 Hz), 7.87 (dt, IH, = 1.2, 8.4 Hz),

7.68 (d, 2H, = 8.8 Hz), 7.52 (t, IH, = 8.8 Hz), 6.91 (s, IH), 4.32 (t, 2H, = 7.6 Hz), 3.43 (t, 2H, 7.6 Hz), 2.07 (s, 3H); Mass

N- ⁷ 0 (LCMS): 375.2 (M+l); Purity: 93.74%.

4-(2-morpholino-2- ^X HNMR (DMSO-d6, 400 MHz) 5: 8.62 (s, oxoethyl)imidazo[ 1,5- IH), 8.23-8.14 (m, 2H), 7.94-7.84 (m, IH), a]quinazolin-5(4H)-one 7.61-7.51 (m, IH), 6.77 (s, IH), 4.90 (s, 2H),

3.75-3.58 (m, 4H), 3.56-3.40 (m, 4H); Mass (LCMS): 313.1 (M+l); Purity: 91.89%.

4-( 1 -oxo- 1 -phenylpropan-2- ^X HNMR (DMSO-d6, 400 MHz) 5: 8.66 (s, yl)imidazo[ 1 ,5-a]quinazolin- IH), 8.16 (d, IH, = 8.4 Hz), 7.99 (d, IH, 5(4H)-one = 7.6 Hz), 7.83 (t, IH, = 7.6 Hz), 7.66 (d,

2H, = 7.6 Hz), 7.48-7.42 (m, 2H), 7.34 (t, 2H, = 7.6 Hz), 7.04 (s, IH), 5.91 (q, IH, = 6.4 Hz), 1.57 (d, 3H, = 6.4 Hz); Mass (LCMS): 318.1 (M+l); Purity: 97.46%.

Example 75^ Preparation of (N-(4-(2-(5-oxoimidazo[l,5-alquinazolin-4(5H)- yl)acetyl)phenyl)benzenesulfonami

Step 1: Synthesis of N-(4-acetylphenyl)benzenesulfonamide:

To a solution of 4-aminoacetophenone (1.0 g, 7.39 mmol) and pyridine (0.76 g, 9.62 mmol) in MDC (60 ml) was added benzene sulfonyl chloride (1.56 g, 8.87 mmol) drop wise at about 0-5 °C. Reaction mixture was allowed to stir at room temperature for about 16 hours and monitored by TLC/LCMS. After completion of reaction, reaction mixture was diluted with water and product was extracted with ethyl acetate (3x100 ml). Combined ethyl acetate layer was dried over anhydrous sodium sulphate, filtered and concentrated to get N-(4- acetylphenyl)benzenesulfonamide (2.0 g, 98%) as white solid. LCMS: 276.1 (M+l).

Step 2: Synthesis of N-(4-(2-bromoacetyl)phenyl)benzenesulfonamide:

To a suspension of N-(4-acetylphenyl)benzenesulfonamide (Step 1, 1 g, 3.63 mmol) in HBr in acetic acid (5 ml) at 0-5 °C was added solution of bromine (523 mg, 3.27 mmol) in acetic acid (5 ml) in a drop-wise manner. The reaction mixture was stirred at room temperature for about one hour. After completion of the reaction, water (20 ml) was added and precipitated solid was filtered and washed with water (2x 5 ml). Solid was dired under vacuum at 50 °C to give N- (4-(2-bromoacetyl)phenyl)benzenesulfonamide (0.98 g, 77%). Mass (LCMs): 353, 355.

Step 3: Synthesis of (N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)- yl)acetyl)phenyl)benzenesulfon

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)benzenesulfonamide (0.023 g, 9.3 %) was obtained as yellowish solid by using procedure as described in Example

No-1. ^NMR (DMSO-d6, 400 MHz) δ: 8.63 (s, 1H), 8.24 (d, 1H, = 8.4 Hz), 8.13 (dd, 1H, = 1.2, 8.0 Hz), 7.99 (d, 2H, = 8.8 Hz), 7.92-7.86 (m, 3H), 7.67-7.58 (m, 3H), 7.53 (t, 1H, = 7.6 Hz), 7.29 (d, 2H, = 8.8 Hz), 6.79 (s, 1H), 5.48 (s, 2H); (LCMS): 459.1 (M+1); Purity: 93.03%.

Following Example 76 has been synthesized by the above procedure described in Example 75 with their corresponding intermediates in similar reaction consitions:

Example 77: Preparation of N-isobutyl-4-(2-(5-oxoimidazo[l,5-alquinazolin-4(5H)- yl)acetyl)benzenesulfonamide:

Step 1: Synthesis of 4-acetyl-N-isobutylbenzenesulfonamide:

To a solution of isobutylamine (0.184 g, 2.46 mmol), in MDC (10 ml) was added triethyamine (0.38 ml, 2.74 mmol) at about 0-5 °C. To this solution was added 4- acetylbenzenesuflonyl chloride (0.50 g, 2.28 mmol) at about 0-5 °C and the reaction mixture was stirred for about 16 hours at room temperature. Reaction was monitored by TLC and after completion of reaction, reaction mixture was diluted with water (15 ml) and MDC (25 ml). Layers were separated and aqueous layer was extracted with MDC (2 x 25 ml). Combined organic extracts were dried on anhydrous sodium sulfate, concentrated to give crude product which was purified by flash column chromatography to give 4-acetyl-N- isobutylbenzenesulfonamide (0.42 g, 72%).

^X HNMR (DMSO-d6, 400 MHz) δ: 8.12 (d, 2H, = 8.4 Hz), 7.91 (d, 2H, = 8.4 Hz), 7.82-7.70 (m, 1H), 2.63 (s, 3H), 2.58-2.54 (m, 2H), 1.66-1.59 (m, 1H), 0.80 (s, 3H), 0.79 (s, 3H).

Step 2: Synthesis of 4-(2-bromoacetyl)-N-isobutylbenzenesulfonamide:

4-(2-bromoacetyl)-N-isobutylbenzenesulfonamide (0.450 g, 86%) was isolated as off- white solid by using procedure as described in Example 75-Step 2. The crude product was used as such for the next step.

Step 3: Synthesis of N-isobutyl-4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)- yl)acetyl)benzenesulfonamide:

N-isobutyl-4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acet yl)benzenesulfonamide was isolated as white solid by using procedure as described in Example No- 1.

¾NMR (DMSO-d6, 400 MHz) δ: 8.67 (s, 1H), 8.30 (d, 2H, = 8.4 Hz), 8.27 (d, 1H, = 8.4 Hz), 8.16 (d, 1H, = 7.6 Hz), 7.99 (d, 2H, = 8.4 Hz), 7.94-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.55 (t, 1H, = 7.6 Hz), 6.88 (s, 1H), 5.65 (s, 2H), 2.61-2.58 (m, 2H), 1.65-1.62 (m, 1H), 0.84 (s, 3H), 0.80 (s, 3H); Mass (LCMS): 439.1 (M+l), Purity: 95.55%.

Following Example 78 & 79 have been synthesized by the above procedure described in Example 77 with their corresponding intermediates in similar reaction consitions: Example

IUPAC Name/Structure Analytical Data

No.

N-benzyl-4-(2-(5- ^X HNMR (CDCb, 400 MHz) δ: 8.67 (s, oxoimidazo[ 1 ,5-a]quinazolin- 1H), 8.41 (t, 1H, / = 6 Hz), 8.31-8.25 4(5H)- (m, 3H), 8.17 (d, 1H, = 8.0 Hz), 7.99 yl)acetyl)benzenesulfonamide (d, 2H, = 8.4 Hz), 7.93 (t, 1H, = 8

78 Hz), 7.56 (t, 1H, = 7.6 Hz), 7.33-7.21

(m, 5H), 6.88 (s, 1H), 5.65 (s, 2H), 4.03 (d, 2H, = 6 Hz); (LCMS): 473 (M+l); Purity: 98.28%.

4-(2-(5-oxoimidazo[l,5- ^X HNMR (CDCI3, 400 MHz) δ: 10.34 (s, a]quinazolin-4(5H)-yl)acetyl)-N- 1H), 8.66 (s, 1H), 8.28-8.22 (m, 3H),

(p-tolyl)benzenesulfonamide 8.14 (d, 1H, = 8 Hz), 7.94-7.9 (m,

79 3H), 7.54 (t, 1H, = 7.6 Hz), 7.09-6.97

(m, 4H), 6.87 (s, 1H), 5.61 (s, 2H), 2.19 (s, 3H); (LCMS): 473 (M+l); Purity: 94.31%.

Example 80: Preparation of l-(4-Fluoro-phenyl)-3-(4-r2-(5-oxo-5H-imidazorL5-alquinazoli n- 4-yl)-acetyll-phenyl}-urea:

Step 1: Synthesis of l-(4-Acetyl-phenyl)-3-(4-fluoro-phenyl)-urea:

To a solution of 4- Amino acetophenone (0.3 g, 2.22 mmol) in DCM (5 mL) was added 4- Fluoro phenyl isocyanate (0.304 g, 2.22 mmol) and reaction mixture was stirred at room temperature for around 16 hours. Reaction mixture was filtered and residue washed with DCM (2x lOmL), dried under vaccum to yield compound l-(4-Acetyl-phenyl)-3-(4-fluoro-phenyl)- urea (0.30 g, 50%).

^NMR (DMSO-d6) δ: 9.86 (s, 1H), 8.80 (s, 1H), 7.88(d, 2H, = 8.4 Hz), 7.56 (d, 2H, = 8.8 Hz), 7.48-7.44 (m, 2H), 7.12 (t, 2H, = 8.8 Hz), 2.50 (s, 3H).

