WO2013153539A1

WO2013153539A1 - Tricyclic compounds as tec kinase inhibitors

Info

Publication number: WO2013153539A1
Application number: PCT/IB2013/052932
Authority: WO
Inventors: Sachin Sundarlal Chaudhari; Sukeerthi Kumar; Abraham Thomas; Neelima Khairatkar-Joshi; Daisy Manish Shah
Original assignee: Glenmark Pharmaceuticals S.A.
Priority date: 2012-04-13
Filing date: 2013-04-12
Publication date: 2013-10-17

Abstract

The present invention is directed to tricyclic compounds of formula (I) as Tec kinase inhibitors, in particular ITK (interleukin-2 inducible tyrosine kinase) inhibitors. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders mediated by ITK.

Description

TRICYCLIC COMPOUNDS AS TEC KINASE INHIBITORS

Related Applications

This application claims benefit of Indian provisional application No(s). 1213/MUM/2012 filed on April 13, 2012; 1492/MUM/2012 filed on May 16, 2012; 2084/MUM/2012 filed on July 20, 2012 and US provisional application No(s). 61/640,445 filed on April 30, 2012; 61/655,967 filed on June 5, 2012; 61/691,424 filed on August 21, 2012. All of which are hereby incorporated by reference in their entirety.

Technical Field of the Invention

The present invention relates to tricyclic compounds which are inhibitors of kinase activity, in particular ITK (interleukin-2 inducible tyrosine kinase) activity, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders.

Background of the Invention

Protein kinases are enzymes which modulate fundamental cellular processes via protein phosphorylation. Protein kinases play a critical role in mediating the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. Kinases are classified in two general groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues (S. K. Hanks and T. Hunter, FASEB. J., 1995, 9, 576-596). Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor (EGFR), insulin receptor (INSR), and platelet derived growth factor receptor, and cytosolic non-receptor kinases such as Src family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 and Syk) and the Tec family kinases (e.g. ITK).

The Tec family kinase includes ITK (IL2-inducible T-cell kinase, Gibson, S. et al, Blood, 1993, 82, 1561-1572), Txk (T-cell expressed kinase; Haire, R. N. et al, Hum. Mol. Genet., 1994, 3, 897-901), Tec (tyrosine kinase expressed in hepatocellular carcinoma cells; Mano et al, Oncogene, 1990, 5, 1781-1786), Btk (Bruton's tyrosine kinase; Vetrie, D. et al, Nature, 1993, 361, 226-233), and Bmx (bone marrow kinase, X-linked; Tamagnon, L. et al., Oncogene, 1994, 9, 3683-3688). ITK or Tsk (T-cell- specific tyrosine kinase) is expressed solely in inflammation cells such as T cells, natural killer (NK) cells, and mast cells with a prominent role of T cell proliferation and production of critical cytokines such as IL2, IL4, IL5, IL10 and IL13. During T cell activation via T cell receptor (TCR) CD3 and CD28 interaction, a cascade of signal transduction events is triggered including Lck activation followed by ZAP70 and ITK phosphorylation. ITK subsequently activates phospholipase C γ (PLC-γ) that further cleaves phosphotidyli-nositol biphosphate to yield diacylgycerol (DAG) and inositol triphosphate (IP3). Finally these two components activate NFKB and NFAT pathways leading to cytokine production, T cell-proliferation and subsequent differentiation. Disruption of T cell signal transduction by inhibition of ITK in the cascade would attenuate T cell mediated inflammation responses, especially in the pathological stage.

The study of genetically manipulated mice in which the gene encoding the ITK protein is deleted reveal that mice lacking ITK have decreased numbers of mature thymocytes, especially CD4+ T cells. The T cells isolated from such mice are compromised in their proliferative response to allogeneic MHC stimulation, and to anti-TCR/CD3 cross-linking (Liao X. C. and Littman, D. R., Immunity, 1995, 3, 757-769). These T cells also exhibit defective PLCyl tyrosine phosphorylation, inositol triphosphate production, Ca²⁺ mobilization, and cytokine production (such as IL-2 and IFNy) in response to TCR cross- linking (Schaeffer, E. M. et al, Science, 1999, 284, 638-641) This genetic evidence indicates that ITK activity plays a requisite role in TCR signal transduction; and selective inhibition of ITK should have immunosuppressive, anti-inflammatory, and anti-pro liferative effects. Recent studies have shown that ITK deficient mice have drastically reduced lung inflammation, eosinophil infiltration, and mucous production in response to OVA induced allergic asthma (Mueller, C; August, A., J. Immunol, 2003, 170, 5056). These studies support a key role for ITK in the activation of T cells, thus inhibitors of ITK should be useful as immunosuppressive or anti-inflammatory agents.

WO2002050071 relates to inhibitors of the Tec family tyrosine kinases, particularly inhibitors of Emt [expressed mainly in T cells] as immunosuppressive, anti-inflammatory, anti-allergic & anti-cancer agents. WO2003041708, WO2004016600, WO2004016609, WO2004016610, WO2004016611, WO2004016270, WO2004016615, WO2004014905, WO2005026175, WO2005056785, WO2005066335, WO2005070420, WO2005079791, WO2007058832, WO2008025820, and WO2008025822 disclose certain ITK inhibitors for the treatment of inflammation, immunological disorders, and allergic disorders. WO2010106016 describe certain ITK inhibitors for the treatment of disorders such as respiratory diseases; allergic diseases; autoimmune diseases; transplant rejection; graft versus host disease; inflammatory disorders; HIV; aplastic anemia; and pain. WO2005095406, WO2006065946, WO2007027528, WO2007027594, WO2007027729, and WO2007076228 describe certain compounds as Tec family kinase inhibitors. WO2007136790 describe certain compounds as ITK and BTK kinase inhibitors, and WO2008025821 disclose certain compounds as ITK or PI3K inhibitors.

Thus, an object of the present invention is to provide novel compounds which are inhibitors of kinase activity, in particular ITK activity. Compounds of the present invention may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular inappropriate ITK activity, for example in the treatment and prevention of disorders mediated by ITK mechanisms. Such disorders include respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and bronchitis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, T cell mediated hypersensitivities, Guillain-Barre Syndrome and Hashimoto's thyroiditis; transplant rejection; graft versus host disease; inflammatory disorders including conjunctivitis, contact dermatitis, inflammatory bowel disease and chronic inflammation; proliferative disorders; immunological disorders; HIV; aplastic anemia; and pain including inflammatory pain.

Summary of the Invention

In one aspect, the p of formula (I)

(I)

or a pharmaceutically acceptable salt thereof,

wherein,

A is carbon or trivalent nitrogen;

each dotted line in the ring represents an optional bond, provided that only one of the two dotted lines can represent a bond;

provided that when A is nitrogen, R¹ is absent;

provided that when A is carbon, R¹ is hydrogen;

Ring B represents

wherein χ and y represents the point of attachment;

P is C₆_i4 aryl, 5- to 14- membered heteroaryl or 3- to 15- membered heterocyclyl, wherein each being optionally substituted with one or more R⁷;

Q is absent or selected from C_6-14 aryl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R⁸;

L is selected from -(CH₂)_nCHR^a-, -(CH₂)_nC(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-; T is selected from hydrogen, hydroxy, Ci_galkyl, haloCi_galkyl, hydroxyCi_galkyl, C₃_ i₂cycloalkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R¹ is absent or hydrogen;

R² is selected from hydrogen, Ci_galkyl, hydroxyCi_galkyl, and 3- to 15- membered heterocyclylC i_₈alkyl;

R³ is selected from hydrogen, Ci_galkyl, haloCi_galkyl, hydroxyCi_galkyl, 3- to 15- membered heterocyclylCi_galkyl, and -(CH₂)_nNR^aR^b -;

R⁴ is selected from hydrogen and Ci_galkyl;

R⁵ is selected from hydrogen, halogen and Ci_galkyl;

R⁶ is selected from hydrogen, halogen and Ci_₈alkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a C₃_i₂cycloalkyl ring which is substituted or unsubstituted and wherein the C₃_ i₂cycloalkyl ring optionally contains one or more hetero atoms selected from O, N or S;

at each occurrence, R⁷ is independently selected from cyano and Ci_₈alkyl;

at each occurrence, R⁸ is independently selected from halogen, cyano, Ci_galkyl and - (CH₂)_nNR^aC(0)R^b;

at each occurrence, R^a and R^b, which may be the same or different, are independently selected from hydrogen and Ci_galkyl; and

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II), (III), (IV), (V), (VI) and (VII), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein L is methyl, ethyl or propyl (according to an embodiment defined below) and Q is absent (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which A is carbon.

According to another embodiment, specifically provided are compounds of formula (I), in which A is trivalent nitrogen.

According to yet another embodiment, specifically provided are compounds of formula (I), in which ring B is

According to yet another embodiment, specifically provided are compounds of formula (I), in which P is

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is

According to yet another embodiment, specifically provided are compounds of formula (I), in which L-T is

According to an embodiment, specifically provided are compounds of formula (I) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

Further embodiments relating to groups B, A, L, T, R¹, P and Q (and groups defined therein) are described hereinafter in relation to the compounds of formula (II), (III), (IV), (V), (VI) or (VII). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), (III), (IV), (V), (VI) or (VII), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II), (III), (IV), (V), (VI) or (VII), wherein Q is absent and consequently there is also provided a compound of formula (I), wherein Q is absent.

The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

(II)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C₆-i4 aryl, 5- to 14- membered heteroaryl or 3- to 15- membered heterocyclyl, wherein each being optionally substituted with one or more R⁷;

L is selected from -(CH₂)„CHR^a- and -(CR^aR^b)_nO-;

T is selected from hydrogen, hydroxy, Ci.galkyl, hydroxyCi.galkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R² is hydrogen;

R⁴ is Ci_₈alkyl;

at each occurrence, R⁷ is independently selected from cyano and Ci.galkyl;

at each occurrence, R⁸ is independently selected from halogen, cyano and Ci_galkyl; at each occurrence, R^a and R^b are hydrogen; and

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein R is CH₃, / ¹ or / (according to an embodiment defined below) and Q is absent (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (II), in which R is Ci_₈alkyl (e or )·

According to another embodiment, specifically provided are compounds of formula

(II), in which R⁴ is CH₃, / ' or

According to yet another embodiment, specifically provided are compounds of formula (II), in which P is

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of formula (II), in which Q is

According to yet another embodiment, specifically provided are compounds of formula (II), in which L-T is

According to an embodiment, specifically provided are compounds of formula (II) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

The invention also provides a compound of formula (III) which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (III)

(III)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C₆_i4 aryl or 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R⁷;

Q is absent or 5- to 14- membered heteroaryl being optionally substituted with one or more R ;

L is selected from -(CH₂)„CHR^a- and -(CR^aR^b)_nO-;

T is selected from Ci.galkyl, hydroxy and hydroxyCi.galkyl;

R² is selected from hydrogen and Ci.galkyl;

R³ is Ci_₈alkyl;

at each occurrence, R⁷ is cyano;

at each occurrence, R⁸ is Ci_₈alkyl ;

at each occurrence, R^a and R^b are hydrogen; and

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (III) as defined above wherein L is methyl, ethyl or propyl (according to an embodiment defined below) and R³ is methyl or ethyl (according to another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (III), in which R² is hydrogen or Ci_₈alkyl (e.g. methyl).

According to another embodiment, specifically provided are compounds of formula (III), in which R² is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R³ is Ci_galkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R³ is methyl or ethyl.

According to yet another embodiment, specifically provided are compounds of formula

(III), in which P

According to yet another embodiment, specifically provided are compounds of formula (III), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of formula (III), in which Q

₀r

According to yet another embodiment, specifically provided are compounds of formula (III), in which L-T is

According to an embodiment, specifically provided are compounds of formula (III) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

The invention also provides a compound of formula (IV), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (IV)

(IV)

or a pharmaceutically acceptable salt thereof, wherein,

P is C₆-i4 aryl or 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R⁷;

Q is absent or 5- to 14- membered heteroaryl, wherein being optionally substituted with one or more R⁸;

L is selected from -(CH₂)_nCHR^a-, -(CH₂)_nC(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-; T is selected from hydrogen, hydroxy, Ci_₈alkyl, hydroxyCi_₈alkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R² is selected from hydrogen, Ci_galkyl and 3- to 15- membered heterocyclylCi_galkyl; R⁵ is selected from hydrogen, halogen and Ci_galkyl;

R⁶ is selected from hydrogen, halogen and Ci_₈alkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a C₃-i₂cycloalkyl ring which is substituted or unsubstituted and wherein the C₃_ i₂cycloalkyl ring optionally contains one or more hetero atoms selected from O, N or S;

at each occurrence, R⁷ is independently selected from cyano;

at each occurrence, R⁸ is independently selected from halogen and Ci_₈alkyl;

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (IV) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (IV) as defined above wherein R⁵ is hydrogen, fluorine or methyl (according to an embodiment

2 : — N o

defined below), R is hydrogen, methyl or \— / (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (IV), in which R² is hydrogen, Ci_galkyl (e.g. methyl) or 3- to 15- membered heterocyclylCi_galkyl

(e.

According to another embodiment, specifically provided are compounds of formula

-N O

(IV), in which R² is hydrogen, methyl or

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁵ is hydrogen, halogen (e.g. fluorine) or Ci_₈alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁵ is hydrogen, fluorine or methyl.

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁶ is hydrogen, halogen (e.g. fluorine) or Ci_₈alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁶ is hydrogen, fluorine or methyl.

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a C₃_i₂cycloalkyl ring (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compounds of formula (IV), in which R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a cyclopropyl ring.

According to yet another embodiment, specifically provided are compounds of formula (IV), in which P is

According to yet another embodiment, specifically provided are compounds of formula (IV), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of formula (IV), in which Q is

According to yet another embodiment, specifically provided are compounds of formula (IV), in which L-T is

According to an embodiment, specifically provided are compounds of formula (IV) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

The invention also provides a compound of formula (V), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (V)

(V)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C₆-i4 aryl or 5- to 14- membered heteroaryl wherein each being optionally substituted with one or more R⁷;

Q is absent or selected from 3- to 15- membered heterocyclyl, wherein being optionally substituted with one or more R⁸;

L is selected from -(CH₂)_nCHR^a-, -(CH₂)_nC(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-;

T is selected from hydrogen, hydroxy, Ci_galkyl, hydroxyCi_galkyl and 3- to 15- membered heterocyclyl;

R² is selected from hydrogen, Ci_₈alkyl and hydroxyCi_₈alkyl;

at each occurrence, R⁷ is independently selected from cyano and Ci_galkyl;

at each occurrence, R^a and R^b, which may be the same or different, are independently selected from hydrogen and Ci_galkyl; and 'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (V) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (V) as defined above wherein R³ is N,N-dimethylethanamine (according to an embodiment defined below), R² is hydrogen, methyl or 2-methylpropan-2-ol (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (V), in which R² is hydrogen, Ci.galkyl (e.g. methyl) or hydroxyCi.galkyl (e.g. 2-methylpropan-2- ol).

According to another embodiment, specifically provided are compounds of formula

(V), in which R² is hydrogen, methyl or 2-methylpropan-2-ol.

According to yet another embodiment, specifically provided are compounds of formula (V), in which R is hydrogen, Ci_galkyl (e.g. methyl, ethyl or / ' ), haloCi_galkyl (e.g. trifluoroethyl), hydroxyCi_galkyl (e.g. 2-methylpropan-2-ol), 3- to 15- membered

heterocyclylC i_galkyl (e.g.

According to yet another embodiment, specifically provided are compounds of formula (V), in which R³ is hydrogen, methyl, ethyl, / ^: , trifluoroethyl, 2-methylpropan-2-

According to yet another embodiment, specifically provided are compounds of formula (V), in which R³ is -(CH₂)„NR^aR^b -. In this embodiment R^a and R^b are Ci_₈alkyl (e.g. methyl) and n is 2.

According to yet another embodiment, specifically provided are compounds of formula (V), in which R³ is N,N-dimethylethanamine. According to yet another embodiment, specifically provided are compounds of

Vi- formula (V), in which R is hydrogen, methyl, ethyl, / ^: , trifluoroethyl, 2-methylpropan-2- ol

or N,N-dimethylethanamine.

According to yet another embodiment, specifically provided are compounds of formula (V), in which P is

According to yet another embodiment, specifically provided are compounds of formula (V), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of formula (V), in which Q is

According to yet another embodiment, specifically provided are compounds of formula (V), in which L-T is

According to an embodiment, specifically provided are compounds of formula (V) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

The invention also provides a compound of formula (VI) which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (VI)

(VI) or a pharmaceutically acceptable salt thereof,

wherein,

P is 5- to 14- membered heteroaryl;

Q is absent or selected from C_6-14 aryl and 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R⁸;

L is -(CH₂)_nC(0)NR^a-;

T is selected from hydroxy, Ci_₈alkyl or C₃_i₂cycloalkyl;

R² is selected from hydrogen, Ci.galkyl, hydroxyCi.galkyl, and 3- to 15- membered heterocyclylC i.galkyl;

R³ is selected from Ci.galkyl and haloCi_galkyl;

at each occurrence, R⁸ is -(CH₂)„NR^aC(0)R^b;

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (VI) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (VI) as

N O

defined above wherein R² is hydrogen, methyl, or \— / (according to an embodiment defined below) and R³ is methyl, ethyl or trifiuoroethyl (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (VI), in which R² is hydrogen, Ci_₈alkyl (e.g. methyl), or 3- to 15- membered heterocyclylCi_₈alkyl

-N O

(e.g. ^-f )·

According to another embodiment, specifically provided are compounds of formula

-N O

(VI), in which R² is hydrogen, methyl, or According to yet another embodiment, specifically provided are compounds of formula (VI), in which R³ is Ci_₈alkyl (e.g. methyl or ethyl) or haloCi-salkyl (e.g. trifluoroethyl).

According to yet another embodiment, specifically provided are compounds of formula (VI), in which R³ is methyl, ethyl or trifluoroethyl.

According to yet another embodiment, specifically provided are compounds of formula (VI), in which P is

According to yet another embodiment, specifically provided are compounds of formula (VI), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of

formula (VI), in which Q is

According to yet another embodiment, specifically provided are compounds of formula (VI), in which L-T is

According to an embodiment, specifically provided are compounds of formula (VI) with an IC₅₀ value of less than 500 nM, preferably, less than 100 nM, more preferably less than 50 nM, with respect to ITK activity.

The invention also provides a compound of formula (VII) which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (VII)

or a pharmaceutically acceptable salt thereof,

wherein,

P is 5- to 14- membered heteroaryl, being optionally substituted with one or more R⁷; Q is absent or 5- to 14- membered heteroaryl, being optionally substituted with one or more R ; L is -(CH₂)_nC(0)NR^a-;

T is selected from hydroxy, Ci.galkyl, haloCi.galkyl or C3_i₂cycloalkyl;

R² is selected from hydrogen, Ci_galkyl and 3- to 15- membered heterocyclylCi_galkyl;

R⁵ is selected from hydrogen and Ci.galkyl;

R⁶ is selected from hydrogen and Ci.galkyl;

at each occurrence, R⁷ is cyano;

at each occurrence, R⁸ is Ci_₈alkyl;

at each occurrence, R^a, which may be the same or different, are independently selected from hydrogen and Ci_galkyl; and

'n' is an integer ranging from 0 to 6, both inclusive.

The compounds of formula (VII) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (VII) as defined above wherein R⁵ is hydrogen or methyl (according to an embodiment defined below), R⁶ is hydrogen or methyl (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (VII), in which R² is hydrogen, Ci_₈alkyl (e.g. methyl), or 3- to 15- membered heterocyclylCi_₈alkyl

According to another embodiment, specifically provided are compounds of formula

-N O

(VII), in which R² is hydrogen, methyl or \— f .

According to yet another embodiment, specifically provided are compounds of formula (VII), in which R⁵ is hydrogen or Ci_₈alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (VII), in which R⁵ is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (VII), in which R⁶ is hydrogen or Ci.galkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (VII), in which R⁶ is hydrogen or methyl. According to yet another embodiment, specifically provided are compounds of

According to yet another embodiment, specifically provided are compounds of formula (VII), in which Q is absent.

According to yet another embodiment, specifically provided are compounds of

formula (VII), in which Q is .

According to yet another embodiment, specifically provided are compounds of formula (VII), in which L-T is

It should be understood that the formulas (I), (II), (III), (IV), (V), (VI) and (VII) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, pharmaceutically acceptable salts and solvates including hydrates that may be contemplated from the chemical structure of the genera described herein.

The present invention also provides a pharmaceutical composition that includes at least one compound described herein or a pharmaceutically acceptable salt thereof 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 compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions described herein are useful for inhibiting kinase activity, in particular ITK activity.

The invention is still further directed to methods of inhibiting ITK activity and treatment of disorders associated therewith using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention is yet further directed towards processes for the preparation of the compounds of the invention.

In another aspect, the present patent application further provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more diseases, conditions and/or disorders selected from the group consisting of respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain and other diseases and disorders associated with ITK, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.

Detailed Description

Terms and Definitions

The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine

(bromo), or iodine (iodo).

The term "alkyl" refers to a straight or branched hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_₈alkyl), and which is attached to the rest of the molecule by a single bond. "Ci_₆ alkyl" is an alkyl group that has from 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 2-methylpropyl (isobutyl), n-pentyl, 1,1-dimethylethyl (t-butyl), and 2,2- dimethylpropyl. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C_2-10 alkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z^'sopropenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C_2-10 alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci.galkoxy). Representative examples of such groups are -OCH₃ and - OC₂H₅. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci.galkoxyCi.galkyl or Ci_₈alkyloxyCi_₈alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, - CH₂OCH₃ and -CH₂OC₂H₅. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_galkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_galkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "hydroxy alkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_₈alkyl). Examples of hydroxyalkyl moiety include, but are not limited to -CH₂OH, -C₂H₄OH and -CH(OH)C₂H₄OH.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C₃_i₂cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group, for example C₃_₈CycloalkylCi_₈alkyl. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted. The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C₃_₈Cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclop entenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C₃_₈CycloalkenylCi_₈alkyl. The cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C₆_ i₄aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C₆-i₄aryloxy). Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C₆-i₄arylCi_₈alkyl, such as -CH₂C₆H₅ and -C₂H₄C₆H₅. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclyl" or "heterocyclic ring" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefmic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylCi_galkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted

5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi-salkyl). The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^x, -C(0)R^x, -C(S)R^X, -C(0)NR^xR^y, -C(0)ONR^xR^y, - NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)S0₂R^y, -NR^xC(0)OR^y, -NR^xR^y, -NR^xC(0)R^y, - NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -SONR^xR^y, -S0₂NR^xR^y, -OR^x, -OC(0)NR^yR^z, -OC(0)OR^y, - OC(0)R^x, -OC(0)NR^xR^y, -SR^X, -SOR^x, -S0₂R^x and -ON0₂, wherein R^x, R^y and R^z are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" can be unsubstituted alkenyl but cannot be "substituted alkenyl".

