HETEROCYCLIC COMPOUNDS AS EZH2 INHIBITORS

Field of the Invention

The present invention relates to heterocyclic compounds (the compounds of formula I), processes for their preparation, pharmaceutical compositions containing them and their use as EZH2 (enhancer of zeste homolog 2) inhibitors, and methods of using said compounds in the treatment of diseases mediated by EZH2.

Background of the Invention

Histone methyl transferases (HMTs) are a family of enzymes, which control selective methylation at specific amino acid sites on hist ones. Covalent modification of histones such as methylation control changes of chromatin structure in eukaryotic cell DNA, leads to heritable alteration in gene expression. These modifications are referred to as epigenetic modifications. Polycomb genes are an illustration of epigenetic effectors structured in multimeric repressive complexes. Aberrant expression and/or activity of enzymes responsible for histone modification result in disease states such as cancer. Therefore, epigenetic modifications can be reversed and consequently, treatment of diseases such as cancer may be effected through selective inhibition of the enzymes involved.

Histone-lysine N-methyltransferase (histone methyltransferase) EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which trimethylates Lys27 of a specific histone H3 (H3K27) and is essential for the self- renewal of cancer stem cells. EZH2 is capable of silencing several anti-metastatic genes, favoring cell-invasion and uncontrolled cell-growth. For instance, somatic mutations of tyrosine 641 of EZH2 are reported to be associated with follicular lymphoma and diffused B-cell lymphoma (Nature Genetics, 2010, 42, 2, 181-185).

Increased levels of trimethylated H3K27 resulting due to an increased expression of EZH2 contribute to cancer aggressiveness, metastasis, shorter disease free survival and increased death rate in many tumor types, for instance, in melanoma, prostate cancer, breast cancer and cancer of the endometrium (Journal of Clinical Oncology, 2006, 24, 4, 268-73). This is further substantiated in Oncogene, 2012, 31, 3827-44, wherein it is reported that EZH2 expression is deregulated in prostate cancer, breast cancer, endometrial cancer, B-cell non-Hodgkin's lymphoma and bladder carcinoma. Increased expression of EZH2 also induces pulmonary artery smooth muscle proliferation (PLoS ONE, 2012, 7 (5): e37712). Increased expression of EZH2 has been further reported to have implication in myelofibrosis (Expert Review of Hematology, 2012, 5, 3, 313-324), HIV (PCT publication WO2012051492 A2), graft versus host diseases (GVHD) (Blood, 2012, 119, 5, 1274-1282), Weaver Syndrome (American Journal of Human Genetics, 2012, 90, 1, 110-118), psoriasis vulgaris (European Journal of Dermatology, 2011, 21, 4, 552-557) and liver fibrogenesis (PCT publication WO2010090723 A2).

PCT Application Publications WO2011140324A1 and WO2012075080A1 disclose indoles as inhibitors of EZH2 and use of said compounds for the treatment of cancers. PCT Application Publication WO2012118812A2 discloses bicyclic heterocyclic compounds as EZH2 inhibitors and their use in the treatment of cancer.

Thus, it is understood from the above discussion that the inhibition of EZH2 activity would effectively decrease cellular proliferation and invasion and thereby provide therapeutic benefit in the treatment of diseases or disorders mediated by EZH2. The compounds of the present invention function as inhibitors of EZH2 and therefore, provide a therapeutic solution for the treatment of diseases or disorders mediated by EZH2 such as cancers.

Summary of the Invention

According to one aspect, the present invention relates to a compound of formula I (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N-oxide thereof.

According to another aspect, the present invention relates to processes for the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof.

According to a further aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula I or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.

According to a further aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof; for use as an EZH2 (enhancer of zeste homolog 2) inhibitor.

According to yet another aspect, the present invention relates to a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof; for use in the treatment of a disease or a disorder mediated by EZH2. According to a further aspect, the present invention relates to a method for the treatment of a disease or disorder mediated by EZH2; comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.

In a further aspect, the present invention relates to a use of a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; in combination with at least one further therapeutically active agent; for the treatment of a disease or disorder mediated by EZH2.

According to yet another aspect, the present invention relates to a use of a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for the manufacture of a medicament for the treatment of a disease or disorder mediated by EZH2.

One or more further aspects of the present inventions are discussed in detail herein below. These and other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description.

Detailed description of the invention

According to the first aspect, the present invention relates to a compound of formula I,

Formula I

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof,

wherein,

ring B represents: a saturated or unsaturated 5- or 6-membered carbocyclic ring; or a saturated or unsaturated 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; wherein the said carbocyclic or heterocyclic ring can be unsubstituted or substituted with one to three groups independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-C ₈ )-alkyl, halo(C ₁ -C ₈ )alkyl, (d-C ₈ )-alkoxy, (C ₂ -C ₈ )-alkenyl, (C ₃ -C ₁₂ )-cycloalkyl, O- (C ₃ -C ₁₂ )-cycloalkyl, (C ₅ -C ₁₀ )-cycloalkenyl, (C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )aryl- (Ci-C ₈ )-alkyl, heteroaryl, heterocyclyl, O-heterocyclyl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b , CON(R ^a )NR ^a R ^b , OC(0)NR ^a R ^b , S(0) _q R ^a , S(0) _r NR ^a R ^b , NR ^a R ^b and (CR ^c R ^d ) _n -0-R ^a ; or two of the substituents on same or adjacent ring atoms in carbocyclic or heterocyclic ring can optionally combine to form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C3-Ci ₂ )-cycloalkyl, (C5-Cio)-cycloalkenyl, (Ce-Cio)-aryl, heterocyclyl or heteroaryl; R ¹ is hydrogen, halogen, hydroxy, cyano, (Ci-C ₈ )-alkyl, (C ₂ -C ₈ )-alkenyl, (Ci-C ₈ )-alkoxy, (C ₃ -C ₁₂ )-cycloalkyl, (C ₅ -C ₁₀ )-cycloalkenyl, halo(d-C ₈ )alkyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl, S(0) _r NR ^a R ^b or (CR ^c R ^d ) _n -0-R ^a ;

R is hydrogen, halogen, hydroxy, cyano, B(OH) ₂ , (Ci-C ₈ )-alkyl, halo(Ci-C ₈ )alkyl, (Q- C ₈ )-alkoxy, (C ₂ -C ₈ )-alkenyl, (C ₃ -C ₁₂ )-cycloalkyl, (C ₆ -C ₁₄ )-aryl-R ⁵ , (C ₆ -C ₁₄ )aryl-(C ₁ -C ₈ )- alkyl, heteroaryl-R ⁵ , heterocyclyl-R ⁵ , COR ^a , C0 ₂ R ^a , CONR ^a R ^b , CON(R ^a )NR ^a R ^b , OC(0)NR ^a R ^b , S(0) _q R ^a , S(0) _r NR ^a R ^b , NR ^a R ^b , NR ^a C(0)R ^b , NR ^a C(0)NR ^a R ^b , NR ^a C(0)OR ^b , NR ^a S(0) _q R ^b , NR ^a S(0) _r NR ^a R ^b , NR ^a NR ^a R ^b , NR ^a NR ^a C(0)R ^b , NR ^a NR ^a C(0)NR ^a R ^b , NR ^a NR ^a C(0)OR ^a or (CR ^c R ^d ) _n -0-R ^a ;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (d-C ₈ )-alkyl, (C ₂ -C ₈ )-alkenyl, (d-C ₈ )-alkoxy, halo(C ₁ -C ₈ )alkyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl and S(0) _r NR ^a R ^b ; or

R ³ and R ⁴ can optionally combine to form a 3-10 membered cyclic ring optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; wherein said cyclic ring can be unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-C ₈ )-alkyl, (C ₂ -C ₈ )- alkenyl, (d-d)-alkoxy, halo(C ₁ -C ₈ )alkyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl and S(0) _r NR ^a R ^b ;

a b

R and R are independently selected from the group consisting of hydrogen, (Ci-C ₈ )- alkyl, (C ₂ -C ₈ )-alkenyl, (C3-Ci ₂ )-cycloalkyl, (d-do)-cycloaikenyl, (C6-Ci ₄ )-aryl, heterocyclyl and heteroaryl; or

R ^a and R ^b can be optionally combined to form a 3-10 membered heterocyclyl ring;

R ^c and R ^d are independently selected from the group consisting of hydrogen, hydroxy, cyano, halogen, (Ci-C ₈ )-alkyl and halo(Ci-C ₈ )alkyl; R ⁵ is hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁ 4)-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -C ₁₄ )-aryl, NH-(C ₆ -C ₁₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, (CR ^c R ^d ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

n is an integer selected from 0, 1, 2, 3, 4 or 5;

q is an integer selected from 0, 1 or 2;

r is an integer selected from 1 or 2;

X ¹ is CR ⁶ or N;

R ⁶ is hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C ₂ -Cg)-alkenyl, (Ci-Cg)-alkoxy, (C ₃ -C ₁₂ )-cycloalkyl, (C ₅ -C ₁₀ )-cycloalkenyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl, S(0) _r NR ^a R ^b or (CR ^c R ^d ) _n -0-R ^a ;

m is an integer selected from 0, 1, 2 or 3;

L is -C(0)NR ^g - -NR ^g C(0)-, -NR ^g C(0)NR ^g -, -NR ^g S(0) _r -, -S(0) _r NR ^g - -CH ₂ NR ^g -, -NR ^g CH ₂ -, -CH(halo)NR ^g -, -NR ^g CH(halo)-, -C(halo) ₂ NR ^g - -NR ^g C(halo) ₂ -, -CH(halo(C Cg) alkyl)NR ^g - -NR ^g CH(halo(C Cg)alk l)-, -C(halo(C ₁ -C ₈ )alkyl) ₂ NR ^g -,

-NR ^g C(halo(C ₁ -C ₈ )alkyl) ₂ -,

R ^g is hydrogen, cyano, (Ci-Cg)-alkyl, (C ₂ -C ₈ )-alkenyl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b CONR ^a NR ^a R ^b ;

A is:

R 7' and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C ₂ -Cg)-alkenyl, (Ci-Cg)-alkoxy, (C3-Ci ₂ )-cycloalkyl, (C _¾ - Cio)-cycloalkenyl, halo(d-Cg)-aikyl, (C ₆ -C ₁₄ )-aryl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b , NR ^a R ^b , S(0) _q R ^a and S(0) _r NR ^a R ^b ;

g

R is hydrogen, hydroxy, halogen, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, halo(Ci-Cg)aikyl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b , S(0) _q R ^a or S(0) _r NR ^a R ^b ;

R ¹⁰ is hydrogen, cyano, (Ci-C ₈ )-alkyl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b , S(0) _q R ^a or S(0) _r NR ^a R ^b ; or

R 7 and R 8 or R 8 and R 9 or R 7 and R 10 or R 9 and R 10 can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, (C6-Cio)-aryl, heteroaryl or heterocyclyl;

wherein:

each of the (Ci-Cg)-alkyl, (C2-Cg)-alkenyl and (Ci-Cg)-alkoxy can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci ₄ )-aryl, 0-(C ₆ - C ₁₄ )-aryl, heterocyclyl, heteroaryl, halo(C Cg)alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NR ^h R ⁱ , NR ^h R', NR ^h C(0)R', NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R ⁱ ;

each of the (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl and (C6-Ci ₄ )-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C ₃ - Ci2)-cycloalkyl, (C6-Ci ₄ )-aryl, 0-(C6-Ci ₄ )-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)alkyl, halo(C ₁ -C ₈ )alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R\ OC(0)NR ^h R ⁱ , NR ^h R', NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R ⁱ ;

heterocyclyl is a 3- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein said heterocyclyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C ₃ -Ci2)-cycloalkyl, (C ₆ - Ci ₄ )-aryl, 0-(C6-Ci ₄ )-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)alkyl, halo(Ci-Cg)alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NR ^h R ⁱ , NR ^h R\ NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R ⁱ ;

heteroaryl is a 5- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from: N, S and O, wherein said heteroaryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C ₃ -Ci2)-cycloalkyl, (C6-Ci ₄ )-aryl, 0-(C ₆ -Ci ₄ )- aryl, heterocyclyl, heteroaryl, halo(C ₁ -C ₈ )alkyl, halo(Ci-C ₈ )alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NR ^h R ⁱ , NR ^h R', NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R'; and

R ^h and R ¹ are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl, (C ₂ -C ₈ )-alkenyl, halo(Ci-C ₈ )alkyl, (C ₃ -C ₁₂ )-cycloalkyl, (C ₆ -C ₁₄ )-aryl, (C ₆ -Ci ₄ )-aryl-(Ci- Cg)-alkyl, heteroaryl and heterocyclyl.

Definitions

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.

It will be understood that "substitution," "substituted" or "substituted with" means that one or more hydrogen(s) of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.

The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds, or reference to "a disease" or "a disorder" includes a plurality of diseases or disorders.

Also, use of "(s)" as part of a term, includes reference to the term singly or in plurality, e.g. the term compound(s) may indicate a single compound or more compounds.

It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

The term "independently" when used in the context of selection of substituents for a variable, it means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

As used herein, the term "(Ci-Cg)-alkyl" or "alkyl" as used herein; alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups. A straight-chain or branched chain alkyl has eight or fewer carbon atoms in its backbone, for instance, Ci-C ₈ for straight chain and C3-C8 for branched chain. As used herein, (Ci-Cg)-alkyl refers to an alkyl group having 1 to 8 (both inclusive) carbon atoms; preferably refers to an alkyl group having 1 to 6 (both inclusive) carbon atoms i.e. (Ci-Ce)-alkyl; and more preferably, refers to an alkyl group having 1 to 4 (both inclusive) carbon atoms i.e. (Ci-C4)-alkyl. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and 3- methylbutyl.

Furthermore, unless stated otherwise, the alkyl group can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups independently selected from halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkoxy, (C ₃ - Ci2)-cycloalkyl, (C6-Ci4)-aryl, 0-(C6-Ci4)-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)- alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NR ^h R ⁱ , NR ^h R\ NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R'; wherein R ^h and R ¹ are independently selected from hydrogen, (Ci-C ₈ )-alkyl, (C2-C ₈ )-alkenyl, halo(Ci-Cg)aikyl, (C ₃ -Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)-aryl-(Ci-C ₈ )-alkyl, heteroaryl and heterocyclyl. Representative examples of substituted alkyls include, but are not limited to, benzyl, hydroxymethyl, hydroxyethyl, N-morpholinomethyl, N-indolomethyl, piperidinylmethyl and aminoethyl.

As used herein, the term "halogen" or "halo" refers to a fluorine, chlorine, bromine, or iodine atom.

As used herein, the term "halo(Ci-C8)alkyl" or "haloalkyl" refers to the alkyl group which is substituted with one or more halogens. A monohalo(Ci-Cg)alkyl radical, for example, can have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(Ci- Cg)alkyl radicals can have two or more of the same or different halogen atoms. Representative examples of halo(Cj-Cg)alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.

As used herein, the term "(C2-Cg)-alkenyl" or "alkenyl", alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon-carbon double bond (two adjacent sp carbon atoms). As used herein, (C2-Cg)-alkenyl refers to an alkenyl group having 2 to 8 (both inclusive) carbon atoms; preferably, refers to alkenyl group having 2 to 6 (both inclusive) carbon atoms i.e. (C ₂ -C6)-alkenyl; and more preferably, alkenyl refers to alkenyl group having 2 to 4 (both inclusive) carbon atoms i.e. (C ₂ -C4)-alkenyl. Depending on the placement of double bond and substituents; if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis or trans. Representative examples of alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl. Furthermore, unless stated otherwise, the alkenyl groups can be unsubstituted or substituted with one or more groups. A substituted alkenyl refers to a (Ci-Cg)-alkenyl substituted with 1-7 groups, preferably with 1-3 groups selected from the groups indicated above as the substituents for the alkyl group.

As used herein, the term "(Ci-Cg)-alkoxy" or "alkoxy" refers to a (Ci-Cg)-alkyl having an oxygen radical attached thereto. The term "(Ci-Cg)-alkoxy" or "O-(Ci-Cg)- alkyl" or alkoxy wherever used in this specification have the same meaning. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy. Furthermore, unless stated otherwise, the alkoxy groups can be unsubstituted or substituted with one or more groups. A substituted alkoxy refers to a (Ci-Cg)-alkoxy substituted with 1-7 groups, preferably with 1-3 groups selected from the groups indicated above as the substituents for the alkyl group.