Step 2: Synthesis of l-[4-(2-Bromo-acetyl)-phenyl]-3-(4-fluoro-phenyl)-urea:

l-(4-Acetyl-phenyl)-3-(4-fluoro-phenyl)-urea (step 1, 0.3 g, 1.1029 mmol) was dissolved in HBr in AcOH (1.5 mL, 5 vol) at about 0 to 5 °C, followed by addition of Br ₂ (0.19 g, 1.21mmol) in AcOH (1 mL) at the same temperature. Reaction mixture was allowed to warm to room temperature and stirred for about 1 hour. Water (15 mL) was added and the solid formed was filtered, dried under vacuum to yield crude compound l-[4-(2-Bromo-acetyl)-phenyl]-3-(4- fluoro-phenyl)-urea, which was used as such for next step. (0.25 g)

Step 3: Synthesis of l-(4-Fluoro-phenyl)-3-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in-4-yl)- acetyl] -phenyl } -urea:

To a stirred solution of 4H-Imidazo[l,5-a]quinazolin-5-one (Example 1-Step 4, 0.1 g, 0.5405 mmol) in DMF (5 mL) was added cesium carbonate (0.26 g, 0.81 mmol) and l-[4-(2- Bromo-acetyl)-phenyl]-3-(4-fluoro-phenyl)-urea (Step 2, 0.21 g, 0.59 mmol) at room temperature and reaction mixture was stirred for about 1 hour. Reaction mixture was diluted with water and solid formed was filtered, dried under vacuum to get crude product, which was purified by silica gel flash column chromatography to obtain desired compound.

XHNMR (DMSO-d6) δ: 9.20 (s, 1H), 8.88 (s, 1H), 8.66 (s, 1H), 8.26 (d, 1H, = 8.4 Hz), 8.17 (d, 1H, = 7.2 Hz), 8.06 (d, 2H, = 8.8 Hz), 7.92 (t, 1H, = 7.2 Hz), 7.66 (d, 2H, = 8.8 Hz), 7.55 (t, 1H, = 7.2 Hz), 7.51-7.47 (m, 2H), 7.15 (t, 2H, = 8.8 Hz), 6.82 (s, 1H), 5.54 (s, 2H); (LCMS): 456.2 (M+l); Purity: 94.97%. Following Example 81-91 have been synthesized by the above procedure described in Example 80 with their corresponding intermediates in similar reaction consitions:

¾NMR (DMSO-d6, 400 MHz) δ: 9.16 (s,

1 -(4-Methoxy-phenyl)-3- { 4- IH), 8.68 (s, IH), 8.65 (s, IH), 8.26 (d, IH, [2-(5-oxo-5H-imidazo [1,5- = 8 Hz), 8.17 (dd, IH, = 1.2, 8 Hz), a]quinazolin-4-yl)-acetyl]- 8.04 (d, 2H, = 8.8 Hz), 7.92 (dt, IH, = phenyl}-urea

1.2, 8 Hz), 7.65 (d, 2H, = 8.8 Hz), 7.55 (t, lH, = 7.6 Hz), 7.38 (d, 2H, = 8.8 Hz), 6.89 (d, 2H, = 9.2 Hz), 6.82 (s, IH), 5.53 (s, 2H), 3.72 (s, 3H); (LCMS): 468.2 (M+1); Purity: 90.73%.

1 -Benzyl-3- { 4-[2-(5-oxo-5H-

¾NMR (DMSO-d6, 400 MHz) δ: 9.13 (s, imidazo[l,5-a] quinazolin-4- IH), 8.65 (s, IH), 8.25 (d, IH, = 8 Hz), yl)-acetyl] -phenyl } -urea

8.16 (d, IH, = 7.6 Hz), 8.01 (d, 2H, = 8.4 Hz), 7.91 (t, IH, = 7.6 Hz), 7.61 (d, 2H, = 8.4 Hz), 7.54 (t, IH, = 8 Hz), 7.34-7.33 (m, 4H), 7.27-7.25 (m, IH), 6.85- 6.83 (m, IH), 6.80 (s, IH), 5.51 (s, 2H), 4.33 (d, 2H, = 5.6 Hz); (LCMS): 452.2 (M+1); Purity: 92.19%.

1 -Cyclohexyl-3- { 4- [2-(5 -oxo-

^X HNMR (DMSO-d6, 400 MHz) δ: 8.84 (s, 5H-imidazo[ 1 ,5-a]

IH), 8.62 (s, IH), 8.23 (d, IH, = 8.4 Hz), quinazolin-4-yl)-acetyl] - 8.16 (dd, IH, = 1.2, 8 Hz), 7.98 (d, 2H, phenyl} -urea

= 8.8 Hz), 7.9 (dt, IH, = 1.6, 8.4 Hz), 7.57-7.53 (m, 3H), 6.78 (s, IH), 6.29 (d, IH, = 8 Hz), 5.49 (s, 2H), 1.84-1.8 (m, 2H), 1.69-1.65 (m, 2H), 1.57-1.52 (m, IH), 1.36- 1.26 (m, 3H), 1.20-1.14 (m, 3H); ); (LCMS):

^Η ό 444.2 (M+1); Purity: 97.25%.

^X HNMR (DMSO-d6, 400 MHz) δ: 9.57 (s,

1 -(2-Fluoro-phenyl)-3- { 4-[2- IH), 8.71-8.65 (m, 2H), 8.26-8.1 (m, 2H), (5-oxo-5H-imidazo [1,5- 7.94-7.88 (m, IH), 7.67-7.53 (m, 4H), 7.27- a]quinazolin-4-yl)-acetyl]- 7.12 (m, 4H), 7.06-7.02 (m, IH), 6.82 (s, phenyl}-urea

IH), 5.55 (s, 2H); (LCMS): 456.2 (M+1); Purity: 90.66%.

^X HNMR (DMSO-d6, 400 MHz) δ: 9.34 (s, l-(2-Fluoro-phenyl)-3-{3-[2- 1H), 8.66 (s, 1H), 8.6 (d, 1H, J = 1.6 Hz), (5-oxo-5H-imidazo [1,5- 8.27 (d, 1H, J = 8.4 Hz), 8.17 (dd, 1H, J = a]quinazolin-4-yl)-acetyl]- 0.8, 8 Hz), 8.15-8.11 (m, 2H), 7.92 (dt, 1H,

89 phenyl}-urea J = 1.2, 8.4 Hz), 7.8 (t, 2H, = 8 Hz), 7.55

(t, 2H J = 8 Hz), 7.27-7.21 (m, 1H), 7.14 (t, 1H, J = 7.6 Hz), 7.05-6.99 (m, 1H), 6.85 (s, 1H), 5.56 (s, 2H); (LCMS): 456.2 (M+1); Purity: 94.6%.

l-(4-(l-hydroxy-2- ^X HNMR (DMSO-d6, 400 MHz) δ: 9.40 (s, (imidazo[l,5-a]quinazolin- 1H), 8.77-8.74 (m, 2H), 7.82 (d, 1H, J = 8.0 4(5H)-yl)ethyl)phenyl)-3- Hz), 7.47-7.42 (m, 7H), 7.36 (d, 2H, J = 8.8

90 phenylurea Hz), 7.29-7.20 (m, 3H), 6.97-6.95 (m, 1H),

5.54 (br. s, 1H), 4.96-4.93 (m, 1H), 4.60-4.49 (m, 2H), 3.32-3.28 (m, 2H); (LCMS): 426.1 (M+1); LCMS; Purity = 91.45%.

l-(3-chloro-4-fluorophenyl)- ¾NMR (CDCb, 400 MHz) δ: 9.26 (s, 1H), 3-(4-(2-(5-oxoimidazo[l,5- 9.04 (s, 1H), 8.65 (s, 1H), 8.26 (d, 1H, J = a]quinazolin-4(5H)- 8.0 Hz), 8.16 (d, 1H, J = 8.0 Hz), 8.06 (d, yl)acetyl)phenyl)urea 2H, J = 8.8 Hz), 7.95-7.88 (m, 1H), 7.83-

91 7.81 (m, 1H), 7.67 (d, 2H, J = 8.8 Hz), 7.55

(t, 1H, J = 7.6 Hz), 7.38-7.32 (m, 2H), 6.82 (s, 1H), 5.54 (s, 2H); (LCMS): 490.1 (M+1); Purity: 99.12%.

Example 92: Preparation of 2-(2,5-Difluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5- al quinazolin-4-yl)-acetyll -phenyl } -acetamide :

Step 1: Synthesis of N-(4-Acetyl-phenyl)-2-(2,5-difluoro-phenyl)-acetamide:

4- Amino acetophenone (0.3 g, 2.22 mmol) was dissolved in DCM (10 mL) followed by addition of 2,5-Difluoro phenyl acetic acid (0.42 g, 2.44 mmol) and di-isopropylethylamine (0.57 g, 4.44 mmol) at 0 °C. T3P solution (50% in Ethyl acetate, 2.1 mL, 3.33 mmol) was added to reaction mixture and it was allowed to warm to room temperature and further stirred for about lhour. Reaction mixture was diluted with water (15 ml) and DCM (10 ml). Organic layer was washed with water (3 x 10 ml), brine, dried over anhydrous sodium sulphate, filtered and concentrated to obtained N-(4-Acetyl-phenyl)-2-(2,5-difluoro-phenyl)-acetamide (0.35g, 54%). ^NMR (CDCls) δ: 7.92 (d, 2H, = 8.4 Hz), 7.59 (d, 2H, = 8.4 Hz), 7.12-7.05 (m, 2H), 7.02- 6.97 (m, 1H), 3.73 (s, 2H), 2.56 (s, 3H).

Step 2: Synthesis of N-[4-(2-Bromo-acetyl)-phenyl]-2-(2, 5-difluoro-phenyl)-acetamide:

N-(4-Acetyl-phenyl)-2-(2,5-difluoro-phenyl)-acetamide (Step 1, 0.35 g, 1.21 mmol) was dissolved in HBr in AcOH (1.75 mL, 5 vol) at 0 to 5° C. Bromine (0.21 g, 1.33 mmol) in AcOH (1.1 ml) was added at same temperature. Reaction mixture was allowed to warm to room temperature and stirred for about 1 hour. Water (15 mL) was added and the solid formed was filtered, dried under vaccum to yield crude N-[4-(2-Bromo-acetyl)-phenyl]-2-(2, 5-difluoro- phenyl)-acetamide, which was used as such for next step. (0.3 g).