The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

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, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

The compound described in the present patent application may form salts. Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application 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 present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application 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 patent application may be separated from one another by the method 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. It is also to be understood that compounds of the invention may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.

Pharmaceutical Compositions The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.

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, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinyl pyrrolidone.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). 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 is used in cases where a sweetened vehicle is employed.

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.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The pharmaceutical forms suitable for injectable or infusing use include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable or infusing solutions, suspension or dispersions.

The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20^th Ed., 2003 (Lippincott Williams & Wilkins).

Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. For example, the daily dosage of the ITK inhibitors can range from about 0.1 to about 200.0 mg/Kg. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.

Methods of Treatment

The present invention provides compounds and pharmaceutical compositions which inhibit kinase activity, particularly ITK activity and are thus useful in the treatment or prevention of disorders associated with ITK. Compounds and pharmaceutical compositions of the present invention selectively inhibit ITK and are thus useful in the treatment or prevention of a range of disorders associated with the activation of ITK which includes, but are not limited to respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, immunological disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain and other diseases and disorders associated with ITK.

In particular, the compounds of the present invention may be used to prevent or treat airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, late asthma and airways hyper- responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; sinusitis, chronic rhinosinusitis, nasosinusal polyposis; pulmonary fibrosis; inflammatory bowel disease; Guillain-Barre syndrome, acute or chronic inflammation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermitides, sebonhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythema, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, for example, migraine, rhinitis and eczema; multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, nephritic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; tuberculosis; organ and bone marrow transplant rejection; graft-versus-host disease.

The compounds of the present invention are useful for the treatment of cancer such as, but are not limited to breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, non- small cell lung cancer, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, and kidney cancer, basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, ovarian tumor, cervical dysplasia, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas.

Compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions may have potential utility in combination with other therapies for the treatment of immune, inflammatory, proliferative, and allergic disorders. Example includes but not limited to co-administration with steroids, leukotriene antagonists, anti-histamines, anti-cancer agents, protein kinase inhibitors, cyclosporine, or rapamycin.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.

General Methods of Preparation

The compounds described herein, including compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1-13 as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention. The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention may be prepared through the reaction scheme as follows.

An approach for the synthesis of compounds of the general formula (I), where R¹, A, B, L, T, P, and Q are described above is depicted in synthetic scheme 1. An appropriately substituted tricyclic amine of general formula (1) can be coupled with a carboxylic acid of formula (2) using a suitable coupling agent to give the compounds of the general formula (I).

Synthetic scheme 1

(1) (I)

An approach for the synthesis of imidazo[4,5-g]quinoxalinone derivatives of the general formula (Ila) (where R⁴, L, T, P, and Q are described above) is depicted in synthetic scheme 2. Thus, l,5-difluoro-2,4-dinitrobenzene (3) on reaction with aminoester of formula (4) (where R is Ci_salkyl) in presence of a suitable base such as N,N-diisopropylethylamine gives amino nitro intermediate (5). Displacement of fluorine atom of intermediate (5) with amine (6) in presence of base such as N,N-diisopropylethylamine gives the intermediate of formula (7). Palladium catalysed reduction of nitro groups with concomitant cyclization of one of the amino groups with the ester functionality gives diaminoquinoxalinone of formula (8). Diamine (8) undergoes cyclization in the presence of cyanogen bromide in a suitable solvent such as ethanol to give 2-amino imidazo[4,5-g]quinoxalin-6-one (9). Coupling of tricyclic amine (9) with a carboxylic acid of formula (2) using l-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 4-dimethylaminopyridine, 1-hydroxybenzotriazole in presence of suitable solvent such Ν,Ν-dimethylformamide to furnish the amides of the general formula (Ila).

Synthetic scheme 2

HCO,NH₄

(3) (5) (7)

°

(^§) (¾ (Ila)

An approach for the synthesis of N-[l-(3-hydroxypropyl)-6-oxo-5,6-dihydro-lH- imidazo[4,5-g]quinoxalin benzamide of the general formula (lib) (where R⁴, P and Q are described above) is depicted in synthetic scheme 3. The nitro fluoro derivative (5) (where R is Ci_8alkyl) undergoes nucleophilic substitution reaction with 3-ethoxypropyl amine (10) in presence of Ν,Ν-diisopropylethylamine to give nitro amine intermediate (11). Intermediate (11) on palladium catalysed nitro group reduction gives diamine (12). Intermediate (12) undergoes cyclization with cyanogen bromide in a suitable solvent such as ethanol to give tricyclic amine which on coupling reaction with a carboxylic acid of formula (2) gives intermediate (13). The intermediate (13) on dealkylation using borontribromide furnishes the hydroxy derivatives of general formula (lib).

Synthetic scheme 3

HC0₂NH₄

(5) (Π)

(12) (13) (lib)

An approach for the synthesis of quinazoline-fused tricyclic derivatives of the general formula (Ilia) (where R , L, T, P and Q are described above) and alkyldiketone tricyclic

2 3

derivatives (III) (where R , R , L, T, P and Q are described above) is depicted in synthetic scheme 4. Thus, 2,4-difluoro-l -nitrobenzene (14) undergoes displacement reaction with alkylamine (15) in presence of suitable base such as potassium carbonate to afford nitroaniline derivative which on nitro group reduction using sodium dithionate and ammonia gives diamine (16). The diamine (16) cyclises with substituted carbonyl ester (17) (where R is Ci_ salkyl) to give 7-fluoro-6-nitro-l,4-dihydroquinoxaline-2,3-dione which on nitration gives the nitro intermediate (18). Intermediate (18) can be coupled with substituted amine (6) in presence of Ν,Ν-diisopropylethylamine to give nitro amine intermediate which on palladium catalysed nitro group reduction gives 6-amino-l,4-dihydroquinoxaline-2,3-dione derivative (19). Intermediate (19) undergoes cyclization reaction with cyanogen bromide to afford the tricyclic amine which on coupling reaction with carboxylic acid of formula (2) in presence of suitable coupling agent furnishes compounds of the general formula (Ilia). Also, intermediate (18) undergoes N-alkylation using compound of formula (20) in presence of suitable base such as potassium carbonate or sodium hydride to give dialkyl intermediate which on fluorine displacement with substituted amine (6) gives nitro amine (21). Intermediate (21) undergoes palladium catalysed nitro group reduction to give diamine which on cyclization with cyanogen bromide gives diketotricyclic amine (22). Coupling reaction of amine (22) with a carboxylic acid of formula (2) in presence of a suitable coupling agent furnishes disubstituted derivatives (III).

Synthetic scheme 4

(18) (21) (22)

l. H₂N — L-T 2. Pd/C,

Q -P- C0₂H (2)

(6) coupling

HC0₂NH₄

(19) (ma) (ΙΠ)

An approach for the synthesis of 2-amino-6,6-dimethyl-3,8-dihydroimidazo[4,5- g][l,4]benzoxazin-7(6H)-one derivatives (IV a) (where R⁵, R⁶, L, T, P and Q are described above) and 2-amino-6,6,8-trimethyl-3,8-dihydroimidazo[4,5-^][l,4]benzoxazin-7(6H)-one derivatives (IV) (where R², R⁵, R⁶, L, T, P and Q are described above) is described in synthetic scheme 5. The 5-fluoro-2-nitrophenol (23) on reaction with appropriately substituted haloester (24) (where R' is Ci_salkyl) gives nitro ester (25) which on nitro group reduction and subsequent cyclization using iron powder and ammonium chloride gives 1 ,4-benzoxazin- 3(4H)-one (26). The nitration of intermediate (26) using concentrated nitric acid in presence of sulphuric acid gives 7-fluoro-6-nitro-2H-l ,4-benzoxazin-3-one derivative (27). The displacement of fluorine atom of intermediate (27) with amine (6) in presence of base such as Ν,Ν-diisopropylethylamine gives the nitro amine which on palladium-catalysed reduction of nitro group affords diamine (28). The intermediate (28) on cyclization with cyanogen bromide affords tricyclic amine which on coupling with a carboxylic acid of formula (2) using EDCI in the presence of DMAP and HOBt in DMF furnishes benzoxazin-7(6H)-one derivatives (IVa). Also, intermediate (27) undergoes N-alkylation reaction using compound of formula (20) in presence of a suitable base such as potassium carbonate to give the N-alkylated compound which on coupling with amine (6) gives intermediate (29). The intermediate (29) undergoes nitro group reduction using ammonium formate in presence of palladium catalyst to give diamine which on cyclization with cyanogen bromide gives tricyclic amine (30). The tricyclic amine of formula (30) on coupling with a carboxylic acid of formula (2) furnishes N- substituted benzoxazin-7(6H)-one derivatives (IV).

Synthetic scheme 5

l. H₂N —L-T 2. reduction Q-P-C0₂H (2) coupling base, solvent

(28) (IVa) (IV)

An approach for the synthesis of 7'-oxo-7',8'-dihydro-3'H- spiro[cyclopropaneimidazo[4,5-^][l ,4]benzoxazin-7(6H)-one derivatives (IVb) (where L, T, P and Q are described above) and 8'-methyl-7'-oxo-7',8'-dihydro-3'H- spiro[cyclopropaneimidazo[4,5-g][l ,4] benzoxazin-7(6H)-one derivatives (IVc) (where R , L, T, P and Q are described above) is depicted in synthetic scheme 6. The 5-fluoro-2-nitrophenol (23) on reaction with appropriately substituted haloester (31) (where R is Ci_salkyl) gives nitro ester (32) which on nitro group reduction and subsequent cyclization using iron powder and ammonium chloride gives l,4-benzoxazin-3(4H)-one (33). The nitration of intermediate (33) using concentrated nitric acid in presence of sulphuric acid gives 7-fluoro-6-nitro-2H- l,4-benzoxazin-3-one derivative (34). The displacement of fluorine atom of intermediate (34) with amine of formula (6) in presence of base such as Ν,Ν-diisopropylethylamine gives the nitro amine which on palladium catalysed reduction of nitro group affords diamine (35). Intermediate (35) on cyclization in the presence of cyanogen bromide affords tricyclic amine which on coupling with a carboxylic acid of formula (2) furnishes the amides of the general formula (IVb). Also, the intermediate (34) undergoes N-alkylation reaction using compound of formula (20) in presence of a suitable base such as potassium carbonate to give the N- alkylated compound which on coupling with amine (6) gives the nitro intermediate (36). The intermediate (36) undergoes nitro group reduction using ammonium formate in presence of palladium catalyst to give diamine which on cyclization with cyanogen bromide gives tricyclic amine (37). The amine of formula (37) on coupling with a carboxylic acid of formula (2) furnishes compounds of the general formula (IVc).

Synthetic scheme 6

l. H₂N— (6) 2. reduction - C0₂H

base, solvent cou ling

An approach for the synthesis of diimidazo derivatives of the general formula (V)

(where R , R , L, T, P and Q are described above) and (Va) (where R , R , L, T, P and Q are described above) is depicted in synthetic scheme 7. The intermediate (16) on reaction with urea affords benzimidazolone (38) (alternatively instead of urea other compounds such as triphosgene, dialkyl carbonate, Ι, -carbonyldiimidazole, alkyl chloroformate etc. can also be used). The nitration of intermediate (38) was achieved by using nitrating agents such as fuming nitric acid in acetic anhydride or mixture of nitric acid and sulfuric acid to afford nitrobenzimidazol-2-one (39). The intermediate (39) couples with substituted amine (6) in presence of Ν,Ν-diisopropylethylamine to give nitro amine intermediate which on palladium catalysed nitro group reduction gives diamino benzimidazolone followed by cyclization with cyanogen bromide affords tricyclic amine of formula (40). The amine of formula (40) couples with a carboxylic acid of formula (2) in presence of suitable base and solvent to furnish monoalkyltricyclic amide derivative (Va). Also, the intermediate (39) undergoes N- methylation using compound of formula (20) in presence of suitable base such as potassium carbonate or sodium hydride to give dialkyl intermediate which on coupling reaction with substituted amine (6) gives nitro intermediate (41). The intermediate (41) undergoes nitro group reduction, cyclization with cyanogen bromide and coupling reaction with a carboxylic acid of formula (2) as described in scheme 6 furnishes diimidazole derivative (V).

Synthetic Scheme 7

(¹⁶) (38) (39) (40)

1 R²X (20)

Q -P - C0₂H (2) coupling 2. H₂N—L-T (6) o

(V) (4i) (^Va)

An approach for the synthesis of diimidazole derivatives of the general formula (Vb)

2 3 2

(where R , R , L, T, P and Q are described above) and (Vc) (where R , L, T, P and Q are described above) is depicted in synthetic scheme 8. The 2,5-difluoronitrobenzene (42) on displacement reaction with appropriately substituted amine (15) affords intermediate (43). The intermediate (43) on nitro group reduction affords the corresponding amine (44). The intermediate (44) on reaction with urea affords benzimidazolone derivative (45) (alternatively, other reagents such as triphosgene, dialkyl carbonate, Ι, -carbonyldiimidazole, alkyl chloroformate etc. can also be used instead of urea). The nitration of intermediate (45) using fuming nitric acid in acetic anhydride or mixture of nitric acid and sulfuric acid affords nitrobenzimidazol-2-one (46). The intermediate (46) couples with substituted amine (6) in presence of Ν,Ν-diisopropylethylamine to give nitro amine intermediate which on palladium catalysed nitro group reduction gives diamino benzimidazolone followed by cyclization with cyanogen bromide affords tricyclic amine (47). The amine of formula (47) is coupled with a carboxylic acid of formula (2) using EDCI and HOBt in presence of suitable base such as DMAP to furnish monoalkyltricyclic amide derivative (Vc). Also, the intermediate (46) undergoes N-alkylation using compound of formula (20) in presence of suitable base such as potassium carbonate or sodium hydride to give dialkyl intermediate which on coupling reaction with substituted amine (6) gives nitro intermediate (48). The intermediate (48) undergoes palladium catalysed nitro group reduction to give diamine which on cyclization with cyanogen bromide gives dialkyltricyclic amine (49). The coupling reaction of amine (49) with a carboxylic acid of formula (2) as described above furnishes diimidazole derivative (Vb).

Synthetic scheme 8

(46) (48) (49)

l. H₂N L-T 2. reduction

Q-P-C0₂H (2) coupling base, solvent 3. NCBr

(47) (Vc) (Vb)

An approach for the synthesis of indole-fused compounds of the general formula (Via) (where R , L, T and Q are described above) is depicted in synthetic scheme 9. The 2,4- difluoro-5-nitroaniline (50) prepared by nitration of 2,4-difluoroaniline undergoes aromatic nucleophilic substitution with an active methylene compound of the formula (51) followed by reductive cyclization affords an indole amine (52). The coupling reaction of formula (52) with compound of formula (53) in presence of suitable base gives intermediate (54). The intermediate (54) undergoes fluorine displacement reaction with alkyl amine (15) to form intermediate (55). The intermediate (55) undergoes nitro group reduction to give amine which on reaction with Ι,Γ-carbonyldiimidazole gives compound bearing fused 2-oxo imidazole ring (56). The intermediate (56) undergoes Suzuki reaction with suitable boronic acid (57) to give compounds of the general formula (Via).

Synthetic Scheme 9

(56) (Via)

An approach for the synthesis of 2,2-dimethyl-3-oxo-oxazino[2,3-f]indole-8- carboxamide derivatives of the general formula (VII) (where R⁵, R⁶, L, T, P and Q are described above) and the general formula (Vila) (where R⁵, R⁶, L, T and Q are described above) is depicted in synthetic scheme 10. The oxazino compound (58) was protected with 1- (chloromethyl)-4-methoxybenzene in presence of suitable base to give compound (59). The intermediate (59) undergoes fluorine displacement reaction with appropriately substituted active methylene nitrile (51) which on reductive cyclisation gives compound (60). The intermediate (60) on deprotection reaction using trifluoroacetic acid and triflic acid gives amine (61). The coupling reaction of compound (61) with compound of formula (53) in presence of suitable base gives intermediate (62). The intermediate (62) undergoes Suzuki coupling with suitable boronic acid (57) to give compounds of the general formula (Vila). Alternatively, compound (61) can be coupled with a carboxylic acid of formula (2) using a standard amide coupling method to furnish compounds of the general formula (VII).

Synthetic scheme 10

(VII)

An approach for the synthesis of substituted oxazino derivatives of the general formula (Vllb) (where R², R⁵, R⁶, L, T and Q are described above) is depicted in synthetic scheme 11. The fluoronitro intermediate (63) undergoes displacement reaction with appropriately substituted active methylene nitrile derivative (51) which on reductive cyclisation gives compound (64). The coupling reaction of compound (64) with compound of formula (53) using appropriate base gives corresponding amide which on Suzuki coupling with suitable boronic acid (57) to give compounds of the general formula (Vllb).

Synthetic scheme 11

A similar approach for the synthesis of substituted imidazolidinone derivatives of the

2 3

general formula (VI) (where R , R , L, T and Q are described above) is depicted in synthetic scheme 12. The imidazolidinone compound (65) undergoes displacement reaction with active methylene nitrile derivative (51) which on reductive cyclisation gives compound (66). The coupling reaction of compound (66) with compound of formula (53) using a suitable base gives corresponding amide which on Suzuki coupling with suitable boronic acid (57) gives compounds of the general formula (VI).

me 12

(65) (66) (VI) An approach for the synthesis of 2,2,2-trifluoroethyl substituted tricyclic compounds of the general formula (Vic) (where R , L, T and Q are described above) is depicted in synthetic scheme 13. The 2,4-difluoronitrobenzene (14) undergoes displacement reaction with 2,2,2-trifluoroethanamine hydrochloride in presence of suitable base to give 2,2,2- trifluoroethyl subbstituted compound which on nitro group reduction gives intermediate (67). The intermediate (67) on cyclization with urea gives imidazo derivatives (68). The intermediate (68) on nitration reaction gives intermediate (69). The intermediate (69) is protected with l-(chloromethyl)-4-methoxybenzene in presence of suitable base to give N- protected compound which on fluorine displacement reaction with active methylene nitrile (51) followed by reductive cyclisation gives compound (70). The intermediate (70) on deprotection reaction using trifluoroacetic acid and triflic acid followed by coupling with compound of formula (53) and finally Suzuki coupling with suitable boronic acid (57) gives compounds of the general formula (VIb). Also Intermediate (69) on N-alkylation using compound of formula (20) gives the corresponding N-alkyl intermediate (71). The intermediate (71) on fluorine displacement reaction with appropriately substituted nitrile (51) followed by reductive cyclization gives compound (72). The intermediate (72) on coupling with compound of formula (53) followed by Suzuki coupling with suitable boronic acid (57) gives compounds of the general formula (Vic).

Synthetic scheme 13

(70)

redu (VIb)

cyclisation

I

(71) (72) (Vic) Experimental Section

The starting materials and reagents required for the synthesis are commercially available or can be prepared by the person skilled in the art. The intermediates 1-102 were prepared according to the synthetic schemes 1-13 described above.

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses. The following abbreviations are used in the text: DMSO-<i₆: Hexadeuterodimethyl sulfoxide; DMF: N,N- dimethyl formamide, /: Coupling constant in units of Hz; RT or rt: room temperature (22- 26°C). Aq.: aqueous; equiv. or eq.: equivalents; DIPEA: Ν,Ν-diisopropylethylamine; DMAP: Ν,Ν-dimethylaminopyridine; HOBt: Hydroxybenzotriazole; EDCI: l-Ethyl-3-(3- dimethylaminopropyl) carbodiimide.

Intermediate 1

2- Amino- 1 -(3 -ethoxypropyl)-7-methyl- 1 ,5 -dihydro-6H-imidazo [4,5 -g] quinoxalin-6-one :

Step 1 : 7-Amino-6-[(3-ethoxypropyl)amino]-3-methylquinoxalin-2(lH)-one: To a stirred solution of l,5-difluoro-2,4-dinitrobenzene (6.5 g, 31.85 mmol) in DMF (20 ml), ethyl-2- aminopropanoate hydrochloride (4.89 g, 31.85 mmol) was added followed by drop wise addition of N,N-diisopropyl ethylamine (11.6 ml, 70.07 mmol) in DMF (10 ml) and the reaction mixture was vigorously stirred for 2 h. To the reaction mixture 3-ethoxypropan-l- amine (3.82 ml, 31.85 mmol) was added followed by diisopropyl ethylamine (5.27 ml, 31.85 mmol) and the resulting mixture was stirred for overnight at room temperature. To the reaction mixture ammonium formate (47.19 g, 748.47 mmol) was added followed by palladium carbon (3 g) in ethanol (10 ml) and the mixture was refluxed at 77-80 °C for overnight. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography to yield 4 g of product as a green solid; 1H NMR (300 MHz, DMSO-J^) δ 1.14 (t, / = 6.9 Hz, 3H), 1.83 (t, / = 7.2 Hz, 2H), 2.26 (s, 3H), 3.09 (t, / = 6.3 Hz, 2H), 3.30- 3.51 (m, 4H), 4.58-4.66 (m, 1H), 5.44-5.52 (m, 2H), 6.38 (s, 1H), 6.58 (s, 1H), 1 1.81 (s, 1H); APCI-MS (m/z) 277.16 (M+H)⁺.

Step 2: 2-Amino-l-(3-ethoxypropyl)-7-methyl-l ,5-dihydro-6H-imidazo[4,5-g]quinoxalin-6- one: To a stirred solution of step 1 intermediate (2.0 g, 7.237 mmol) in ethanol (50 ml), cyanogen bromide (920 mg, 8.685 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to yield 1.5 g of product as a brown solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.05 (t, / = 6.9 Hz, 3H), 1.93 (t, / = 6.3 Hz, 2H), 2.20 (s, 3H), 3.24-3.38 (m, 4H), 4.19 (t, / = 6.9 Hz, 2H), 7.20 (s, 1H), 7.77 (s, 1H), 8.62 (br s, 2H), 12.34 (s, 1H); ESI-MS (m/z) 302.34 (M+H)⁺.