As used herein, the term "halo(Ci-Cg)alkoxy" or "haloalkoxy" refers to the alkoxy group which is substituted with one or more halogens. A monohalo(Ci-Cg)aikoxy radical, for example, can have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(Ci-Cg)alkoxy radicals can have two or more of the same or different halogen atoms. Representative examples of halo(Ci-Cg)alkoxy include, but are not limited to, chloromethoxy, dichloromethoxy, trichloromethoxy, dichloroethoxy, dichloropropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy or the like groups.

As used herein, the term "carbocyclic ring" refers to a 5- or 6-membered cyclic ring or ring system whose ring atoms are all carbon, and includes aryl, cycloalkyl or cycloalkenyl.

As used herein, the term "(C3-Ci ₂ )-cycloalkyl" or "cycloalkyl", whether used alone or as part of a substituent group, refers to a saturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings, which may be optionally substituted by one or more substituents. The term cycloalkyl includes bridged, fused and spiro ring systems. As used herein, (C3-Ci2)-cycloalkyl refers to a cycloalkyl group having 3 to 12 (both inclusive) carbon atoms; preferably, refers to cycloalkyl group having 3 to 10 (both inclusive) carbon atoms i.e. (C3-Cio)-cycloalkyl; and more preferably, refers to cycloalkyl group having 3 to 7 (both inclusive) carbon atoms i.e. (C3-C7)-cycloalkyl. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, and spiro[3.3]heptanes.

As used herein, the term "(Cs-Cio)-cycloalkenyl" or "cycloalkenyl", whether used alone or as part of a substituent group, refers to a partially unsaturated monocyclic hydrocarbon radical containing a total of 5 to 10 carbon atoms forming the ring, which can be optionally substituted by one or more substituents. Representative examples of (C _¾ - Cio)-cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, 1,2,3,3a- tetrahydropentalenyl and 1,2,3,4-tetrahydronaphthalenyl.

Furthermore, unless stated otherwise, "the cycloalkyl" or "the cycloalkenyl" group can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups independently selected from halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, 0-(C6-Ci4)-aryl, heterocyclyl, heteroaryl, halo(Ci-Cg)-alkyl, halo(Ci-C ₈ )-alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NR ^h R ⁱ , NR ^h R\ NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R ⁱ ; wherein R ^h and R ^{ are as defined above.

The term "(C6-Ci4)-aryl" or "aryl" as used herein refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms i.e. "(C6-Cio)-aryl" in which the carbocyclic ring(s) present have a conjugated pi electron system, which may be optionally substituted by one or more groups. Representative examples of (C6-Ci4)-aryl include, but are not limited to, phenyl, naphthyl, fluorenyl or anthracenyl.

Furthermore, unless stated otherwise, the aryl group can be unsubstituted or substituted with one or more groups. A substituted aryl refers to a (C6-Ci4)-aryl substituted with one or more groups, preferably 1-7 groups and more preferably 1-3 groups independently selected from halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Ci-Cg)-alkoxy, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, 0-(C6-Ci4)-aryl, heterocyclyl, heteroaryl, halo(Ci- Cg)alkyl, halo(C ₁ -C ₈ )alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NR ^h R ⁱ , OC(0)NRV, NR ^h R\ NR ^h C(0)R ⁱ , NR ^h C(0)NR ^h R ⁱ , S(0) _q R ^h , S(0) _r NR ^h R ⁱ and NR ^h S(0) _q R'; wherein R ^h and R ¹ are as defined above.

As used herein, the term "(C6-Ci4)-aryl-(Ci-Cg)-alkyl" or "ar-(Ci-C8)-alkyl" refers to an alkyl group substituted with an (C6-Ci4)-aryl group, wherein the terms alkyl and aryl are as defined above. Exemplary aralkyl group include (CH2) _P -phenyl, wherein p is an integer from 1 to 6, such as benzyl wherein p is 1. The aryl of the (C6-Ci4)-aralkyl group can be unsubstituted or substituted with groups selected from the groups indicated above as the substituents for the aryl group.

The term "heteroatom" as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.

As used herein, the terms "heterocyclyl" or "heterocyclic" whether used alone or as part of a substituent group, refers to a 3- to 10-membered saturated, partially unsaturated, monocyclic or bicyclic ring system containing 1 to 4 identical or different heteroatoms independently selected from oxygen, nitrogen and sulfur. Saturated heterocyclic ring systems do not contain any double bond, whereas partially unsaturated heterocyclic ring systems, contain at least one double bond, but do not form an aromatic system containing a hetero atom. Representative examples of heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyranyl, tetrahydropyranyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1, 1- dioxide, quinoxalinyl, quinolinyl and thiophenyl. The oxidized form of the ring nitrogen and sulfur atom contained in the heterocyclyl to provide the corresponding N-oxide, S- oxide or S,S-dioxide is also encompassed in the scope of the present invention.

Furthermore, unless stated otherwise, the heterocyclyl groups can be unsubstituted or substituted with one or more groups, preferably with 1-7 groups, more preferably with 1-3 groups independently selected from halogen, hydroxy, oxo, cyano, (Ci-Cg)-alkyl, (Q- Cg)-alkoxy, (C3-C ₁ 2)-cycloalkyl, ( C^-aryl, (X C^-aryl, heterocyclyl, heteroaryl, halo(C ₁ -C ₈ )-alkyl, halo(C ₁ -C ₈ )-alkoxy, C(0)R ^h , OC(0)R ^h , COOR ^h , C(0)NRV, OC(0)NR ^h R ⁱ , NRV, NR ^h C(0)R\ NR ^h C(0)NR ^h R\ S(0) _q R ^h , S(0) _r NR ^h R ⁱ or NR ^h S(0) _q R'; wherein R ^h and R ¹ are as defined above. As used herein, the term "heteroaryl" whether used alone or as part of a substituent group, refers to 5- to 10-membered heterocyclyl having an aromatic ring containing one to four identical or different hetero atoms selected from: nitrogen, sulphur or an oxygen atom. Representative examples of heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, oxadiazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, pyrido[2,3- b]pyrazine. The oxidized form of the ring nitrogen and sulfur atom contained in the heteroaryl to provide the corresponding N-oxide, S-oxide or S,S-dioxide is also encompassed in the scope of the present invention.

Furthermore, unless stated otherwise, the heteroaryl groups can be unsubstituted or substituted with one or more groups; preferably with 1-7 groups, more preferably with 1-3 groups selected from the groups indicated above as the substituents for the heterocyclyl group.

Within the context of this present invention and as used herein the term "isotopic forms" or "isotopically labeled forms" is a general term used for isotopic forms of the compound of formula I, wherein one or more atoms of the compound of formula I are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T), carbon such as ⁿ C, ¹³ C and ¹⁴ C, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as 15 O, 17 O and 18 O, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as 35 S. Substitution with heavier isotopes, for example, replacing one or more key carbon- hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence may be preferred in certain circumstances.

Representative examples of isotopic forms of a compound of formula I can include, without limitation, deuterated compound of formula I. The term "deuterated" as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. For example, the compounds of formula I can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.

The term "deuterated-alkyl" refers to an (Ci-Cg)-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. Analogously, the term "deuterated" and the terms deuterated-heterocyclyl, deuterated- heteroaryl, deuterated-cycloalkyl, deuterated-aryl and deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.

The term "pharmaceutically acceptable solvate(s)" or "solvate(s)" as used herein refers to a compound formed by the interaction of a solute (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid or mixtures thereof. Most preferably, the solvent used is water and the solvates obtained are referred to as hydrates. Examples for suitable solvates are the mono- or di-hydrates or alcoholates of the compounds of the present invention.

Within the context of the present invention and as used herein, the term "stereoisomer" or "stereoisomeric form" is a general term used for all isomers of individual compounds (in the present invention, a compound of formula I) that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).

The term "tautomer" refers to the coexistence of two or more compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers or an amide-imidic acid tautomers. As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, excipient and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "pharmaceutically acceptable salt(s)" as used herein includes a salt or salts of the active compound i.e. the compound of formula I, which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.

Within the context of the present invention and as used herein the term "polymorph" or "polymorphic form" refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule (in the present invention, a compound of formula I) in the crystal lattice.

Within the context of the present invention and as used herein, "N-oxide" refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N-^O bond.

Within the context of the present invention and as used herein "S-oxide" refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur-containing heteroaryl or heterocycle. S-oxide and S, S-dioxides can be formed in the presence of an oxidizing agent for example, peroxide such as m-chloroperbenzoic acid or oxone.

Within the context of the present invention and as used herein, "a prodrug" or "prodrugs" refers to any compound, which are derivatives of a parent compound (in the present invention, a compound of formula I), which following administration, release(s) the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.

In the context of the present invention, the term "compound(s) of formula I" or "compounds of the present invention" are used interchangeably and includes all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, N-oxides and S-oxides thereof. The compound(s) of formula I can also be referred to herein as "the active compound" or "the active ingredient".

The term "EZH2 inhibitor" refers to an agent (in the present invention, a compound of formula I) which is capable of inhibiting the increased expression of Histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2), which is a catalytic subunit of Polycomb repressive complex 2 (PRC2), responsible for methylation of Lys27 of a specific histone H3 (H3K27) and essential for the self -renewal of stem cells.

The term, "disease or disorder mediated by EZH2" refers to an abnormal condition in a subject due to aberrant expression of the enzyme 'Histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2)' leading to abnormal epigenetic modifications.

The diseases or disorders mediated by EZH2 can be selected from cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases, Weaver Syndrome, psoriasis vulgaris or liver fibrogenesis. The cancers mediated by EZH2 include, but are not limited to, thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer and oral cancer.

The term, "therapeutically effective amount" as used herein means an amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a composition comprising a compound of formula I or a salt thereof, effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder mediated by EZH2. An example of a disease or disorder mediated by EZH2 is cancer. Particularly, the term "therapeutically effective amount" includes the amount of a compound (in the context of the present invention, the compound of Formula I or a pharmaceutically acceptable salt thereof), when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, consideration is also given that the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition (in the context of the present invention, the disease or disorder that is mediated by EZH2) being treated, the age and physical condition of the subject, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other related factors.

As used herein, the term "pharmaceutically acceptable carrier" refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary or excipient of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.

The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm-blooded vertebrate animals of the class 'mammalia' , including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young, the term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.

As used herein, the terms "treatment" "treat" and "therapy" and the like refer to alleviate, slow the progression, attenuation, prophylaxis or as such treat the existing diseases or condition (e.g. cancer). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.

Embodiments

The invention encompasses all the compounds described by the formula I without limitation, however, for the purposes of further illustrations, preferred aspects and elements of the invention are discussed herein the form of the following embodiments.

In an embodiment, the present invention relates to a compound of formula I;

wherein ring B represents a saturated or unsaturated 5- or 6-membered carbocyclic ring; wherein the said carbocyclic ring can be unsubstituted or substituted with one to three groups as defined in the first aspect of the invention; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof. In an embodiment, the present invention relates to a compound of formula I; wherein ring B represents a saturated or unsaturated 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; wherein the said heterocyclic ring can be unsubstituted or substituted with one to three groups as defined in the first aspect of the invention; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I; wherein ring B represents: a saturated or unsaturated 5-membered carbocyclic ring; or a saturated or unsaturated 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; wherein the said carbocyclic or heterocyclic ring can be unsubstituted or substituted with one to three groups as defined in the first aspect of the invention; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I; wherein ring B represents: a saturated or unsaturated 6-membered carbocyclic ring; or a saturated or unsaturated 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; wherein the said carbocyclic or heterocyclic ring can be unsubstituted or substituted with one to three groups as defined in the first aspect of the invention; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein when ring B represents: a saturated or unsaturated 5-membered carbocyclic ring; or a saturated or unsaturated 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; it is selected from the following structural formulae B-l, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-l l or B-12;

wherein in one or more of the formulae B-l to B-12:

X ² is selected from NT ¹ , S or O;

T ¹ is selected from hydrogen, cyano, (Ci-Cg)-alkyl, (C ₂ -Cg)-alkenyl, (Ci-Cg)-alkoxy, (C ₃ - C ₁₂ )-cycloalkyl, (C ₅ -C ₁₀ )-cycloalkenyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl, S(0) _r NR ^a R ^b or (CR ^c R ^d ) _n -0-R ^a ;

2 and 3

T T at each occurrence are independently selected from hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, halo(Ci-Cg)alkyl, (Ci-Cg)-alkoxy, (C ₂ -Cg)-alkenyl, (C ₃ - C ₁₂ )-cycloalkyl, (C ₆ -C ₁₄ )-aryl, (C ₆ -C ₁₄ )aryl-(C ₁ -Cg)-alkyl, heteroaryl, heterocyclyl, COR ^a , C0 ₂ R ^a , CONR ^a R ^b , CON(R ^a )NR ^a R ^b , OC(0)NR ^a R ^b , S(0) _q R ^a , S(0) _r NR ^a R ^b , NR ^a R ^b or (CR ^c R ^d ) _n -0-R ^a ; or

T 2 and T 3 can combine to form a 3-12 membered cyclic ring; wherein the said cyclic ring is selected from (C ₃ -Ci ₂ )-cycloalkyl, (Cs-Cio)-cycloalkenyl, (Ce-Cio)-aryl, heterocyclyl or heteroaryl;

R ^J is independently selected from hydrogen, halogen, hydroxy, cyano, (Ci-Cg)-alkyl, (C ₂ - Cg)-alkenyl, (d-Cg)-alkoxy, (C ₃ -C ₁₂ )-cycloalkyl, 0-(C ₃ -C ₁₂ )-cycloalkyl, (C ₅ -C ₁₀ )- cycloalkenyl, halo(C Cg)alkyl, (C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl, O-heterocyclyl, NR ^a R ^b , COOR ^a , CONR ^a R ^b , S(0) _q (C ₁ -C ₆ )-alkyl, S(0) _r NR ^a R ^b and (CR ^c R ^d ) _n -0-R ^a ;

" " represents an optional bond;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein:

ring B is:

X ² , T ² , T ³ and " " are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein:

ring B is:

X ² , T ² , T ³ and " " are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein:

ring B is:

X ² , T ² and T ³ are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein:

ring B is:

X ² , T ² and T ³ are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein:

ring B is:

wherein X and T are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein: X ¹ is CR ⁶ ; ring B is:

wherein X ² is NT ¹ ; wherein R ⁶ , T ¹ , T ² and T ³ are as defined above; or an isotopic form, stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein: X ¹ is CR ⁶ ; ring B is:

wherein X ² is CR^T ¹ ; T ¹ is NR ^a R ^b ; wherein R ⁶ , R ^j , T ² , T ³ , R ^a and R ^b are as defined above; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein: A is:

wherein R 7 , R 8 and R 9 are as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In another embodiment, the present invention relates to a compound of formula I, wherein: A is:

wherein R 7 and R 8 can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is selected from (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, (Ce-Cio)-aryl, heteroaryl or heterocyclyl; and R ⁹ is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In another embodiment, the present invention relates to a compound of formula I, wherein: A is:

wherein R ⁸ and R ⁹ can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is selected from (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, (Ce-Cio)-aryl, heteroaryl or heterocyclyl; and R ⁷ is as defined in the first aspect, or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In yet another embodiment, the present invention relates to a compound of formula

I,

wherein: A is:

wherein R 7 , R 8 and R 9 are as defined in the first aspect, or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In another embodiment, the present invention provides a compound of formula I, wherein: A is:

wherein R ⁷ and R ⁸ can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is selected from (C3-Ci2)-cycloalkyl, (Cs-Cio)-cycloalkenyl, (C6-Cio)-aryl, heteroaryl or heterocyclyl; and R ⁹ is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In still another embodiment, the present invention relates to a compound of formula I,

wherein: A is

wherein R 8 and R 9 can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is selected from (Cs-C^-cycloalkyl, (Cs-Cu t-cycloaikenyl, (C ₆ -Qo)-aryl, heteroaryl or heterocyclyl; and R ⁷ is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein: L is selected from -C(0)NR ^g - -NR ^g C(0)-, -CH ₂ NR ^g - -NR ^g CH ₂ - -NR ^g S(0)r- or -S(0)rNR ^g -;

wherein R ^g and the integer r are as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In another embodiment, the present invention relates to a compound of formula I, wherein: L is selected from -CH(halo)NR ^g - -NR ^g CH(halo)-, -C(halo) ₂ NR ^g - -NR ^g C(halo) ₂ - -CH(halo-(d -C ₈ )-alkyl)NR ^g -, -NR ^g CH(halo-(d -C ₈ )-alkyl)-,