^NMR (CDCls) δ: 7.93 (d, 2H, = 8.4 Hz), 7.63 (d, 2H, = 8.4 Hz), 7.1-7.04 (m, 2H), 7.02- 6.97 (m, 1H), 4.40 (s, 2H), 3.73 (s, 2H).

Step 3: Synthesis of 2-(2,5-Difluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quin azolin-4- yl)-acetyl] -phenyl } -acetamide:

To a stirred solution of 4H-Imidazo[l,5-a]quinazolin-5-one (Example 1-Step 4, 0.1 g, 0.5405 mmol) in DMF (5 mL) was added cesium carbonate (0.26 g, 0.81 mmol) and N-[4-(2- Bromo-acetyl)-phenyl]-2-(2, 5-difluoro-phenyl)-acetamide (0.21 g, 0.59 mmol) at room temperature and was stirred for about 1 hour. Reaction mixture was diluted with water and solid formed was filtered, dried to get crude product, which was purified by silica gel flash column chromatography to get 2-(2,5-Difluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quin azolin-4- yl)-acetyl] -phenyl }-acetamide (15 mg, 6%).

¾NMR (DMSO-d6, 400 MHz) δ: 10.67 (s, 1H), 8.64 (s, 1H), 8.23 (d, 1H, = 8.4 Hz), 8.16 (d, 1H, = 8.4 Hz), 8.08 (d, 2H, = 8.8 Hz), 7.91 (t, 1H, 7 = 8.4 Hz), 7.79 (d, 2H, = 8.4 Hz), 7.55 (t, 1H, = 8 Hz), 7.29-7.15 (m, 3H), 6.80 (s, 1H), 5.53 (s, 2H), 3.81 (s, 2H); (LCMS): 473.2 (M+1); Purity: 91.15%

Following Example 93-138 have been synthesized by the above procedure described in Example 92 with their corresponding intermediates in similar reaction consitions:

phenyl } -acetamide = 8.4 Hz), 7.91 (t, 1H, = 7.6 Hz),

(M+l); Purity: 90.99%. 8.4

Hz), 1.23 (dd, IH, = 4.4, 12 Hz);

(LCMS): 445.2 (M+l); Purity: 92.94%.

2-(2-Chloro-phenyl)-N- { 4-[2-(5- ¾NMR (DMSO-d6, 400 MHz) 5: 10.66 oxo-5H-imidazo[ 1 ,5-a] (s, IH), 8.65 (s, IH), 8.26 (d, IH, = 8 quinazolin-4-yl)-acetyl] - Hz), 8.16 (d, IH, = 7.6 Hz), 8.09 (d, phenyl } -acetamide 2H, = 7.2 Hz), 7.92 (t, IH, = 7.2

115

Hz), 7.81 (d, 2H, = 7.6 Hz), 7.57-7.53 (m, IH), 7.45-7.29 (m, 4H), 6.81 (s, IH), 5.55 (s, 2H), 3.92 (s, 2H); (LCMS): 471.2 (M+l); Purity: 90.17%.

N-{4-[2-(5-Oxo-5H- ¾NMR (DMSO-d6, 400 MHz) δ: 10.54 imidazo[ 1 ,5-a]quinazolin-4-yl)- (s, IH), 8.65 (s, IH), 8.26-8.25 (m, IH), acetyl] -phenyl } -2-p-tolyl- 8.16-8.15 (m, IH), 8.08-8.07 (m, 2H), acetamide 7.91-7.9 (m, IH), 7.81-7.8 (m, 2H), 7.56-

116 7.53 (m, IH), 7.22-7.14 (m, 4H), 6.81 (s,

IH), 5.54 (s, 2H), 3.66 (s, 2H), 2.28 (s, 3H); (LCMS): 451.2 (M+l); Purity: 95.04%.

2-Propyl-pentanoic acid {4- [2- ¾NMR (DMSO-d6, 400 MHz) δ: 10.28 (5-oxo-5H-imidazo[l,5-a] (s, IH), 8.65 (s, IH), 8.26 (d, IH, = 8.4 quinazolin-4-yl)-acetyl] - Hz), 8.16 (dd, IH, = 1.2, 8 Hz), 8.07 phenyl} -amide (d, 2H, = 8.8 Hz), 7.91 (dt, IH, =

1.6, 8.4 Hz), 7.84 (d, 2H, = 8.8 Hz),

117

7.54 (dt, IH, = 0.4, 8 Hz), 6.80 (s, IH), 5.54 (s, 2H), 2.47-2.44 (m, IH), 1.61-

₀ <=k^— - 1.54 (m, 2H), 1.43-1.38 (m, 2H), 1.31- 1.24 (m, 4H), 0.88 (t, 6H, = 3.2 Hz); (LCMS): 445.3 (M+l); Purity: 94.92%.

2-(4-Chloro-phenyl)-N- { 4-[2-(5- ^X HNMR (DMSO-d6, 400 MHz) δ: 10.6

118

oxo-5H-imidazo[ 1 ,5-a] (s, IH), 8.86 (s, IH), 8.28 (d, IH, = 8 quinazolin-4-yl)-acetyl] - Hz), 8.18 (dd, IH, J = 1.2, 8 Hz), 8.08 phenyl } -acetamide (d, 2H, J = 8.8 Hz), 7.94 (dt, IH, J =

1.2, 8.4 Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.58 (t, IH, J = 7.6 Hz), 7.41-7.35 (m, 4H), 6.95 (s, IH), 5.55 (s, 2H), 3.73 (s, 2H); (LCMS): 471.1 (M+l); Purity: 91.68%.

2-(3-Fluoro-phenyl)-N- { 4-[2-(5- ^X HNMR (DMSO-d6, 400 MHz) δ: 10.6 oxo-5H-imidazo[ 1,5- (s, IH), 8.65 (s, IH), 8.26 (d, IH, J = 8.4 a]quinazolin-4-yl)-acetyl]- Hz), 8.16 (d, IH, J = 8 Hz), 8.08 (d, 2H, phenyl } -acetamide J = 8.8 Hz), 7.92 (dt, IH, J = 1.2, 8.4

Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.55 (t,

119

IH, J = 7.6 Hz), 7.38 (dd, IH, J = 8, 14.4 Hz), 7.18 (d, 2H, J = 8.8 Hz), 7.12- 7.08 (m, IH), 6.81 (s, IH), 5.54 (s, 2H), 3.76 (s, 2H); (LCMS): 455.2 (M+l); Purity: 91.24%.

5-Methyl-isoxazole-4-carboxylic ¾NMR (DMSO-d6, 400 MHz) δ: 10.40 acid {4-[2-(5-oxo-5H- (s, IH), 9.12 (s, IH), 8.66 (d, IH, J = 0.8 imidazo[ 1 ,5-a]quinazolin-4-yl)- Hz), 8.27 (d, IH, J = 8 Hz), 8.17 (dd, acetyl] -phenyl } - amide IH, J = 1.2, 8 Hz), 8.14 (d, 2H, J = 8.8

120 Hz), 7.94-7.90 (m, 3H), 7.55 (dt, IH, J =

1.2, 8 Hz), 6.84 (d, IH, J = 0.8 Hz), 5.57

<y°Yi (s, 2H), 2.71 (s, 3H); (LCMS): 428.1

(M+l); Purity: 98.11%.

N-{4-[2-(5-Oxo-5H- ¾NMR (DMSO-d6, 400 MHz) δ: 10.65 imidazo[ 1 ,5-a]quinazolin-4-yl)- (s, IH), 8.68 (s, IH), 8.26 (d, IH, J = 8.4

121 acetyl] -phenyl } -2-(3 - Hz), 8.16 (d, IH, J = 7.2 Hz), 8.09 (d, trifluoromethyl-phenyl)- 2H, J = 8.8 Hz), 7.92 (t, IH, J = 8.4 acetamide Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.72 (s, 1H), 7.66-7.63 (m, 2H), 7.59 (d, IH, =

7.6 Hz), 7.55 (t, IH, = 7.6 Hz), 6.83 (s, IH), 5.54 (s, 2H), 3.87 (s, 2H) (LCMS): 505.2 (M+l); Purity: 96.1%.

2-(3,4-Dichloro-phenyl)-N- { 4- ^X HNMR (DMSO-d6, 400 MHz): 58.36 [2-(5-oxo-5H-imidazo [1,5- (d, IH, = 8 Hz), 8.11 (s, IH), 8.01 (d, a]quinazolin-4-yl)-acetyl]- 2H, = 8.4 Hz), 7.78-7.73 (m, 2H), 7.65

122 phenyl } -acetamide (d, 2H, = 8.4 Hz), 7.51-7.46 (m, 3H),

7.37-7.34 (m, IH), 7.22-7.18 (m, IH), 6.53 (s, IH), 5.40 (s, 2H), 3.72 (s, 2H); (LCMS): 505.1 (M+l); Purity: 91.09%.