The Intermediates 2-8 were obtained in the manner as described above in intermediate 1. The structural formulas, chemical names and 1H NMR data are provided in table- 1.

Table- 1 : Structure, chemical name and ^lH NMR data of intermediates 2-8.

Intermediate 9

-Amino-l-(3-ethoxypropyl)-8-methyl-5,8-dihydro-lH-imidazo[4,5-^]quinoxaline-6,7-dione

Step 1 : 5-Fluoro-N-methyl-2-nitroaniline: 40 % Methylamine solution (48 ml, 1257.15) was added to 2,4-difluoronitrobenzene (25 g, 157.14 mmol) at 0 °C and the reaction mixture was stirred at same temperature for 2 h. The reaction mixture was poured in water (50 ml) and precipitated solid was separated by filtration. The solid was dried to yield 25 g of product. 1H NMR (300 MHz, DMSO-J₆) δ 2.92 (d, / = 4.8 Hz, 3H), 6.47-6.57 (m, 1H), 6.70-6.82 (m, 1H), 8.1 1-8.20 (m, 1H), 8.33 (br s, 1H); APCI-MS (m/z) 171.05 (M+H)⁺.

Step 2: 4-Fluoro-N -methylbenzene-l ,2-diamine: To a stirred solution of step 1 intermediate (25 g, 147.01 mmol) in aqueous solution of ammonia (250 ml) and THF (100 ml), sodium dithionate (102 mg, 588.06 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (250 ml) and water (250 ml). The reaction mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (150 ml) and brine (100 ml). The reaction mixture was dried (Na₂S0₄) and concentrated under reduced pressure to yield 15 g of product. 1H NMR (300 MHz, DMSO-J₆) δ 2.68 (d, / = 4.2 Hz, 3H), 4.28 (br s, 2H), 4.85-4.94 (m, 1H), 6.10-6.20 (m, 2H), 6.40-6.51 (m, 1H); APCI-MS (m/z) 141.03 (M+H)⁺.

Step 3 : 7-Fluoro-l-methyl-l ,4-dihydroquinoxaline-2,3-dione: To a stirred solution of step 2 intermediate (5.0 g, 35.714 mmol) in dichloroethane (40 ml), triethylamine (12.5 ml, 89.285 mmol) was added followed by addition of ethyl chloro(oxo)acetate (8.12 ml, mmol) at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was further stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 ml) and ethyl acetate (200 ml). The mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (150 ml) and brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure to yield 4.0 g of product as a white solid. 1H NMR (300 MHz, DMSO-J₆) δ 3.33 (s, 3H), 7.04 (t, / = 8.1 Hz, 1H), 7.10-7.20 (m, 1H), 7.29 (d, / = 10.8 Hz, 1H), 12.02 (br s, 1H); APCI-MS (m/z) 193.07 (M-H)^~.

Step 4: 7-Fluoro-l-methyl-6-nitro-l ,4-dihydroquinoxaline-2,3-dione: To ice-cooled sulphuric acid (5 ml), step 3 intermediate (500 mg, 2.575 mmol) was added followed by drop wise addition of nitric acid (1 19 μΐ, 2.832 mmol) at 0 °C and the reaction mixture was stirred at same temperature for 30 min. The reaction mixture was quenched with ice-cooled water. The solid precipitated was filtered and dried to yield 510 mg of product as a pale yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 3.49 (s, 3H), 7.61 (d, / = 13.6 Hz, 1H), 7.88 (d, / = 7.5 Hz, 1H), 12.21 (s, 1H); APCI-MS (m/z) 238.00 (M-H)^". Step 5 : 7-[(3-Ethoxypropyl)amino]-l-methyl-6-nitro-l ,4-dihydroquinoxaline-2,3-dione: 3- Ethoxypropyl amine (31 1 μΐ, 2.508 mmol), was added to a mixture of step 4 intermediate (500 mg, 2.090 mmol), N,N-diisopropylethylamine (1.038 ml, 6.27 mmol) in dry DMF (5 ml) and the resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). The mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure to yield 500 mg of product an orange solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.14 (t, / = 7.5 Hz, 3H), 1.84-1.93 (m, 2H), 3.30-3.57 (m, 9H), 6.56 (s, 1H), 7.85 (s, 1H), 8.30-8.39 (m, 1H), 1 1.87 (s, 1H); APCI-MS (m/z) 321.13 (M-H)^".

Step 6: 6-Amino-7-[(3-ethoxypropyl)amino]- 1 -methyl- 1 ,4-dihydroquinoxaline-2,3-dione: A mixture of step 5 intermediate (500 mg, 1.551 mmol), palladium carbon (200 mg) and ammonium formate (1.12 g, 17.839 mmol) in ethanol (50 ml) was stirred for 1 h at reflux temperature. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. To the residue water (150 ml) and ethyl acetate (150 ml) was added and stirred for 15 min. the organic layer was separated and washed with brine (100 ml). The reaction mixture was dried (Na₂S0₄) and concentrated under reduced pressure. The product was purified by column chromatography to yield 400 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.09-1.19 (m, 3H), 1.81-1.89 (m, 2H), 3.10-3.22 (m, 4H), 3.44-3.60 (m, 5H), 4.51-4.59 (m, 1H), 4.71-4.78 (m, 2H), 6.29 (s, 1H), 6.43 (s, 1H), 1 1.61 (br s, 1H).

Step 7: 2-Amino-l-(3-ethoxypropyl)-8-methyl-5,8-dihydro-lH-imidazo[4,5-^]quinoxaline- 6,7-dione: This intermediate was prepared by reaction of step 6 intermediate (500 mg, 1.710 mmol) with cyanogen bromide (197 mg, 1.881 mmol) in DMF (10 ml) as described in step 2 of intermediate 1 to afford 200 mg of product an off-white solid; 1H NMR (300 MHz, DMSO- d₆) δ 1.01 (t, / = 6.9 Hz, 3H), 1.93-2.01 (m, 2H), 3.24-3.48 (m, 4H), 3.53-3.65 (m, 3H), 4.21- 4.28 (m, 2H), 7.23 (s, 1H), 7.50 (s, 1H), 8.70 (s, 2H), 12.1 1 (s, 1H); APCI-MS (m/z) 318.26 (M+H)⁺.

The Intermediates 10-13 were obtained in the manner as described above in intermediate 9. The structural formulas, chemical names and 1H NMR data are provided in table-2.

Table-2: Structure, chemical name and ^lH NMR data of intermediates 10-13.

Structure Chemical name and H NMR data

Intermediate 14

2-Amino-l-(3-ethoxypropyl)-5,8-dimethyl-5,8-dihydro-lH-imidazo[4,5-^]quinoxaline-6,7- dione

CH₃

N

O^N N

I

CH, -o

CH,

Step 1 : 6-Fluoro-l ,4-dimethyl-7-nitro-l ,4-dihydroquinoxaline-2,3-dione: Potassium carbonate (578 mg, 4.180 mmol) was added to a stirred mixture of 7-fluoro-l-methyl-6-nitro-l ,4- dihydroquinoxaline-2,3-dione (500 mg, 2.090 mmol), methyl iodide (405 μΐ, 6.271 mmol) in dry DMF (5 ml) at room temperature under nitrogen atmosphere and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and water (150 ml) was added to it. The mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (150 ml) and brine (100 ml). The mixture was dried and concentrated under reduced pressure. The solid was purified by column chromatography to yield 460 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-J₆) δ 3.53 (s, 3H), 3.57 (s, 3H), 7.68 (d, / = 12.9 Hz, 1H), 8.03 (d, / = 7.5 Hz, 1H); APCI-MS (m/z) 254.13 (M+H)⁺.

Step 2: 6-[(3-Ethoxypropyl)amino]-l ,4-dimethyl-7-nitro-l ,4-dihydroquinoxaline-2,3-dione: This intermediate was prepared by coupling reaction of step 1 intermediate (450 mg, 1.770 mmol) with 3-ethoxypropyl amine (256 μΐ, 2.132 mmol) in presence of N,N- diisopropylethylamine (880 μΐ, 5.31 mmol) in dry THF (10 ml) as described in step 5 of intermediate 9 to afford 603 mg of product as an orange solid. 1H NMR (300 MHz, DMSO-<i₆) δ 1.14 (t, / = 7.2 Hz, 3H), 1.90 (t, / = 7.2 Hz, 2H), 3.30-3.39 (m, 4H), 3.44-3.57 (m, 8H), 6.63 (s, 1H), 7.89 (s, 1H), 8.41 (br s, 1H); APCI-MS (m/z) 337.28 (M+H)⁺.

Step 3 : 6-Amino-7-[(3-ethoxypropyl)amino]-l ,4-dimethyl-l ,4-dihydroquinoxaline-2,3-dione: This intermediate was prepared by reaction of step 2 intermediate (600 mg, 2.327 mmol) with ammonium formate (1.68 g, 26.761 mmol) using palladium carbon (200 mg) in ethanol (50 ml) as described in step 6 of intermediate 9 to afford 555 mg of product as a yellow solid. The product was directly used in the next step.

Step 4: 2- Amino- 1 -(3 -ethoxypropyl)-5 , 8-dimethyl-5 , 8-dihydro- 1 H-imidazo [4,5 -g] quinoxaline- 6,7-dione: This intermediate was prepared by reaction of step 3 intermediate (550 mg, 2.665 mmol) with cyanogen bromide (308 mg, 2.93 mmol) in ethanol (50 ml) as described in step 2 of intermediate 1 to afford 400 mg of product as a pale yellow solid. ^lH NMR (300 MHz, DMSO-J₆) δ 1.01 (t, / = 6.9 Hz, 3H), 1.94-2.13 (m, 2H), 3.24-3.43 (m, 4H), 3.58 (s, 3H), 3.62 (s, 3H), 4.24-4.31 (m, 2H), 7.34 (s, 1H), 7.56 (s, 1H), 8.66 (s, 1H); APCI-MS (m/z) 332.28 (M+H)⁺.

Intermediate 15 was obtained in the manner as described above in intermediate 14. The structural formulas, chemical names and 1H NMR data are provided in table-3.

Table-3 : Structure, chemical name and ^lH NMR data of intermediate 15.

Structure Chemical name and H NMR data Structure Chemical name and ^XH NMR data

CH₃ 2-Amino-l-(3-hydroxy-3-methylbutyl)-5,8-dimethyl-5,8-

111 ΉΝΗ₂ dihydro-lH-imidazo[4,5-^]quinoxaline-6,7-dione: 1H NMR (300 CH₃ MHz, DMSO-J₆) δ 1.19 (s, 6H), 1.75-1.85 (m, 2H), 3.58 (s, 3H),

HO 3.62 (s, 3H), 4.23-4.30 (m, 2H), 4.68-4.75 (m, 1H), 7.35 (s, 1H),

Intermediate 15 7.45 (s, 1H), 8.64 (s, 2H).

Intermediate 16

2-Amino-3-(3-ethoxypropyl)-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin-7(6H)-one

Step 1 : Ethyl (5-fluoro-2-nitrophenoxy)acetate: To a stirred solution of 5-fluoro-2-nitrophenol (10 g, 63.690 mmol), in ethyl bromoacetate (7.76 ml, 63.690), mixture of potassium carbonate (17.5 g, 127.37 mmol) was added in acetonitrile (80 ml) under nitrogen atmosphere and the reaction mixture was refluxed for 1 h. The reaction mixture was cooled at room temperature and filtered. The filtrate was washed with brine (250 ml), dried (Na₂S0₄) and concentrated under reduced pressure to yield 12 g of product as viscous liquid. 1H NMR (300 MHz, DMSO- d₆) δ 1.20 (t, / = 7.8 Hz, 3H), 4.16 (q, / = 7.2 Hz, 2H), 5.06 (s, 2H), 7.02 (d, / = 6.9 Hz, 1H), 7.34 (t, / = 10.8 Hz, 1H), 8.03 (t, / = 6.3 Hz, 1H).

Step 2: 7-Fluoro-2H-l ,4-benzoxazin-3(4H)-one: Ammonium chloride (1 1 g, 205.58 mmol) was added to stirred suspension of step 1 intermediate (5.0 g, 20.558 mmol), methanol (30 ml) and water (80 ml) followed by addition of iron powder (6.8 g, 123.306), the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. To the residue, water (150 ml) and ethyl acetate (150 ml) was added and stirred for 15 min. the organic layer was separated and washed with brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure. The product was purified by column chromatography to yield 2.75 g of product as an off-white solid; 1H NMR (300 MHz, DMSO-J₆) δ 4.58 (s, 2H), 6.77-6.89 (m, 3H), 10.72 (br s, 1H); APCI-MS (m/z) 166.24 (M-H)^".

Step 3 : 7-Fluoro-6-nitro-2H-l ,4-benzoxazin-3(4H)-one: To a stirred solution of step 2 intermediate (2.7 g, 16.157 mmol) in sulphuric acid (3 ml) a mixture of nitric acid (69 %, 0.72 ml, 16.157 mmol) and concentrated sulphuric acid (2 ml) was drop wise added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with ice-cooled water and solid was precipitated. The precipitated solid was dissolved in ethyl acetate (30 ml) and washed with aqueous saturated solution of sodium bicarbonate (150 ml). The ethyl acetate layer was dried and filtered and dried (Na₂S0₄) and concentrated to yield 2.6 g of product as yellow solid. 1H NMR (300 MHz, DMSO-d₆) δ 4.79 (s, 2H), 7.26 (d, J = 12.0 Hz, 1H), 7.63 (d, / = 7.2 Hz, 1H), 1 1.03 (br s, 1H).

Step 4: 6-Amino-7-[(3-ethoxypropyl)amino]-2H-l ,4-benzoxazin-3(4H)-one: To a solution of step 3 intermediate (2.5 g, 1 1.786 mmol) in DMF (25 ml), 3-ethoxypropyl amine (2.1 1 ml, 17.680 mmol) was added followed by drop wise N,N-diisopropylethylamine (3.9 ml, 23.572 mmol) at room temperature and the reaction mixture was stirred for 3 h at same temperature. The palladium carbon (1.8 g) and ammonium formate (8.54 g, 135.539 mmol) in ethanol (50 ml) was added to the reaction mixture at 80 °C and refluxed for 4 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. To the residue water (150 ml) and ethyl acetate (150 ml) was added and stirred for 15 min. The organic layer was separated and washed with brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure. The product was purified by column chromatography to yield 2.78 g of product as an yellow solid; 1H NMR (300 MHz, DMSO-d₆) δ 1.08-1.20 (m, 3H), 1.71-1.80 (m, 2H), 2.92-3.02 (m, 2H), 3.08- 3.18 (m, 4H), 4.31 (s, 2H), 6.06 (s, 1H), 6.19 (s, 1H), 7.85-7.95 (m, 2H), 10.16 (s, 1H).

Step 5 : 2-Amino-3-(3-ethoxypropyl)-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin-7(6H)-one: This intermediate was prepared by reaction of step 4 intermediate (1.0 g, 3.769 mmol) with cyanogen bromide (593 mg, 5.655 mmol) in ethanol (20 ml) as described in step 2 of intermediate 1 to afford 500 mg of product an off-white solid; 1H NMR (300 MHz, DMSO- d₆) δ 1.05 (t, / = 6.6 Hz, 3H), 1.84-1.92 (m, 2H), 3.25-3.35 (m, 4H), 4.02-4.12 (m, 2H), 4.52 (s, 2H), 6.88 (s, 1H), 7.08 (s, 1H), 7.91 (br s, 2H), 10.67 (s, 1H); APCI-MS (m/z) 291.21 (M+H)⁺.

The intermediates 17-20 were obtained in the manner as described above in intermediate 16. The structural formulas, chemical names and 1H NMR data are provided in table-4.

Table-4: Structure, chemical name and ^lH NMR data of intermediates 17-20.

Structure Chemical name and H NMR data

Intermediate 21

2-Amino-3-(3-ethoxypropyl)-6,6-dimethyl-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin-7(6H)- one

The title compound was prepared in the following five steps: (i) reaction of 5-fluoro-2- nitrophenol (5 g, 31.826 mmol) with ethyl 2-bromo-2-methylpropanoate (4.72 ml, 31.826 mmol), (ii) reductive cyclisation using ammonium chloride (7.88 g, 147.47 mmol) in presence of iron powder (4.9 g, 88.482), (iii) nitration using nitric acid (0.75 ml, 1 1.783 mmol) in sulphuric acid (10 ml), (iv) displacement reaction with 3-ethoxypropyl amine (374 μΐ, 3.122 mmol) and finally (v) reaction with cyanogen bromide (536 mg, 5.113 mmol) as described in Intermediate 16 to yield 500 mg of product an off-white solid; 1H NMR (300 MHz, DMSO- d₆) δ 1.05 (t, / = 6.9 Hz, 3H), 1.36 (s, 6H), 1.84-1.94 (m, 2H), 3.24-3.36 (m, 4H), 4.00-4.09 (m, 2H), 6.83 (s, 1H), 7.02 (s, 1H), 7.62 (br s, 2H), 10.53 (s, 1H); APCI-MS (m/z) 319.31 (M+H)⁺.

The intermediates 22-31 were obtained in the manner as described above in intermediate 21. The structural formulas, chemical names and 1H NMR data are provided in table-5.

Table 5 : Structure, chemical name and 1H NMR data of intermediates 22-31.

Intermediate 32

2-Amino-3-(3-ethoxypropyl)-6,6,8-trimethyl-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin- 7(6H)-one

CH₃

Step 1 : 7-Fluoro-2,2,4-trimethyl-6-nitro-2H-l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by N-methylation of 7-fluoro-2,2-dimethyl-6-nitro-2H-l ,4-benzoxazin-3(4H)-one (500 mg, 2.081 mmol) using methyl iodide (395 μΐ, 6.245 mmol) in presence of potassium carbonate (575 mg, 4.163 mmol) in DMF (10 ml) as described in step 1 of intermediate 14 to yield 600 mg of product a brown solid; 1H NMR (300 MHz, CDC1₃) δ 1.56 (s, 6H), 3.41 (s, 3H), 6.86 (d, / = 12.3 Hz, 1H), 7.69 (d, / = 7.2 Hz, 1H).

Step 2: 6-Amino-7-[(3-ethoxypropyl)amino]-2,2,4-trimethyl-2H- 1 ,4-benzoxazin-3(4H)-one: This intermediate was prepared by coupling reaction step 1 intermediate (600 mg, 2.360 mmol) with 3-ethoxypropyl amine (565 μΐ, 4.720 mmol) in presence of N,N- diisopropylethylamine (0.73 ml, 4.720 mmol) followed by nitro group reduction using ammonium formate (1.7 g, 27.145 mmol) in presence of palladium carbon (500 mg) in ethanol (40 ml) as described in step 4 of intermediate 16 to yield 1.02 g of product as an off- white solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.05-1.17 (m, 3H), 1.43 (s, 6H), 3.09 (q, / = 9.0 Hz, 2H), 3.20-3.46 (m, 9H), 6.59 (s, 1H), 7.67 (s, 1H), 8.46 (br s, 1H).

Step 3 : 2-Amino-3-(3-ethoxypropyl)-6,6,8-trimethyl-3,8-dihydroimidazo[4,5- g][l ,4]benzoxazin-7(6H)-one: This intermediate was prepared by reaction of step 4 intermediate (1.0 g, 3.253 mmol) with cyanogen bromide (512 mg, 4.88 mmol) in ethanol (20 ml) as described in step 2 of intermediate 1 to afford 300 mg of product an off-white solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.08 (t, / = 7.2 Hz, 3H), 1.34 (s, 6H), 1.79-1.85 (m, 2H), 3.24- 3.33 (m, 7H), 3.93-3.99 (m, 2H), 6.64-6.71 (m, 2H), 6.89 (d, / = 1 1.7 Hz, 2H).

The intermediates 33-34 were obtained in the manner as described above in intermediate 32. The structural formulas, chemical names and 1H NMR data are provided in table-6.

Table-6: Structure, chemical name and ^lH NMR data of intermediates 32-34.

Structure Chemical name and 1H NMR data Structure Chemical name and ^XH NMR data

CH₃ 2-Amino-3 -(3 -hydroxy-3 -methylbutyl)-6,6, 8-trimethyl-3 , 8- dihydroimidazo[4,5-g][l ,4]benzoxazin-7(6H)-one: 1H NMR (300 MHz, DMSO-J₆) δ 1.15 (s, 6H), 1.22 (s, 3H), 1.31-1.42 (m, 6H), 1.64-1.72 (m, 2H), 3.95-4.06 (m, 2H), 4.56 (s, 1H),

Intermediate 33 6.91-6.99 (m, 4H); ESI-MS (m/z) 333.25 (M+H)⁺.

CH₃ 2-Amino-6,6, 8-trimethyl-3 - [2-(morpholin-4-yl)ethyl] -3,8- dihydroimidazo[4,5-g][l ,4]benzoxazin-7(6H)-one: 1H NMR (300 MHz, DMSO-J₆) δ 1.37 (s, 6H), 2.41-2.52 (m, 6H), 2.58 (t, / = 6.0 Hz, 2H), 3.41-3.50 (m, 4H), 4.12 (t, / = 6.3 Hz, 3H), 7.00 (s, 1H), 7.1 1 (s, 1H), 7.64 (s, 2H); ESI-MS (m/z) 360.64 (M+H)⁺.

Intermediate 34

Intermediate 35

2'-Amino-3'-(3-ethoxypropyl)-3',8'-dihydro-7'H-spiro[cyclopropane-l ,6'-imidazo[4,5- g] [ 1 ,4]benzoxazin]-7'-one

CH₃

Step 1 : Ethyl 4-bromo-2-(5-fluoro-2-nitrophenoxy)butanoate: To a stirred solution of 5- fluoro-2-nitrophenol (7.4 g, 47.103 mmol) in DMF (15 ml), ethyl 2,4-dibromobutanoate (12.9 g, 47.13 mmol) and potassium carbonate (6.512 g, 47.103) was added. The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with 1 N HCl (200 ml) and the mixture was extracted with ethyl acetate (3 x 300 ml). Combined extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 6.4 g of product as pale yellow solid. APCI-MS (m/z) 350.00 (M+H)⁺.