-C(halo-(C ₁ -C ₈ )-alkyl) ₂ NR ^g - or

wherein R ^g is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In yet another embodiment, the present invention relates to a compound of formula

I,

wherein:

wherein R ^g is as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment, the present invention relates to a compound of formula I, wherein: X ¹ is CR ⁶ ;

wherein R ⁶ is as defined in the first aspect, or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In yet another embodiment, the present invention relates to a compound of formula I, wherein: X is N; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment the present invention relates to a compound of formula I, wherein,

ring B is

X ² is selected from

R ^J is hydrogen;

T ¹ is selected from hydrogen, (Ci-Cg)-alkyl, (C ₃ -C ₁₂ )-cycloalkyl or NR ^a R ^b ;

T 2 and T 3 at each occurrence are independently selected from hydrogen, (Ci-Cg)-alkyl, halo(Ci-Cg)aikyl and heterocyclyl;

" " represents an optional bond;

R ¹ is hydrogen, (d-Cg)-aikyl or halo(C ₁ -Cg)alkyl;

R 2 is halogen, 5 aryl-R 5

(C6-Ci4)-aryl-R , (C6-Ci4)aryl-(Ci-Cg)-alkyl, hetero or heterocyclyl- R ⁵ ;

R ³ and R ⁴ are hydrogen;

R ^a and R ^b are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and heterocyclyl;

R ⁵ is selected from hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -Ci ₄ )-aryl, NH-(C ₆ -Ci ₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, c d

(CR R ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

R ^c and R ^d are independently selected from hydrogen, hydroxy, cyano, halogen, (Ci-Cg)- alkyl and halo(C ₁ -Cg)alkyl;

n is an integer selected from 0, 1, 2, 3, 4 or 5;

X ¹ is CR ⁶ ;

R ⁶ is hydrogen;

m is 1 ;

L is -C(0)NR ^g - or -NR ^g C(0)-;

R ^g is hydrogen;

A is

R 7' and R 9 are independently selected from (Ci-Cg)-alkyl or halo(Ci-Cg)-alkyl;

Q

R is hydrogen; or

8 9

R and R can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C ₃ -C ₁₂ )-cycloalkyl;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment the present invention relates to a compound of formula I, wherein,

ring B is

X ² is selected from CR^T ¹ or NT ¹ ;

R ^J is hydrogen;

T ¹ is selected from hydrogen, (C C ₈ )-alkyl, C ₃ -C ₁₂ )-cycloalkyl or NR ^a R ^b ;

T 2 and T 3 at each occurrence are independently selected from hydrogen, (Ci-Cg)-alkyl, halo(Ci-Cg)aikyl and heterocyclyl;

" " represents an optional bond;

R ¹ is hydrogen, (d-Cg)-aikyl or halo(C ₁ -Cg)alkyl;

2 5 5

R is halogen, (C6-Ci4)-aryl-R , (C6-Ci4)aryl-(Ci-Cg)-alkyl, heteroaryl-R or heterocyclyl- R ⁵ ;

R ³ and R ⁴ are hydrogen;

R ^a and R ^b are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and heterocyclyl;

R ⁵ is selected from hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -C ₁₄ )-aryl, NH-(C ₆ -C ₁₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, (CR ^c R ^d ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

R ^c and R ^d are independently selected from hydrogen, hydroxy, cyano, halogen, (Ci-Cg)- alkyl and halo(C ₁ -Cg)alkyl; n is an integer selected from 0, 1, 2, 3, 4 or 5;

X ¹ is CR ⁶ ;

R ⁶ is hydrogen;

m is 1 ;

L is -C(0)NR ^g - or -NR ^g C(0)-;

R ^g is hydrogen;

A is

R ⁷ and R ⁹ are (C ₁ -C ₈ )-alkyl or halo(Ci-C ₈ )-alkyl;

Q

R is hydrogen; or

R 8 and R 9 can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C3-Ci2)-cycloalkyl;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.

In an embodiment the present invention relates to a compound of formula I, wherein,

ring B is

X ² is selected from CR^T ¹ or NT ¹ ;

R ^J is hydrogen;

T ¹ is selected from hydrogen, (Ci-C ₈ )-alkyl, (C ₃ -C ₁₂ )-cycloalkyl or NR ^a R ^b ;

T 2 and T 3 at each occurrence are independently selected from hydrogen, (Ci-Cg)-alkyl, halo(Ci-C ₈ )alkyl and heterocyclyl;

R ¹ is hydrogen, (Ci-C ₈ )-alkyl or halo(C ₁ -C ₈ )alkyl;

R 2 is halogen, 5

i4)aryl-(Ci-Cg)-alkyl, heteroaryl-R 5

(C6-Ci4)-aryl-R , (C6-C or heterocyclyl- R ⁵ ;

R ³ and R ⁴ are hydrogen; R ^a and R ^b are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and heterocyclyl;

R ⁵ is selected from hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -Ci ₄ )-aryl, NH-(C ₆ -Ci ₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, (CR ^c R ^d ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

R ^c and R ^d are independently selected from hydrogen, hydroxy, cyano, halogen, (Ci-Cs)- alkyl and halo(C ₁ -C ₈ )alkyl;

n is an integer selected from 0, 1, 2, 3, 4 or 5;

X ¹ is CR ⁶ ;

R ⁶ is hydrogen;

m is 1 ;

L is -C(0)NR ^g - or -NR ^g C(0)-;

R ^g is hydrogen;

A is

R ⁷ and R ⁹ are (C ₁ -C ₈ )-alkyl or

Q

R is hydrogen; or

R 8 and R 9 can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C3-Ci2)-cycloalkyl;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.

In an embodiment the present invention relates to a compound of formula I, wherein,

ring B is

X ² is selected from CR^T ¹ or NT ¹ ;

R ^J is hydrogen;

T ¹ is selected from hydrogen, C ₃ -C ₁₂ )-cycloalkyl or NR ^a R ^b ; 2 3

T and T at each occurrence are independently selected from hydrogen, (Ci-Cg)-alkyl, halo(Ci-Cg)aikyl and heterocyclyl;

R ¹ is hydrogen, (Ci-Cg)-alkyl or halo(Ci-Cg)alkyl;

2 5 5

R is halogen, (C6-Ci4)-aryl-R , (C6-Ci4)aryl-(Ci-Cg)-alkyl, heteroaryl-R or heterocyclyl- R ⁵ ;

R ³ and R ⁴ are hydrogen;

R ^a and R ^b are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and heterocyclyl;

R ⁵ is selected from hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -Ci ₄ )-aryl, NH-(C ₆ -Ci ₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, (CR ^c R ^d ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

R ^c and R ^d are independently selected from hydrogen, hydroxy, cyano, halogen, (Ci-Cg)- alkyl and halo(C ₁ -Cg)alkyl;

n is an integer selected from 0, 1, 2, 3, 4 or 5;

X ¹ is CR ⁶ ;

R ⁶ is hydrogen;

m is 1 ;

L is -C(0)NR ^g - or -NR ^g C(0)-;

R ^g is hydrogen;

A is

R ⁷ and R ⁹ are (d-Cg)-alkyl or halo(Ci-C ₈ )-alkyl;

Q

R is hydrogen; or

8 9

R and R can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C ₃ -C ₁₂ )-cycloalkyl;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.

In an embodiment the present invention relates to a compound of formula I, wherein,

ring B is

X ^z is S;

T is hydrogen, (Ci-Cg)-alkyl, halo(Ci-Cg)aikyl and heterocyclyl;

R ¹ is hydrogen, (Ci-Cg)-alkyl or halo(Ci-Cg)alkyl;

2 5 5

R is halogen, (C6-Ci4)-aryl-R , (C6-Ci4)aryl-(Ci-Cg)-alkyl, heteroaryl-R or heterocyclyl- R ⁵ ;

R ³ and R ⁴ are hydrogen;

R ^a and R ^b are independently selected from the group consisting of hydrogen, (Ci-Cg)-alkyl and heterocyclyl;

R ⁵ is selected from hydrogen, (CR ^c R ^d ) _n -(C ₆ -C ₁₄ )-aryl, 0-(C ₆ -C ₁₄ )-aryl-(C ₁ -C ₈ )-alkyl, 0-(C ₆ -Ci ₄ )-aryl, NH-(C ₆ -Ci ₄ )-aryl, (CR ^c R ^d ) _n -heteroaryl, O-heteroaryl, NH-heteroaryl, (CR ^c R ^d ) _n - heterocyclyl, O-heterocyclyl or NH-heterocyclyl;

R ^c and R ^d are independently selected from hydrogen, hydroxy, cyano, halogen, (Cj-Cg)- alkyl and halo(C ₁ -Cg)alkyl;

n is an integer selected from 0, 1, 2, 3, 4 or 5;

X ¹ is CR ⁶ ;

R ⁶ is hydrogen;

m is 1 ;

L is -C(0)NR ^g - or -NR ^g C(0)-;

R ^g is hydrogen;

A is

R ⁷ and R ⁹ are (C ₁ -Cg)-alkyl or halo(CrCg)-alkyl;

Q

R is hydrogen; or

8 9

R and R can together form a 3-12 membered cyclic ring; wherein the said cyclic ring is (C3-Ci2)-cycloalkyl;

or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof. Representative compounds of formula I encompassed in accordance with the present invention include:

4-Bromo-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -ethyl-7-methyl- 1H- indole-6-carboxamide;

4-Bromo- 1 -ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)- lH-indole-6-carboxamide;

N-((4,6-Dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -ethyl-7-methyl-4-(4- (morpholinomethyl)phenyl)- 1 H-indole-6-carboxamide ;

N-((4,6-Dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l-ethyl-3,7-dimethyl-4-(4- (mo holinomethyl)phenyl)- 1 H-indole-6-carboxamide ;

1 -Ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

N-((4,6-Dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -ethyl-7-methyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

1 -Ethyl-7-methyl-N-((6-methyl-2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3- yl)methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-ind ole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6-

(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxa rnide;

N-((4,6-Dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -isopropyl-7-methyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l ,2-dihydropyridin-3-yl)methyl)-4-(6-(4- methylpiperazin- l-yl)pyridin-3-yl)- 1 -propyl- 1 H-indole-6-carboxamide;

1 ,7-Dimethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

1 -Isobutyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6-

(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxa rnide;

N-((4,6-Dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l-ethyl-3,7-dimethyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

l-Ethyl-7-methyl-N-((l-methyl-3-oxo-2,3, 5,6,7, 8-hexahydroisoquinolin-4-yl)methyl)-4- (6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl)- 1 H-indole-6-carboxamide ;

l-Ethyl-7-methyl-N-((l-methyl-3-oxo-3,5,6,7-tetrahydro-2H -cyclopenta[c]pyridin-4- yl)methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-ind ole-6-carboxamide; l-Isopropyl-7-methyl-N-((l-methyl-3-oxo-2,3, 5,6,7, 8-hexahydroisoquinolin-4-yl)methyl)- 4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)- 1 H-indole-6-carboxamide ;

l,7-Dimethyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoq uinolin-4-yl)methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

l-Isobutyl-7-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahy droisoquinolin-4-yl)methyl)- 4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)- 1 H-indole-6-carboxamide ;

1 -Ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6- mo holinopyridin-3-yl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6- mo holinopyridin-3-yl)- lH-indole-6-carboxamide;

N-((4,6-Dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -ethyl-7-methyl-4-(4- (morpholinomethyl)phenyl)indoline-6-carboxamide;

4-Bromo- 1 -ethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)- 1H- indole-6-carboxamide;

1 -Ethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6-(4-methyl piperazin- 1 -yl)pyridin-3-yl)- 1 H-indole-6-carboxamide ;

4-Bromo-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-7-methyl- lH-indole-6- carboxamide;

4-Bromo-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-7-methyl indoline-6- carboxamide;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(6-(4-methyl piperazin- 1 -yl)pyridin-3-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-indole-6- carboxamide;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-l-((tetrahydro-2H-pyran-4 -yl)methyl)-lH-indole-6- carboxamide;

4-Bromo- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydro pyridin-3-yl) methyl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4- (pyrido[2,3-b]pyrazin-7-yl)-lH-indole-6-carboxamide; 4-(2-(Benzyloxy)-5-chloropyridin-3-yl)-l-isopropyl-7-methyl- N-((6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxami de;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (2-mo holinopyridin-3-yl)-lH-indole-6-carboxamide;

tert-Butyl 4-(5-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydro pyridin-

3- yl)methyl)carbamoyl)-lH-indol-4-yl)pyridin-2-yl)piperazine-l -carboxylate;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (6-(piperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide;

4- (2-Fluoro- [1,1 '-biphenyl] -4-yl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)- 1 H-indole-6-carboxamide ;

4-(4-Cyclohexylphenyl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

4-(4-(l,l, l,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)-l-isopropyl- 7-methyl-N-((6- methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-lH-ind ole-6-carboxamide;

4-(3,5-Dimethylisoxazol-4-yl)-l-isopropyl-7-methyl-N-((6- methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

4-(3,5-Dimethyl-lH-pyrazol-4-yl)-l-isopropyl-7-methyl-N-((6- methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (naphthalen- 1 -yl)- 1 H-indole-6-carboxamide ;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4-

(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-lH-indole-6-car boxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4-

(5,6,7,8-tetrahydronaphthalen-2-yl)-lH-indole-6-carboxami de;

4-(3-Fluoro- [1,1 '-biphenyl] -4-yl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

4-(4-(5-Amino-l,3,4-thiadiazol-2-yl)phenyl)-l-isopropyl-7-me thyl-N-((6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxami de;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)- lH,l'H-[4,5'-biindole]-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)- 1 H, ΓΗ- [4,4'-biindole] -6-carboxamide ; 1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-lH-indole-6-c arboxamide;

4-( 1 H-Indazol-4-yl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl)- 1 H-indole-6-carboxamide ;

4-(2,4-Dimethoxypyrimidin-5-yl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(et hyl(tetrahydro-2H-pyran-4- yl)amino)-5-(3-fluorooxetan-3-yl)-2-methylbenzamide;

l-Isopropyl-7-methyl-4-(4-(5-methyl-l,3,4-oxadiazol-2-yl) phenyl)-N-((6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxami de;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4-

(2-(4-methylpiperazin- 1 -yl)pyridin-4-yl)- 1 H-indole-6-carboxamide ;

4-(3-Fluoro-4-morpholinophenyl)- 1 -isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

tert-Butyl 4-(3-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydro pyridin- 3-yl)methyl)carbamoyl)-lH-indol-4-yl)pyridin-2-yl)piperazine -l-carboxylate;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (2-(4-methylpiperazin-l-yl)pyrimidin-5-yl)-lH-indole-6-carbo xamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (2-methyl-2H-indazol-6-yl)-lH-indole-6-carboxamide;

teri-Butyl 4-(5-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydro pyridin- 3-yl)methyl)carbamoyl)-lH-indol-4-yl)-3-methylpyridin-2-yl) piperazine-l-carboxylate; 4-(4-Acetyl-3-fluorophenyl)-l-isopropyl-7-methyl-N-((6-methy l-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (5-methyl-6-mo holinopyridin-3-yl)-lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(6- (piperidin- 1 -yl)pyridin-3-yl)- lH-indole-6-carboxamide;

1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-4- (quinolin-3-yl)-lH-indole-6-carboxamide; 1 -Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-4-(5- (piperidin- 1 -ylmethyl)thiophen-2-yl)- 1 H-indole-6-carboxamide;

4-Bromo- 1 -cyclopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydro pyridin-3- yl)methyl)-lH-indole-6-carboxamide;