2-(3-Cmoro-4-fluoro-phenyl)-N- ¾NMR (DMSO-d6, 400 MHz): δ 10.60 {4-[2-(5-oxo-5H-imidazo[l,5- (s, IH), 8.71 (s, IH), 8.26 (d, IH, = 8.4 a]quinazolin-4-yl)-acetyl]- Hz), 8.16 (d, IH, = 8 Hz), 8.09 (d, 2H, phenyl } -acetamide = 8.8 Hz), 7.92 (t, IH, = 8Hz), 7.80

(d, 2H, = 8.8 Hz), 7.56 (t, 2H, = 7.6

123

Hz), 7.38-7.35 (m 2H), 6.85 (s, IH), 5.55 (s, 2H), 3.76 (s, 2H); (LCMS): 489.2 (M+l); Purity: 91.49%

2-Cyclopropyl-N- { 4- [2-(5 -oxo- ¾NMR (DMSO-d6, 400 MHz): δ 10.24 5H-imidazo[ 1 ,5-a]quinazolin-4- (s, IH), 8.65 (s, IH), 8.26 (d, IH, = 8.4 yl)-acetyl] -phenyl } -acetamide Hz), 8.16 (dd, IH, = 1.6, 7.6 Hz), 8.07

(d, 2H, = 8.8 Hz), 7.94-7.90 (m, IH), 7.81 (d, 2H, = 8.8 Hz), 7.57-7.53 (m,

124 IH), 6.82 (s, IH), 5.54 (s, 2H), 2.29 (s,

IH), 2.27 (s, IH), 1.10-1.05 (m, IH), 0.52-0.46 (m, 2H), 0.23-0.20 (m, 2H) (LCMS): 401.2 (M+l); Purity: 90.43%

N-Methyl-N- { 4- [2-(5 -oxo-5H- ¾NMR (DMSO-d6, 400 MHz): δ 8.37

125

imidazo[ 1 ,5-a]quinazolin-4-yl)- (d, IH, = 7.6 Hz), 8.15 (s, IH), 8.08 acetyl] -phenyl } -2-phenyl- (d, 2H, = 8.4 Hz), 7.80-7.77 (m, 2H), acetamide 7.52-7.49 (m, 1H), 7.31 (d, 2H, = 8.4

Hz), 7.28-7.22 (m, 3H), 7.09 (d, 2H, = 7.2 Hz), 6.57 (s, 1H), 5.44 (s, 2H), 3.56 (s, 2H), 3.33 (s, 3H) (LCMS): 451.1

1 (M+l); LCMS purity = 95.26%

N-{4-[2-(5-Oxo-5H-imidazo ^X HNMR (DMSO-d6, 400 MHz): δ 10.65 [l,5-a]quinazolin -4-yl)-acetyl]- (s, 1H), 8.65 (s, 1H), 8.54 (d, 1H, = 1.6 phenyl}-2-pyridin-3-yl- Hz), 8.48 (dd, 1H, J = 1.6, 4.8Hz), 8.26 acetamide (d, 1H, = 8.4 Hz), 8.16 (dd, 1H, =

1.2, 6.8Hz), 8.09 (d, 2H, = 8.8 Hz), 7.91 (dt, 1Η, / = 1.6, 8.8 Hz), 7.11 (d, 2H, = 8.8Hz), 7.76 (d, 1Η, = 7.6 Hz), 7.54 (t, 1H, = 8.0Hz), 7.38 (dd, 1H, = 4.8, 7.6Hz), 6.81(s, 1H), 5.54 (s, 2H), 3.79 (s, 2H) (LCMS): 438.2 (M+l); Purity: 97.99%

2-Cyclohexyl-N- { 4- [2-(5 -oxo- ¾NMR (DMSO-d6, 400 MHz): δ 10.27 5H-imidazo[l,5-a] quinazolin-4- (s, 1H), 8.65 (s, 1H), 8.26 (d, 1H, = 8.4 yl)-acetyl] -phenyl } -acetamide Hz), 8.16 (dd, 1H, = 1.2, 7.6Hz), 8.06

(d, 2H, = 8.8Hz), 7.91 (dt, 1H, = 1.6, 8.8 Hz), 7.80 (d, 2H, = 8.8Hz), 7.55 (t, 1H, = 8.0Hz), 6.81 (s, 1H), 5.54 (s, 2H), 2.25 (d, 2H, = 8.0Hz), 1.80-1.76 (m, 1H), 1.72-1.60 (m, 5H), 1.34-1.29 (m, 1H), 1.28-1.18 (m, 2H), 1.12-1.03 (m, 2H) (LCMS): 443.2 (M+l); Purity: 95.77% 4-(2-(4-(dimethylamino)phenyl)- ^X HNMR (CDCb, 400 MHz) δ: 8.65 (s, 2-oxoethyl)imidazo [ 1 , 5 - IH), 8.26 (d, IH, = 8.0 Hz), 8.16 (d, a]quinazolin-5(4H)-one IH, = 7.6 Hz), 7.96-7.88 (m, 3H), 7.54

(t, IH, = 7.6 Hz), 6.8-6.74 (m, 3H), 5.45 (s, 2H), 3.05 (s, 6H); (LCMS): 347.1 (M+1); Purity: 95.87%.

1

2-fluoro-N-(3-(2-(5- ¾NMR (DMSO-d6, 400 MHz) δ: 10.68 oxoimidazo[ 1 ,5-a]quinazolin- (s,lH), 8.66 (s, IH), 8.39 (s, IH), 8.27 (d, 4(5H)- IH, = 8.4 Hz), 8.17 (dd, IH, = 1.2, yl)acetyl)phenyl)benzamide 8.0 Hz), 8.08 (d, IH, = 8.0 Hz), 7.95- 7.90 (m, 2H), 7.72-7.68 (m, IH), 7.64- 7.53 (m, 3H), 7.39-7.33 (m, 2H), 6.87 (s, IH), 5.59 (s, 2H); (LCMS): 441.1 (M+1); Purity: 95.01 %.

N-(4-(2-(5-oxoimidazo[l,5- ¾NMR (DMSO-d6, 400 MHz) δ: 10.82 a]quinazolin-4(5H)- (s, IH), 9.14 (s, IH), 8.79 (d, IH, = 3.6 yl)acetyl)phenyl)nicotinamide Hz), 8.65 (s, IH), 8.33 (d, IH, = 8.0

Hz), 8.26 (d, IH, = 8.0 Hz), 8.17-8.14 (m, 3H), 8.01 (d, 2H, = 8.4 Hz), 7.91 (t, IH, = 7.6 Hz), 7.61-7.53 (m, 2H), 6.84 (s, IH), 5.58 (s, 2H); (LCMS): 424.1

(M+1); Purity: 94.69%.

2-(2-fluorophenyl)-N-(3-(2-(5- ¾NMR (CDCb, 400 MHz) δ: 10.49 (s, oxoimidazo[l,5-a] quinazolin- IH), 8.65 (s, IH), 8.30-8.20 (m, 2H), 8.16 4(5H)-yl)acetyl)phenyl) (d, IH, = 7.6 Hz), 7.90-7.86 (m, 3H), acetamide 7.60-7.5 (m, 2H), 7.42-7.29 (m, IH), 7.32- 7.31 (m, IH), 7.20-7.14 (m, 2H), 6.85 (s, IH), 5.55 (s, 2H), 3.77 (s, 2H); LCMS): 455.2 (M+1); Purity: 97.35%. N-(4-(2-(5- oxoimidazo[l,5- ^X HNMR (CDCls, 400 MHz) δ: 10.64 (s, a]quinazolin-4(5H)- 1H), 8.65 (s, 1H), 8.27-8.25 (m, 2H), yl)acetyl)phenyl)-2-(2- 8.17-8.15 (m, 2H), 8.14-8.12 (m, 1H),

(trifluoromethyl)phenyl)acetami 8.10-8.07 (m, 2H), 7.93-7.90 (m, 2H),

132 de 7.81-7.54 (m, 3H), 6.81 (s, 1H), 5.54 (s,

2H), 4.0 (s, 2H); (LCMS): 505.2 (M+1); Purity: 92.13%.

N-(3-(2-(5-oxoimidazo[l,5- ^X HNMR (CDCls, 400 MHz) δ: 10.71 (s, a]quinazolin-4(5H)- 1H), 9.14 (d, 1H, = 1.6 Hz), 8.76 (dd, yl)acetyl)phenyl)nicotinamide 1H, = 1.6, 4.8 Hz), 8.67 (s, 1H), 8.43 (s,

1H), 8.34-8.31 (m, 1H), 8.27 (d, 1H, =

133 8.4 Hz), 8.17 (d, 2H, = 8.0 Hz), 7.97- 7.90 (m, 2H), 7.64 (t, 1H = 7.6 Hz), 7.60-7.54 (m, 2H), 6.88 (s, 1H), 5.60 (s, 2H); (LCMS): 424 (M+1); Purity: 96.04%.

2-cyclohexyl-N-(3-(2-(5- ¾NMR (CDCls, 400 MHz) δ: 10.14 (s, oxoimidazo[ 1 ,5-a]quinazolin- 1H), 8.67 (s, 1H), 8.28-8.24 (m, 2H), 8.16 4(5H)- (d, 1H, = 7.6 Hz), 7.97-7.90 (m, 2H), yl)acetyl)phenyl)acetamide 7.85 (d, 1H, = 8.0 Hz), 7.56-7.54 (m,

134

2H), 6.86 (s, 1H), 5.56 (s, 2H), 2.24-2.17 (m, 2H), 1.74-1.55 (m, 6H), 1.27-1.14 m, 3H), 1.01 - 0.92 (m, 2H); (LCMS): 443.2 (M+1); Purity: 91.50%.

N-(4-(2-(5-oxoimidazo[l,5- ¾NMR (CDCls, 400 MHz) δ: 10.3 (s, a]quinazolin-4(5H)- 1H), 8.65 (s, 1H), 8.28-8.76 (m, 7H),

135 yl)acetyl)phenyl)propionamide 7.59-7.50 (m, 1H), 6.82 (s, 1H), 5.54 (s,

2H), 2.44-2.25 (m, 2H), 1.16-1.0 (m, 3H); (LCMS): 375.1 (M+1); Purity: 90.66%. H

4-(2-oxo-2-(5,6,7,8- ¾NMR (CDCI3, 400 MHz) δ: 8.65 (s, tetrahydronaphthalen-2- IH), 8.25 (d, IH, = 8.0 Hz), 8.16 (d, yl)ethyl)imidazo [ 1,5- IH, = 7.2 Hz), 7.91 (t, IH, = 6.8 Hz), a]quinazolin-5(4H)-one 7.83 (s, IH), 7.79 (d, IH, = 7.2 Hz),

136 7.54 (t, IH, = 7.2 Hz), 7.27 (d, IH, = o 7.2 Hz), 6.81 (s, IH), 5.55 (s, 2H), 2.90- 2.74 (m, 4H), 1.84-1.68 (m, 4H); (LCMS): 358.1(M+1); Purity: 99.05%.