Step 2: Ethyl l-(5-fluoro-2-nitrophenoxy)cyclopropanecarboxylate: To a stirred solution of step 1 intermediate (9 g, 25.704 mmol) in THF (20 ml) was added potassium- ie/t-butoxide (3.141 g, 25.704 mmol) and reaction mixture was stirred at room temperature for overnight. The reaction was diluted with ethyl acetate (200 ml). The mixture was washed with 1 N HCl (150 ml) and dried over sodium sulphate. The compound was concentrated under reduced pressure and purified by column chromatography to yield 6.4 g of product as pale yellow solid. APCI-MS (m/z) 270.04 (M+H)⁺. Step 3 : 7-Fluorospiro[l ,4-benzoxazine-2, -cyclopropan]-3(4H)-one: This intermediate was prepared by reductive cyclisation of step 2 intermediate (1 g, 3.712 mmol) using ammonium chloride (1.986 g, 37.12 mmol) and iron powder (1.24 g, 22.272 mmol) in methanol (6 ml) and water (6 ml) as described in step 2 of intermediate 16 to yield 550 mg of product as dark brown solid. APCI-MS (m/z) 194.12 (M+H)⁺.

Step 4: 7-Fluoro-6-nitrospiro[ 1 ,4-benzoxazine-2, 1 '-cyclopropan]-3(4H)-one: This intermediate was prepared by nitration of step 3 intermediate (550 mg, 2.847 mmol) using nitric acid (180 μΐ) and sulfuric acid (3 ml) as described in step 3 of intermediate 16 to yield 400 mg of product as red solid. APCI-MS (m/z) 239.04 (M+H)⁺.

Step 5 : 6-Amino-7-[(3-ethoxypropyl)amino]spiro[ 1 ,4-benzoxazine-2, 1 '-cyclopropan]-3(4H)- one: This intermediate was prepared by displacement reaction of step 4 intermediate (150 mg, 0.629 mmol) with 3-ethoxypropan-l-amine (129 mg, 1.259 mmol) followed by nitro group reduction using ammonium formate (456 mg, 7.242 mmol) in presence of palladium carbon (200 mg) as described in step 4 of intermediate 16 to yield 206 mg of product as yellow solid. Step 6: 2'-Amino-3'-(3-ethoxypropyl)-3',8'-dihydro-7'H-spiro[cyclopropane- 1 ,6'-imidazo[4,5- g][l ,4]benzoxazin]-7'-one: The title compound was prepared by reaction of step 5 intermediate (200 mg, 0.623 mmol) with cyanogen bromide (256 mg, 0.934 mmol) as described in step 2 of intermediate 1 to yield 65 mg of product as a dark brown viscous liquid; 1H NMR (300 MHz, DMSO-J₆) δ 1.18 (d, / = 12.3 Hz, 6H), 1.36 (s, 6H), 3.87 (s, 2H), 5.20 (s, 1H), 6.83 (s, 1H), 7.15 (s, 1H), 7.37 (br s, 2H), 10.51 (s, 1H); APCI-MS (m/z) 305.19 (M+H)⁺.

Intermediate 36

2'-Amino-3'-(3-hydroxy-3-methylbutyl)-3',8'-dihydro-7'H-spiro[cyclopropane-l ,6'- imidazo[4,5-g][l ,4]benzoxazin]-7'-one

The title compound was prepared in the following three steps: (i) displacement reaction of 7- fluoro-6-nitrospiro[l ,4-benzoxazine-2, -cyclopropan]-3(4H)-one (150 mg, 0.629 mmol) with 4-amino-2-methylbutan-2-ol (129 mg, 1.259 mmol), (ii) nitro group reduction using ammonium formate (456 mg, 7.242 mmol) in presence of palladium carbon (200 mg) and finally (iii) reaction with cyanogen bromide (162 mg, 1.544 mmol) as described in intermediate 14 to yield 70 mg of product as a red solid; 1H NMR (300 MHz, DMSO-d₆) δ 1.12-1.40 (m, 10H), 1.65-1.80 (m, 2H), 3.95-4.06 (m, 2H), 5.39 (s, 1H), 6.86 (d, / = 7.5 Hz, 1H), 6.92 (s, 1H), 7.60-7.75 (m, 2H), 10.59 (s, 1H).

Intermediate 37

2'-Amino-3'-(3-hydroxy-3-methylbutyl)-8'-methyl-3',8'-dihydro-7'H-spiro[cyclopropane-l ,6'- imidazo[4,5-g][l ,4]benzoxazin]-7'-one

The title compound was prepared in the following five steps: (i) N-methylation of 7-fluoro-6- nitrospiro[l ,4-benzoxazine-2, -cyclopropan]-3(4H)-one (150 mg, 0.629 mmol) using methyl iodide (0.079 ml, 1.259 mmol) in presence of potassium carbonate (174 mg, 1.259); (ii) reductive cyclisation using ammonium formate (862 mg, 13.673 mmol) in presence of palladium carbon (200 mg); (iv) displacement reaction with 4-amino-2-methylbutan-2-ol (245 mg, 2.379 mmol) and finally (v) reaction with cyanogen bromide (128 mg, 1.228 mmol) as described in intermediate 14 to yield 90 mg of product as a red solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.10-1.26 (m, 10H), 1.67 (t, / = 6.0 Hz, 2H), 3.35 (s, 3H), 3.96 (t, / = 6.0 Hz, 2H), 4.51 (s, 1H), 6.43 (s, 2H), 6.87 (s, 1H), 6.95 (s, 1H); ESI-MS (m/z) 331.31 (M+H)⁺.

Intermediate 38

2-Amino-3-(3-ethoxypropyl)-6,6-difluoro-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin-7(6H)- one

Step 1 : 2-Bromo-2,2-difluoro-N-(4-fluoro-2-hydroxyphenyl)acetamide: To a stirred solution of 2-amino-5-fluorophenol (5.0 g, 39.332 mmol) in dry THF (30 ml) at 0 °C, sodium hydride (1.57 g, 39.332 mmol) was added and the reaction mixture was stirred at -15 °C for 20 min. To reaction mixture ethyl bromo(difluoro)acetate (5.55 ml, 43.266 mmol) was drop-wise added and was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (200 ml) and extracted with ethyl acetate (3 x 150 ml). The combined extracts were washed with brine (250 ml), dried (Na₂S0₄) and concentrated under reduced pressure to yield 5.05 g of product as red solid. APCI-MS (m/z) 204.02 (M+H)⁺.

Step 2: 2,2,7-Trifluoro-2H-l ,4-benzoxazin-3(4H)-one: To a stirred solution of step 1 intermediate (5.0 g, 17.605 mmol) in toluene (25 ml), l ,8-diazabicyclo[5.4.0]undec-7-ene (2.68 g, 17.605 mmol) was added and the reaction mixture was stirred at 80 °C for overnight. The reaction mixture was cooled to room temperature and quenched with saturated aqueous solution of ammonium chloride (150 ml). The reaction mixture was extracted with ethyl acetate (3 x 200 ml) and washed with brine (200 ml). The reaction mixture was dried over sodium sulphate and concentrated under reduced pressure to yield 2.75 g of product as an off- white solid. APCI-MS (m/z) 204.02 (M+H)⁺.

Step 3 : 2,2,7-Trifluoro-6-nitro-2H-l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by nitration of step 2 intermediate (2.0 g, 9.846 mmol) using nitric acid (69 %, 0.59 ml, 9.846 mmol) and concentrated sulphuric acid (31.6 ml) as described in step 3 of intermediate 16 to yield 2.0 g of product as an off-white solid. APCI-MS (m/z) 249.1 1 (M+H)⁺.

Step 4: 6-Amino-7-[(3-ethoxypropyl)amino]-2,2-difluoro-2H-l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by displacement reaction of step 3 intermediate (500 mg, 2.015 mmol) with 3-ethoxypropyl amine (0.415 mg, 4.03 mmol) followed by reduction of nitro group using ammonium formate (4.32 g, 68.506 mmol) in presence of palladium carbon (800 mg) as described in step 4 of intermediate 16 to yield 507 mg of product as an yellow solid; APCI-MS (m/z) 302.31 (M+H)⁺.

Step 5 : 2-Amino-3-(3-ethoxypropyl)-6,6-difluoro-3,8-dihydroimidazo[4,5-^][l ,4]benzoxazin- 7(6H)-one: This intermediate was prepared by reaction of step 4 intermediate (500 mg, 1.654 mmol) with cyanogen bromide (260 mg, 2.482 mmol) in ethanol (20 ml) as described in step 2 of intermediate 1 to afford 150 mg of product an off- white solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.38 (s, 6H), 2.80 (t, / = 6.3 Hz, 2H), 3.07-3.20 (m, 4H), 3.44-3.59 (m, 4H), 4.22 (t, / = 6.3 Hz, 2H), 6.89 (s, 1H), 7.19 (s, 1H), 8.09-8.17 (m, 2H), 10.64 (s, 1H); APCI-MS (m/z) 327.23 (M+H)⁺.

The intermediates 39-41 were obtained in the manner as described above in intermediate 38. The structural formulas, chemical names and 1H NMR data are provided in table-7.

Table-7: Structure, chemical name and H NMR data of intermediates 39-41.

Structure Chemical name and H NMR data

Intermediate 42

2-Amino-6,6-difluoro-3-(3-hydroxy-3-methylbutyl)-8-methyl-3,8-dihydroimidazo[4,5- g] [ 1 ,4]benzoxazin-7(6H)-one

The title compound was prepared in the following four steps: (i) N-methylation of 2,2,7- trifluoro-6-nitro-2H-l ,4-benzoxazin-3(4H)-one (500 mg, 2.015 mmol) using methyl iodide (858 mg, 6.045 mmol), (ii) displacement reaction of 2,2,7-trifluoro-4-methyl-6-nitro-2H-l ,4- benzoxazin-3(4H)-one (500 mg, 1.907 mmol) with 4-amino-2-methylbutan-2-ol (295 mg, 2.861 mmol), (iii) nitro group reduction using ammonium formate (1.383 g, 21.934 mmol) in presence of palladium carbon (500 mg) and finally (iv) reaction with cyanogen bromide (174 mg, 1.665 mmol) as described in intermediate 14 to yield 204 mg of product as a red solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.15 (s, 6H), 1.69 (t, / = 6.3 Hz, 2H), 3.29-3.40 (m, 3H), 3.98-4.07 (m, 2H), 4.55 (s, 1H), 6.71 (s, 2H), 7.15 (s, 1H), 7.20 (s, 1H); APCI-MS (m/z) 341.21 (M+H)⁺. Intermediate 43

2-Amino-3-(3-ethoxypropyl)-6,6-dimethyl-8-[2-(morpholin-4-yl)ethyl]-3,8- dihydroimidazo[4,5-g][l ,4]benzoxaz -7(6H)-one

Step 1 : 7-Fluoro-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-6-nitro-2H-l ,4-benzoxazin-3(4H)- one: This intermediate was prepared by alkylation reaction of 7-fluoro-2,2-dimethyl-6-nitro- 2H-l ,4-benzoxazin-3(4H)-one (500 mg, 2.081 mmol) with 4-(2-chloroethyl)morpholine hydrochloride (1.7 g, 9.159 mmol) in presence of potassium carbonate (1.38 g, 9.992 mmol) in DMF (10 ml) as described in step 1 of intermediate 14 to yield 1.5 g of product as yellow solid. ESI-MS (m z) 354.16 (M+H)⁺.

Step 2: 6-Amino-7-[(3-ethoxypropyl)amino]-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-2H- l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by coupling reaction step 1 intermediate (500 mg, 1.415 mmol) with 3-ethoxypropyl amine (0.33 ml, 2.830 mmol) in presence of N,N-diisopropylethylamine (0.70 ml, 4.245 mmol) followed by nitro group reduction using ammonium formate (0.830 g, 13.175 mmol) in presence of palladium carbon (100 mg) in ethanol (50 ml) as described in step 4 of intermediate 16 to yield 440 mg of product as brown solid. ESI-MS (m/z) 407.27 (M+H)⁺.

Step 3_i 2-Amino-3-(3-ethoxypropyl)-6,6-dimethyl-8-[2-(morpholin-4-yl)ethyl]-3,8- dihydroimidazo[4,5-g][l ,4]benzoxazin-7(6H)-one: This intermediate was prepared by reaction of step 2 intermediate (0.430 g, 1.057 mmol) with cyanogen bromide (168 mg, 1.586 mmol) in ethanol (50 ml) as described in step 2 of intermediate 1 to afford 300 mg of product as brown solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.01 (t, / = 6.9 Hz, 3H), 1.39 (s, 6H), 1.85-1.95 (m, 2H), 2.65-2.75 (m, 4H), 3.21-3.35 (m, 6H), 3.58-3.68 (m, 4H), 4.13 (t, / = 5.1 Hz, 4H), 7.19-7.28 (m, 2H), 8.42 (s, 2H); ESI-MS (m/z) 432.25 (M+H)⁺.

Intermediate 44

6- Amino-5 -(3 -ethoxypropyl)-3 ,5 -dihydroimidazo [4,5 -/]benzimidazol-2( 1 H)-one

Step 1 : 5-Fluoro-6-nitro-l ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by nitration of 5-fluoro-l ,3-dihydro-2H-benzimidazol-2-one (1.2 g, 7.887 mmol) using nitric acid (385 μΐ, 8.67 mmol) and cone, sulfuric acid (10 ml) as described in step 3 of intermediate 16 to yield 1.1 g of product as an off-white solid. 1H NMR (300 MHz, DMSO-J₆) δ 7.08 (d, / = 1 1.7 Hz, 1H), 7.58 (d, / = 6.9 Hz, 1H), 1 1.16 (s, 1H), 1 1.55 (s, 1H); APCI-MS (m/z) 196.27 (M-H)^~.

Step 2: 5 - [(3 -Ethoxypropyl)amino] -6-nitro- 1 ,3 -dihydro-2H-benzimidazol-2-one : 3 - Ethoxypropyl amine (365 μΐ, 2.536 mmol) was added to a mixture of step 1 intermediate (580 mg, 3.043 mmol), N,N-diisopropylethylamine (1.3 ml, 7.609 mmol) in dry DMSO (5 ml) and the reaction mixture was stirred at 80 °C for overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). The reaction mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The reaction mixture was dried over sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to yield 752 mg of product as red solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.09 (t, / = 7.8 Hz, 3H), 1.82-1.90 (m, 2H), 2.45-2.52 (m, 2H), 3.31-3.40 (m, 4H), 6.34 (s, 1H), 7.49 (s, 1H), 8.56 (s, 1H), 10.71- 10.80 (m, 2H); APCI-MS (m/z) 281.1 1 (M+H)⁺.

Step 3 : 5-Amino-6-[(3-ethoxypropyl)amino]-l ,3-dihydro-2H-benzimidazol-2-one: A mixture of step 2 intermediate (745 mg, 2.658 mmol), palladium carbon (250 mg) and ammonium formate (1.9 g, 17.583 mmol) in ethanol (50 ml) was stirred for 1 h at reflux temperature. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. To the residue, water (100 ml) and ethyl acetate (100 ml) was added and it was stirred for 15 min. Organic layer was separated and washed with brine (100 ml). The mixture was dried over sodium sulfate and concentrated under reduced pressure to yield 820 mg of product as red solid. APCI-MS (m/z) 251.27 (M+H)⁺.

Step 4: 6-Amino-5-(3-ethoxypropyl)-3,5-dihydroimidazo[4,5-/]benzimidazol-2(lH)-one: This intermediate was prepared by reaction of step 3 intermediate (820 mg, 3.27 mmol) with cyanogen bromide (520 mg, 4.914 mmol) ethanol (20 ml), as described in step 2 of intermediate 1 to yield 318 mg of product as an off-white solid. 1H NMR (300 MHz, DMSO- d₆) δ 1.1 1 (t, / = 6.9 Hz, 3H), 1.75-1.86 (m, 2H), 3.21-3.40 (m, 4H), 3.94 (t, / = 6.0 Hz, 2H), 6.07 (s, 2H), 6.66 (s, 2H), 10.17 (s, 1H), 10.27 (s, 1H); APCI-MS (m/z) 276.25 (M+H)⁺. The intermediates 45-49 were obtained in the manner as described above intermediate 44. The structural formulas, chemical names and 1H NMR data are provided table-8.

Table-8: Structure, chemical name and ^lH NMR data of intermediates 45-49.

Intermediate 50

6- Amino-5 -(3 -ethoxypropyl)-3 -methyl-3 ,5 -dihydroimidazo [4,5 -/]benzimidazol-2( 1 H)-one

CH₃

Step 1 : 5-Fluoro-N-methyl-2-nitroaniline: 40 % methylamine solution (48 ml, 1257.15) was added to 2,4-difluoronitrobenzene (25 g, 157.14 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured in water (50 ml) and solid precipitated was separated by filtration. The solid was dried to yield 25 g of product. 1H NMR (300 MHz, DMSO-J₆) δ 2.92 (d, / = 4.8 Hz, 3H), 6.47-6.57 (m, 1H), 6.70-6.82 (m, 1H), 8.1 1-8.20 (m, 1H), 8.33 (br s, 1H); APCI-MS (m/z) 171.05 (M+H)⁺.

Step 2: 4-Fluoro-N -methylbenzene-l ,2-diamine: To a stirred solution of 5-fluoro-N-methyl-2- nitroaniline (25 g, 147.01 mmol) in aqueous solution of ammonia (250 ml) and THF (100 ml), sodium dithionate (102 g, 588.06 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (250 ml) and water (250 ml). The mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (150 ml) and brine (100 ml). The mixture was dried over sodium sulfate and concentrated under reduced pressure to yield 15 g of product. 1H NMR (300 MHz, DMSO-J₆) δ 2.68 (d, / = 4.2 Hz, 3H), 4.28 (br s, 2H), 4.85-4.94 (m, 1H), 6.10-6.20 (m, 2H), 6.40-6.51 (m, 1H); APCI-MS (m/z) 141.03 (M+H)⁺.

Step 3 : 6-Fluoro-l-methyl-l ,3-dihydro-2H-benzimidazol-2-one: A mixture of step 2 intermediate (5.0 g, 35.673 mmol) and urea (10.7 g, 178.367 mmol) was stirred at 160 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water (150 ml) and ethyl acetate (150 ml). The mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The mixture was dried over sodium sulfate and concentrated under reduced pressure to yield 3.8 g of product as a buff solid. 1H NMR (300 MHz, DMSO-J₆) δ 3.25 (s, 3H), 6.70-6.82 (m, 1H), 6.88-6.95 (m, 1H), 7.02-7.10 (m, 1H), 10.86 (s, 1H). APCI-MS 167.22 (M+H)⁺.

Step 4: 6-Fluoro-l-methyl-5-nitro-l ,3-dihydro-2H-benzimidazol-2-one: A solution of fuming nitric acid (152 μΐ, 3.61 1 mmol) in acetic anhydride (1 ml) was added to a stirred suspension of step 3 intermediate (500 mg, 3.009 mmol) in acetic anhydride (4 ml) at 0 °C and the resulting suspension was stirred for 30 min at 0 °C temperature. The reaction mixture was poured in ice cooled water and extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with brine (100 ml). The mixture was dried and concentrated under reduced pressure to yield 595 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 3.31 (s, 3H), 7.44 (t, / = 1 1.7 Hz, 1H), 7.62 (d, / = 6.9 Hz, 1H), 1 1.43 (s, 1H); APCI-MS (m/z) 210.26 (M-H)^~.

Step 5 : 6-[(3 -Ethoxypropyl)amino] - 1 -methyl-5 -nitro- 1 ,3 -dihydro-2H-benzimidazol-2-one : This intermediate was prepared by coupling reaction of step 4 intermediate (580 mg, 2.746 mmol) with 3-ethoxypropyl amine (395 μΐ, 3.296 mmol) using N,N-diisopropylethylamine (1.4 ml, 8.241 mmol) in dry DMF (5 ml) as described in step 2 of intermediate 44 to yield 461 mg of product as yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.13 (t, / = 6.6 Hz, 3H), 1.85-1.95 (m, 2H), 2.78 (s, 3H), 3.28-3.35 (m, 2H), 3.40-3.53 (m, 4H), 6.56 (s, 1H), 7.52 (s, 1H), 8.55-8.63 (m, 1H), 10.85 (s, 1H); APCI-MS (m/z) 295.08 (M+H)⁺.

Step 6: 5-Amino-6-[(3-ethoxypropyl)amino]- 1 -methyl- 1 ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by reduction of step 5 intermediate (450 mg, 1.529 mmol) using ammonium formate (1.1 g, 17.583 mmol) in presence of palladium carbon (250 mg) in ethanol (50 ml) as described in step 3 of intermediate 44 to yield 425 mg of product as a viscous liquid. APCI-MS (m/z) 265.27 (M+H)⁺.

Step 7: 6-Amino-5 -(3 -ethoxypropyl)-3 -methyl-3 ,5 -dihydroimidazo [4,5 -/]benzimidazol- 2(lH)-one: The title compound was prepared by reaction step 6 intermediate (240 mg, 2.269 mmol) with cyanogen bromide (240 mg, 1.513 mmol) in DMF (5 ml) and ethanol (5 ml) as described in step 2 of intermediate 1 to yield 265 mg of product as an off-white solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.14 (t, / = 6.9 Hz, 3H), 1.83-1.93 (m, 2H), 3.25-3.43 (m, 9H), 3.95-4.03 (m, 2H), 6.74 (s, 1H), 6.89 (s, 1H), 10.43 (s, 1H); APCI-MS (m/z) 290.29 (M+H)⁺.

The intermediates 51-73 were obtained in the manner as described above in intermediate 50. The structural formulas, chemical names and 1H NMR data are provided in table-9.

Table-9: Structure, chemical name and ^lH NMR data of Intermediates 51-73.

Intermediate 68

Structure Chemical name and H NMR data

ESI-MS (m/z) 402.31 (M+H)⁺.

Intermediate 74

3-[2-Amino-5-(2-hydroxy-2-methylpropyl)-6-oxo-6,7-dihydroimidazo[4,5-/]benzimidazol- 1 (5H)-yl] -N,N-dimethylpropanamide

Step 1 : l-[(4-Fluoro-2-nitrophenyl)amino]-2-methylpropan-2-ol: This intermediate was prepared by coupling reaction of 1 ,4 difluoro-2 -nitrobenzene (5.0 g, 31.428 mmol) with 1- amino-2-methylpropan-2-ol (3.08 mg, 34.571 mmol) in presence of N,N- diisopropylethylamine (15.6 ml, 94.286 mmol) in dry DMF (10 ml) as described in step 2 of intermediate 44 to afford 4.5 g of product as a red solid. ESI-MS (m/z) 229.10 (M+H)⁺.