1 -Cyclopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)- 4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)- 1 H-indole-6-carboxamide ;

4-Bromo-7-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)- 1 - (2,2,2-trifluoroethyl)-lH-indole-6-carboxamide;

4-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-7-methyl-l-(2,2,2- trifluoroethyl)- 1 H-indole-6-carboxamide ;

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)- lH-indole-6-carboxamide; 7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(6- mo holinopyridin-3-yl)- 1 -(2,2,2-trifluoroethyl)- 1 H-indole-6-carboxamide;

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3 -yl)methyl)-4-(l-(2- mo holinoethyl)-lH-pyrazol-4-yl)-l-(2,2,2-trifluoroethyl)-lH-in dole-6-carboxamide; 7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(4- mo holinophenyl)- 1 -(2,2,2-trifluoroethyl)- 1 H-indole-6-carboxamide ;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7- methyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)- lH-indole-6-carboxamide; N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(4- (morpholinomethyl)phenyl)-l-(2,2,2-trifluoroethyl)-lH-indole -6-carboxamide;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7- methyl-4-(6- mo holinopyridin-3-yl)- 1 -(2,2,2-trifluoroethyl)- 1 H-indole-6-carboxamide;

N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7- methyl-4-(l-(2- moφholinoethyl)-lH-pyrazol-4-yl)-l-(2,2,2-trifluoroethyl)-l H-indole-6-carboxamide; N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(4- moφholinophenyl)- 1 -(2,2,2-trifluoroethyl)- 1 H-indole-6-carboxamide ;

7-Bromo-3-(dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-m ethyl-2-oxo-4- propylpyridin-3-yl)methyl)-4-methyl-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl)methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-y l)-lH-indene-5- carboxamide; 3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl)methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-y l)-lH-indene-5- carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl)methyl)-4-methyl-7-(2-(4-methylpiperazin-l-yl)pyrimidin-5 -yl)-lH-indene-5- carboxamide;

3-(Dimethylamino)-2, 3-dihydro-N-((l ,2-dihydro-6-methyl-2-oxo-4-propyl pyridin-3- yl)methyl)-4-methyl-7-(6-mo holinopyridin-3-yl)-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2- oxo-4-propyl pyridin-3- yl)methyl)-4-methyl-7-(4-(mo holinomethyl)phenyl)-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl)methyl)-4-methyl-7-(4-(l-mo holinoethyl)phenyl)-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2- oxo-4-propyl pyridin-3- yl)methyl)-4-methyl-7-(4-( 1 -(piperidin- 1 -yl)ethyl)phenyl)- 1 H-indene-5-carboxamide ; 7-Bromo-3-(dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-di methyl-2-oxopyridin-3- yl)methyl)-4-methyl-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-dimethyl-2 -oxo pyridin-3- yl)methyl)-4-methyl-7-(4-(mo holinomethyl)phenyl)-lH-indene-5-carboxamide;

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-dimethy l-2-oxo pyridin-3- yl)methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-y l)-lH-indene-5- carboxamide;

3-(N-Ethyl-N-(tetrahydro-2H-pyran-4-yl)amino)-7-bromo-2,3-di hydro-N-((l,2-dihydro-6- methyl-2-oxo-4^ropylpyridin-3-yl)methyl)-4-methyl-lH-indene- 5-carboxamide;

3-(N-Ethyl-N-(tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydro -N-((l,2-dihydro-6-methyl-2- oxo-4-propylpyridin-3-yl)methyl)-4-methyl-7-(6-(4-methyl piperazin- 1 -yl)pyridin-3-yl)- 1 H-indene-5 -carboxamide ;

7-Bromo-2-isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydro pyridin-3- yl)methyl)benzo[d]thiazole-5-carboxamide;

7-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-2-isopropyl-4- methylbenzo[d]thiazole-5-carboxamide;

7-Bromo-2,4-dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3- yl)methyl)benzo[d]thiazole-5-carboxamide; 7-Bromo-2-(tert-butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3- yl)methyl)benzo[d]thiazole-5-carboxamide;

7-Bromo-4-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-2- neopentylbenzo[d]thiazole-5-carboxamide;

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-7-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5-carb oxamide;

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)-7-(4- (morpholinomethyl)phenyl)benzo [d] thiazole- 5 -carboxamide ;

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)-7-(4- morpholinophenyl)benzo [d] thiazole-5 -carboxamide ;

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)-7-(6- mo holinopyridin-3-yl)benzo[d]thiazole-5-carboxamide;

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)-7-(l-

(2-mo holinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5-carboxamide;

N-((4,6-Dimemyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-i sopropyl-4-methyl-7-(6-(4- methylpiperazin- 1 -yl)pyridin-3 -yl)benzo [d] thiazole- 5 -carboxamide ;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(6-(4- methylpiperazin- 1 -yl)pyridin-3 -yl)benzo [d] thiazole- 5 -carboxamide ;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(6-(4- methylpiperazin- 1 -yl)pyridin-3 -yl)benzo [d] thiazole- 5 -carboxamide ;

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(l-(2- mo holinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5-carboxamide;

7-Bromo-2-isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8- hexahydro isoquinolin-4- yl)methyl)benzo[d]thiazole-5-carboxamide;

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexah ydro isoquinolin-4-yl) methyl)-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]th iazole-5-carboxamide;

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexah ydro isoquinolin-4-yl) methyl)-7-(4-(mo holinomethyl)phenyl)benzo[d]thiazole-5-carboxamide;

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydr o isoquinolin-4-yl) methyl)-7-( 1 -(2-rrH^holinoethyl)- 1 H-pyrazol-4-yl)benzo[d] thiazole-5-carboxamide ;

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyrid in-3-yl) methyl)-7-(6-(4- methylpiperazin- 1 -yl)pyridin-3 -yl)benzo [d] thiazole- 5 -carboxamide ; 2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-7-(4- (morpholinomethyl)phenyl)benzo [d] thiazole- 5 -carboxamide ;

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-7-(6- mo holinopyridin-3-yl)benzo[d]thiazole-5-carboxamide;

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyrid in-3-yl) methyl)-7-(l-(2- mo holinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5-carboxamide;

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-d ihydropyridin-3-yl)methyl)-7- (6-(4-methylpiperazin- 1 -yl)pyridin-3 -yl)benzo[d] thiazole-5-carboxamide ;

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-d ihydropyridin-3-yl)methyl)-7- (4-(morpholinomethyl)phenyl)benzo[d]thiazole-5-carboxamide;

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)-7- (6-mo holinopyridin-3-yl)benzo[d]thiazole-5-carboxamide;

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl) methyl)-7-

(4-(l-(piperidin-l-yl)emyl)phenyl)benzo[d]miazole-5-carbo xamide;

4-Methyl-N-((6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl)-7-(6-(4-methyl piperazin-l-yl)pyridin-3-yl)-2-neopentylbenzo[d]thiazole-5-c arboxamide;

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(4-

(mo holino methyl)phenyl)-2-neopentylbenzo[d]thiazole-5-carboxamide;

4-Methyl-N-((6-methyl-2-oxo-4 ropyl-l,2-dihydropyridin-3-yl)methyl)-7-(6-moφholino pyridin-3-yl)-2-neopentylbenzo[d]thiazole-5-carboxamide;

7-Bromo-4-methyl-N-((6-methyl-2-oxo-4 ropyl- 1 ,2-dihydropyridin-3-yl) methyl)-2-

(tetrahydro-2H yran-4-yl)benzo[d]thiazole-5-carboxamide;

4-Methyl-N-((6-methyl-2-oxo-4 ropyl-l,2-dihydropyridin-3-yl)methyl)-7-(6-(4-methyl piperazin- 1 -yl)pyridin-3-yl)-2-(tetrahydro-2^pyran-4-yl)benzo[d] thiazole-5- carboxamide;

4-Methyl-N-((6-methyl-2-oxo-4 ropyl-l,2-dihydropyridin-3-yl)methyl)-7-(4- (moφholino methyl)phenyl)-2-(tetrahydro-2H yran-4-yl)benzo[d]thiazole-5- carboxamide; and

4-Methyl-N-((6-methyl-2-oxo-4 ropyl-l,2-dihydropyridin-3-yl)methyl)-7-(6-moφholino pyridin-3-yl)-2-(tetrahydro-2H yran-4-yl)benzo[d]thiazole-5-carboxamide;

or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof. The compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, solvates, prodrugs, N-oxides, S-oxides and polymorphs.

According to another aspect of the present invention, there are provided processes for the preparation of the compound(s) of formula I.

Thus, the compound(s) of formula I can be prepared by various methods including using methods well known to a person skilled in the art. Examples of processes for the preparation of a compound of formula I are described below and illustrated in the following scheme but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.

The reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references.

In the following scheme and the description of the processes for the synthesis of the compound(s) of formula I, the starting compounds and the intermediates used for the synthesis of the compounds of the present invention, are designated as compounds A, B, C, D, E, F and G, for ease of reference. Unless stated otherwise, throughout the process description, the corresponding substituent groups in the various formulae representing starting compounds and intermediates have the same meanings as that for the compound(s) of formula I as indicated in one or more embodiments described above. In one or more schemes illustrating process (es) for the preparation of the compounds of Formula I, the process steps are referred to by general symbols namely a, b, c, d, e, f, g, h and i for ease of reference.

Scheme 1 depicts a process for the preparation of the compound of formula I, wherein R ¹ , R ² , R ³ , R ⁴ , T ¹ , T ² , T ³ , X ¹ , A and m are as defined above, L is CONR ^g and X ² is NT ¹ .

Scheme 1

Reaction step (a): Preparation of the compound of formula B The compound of formula A (wherein X is bromine; X and R are as defined above) is reacted with methyl iodide and sodium carbonate in a solvent such as N,N- dimethylformamide (DMF) at a temperature range of 45-75 °C for 8-12 hours to obtain the following compound of formula B (wherein X is bromine; X ¹ and R ¹ are as defined above).

Reaction step (b): Preparation of the compound of formula C

The compound of formula B obtained in the reaction step (a), is reacted with a reagent A,

reagent A

(wherein T 2 and T 3 are as defined herein above)

and aqueous ammonium chloride (NH ₄ CI), at the temperature range of -35 °C to -50 °C in the presence of a solvent such as tetrahydrofuran (THF) for 30 minutes to obtain the

following compound of formula C (wherein X is bromine, ring B is X s defined above).

Reaction step (c): Preparation of the co . is NH, L is CONR ^g ; X ¹ , R ¹ , T ² and T ³ are a

mpound of formula D

The compound of formula C obtained in reaction step (b) is reacted with T ^J -Y

(wherein Y is I or Br and T ¹ is as defined above), in the presence of a base such as sodium hydride in a solvent such as DMF at a temperature range of 55-75 °C for 4-6 hours to obtain the following compound of formula D (wherein X is bromine, ring B is X ² is NT ¹ ; X ¹ , R ¹ , T ¹ , T ² and T ³ are as defined above).

Reaction step (d): Preparation of the compound of formula E

The compound of formula D obtained in the reaction step (c) is reacted with an alkaline base such as lithium hydroxide (LiOH), sodium hydroxide (NaOH) or potassium hydroxide (KOH) in a solvent such as a mixture of methanol and THF at room temperature (20-35 °C) for 12-18 hours, to obtain the following compound of formula E (wherein X is bromine, ring B is X 2" is NT 1 ¹ ; X1 ¹ , R1 , T1 , T2 and T 3 ^J are as defined above).

Reaction step (f): Preparation of the compound of formula F

The compound of formula D obtained in the reaction step (c) is coupled with the reagent D,

reagent D

(wherein R is as defined herein above),

in the presence of l,l'-Bis(diphenylphosphino)ferrocene palladium-dichloromethane adduct and a base such as sodium carbonate in a solvent such as a mixture of dioxane and water at a temperature of 50- °C for 0.5-4 hours to obtain the following compound of

Formula F (wherein ring B is , X ² is NT ¹ ; X ¹ , R ¹ , R ² , T ¹ , T ² and T ³ are as defined above).

Reaction step (g): Preparation of the compound of formula G

The compound of formula F obtained in reaction step (f) is reacted with an alkaline base such as LiOH, NaOH or KOH in a solvent such as a mixture of methanol and THF at room temperature (20-35 °C) for 12-18 hours, to obtain the following compound of

formula G (wherein ring B X ² is NT ¹ ; X ¹ , R ¹ , R ² , T ¹ , T ² and T ³ are as defined above).

Reaction step (h): Preparation of the compound of formula I

The compound of formula G obtained in reaction step (g) is reacted with an amine or an amine salt represented by the following formulae,

(wherein A, R ³ , R ⁴ , R ^g and m are as defined herein above)

in the presence of a base selected from triethylamine (TEA), NaOH or KOH and a coupling reagent, 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), in a solvent such as DMF at a temperature range of 25-80 °C for 4-6 hours to obtain the following compound of formula I (wherein ring B is X ² is NT ¹ , L is CONR ^g ; X ¹ , A, R ¹ , R ² , R ³ , R ⁴ , T ¹ , T ² , T ³ , R ^g and m are as defined above).

Reaction step (e): Preparation of the compound of formula I

The compound of formula E obtained in the reaction step (d) is reacted with an amine or an amine salt represented by the following formulae,

(wherein A, R ³ , R ⁴ , R ^g and m are as defined herein above)

in the presence of a base selected from TEA, NaOH or KOH and a coupling reagent, HATU, in a solvent such as DMF at a temperature °C for 4-6 hours to

obtain the compound of Formula I (wherein ring B is R 2 is bromine, X 2 is

NT ¹ , L is CONR ^g ; X ¹ , A, R ¹ , R ³ , R ⁴ , T ¹ , T ² , T ³ , R ^g and m are as defined herein above). Reaction step (i): Preparation of the compound of formula I

The compound of formula I (obtained in reaction step (e) and step (h)) in acetic acid, is reacted with sodium cyanoborohydride at room temperature (20-35 °C) for 5-12

is CONR ^g ; A, X ¹ , R ¹ , R ² , R ³ , R ⁴ , T ¹ , T ² , T ³ , R ^g and m are as defined herein above).

The compounds of formula I, can be converted into their pharmaceutically acceptable salts.

Scheme 2

Reaction step (a): Preparation of the compound of formula B

The compound of formula A (wherein X is bromine; X ¹ and R ¹ are as defined above)

is reacted with methyl iodide and sodium carbonate in a solvent such as N,N- dimethylformamide (DMF) at a temperature range of 45-75 °C for 8-12 hours to obtain the following compound of formula B (wherein X is bromine; X ¹ and R ¹ are as defined above). Reaction step (b): Preparation of the compound of formula H

The compound of formula B obtained in the reaction step (a), is reacted with iron powder in the presence of ammonium chloride under reflux condition in a mixture of solvent such as ethanol, THF and water to obtain the compound of formula H (wherein X is bromine; X ¹ and R are as defined above).

Reaction step (c): Preparation of the compound of formula J

The compound of formula H obtained in reaction step (b) is reacted with acyl

2 2

choride of formula T -COC1 (wherein T is as defined above), in the presence of a base such as TEA, DIPEA in a solvent such as THF at a temperature range of 25-30 °C for 2-4 hours to obtain the compound of formula J (wherein X is bromine; X 1 , R1 and T 2 are as defined above).

Reaction step (d): Preparation of the compound of formula K

The compound of formula J obtained in the reaction step (c) is reacted with 2,4-

Bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dith ione (Lawessons's reagent) in a solvent such as 1,4-dioxane under reflux for 2-4 hours, to obtain the compound of formula K (wherein X is bromine; X 1 , R1 and T 2 are as defined above).

Reaction step (e): Preparation of the compound of formula L

The compound of formula K obtained in the reaction step (d) is reacted with the reagent potassium ferricyanide in presence of base such as LiOH, NaOH or KOH solution at a temperature range of 25-30 °C for 2-4 hours to obtain the compound of formula L

(wherein X is bromine; ring B is , X is S, X , R and T are as defined above).