4-(2-oxo-2-(4-(piperidin- 1 - ¾NMR (CDCb, 400 MHz) δ: 8.64 (s, yl)phenyl)ethyl)imidazo[ 1 ,5- IH), 8.25 (d, IH, = 8.0 Hz), 8.16 (d, a]quinazolin-5(4H)-one IH, = 7.6 Hz), 7.95-7.88 (m, 3H), 7.55

(t, IH, = 7.2 Hz), 7.01 (d, 2H, = 8.8

137

Hz), 6.76 (s, IH), 5.45 (s, 2H), 3.48-3.4 (m, 4H), 1.67-1.55 (m, 6H); (LCMS): 387.1 (M+l); Purity: 95.45%.

2-fluoro-N-(4-(2-(5- ¾NMR (CDCb, 400 MHz) δ: 10.84 (s, oxoimidazo[ 1 ,5-a]quinazolin- IH), 8.66 (s, IH), 8.26 (d, IH, = 7.6

4(5H)- Hz), 8.18-8.13 (m, 3H), 7.96-7.9 (m, 3H), yl)acetyl)phenyl)benzamide 7.72 (t, IH, = 6.8 Hz), 7.62-7.59 (m,

138

IH), 7.55 (t, IH, = 7.2 Hz), 7.40 -7.34 (m, 2H), 6.84 (s, IH), 5.57 (s, 2H); (LCMS): 441 (M+l); Purity: 95.35%. Example 139: Preparation of 4-(2-oxo-2-phenylethyl)-6J,8,9-tetrahydroimidazori,5- al quinazolin-5 (4H)-one:

Step 1: Synthesis of N-((4-oxo-3,4,5,

N-formylation of 2-(aminomethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (synthesized as described in WO 2013012723A1 and WO 2013010092A1) was carried out using the same procedure as described in Example No-1, step-3 to give N-((4-oxo-3, 4,5, 6,7,8- hexahydroquinazolin-2-yl)methyl)formamide as yellow solid (0.22 g, 50.5%). ^χ ΗΝΜΡν (DMSO- d6, 400 MHz) δ: 12.13 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 4.14 (d, 2H, J - 5.6 Hz), 2.49-244 (m, 2H), 2.3-2.28 (m, 2H), 1.72-1.60 (m, 4H); LCMS: 208.1 (M+l).

Step 2: Synthesis of 6,7,8,9-tetrahydro uinazolin-5(4H)-one):

Cyclization reaction of N-((4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2- yl)methyl)formamide using the same procedure as described in Example 1-step 4 to give 4H- Imidazo[l,5-a]quinazolin-5-one. 6,7,8,9-tetrahydroimidazo[l,5-a]quinazolin-5(4H)-one as pale yellow solid (0.61 g, 66.8%).

^NMR (DMSO-d6, 400 MHz) δ: 11.74 (s, 1H), 8.01 (s, 1H), 6.74 (s, 1H), 2.60 (t, 2H, = 5.6 Hz), 2.39 (t, 2H, = 5.6 Hz), 1.74-1.76 (m, 4H); LCMS: 190.1 (M+l).

Step 3: Synthesis of 4-(2-oxo-2-phenylethyl)-6,7,8,9-tetrahydroimidazo[l,5-a]quin azolin- 5(4H)-one:

4-(2-oxo-2-phenylethyl)-6,7,8,9-tetrahydroimidazo[l,5-a]quin azolin-5(4H)-one was obtained as pale yellow solid (0.017 g, 10.5%) by using the same procedure as described in Example No 1.

lUNMR (CDCb, 400 MHz) δ: 8.99 (s, 1H), 8.07 (d, 2H, = 7.6 Hz), 7.76 (t, 1H, = 7.2 Hz), 7.63 (t, 2H, = 7.2 Hz), 7.34 (s, 1H), 6.09 (s, 2H), 4.10-4.08 (m, 2H), 2.75-2.60 (m, 2H), 1.85- 1.70 (m, 4H); (LCMS): 308.1 (M+1); Purity: 97.39 %.

Following Example 140 has been synthesized by the above procedure described in Example 139 with their corresponding intermediates in similar reaction consitions:

Example 141: Prepartion of 4-(2-(l-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-2- oxoethyl)imidazo[l,5-alquinazolin- -one:

Step 1: Synthesis of 4-acetylpiperidin-l-yl)-2-(2-fluorophenyl)ethan-l-one:

4-aetyl piperidine was coupled with 2-fluorophenylacetic acid using T3P/DIPEA conditions to give 4-acetylpiperidin- l-yl)-2-(2-fluorophenyl)ethan-l -one by using experimental procedure as described in Example 92-step 1. 4-acetylpiperidin- l-yl)-2-(2-fluorophenyl)ethan-l- one was confirmed by LCMS analysis 264.1 (M+l).

Step 2: Synthesis of 2-bromo-l-(l-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)ethan- l-one:

Bromination of 4-acetylpiperidin- l-yl)-2-(2-fluorophenyl)ethan-l -one was carried out using bromine and HBr in acetic acid as described in Example 92-step 2 to give 2-bromo-l-(l- (2-(2-fluorophenyl)acetyl)piperidin-4-yl)ethan-l-one. This was used as such for the next reaction.

Step 3: Synthesis of 4-(2-(l-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-2-oxoethyl )imidazo[l,5- a] quinazolin-5 (4H)-one:

4H-Imidazo[l,5-a]quinazolin-5-one was coupled with 2-bromo-l-(l-(2-(2- fluorophenyl)acetyl)piperidin-4-yl)ethan-l-one using cesium carbonate as base and DMF as solvent as experimental procedure described in Example 92-step 3.

^NMR (CDCls, 400 MHz) δ: 8.63 (s, IH), 8.23 (d, IH, = 8.4 Hz), 8.15 (dd, IH, = 1.2, 8 Hz), 7.90 (dt, IH, = 1.6, 8.4Hz), 7.54 (t, IH, = 7.6 Hz), 7.33- 7.22 (m, 2H), 7.17-7.10 (m, 2H), 6.75 (s, IH), 5.04 (s, 2H), 4.35 (d, IH, = 12.8 Hz), 4.03-3.99 (m, IH), 3.75 (d, 2H, = 4.4 Hz), 3.22-3.14 (m, IH), 3.01-3.95 (m, IH), 2.77-2.72 (m, IH), 1.98-1.94 (m, 2H), 1.54-1.34 (m, 2H); LCMS): 447.3 (M+l) Purity: 94.82%. Following Example 142 has been synthesized by the above procedure described in

Example 141 with their corresponding intermediates in similar reaction consitions:

Example 143: Preparation of 4-(2-hvdroxy-2-( 1 -(2-phenylacetyl)piperidin-4- yl)ethyl)imidazo[l,5-alquinazolin- -one:

4-(2-(l-(2-phenylacetyl)piperidin-4-yl)-2-oxoethyl)imidazo[l ,5-a]quinazolin-5(4H)-one (Example 142) was treated with sodium borohydride by using experimental procedure as described in Example 2 to obtain 4-(2-hydroxy-2-( 1 -(2-phenylacetyl)piperidin-4- yl)ethyl)imidazo[l,5-a]quinazolin-5(4H)-one.

¾NMR (CDCls, 400 MHz) δ: 8.6 (s, IH), 8.22-8.12 (m, 2H), 7.90-7.78 (m, IH), 7.54-7.46 (m, IH), 7.36-7.11 (m, 5H), 6.75 (s, IH), 4.90-4.82 (m, IH), 4.50-4.38 (m, IH), 4.10-3.65 (m, 4H), 3.0-2.85 (m, IH), 1.90-1.75 (m, IH), 1.70-1.55 (m, 3H), 1.30-1.05 (m, 3H); (LCMS): 431.1 (M+l); Purity: 94.67%.

Example 144: Preparation of N-benzyl-4-methyl-N-(4-(2-(5-oxoimidazo[l,5-alquinazolin- 4(5H)-yl)acetyl)phenyl)benzenesulfonamide:

Step 1: Synthesis of N-(4-acetylphenyl)-4-methylbenzenesulfonamide:

To a solution of 4-aminoacetophenone (5.0 g, 36.99 mmol) and pyridine (3.4 g, 44.3 mmol) in MDC (60 ml) was added j?-toluenesulfonyl chloride (8.2 g, 44.3 mmol) drop wise at about 0-5 °C. Reaction mixture was allowed to stir at room temperature for about 16 hours and monitored by TLC/LCMS. After completion of reaction was diluted with H ₂ 0 and precipitated solid was filtered and washed with water and hexane. Solid was dried under vacuum at about 50 °C to give N-(4-acetylphenyl)-4-methylbenzenesulfonamide (10.0 g, 93.4%) as white solid. Product was confirmed by LCMS: 290.1 (M+l).