Step 2: l-[(2-Amino-4-fluorophenyl)amino]-2-methylpropan-2-ol: This intermediate was prepared by reaction of step 1 intermediate (4.5 g, 19.714 mmol) with ammonium formate (14.29 g, 226.715 mmol) in presence of palladium carbon (500 mg) in ethanol (100 ml) as described in step 3 of intermediate 44 to afford 3.8 g of product as a brown liquid. APCI-MS (m/z) 198.94 (M+H)⁺.

Step 3 : 5-Fluoro-l-(2-hydroxy-2-methylpropyl)-l ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by cyclisation reaction of step 2 intermediate (3.5 g, 17.653 mmol) with urea (5.3 g, 88.267 mmol) as described in step 3 of intermediate 50 to yield 2.85 g of product as a red solid. ESI-MS 225.05 (M+H)⁺ (m/z).

Step 4: 5 -Fluoro- 1 -(2-hydroxy-2-methylpropyl)-6-nitro- 1 ,3 -dihydro-2H-benzimidazol-2-one : This intermediate was prepared by nitration reaction of step 3 intermediate (2.8 g, 12.488 mmol) using nitric acid (750 μΐ, 12.488 mmol) and sulfuric acid (15 ml) as described in step 4 of intermediate 9 to yield 3.0 g of product as a pale orange solid. ESI-MS 268.29 (Μ-Η)^" (m/z).

Step 5 : 3- {[l-(2-Hydroxy-2-methylpropyl)-6-nitro-2-oxo-2,3-dihydro-lH-benzimidazol-5- yl] amino }-N,N-dimethylpropanamide: This intermediate was prepared by coupling reaction of step 4 intermediate (700 mg, 1.845 mmol) with 3-amino-N,N-dimethylpropanamide (257 mg, 2.214 mmol) in presence of N,N-diisopropylethylamine (0.947 ml, 5.535 mmol) in dry DMSO (10 ml) as described in step 5 of intermediate 9 to afford 500 mg of product as a red solid. ESI-MS (m/z) 366.09 (M+H)⁺.

Step 6: 3- {[6-Amino-l-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-lH-benzimidazol-5- yl] amino }-N,N-dimethylpropanamide: This intermediate was prepared by reaction of step 5 intermediate (500 mg, 1.368 mmol) with ammonium formate (992 mg, 15.737 mmol) in presence of palladium carbon (100 mg) in ethanol (100 ml) as described in step 6 of intermediate 9 to afford 350 mg of product as a brown liquid. ESI-MS (m/z) 336.20 (M+H)⁺.

Step 7_i 3-[2-Amino-5-(2-hydroxy-2-methylpropyl)-6-oxo-6,7-dihydroimidazo[4,5-

/]benzimidazol-l(5H)-yl]-N,N-dimethylpropanamide: This intermediate was prepared by reaction of step 6 intermediate (300 mg, 0.894 mmol) with cyanogen bromide (142 mg, 1.341 mmol) in ethanol (50 ml) as described in step 2 of intermediate 1 to afford 145 mg of product as brown solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.14 (s, 6H), 2.73-2.83 (m, 6H), 2.90 (s, 2H), 3.70 (s, 2H), 4.27 (t, / = 6.0 Hz, 2H), 4.73 (s, 1H), 7.13 (br s, 2H), 7.25 (s, 1H), 8.05 (s, 1H), 1 1.00 (s, 1H); ESI-MS (m/z) 361.39 (M+H)⁺.

Intermediate 75 was obtained in the manner as described above in intermediate 74.

The structural formulas, chemical names and 1H NMR data are provided in table- 10.

Table- 10: Structure, chemical name and ^lH NMR data of intermediate 75.

Intermediate 76

6-Amino-5-(3-ethoxypropyl)-l ,3-dimethyl-3,5-dihydroimidazo[4,5-/]benzimidazol-2(lH)-one

H₃C

0=< 1 J NH₂

H₃C

^CH₃

Step 1 : 5-Fluoro-l ,3-dimethyl-6-nitro-l ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by N-methylation of 6-fluoro-l-methyl-5-nitro-l ,3-dihydro-2H-benzimidazol-2- one (500 mg, 2.367 mmol) using methyl iodide (458 μΐ, 7.103 mmol) in presence potassium carbonate (654 mg, 4.735 mmol) as described in step 1 of intermediate 14 to yield 480 mg of product as a pale yellow solid; 1H NMR (300 MHz, DMSO-J₆) δ 3.30-3.40 (m, 6H), 7.50 (d, / = 1 1.7 Hz, 1H), 7.98 (d, / = 6.6 Hz, 3H).

Step 2: 5-[(3-Ethoxypropyl)amino]-l ,3-dimethyl-6-nitro-l ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by coupling reaction of step 1 intermediate (470 mg, 2.087 mmol) with 3-ethoxypropyl amine (500 μΐ, 4.174 mmol) in presence of N,N- diisopropylethylamine (1.1 ml, 6.261 mmol) in dry THF (10 ml) as described in step 2 of intermediate 44 to afford 600 mg of product as a pale yellow solid. ^lH NMR (300 MHz, DMSO-J₆) δ 1.14 (t, / = 9.0 Hz, 3H), 1.85-1.95 (m, 2H), 3.27-3.55 (m, 12H), 6.63 (s, 1H), 7.65-7.75 (m, 1H), 8.65 (br s, 1H); APCI-MS (m/z) 309.04 (M+H)⁺.

Step 3 : 5-Amino-6-[(3-ethoxypropyl)amino]- 1 ,3-dimethyl- 1 ,3-dihydro-2H-benzimidazol-2- one: This intermediate was prepared by reaction of step 2 intermediate (590 mg, 1.913 mmol) with ammonium formate (1.4 g, 22.005 mmol) using palladium carbon (250 mg) in ethanol (100 ml) as described in step 3 of intermediate 44 to afford 365 mg of product as a viscous liquid. 1H NMR (300 MHz, DMSO-J₆) δ 1.12 (t, / = 6.9 Hz, 3H), 1.80-1.89 (m, 2H), 3.05- 3.50 (m, 10H), 4.05-4.15 (m, 2H), 6.30-6.55 (m, 3H), 7.26 (d, / = 6.6 Hz, 1H), 8.31 (s, 1H); APCI-MS (m/z) 279.20 (M+H)⁺.

Step 4: 6-Amino-5 -(3 -ethoxypropyl)- 1 ,3 -dimethyl-3 ,5 -dihydroimidazo [4,5 -/]benzimidazol- 2(lH)-one: This intermediate was prepared by reaction of step 3 intermediate (360 mg, 1.293 mmol) with cyanogen bromide (205 mg, 1.94 mmol) in ethanol (10 ml) as described in step 2 of intermediate 1 to afford 210 mg of product as an off-white solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.14 (t, / = 7.2 Hz, 3H), 1.89 (t, / = 6.6 Hz, 2H), 3.28-3.42 (m, 10H), 4.02 (t, / = 6.3 Hz, 2H), 6.15 (s, 2H), 6.94 (d, / = 9.0 Hz, 2H); APCI-MS (m/z) 304.26 (M+H)⁺.

The intermediates 77-82 were obtained in the manner as described above in intermediate 76. The structural formulas, chemical names and 1H NMR data are provided in table-1 1.

Table- 1 1 : Structure, chemical name and ^lH NMR data of intermediates 77-82.

Intermediate 83

6- { [(5 -Bromothiophen-2-yl)carbonyl] amino } -N-ethyl- 1 -methyl-2-oxo- 1 ,2,3,5- tetrahydroimidazo[4,5-/]indole-7-carboxamide

Step 1 : 2,4-Difluoro-5-nitroaniline: This intermediate was prepared nitration of 2,4- difluoroaniline (7.8 ml, 77.453 mmol) using nitric acid (70 %, 4.9 ml, 77.448 mmol) and sulphuric acid (100 ml) as described in step 3 of intermediate 16 to yield 4.5 g of product as dark brown solid. 1H NMR (300 MHz, DMSO-J₆) δ 3.91 (br s, 2H), 6.97 (t, / = 10.2 Hz, 1H), 7.50 (t, 7 = 7.8 Hz, 1H); APCI-MS (m/z) 175.17 (M+H)⁺.

Step 2: 2-Amino-N-ethyl-5-fluoro-6-nitro-lH-indole-3-carboxamide: To a stirred solution of step 1 intermediate (2.0 g, 1 1.487 mmol) in DMF (20 ml), solution of potassium tertiary butoxide (2.8 g, 22.91 1 mmol) and 2-cyano-N-ethylacetamide (2.57 g, 22.973 mmol) in DMF (10 ml) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The mixture was poured in ice cooled water (100 ml) and 2 N HC1 was added to it to adjust pH at 5-6. The mixture was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure. The residue obtained was dissolved in DMF (20 ml) and stirred at 55 °C for 2 h. The reaction mixture was cooled and poured in ice-cooled water (30 ml). The resulting crystalline solid was filtered and dried to yield 1.5 g of product as a dark brown solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.10 (t, / = 7.2 Hz, 3H), 3.23-3.35 (m, 2H), 7.10-7.17 (m, 1H), 7.49-7.59 (m, 3H), 7.86 (d, / = 14.1 Hz, 1H), 10.98 (s, 1H); APCI-MS (m/z) 267.08 (M+H)⁺.

Step 3 : 2- {[(5-Bromothiophen-2-yl)carbonyl]amino} -N-ethyl-5-fluoro-6-nitro- lH-indole-3- carboxamide: 5-Bromothiophene-2-carboxylic acid (1.16 g, 5.634 mmol) was stirred in thionyl chloride (10 ml) at reflux temperature for 3 h. The reaction mixture was cooled at room temperature and thionyl chloride was evaporated under reduced pressure. The reaction mixture was diluted with tetrahydrofuran (10 ml) and drop-wise added to the solution of step 2 intermediate (1.0 g, 3.756 mmol) in tetrahydrofuran (10 ml) followed by addition of pyridine (1 ml, 0.012 mmol) at 0-5 °C. The reaction mixture was stirred for 12 h at refluxed temperature. The solvent was evaporated under reduced pressure. The reaction was quenched with 1 N HC1 (50 ml). The reaction mixture was extracted with ethyl acetate (2 x 100 ml). The ethyl acetate layer was washed with water (100 ml), brine (100 ml) and dried (Na₂S0₄). The reaction mixture was concentrated under reduced pressure to yield product and purified by column chromatography to yield 507 mg of the product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.18 (d, / = 6.9 Hz, 3H), 3.32-3.40 (m, 2H), 7.46 (s, 1H), 7.60 (s, 1H), 7.75-7.85 (m, 1H), 8.03 (d, / = 14.1 Hz, 1H), 8.36 (s, 1H), 12.64 (s, 1H), 12.96 (s, 1H).

Step 4: 2- { [(5 -Bromothiophen-2-yl)carbonyl]amino } -N-ethyl-5 -(methylamino)-6-nitro- 1 H- indole-3-carboxamide: To a stirred solution of step 3 intermediate (300 mg, 0.659 mmol) in DMSO (5 ml), aqueous methylamine solution (40 %, 5 ml) was added at room temperature and the reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). The mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure to yield 255 mg of product as an orange solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.18 (t, / = 7.2 Hz, 3H), 3.00- 3.07 (m, 3H), 3.35-3.45 (m, 2H), 6.92 (s, 1H), 7.45 (d, / = 3.9 Hz, 1H), 7.60 (d, / = 3.9 Hz, 1H), 7.68 (br s, 1H), 7.85-7.95 (m, 1H), 8.31 (s, 1H), 12.08 (s, 1H), 13.05 (s, 1H); APCI-MS (m/z) 464.09 (M-H)^~.

Step 5 : 6- Amino-2- { [(5 -bromothiophen-2-yl)carbonyl] amino } -N-ethyl-5 -(methylamino)- 1 H- indole-3-carboxamide: To a stirred solution of step 4 intermediate (250 mg, 0.536 mmol) in tetrahydrofuran (10 ml) and aqueous ammonia (10 ml), sodium dithionate (46 mg, 2.681 mmol) was added in portions at room temperature and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was diluted with ethyl acetate (75 ml) and water (75 ml). The mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml). The mixture was dried (Na₂S0₄) and concentrated under reduced pressure to yield 206 mg of product as a brown solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.17 (t, / = 7.5 Hz, 3H), 2.81 (s, 3H), 3.30-3.41 (m, 2H), 4.43 (br s, 2H), 6.80 (s, 1H), 6.86 (s, 1H), 7.24-7.32 (m, 1H), 7.41 (d, / = 3.9 Hz, 1H), 7.50-7.58 (m, 1H), 1 1.36 (s, 1H), 12.77 (s, 1H), +NH; APCI-MS (m/z) 436.09 (M+H)⁺.

Step 6: 6- {[(5-Bromothiophen-2-yl)carbonyl]amino}-N-ethyl-l-methyl-2-oxo-l ,2,3,5- tetrahydroimidazo[4,5-/]indole-7-carboxamide: To a stirred solution of step 5 intermediate (200 mg, 0.458 mmol) in tetrahydrofuran (10 ml), Ι ,Γ-carbonyldiimidazole (80 mg, 0.55 mmol) was added at room temperature and the reaction mixture was heated at reflux temperature for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to yield 120 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.19 (t, / = 7.5 Hz, 3H), 3.30-3.39 (m, 3H), 3.40-3.49 (m, 2H), 7.21 (s, 1H), 7.43 (s, 1H), 7.50-7.59 (m, 3H), 10.64 (s, 1H), 1 1.88 (s, 1H), 12.92 (s, 1H); APCI-MS (m/z) 460.07 (M-H)^". The intermediates 84-86 were obtained in the manner as described above intermediate 83. The structural formulas, chemical names and 1H NMR data are provided table- 12.

Table-12: Structure, chemical name and ^lH NMR data of intermediates 84-86.

Intermediate 87

6- {[(5-Bromothiophen-2-yl)carbonyl]amino}-N-methyl-2-oxo-l-(2,2,2-trifluoroethyl)- l ,2,3,5-tetrahydroimidazo[4,5-/]indole-7-carboxamide

Step 1 : 5-Fluoro-2-nitro-N-(2,2,2-trifluoroethyl)aniline: To a stirred solution of 2,4- difluoronitrobenzene (10.3 ml, 94.286 mmol) in THF (100 ml), 2,2,2-trifluoroethanamine hydrochloride (12.75 g, 94.286 mmol) was added followed by DIPEA (46.8 ml, 282.85 mmol) and the reaction mixture was stirred at reflux temperature for overnight. The reaction mixture was cooled to room temperature and quenched with water (250 ml). The mixture was extracted with ethyl acetate (3 x 300) and washed with brine (300 ml). The mixture was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 17 g of product as yellow solid. APCI-MS (m/z) 239.21 (M+H)⁺.

Step 2: 4-Fluoro-N -(2,2,2-trifluoroethyl)benzene-l,2-diamine: This intermediate was prepared by reaction of step 1 intermediate (10 g, 41.992 mmol) with ammonium formate (30.45 g, 482.90 mmol) using palladium carbon (1 g) in ethanol (150 ml) as described in step 3 of intermediate 44 to yield 6.5 g of product as dark brown solid. APCI-MS (m/z) 208.13 (M+H)⁺.

Step 3 : 6-Fluoro- 1 -(2,2,2-trifluoroethyl)- 1 ,3-dihydro-2H-benzimidazol-2-one : This intermediate was prepared by reaction of step 2 intermediate (7.0 g, 33.631 mmol) with urea (10.0 g, 168.15 mmol) as described in step 3 of intermediate 50 to yield 6.2 g of product as grey solid. APCI-MS (m/z) 235.18 (M+H)⁺.

Step 4: 6-Fluoro-5-nitro-l-(2,2,2-trifluoroethyl)-l ,3-dihydro-2H-benzimidazol-2-one: This intermediate was prepared by nitration reaction of step 3 intermediate (3.5 g, 14.494 mmol) using nitric acid (69 %, 0.94 ml, 14.947 mmol) and concentrated sulphuric acid (30 ml) as described in step 3 of intermediate 16 to yield 3.5 g of product as grey solid. APCI-MS (m/z) 280.30 (M+H)⁺.

Step 5 : 5-Fluoro-l-(4-methoxybenzyl)-6-nitro-3-(2,2,2-trifluoroethyl)-l ,3-dihydro-2H- benzimidazol-2-one: To a stirred solution of step 4 intermediate (6 g, 21.493 mmol) in DMF (50 ml), potassium carbonate (5.9 g, 42.986 mmol) was added followed by addition of 4- methoxy benzyl chloride (5.8 ml, 42.972 mmol) at room temperature and the reaction mixture was stirred at same temperature for 16 h. The reaction was quenched with water (250 ml) and extracted with ethyl acetate (3 x 300 ml). The organic extracts were washed with brine (200 ml) and concentrated under reduced pressure. The residue was stirred in diethyl ether, filtered and dried to yield 7.5 g of product as yellow solid. APCI-MS (m/z) 280.30 (M+H)⁺.

Step 6: 6-Amino-3-(4-methoxybenzyl)-N-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-l , 2,3,5- tetrahydroimidazo[4,5-/]indole-7-carboxamide: To a solution of 2-cyano-N-methylacetamide (1.47 g, 15.026 mmol) in dry DMF (30 ml), sodium hydride (600 mg, 15.00 mmol) was added and the resulting mixture was stirred for 30 min at room temperature. To this mixture step 5 intermediate (3.0 g, 7.513 mmol) was added and stirred for 1 h. The reaction mixture was acidified and ferric chloride (3.65 g, 22.539 mmol) was added to it followed by portion wise addition of zinc dust (4.9 g, 75.131 mmol). The reaction mixture was stirred at 100 °C for 1 h and cooled at room temperature. The reaction mixture was quenched with saturated solution of sodium bicarbonate (100 ml) and ethyl acetate (150 ml) was added to it. The mixture was filtered and dried over sodium sulphate. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain 1.8 g of product as grey solid. APCI-MS (m/z) 448.41 (M+H)⁺.

Step 7: 6-Amino-N-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2,3,5-tetrahydroimidazo[4,5- /]indole-7-carboxamide To a stirred solution of step 6 intermediate (1.6 g, 3.576 mmol) in dichloromethane (10 ml), trifluoroacetic acid (8.5 ml, 1 1 1.37 mmol) was added followed by triflic acid (3.1 ml, 3.5714 mmol) at room temperature and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was added drop wise to saturated aqueous solution of sodium bicarbonate (200 ml) and extracted with ethyl acetate (2 x 150 ml). The organic extracts were washed with brine (150 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 1.19 g of grey solid. APCI-MS (m/z) 328.31 (M+H)⁺.

Step 8_i 6- {[(5-Bromothiophen-2-yl)carbonyl]amino} -N-methyl-2-oxo- 1 -(2,2,2- trifluoroethyl)-l ,2,3,5-tetrahydroimidazo[4,5-/]indole-7-carboxamide: This intermediate was prepared by coupling reaction of step 7 intermediate (1.1 g, 3.361 mmol) with 5- bromothiophene-2-carboxylic acid (1.39 g, 6.722 mmol) in presence of pyridine (1.1 ml) in THF (10 ml) as described in step 3 of intermediate 83 to yield 500 mg of the product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 2.94 (d, / = 4.5 Hz, 3H), 4.65-4.75 (m, 2H), 7.27-7.35 (m, 2H), 7.44 (d, / = 3.9 Hz, 1H), 7.59 (d, / = 3.9 Hz, 1H), 7.72 (s, 1H), 10.96 (s, 1H), 1 1.97 (s, 1H), 12.90 (s, 1H); APCI-MS (m/z) 516.09 (M+H)⁺.

The intermediates 88-91 were obtained in the manner as described above in intermediate 87. The structural formulas, chemical names and 1H NMR data are provided in table-13.

Table-13 : Structure, chemical name and ^lH NMR data of intermediates 88-91.

Intermediate 92

7- {[(5-Bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-3-oxo-2,3,4,6- tetrahydro[l ,4]oxazino[2,3-/]indol -8-carboxamide

Step 1 : 7-Fluoro-4-(4-methoxybenzyl)-6-nitro-2H-l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by reaction of 7-fluoro-6-nitro-2H-l ,4-benzoxazin-3(4H)-one (10 g, 47.140 mmol) with 4-methoxy benzyl chloride (12.83 ml, 94.281 mmol) in presence of potassium carbonate (13.03 g, 94.281 mmol) in DMF (25 ml) as described in step 5 of intermediate 87 to yield 8 g of product as brown solid. APCI-MS (m/z) 333.09 (M+H)⁺. Step 2: 7-Amino-N-cyclopropyl-4-(4-methoxybenzyl)-3-oxo-2,3,4,6- tetrahydro[l ,4]oxazino[2,3-/]indole-8-carboxamide: This intermediate was prepared by reaction of step 1 intermediate (5.0 g, 15.047 mmol) with 2-cyano-N-cyclopropylacetamide (3.73 g, 30.095 mmol) using sodium hydride (1.2 g, 30.095 mmol) followed by reaction with ferric chloride (7.3 g, 45.003 mmol using zinc dust (9.8 g, 150.47 mmol) in dry DMF (25 ml) as described in step 6 of intermediate 87 to obtain 4.1 g of brown solid. APCI-MS (m/z) 407.18 (M+H)⁺.

Step 3 : 7-Amino-N-cyclopropyl-3-oxo-2,3,4,6-tetrahydro[l ,4]oxazino[2,3-/]indole-8- carboxamide: This intermediate was prepared by deprotection reaction of step 2 intermediate (4 g, 9.841 mmol) using trifluoroacetic acid (1 1.29 ml) and triflic acid (4.3 ml) in dichloromethane (25 ml) as described in step 7 of intermediate 87 to yield 1.22 g of grey solid. APCI-MS (m/z) 287.1 1 (M+H)⁺.

Step 4: 7-{[(5-Bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-3-oxo-2, 3,4,6- tetrahydro[l ,4]oxazino[2,3-/]indole-8-carboxamide: This intermediate was prepared by coupling reaction of step 3 intermediate (1.2 g, 4.191 mmol) with 5-bromothiophene-2- carboxylic acid (1.04 g, 5.029 mmol) in presence of pyridine (1.5 ml) in THF (15 ml) as described in step 3 of intermediate 83 to yield 700 mg of the product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.72 (m, 4H), 2.79-2.83 (m, 1H), 4.50 (s, 2H), 7.17 (s, 1H), 7.44 (d, / = 5.4 Hz, 2H), 7.50 (s, 1H), 7.61 (d, / = 4.5 Hz, 1H), 10.71 (s, 1H), 1 1.96 (s, 1H), 12.69 (s, 1H); APCI-MS (m/z) 472.86 (M-H)^".