Reaction step (f): Preparation of the compound of formula I

The compound of formula L obtained in reaction step (e) is reacted with an amine or an amine salt represented by the following formulae,

(wherein A, R ³ , R ⁴ , R ^g and m are as defined herein above) in the presence of a base selected from triethylamine (TEA), NaOH or KOH and a coupling reagent, 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), in a solvent such as DMF at a temperature range of 25-80 ° -6 hours to obtain the following compound of formula I (wherein ring B is , X ² is S, R ² is Br, L is CONR ^g ; X ¹ , A, R ¹ , R ³ , R ⁴ , T ² , R ^g and m are as defined above).

Reaction step (g): Preparation of the compound of formula I

The compound of formula I obtained in the reaction step (f) is coupled with the reagent D, (as defined in step (f) of scheme 1) in the presence of 1,1'- bis(diphenylphosphino) ferrocene palladium-dichloromethane adduct and a base such as sodium carbonate in a solvent such as a mixture of dioxane and water at a temperature of 50-90 °C for 0.5-4 hours to obtain the compound of formula (I).

The compounds of formula I, can be converted into their pharmaceutically acceptable salts.

Scheme 3

I I Reaction step (a): Preparation of the compound of formula 3B

The compound of formula 3A (wherein X ¹ and R ¹ are as defined above) is reacted with ethyl iodide and sodium carbonate in a solvent such as N,N-dimethylformamide (DMF) at a temperature range of 45-75 °C for 8-16 hours to obtain the following compound of formula B (wherein X ¹ and R ¹ are as defined above).

Reaction step (b): Preparation of the compound of formula 3C

The compound of formula 3B obtained in the reaction step (a), is reacted with ethyl acrylate powder in the presence of a base such as potassium carbonate and catalyst palladium (II) acetate and N,N-dimethylaniline in solvents such as N-methyl-2- pyrrolidinone at a temperature range of 120-130 °C for 14-18 hours to obtain the compound of formula 3C (wherein X ¹ and R ¹ are as defined above).

Reaction step (c): Preparation of the compound of formula 3D

The compound of formula 3C obtained in the reaction step (b) is hydrogenated using palladium carbon in a solvent such as ethanol for 2-3 hours to obtain the compound of formula 3D (wherein X ¹ and R ¹ are as defined above).

Reaction step (d): Preparation of the compound of formula 3E

The compound of formula 3D obtained in the reaction step (c) is hydrolysed using sodium hydroxide in a solvent such as THF and methanol to obtain the compound of formula 3E (wherein X ¹ and R ¹ are as defined above).

Reaction step (e): Preparation of the compound of formula 3F

The compound of formula 3E obtained in the reaction step (d) is reacted with sodium chloride and aluminium chloride at a temperature range of 180-190 °C for 1-2 hours to obtain the compound of formula 3F (wherein X ¹ and R ¹ are as defined above). Reaction step (f): Preparation of the compound of formula 3G

The compound of formula 3F obtained in reaction step (e) is reacted with sulfuric acid in methanol under reflux for 6-9 hours to obtain the compound of formula 3G (wherein X ¹ and R ¹ are as defined above).

Reaction step (g): Preparation of the compound of formula 3H

The compound of formula 3G obtained in reaction step (f) is reacted with 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione in sulfuric acid at a temperature range of 25-30 °C for 1-2 to obtain the compound of formula 3H (wherein X ¹ and R ¹ are as defined above).

Reaction step (h): Preparation of the compound of formula 31 The compound of formula 3H obtained in reaction step (g) is reacted with hydroxylamine hydrochloride in a solvent such as methanol for 4-6 hours to obtain the compound of formula 31 (wherein X ¹ and R ¹ are as defined above).

Reaction step (i): Preparation of the compound of formula 3 J

The compound of formula 31 obtained in reaction step (h) is reacted with hydrochloric acid and zinc at a temperature range of 65-75 °C for 4-6 hours to obtain the compound of formula 3J (wherein X ¹ and R ¹ are as defined above).

Reaction step (j): Preparation of the compound of formula 3K

The compound of formula 3J obtained in reaction step (i) is reacted with sodium hydride and methyl iodide in a solvent such as THF for 2-4 hours to obtain the compound of formula 3K (wherein X ¹ and R ¹ are as defined above).

Reaction step (k): Preparation of the compound of formula 3L

The compound of formula 3K obtained in reaction step (j) is reacted with sodium hydroxide in a solvent such as THF at a temperature range of for 2-4 hours to obtain the compound of formula 3L (wherein X ¹ and R ¹ are as defined above).

Reaction step (1): Preparation of the compound of formula I

The compound of formula 3L obtained in reaction step (e) is reacted with an amine or an amine salt represented by the following formulae,

(wherein A, R ³ , R ⁴ , R ^g and m are as defined herein above)

in the presence of a base selected from triethylamine (TEA), NaOH or KOH and a coupling reagent, 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), in a solvent such as DMF at a temperature range of 25-80 ° urs to obtain the following compound of formula I (wherein ring B is , X ² is CR ^j T ^J ; R ^j is hydrogen; T ¹ is NR ^a R ^b ; T ² and T ³ are hydrogen; " " represents no bond, R ^a and R ^b are methyl; R ² is Br; L is CONR ^g ; X ¹ , A, R ¹ , R ³ , R ⁴ , R ^g and m are as defined above).

Reaction step (j): Preparation of the compound of formula I The compound of formula I obtained in the reaction step (i) is coupled with the reagent D, (as defined in step (f) of scheme 1) in the presence of 1,1'- bis(diphenylphosphino) ferrocene palladium-dichloromethane adduct and a base such as sodium carbonate in a solvent such as a mixture of dioxane and water at a temperature of 50-90 °C for 0.5-4 hours to obtain the compound of formula (I).

The compounds of formula I, can be converted into their pharmaceutically acceptable salts.

The present invention also includes within its scope the pharmaceutically acceptable salts of the compounds of formula I.

The term "pharmaceutically acceptable salts" as used herein refers to organic and inorganic salts of a compound of the present invention (the compounds of formula I), depending on the particular group (acidic or basic group) present in the said compounds. When compounds of the present invention contain relatively acidic groups, base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or organic base salt. Examples of pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like.

When compounds of the present invention contain relatively basic groups, acid addition salts can be obtained by contacting the compound of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydroiodic acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The compound of formula I may be regenerated from their corresponding salts by contacting the said salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner. The corresponding salts of the compounds differ from their parent compounds with respect to certain physical properties, for example solubility.

The present invention also encompasses within its scope the solvates of the compounds of Formula I.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Various polymorphs of the compounds of formula I can be prepared by crystallization of the compounds under different conditions. The different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs can be determined by infra-red (IR) spectroscopy, solid probe nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

Those skilled in the art will recognize that stereocenters exist in the compound(s) of formula I. Accordingly, the present invention includes all possible stereoisomers and geometric isomers of the compound of formula I and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula I is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).

Additionally, in situations wherein tautomers of the compound of formula I are possible, the present invention is intended to include all tautomeric forms of the compounds.

The present invention also encompasses within its scope prodrugs of the compound(s) of formula I. Preferably, prodrugs are those compounds that are converted intracellularly, more preferably, where the cellular converting location is the site of therapeutic action. For instance, preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid. Examples of pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like esters which are conventionally known in the art. (An introduction to Medicinal Chemistry, Graham L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).

In another further aspect, the present invention relates to pharmaceutical compositions that contain a therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable carrier. The present invention also relates to a process for the production of the pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable excipient or a carrier and, if appropriate, further suitable a pharmaceutically acceptable carriers, additives or auxiliaries. The pharmaceutical compositions containing the compounds of Formula I according to the invention are prepared in a manner known to one skilled in the art.

The pharmaceutical compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.

For the production of oral dosages form of the compounds of Formula I such as the pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc. Pharmaceutically acceptable carriers that can be used for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc. Suitable pharmaceutically acceptable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the said solvents.

The pharmaceutical compositions normally contain about 1 to 99 , for example, about 5 to 70 , or from about 10 to about 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt. The amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical compositions normally is from about 5 to 500 mg or may be lower than or higher than the lower and the upper limit respectively. The dose of the compound of formula I, which is to be administered, can cover a wide range depending on the type of disease or disorder to be treated. The dose to be administered daily is to be selected to suit the desired effect. A suitable dosage is about 0.01 to 100 mg/kg of the compound of formula I or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, about 0.1 to 50 mg/kg/day of a compound of formula I or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.

The selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention, or its salt employed, the route of administration, the time of administration, the rate of excretion of the particular compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.

In addition to the compound of formula I or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier substances, the pharmaceutical compositions of the present invention can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain more than one compound of formula I or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula I or its pharmaceutically acceptable salt, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active agents.

The present invention also encompasses within its scope the use of a compound of formula I or its pharmaceutically acceptable salt in combination, with other therapeutically active agents; wherein the compound of formula I and the further therapeutic agent are administered either simultaneously or sequentially.

The therapeutically active agents used in combination with one or more compounds of formula I or its pharmaceutically acceptable salt can be selected from anti- neoplastic agents or chemotherapeutic compounds such as anti-microtubule agents (diterpenoids (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine, vinorelbine)); platinum coordination complexes (cisplatin, carboplatin), alkylating agents (nitrogen mustards (oxazaphosphorines, cyclophosphamide, melphalan, chlorambucil)); alkyl sulfonates (busulfan); nitrosoureas (carmustine); triazenes (dacarbazine); topoisomerase I inhibitors (camptothecins (irinotecan, topotecan)); topoisomerase II inhibitors (epipodophyllotoxins (etoposide, teniposide)); antimetabolite neoplastic agents (fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, gemcitabine); hormones and hormonal analogues (retinoids, histone deacetylase inhibitors); DNA methyltransferase inhibitors (azacitidine, decitabine); non-receptor tyrosine kinase angiogenesis inhibitors (endostatin, angiostatin); antibiotics (daunorubicin, doxorubicin, bleomycin); inhibitors of growth factor receptors (VEGFR inhibitors (pazopanib, ZD6474 (vandetanib, AstraZeneca), AZD2171 (cediranib, Astrazeneca), vatalanib, sunitinib and sorafenib), trastuzumab, cetuximab, bevacizumab, lapatinib, erlotinib, imatinib mesylate) or cell cycle signaling inhibitors (CDK inhibitors (ABT-751 (Eisai), veliparib)).

In one aspect, the present invention relates to a method for the treatment of a disease or a disorder mediated by EZH2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof; for the treatment of a disease or a disorder mediated by EZH2.

In yet another aspect, the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by EZH2.

In an embodiment, the disease or disorder mediated by EZH2 is selected from cancer, pulmonary arterial hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host diseases (GVHD), Weaver Syndrome, psoriasis vulgaris or liver fibrogenesis. In an embodiment of the present invention, the disease or disorder mediated by EZH2 is cancer. Cancers also include metastatic or malignant tumors.

In an embodiment, cancers that can be treated by the compound of formula I of the invention or pharmaceutical compositions containing the said compounds; are selected from: thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.

According to an embodiment of the present invention, the cancer is cardiac sarcoma selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, rhabdomyoma, fibroma, lipoma or teratoma.

According to another embodiment of the present invention, the cancer is lung carcinoma selected from squamous cell carcinoma, undifferentiated small or large cell carcinoma, adenocarcinoma, bronchiolar carcinoma, bronchial adenoma, bronchial sarcoma or bronchial lymphoma.

According to yet another embodiment of the present invention, the cancer is gastrointestinal carcinoma selected from stomach carcinoma, stomach lymphoma, pancreatic carcinoma (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma), small bowel carcinoma (adenocarcinoma, lymphoma, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma) or large bowel carcinoma (adenocarcinoma, tubular adenoma).

According to another embodiment of the present invention, the cancer is genitourinary tract carcinoma selected from carcinoma of kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), malignant rhabdoid tumor of kidney, carcinoma of bladder and urethra (squamous cell carcinoma, adenocarcinoma), carcinoma of prostate (adenocarcinoma, sarcoma), or carcinoma of testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, lipoma).

According to yet another embodiment of the present invention, the cancer is liver carcinoma selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma or hepatocellular adenoma. According to yet another embodiment of the present invention, the cancer is bone sarcoma selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumors.

According to another embodiment of the present invention, the cancer is an oral cancer selected from tongue cancer, squamous cell carcinoma, Kaposi's sarcoma, teratoma, adenocarcinoma derived from a major or minor salivary gland, lymphoma from tonsillar or other lymphoid tissue, or melanoma from the pigment-producing cells of the oral mucosa.

According to another embodiment of the present invention, the cancer is sarcoma of the nervous system selected from sarcoma of skull (osteoma, granuloma, xanthoma), meninges (meningioma, meningiosarcoma, gliomatosis), sarcoma of brain (astrocytoma, medulloblastoma, glioma, glioblastoma multiform, oligodendroglioma, retinoblastoma, congenital tumors), sarcoma of spinal cord (neurofibroma, meningioma, glioma, sarcoma) or malignant rhabdoid tumor of brain.

According to yet another further embodiment of the present invention, the cancer is carcinoma of gynaecological organs selected from carcinoma of uterus (endometrial carcinoma), carcinoma of cervix (cervical carcinoma, ovary carcinoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, embryonal rhabdomyosarcoma) or carcinoma of fallopian tubes.

According to another embodiment of the present invention, the cancer is haematological cancer selected from blood cancer (acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, B- cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (Hodgkin's disease), non-Hodgkin's lymphoma (malignant lymphoma) or mantle cell lymphoma.

According to another embodiment of the present invention, the cancer is a skin cancer selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, angioma or dermatofibroma. It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention. The following abbreviations or terms are used herein:

CDCh : Deuterated chloroform

DMF : N,N-Dimethylformamide

DMSO : Dimethylsulfoxide

HATU : 2-(7- Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-teti-amethyluronium

hexafluorophosphate)

HC1 : Hydrochloric acid

LiOH : Lithium hydroxide

MeOH : Methanol

Na2C(¾ : Sodium carbonate

NaHCC>3 : Sodium bicarbonate

NaOH : Sodium hydroxide

NH4CI : Ammonium chloride

TEA : Triethylamine

THF : Tetrahydrofuran

g : Gram

kg : Kilogram

mg : Milligram

mL : Millilitre

μL· : Microlitre

μΜ : Micromolar

mmol : Millimolar

M : Molar

mol : Mole

ng : Nanogram

nM : Nanomolar

°C : Degree Centigrade

MS : Mass spectroscopy Preparation of Intermediate compounds

Intermediate 1-1: Methyl 5-bromo-2-methyl-3-nitrobenzoate

To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (10 g, 38.5 mmol) in DMF (100 mL) were added sodium carbonate (16.30 g, 154 mmol) and methyl iodide (9.62 mL, 154 mmol) at room temperature and the reaction mixture was stirred at 55 °C for 10 hours. On completion, the reaction mixture was filtered and the inorganic solid residue was washed with ethyl acetate. The filtrate was concentrated under vacuum till dry and re- dissolved in ethyl acetate before washing with 5 % sodium bicarbonate solution (70 mL) followed by 5.0 M HC1 solution (30 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to yield 10 g (95%) of the title compound. ^J H NMR (CDC1 ₃ , 300 MHz) δ ppm: 8.12 (d, J= 1.8 Hz, 1H), 7.98 (d, J= 2.1 Hz, 1H), 3.94 (s, 3H), 2.56 (s, 3H). MS (ESI+): 275.9 (M+H) ⁺ .

Intermediate 1-2: Methyl 4-bromo-7-methyl-lH-indole-6-carboxylate

To a solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (Intermediate 1-1, 12 g, 43.8 mmol) in dry THF (120 mL) was added vinyl magnesium bromide (175 mL, 175 mmol) at -40 °C and stirred at the same temperature for 30 minutes. Aqueous NH4CI solution was added at the same temperature and then, the temperature was raised to room temperature. The reaction mixture was extracted with ethyl acetate, concentrated and purified by column chromatography using 1-10 % ethyl acetate in petroleum ether to yield 4.0 g (34 %) of the title compound. ^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 11.88 (s, 1H), 7.69 (s, 1H), 7.66 (t, J= 2.4 Hz, 1H), 6.46 (s, 1H), 3.81 (s, 3H), 2.70 (s, 3H). MS (ESI-): 265.8 [M-H] ⁺ .