Step 2: Synthesis of N-(4-acetylphenyl)-N-benzyl-4-methylbenzenesulfonamide:

Into a DMF (20 ml) solution of N-(4-acetylphenyl)-4-methylbenzenesulfonamide (Step 1, 1.0 g, 3.45 mmol) was added K2CO3 (0.715 g, 5.18 mmol) and reaction mixture was cooled to about 0 °C. Benzyl bromide (0.65 g, 3.80 mmol) was added to reaction mixture drop wise and allowed to stir at room temperature for about 16 hours. Reaction was monitored by TLC/LCMS. After completion reaction mixture was poured on to the ice-water and product was extracted with ethyl acetate (3x200 ml). Combined ethyl acetate was dried over anhydrous sodium sulphate, filtered and concentrated to give N-(4-acetylphenyl)-N-benzyl-4-methylbenzenesulfonamide (1.2 g, 91.6%) as pale yellow solid. This was used as such for next step without further purification. LCMS: 380.1 (M+l)

Step 3: Synthesis of N-benzyl-N-(4-(2-bromoacetyl)phenyl)-4-methylbenzenesulfonam ide:

Bromination of N-(4-acetylphenyl)-N-benzyl-4-methylbenzenesulfonamide was carried out using experimental procedure as described in Example 92-step 2 to give N-benzyl-N-(4-(2- bromoacetyl)phenyl)-4-methylbenzenesulfonamide (0.370 g, 61.2%) as yellowish solid. This was used as such for next step without further purification. LCMS: 458.

Step 4: Synthesis of N-benzyl-4-methyl-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5 H)- yl)acetyl)phenyl)benzenesulfonamide:

N-benzyl-4-methyl-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5 H)- yl)acetyl)phenyl)benzenesulfonamide (0.195 g, 53.4 %) was obtained as yellowish solid by using procedure as described in the Example 1. ^X HNMR (DMSO d6, 400 MHz) δ: 8.34 (dd, 1H, = 1.2, 8.4 Hz), 8.10 (s, 1H), 7.89 (d, 2H, = 8.0 Hz), 7.80-7.73 (m, 2H), 7.54 (d, 2H, = 8.0 Hz), 7.48 (dt, 1H, = 1.2, 8.0 Hz), 7.31 (d, 2H, = 8.0 Hz), 7.24-7.18 (m, 7H), 6.50 (s, 1H), 5.35 (s, 2H), 4.79 (s, 2H), 2.45 (s, 3H). LCMS: 563.1 (M+l). Example 145: Preparation of (4-(2-(4-(benzylamino)phenyl)-2-oxoethyl)imidazo|T,5- al quinazolin-5 (4H)-one) :

N-benzyl-4-methyl-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5 H)- yl)acetyl)phenyl)benzenesulfonamide (Example 144, 0.12 g, 0.213 mmol) was suspended in 50% aq H2SO4 (5.0 ml) and stirred at 75 °C for 4-5 h. Reaction was monitored TLC/LCMS. After completion of reaction mixture was quenched with aq NaHC0 ₃ solution under cooling. Compound was extracted in ethyl acetate (3x100 ml). Combined ethyl acetate was dried over anhydrous sodium sulphate, filtered and concentrated. Crude product was purified using preparative HPLC to get (4-(2-(4-(benzylamino)phenyl)-2-oxoethyl)imidazo[l,5-a]quina zolin- 5(4H)-one) (10 mg, 11.5%).

XHNMR (DMSO-d6, 400 MHz) δ: 8.37 (d, 1H, = 8.0 Hz), 8.10 (s, 1H), 7.90 (d, 2H, = 8.8 Hz), 7.78-7.72 (m, 2H), 7.49-7.44 (m, 1H), 7.39-7.29 (m, 5H), 6.65 (d, 2H, = 8.8 Hz), 6.54 (s, 1H), 5.35 (s, 2H), 4.71 (t, 1H, = 5.2 Hz), 4.44 (d, 2H, = 5.2 Hz); (LCMS): 409.1 (M+l); Purity: 93.58%. Example 146: N-(4-(2-(5-oxoimidazo[l,5-alquinazolin-4(5H)-yl)acetyl)benzy l)benzamide:

Step 1: Synthesis of N-(4-acetylbenzyl)benzamide:

To a solution of benzoic acid (197 mg, 1.61 mmol) in DMF (8 ml) was added HATU (631 mg, 1.94 mmol), DIPEA (0.71 ml, 4.03 mmol) and 4-acetylbenzylamine (300 mg, 1.61 mmol). The reaction mixture was stireed at room temperature for about three hours and diluted with water (25 ml). Precipitated solid was filtered, washed with water (2x 10 ml) and dried under vacuum to give N-(4-acetylbenzyl)benzamide (0.25 g, 61.2 %) as white solid. ^X HNMR (DMSO d6, 400 MHz) δ: 7.93 (d, 2H, = 8.4 Hz), 7.81 (d, 2H, = 8.4 Hz), 7.52 (t, 1H, = 7.2 Hz), 7.46 (d, 2H, = 7.6 Hz), 7.44 (d, 2H, = 7.6 Hz), 6.58 (br. s, 1H), 4.71 (d, 2H, = 6 Hz), 2.59 (s, 3H); (LCMS): 254.1 (M+l).

Step 2: Synthesis of N-(4-(2-bromoacetyl)benzyl)benzamide:

N-(4-acetylbenzyl)benzamide (Step 1, 0.25 g, 0.988 mmol) was dissolved in diethyl ether (20 ml). To the above reaction mixture was added bromine (0.157g, 0.988 mmol) followed by catalytic amount of AlCb at about 0-10 °C. Reaction mixture was stirred at room temperature for about 5-6 hours, monitored by TLC/LCMS. After completion of reaction, reaction mixture was diluted with water and stirred for about 10 minutes. Product was extracted with ethyl acetate (3x100 ml). Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to give N-(4-(2-bromoacetyl)benzyl)benzamide (0.28 g, 85.3 %) as yellowish solid. Confirmed by LCMS: 332.1 (M+l) & 334.1 (M+2).

Step 3: Synthesis of N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)- yl)acetyl)benzyl)benzamide:

N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)benzy l)benzamide) (0.023 g, 13.6 %) was obtained as yellowish solid by using procedure as described in Example 1.

¾NMR (DMSO-d6, 400 MHz) δ: 9.18 (t, 1H, = 6.0 Hz), 8.66 (s, 1H), 8.26 (d, 1H, = 8.0 Hz), 8.16 (d, 1H, = 7.2 Hz), 8.08 (d, 2H, = 8.4 Hz), 7.93-7.90 (m, 3H), 7.56-7.47 (m, 6H), 6.82 (s, 1H), 5.58 (s, 2H), 4.59 (d, 2H, = 6.0 Hz); (LCMS): 437.1 (M+l); Purity: 99.10%.

Example 148: Preparation of 2-(4-(2-(5-oxoimidazorL5-alquinazolin-4(5H)- yl)acetyl)phenyl)isoindoline- 1 ,3-dione:

2-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)isoindoline-l,3-dione was prepared by using procedure as described in Example 1 with the corresponding intermediate of 2-(4-(2-bromoacetyl)phenyl)isoindoline-l,3-dione [prepared as described in Microchemical Journal, 1963, Vol. 7, p. 390-399 & Chem.Abstr., 1964 , vol. 60, p. 11934c.

^NMR (DMSO-d6, 400 MHz): δ 8.60 (s, 1H), 8.25(t, 2H, = 8.4 Hz), 8.17 (d, 2H, = 7.6 Hz), 8.01-7.98 (m, 2H), 7.93-7.90 (m, 3H), 7.86-7.78 (m, 2H), 7.55 (t, 1H, = 7.6 Hz), 6.90 (s, 1H), 5.63 (s, 2H); mass (LCMS): 449.2 (M+l). Example 149: Preparation of 2-((4-(2-(5-oxoimidazo[l,5-alquinazolin-4(5H)- yl)acetyl)phenyl)carbamoyl)benzoic acid:

To a solution of 2-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)- yl)acetyl)phenyl)isoindoline-l,3-dione (Example 148, 100 mg, 0.22 mmol) in methanol (5 ml) at room temperature was added KOH (15 mg, 0.26 mmol) and water (0.5 ml). The reaction mixture was stirred at about 60 °C for about 3-4 hours and monitored by TLC. After completion of reaction, reaction mixture was concentrated and residue was dissolved in water, washed with ethyl acetate and pH of aqueous layer was adjusted with dilute hydrochloric acid. The precipitated solid was filtered and washed with water followed by cyclohexane and dried under vacuum. Crude product was purified using trituration to give the title compound (30 mg, 29%). ^NMR (DMSO-d6, 400 MHz): δ 13.11 (s, 1H), 10.76 (s, 1H), 8.67 (s, 1H), 8.27 (d, 1H, = 8.0 Hz), 8.16 (d, 1H, = 7.6 Hz), 8.11 (d, 2H, = 8.4 Hz), 7.93-7.89 (m ,4H), 7.72-7.67 (m, 1H), 7.63-7.54 (m, 3H), 6.83 (s, 1H), 5.57 (s, 2H); LCMS:467.1 (M+l). xample 150: Preparation of 2-(5-oxoimidazori,5-alquinazolin-4(5H)-yl)-N-phenylacetamide :

Step 1: Synthesis of lithium 2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetate:

4H-Imidazo[l,5-a]quinazolin-5-one (Example 1-Step 4, 0.5 g, 2.7 mmol) was treated with ethylbromoacetate (0.451 g, 2.7 mmol) and cesium carbonate (1.32 g, 4.05 mmol) employing coupling procedure described for Example- 1 at about 70 °C for about 2 hours to give crude ethyl 2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetate. The crude product was subjected to hydrolysis using lithium hydroxide monohydrate (110 mg, 2.7 mmol) and methanol (2.5 ml) and tetrahydrofuran (2.5 ml) and stirred at room temperature for about 16 hours. Reaction mixture was concentrated to give crude lithium salt which was triturated with MDC (10 ml) to give 158 mg of 2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetate. This was used as such for the next step.