Intermediate 93

7-Amino-N-cyclopropyl-2,2-dimethyl-3-oxo-2,3,4,6-tetrahydro[l ,4]oxazino[2,3-/]indole-8- carboxamide

Step 1 : 7-Fluoro-4-(4-methoxybenzyl)-2,2-dimethyl-6-nitro-2H-l ,4-benzoxazin-3(4H)-one: This intermediate was prepared by reaction of 7-fluoro-2,2-dimethyl-6-nitro-2H-l ,4- benzoxazin-3(4H)-one (3 g, 12.490 mmol) with 4-methoxy benzyl chloride (3.3 ml, 24.966 mmol) in presence of potassium carbonate (3.4 g, 24.98 mmol) in DMF (30 ml) as described in step 5 of intermediate 87 to yield 2.5 g of product as yellow solid. ESI-MS (m/z) 361.21 (M+H)⁺. Step 2: 7-Amino-N-cyclopropyl-4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-2, 3,4,6- tetrahydro[l,4]oxazino[2,3-/]indole-8-carboxamide: This intermediate was prepared by reaction of step 1 intermediate (2.4 g, 6.66 mmol) with 2-cyano-N-cyclopropylacetamide (1.65 g, 13.292 mmol) using sodium hydride (500 mg, 12.916 mmol) followed by reaction with ferric chloride (3.24 g, 19.981 mmol using zinc dust (4.35 g, 66.603 mmol) in dry DMF (25 ml) as described in step 6 of intermediate 87 to obtain 1.2 g of grey solid. ESI-MS (m/z) 435.20 (M+H)⁺.

Step 3 : 7-Amino-N-cyclopropyl-2,2-dimethyl-3-oxo-2,3,4,6-tetrahydro[l,4]oxazino[2,3- /]indole-8-carboxamide: This intermediate was prepared by deprotection reaction of step 2 intermediate (1.5 g, 3.452 mmol) using trifluoroacetic acid (8.2 ml) and triflic acid (3.0 ml, 34.514) in dichloromethane (20 ml) as described in step 7 of intermediate 87 to yield 600 mg of grey solid. 1H NMR (300 MHz, DMSO-J₆) δ 0.55-0.67 (m, 4H), 1.33 (s, 6H), 2.68-2.75 (m, 1H), 6.63-6.75 (m, 4H), 7.07 (s, 1H), 10.33 (s, 1H), 10.41 (s, 1H); ESI-MS (m/z) 315.16 (M+H)⁺.

Intermediate 94

7-{[(5-Bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-2,2-dimethyl-3-oxo-2,3,4,6- tetrahydro[l,4]oxazino[2,3-/]indol -8-carboxamide

The title compound was prepared by coupling reaction of intermediate 93 (500 mg, 1.591 mmol) with 5-bromothiophene-2-carboxylic acid (650 mg, 3.181 mmol) in presence of pyridine (0.5 ml) in THF (15 ml) as described in step 3 of intermediate 83 to yield 200 mg of the product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.75 (m, 4H), 1.38 (s,

6H), 2.81-2.90 (m, 1H), 7.16 (s, 1H), 7.38-7.45 (m, 3H), 7.60 (d, / = 3.6 Hz, 1H), 10.59 (s,

1H), 11.95 (s, 1H), 12.77 (s, 1H); APCI-MS (m/z) 502.88 (M-H)^".

The intermediates 95-99 were obtained in the same manner as described above in intermediate 92. The structural formulas, chemical names and 1H NMR data are provided in table- 14.

Table-14: Structure, chemical name and ^lH NMR data of Intermediates 95-99.

Structure Chemical name and ^XH NMR data

Intermediate 100 7- {[(5-Bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-2,2,4-trimethyl-3-oxo-2,3,4,6- tetrahydro[l ,4]oxazino[2,3-/]indol -8-carboxamide

The title compound was prepared in the following five steps: (i) displacement of 7-fluoro- 2,2,4-trimethyl-6-nitro-2H-l ,4-benzoxazin-3(4H)-one (2 g, 7.86 mmol) with 2-cyano-N- cyclopropylacetamide (1.95 g, 15.708 mmol) (ii) reductive cyclisation using FeCl₃ (3.82 g, 23.602 mmol) in presence of zinc dust (5.14 g, 78.675 mmol) in DMF (25 ml) (iii) coupling reaction with 5-bromothiophene-2-carboxylic acid (1.26 g, 6.09 mmol) as described in intermediate 92 to afford 400 mg of product as yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 0.65 (d, / = 5.4 Hz, 4H), 1.38 (s, 6H), 2.81-2.90 (m, 1H), 3.25-3.35 (m, 3H), 7.29 (s, 1H), 7.43 (d, / = 3.9 Hz, 1H), 7.51 (s, 2H), 7.60 (d, / = 3.9 Hz, 1H), 11.98 (s, 1H), 12.75 (s, 1H); APCI-MS (m/z) 515.07 (M-H)^~.

Intermediate 101

6- { [(5 -Bromothiophen-2-yl)carbonyl] amino } -N-cyclopropyl- 1 -methyl-3 -[2-(morpholin-4- yl)ethyl]-2-oxo-l ,2,3,5-tetrahydroimidazo[4,5-/]indole-7-carboxamide

The title compound was prepared in the following five steps: (i) reaction of 6-fluoro-l- methyl-5-nitro-l ,3-dihydro-2H-benzimidazol-2-one (1.5 g, 7.107 mmol) with 4-(2- chloroethyl)morpholine hydrochloride (1.587 g, 8.528 mmol) using potassium carbonate (1.08 g, 7.818 mmol), (ii) displacement with 2-cyano-N-cyclopropylacetamide (1.14 g, 9.250 mmol), (iii) reductive cyclisation using FeCl₃ (2.25 g, 13.875 mmol) in presence of zinc dust (3.02 g, 46.252 mmol) in DMF (15 ml) and finally (iv) coupling reaction with 5- bromothiophene-2-carboxylic acid (620 mg, 3.01 1 mmol) as described in intermediate 92 to afford 90 mg of product as yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.75 (m, 4H), 2.44-2.59 (m, 4H), 2.75-2.83 (m, 1H), 2.93-3.01 (m, 2H), 3.31-3.40 (m, 3H), 3.49-3.56 (m, 4H), 3.85-3.96 (m, 2H), 7.32 (s, 1H), 7.43 (s, 1H), 7.48 (s, 2H), 7.55-7.63 (m, 2H), 1 1.94 (s, 1H), 12.69 (s, 1H).

Intermediate 102

7- {[(5-bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-2,2-dimethyl-4-[2-(morpholin-4- yl)ethyl]-3-oxo-2,3,4,6-tetrahydro[l ,4]oxazino[2,3-/]indole-8-carboxamide

Step 1 : 7-Fluoro-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-6-nitro-2H- 1 ,4-benzoxazin-3(4H)- one: This intermediate was prepared by reaction of 7-fluoro-2,2-dimethyl-6-nitro-2H-l ,4- benzoxazin-3(4H)-one (6.0 g, 21.493 mmol) in dry DMF (20 ml) with 4-(2- chloroethyl)morpholine hydrochloride (1.7 g, 9.159 mmol) using was added potassium carbonate (5.9 g, 42.987 mmol) as described in step 5 of intermediate 87 to obtain 1.3 g of product as brown solid. APCI-MS (m/z) 354.20 (M+H)⁺.

Step 2: 7-Amino-N-cyclopropyl-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-3-oxo-2, 3,4,6- tetrahydro[l ,4]oxazino[2,3-/]indole-8-carboxamide: This intermediate was prepared by reaction of step 1 intermediate (2.0 g, 5.660 mmol) with 2-cyano-N-methylacetamide (1.40 g, 1 1.277 mmol) using added sodium hydride (450 mg, 1 1.25 mmol) followed by reaction with ferric chloride (2.75 g, 16.98 mmol) and zinc dust (3.7 g, 56.601 mmol), as described in step 6 of intermediate 87 to obtain 1.2 g of product as grey solid. APCI-MS (m/z) 428.50 (M+H)⁺. Step 3 : 7- {[(5-Bromothiophen-2-yl)carbonyl]amino}-N-cyclopropyl-2,2-dimethyl-3-oxo- 2,3,4,6-tetrahydro[l ,4]oxazino[2,3-/]indole-8-carboxamide: This intermediate was prepared by reaction of Step 2 intermediate with 5-bromothiophene-2-carboxylic acid (1.39 g, 6.722 mmol) using pyridine (1 ml) as described in step 3 of intermediate 83 yield 1 10 mg of the title compound as a yellow solid; 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.72 (m, 4H), 1.39 (s, 6H), 2.45-2.53 (m, 4H), 2.81-2.89 (m, 1H), 3.34 (s, 2H), 3.55-3.63 (m, 4H), 3.95-4.03 (m, 2H), 7.39 (s, 1H), 7.42 (d, / = 3.9 Hz, 1H), 7.53 (s, 2H), 7.62 (d, / = 3.9 Hz, 1H) 12.00 (s, 1H), 12.79 (s, 1H); APCI-MS (m/z) 616.10 (M-H)^". Examples

The following examples described below were prepared using the intermediates and synthetic schemes discussed above. However, the following examples are illustrative and are not intended to limit the broad scope of the invention. The person skilled in the art can readily recognize a variety of non-critical parameters which can be modified or altered to yield similar results. The heteroaryl or aromatic carboxylic acids required in the preparation of the compounds of the present invention are commercially available.

Example 1

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2-yl)-5-(4- fluorophenyl)thiophene-2-carboxamide

To a stirred mixture of 5-(4-fluorophenyl)thiophene-2-carboxylic acid (100 mg, 0.448 mmol), EDCI (102 mg, 0.538 mmol) in DMF (5 ml), HOBt (72 mg, 0.538 mmol) was added followed by DMAP (82 mg, 0.672 mmol) and the reaction mixture was stirred at room temperature for 1 h. To the mixture intermediate 1 (134 mg, 0.448 mmol) was added and the reaction mixture was stirred at 80 °C for overnight. The mixture was diluted with ethyl acetate (50 ml) and washed with water (75 ml), saturated solution of sodium bicarbonate (75 ml) followed by brine (75 ml). The mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 50 mg of product as a pale yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.06 (t, / = 6.6 Hz, 3H), 2.01-2.10 (m, 2H), 2.40 (s, 3H), 3.35-3.45 (m, 4H), 4.26-4.35 (m, 2H), 7.29 (d, / = 9.3 Hz, 2H), 7.44 (s, 1H), 7.52 (s, 1H), 7.70-7.80 (m, 4H), 12.36 (s, 1H), 12.72 (s, 1H); APCI-MS (m/z) 506.05 (M+H)⁺.

The examples 2-95 were obtained in the manner using corresponding intermediates and acids as procedure described above in example 1. The structural formulas, chemical names, 1H NMR and MS data are provided in table-15.

Table-15 : Structure, chemical name, 1H NMR and MS data of examples 2-95.

(s,

Example 96

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2-yl]-5- ( 1 H-pyrazol-4-yl)thiophene-2-carboxamide

Step 1 : N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-^]quinoxalin-2- yl]-5-[ 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-4-yl]thiophene-2-carboxamide: This intermediate was prepared by reaction of intermediate 1 (54 mg, 0.179 mmol) with 5-[l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl]thiophene-2-carboxylic acid (50 mg, 0.179 mmol) using EDCI (41 mg, 0.215 mmol), HOBt (29 mg, 0.215 mmol), DMAP (32 mg, 0.269 mmol) in DMF (3 ml) as described in example 1 to yield 55 mg of product as a yellow solid. Step 2: N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide: the saturated solution of hydrochloric acid in methanol (1 ml) was added to a stirred suspension of step 1 intermediate (55 mg, 0.0979 mmol) in chloroform (5 ml) at 0 °C and the reaction mixture was stirred at the same temperature under nitrogen atmosphere for 1 h. The solvent was evaporated under reduced pressure. The residue was neutralized with aqueous saturated solution of sodium bicarbonate (100 ml), filtered and washed with water (100 ml). The solid was dried and purified by column chromatography to yield 20 mg of product as a yellow solid. ^lH NMR (300 MHz, DMSO-J₆) δ 1.06 (t, / = 6.6 Hz, 3H), 2.00-2.09 (m, 2H), 2.40 (s, 3H), 3.32 (q, / = 6.6 Hz, 2H), 3.41 (t, / = 6.3 Hz, 2H), 4.20-4.29 (m, 2H), 7.24 (d, / = 3.9 Hz, 1H), 7.45 (s, 1H), 7.69 (d, / = 3.9 Hz, 1H), 7.78 (s, 1H), 8.03 (br s, 3H), 10.36 (br s, 2H); ESI-MS (m/z) 478.10 (M+H)⁺.

The examples 97-167 were obtained in the manner using corresponding intermediates and acids as procedure described above in example 96. The structural formulas, chemical names, 1H NMR and MS data are provided in table-16.

Table-16: Structure, chemical name, 1H NMR and MS data of examples 97-167.

Sr. Structure Chemical Name, H NMR and Mass spectrum No analysis

DMSO-J₆) δ 1.08 (t, / = 6.6 Hz, 3H), 1.17 (s, 6H), 2.03 (t, / = 4.2 Hz, 2H), 3.31-3.45 (m, 4H), 3.74 (s, 2H), 4.25 (s, 2H), 4.72 (s, 1H), 7.14-7.21 (m, 2H), 7.37 (s, 1H), 7.61 (d, / = 3.3 Hz, 1H), 7.83 (s, 1H), 8.17 (s, 1H), 10.85 (s, 1H), 12.46 (s, 1H), 13.08 (s, 1H); APCI-MS (m/z) 524.14 (M+H)⁺.

155 N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-7-(2- hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 1.17 (s, 6H), 2.84 (s, 3H), 2.95 (s, 3H), 3.31-3.42 (m, 2H), 3.76 (s, 2H), 4.37 (t, / = 5.1 Hz, 2H), 4.73 (s, 1H), 7.12-7.21 (m, 2H), 7.45 (s, 1H), 7.61 (s, 1H), 7.84 (s, 1H), 8.18 (s, 1H), 10.86 (s, 1H), 12.48 (s, 1H), 13.09 (s, 1H); APCI-MS (m/z) 535.26 (M-H)^~.

156 N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-5-(2- hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 1.15 (s, 6H), 2.79 (s, 3H), 2.86 (t, / = 5.1 Hz, 2H), 2.93 (s, 3H), 3.67 (m, 5H), 4.36 (t, / = 4.5 Hz, 1H), 7.1 1 (s, 1H), 7.18 (s, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 7.83 (s, 1H), 8.15 (s, 1H), 10.92 (s, 1H), 12.45 (s, 1H), 13.06 (s, 1H); APCI-MS (m/z) 537.21 (M+H)⁺.

157 N- {5 -(2-Hydroxy-2-methylpropyl)- 1 - [2- (morpholin-4-yl)ethyl]-6-oxo-l ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 1.15 (s, 6H), 2.44-

Sr. Structure Chemical Name, ^XH NMR and Mass spectrum No analysis

160 N- {7-[2-(Morpholin-4-yl)ethyl]-6-oxo-l-[3- (propan-2-yloxy)propyl]-l ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 1.03 (d, / = 5.7 Hz, 6H), 2.00-2.07 (m, 2H), 2.49-2.52 (m, 2H), 2.72 (t, / = 6.0 Hz, 2H), 3.31-3.53 (m, 9H), 3.95 (t, / = 5.7 Hz, 2H), 4.28 (t, / = 6.0 Hz, 2H), 7.16-7.25 (m, 2H), 7.33 (s, 1H), 7.61 (d, / = 3.3 Hz, 1H), 7.80-7.86 (m, 1H), 8.15 (s, 1H), 10.82 (s, 1H), 12.46 (br s, 1H), 13.07 (s, 1H); APCI-MS (m/z) 579.35 (M+H)⁺.

161 N- { 1 -(3-Hydroxy-3-methylbutyl)-7-[2-(morpholin- 4-yl)ethyl]-6-oxo- 1 ,5 ,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-

yl)thiophene-2-carboxamide: 1H NMR (300 MHz,

DMSO-J₆) δ 1.24 (s, 6H), 1.86 (t, / = 7.2 Hz, 2H), 2.53-2.65 (m, 4H), 3.49-3.56 (m, 6H), 3.96 (t, / = 6.3 Hz, 2H), 4.25-4.35 (m, 2H), 4.54-4.60 (m, 1H), 7.15-7.23 (m, 5H), 7.61 (d, / = 3.3 Hz, 1H), 7.97 (s, 2H), 10.83 (br s, 1H); APCI-MS (m/z) 565.32 (M+H)⁺.

162 N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-7-[2- (morpholin-4-yl)ethyl]-6-oxo-l ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 2.41-2.53 (m, 4H), 2.61 (t, / = 4.8 Hz, 2H), 2.81 (s, 3H), 2.86 (t, / = 5.4 Hz, 2H), 2.93 (s, 3H), 3.3.47-3.56 (m, 4H), 3.94 (t, / = 3.3 Hz, 2H), 4.40 (t, / = 5.4 Hz, 2H), 7.16 (s, 1H), 7.18 (d, / = 3.0 Hz, 1H), 7.43 (s, 1H), 7.59 (d, / = 3.0 Hz, 1H), 7.82 (s, 1H), 8.16 (s, 1H), 10.79 (s,

Sr. Structure Chemical Name, ^XH NMR and Mass spectrum No analysis

166 N- { 1 -[3-(dimethylamino)-3-oxopropyl]-5-methyl-6- oxo-7-(2,2,2-trifluoroethyl)-l ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-

(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 2.82 (s, 3H), 2.85 (t, / = 4.8 Hz, 2H), 2.94 (s, 3H), 3.37 (s, 3H), 4.39 (t, / = 6.0 Hz, 2H), 4.80 (q, / = 6.6 Hz, 2H), 7.19 (s, 1H), 7.27 (s, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.83 (s, 1H), 8.17 (s, 1H), 12.61 (s, 1H), 13.07 (s, 1H); ESI- MS (m/z) 561.16 (M+H)⁺.

167 N-[ 1 -(3-Ethoxypropyl)-7-(2-hydroxy-2- methylpropyl)-5-methyl-6-oxo-l ,5,6,7-

^" OH tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl]-5-

^CH₃ (lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H

NMR (300 MHz, DMSO-J₆) δ 1.07 (t, / = 5.4 Hz, 3H), 1.16 (s, 6H), 2.00-2.07 (m, 2H), 3.27-3.39 (m, 5H), 3.40 (t, / = 4.5 Hz, 2H), 3.77 (s, 2H), 4.26 (t, / = 4.8 Hz, 2H), 4.69 (s, 1H), 7.20 (d, / = 6.6 Hz, 2H), 7.43 (s, 1H), 7.60 (d, / = 3.3 Hz, 1H), 7.82 (s, 1H), 8.15 (s, 1H), 12.52 (s, 1H), 13.06 (s, 1H); ESI- MS (m/z) 538.32 (M+H)⁺.

Example 168

N-[l-(3-Hydroxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2-yl]-5- (pyridin-4-yl)thiophene-2-carboxamide

To a stirred mixture of example 4 (75 mg, 0.149 mmol) in dichloromethane (15 ml) was added boron tribromide (372.76 mg, 1.491 mmol) drop wise at -78 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (75 ml), saturated solution of sodium bicarbonate (75 ml) followed by brine (75 ml). The mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 20 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.92-2.02 (m, 2H), 2.40 (s, 3H), 3.42-3.55 (m, 2H), 4.25-4.35 (m, 2H), 4.60-4.70 (m, 1H), 7.46 (s, 1H), 7.73 (d, / = 6.0 Hz, 2H), 7.78-7.85 (m, 3H), 8.61 (d, / = 6.0 Hz, 2H), 12.37 (s, 1H), 12.76 (s, 1H); APCI-MS (m/z) 459.13 (M-H)^~.

Example 169

N-[l-(3-Hydroxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2-yl]-4- (pyridin-4-yl)benzamide

The title compound was prepared by reaction of example 14 (70 mg, 0.145 mmol) with boron tribromide (363 mg, 1.451 mmol) in dichloromethane (10 ml) as described in example 168 to yield 1 1 mg of product as a yellow solid; 1H NMR (300 MHz, DMSO-J₆) δ 1.95-2.03 (m, 2H), 2.41 (s, 3H), 3.47-3.57 (m, 2H), 4.32-4.44 (m, 2H), 4.69 (br s, 1H), 7.48 (s, 1H), 7.79 (d, / = 4.2 Hz, 2H), 7.85 (s, 1H), 7.93 (d, / = 7.5 Hz, 2H), 8.37 (d, / = 7.8 Hz, 2H), 8.67 (d, / = 4.2 Hz, 2H), 12.36 (br s, 1H), 12.73 (br s, 1H); ESI-MS (m/z) 455.15 (M+H)⁺.

Example 170

N-Ethyl-l-methyl-2-oxo-6-({[5-(pyridin-4-yl)thiophen-2-yl]carbonyl} amino)- 1 ,2,3,5- tetrahydroimidazo[4,5-f]indole-7-carboxamide

To a stirred solution of intermediate 83 (50 mg, 0.108 mmol) in toluene (10 ml), aqueous solution of sodium carbonate (68 mg, 0.648 mmol; in 2 ml water) was added followed by pyridine 4-boronic acid (19 mg, 0.162 mmol) in ethanol (2 ml). The reaction mixture was degassed with nitrogen gas for 15 min and tetrakis(triphenylphosphine)palladium (51 mg, 0.044 mmol) was added. The reaction mixture stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to yield 14 mg of product as a yellow solid. ^lH NMR (300 MHz,

DMSO-J₆) δ 1.18-1.25 (m, 3H), 3.33 (s, 3H), 3.42-3.50 (m, 2H), 7.26 (s, 1H), 7.57 (s, 2H), 7.75-7.85 (m, 3H), 7.97 (s, 1H), 8.65 (s, 2H), 10.66 (s, 1H), 1 1.94 (s, 1H), 13.02 (s, 1H); APCI-MS (m/z) 460.07 (M-H)^~.

Example 171

N-Ethyl-l-methyl-2-oxo-6-[(thiophen-2-ylcarbonyl)amino]-l ,2,3,5-tetrahydroimidazo [4,5- f]indole-7-carboxamide

This compound was formed as a side product in the Suzuki reaction in example 170. It was separated and purified by column chromatography to yield 13 mg of a pale yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.21 (t, / = 6.9 Hz, 3H), 3.30-3.45 (m, 5H), 7.24 (s, 1H), 7.31 (t, / = 4.2 Hz, 1H), 7.50-7.59 (m, 3H), 7.77 (s, 1H), 7.99 (d, / = 3.9 Hz, 1H), 10.65 (s, 1H), 1 1.90 (s, 1H), 12.91 (s, 1H); APCI-MS (m/z) 384.05 (M+H)⁺.