Intermediate 1-3: Methyl 4-bromo-l-ethyl-7-methyl-lH-indole-6-carboxylate

To a solution of methyl 4-bromo-7-methyl-lH-indole-6-carboxylate (Intermediate 1-2, 3 g, 11.19 mmol) in DMF (15 mL) was added NaH (582 mg, 14.55 mmol) and the reaction mixture was stirred at room temperature for 1-5 minutes. To this mixture ethyl iodide (1.35 mL, 16.78 mmol) was added and the reaction mixture was stirred at 65 °C for 1 hour. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and concentrated. This was further purified by column chromatography using 5 % ethyl acetate in petroleum ether to yield 2.75 g (83 %) of the title compound. ^J H NMR (CDCI3, 500 MHz) δ ppm: 7.77 (s, 1H), 7.23 (d, J= 3 Hz, 1H), 6.57 (d, J= 2.5 Hz, 1H), 4.47 (q, J= 7 Hz, 2H), 3.92 (s, 3H), 2.91 (s, 3H), 1.45 (t, J=7.5 Hz, 3H). MS (ESI+): 299.0 [M+H] ⁺ , 297.0 [M-H] ⁺ .

The intermediates 1-4 to 1-7 were prepared analogous to the intermediate 1-3 by reaction of the Intermediate 1-2 with appropriate alkylating agent.

Intermediate 1-4: Methyl 4-bromo-l-isopropyl-7-methyl-lH-indole-6-carboxylate.

^J H NMR (CDC1 ₃ , 300 MHz) δ ppm: 7.83 (s, 1H), 7.49 (d, J= 2.1 Hz, 1H), 6.50 (d, J= 2.5 Hz, 1H), 5.24 (m, 1H), 3.83 (s, 3H), 2.80 (s, 3H), 1.47 (d, J=4.2 Hz, 6H). MS (ESI+): 310.0 [M+H] ⁺ .

Intermediate 1-5: Methyl 4-bromo-7-methyl-l-propyl-lH-indole-6-carboxylate.

JH NMR (CDCI ₃ , 300 MHz) δ ppm: 7.64 (d, J=3.3Hz, 1H), 7.56 (s, 1H), 6.44 (d, J= 3Hz, 1H), 4.41 (t, J=7.2Hz, 2H), 3.82 (s, 3H), 2.79 (s, 3H), 1.76 (m, 2H), 1.47 (t, J=7.5 Hz, 3H). MS (ESI+): 310.0 [M+H] ⁺ .

Intermediate 1-6: Methyl 4-bromo-l-isobutyl-7-methyl-lH-indole-6-carboxylate.

^J H NMR (CDCI ₃ , 500 MHz) δ ppm: 7.77 (s, 1H), 7.18 (d, / = 3.0 Hz, 1H), 6.54 (d, / = 3.0 Hz, 1H), 4.16 (d, / = 7.0 Hz, 2H), 3.92 (s, 3H), 2.87 (s, 3H), 2.11 - 2.07 (m, 1H), 0.9 (d, / = 6.5 Hz, 6H). MS (ESI+): 324.9 [M+H] ⁺ .

Intermediate 1-7: Methyl 4-bromo-l, 7-dimethyl-lH-indole-6-carboxylate.

^J H NMR (CDCI ₃ , 500 MHz) δ ppm: 7.76 (s, 1H) δ 7.12 (d, J= 3 Hz, 1H), δ 6.52 (d, J= 3 Hz, 1H), δ 4.13 (s 3H), δ 3.92 (s, 3H), 2.96 (s, 3H). MS (ESI+): 282.0 [M+H] ⁺ .

Intermediate 1-8: Methyl l-ethyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)-lH-indole-6-carboxylate.

To a solution of methyl 4-bromo-l -ethyl-7-methyl-lH-indole-6-carboxylate (Intermediate 1-3, 1.8 g, 6.08 mmol) in dioxane (20 mL) and water (10 mL), were added 1- methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idin-2-yl)piperazine (2.396 g, 7.90 mmol) and 2.0 M solution of sodium carbonate (9.12 mL, 18.23 mmol). Argon was bubbled through the mixture for 20 minutes at room temperature. To this mixture was added PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.496 g, 0.608 mmol) and heated to 80 °C for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered through celite, and concentrated. Water was added and extracted with ethyl acetate and concentrated. Further purification by column chromatography using 2-5 % MeOH in chloroform provided the title compound (1.5 g, 3.82 mmol, 62.9 % yield) as a solid. ^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 8.34 (s, 1H), 7.77 (d, J=8.5 Ηζ,ΙΗ), 7.56 (d, J=3 Ηζ,ΙΗ), 7.36 (s, 1H), 6.96 (d, J=5.4 Hz, 1H), 6.52 (d, J=2.5 Ηζ,ΙΗ), 4.52 (m, 2H), 3.84 (s, 3H), 3.54 (bs, 4H), 2.86 (s, 3H), 2.42 (bs, 4H), 2.23 (s,3H), 1.38 (t, J=7 Hz 3H). MS (ESI- ): 393.4 [M+H] ⁺ .

The intermediates 1-9 to 1-13 were prepared analogous to the intermediate 1-8 by reaction of the intermediates 1-4 to 1-7 with appropriate reagent D, l-methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine and 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine.

Intermediate 1-9: Methyl l-isopropyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin- 3-yl) - lH-indole-6-carboxylate.

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 8.33 (s, IH), 7.77 (s, 2H), 7.32 (s, IH), 6.96 (d, J= 9 Hz, IH), 6.57 (d, J=3.3 Hz, IH), 5.28 (m, IH), 3.83 (s, 3H), 3.53 (s, 4H), 2.84 (s, 3H), 2.49 (s, 4H), 2.22 (s, 3H), 1.49 (d, J=3.6 Hz, 6H). MS (ESI+): 407 [M+H] ⁺ .

Intermediate I- 10: Methyl l-isopropyl-7-methyl-4-(6-morpholinopyridin-3-yl)-lH- indole-6-carboxylate.

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 8.35 (d, J=2.4Hz, IH), 7.81 (dd, J=8.7, 2.1Hz, IH), 7.75 (d, J=3.3Hz, IH), 7.33 (s, IH), 6.97 (d, J=8.7Hz, IH), 6.57 (d, J=3.3Hz, IH), 5.30 (m, IH), 3.83 (s, 3H), 3.74 (m, 4H), 3.51 (m, 4H), 2.84 (s, 3H), 1.49 (d, J=5.4 Hz, 6H). MS (ESI+): 394 [M+H] ⁺ .

Intermediate 1-11: Methyl 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l- propyl-lH-indole-6-carboxylate.

JH NMR (CDCI ₃ , 300 MHz) δ ppm: 8.33 (d, J=2.1Hz, IH), 7.78 (dd, Jl=8.7Hz, J2=2.4Hz, IH), 7.55 (d, J=3.3Hz, IH), 7.35 (s, IH), 6.95 (d, J=8.7 Hz, IH), 6.50 (d, J=3 Hz, IH), 4.42 (t, J=7.2Hz, 2H), 3.83 (s, 3H), 3.53 (m, 4H), 2.83 (s, 3H), 2.43 (m, 4H), 2.22 (s, 3H), 1.78 (m, 2H), 0.883 (t, J=7.5 Hz, 3H). MS (ESI+): 407 [M+H] ⁺ .

Intermediate 1-12: Methyl 1, 7-dimethyl-4-(6-(4-methylpiperazin-l-yl) pyridin-3-yl)- lH-indole-6-carboxylate.

^J H NMR (DMSO-de, 500 MHz) δ ppm: 8.34 (s, IH), 7.77 (d, J= 8.5 Hz, IH), 7.56 (m, J= 7 Hz, IH), 7.46 (s, IH), 6.95 (d, J= 9 Hz, IH), 6.47 (s, IH), 4.21 (s 3H), 3.83 (s, 3H), 3.54 (bs, 4H), 2.92 (s, 3H), 2.42 (bs, 4H), 2.23 (s, 3H). MS (ESI-): 379 [M-H] ⁺ .

Intermediate 1-13: Methyl l-isobutyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin- 3-yl)-lH-indole-6-carboxylate.

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 8.52 (s, IH), 7.82 - 7.79 (m, IH), 7.55 (s, IH), 7.17 (d, / = 3.0 Hz, IH), 6.79 - 6.77 (m, IH), 6.60 (d, / =3.0 Hz, IH), 4.19 (d, / = 7.2 Hz, 2H), 3.93 (s, 3H), 3.67 - 3.63 (m, 4H), 2.93 (s, 3H), 2.60 - 2.57 (m, 4H), 2.39 (s, 3H), 2.16 - 2.11 (m, 1H), 0.93 (d, / = 6.6 Hz, 6H). MS (ESI+): 421.6 [M+H] ⁺ .

Intermediate 1-14: 4-Bromo-l-ethyl-7-methyl-lH-indole-6-carboxylic acid.

To a solution of methyl 4-bromo-l-ethyl-7-methyl-lH-indole-6-carboxylate (Intermediate 1-3, 1 g, 3.38 mmol) in MeOH (10 mL) and THF (10 mL) was added IN NaOH (13.51 mL, 13.51 mmol). The reaction mixture was stirred at 70 °C for 16 hours. After completion of the reaction, solvent was removed and the pH of the reaction mixture was adjusted to acidic condition using dilute HC1. The solid precipitated was filtered, washed with water and dried to yield 835 mg (85 %) of title compound. ^J H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 12.84 (s, 1H), 7.62 (d, J=2.5Hz, 1H), 7.58 (s, 1H), 6.44 (d, J=2.5Hz, 1H), 4.49 (q, J=7Hz, 2H), 2.84 (s, 3H), 1.35 (t, J=7Hz, 3H). MS (ESI+): 305.1 [M+Na] ⁺ .

Intermediate 1-15: l-Ethyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)- lH- indole-6-carboxylic acid.

To a solution of methyl l-ethyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)-lH-indole-6-carboxylate (Intermediate 1-8, 1.5 g, 3.82 mmol) in THF and MeOH was added 1.0 N solution of NaOH (15.29 mL, 15.29 mmol) and stirred at 70 °C for 3 hours. After completion of the reaction, the solvent was removed and the pH of the reaction mixture was adjusted to acidic condition using dilute HC1 and the solid precipitated was filtered, washed with water and then with ethyl acetate. The solid was dried to yield the title compound (1.3 g, 3.43 mmol, 90 % yield). ^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm:

8.36 (s, 1H), 7.83 (d, J=14 Ηζ,ΙΗ), 7.53 (bs, 1H), 7.37 (s, 1H), 7.04 (d, J=14.5 Hz, 1H), 6.49 (s, 1H), 4.50 (d, J=11.5, 2H), 3.73 (bs, 4H), 2.96 (s, 3H), 2.88 (bs, 4H), 2.59 (s, 3H),

1.37 (t, J=11.5 Hz 3H). MS (ESI-): 379 [M+H] ⁺ .

The intermediates 1-16 to 1-20 were prepared analogous to the intermediate 1-15 by using intermediates 1-9 to 1-13 in place of 1-8.

Intermediate 1-16: l-isopropyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)- lH-indole-6-carboxylic acid.

^J H NMR (CDC1 ₃ , 300 MHz) δ ppm: 8.36 (d, J=2.1Hz, 1H), 7.82 (d, J=8.7Hz, 1H), 7.72 (d, J=3.3Hz, 1H), 7.35 (s, 1H), 7.02 (d, J=8.7Hz, 1H), 6.55 (d, J=3.3Hz, 1H), 5.30 (m, 1H), 3.68 (s, 3H), 3.26 (bs, 4H), 2.87 (bs, 4H), 2.80 (s, 3H), 1.49 (d, J=6.6 Hz, 6H). MS (ESI+): 393[M+H] ⁺ . Intermediate 1-17: l-isopropyl-7-methyl-4-(6-morpholinopyridin-3-yl)-lH-indole- 6- carboxylic acid.

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 8.35 (s, IH), 7.80 (d, J=8.7Hz, IH), 7.70 (d, J=3Hz, IH), 7.31 (s, IH), 6.96 (d, J=8.7Hz, IH), 6.54 (d, J=3.3Hz, IH), 5.27 (m, IH), 3.72 (m, 4H), 3.49 (m, 4H), 2.86 (s, 3H), 1.48 (d, J=6.6 Hz, 6H). MS (ESI+): 380 [M+H] ⁺ .

Intermediate I- 18 : 7-methyl-4- (6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)- 1 -propyl- 1H- indole-6-carboxylic acid.

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 11.11 (bs, IH), 8.36 (s, IH), 7.96 (d, J=8.4Hz, IH), 7.56 (s, IH), 7.40 (s, IH), 7.18 (d, J=8.7 Hz, IH), 6.48 (d, J=3 Hz, IH), 4.50 (m, 2H), 4.40 (m, 2H), 3.51 (m, 2H), 3.43 (m, 2H), 3.31 (m, 2H), 2.87 (s, 3H), 2.80 (s, 3H), 1.75 (m, 2H), 0.881 (t, J=7.2 Hz, 3H). MS (ESI+): 393 [M+H] ⁺ .

Intermediate 1-19: 1, 7-dimethyl-4-(6-(4-methylpiperazin-l-yl) pyridin-3-yl)-lH- indole-6-carboxylic acid.

^J H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 12.68 (s, IH), 8.38 (s, IH), 7.92 (d, J=8.5 Hz, IH), 7.57 (d, J=3 Hz, IH), 7.47 (d, J=2.5 Hz, IH), 7.14 (d, J=8.5 Hz, IH), 6.45 (d, J=2.5

Hz, IH), 4.48 (d, J=13.5 Hz 2H), 4.15 (s, 3H), 3.51 (d, J=12 Hz 2H), 3.381 (m, J=12.5 Hz,

2H), 3.13 (m, J=9.5 Hz, 2H), 2.96 (s, 3H), 2.80 (d, J=4, 3H). MS (ESI-): 378 [M+H] ⁺ .

Intermediate 1-20: l-isobutyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-y l)- lH-indole-6-carboxylic acid.

JH NMR (CDCI ₃ , 300 MHz) δ ppm: 12.59 (s, IH), 8.40 (s, IH), 7.88-7.85 (m, IH), 7.52

(d, J=3.0 Hz, IH), 7.09-7.06 (m, IH), 6.87 (s, IH), 6.49 (d, J=3.0 Hz, IH), 4.23 (d, J=6.9

Hz, 2H), 3.20 (m, 4H), 2.86 (s, 3H), 2.76 (bs, 4H), 2.18 (s, 3H), 2.0 (m, IH), 0.84 (d,

J=6.3 Hz, 6H). MS (ESI+): 407.4 [M+H] ⁺ .

Intermediate 1-21: (E)-Methyl 3-bromo-4-(2-(dimethylamino)vinyl)-5-nitrobenzoate To a solution of methyl 3-bromo-4-methyl-5-nitrobenzoate (7 g, 25.5 mmol) in DMF (70 mL) was added DMF-DMA (10.26 mL, 77 mmol) and the reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was cooled to RT, concentrated, added water, extracted with ethyl acetate and purified by column chromatography (silica gel, 10-20 % ethyl acetate in pet ether) to obtain the title compound.

Yield: 3.2 g (38 ); ^J H NMR (CDCI ₃ ; 300 MHz): δ 8.26 (d, J= 1.8 Hz, IH), 8.05 (d, J= 1.8 Hz, IH), 6.80 (d, J= 13.5 Hz, IH), 5.17 (d, J= 13.5 Hz, IH), 3.91 (s, 3H), 2.93 (s, 6H), MS (ESI+): m/z 338.

Intermediate 1-22: Methyl 4-bromo-lH-indole-6-carboxylate To a solution of (E)-methyl 3-bromo-4-(2-(dimethylamino)vinyl)-5-nitrobenzoate (1-21, 3.1 g, 9.42 mmol) in acetic acid (2 mL) was added iron (2.104 g, 37.7 mmol) at 50 °C and the reaction mixture was stirred at 85-90 °C for 2 h. After completion of reaction, cooled to RT, filtered through celite, residue washed with ethyl acetate and organic layer was washed with water and mother liquor was concentrated which was further purified by column chromatography (silica gel, 20-30% ethyl acetate in pet ether) to obtain the title compound.