Step 2 : Synthesis of 2-(5-oxoimidaz -a]quinazolin-4(5H)-yl)-N-phenylacetamide:

To a solution of crude 2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetate (Step 1, 150 mg) in DMF (2 ml) was added DIPEA (112 mg, 0.86 mmol), HATU (382 mg, 0.86 mmol), aniline (53 mg, 0.57 mmol) and the reaction mixture was stirred for about 16 hours at room temperature. After completion of reaction, reaction mixture was partitioned between water (10 ml) and ethyl acetate (10 ml). Aqueous layer was extracted with ethyl acetate (3 x 10 ml). Combined organic extact was dried over sodium sulfate and concentrated to give crude product which was purified by flash column chromatography to give 2-(5-oxoimidazo[l,5-a]quinazolin- 4(5H)-yl)-N-phenylacetamide (50 mg). ^X HNMR (DMSO-d6, 400 MHz) δ: 10.35 (br. s, 1H), 8.66 (s, 1H), 8.30-8.16 (m, 2H), 7.93-7.89 (m, 1H), 7.66-7.50 (m, 2H), 7.36-7.28 (m, 2H), 7.09-7.04 (m, 1H), 6.86 (s, 1H), 4.81 (s, 2H); Mass (LCMS): 319.1 (M+l); Purity: 96.32%. Example 151: Preparation of 2-(2-fluorophenyl)-N-(4-(2-(imidazo[l,5-alquinazolin-4(5H)-y l)-

2-oxoethyl)phenyl)acetamide :

Step 1: Synthesis of 4,5-dihydroimidazo[l -a]quinazoline:

To a suspension of imidazo[l,5-a]quinazolin-5(4H)-one (0.5 g, 2.7 mmol) in THF (50 ml) was added LAH (0.5 g, 13.15 mmol) portion wise at room temperature. Reaction mixture was then stirred at about 75 °C for about 2-3 hours, and was monitored by TLC/LCMS. After completion of reaction was cooled to about 0-5 °C and quenched with sodium sulfate deca- hydrate. Reaction mixture was stirred for about 5-10 minutes and then filtered through Hyflo bed. Filtrate was concentrated on rotary evaporator at about 40 °C to give 4,5- dihydroimidazo[l,5-a]quinazoline as brownish oil (229 mg, 50%). LCMS: 172.1 (M+l).

Step 2: Synthesis of tert-butyl (4-(2-(imidazo[l,5-a]quinazolin-4(5H)-yl)-2- oxoethyl)phenyl)carbamate:

Boc-(4-aminophenyl)acetic acid (0.36 g, 1.45 mmol) was dissolved in DMF (10 ml) and cooled to about 5-10 °C. In to the above solution was added HATU (0.568 g, 1.74 mmol), DIPEA (0.63 ml, 2.5 mmol) and stirred for about 10-15 minutes. DMF solution of 4,5- dihydroimidazo[l,5-a]quinazoline (step 1, 220 mg, 12.8 mmol) was then added to above reaction mixture at about 5-10 °C. Reaction mixture was then allowed to stir at room temperature for about 2-3 hours and monitored by TLC/LCMS. After completion reaction was quenched with water and product was extracted with ethyl acetate (3x100 ml). Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to give tert-butyl (4-(2- (imidazo[l,5-a]quinazolin-4(5H)-yl)-2-oxoethyl)phenyl)carbam ate (0.22 g, 20.12 % after two steps).

¾NMR (CDCls) δ: 7.91 (s, 1H), 7.43-7.26 (m, 5H), 7.08 (d, 2H, / = 8 Hz), 6.90 (s, lh), 6.46 (s, 1H), 4.99 (s, 2H), 3.90 (s, 2H), 1.50 (s, 9H).

Step 3: Synthesis of 2-(4-aminophenyl)-l-(imidazo[l,5-a]quinazolin-4(5H)-yl)ethan -l-one:

tert-butyl (4-(2-(imidazo[ 1 ,5-a]quinazolin-4(5H)-yl)-2-oxoethyl)phenyl)carbamate (Step 2, 0.18 g, 0.44 mmol) was suspended in l,4-dioxane:HCl (25 ml) at about 0-5 °C. Reaction stirred at room temperature for 3-4 h and monitored by TLC. After completion of reaction, MTBE (50 ml) was added to reaction mixture and precipitated solid was filtered, washed with MTBE (2x10 ml) then dried under vacuum at about 40 °C to get 2-(4-aminophenyl)-l- (imidazo[l,5-a]quinazolin-4(5H)-yl)ethan-l-one (0.12 g, 88.9%) as a white solid. This was used for the next step without further purification. LCMS: 305.1 (M+l).

Step 4: Synthesis of 2-(2-fluorophenyl)-N-(4-(2-(imidazo[l,5-a]quinazolin-4(5H)-y l)-2- oxoethyl)phenyl)acetamide:

Same as preparation of above step-2 using HATU as coupling agent and 2-(4- aminophenyl)-l-(imidazo[l,5-a]quinazolin-4(5H)-yl)ethan-l-on e and 2-fluorophenylacetic acid are as coupling partners to give 2-(2-fluorophenyl)-N-(4-(2-(imidazo[l,5-a]quinazolin-4(5H)-y l)- 2-oxoethyl)phenyl)acetamide (0.030 g, 23%) as pale yellow solid. ^X HNMR (DMSO-d6, 400 MHz) δ: 10.14 (s, 1H), 8.39-8.29 (m, 1H), 7.78 (d, 1H, = 8.0 Hz), 7.60-7.38 (m, 4H), 7.39-7.35 (m, 1H), 7.34-7.26 (m, 2H), 7.24-7.00 (m, 5H), 5.07-4.95 (m, 2H), 3.96 (s, 2H), 3.70 (s, 2H); (LCMS): 441.2 (M+l); Purity: 96.5%. Following Example 152 has been synthesized by the above procedure described in

Example 151 with their corresponding intermediates in similar reaction consitions:

Example 153: Preparation of N-(4-(l-fluoro-2-(5-oxoimidazo[l,5-alquinazolin-4(5H)- yl)ethyl)phenyl)-2-phenylacetamide:

To a solution of N-{4-[2-(5-Oxo-5H-imidazo[l,5-a]quinazolin -4-yl)-acetyl]-phenyl}-2- phenyl- acetamide (Example 94, 0.125 g, 0.28 mmol) in methanol (5 ml) was added sodium borohydride (16 mg, 0.42 mmol) at room temperature and reaction mixture was stirred for about 0.5 hour. Reaction was monitored by TLC and after completion of reaction water (25 ml) was added and precipitated solid was filtered and suck dried. The solid was dissolved in MDC and treated with anhydrous sodium sulphate. The solution was filtered concentrated and used as such for the next reaction. The residue was dissolved in MDC (10 ml) under nitrogen atmosphere and diethylaminosulfur trifluoride (DAST, 33 mg, 0.20 mmol) was added at room temperature and reaction mixture was stirred for anout 16 hours at the same temperature. Upon completion of reaction, reaction mixture was diluted with water (10 ml) and layers were separated. Aqueous layer was extracted with MDC (2 x 10 ml). Combined MDC layer was washed with aqueous sodium bicarbonate solution, dried over sodium sulphate and concentrated to give crude residue, which was purified using flash column chromatography to give pure product (13 mg, 10% over two steps).

^NMR (CDCb, 400 MHz) δ: 10.3 (s, IH), 8.65 (s, IH), 8.22 (d, IH, = 8.4 Hz), 8.18 (dd, IH, J = 1.2, 8 Hz), 7.89 (t, IH, = 8.4 Hz), 7.67 (d, 2H, = 8.4 Hz), 7.55-7.49 (m, 3H), 7.36-7.30 (m, 4H), 7.26-7.22 (m, IH), 6.97 (s, IH), 5.95-5.80 (m, IH), 4.55-4.48 (m, IH), 4.33-4.21 (m, IH), 3.65 (s, 2H); (LCMS): 441 (M+l); Purity: 90.31%.

Example 154: Preparation of 4-(2-(3-chlorophenyl)-2-fluoroethyl)imidazo[l,5-alquinazolin - 5(4H)-one:

To a solution of 4-[2-(3-Chloro-phenyl)-2-hydroxy-ethyl]-4H-imidazo[l,5-a]qui nazolin - 5-one (Example 19, 80 mg, 0.23 mmol) in MDC (5 ml) at about 0-5 °C was added diethylaminosufur trifuoride (96 mg, 0.70 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for about 16 hours. After completion of the reaction, the reaction mixture was poured on ice-water (10 ml) and extracted with MDC (3 x 10 ml). Combined organic extracts were dried over sodium sulfate and concentrated to give crude residue which was purified by flash colum chromatography to give 4-(2-(3-chlorophenyl)-2- fluoroethyl)imidazo[l,5-a]quinazolin-5(4H)-one (11 mg, 14%).

¾NMR (DMSO-d6, 400 MHz) δ: 8.36 (d, IH, = 8.0 Hz), 8.13 (s, IH), 7.81-7.73 (m, 2H), 7.54-7.46 (m, 2H), 7.42-7.35 (m, 3H), 6.83 (s, IH), 6.01-5.86 (m, IH), 4.54-4.42 (m, IH), 4.28- 4.21 (m, IH); Mass (LCMS): 342.1 (M+l); Purity: 94.03%.

Example 155: Preparation of 2-(2-fluorophenyl)-N-(4-(2-(5-oxoimidazori,5-alquinazolin- 4(5H)-yl)acetyl)phenyl)acetamide hydrochloride:

2-(2-Fluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in -4-yl)-acetyl]- phenylj-acetamide (Example 101, 40 mg, 0.088 mmol) was suspended in l,4-dioxane:HCl (2.0 ml) at room temperature and stirred for about 2 hours. Solvents were removed under vaccum at about 40°C to give 2-(2-fluorophenyl)-N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4( 5H)- yl)acetyl)phenyl)acetamide hydrochloride (40 mg, 92.5%).