The examples 172-173 were obtained in the manner using corresponding intermediate and acid as procedure as described above in example 170. The structural formulas, chemical names, 1H NMR and MS data are provided in table-17.

Table-17: Structure, chemical name, 1H NMR and MS data of examples 172-173.

Sr. Structure Chemical Name, ^XH NMR and Mass spectrum No analysis

(m, 2H), 7.26 (s, 1H), 7.39-7.64 (m, 6H), 7.76 (s, 1H), 8.04 (s, 1H), 10.13 (s, 1H), 10.64 (s, 1H), 1 1.93 (s, 1H), 12.98 (s, 1H); ESI-MS (m/z) 530.99 (M)⁺.

Example 174

N-Cyclopropyl-2,2-dimethyl-3-oxo-7-({[5-(pyridin-4-yl)thiophen-2-yl]carbonyl}amino)- 2,3,4,6-tetrahydro[l ,4]oxazino[2, -f]indole-8-carboxamide

5-(pyridin-4-yl)thiophene-2-carboxylic acid (196 mg, 0.954 mmol) was stirred in thionyl chloride (5 ml) at reflux temperature for 3 h. The reaction mixture was cooled at room temperature and thionyl chloride was evaporated under reduced pressure. The reaction mixture was diluted with tetrahydrofuran (10 ml) and drop-wise added to the solution of intermediate 93 (150 g, 0.477 mmol) in tetrahydrofuran (10 ml) followed by addition of pyridine (0.15 ml) at 0-5 °C and the reaction mixture was stirred for 12 h at refluxed temperature. The solvent was evaporated under reduced pressure. The reaction was quenched with 1 N HC1 (50 ml). The reaction mixture was extracted with ethyl acetate (2 x 100 ml). The ethyl acetate layer was washed with water (100 ml), brine (100 ml) and dried (Na₂S0₄). The reaction mixture was concentrated under reduced pressure to yield product which was then purified by column chromatography to yield 40 mg of orange solid; 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.76 (m, 4H), 1.35-1.43 (m, 6H), 2.85-2.92 (m, 1H), 7.18 (s, 1H), 7.35-7.45 (m, 2H), 7.68 (s, 2H), 7.78 (s, 1H), 7.97 (s, 1H), 8.65 (s, 2H), 10.60 (s, 1H), 12.00 (s, 1H), 12.84 (s, 1H); ESI-MS (m/z) 502.17 (M+H)⁺.

Example 175

N-Cyclopropyl-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-3-oxo-7-[(pyridin-2- ylcarbonyl)amino]-2,3,4,6-tetrahydro[l ,4]oxazino[2,3-f]indole-8-carboxamide

The title compound was prepared by coupling reaction of step 2 of intermediate 102 (150 mg, 0.351 mmol) with 2-picolinic acid (86 mg, 0.701 mmol) in presence of thionyl chloride (5 ml) and pyridine (0.2 ml) in THF (10 ml) as described in example 174 to yield 70 mg of yellow solid; 1H NMR (300 MHz, DMSO-J₆) δ 0.65-0.76 (m, 4H), 1.23 (s, 6H), 2.45-2.55 (m, 6H), 2.83-2.91 (m, 1H), 3.55-3.65 (m, 4H), 4.01 (t, / = 6.3 Hz, 2H), 7.42-7.50 (m, 3H), 7.71-7.80 (m, 1H), 7.76 (t, / = 3.0 Hz, 1H), 8.27 (s, 1H), 8.84 (s, 1H), 12.12 (s, 1H), 13.20 (s, 1H); ESI- MS (m/z) 533.24 (M+H)⁺.

Example 176

N-Ethyl-l-methyl-2-oxo-6-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl} amino)- 1 ,2, 3,5- tetrahydroimidazo[4,5-f]indole-7-carboxamide

Step 1 : N- Ethyl- 1 -methyl-2-oxo-6-[({5-[ 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-4- yl]thiophen-2-yl}carbonyl)amino]-l ,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide: To a stirred solution of intermediate 83 (60 mg, 0.129 mmol) in DMF (2 ml), aqueous solution of potassium carbonate (53 mg, 0.389 mmol; in 1 ml water) was added followed by 1- (tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (44 mg, 0.161 mmol) and the mixture was degassed for 15 min under nitrogen atmosphere. To this mixture [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 mg, 0.002 mmol) was added and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled at room temperature and water (20 ml) was added to it. The mixture was extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with brine (75 ml), dried (Na₂S0₄) and concentrated under reduced pressure. The residue was purified by column chromatography to yield 50 mg of product as a yellow solid. ^lH NMR (300 MHz,

DMSO-J₆) δ 1.10-1.96 (m, 8H), 1.21 (t, / = 6.3 Hz, 3H), 3.40-3.46 (m, 3H), 3.62-3.70 (m 2H), 3.89-3.96 (m, 1H), 7.25 (s, 1H), 7.40-7.60 (m, 3H), 7.70 (s, 1H), 7.97 (s, 1H), 8.48 (s 1H), 10.65 (s, 1H), 1 1.90 (s, 1H), 12.85 (s, 1H); APCI-MS (m/z) 533.97 (M+H)⁺. Step 2: N- Ethyl- 1 -methyl-2-oxo-6-( {[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl} amino)-

I , 2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide: The saturated solution of hydrochloric acid in methanol (10 ml) was added to step 1 intermediate (40 mg, 0.075 mmol) and the resulting suspension was stirred at room temperature under nitrogen atmosphere for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and neutralized with saturated solution of sodium bicarbonate (100 ml). The mixture was washed with water (100 ml), brine (100 ml). The mixture was dried (Na₂S0₄) and purified by column chromatography to yield 10 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J₆) δ 1.20-1.28 (m, 3H), 3.29-3.37 (m, 3H), 3.42-3.52 (m, 2H), 7.25 (s, 1H), 7.40 (s, 1H), 7.50-7.60 (m, 2H), 7.69 (s, 1H), 7.94 (br s, 1H), 8.31 (s, 1H), 10.63 (s, 1H),

I I .88 (s, 1H), 12.88 (s, 1H), 13.20 (s, 1H); APCI-MS (m/z) 450.09 (M+H)⁺.

The examples 177-194 were obtained in the manner using corresponding intermediates as procedure described above in example 176. The structural formulas, chemical names, 1H NMR and MS data are provided in table-18.

Table-18: Structure, chemical name, 1H NMR and MS data of Examples 177-194.

Pharmacological Activity

In-vitro ITK inhibition assay of compounds of the invention:

The compounds of the present invention were evaluated as inhibitors of human recombinant ITK using TR-FRET (time resolved fluorescence resonance energy transfer) based LANCE Ultra assay.

LANCE Ultra Assay Principle: The phosphorylation of an XJLight peptide substrate is detected with a specific anti phospho- peptide antibody (Ab) labeled with europium chelate molecules (Eu). The binding of the Eu-antibody to the phosphorylated XJLight peptide substrate brings both the donor and acceptor dye molecules into close proximity.

Upon irradiation at 320 or 340 nm, the excited europium chelate donor dye transfers its energy to the nearby XJLight acceptor dye molecule that will in turn emit light at 665 nm. The intensity of light emission is proportional to the level of the XJLight peptide phosphorylation.

The ITK assay utilized recombinant human ITK fused with GST. The assay was carried out in the 384 well white optiplates on the automated robotic system. 2.5 μΐ of test compounds (or controls at final 1% DMSO concentration) were added to 384 well plate, followed by 2.5 μΐ of ITK enzyme in the kinase assay buffer and the reaction was started by adding 5 μΐ of ATP / peptide substrate mix in the kinase assay buffer. The kinase assay components contained 50 mM Hepes pH 7.5, 5 mM MgC12, 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.75 nM ITK enzyme, 100 nM XJlight-?o\yGl substrate and 3 μΜ ATP in 10 μΐ volume. Incubation was carried out at 23 °C for 15 minutes on the shaker. The assay was stopped by adding EDTA. This was followed by the addition of detection reagent Europium anti-phospho-substrate antibody. The fluorescence was measured at 665/620 nm on htrf reader after incubation for 1 hour at RT. IC₅₀ values were calculated from non-linear regression analysis of the initial rate data using the GraphpadPrism software.

The compounds prepared were tested using the above assay procedure and the results obtained are given in table-19. Percentage inhibition of ITK at concentrations of 1.0 and 10.0 μΜ is given in the Table 1.

The IC₅₀ (nM) values of the compounds are set forth in table-19 wherein "A" refers to an IC₅₀ value of less than 10 nM, "B" refers to IC₅₀ value in range of 10.01 to 50 nM, and "C" refers to an IC₅₀ value in range of 50.01 nM.

Table-19: In-vitro screening results of compounds of invention Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

1 7 0 -

2 15.1 9.4 -

3 38.2 43.43 -

4 78 78 -

5 19.5 37.1 -

6 40.02 24.04 -

7 34.14 42.27 -

8 25.85 33.7 -

9 14.7 13.9 -

10 84.8 89.6 B

1 1 46.2 43.7 -

12 11.35 46.74 -

13 27.01 28.11 -

14 0 0 -

15 19.73 19.4 -

16 7.65 33.8 -

17 35.65 41.9 -

18 18.51 34.65 -

19 71.44 76.06 -

20 75.87 75.64 -

21 79 76 -

22 41.1 42.1 -

23 14.4 35.8 -

24 1.33 11.98 -

25 59.4 69.2 -

26 27.4 42.08 -

27 59.7 68.1 -

28 0 0 -

29 14.9 5.7 -

30 20.21 30.47 -

31 65 76 C Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

32 9.19 5.79 -

33 0 0 -

34 26.54 38.52 -

35 70.97 88.9 C

36 16 37 -

37 51.6 69.6 -

38 74.9 79.6 -

39 38.5 41.25 -

40 82.4 66.18 -

41 85.2 83.5 B

42 57.11 72.61 -

43 84.01 88.6 B

44 6.34 8.09 -

45 89.29 93.38 A

46 90.3 92.5 B

47 84.9 85.5 B

48 81.3 77.9 -

49 87.4 97.4 -

50 86.16 77.44 A

51 65.7 72.5 -

52 67.82 56.7 -

53 83 85.3 B

54 91.1 94 A

55 86.5 84.2 A

56 81.2 79.2 -

57 89.7 93.4 A

58 92.04 97.40 A

59 87.0 89.1 B

60 85.8 92.4 B

61 85.38 83.26 B

62 66.5 72.6 - Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

63 77.1 74.9 -

64 82.1 87.3 C

65 54.9 61.3 -

66 91.0 83.3 A

67 81.47 92.07 B

68 77.65 90.5 B

69 56.88 74.54 -

70 90.83 88.63 A

71 89.48 91.3 B

72 95.11 86.92 B

73 73.2 74.4 -

74 88.98 93.51 B

75 91.4 92.0 B

76 87.8 91.0 B

77 90.4 92.5 B

78 98.11 93.74 B

79 83.7 89.3 B

80 87.2 79.5 B

81 89.3 78.3 A

82 67.96 60.23 -

83 88.40 77.93 B

84 93.0 93.6 A

85 86.63 89.62 B

86 86.11 89.69 B

87 71.78 87.21 C

88 92.22 92.69 A

89 12.7 29.6 -

90 68.25 89.29 C

91 83.08 84.13 B

92 83.64 78.51 B

93 67.86 87.33 C Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

94 0 20 -

95 83.32 90.3 B

96 88.9 91 A

97 90.29 94.72 A

98 78.34 81.01 B

99 45 77 -

100 50.3 74.3 -

101 2.78 6.78 -

102 87.59 84.99 B

103 13.25 21.84 -

104 92.5 93.6 A

105 84.1 87.9 A

106 80.99 83.55 B

107 93.6 A

108 91.2 86.5 A

109 80.4 81.8 -

110 99.2 100 A

111 83.7 86.8 B

112 89.4 79.4 B

113 91.69 A

114 92.6 93.3 A

115 92.7 88.1 A

116 89.2 89.1 B

117 94.40 94.80 A

118 91.3 93.3 A

119 90.7 83.8 A

120 91.1 87.5 A

121 91.6 89.6 A

122 93.09 86.81 A

123 85.81 86.43 A

124 83.66 63.66 B Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

125 89.0 91.3 B

126 88.4 79.6 B

127 78.6 84.9 C

128 88.4 88.8 B

129 87.8 85.2 B

130 63.6 53.9 -

131 82.7 87.4 B

132 90.14 89.99 A

133 92.0 92.9 A

134 86.39 86.43 A

135 89.90 89.24 A

136 89.99 90.20 A

137 84.29 79.17 B

138 93.13 92.08 A

139 87.81 87.14 B

140 84.7 79.93 B

141 93.8 95.9 A

142 93.3 93.8 A

143 91.4 88.9 A

144 93.3 93.9 A

145 89.34 85.84 A

146 91.58 89.5 B

147 88.3 87.1 B

148 87.5 86.1 B

149 91.3 91.2 A

150 94.6 92.0 A

151 92.3 93.7 A

152 62.39 78.93 -

153 88.17 87.21 B

154 93.3 92.1 A

155 89.79 86.83 A Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

156 86.05 89.37 B

157 86.45 86.60 C

158 88.68 82.87 A

159 92.4 94.5 A

160 92.1 92.3 A

161 92.30 92.18 A

162 89.08 88.81 A

163 93.53 89.68 B

164 86.0 87.2 B

165 90.9 90.6 A

166 88.93 90.88 B

167 88.63 88.70 B

168 67.16 67.35 -

169 4.47 10.41 -

170 36.1 43.9 -

171 24.2 42.6 -

172 41.6 44 -

173 7.6 26.6 -

174 59.60 44.2 -

175 54.23 78.43 -

176 86.9 88.4 B

177 89.9 90.1 A

178 87.7 86.7 A

179 89.45 91.00 A

180 68.12 69.22 -

181 48.70 71.90 -

182 55.22 75.18 -

183 51.04 66.50 -

184 33.87 37.67 -

185 87.61 88.84 A

186 86.28 90.16 B Example No % inhibition of ITK at ICso (nM)

1.0 μΜ 10.0 μΜ

187 88.99 88.49 B

188 78.28 84.50 C

189 81.14 88.15 C

190 73.65 86.21 C

191 89.55 88.35 A

192 86.06 88.12 B

193 89.98 87.01 A

194 90.82 87.90 A

Claims

Claims:

1. A compound of formula (I)

(I)

or a pharmaceutically acceptable salt thereof,

wherein,

A is carbon or trivalent nitrogen;

provided that when A is nitrogen, R¹ is absent;

provided that when A is carbon, R¹ is hydrogen;

Ring B represents

; wherein x and y represents the point of attachment;

Q is absent or selected from C₆-i4 aryl, 3- to 15- membered heterocyclyl and 5- to 14-

Q

membered heteroaryl, wherein each being optionally substituted with one or more R ;

L is selected from -(CH₂)„CHR^a-, -(CH₂)„C(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-;

T is selected from hydrogen, hydroxy, Ci_salkyl, haloCi-salkyl, hydroxyCi_salkyl, C₃_ i₂cycloalkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R¹ is absent or hydrogen;

R is selected from hydrogen, Ci-salkyl, hydroxyCi_salkyl, and 3- to 15- membered heterocyclylC i_salkyl;

R is selected from hydrogen, Ci_salkyl, haloCi_salkyl, hydroxyCi_salkyl, 3- to 15- membered heterocyclylCi_salkyl, and -(CH₂)_nNR^aR^b -;

R⁴ is selected from hydrogen and Ci_salkyl; R⁵ is selected from hydrogen, halogen and Ci_salkyl;

R⁶ is selected from hydrogen, halogen and Ci_salkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a C3-i₂cycloalkyl ring which is substituted or unsubstituted and wherein the C_3- i₂cycloalkyl ring optionally contains one or more hetero atoms selected from O, N or S;

at each occurrence, R⁷ is independently selected from cyano and Ci_salkyl;

at each occurrence, R is independently selected from halogen, cyano, Ci_salkyl and - (CH₂)_nNR^aC(0)R^b;

at each occurrence, R^a and R^b, which may be the same or different, are independently selected from hydrogen and Ci_salkyl; and

'n' is an integer ranging from 0 to 6, both inclusive.

2. A compound of formula (II)

(II)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C_6-14 aryl, 5- to 14- membered heteroaryl or 3- to 15- membered heterocyclyl, wherein each being optionally substituted with one or more R⁷;

Q is absent or selected from C_6-14 aryl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R ;

L is selected from -(CH₂)_nCHR^a- and -(CR^aR^b)_nO-;

T is selected from hydrogen, hydroxy, Ci_salkyl, hydroxyCi_salkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R is hydrogen;

R⁴ is Ci_₈alkyl;

at each occurrence, R⁷ is independently selected from cyano and Ci_salkyl;

at each occurrence, R is independently selected from halogen, cyano and Ci_salkyl; at each occurrence, R^a and R^b are hydrogen; and

'n' is an integer ranging from 0 to 6, both inclusive. The compound according to claim 2, wherein R is C¾ or

The compound according to claim 2 or 3, wherein P is

5. The compound according to any one of claims 2 to 4, wherein Q is absent.

6. The compound according to any one of claims 2 to 4, wherein Q is

7. The compound according to any one of claims 2 to 6, wherein L-T is

8. A compound selected from

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-5-(4-fluorophenyl)thiophene-2-carboxamide;

5-(4-Cyanophenyl)-N-[ 1 -(3-ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro- 1H- imidazo[4,5-g]quinoxalin-2-yl]thiophene-2-carboxamide;

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-5-(pyridin-3-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-5-(pyrimidin-5-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-2-(lH-imidazol-l-yl)-l,3-thiazole-5-carboxamide; N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-2-(pyridin-4-yl)- 1 ,3-thiazole-5-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-2-(lH-imidazol-l-yl)-l ,3-thiazole-4-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-2-(lH-imidazol-l-yl)-5-methyl-l ,3-thiazole-4-carboxamide;

5-(3,5-Dimethyl-lH-pyrazol-4-yl)-N-[l-(3-ethoxypropyl)-7-methyl-6-oxo-5,6- dihydro- 1 H-imidazo [4,5 -g] quinoxalin-2-yl]thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-2-(pyridin-4-yl)- 1 ,3-thiazole-4-carboxamide;

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-4-( 1 H-imidazol- 1 -yl)benzamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl] -3 -(pyridin-4-yl)benzamide;

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-4-(pyridin-4-yl)benzamide

N-(l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-4-morpholinobenzamide;

l-(5-Cyanopyridin-2-yl)-N-[l-(3-ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH- imidazo[4,5-g]quinoxalin-2-yl]piperidine-4-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]- lH-indazole-6-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]- lH-indazole-5-carboxamide;

N-{7-Methyl-6-oxo-l-[3-(propan-2-yloxy)propyl]-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3 -Hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 - g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

5 -(2-Fluoropyridin-4-yl)-N-[ 1 -(3 -hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6- dihydro- 1 H-imidazo [4,5 -g] quinoxalin-2-yl]thiophene-2-carboxamide;

N-[ 1 -(3 -Hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 - g]quinoxalin-2-yl]-2-(pyridin-4-yl)-l ,3-thiazole-5-carboxamide;

N-[ 1 -(3 -Hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 - g]quinoxalin-2-yl]-2-(pyridin-4-yl)-l ,3-thiazole-4-carboxamide; N- [ 1 -(3 -Hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 - g] quinoxalin-2-yl] -4-(pyridin-4-yl)benzamide;

N-{7-Methyl-6-oxo-l-[3-(2-oxopyrrolidin-l-yl)propyl]-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{ 1 -[3-(lH-Imidazol- 1 -yl)propyl]-7-methyl-6-oxo-5,6-dihydro- 1 H-imidazo [4,5- g]quinoxalin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{7-Methyl-l-[3-(morpholin-4-yl)propyl]-6-oxo-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl]thiophene-2-carboxamide;

4-Cyano- V-[ 1 -(3-ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro- 1H- imidazo[4,5-g]quinoxalin-2-yl]benzamide;

N-[l-(3-Ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro-lH-imidazo[4,5- g] quinoxalin-2-yl] -5 -(pyridin-3 -yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro- lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-(l-(3-Ethoxypropyl)-7-isobutyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-4-(pyridin-4-yl)benzamide;

N-(l-(3-Ethoxypropyl)-7-isobutyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl)-4-morpholinobenzamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3 -Hydroxy-3 -methylbutyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 - g]quinoxalin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{7-Methyl-6-oxo-l-[3-(2-oxopyrrolidin-l-yl)propyl]-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-6-oxo-7-(propan-2-yl)-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-(2-methylpropyl)-6-oxo-5,6-dihydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(3-methyl-l ,2,4-oxadiazol-5-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxypropyl)-7-methyl-6-oxo-5,6-dihydro-lH-imidazo[4,5-g]quinoxalin-2- yl]-5-(pyridin-4-yl)thiophene-2-carboxamide; N-[ 1 -(3 -Hydroxypropyl)-7-methyl-6-oxo-5 ,6-dihydro- 1 H-imidazo [4,5 -g] quinoxalin-2- yl]-4-(pyridin-4-yl)benzamide;

and pharmaceutically acceptable salts thereof.

9. A compound of formula (III)

(III)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C_6-14 aryl or 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R⁷;

L is selected from -(CH₂)„CHR^a- and -(CR^aR^b)_nO-;

T is selected from Ci_salkyl, hydroxy and hydroxyCi

R is selected from hydrogen and Ci_salkyl;

R³ is Ci-galkyl;

at each occurrence, R is cyano;

Q

at each occurrence, R is Ci_salkyl ;

at each occurrence, R^a and R^b are hydrogen; and

'n' is an integer ranging from 0 to 6, both inclusive.