Yield: 1.6 g (67 %); ^J H NMR (DMSO-de; 300 MHz): 6 11.90 (s, 1H), 7.76 (s, 1H), 7.73 (t, J= 4.8 Hz, 1H), 6.49 (sz, 1H), 3.87 (s, 3H); MS (ESI+): m/z 223.9.

Intermediate 1-23: Methyl 4-bromo-l-ethyl-lH-indole-6-carboxylate

To a solution of methyl 4-bromo-lH-indole-6-carboxylate (1-22, 800 mg, 3.15 mmol) in DMF (8 mL) was added NaH (126 mg, 3.15 mmol) and the reaction mixture was stirred at RT for 5 minutes and added ethyl iodide (0.382 mL, 4.72 mmol) and stirred at RT for 0.5 h. After completion of reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water and concentrated which was further purified by column chromatography (silica gel, 5-10 % ethyl acetate in pet ether) to obtain the title compound.

Yield: 511 mg (57 %); ^J H NMR (DMSO-d ₆ ; 300 MHz): 68.08 (s, 1H), 7.98 (s, 1H), 7.34 (d, J= 3 Hz, 1H), 6.60 (d, J = 3 Hz, 1H), 4.27 (q, J= 7.5 Hz, 2H), 3.96 (s, 3H), 1.50 (t, J= 7.5 Hz, 3H); MS (ESI+): m/z 203.

Intermediate 1-24: 4-Bromo-l-ethyl-lH-indole-6-carboxylic acid

To a solution of methyl 4-bromo-l -ethyl- lH-indole-6-carboxylate (1-23, 500 mg, 1.772 mmol) in MeOH (10 mL) and added 1 N sodium hydroxide (7.09 mL, 7.09 mmol) and stirred at 55 °C for 1 h. After completion of reaction, solvent was removed and acidified using dil HCl and the solid obtained was filtered, washed with water and dried to obtain the title compound.

Yield: 390 mg; ^J H NMR (DMSO-de; 300 MHz): 612.94 (s, 1H), 8.13 (s, 1H), 7.76 (d, J= 5.1 Hz, 2H), 6.49 (d, J = 2.7 Hz, 1H), 4.32 (q, J= 7.2 Hz, 2H), 1.36 (t, J= 7.2 Hz, 3H), MS (ESI+): m/z 269.9.9 [M+H] ⁺ .

Intermediate 1-25: Methyl 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH- indole-6-carboxylate To a solution of methyl 4-bromo-7-methyl-lH-indole-6-carboxylate (Intermediate 1-2, 1.5 g, 5.59 mmol) and l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl)piperazine (2.54 g, 8.39 mmol) in 1,4-Dioxane (25 mL) and water (12.50 mL) was added 2M Na ₂ CC>3 (8.39 mL, 16.78 mmol) solution and argon was bubbled for 30 minutes at RT. After completion of the reaction, the reaction mixture was cooled to RT and filtered through celite, extracted with ethyl acetate and DCM and purified by column chromatography (silica gel, 1-2 % MeOH in CHCI ₃ ) to obtain the title compound.

Yield: 1.2 g; ^J H NMR (DMSO-de; 300 MHz): δ 11.62 (s, 1H), 8.40 (s, 1H), 7.81 (d, J = 5.1 Hz, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 6.96 (d, J= 5.4 Hz, 1H), 6.60 (s, 1H), 3.84 (s, 3H), 3.54 (s, 4H), 2.76 (s, 3H), 2.43 (s, 4H), 2.23 (s, 3H); MS (ESI+): 365.3 [M+H] ⁺ ; HPLC purity: 99.08 %.

Intermediate 1-26: Methyl 4-bromo-7-methyl-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-indole-6-carboxylate

To a solution of methyl 4-bromo-7-methyl-lH-indole-6-carboxylate (Intermediate 1-2, 830 mg, 3.10 mmol) in DMF (2 mL) was added sodium hydride (186 mg, 4.64 mmol) and stirred at RT for 10 minutes. 4-(Iodomethyl)tetrahydro-2H-pyran (1050 mg, 4.64 mmol) was added and stirred at 65-70 °C for 16 h. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was purified by column chromatography (silica gel, 5-8% ethyl acetate in pet ether) to obtain the title compound. Yield: 350 mg (30 %); ^J H NMR (CDCI ₃ ; 300 MHz): δ 7.77 (s, 1H), 7.16 (d, J = 3 Hz, 1H), 6.54 (d, J= 3.3 Hz, 1H), 4.24 (d, J= 7.2 Hz, 2H), 3.93-3.97 (m, 2H), 3.92 (s, 3H), 2.24-2.29 (m, 2H), 2.87 (s, 3H), 1.96-1.99 (m, 1H), 1.39-1.42 (m, 4H); MS (ESI+): 367.9 [M+H] ⁺ ; HPLC purity: 96.71 %.

Intermediate 1-27: Methyl 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l- ((tetra hydro-2H-pyran-4-yl)methyl)-lH-indole-6-carboxylate

To a solution of methyl 4-bromo-7-methyl-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH- indole-6-carboxylate (Intermediate 1-26, 350 mg, 0.956 mmol) and l-methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (435 mg, 1.433 mmol) in 1,4- dioxane (10 mL) and water (5 mL) was added 2 M Na ₂ C(¾ (1.433 mL, 2.87 mmol) and argon was bubbled for 20 minutes at RT. To the reaction mixture, was added PdCl ₂ (dppf)- CH ₂ CI ₂ adduct (78 mg, 0.096 mmol) and stirred at 78 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, the solid obtained was washed with MeOH and purified by column chromatography (silica gel, 2-3 % MeOH in chloroform) to obtain the title compound.

Yield: 398 mg (90 ); ^J H NMR (CDC1 ₃ ; 300 MHz): δ 8.32 (d, J= 2.4 Hz, 1H), 7.75 (dd, J = 8.7 & 2.4 Hz, 1H), 7.51 (d, J= 3.3 Hz, 1H), 7.35 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 6.48 (d,J= 3 Hz, 1H), 4.31 (d, J= 6.9 Hz, 2H), 3.82 (s, 3H), 3.76-3.81 (m, 2H), 3.52 (s, 4H), 3.10-3.18 (m, 2H), 2.83 (s, 3H), 2.40 (s, 4H), 2.21 (s, 3H), 1.85-1.92 (m, 1H), 1.21-1.28 (m, 4H); MS (ESI+): 463.3 [M+H] ⁺ ; HPLC purity 99.66 %.

Intermediate 1-28 : 7-Methyl-4-(6- (4-methylpiperazin- 1 -yl)pyridin-3 -yl)-l- ((tetrahydro-2H-pyran-4-yl)methyl)-lH-indole-6-carboxylic acid

To a solution of methyl 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l- ((tetrahydro-2H-pyran-4-yl)methyl)-lH-indole-6-carboxylate (Intermediate 1-27, 350 mg, 0.757 mmol) in MeOH (10 mL) was added IN sodium hydroxide (3.03 mL, 3.03 mmol) and stirred the reaction mixture at 55 °C for 5 h. After completion of reaction, solvent was removed and dilute HCl was added and solid impurity was filtered off. The filtrate was concentrated and the resulting solid was washed with DCM, added MeOH and stirred at RT. The solid obtained was filtered and to the filtrate added ether, the solid obtained was filtered and dried to obtain the title compound.

Yield: 285 mg (82 ); ^J H NMR (CDC1 ₃ ; 300 MHz): δ 12.69 (s, 1H), 8.37 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.50 (d, J= 3.3 Hz, 1H), 7.38 (s, 1H), 7.05 (d, J= 8.7 Hz, 1H), 6.46 (d,J= 3 Hz, 1H), 4.31 (d, J= 6.9 Hz, 2H), 3.80 (d, J= 11.1 Hz, 2H), 3.18-3.33 (m, 2H), 3.10-3.18 (m, 4H), 2.86 (s, 3H), 2.72 (s, 3H), 1.85-1.92 (m, 1H), 1.28-1.31 (m, 4H), 1.21 (s, 3H); MS (ESI+): 449.3 [M+H] ⁺ ; HPLC purity: 97.35 %.

Intermediate 1-29: Methyl 4-bromo-7-methyl-l-(2,2,2-trifluoroethyl)-lH-indole-6- carboxylate

To a solution of methyl 4-bromo-7-methyl-lH-indole-6-carboxylate (Intermediate 1-2, 1.1 g, 4.10 mmol) in DMF (22 mL) was added cesium carbonate (4.01 g, 12.31 mmol) and the reaction mixture was stirred at RT for 10 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.774 mL, 12.31 mmol) was added and stirred at RT for 2 h. After completion of the reaction, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated to obtain crude and the crude obtained was purified by flash chromatography using 0.5: 9.5% ethyl acetate:petroleum ether to obtain the title compound. Yield: 1.3 g (90 ); H NMR (CDCI ₃ , 500 MHz): δ 7.81 (s, 1H), 7.23 (d, J = 3.0 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 5.02 (q, J = 8.0 Hz, 2H), 3.93 (s, 3H), 2.86 (s, 3H); MS (ESI+): 351.2 [M+H] ⁺ ; HPLC purity: 99.90 %.

Intermediate 1-30: 4-Bromo-7-methyl-l-(2,2,2-trifluoroethyl)-lH-indole-6-carbox ylic acid

To a solution of methyl 4-bromo-7-methyl-l-(2,2,2-trifluoroethyl)-lH-indole-6- carboxylate (Intermediate 1-29, 800 mg, 2.285 mmol) in MeOH (16 mL) and THF (16.00 mL) was added 1 M NaOH solution (9.14 mL, 9.14 mmol) and heated at 65 °C for 2 h. The reaction mass was cooled and the solvent was removed. The residue obtained was dissolved in water, acidified with dilute HCl and extracted with ethyl acetate. The organic layer was washed with brine and evaporated the solvent to obtain the title compound. Yield: 730 mg (95 ); ^J H NMR (DMSO-d ₆ , 500 MHz): δ 13.03 (s, 1H), 7.65 (s, 2H), 6.60 (s, 1H), 5.47 (q, J = 8.5 Hz, 2H), 2.79 (s, 3H); MS (ESI+): m/z 336 [M+H] ⁺ ; HPLC purity: 99.68 %.

Intermediate 1-31: Ethyl 4-bromo-2-methylbenzoate

To a stirred solution of 4-bromo-2-methylbenzoic acid (25 g, 116 mmol) in DMF (150 mL) sodium carbonate (49.3 g, 465 mmol) and ethyl iodide (37.6 mL, 465 mmol) were added. The reaction mass was heated at 60 °C for 16 h .On completion of the reaction, solvent was evaporated to dryness, added ice cold water, extracted using diethyl ether, dried organic layer on sodium sulfate and concentrated to obtain the crude compound, which was purified by column chromatography to obtain the title compound.

Yield: 27.5 g, (97 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 7.80 (d, 1H, J=8.4 Hz), 7.41 (s, 1H), 7.39 (d, 1H, J= 8.4 Hz,), 4.38 (q, 2H), 2.58 (s, 3H), 1.39 (t, 3H); MS (ESI+): m/z 244 (M+H) ⁺ .

Intermediate 1-32: (E)-Ethyl 4-(3-ethoxy-3-oxoprop-l-en-l-yl)-2-methylbenzoate

To a stirred solution of ethyl 4-bromo-2-methylbenzoate (Intermediate 1-31, 10 g, 41.1 mmol) in N-methyl-2-pyrrolidinone (100 mL), ethyl acrylate (5.70 mL, 53.5 mmol) and potassium carbonate (11.48 g, 83 mmol) were added. The reaction mixture was degassed using nitrogen for 30 minutes, added palladium(II) acetate (0.924 g, 4.11 mmol) and N,N- dimethylaniline (0.944 mL, 7.40 mmol), degassed for 30 minutes and the reaction mass was heated at 130 °C for 16 h. On completion of the reaction, the reaction mass was filtered using celite bed, washed celite bed by methanol, added water to reaction mass, extracted using diethyl ether, dried on sodium sulfate, concentrated to obtain crude compound, which was purified by column chromatography to obtain the title compound. Yield: 5.3 g (49.1 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 7.94 (d, 1H, J=7.8 Hz), 7.68 (d, 1H, J=16.2 Hz), 7.41 (d, 1H, J= 8.1 Hz,), 7.38 (s, 1H), 6.52 (d, 1H, J=15.9 Hz), 4.38 (q, 2H), 4.29 (q, 2H), 2.62 (s, 3H), 1.40 (t, 3H), 1.35 (t, 3H); MS (ESI+): m/z 263 (M+H) ⁺ .

Intermediate 1-33: Ethyl 4-(3-ethoxy-3-oxopropyl)-2-methylbenzoate

To a solution of (E)-ethyl 4-(3-ethoxy-3-oxoprop-l-en-l-yl)-2-methylbenzoate (Intermediate 1-32, 6 g, 22.87 mmol) in ethanol (100 mL) was added palladium on carbon (1.217 g, 11.44 mmol) and the reaction mass was stirred under hydrogen pressure for 2 h. On completion of the reaction, the reaction mass was filtered through celite bed and concentrated the filtrate to obtain the title compound.

Yield: 5.3 g (88 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 7.87 (d, 1H, J=8.4 Hz), 7.08 (bs, 2H), 4.38 (q, 2H), 4.16 (q, 2H), 2.97 (t, 2H), 2.65 (t, 2H), 2.58 (s, 3H), 1.41 (t, 3H), 1.26 (t, 3H); MS (ESI+): m/z 265 (M+H) ⁺ .

Intermediate 1-34: 4-(2-Carboxyethyl)-2-methylbenzoic acid

To a solution of ethyl 4-(3-ethoxy-3-oxopropyl)-2-methylbenzoate (Intermediate 1-33, 5.3 g, 20.05 mmol) in tetrahydrofuran (50 mL): MeOH (50 mL) was added sodium hydroxide (4.01 g, 100 mmol) and the reaction mass was stirred at 80 °C for 2 h . On completion of the reaction, solvent was evaporated, added water and acidified using 6 M HC1. The reaction mass was extracted with ethyl acetate, organic layer was dried over sodium sulfate and concentrated to obtain the title compound.

Yield: 4 g (96 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 12.40 (bs, 2H), 7.75 (d, 1H, J=7.8 Hz), 7.14 (bs, 1H), 7.11 (bs, 1H), 2.83 (t, 2H), 2.56 (t, 2H), 2.49 (s, 3H); MS (ESI+): m/z 209 (M+H) ⁺ .

Intermediate 1-35: 4-Methyl-3-oxo-2,3-dihydro-lH-indene-5-carboxylic acid

4-(2-Carboxyethyl)-2-methylbenzoic acid (Intermediate 1-34, 12.8 g, 61.5 mmol), sodium chloride (17.96 mL, 307 mmol) and aluminium chloride (123 g, 922 mmol) were heated at 190 °C for 1 h. On completion of the reaction, the reaction mass was cooled to RT and quenched with ice cold water and then acidified using 6 M HC1. The reaction mass was extracted using diethyl ether, washed the organic layer using brine solution, dried on sodium sulfate and concentrated to obtain the title compound. Yield: 11 g, (94 ); H NMR (DMSO-d ₆ , 300 MHz): δ 13.07 (bs, 1H), 7.98 (d, 1H, J=7.8 Hz), 7.45 (d, 1H, J= 8.1 Hz,), 3.12 (m, 2H), 2.64 (m, 2H), 2.61(s, 3H); MS (ESI+): m/z 191 (M+H) ⁺ .

Intermediate 1-36: Methyl 4-methyl-3-oxo-2,3-dihydro-lH-indene-5-carboxylate To a solution of mixture of 4-methyl-3-oxo-2,3-dihydro-lH-indene-5-carboxylic acid (Intermediate 1-35, 11 g, 57.8 mmol) in MeOH (50 mL) was added sulfuric acid (5.67 g, 57.8 mmol) and the reaction mass was refluxed for 8 h. On completion of the reaction, reaction mass was concentrated, basified using sodium carbonate, extracted using ethyl acetate, dried over sodium sulfate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound.

Yield: 3.9 g (33.0 %). ^J H NMR (CDC1 ₃ , 300 MHz): δ 8.03 (d, 1H, J=8.1 Hz), 7.34 (d, 1H, J= 8.1 Hz), 3.92 (s, 3H), 3.12 (t, 2H), 2.91 (s, 3H), 2.74 (t, 2H); MS (ESI+): m/z 205 (M+H) ⁺ .