^NMR (DMSO-d6, 400 MHz) 5: 10.79 (s, 1H), 9.72 (s, 1H), 8.37 (d, 1H, = 8.4 Hz), 8.25 (dd, 1H, = 1.2, 8.0 Hz), 8.10 (d, 2H, = 8.8 Hz), 8.03 (dt, 1H, = 1.6, 8.8 Hz), 7.84 (d, 2H, = 8.8 Hz), 7.71 (t, 1H, = 7.6 Hz), 7.49 (s, 1H), 7.41 (dt, 1H, = 1.6, 7.6 Hz), 7.37-7.30 (m, 1H), 7.21-7.16 (m, 2H), 5.62 (s, 2H), 3.83 (s, 2H); (LCMS): 455 (M+l); Purity: 91.38 %.

Example 156: Preparation of 2-(2-fluorophenyl)-N-(4-(2-(5-oxoimidazo[l,5-alquinazolin-

4(5H)-yl)acetyl)phenyl)acetamide methaneslfonate:

2-(2-Fluoro-phenyl)-N-{4-[2-(5-oxo-5H-imidazo[l,5-a]quinazol in -4-yl)-acetyl]- phenylj-acetamide (Example 101, 50 mg, 0.110 mmol) was suspended in MDC (2.0 ml). Methane sulfonic acid (12.7 mg, 0.132 mmol) was added to the reaction mixture and stirred for about 2 hours. Solvents were removed under vaccum at about 40°C to give 2-(2-fluorophenyl)- N-(4-(2-(5-oxoimidazo[l,5-a]quinazolin-4(5H)-yl)acetyl)pheny l)acetamide methaneslfonate was obtained (50 mg, 83.3%).

^X HNMR (DMSO-d6, 400 MHz) 5: 10.68 (s, 1H), 9.77 (s, 1H), 8.36 (d, 1H, = 8.4 Hz), 8.26 (d, 1H, = 8.0 Hz), 8.10 (d, 2H, = 8.8 Hz), 8.05 (t, 1H, 7 = 8.0 Hz), 7.83 (d, 2H, = 8.8 Hz), 7.73 (t, 1H, = 7.6 Hz), 7.54 (s, 1H), 7.14 (dt, 1H, = 1.6, 8.0 Hz), 7.37-7.31 (m, 1H), 7.21- 7.16 (m, 2H), 5.63 (s, 2H), 3.82 (s, 2H), 2.33 (s, 3H); (LCMS): 455 (M+l); Purity: 91.68 %. METHOD FOR PREPARATIVE SEPARATION OF ISOMERS:

Above exemplified isomer compounds were separated by using both reverse phase and normal phase chiral preparative HPLC methods. The column specification are as follows: Reverse phase preparative column : YMC C-18 (300 x 25 mm), 10 μιτι, Normal Phase chiral preparative column: YMC-SA (250 x 20 mm), 10 μιτι.

BIOLOGICAL ASSAYS

In-vitro human indoleamine 2,3-dioxygenase 1 (IDOl) enzyme assay:

In the in-vitro human indoleamine 2,3-dioxygenase 1 (hIDOl) enzyme assay for screening inhibitor compounds, hIDOl with an N-terminal histidine tag expressed and purified from E. coli (BPS Bioscience, San Diego, CA, USA) was used. All other materials were procured from Sigma- Aldrich, St. Louis, MO, USA.

The assay method for monitoring the conversion of L-tryptophan to N-formylkynurenine by hIDOl was carried out as follows. hIDOl (50 ng) was incubated with tryptophan (80 μΜ) in the presence of ascorbic acid (10 mM), methylene blue (10 μΜ), catalase (100 μ^ιτιΐ) and 0.01% Tween-20 in sodium phosphate buffer (50 mM; pH 6.5) at 37°C for 60 min. The reaction was terminated with 200 mM piperidine (PIP) and further incubated at about 65 °C for about 20 minutes to convert N-formylkynurenine (NFK) to NFK-PIP. The reaction mixture was then incubated at room temperature for about 1 hour. The fluorescence intensity was read in a fluorescence microplate reader at an excitation wavelength of 400 nm and emission wavelength of 500 nm. Percent inhibition at each concentration of test compounds was determined by estimating the decrease in NFK-PIP. Data were analyzed using nonlinear regression to generate IC50 values using Graph Pad Prism ^® 6.

The % inhibition values for hIDOl enzyme at 10.0 μΜ concentration of the compounds of present invention are as follows (A: > 50%, B: < 50%):

5 B 43 B 80 A 117 B

6 B 44 A 81 A 118 A

7 B 45 B 82 A 119 A

8 B 46 B 83 B 120 B

9 B 47 B 84 B 121 A

10 B 48 B 85 A 122 A

11 B 49 B 86 A 123 A

12 A 50 B 87 A 124 A

13 B 51 B 88 A 125 A

14 B 52 B 89 B 126 A

15 B 53 B 90 A 127 A

16 B 54 B 91 B 128 B

17 B 55 B 92 A 129 B

18 A 56 A 93 A 130 A

19 B 57 B 94 A 131 A

20 B 58 A 95 B 132 A

21 B 59 B 96 A 133 B

22 B 60 B 97 A 134 A

23 B 61 B 98 B 135 A

24 B 62 B 99 A 136 B

25 B 63 B 100 B 138 A

26 B 64 B 101 A 139 B

27 B 65 A 102 B 140 B

28 B 66 B 103 A 141 A

29 B 67 A 104 B 142 B

30 B 68 B 105 A 143 B

31 B 69 B 106 A 144 B

32 B 70 B 107 A 145 B

33 B 71 B 108 A 146 B

34 A 72 B 109 A 147 B

35 B 73 B 110 B 149 A

36 B 74 B 111 B 153 A

37 B 75 A 112 A 151 B

38 A 152 B 154 B 150 B

The % inhibition values for hIDOl enzyme at 1.0 μΜ concentration of the compounds of present invention are as follows (A: > 50%, B: < 50%): 75 B 103 A 124 A 138 B

76 B 112 A 125 B 139 B

77 B 113 B 126 A 140 B

78 B 114 A 127 A 141 B

79 B 115 A 128 B 142 B

86 A 116 A 129 B 143 B

87 A 117 B 130 A 144 B

88 A 118 A 131 A 145 B

89 B 119 A 132 A 146 B

90 B 120 B 133 B 149 B

91 B 121 A 134 A 151 B

92 A 122 A 135 B 152 B

99 A 153 B

The IC50 values for hIDOl enzyme of the compounds of present invention are as follows:

In-vitro human tryptophan 2,3-dioxygenase (TDO) enzyme assay:

In the in-vitro human tryptophan 2,3-dioxygenase (hTDO) enzyme assay for screening inhibitor compounds, hTDO with an N-terminal histidine tag expressed and purified from E. coli (BPS Bioscience, San Diego, CA, USA) was used. All other materials were procured from Sigma-Aldrich, St. Louis, MO, USA.

The assay monitoring method for the conversion of L-tryptophan to N-formylkynurenine by hTDO was carried out as follows. hTDO (125 ng) was incubated in the presence of 200 μΜ L-tryptophan, 100 mM sodium phosphate buffer (pH 7.0), 0.01 % Tween-20 and 100 μΜ ascorbic acid at about 37°C for about 60 minutes. The reaction was terminated with 200 mM piperidine (PIP) and further incubated at about 65 °C for about 20 minutes to convert N- formylkynurenine (NFK) to NFK-PIP. The reaction mixture was then incubated at room temperature for about 75 minutes. The fluorescence intensity was read in a fluorescence microplate reader at an excitation wavelength of 400 nm and emission wavelength of 500 nm. Percent inhibition at each concentration of test compounds was determined by estimating the decrease in NFK-PIP. Data were analyzed using nonlinear regression to generate IC50 values using Graph Pad Prism ^® 6.

The % inhibition values for hTDO enzyme at 10.0 μΜ concentration of the compounds of present invention are as follows (A: > 50%, B: < 50%):

32 B 64 B 102 B 151 B

152 B 154 B

The % inhibition values for hTDO enzyme at 1.0 μΜ concentration of the compounds of present invention are as follows (A: > 50%, B: < 50%):

Few of these compounds have shown good (> 0.5 μΜ) ICso values against hTDO-enzyme assay.

In-vitro human indoleamine 2, 3-dioxygenase 1 (IDOl) HEK293 cell based assay:

Human indoleamine 2, 3-dioxygenase 1 (hIDOl) cell based assay for screening inhibitor compounds used a stable recombinant HEK293 cell line, human ID01-HEK293, expressing tetracycline-inducible human indoleamine 2, 3-dioxygenase (Genbank accession number NM_002164) procured from BPS Bioscience, San Diego, CA, USA. All other materials were procured from Sigma- Aldrich, St. Louis, MO, USA.

Human ID01-HEK293 cells were seeded at 25,000 cells, with MEM media containing 10% FBS, in a tissue culture-treated 96-well plate followed by incubation at about 37°C in a C02 incubator overnight. The next day medium was replaced with different concentrations of reference or test compounds in growth medium (100 μΐ) and 100 μΐ of growth medium containing 0.2 μg/ml of doxycycline and 200 μg/ml L-Tryptophan to induce IDOl expression followed by incubation at about 37°C in a C02 incubator around 24 hours. 140 μΕ of medium was then transferred to a fresh 96 well plate followed by addition of 10 μΙ_, of 6.1 N trichloroacetic acid to each well and incubated at about 50°C for about 30 minutes followed by centrifugation at 2500 xg for about 10 minutes. 100 μΕ of clear supernatant was transferred to a transparent 96-well plate and mixed with 100 μΕ of freshly prepared 2% 4-(Dimethylamino) benzaldehyde in glacial acetic acid. The plate was incubated at room temperature for about 10 minutes and absorbance measured at 480 nm using a micro plate reader. Data were analyzed using nonlinear regression to generate IC50 values using Graph Pad Prism® 6.

Many of the present invention compounds that showed activity in the enzyme based biochemical hIDO 1 assay were also active in the hIDO-HEK293 cell line based assay.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All the publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.