10. The compound according to claim 9, wherein R is hydrogen or methyl.

11. The compound according to claim 9 or 10, wherein R is methyl or ethyl.

12. The compound according to any one of claims 9 to 11, wherein P is

13. The compound according to any one of claims 9 to 12, wherein Q is absent.

14. The compound according to any one of claims 9 to 12, wherein Q is

The compound according to any one of claims 9 to 14, wherein L-T

16. A compound selected from

4-Cyano- V-[ 1 -(3-ethoxypropyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro- 1H- imidazo[4,5-g]quinoxalin-2-yl]benzamide;

N-[l-(3-Ethoxypropyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

4-Cyano-N-[l-(3-ethoxypropyl)-5,8-dimethyl-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]benzamide;

N-[l-(3-Ethoxypropyl)-5,8-dimethyl-6,7-dioxo-5,6,7,8-tetrahydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(2-hydroxy-2-methylpropyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

4-Cyano-N-[l-(3-hydroxy-3-methylbutyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]benzamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro- 1H- imidazo[4,5-g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[8-Ethyl-l-(3-hydroxy-3-methylbutyl)-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxy-3-methylbutyl)-5,8-dimethyl-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{8-Methyl-6,7-dioxo-l-[3-(propan-2-yloxy)propyl]-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH-imidazo[4,5- g]quinoxalin-2-yl]-4-(2H-tetrazol-5-yl)benzamide;

N-[l-(3-Hydroxy-3-methylbutyl)-8-methyl-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo[4,5-g]quinoxalin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[8-Ethyl-l-(3-hydroxy-3-methylbutyl)-6,7-dioxo-5,6,7,8-tetrahydro-lH- imidazo [4,5 -g] quinoxalin-2-yl] -5 -( lH-pyrazol-4-yl)thiophene-2-carboxamide;

and pharmaceutically acceptable salts thereof.

17. A compound of formula

(IV)

or a pharmaceutically acceptable salt thereof,

wherein,

L is selected from -(CH₂)„CHR^a-, -(CH₂)„C(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-; T is selected from hydrogen, hydroxy, Ci_salkyl, hydroxyCi_salkyl, 3- to 15- membered heterocyclyl and 5- to 14- membered heteroaryl;

R is selected from hydrogen, Ci_salkyl and 3- to 15- membered heterocyclylCi_salkyl; R⁵ is selected from hydrogen, halogen and Ci_salkyl;

R⁶ is selected from hydrogen, halogen and Ci_salkyl;

or R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a C₃-i₂cycloalkyl ring which is substituted or unsubstituted and wherein the C_3- i₂cycloalkyl ring optionally contains one or more hetero atoms selected from O, N or S;

at each occurrence, R⁷ is cyano;

at each occurrence, R is independently selected from halogen and Ci_salkyl;

'n' is an integer ranging from 0 to 6, both inclusive.

mpound according to claim 17, wherein R is hydrogen, methyl or

19. The compound according to claim 17 or 18, wherein R⁵ is hydrogen, fluorine or methyl.

20. The compound according to any one of claims 17 to 19, wherein R⁶ is hydrogen, fluorine or methyl.

21. The compound according to any one of claims 17 to 20, wherein R⁵ and R⁶ are taken together with the carbon atom to which they are attached to form a cyclopropyl ring.

22. The compound according to any one of claims 17 to 21, wherein P is

23. The compound according to any one of claims 17 to 22, wherein Q is absent.

24. The compound according to any one of claims 17 to 22, wherein Q is

ound according to any one of claims 17 to 24, wherein L-T

26. A compound selected from

4-Cyano-N-[3-(3-ethoxypropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]benzamide;

N-[3-(3-Ethoxypropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5-^][l,4]benzoxazin-2-yl]- 5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(2-Hydroxy-2-methylpropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Hydroxy-3-methylbutyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{7-Oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Amino-3-oxopropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5-g][l,4]benzoxazin- 2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide; N-[3-(3-Ethoxypropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g][l,4]benzoxazin-2-yl]-5-(l-methyl-lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6,8-trimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(2-Hydroxy-2-methylpropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Hydroxy-3-methylbutyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{6,6-Dimethyl-7-oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Amino-3-oxopropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{3-[3-(Dimethylamino)-3-oxopropyl]-6,6-dimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l,4]benzoxazin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamid^ N-{6,6-Dimethyl-7-oxo-3-[3-(2-oxopyrrolidin-l-yl)propyl]-3,6,7,8- tetrahydroimidazo[4,5-g][l,4]benzoxazin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamid^

N-{3-[3-(lH-Imidazol-l-yl)propyl]-6,6-dimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l,4]benzoxazin-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamid^

N-{6,6-Dimethyl-3-[2-(morpholin-4-yl)ethyl]-7-oxo-3,6,7,8-tetrahydroimidazo g] [ 1 ,4]benzoxazin-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6-difluoro-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[6,6-Difluoro-3-(2-hydroxy-2-methylpropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[6,6-Difluoro-3-(3-hydroxy-3-methylbutyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{6,6-Difluoro-7-oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5-g][l,4]benzoxazin-2-yl]- 5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(2-Hydroxy-2-methylpropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(3-Hydroxy-3-methylbutyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide; N-{7-Oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

5-(3,5-Dimethyl-lH-pyrazol-4-yl)-N-[3-(3-ethoxypropyl)-6,6-dimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl]thiophene-2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6,8-trimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(2-Hydroxy-2-methylpropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(3-Hydroxy-3-methylbutyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3-(3-Hydroxy-3-methylbutyl)-6,6,8-trimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{6,6-Dimethyl-7-oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{3-[3-(Dimethylamino)-3-oxopropyl]-6,6-dimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide;

N-[3-(3-Amino-3-oxopropyl)-6,6-dimethyl-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{6,6-Dimethyl-7-oxo-3-[3-(2-oxopyrrolidin-l-yl)propyl]-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide;

N-{3-[3-(lH-Imidazol-l-yl)propyl]-6,6-dimethyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide;

N-{6,6-Dimethyl-3-[2-(morpholin-4-yl)ethyl]-7-oxo-3,6,7,8-tetrahydroimidazo g] [ 1 ,4]benzoxazin-2-yl} -5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{6,6-Dimethyl-3-[3-(morpholin-4-yl)propyl]-7-oxo-3,6,7,8-tetrahydroimidazo[4,^ g] [ 1 ,4]benzoxazin-2-yl} -5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{6,6-Dimethyl-3-[3-(morpholin-4-yl)-3-oxopropyl]-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide; 5-(lH-Pyrazol-4-yl)-N- {6,6,8-trimethyl-3-[2-(morpholin-4-yl)ethyl]-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}thiophene-2-carboxamide;

N-[3'-(3-Ethoxypropyl)-7'-oxo-7',8'-dihydro-3'H-spiro[cyclopropane-l ,6'-imidazo[4,5- g][l ,4]benzoxazin]-2'-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[3*-(3-Hydroxy-3-methylbutyl)-8^,-methyl-7^,-oxo-7*,8^,-dihydro-3^,H- spiro[cyclopropane-l ,6'-imidazo[4,5-g][l ,4]benzoxazin]-2'-yl]-5-(lH-pyrazol-4-yl)thiophene- 2-carboxamide;

N-[3-(3-Ethoxypropyl)-6,6-difluoro-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[6,6-Difluoro-3-(2-hydroxy-2-methylpropyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[6,6-Difluoro-3-(3-hydroxy-3-methylbutyl)-7-oxo-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide

N-[6,6-Difluoro-3-(3-hydroxy-3-methylbutyl)-8-methyl-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{6,6-Difluoro-7-oxo-3-[3-(propan-2-yloxy)propyl]-3,6,7,8-tetrahydroimidazo[4,5- g] [ 1 ,4]benzoxazin-2-yl} -5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{3-(3-Ethoxypropyl)-6,6-dimethyl-8-[2-(morpholin-4-yl)ethyl]-7-oxo-3,6,7,8- tetrahydroimidazo[4,5-g][l ,4]benzoxazin-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide;

and pharmaceutically acceptable salts thereof.

27. A compound of formula

(V)

or a pharmaceutically acceptable salt thereof,

wherein,

P is C_6-14 aryl or 5- to 14- membered heteroaryl wherein each being optionally substituted with one or more R⁷;

Q is absent or selected from 3- to 15- membered heterocyclyl, wherein being

Q

optionally substituted with one or more R ;

L is selected from -(CH₂)_nCHR^a-, -(CH₂)_nC(0)-, -(CH₂)_nC(0)NR^a-, and -(CR^aR^b)_nO-; T is selected from hydrogen, hydroxy, Ci_salkyl, hydroxyCi.salkyl and 3- to 15- membered heterocyclyl;

R is selected from hydrogen, Ci_salkyl and hydroxyCi_salkyl;

R is selected from hydrogen, Ci_salkyl, haloCi_salkyl, hydroxyCi_salkyl, 3- to 15- membered heterocyclylCi_₈alkyl, and -(CH₂)_nNR^aR^b -;

at each occurrence, R⁷ is independently selected from cyano and Ci.salkyl;

at each occurrence, R is independently selected from halogen and Ci.salkyl;

'n' is an integer ranging from 0 to 6, both inclusive.

28. The compound according to claim 27, wherein R² is hydrogen, methyl or 2- methylpropan-2-ol.

29. The compound according to claim 27 or 28, wherein R is hydrogen, methyl, ethyl, trifluoroethyl, 2-methylpropan-2-ol, N / or N,N-dimethylethanamine.

30. The compound according to any one of claims 27 to 29, wherein P is

31. The compound according to any one of claims 27 to 30, wherein Q is absent.

32. The compound according to any one of claims 27 to 30, wherein Q is

33. The compound according to any one of claims 27 to 32, wherein L-T is

34. A compound selected from

N-[l-(3-Ethoxypropyl)-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5- (pyridin-4-yl)thiophene-2-carboxamide; N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-2-(pyridin-4-yl)-l,3-thiazole-4-carboxamide;

N- {7-Methyl-6-oxo- 1 -[3-(propan-2-yloxy)propyl]- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl}-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(2-Hydroxy-2-methylpropyl)-7-methyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxy-3-methylbutyl)-7-methyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

5-(2-Fluoropyridin-4-yl)-N-[l-(3-hydroxy-3-methylbutyl)-7-methyl-6-oxo-l,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]thiophene-2-carboxamide;

N-[ 1 -(3-Amino-3-oxopropyl)-7-methyl-6-oxo-l ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-7-ethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[7-Ethyl-l-(3-hydroxy-3-methylbutyl)-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Amino-3-oxopropyl)-7-ethyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-6-oxo-7-(propan-2-yl)-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5 ,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(2-Hydroxy-2-methylpropyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxam

N-[ 1 -(3-Hydroxy-3-methylbutyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(l-methyl-lH-pyrazol-4-yl)thiophene-2- carboxamide; N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-7-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(^^

N-{ 1 -[3-(Dimethylamino)-3-oxopropyl]-7-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{7-(2-Hydroxy-2-methylpropyl)-l-[2-(morpholin-4-yl)ethyl]-6-oxo-l,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-5-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

N-{ l-(3-Ethoxypropyl)-7-[2-(morpholin-4-yl)ethyl]-6-oxo-l, 5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5-(pyridin-4-yl)thiophene-2-carboxamide;

4- Cyano-N-[l-(3-ethoxypropyl)-5,7-dimethyl-6-oxo-l,5,6,7-tetrahydrobenzo[l,2- d:4,5-d']diimidazol-2-yl]benzamide;

N-[ 1 -(3-Ethoxypropyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

5- (2-Fluoropyridin-4-yl)-N-[l-(3-hydroxy-3-methylbutyl)-5,7-dimethyl-6-oxo-l,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl]thiophene-2-carboxamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-2-(pyridin-4-yl)-l,3-thiazole-4-carboxamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-4-methyl-2-(pyridin-4-yl)-l,3-thiazole-5-carboxamide;

N-[ 1 -(3-Amino-3-oxopropyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl]-5-(pyridin-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5- (lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxy-3-methylbutyl)-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-6-oxo-l ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{l-[2-(Morpholin-4-yl)ethyl]-6-oxo-l,5,6,7-tetrahydrobenzo[l,2-d:4,5- d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide; N- {6-Oxo- 1 -[3-(2-oxopyrrolidin-l -yl)propyl]- 1 ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{ l-[3-(Morpholin-4-yl)-3-oxopropyl]-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Ethoxypropyl)-7-methyl-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxy-3-methylbutyl)-7-methyl-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Amino-3-oxopropyl)-7-methyl-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-7-ethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[7-Ethyl-l-(3-hydroxy-3-methylbutyl)-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Amino-3-oxopropyl)-7-ethyl-6-oxo-l ,5,6,7-tetrahydrobenzo[l ,2-d:4,5- d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-7-ethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5 ,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

5-(3,5-Dimethyl-lH-pyrazol-4-yl)-N-[l-(3-ethoxypropyl)-6-oxo-7-(2,2,2- trifluoroethyl)-l ,5,6,7-tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]thiophene- carboxamide;

N- {6-Oxo- 1 -[3-(propan-2-yloxy)propyl]-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(2-Hydroxy-2-methylpropyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide

N-[ 1 -(3-Hydroxy-3-methylbutyl)-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l ,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[ 1 ,2-d:4,5-d']diimidazol-2-yl} -5 -(1 -methyl- lH-pyrazol-4-yl)thiophene-2- carboxamide; N- { 1 -[2-(Morpholin-4-yl)ethyl]-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxam

N-[ 1 -(3-Ethoxypropyl)-7-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-7-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(Dimethylamino)-3-oxopropyl]-5-(2-hydroxy-2-methylpropyl)-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- (5-(2-Hydroxy-2-methylpropyl)- 1 -[2-(morpholin-4-yl)ethyl]-6-oxo- 1 ,5 ,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{7-[2-(Dimethylamino)ethyl]-l-[3-(dimethylamino)-3-oxopropyl]-6-oxo-l,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{l-(3-Ethoxypropyl)-7-[2-(morpholin-4-yl)ethyl]-6-oxo-l,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- {7-[2-(Morpholin-4-yl)ethyl]-6-oxo- 1 -[3-(propan-2-yloxy)propyl]- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -(3-Hydroxy-3-methylbutyl)-7-[2-(morpholin-4-yl)ethyl]-6-oxo- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-{l-[3-(Dimethylamino)-3-oxopropyl]-7-[2-(morpholin-4-yl)ethyl]-6-oxo-l, 5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Hydroxy-3-methylbutyl)-5,7-dimethyl-6-oxo- 1 ,5,6,7-tetrahydrobenzo[ 1 ,2- d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[ 1 -(3-Ethoxypropyl)-5-methyl-6-oxo-7-(2,2,2-trifluoroethyl)- 1 ,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N-[l-(3-Hydroxy-3-methylbutyl)-5-methyl-6-oxo-7-(2,2,2-trifluoroethyl)-l,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;

N- { 1 -[3-(dimethylamino)-3-oxopropyl]-5-methyl-6-oxo-7-(2,2,2-trifluoroethyl)- l,5,6,7-tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl}-5-(lH-pyrazol-4-yl)thiophene-2- carboxamide;

N-[l-(3-Ethoxypropyl)-7-(2-hydroxy-2-methylpropyl)-5-methyl-6-oxo-l,5,6,7- tetrahydrobenzo[l,2-d:4,5-d']diimidazol-2-yl]-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide; and pharmaceutically acceptable salts thereof.

35. A compound of formula (VI)

(VI)

or a pharmaceutically acceptable salt thereof,

wherein,

P is 5- to 14- membered heteroaryl;

Q is absent or selected from C_6-14 aryl and 5- to 14- membered heteroaryl, wherein each being optionally substituted with one or more R ;

L is -(CH₂)„C(0)NR^a-;

T is selected from hydroxy, Ci_salkyl or C3_i₂cycloalkyl;

R is selected from hydrogen, Ci_salkyl, hydroxyCi_salkyl, and 3- to 15- membered heterocyclylC i_salkyl;

R is selected from Ci_salkyl and haloCi_salkyl;

at each occurrence, R⁸ is -(CH₂)_nNR^aC(0)R^b;

'n' is an integer ranging from 0 to 6, both inclusive.

36. The compound according to claim 35, wherein R is hydrogen, methyl, or N— / .

37. The compound according to claim 35 or 36, wherein R is methyl, ethyl or trifluoroethyl.

38. The compound according to any one of claims 35 to 37, wherein P is

39. The compound according to any one of claims 35 to 38, wherein Q is absent.

40. The compound according to any one of claims 35 to 38, wherein Q is

The compound according to any one of claims 35 to 40, wherein L-T

A compound selected from N-Ethyl-l-methyl-2-oxo-6-({[5-(pyridin-4-yl)thiophen-2-yl]carbonyl} amino)- 1,2, 3,5- tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N-Ethyl-l-methyl-2-oxo-6-[(thiophen-2-ylcarbonyl)amino]-l,2,3,5-tetrahydroimidazo [4,5-f]indole-7-carboxamide;

N-Cyclopropyl- 1 -methyl-2-oxo-6-( {[5 -(pyridin-4-yl)thiophen-2 -yljcarbonyl} amino)- l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

6-[({5-[3-(Acetylamino)phenyl]thiophen-2-yl}carbonyl)amino]-N,l-diethyl-2-oxo- l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N-Ethyl-l-methyl-2-oxo-6-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl}amino)- l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N-Cyclopropyl- 1 -methyl-2-oxo-6-( {[5-(lH-pyrazol-4-yl)thiophen-2- yl]carbonyl}amino)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N, 1 -Diethyl-2-oxo-6-( {[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl} amino)- 1 ,2,3,5- tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N-Cyclopropyl- 1 -ethyl-2-oxo-6-( { [5-( lH-pyrazol-4-yl)thiophen-2- yl]carbonyl}amino)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

6-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-methyl-2-oxo-l -(2,2,2- trifluoroethyl)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

6-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-2-oxo-l -(2,2,2- trifluoroethyl)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N,N-Dimethyl-2-oxo-6-( { [5-( lH-pyrazol-4-yl)thiophen-2 -yljcarbonyl} amino)- 1 - (2,2,2-trifluoroethyl)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N,N,3-Trimethyl-2-oxo-6-( {[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl} amino)- 1 - (2,2,2-trifluoroethyl)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide;

N-Cyclopropyl-3-methyl-2-oxo-6-({[5-(lH-pyrazol-4-yl)thiophen-2- yljcarbonyl} amino)- 1 -(2,2,2-trifluoroethyl)- 1 ,2,3,5-tetrahydroimidazo[4,5-f]indole-7- carboxamide;

N-Cyclopropyl-l-methyl-3-[2-(morpholin-4-yl)ethyl]-2-oxo-6-({[5-(lH-pyrazol-4- yl)thiophen-2-yl]carbonyl}amino)-l,2,3,5-tetrahydroimidazo[4,5-f]indole-7-carboxamide; and pharmaceutically acceptable salts thereof.

43. A compound of formula (VII)

(VII)

or a pharmaceutically acceptable salt thereof,

wherein,

P is 5- to 14- membered heteroaryl, being optionally substituted with one or more R⁷; Q is absent or 5- to 14- membered heteroaryl, being optionally substituted with one or more R ;

L is -(CH₂)_nC(0)NR^a-;

T is selected from hydroxy, Ci_salkyl, haloCi_salkyl or C₃_i₂cycloalkyl;

R is selected from hydrogen, Ci_salkyl and 3- to 15- membered heterocyclylCi

R⁵ is selected from hydrogen and Ci_salkyl;

R⁶ is selected from hydrogen and Ci_salkyl;

at each occurrence, R is cyano;

at each occurrence, R is Ci_salkyl;

at each occurrence, R^a, which may be the same or different, are independently selected from hydrogen and Ci_salkyl; and

'n' is an integer ranging from 0 to 6, both inclusive.

pound according to claim 43, wherein R is hydrogen, methyl

45. The compound according to claim 43 or 44, wherein R⁵ is hydrogen or methyl.

46. The compound according to any one of claims 43 to 45, wherein R⁶ is hydrog methyl.

47. The compound according to any one of claims 43 to 46, wherein P is

48. The compound according to any one of claims 43 to 47, wherein Q is absent.

und according to any one of claims 43 to 47, wherein Q is

50. The compound according to any one of claims 43 to 49, wherein L-T is

51. A compound selected from

N-Cyclopropyl-2,2-dimethyl-3-oxo-7-({[5-(pyridin-4-yl)thiophen-2- yl]carbonyl}amino)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N-Cyclopropyl-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-3-oxo-7-[(pyridin-2- ylcarbonyl)amino]-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N-Cyclopropyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl}amino)- 2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

7-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N,2,2-trimethyl-3-oxo-2, 3,4,6- tetrahydro-[ 1 ,4]oxazino[2,3-f]indole-8-carboxamide;

N-Ethyl-2,2-dimethyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl}amino)- 2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

2,2-Dimethyl-3-oxo-N-(propan-2-yl)-7-({[5-(lH-pyrazol-4-yl)thiophen-2- yl]carbonyl}amino)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

2,2-Dimethyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl}amino)-N- (2,2,2-trifluoroethyl)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N,N,2,2-Tetramethyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2-yl]carbonyl}amino)- 2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N-Cyclopropyl-2,2-dimethyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2- yl]carbonyl}amino)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N-Cyclopropyl-2,2,4-trimethyl-3-oxo-7-({[5-(lH-pyrazol-4-yl)thiophen-2- yl]carbonyl}amino)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8-carboxamide;

N-Cyclopropyl-2,2-dimethyl-4-[2-(morpholin-4-yl)ethyl]-3-oxo-7-({[5-(lH-pyrazol-4- yl)thiophen-2-yl]carbonyl}amino)-2,3,4,6-tetrahydro[l,4]oxazino[2,3-f]indole-8- carboxamide;

and pharmaceutically acceptable salts thereof.

52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 and a pharmaceutically acceptable excipient.

53. The pharmaceutical composition according to claim 52, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

54. A method of treating ITK mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 51.

55. A method of treatment of disorder or disease selected from the group consisting of respiratory disease, an allergic disease, an autoimmune disease, an inflammatory disorder, a proliferative disorder, diabetes, transplant rejection, graft versus host disease, HIV, aplastic anemia, and pain administering an effective amount of a compound according to any one of claims 1 to 51.

56. A method of treatment of disorder or disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, T cell mediated hypersensitivity, Guillain-Barre Syndrome, Hashimoto's thyroiditis, cancer, transplant rejection, graft versus host disease, conjunctivitis, contact dermatitis, inflammatory bowel disease, chronic inflammation, HIV, aplastic anemia, and inflammatory pain administering an effective amount of a compound according to any one of claims 1 to 51.

57. A method according to claim 56, wherein the disorder or disease is asthma or chronic obstructive pulmonary disease (COPD).

58. A method according to claim 56, wherein the disorder or disease is allergic rhinitis.

59. A method according to claim 56, wherein the disorder or disease is atopic dermatitis. 60. A method according to claim 56, wherein the disorder or disease is rheumatoid arthritis.