Intermediate 1-37: Methyl 7-bromo-4-methyl-3-oxo-2,3-dihydro-lH-indene-5- carboxylate

To a solution of methyl 4-methyl-3-oxo-2,3-dihydro-lH-indene-5-carboxylate (Intermediate 1-36, 3.2 g, 15.67 mmol) in sulfuric acid (20 mL, 375 mmol) was added 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione (2.240 g, 7.83 mmol) and the reaction mass was stirred at 25 °C for 1 h. To the reaction mass was added saturated solution of sodium carbonate and extracted using ethyl acetate, washed with water and brine and concentrated to obtain the title compound.

Yield: 2.7 g (60.9 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 8.20 (s, 1H), 3.93 (s, 3H), 3.06 (m, 2H), 2.86 (s, 3H), 2.78 (m, 2H); MS (ESI+): m/z 284 (M+H) ⁺ .

Intermediate 1-38: Methyl 7-bromo-3-(hydroxyimino)-4-methyl-2,3-dihydro-lH- indene-5-carboxylate

To a solution of methyl 7-bromo-4-methyl-3-oxo-2,3-dihydro-lH-indene-5-carboxylate (Intermediate 1-37, 2.7 g, 9.54 mmol) in MeOH (150 mL) was added hydroxylamine hydrochloride (1.988 g, 28.6 mmol) portion wise and the reaction mass was heated for 5 h. On completion of the reaction, the solvent was evaporated, added water and extracted using ethyl acetate (50 mL X 2). The organic layer was dried over sodium sulfate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound. Yield: 2.8 g (98 ); H NMR (CDCI ₃ , 300 MHz): δ 7.96 (s, 1H), 7.61 (s, 1H), 3.92 (s,

3H), 3.04 (s, 4H), 2.76 (s, 3H); MS (ESI+): m/z 299 (M+H) ⁺ .

Intermediate 1-39: Methyl 3-amino-7-bromo-2,3-dihydro-4-methyl-lH-indene-5- carboxylate

To a solution of methyl 7-bromo-3-(hydroxyimino)-4-methyl-2,3-dihydro-lH-indene-5- carboxylate (Intermediate 1-38, 2.6 g, 8.72 mmol) in hydrochloric acid (5.000 mL, 165 mmol) was added zinc (0.773 g, 11.82 mmol) at room temperature and the reaction mass was heated at 70 °C for 4 h. On completion of reaction, the reaction mass was filtered through celite bed, solvent was evaporated, added water and extracted using ethyl acetate (50 mL X 2). The organic layer was dried on sodium sulfate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound.

Yield: 1.4 g (62.5 ); ^J H NMR (DMSO-D ₆ , 300 MHz): δ 7.76 (s, 1H), 4.47 (d, 1H), 3.80 (s, 3H), 3.15 (m, 1H), 2.78 (m, 1H), 2.46 (s, 3H), 2.25 (m, 1H), 1.95 (bs,2H), 1.86 (m,lH); MS (ESI+): m/z 284 (M+H) ⁺ .

Intermediate 1-40: Methyl 7-bromo-3-(dimethylamino)-4-methyl-2,3-dihydro-lH- indene-5-carboxylate

To a solution of methyl 3-amino-7-bromo-4-methyl-2,3-dihydro-lH-indene-5-carboxylate (Intermediate 1-39, 500 mg, 1.760 mmol) in THF (10 mL), sodium hydride (84 mg, 3.52 mmol) was added and stirred for 30 minutes. Added methyl iodide (0.275 mL, 4.40 mmol) and stirred for 2 h. On completion of reaction, added water to the reaction mass and extracted using ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound.

Yield: 420 mg (76 ); ^J H NMR (CDCI3, 300 MHz): δ 7.94 (s, 1H), 4.46 (d, 1H), 3.88 (s, 3H), 2.94 (m, 2H), 2.57 (s, 3H), 2.31 (m, 1H), 2.13 (s, 6H), 1.92 (m, 1H); MS (ESI+): m/z 244 (M+H) ⁺ .

Intermediate 1-41: 7-Bromo-3-(dimethylamino)-2,3-dihydro-4-methyl-lH-indene-5- carboxylic acid

To a solution of methyl 7-bromo-3-(dimethylamino)-4-methyl-2,3-dihydro-lH-indene-5- carboxylate (Intermediate 1-40, 420 mg, 1.345 mmol) in THF (5 mL) was added sodium hydroxide (269 mg, 6.73 mmol) and the reaction mass was stirred at 60 °C for 3 h. On completion of reaction, added water to the reaction mass, extracted using ethyl acetate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound.

Yield: 260 mg (64.8 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.21 (bs, 1H), 7.99 (s, 1H), 5.18 (d, 1H), 3.32 (m, 1H), 2.93 (m, 1H), 2,75 (bs, 3H), 2.60 (bs, 4H), 2.49 (bs, 3H), 2.49 (m,lH); MS (ESI+): m/z 299 (M+H) ⁺ .

Intermediate 1-42: Methyl 7-bromo-4-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)- 2,3-dihydro-lH-indene-5-carboxylate

To a solution of methyl 3-amino-7-bromo-4-methyl-2,3-dihydro-lH-indene-5-carboxylate (Intermediate 1-41, 800 mg, 2.82 mmol) and dihydro-2H-pyran-4(3H)-one (0.390 mL, 4.22 mmol) in MeOH (20 mL), acetic acid was added and the reaction mass was heated to 60 °C for 2 h. The reaction mass was cooled, added sodium cyanoborohydride (212 mg, 3.38 mmol) and stirred for 1 h at room temperature. On completion of reaction, added brine solution to reaction mass, extracted using ethyl acetate, the organic layer was dried over sodium sulfate, concentrated and purified through column chromatography to obtain the title compound.

Yield: 400 mg (38.6 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 7.78 (s, 1H), 4.45 (s, 1H), 3.80 (bs, 4H), 3.11 (m, 3H), 2.77 (m, 3H), 2.49 (bs, 4H), 2.04 (m, 4H), 1.61 (m, 2H), 1.29 (m, 2H); MS (ESI+): m/z 369 (M+H) ⁺ .

Intermediate 1-43: Methyl 7-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl -2,3-dihydro-lH-indene-5-carboxylate

To a solution of methyl 7-bromo-4-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)-2,3- dihydro-lH-indene-5-carboxylate (Intermediate 1-42, 210 mg, 0.570 mmol) in acetonitrile (5 mL), potassium carbonate (158 mg, 1.140 mmol) and ethyl iodide (0.230 mL, 2.85 mmol) were added and the reaction mass was stirred at 70 °C for 16 h. On completion of reaction, added water to reaction mass and extracted using diethyl ether, dried on sodium sulfate and concentrated to obtain the title compound.

Yield: 170 mg (75 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 7.93 (s, 1H), 4.79 (t , 1H), 4.02 (m, 2H), 3.88 (s, 3H), 3.42 (m, 2H), 2.97 (m, 2H), 2.74 (m, 1H), 2.58 (bs, 3H), 2.55 (m, 1H), 2.30 (m, 1H), 2.11 (m, 1H), 1.88 (m,2H), 1.68 (m, 3H), 0.85 (t, 3H); MS (ESI+): m/z 397(M+H) ⁺ .

Intermediate 1-44: 7-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-2, 3- dihydro-lH-indene-5-carboxylic acid To a solution of methyl 7-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-2, 3- dihydro-lH-indene-5-carboxylate (Intermediate 1-43, 580 mg, 1.463 mmol) in acetonitrile was added sodium hydroxide (293 mg, 7.32 mmol) and stirred the reaction mass for 3 h at 60 °C. On completion of reaction, added water to reaction mass, extracted using ethyl acetate and concentrated to get crude compound, which is purified by column chromatography to obtain the title compound.

Yield: 350 mg (62.6 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 13.30 (bs, 1H), 7.98 (s, 1H), 5.57 (d, 1H), 5.37 (bs, 1H), 4.01-3.05 (m, 4H), 2.96-2.02 (m, 8H), 1.79 (m, 2H), 1.19 (t, 3H), 0.98 (t, 3H); MS (ESI+): m/z 382 (M+H) ⁺ .

Intermediate 1-45: Methyl 3-amino-5-bromo-2-methylbenzoate

To a solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (80 g, 292 mmol) in ethanol (800 mL) and THF (320 mL) was added iron (48.9 g, 876 mmol), ammonium chloride (46.8 g, 876 mmol) followed by water (320 mL) and heated to 80 °C for 3 h. The reaction mixture was cooled, filtered through celite and filtrate was concentrated. The residue obtained was dissolved in ethyl acetate, water, organic layer was washed with brine solution, dried over sodium sulphate and evaporated to obtain brown residue. The residue was purified by flash chromatography using 2:8 ethyl acetate: petroleum ether to obtain the title compound.

Yield: 64 g (90 ); ^J H NMR (DMSO-de, 300 MHz): δ 6.94 (s, 2H), 5.44 (s, 2H), 3.76 (s, 3H), 2.09 (s, 3H); MS (ESI+): m/z 245.2 [M+H] ⁺ .

Intermediate 1-46: Methyl 5-bromo-3-isobutyramido-2-methylbenzoate

To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (Intermediate 1-45, 2.5 g, 10.24 mmol) in THF (50 mL) was added isobutyryl chloride (1.127 mL, 10.75 mmol) followed by TEA (2.86 mL, 20.48 mmol) and stirred at 27 °C for 2 h. After completion of reaction, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to obtain pale brown solid. The solid obtained was crystallized in CH ₂ CI ₂ - petroleum ether to obtain the title compound.

Yield: 2.7 g (84 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 9.50 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 4.05 (s, 3H), 2.65 (m, 1H), 2.23 (s, 3H), 1.11 (d, /= 6.9 Hz, 6H); MS (ESI+): m/z 314.1 [M+H] ⁺ .

Intermediate 1-47: Methyl 5-bromo-2-methyl-3-(2- methylpropanethioamido)benzoate To a solution of methyl 5-bromo-3-isobutyramido-2-methylbenzoate (Intermediate 1-46, 2 g, 6.37 mmol) in dioxane (50 mL) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadi phosphetane-2,4-disulfide (2.57 g, 6.37 mmol) and the reaction mixture was stirred at 102 °C for 3 h. After completion of reaction, reaction mixture was cooled to RT, saturated Na2C(¾ solution was added and reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine solution, solvent was removed to obtain brown residue, which was purified by flash chromatography using 3:7 ethyl acetate:petroleum ether to obtain crude solid. The solid obtained was crystallized in chloroform - petroleum ether to obtain the title compound.

Yield: 1.86 g (88 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.33 (s, 1H), 7.84 (d, J= 1.8 Hz, 1H), 7.59 (d, J= 1.8 Hz, 1H), 3.82 (s, 3H), 3.06 (m, 1H), 2.24 (s, 3H), 1.23 (d, J= 6.9 Hz, 6H); MS (ESI+): m/z 330.1 [M+H] ⁺ .

Intermediate 1-48: 7-Bromo-2-isopropyl-4-methylbenzo[d]thiazole-5-carboxylic acid

To a solution of methyl 5-bromo-2-methyl-3-(2-methylpropanethioamido)benzoate (Intermediate 1-47, 1.8 g, 5.45 mmol) in 1.5 M NaOH solution (182 mL, 273 mmol) was added freshly prepared 0.6 M potassium ferricyanide solution (27.3 mL, 16.35 mmol) and reaction mixture was stirred for 2 h at RT. Adjusted pH of the reaction mixture to 2 and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and solvent was evaporated to obtain solid. The solid obtained was stirred in dichloromethane, filtered and dried to obtain the title compound.

Yield: 1.46 g (85 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 7.97 (s, 1H), 3.44 (m, 1H), 2.84 (s, 3H), 1.41 (d, J= 6.9 Hz, 6H); MS (ESI+): m/z 314 [M+H] ⁺ .

The intermediates 1-49 to 1-60 were prepared analogous to the intermediate 1-46 to 1-48 by using appropriate reagents.

Intermediate 1-49: Methyl 3-acetamido-5-bromo-2-methylbenzoate

Yield: 78 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 9.57 (s, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 3.81 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); MS (ESI+): m/z 286 [M+H] ⁺ .

Intermediate 1-50: Methyl 5-bromo-3-ethanethioamido-2-methylbenzoate

Yield: 88 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, 1H), 7.83 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 3.82 (s, 3H), 2.60 (s, 3H), 2.18 (s, 3H); MS (ESI+): m/z 302 [M+H] ⁺ .

Intermediate 1-51: 7-Bromo-2,4-dimethylbenzo[d]thiazole-5-carboxylic acid Yield: 81 ; H NMR (DMSO-d ₆ , 300 MHz): δ 13.98 (bs, 1H), 7.95 (s, 1H), 2.86 (s, 6H); MS (ESI+): m/z 288 [M+H] ⁺ .

Intermediate 1-52: Methyl 5-bromo-2-methyl-3-pivalamidobenzoate

Yield: 89 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 9.16 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 1.22 (s, 9H); MS (ESI+): m/z 328.1 [M+H] ⁺ .

Intermediate 1-53: Methyl 5-bromo-3-(2,2-dimethylpropanethioamido)-2-methyl benzoate

Yield: 82 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 10.75 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 3.85 (s, 3H), 2.19 (s, 3H), 1.39 (s, 9H); MS (ESI+): m/z 344.1 [M+H] ⁺ .

Intermediate 1-54: 7-Bromo-2-(tert-butyl)-4-methylbenzo[d]thiazole-5-carboxylic acid

Yield: 85 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.28 (bs, 1H), 8.00 (s, 1H), 2.87 (s, 3H), 1.48 (s, 9H); MS (ESI+): m/z 328 [M+H] ⁺ .

Intermediate 1-55: Methyl 5-bromo-3-(3,3-dimethylbutanamido)-2-methylbenzoate

Yield: 88 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 9.48 (s, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 3.82 (s, 3H), 2.26 (s, 2H), 2.24 (s, 3H), 1.03 (s, 9H); MS (ESI+): m z 342.1 [M+H] ⁺ .

Intermediate 1-56: Methyl 5-bromo-3-(3,3-dimethylbutanethioamido)-2- methylbenzoate

Yield: 81 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.23 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 3.84 (s, 3H), 2.75 (s, 2H), 2.25 (s, 3H), 1.10 (s, 9H); MS (ESI+): m/z 358 [M+H] ⁺ .

Intermediate 1-57: 7-Bromo-4-methyl-2-neopentylbenzo[d]thiazole-5-carboxylic acid

Yield: 80 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.32 (bs, 1H), 7.99 (s, 1H), 3.04 (s, 2H), 2.87 (s, 3H), 1.04 (s, 9H); MS (ESI+): m/z 342 [M+H] ⁺ .

Intermediate 1-58: Methyl 5-bromo-2-methyl-3-(tetrahydro-2H-pyran-4- carboxamido) benzoate

Yield: 93 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 9.55 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 3.92 (m, 2H), 3.83 (s, 3H), 3.39 (m, 2H), 2.69 (m, 1H), 2.25 (s, 3H), 1.72 (m, 4H); MS (ESI+): m/z 356.1 [M+H] ⁺ . Intermediate 1-59: Methyl 5-bromo-2-methyl-3-(tetrahydro-2H-pyran-4-carbothio amido)benzoate

Yield: 94 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.37 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 3.97 (m, 2H), 3.84 (s, 3H), 3.39 (m, 2H), 3.04 (m, 1H), 2.21 (s, 3H), 1.89 (m, 2H), 1.72 (m, 2H); MS (ESI+): m/z 373 [M+H] ⁺ .

Intermediate 1-60: 7-Bromo-4-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol e- 5-carboxylic acid

Yield: 71 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.30 (bs, 1H), 8.01 (s, 1H), 3.95 (m, 2H), 3.46 (m, 2H), 3.33 (m, 1H), 2.87 (s, 3H), 2.08 (m, 2H), 1.84 (m, 2H); MS (ESI+): m/z 357.9 [M+H] ⁺ .

Preparation of the representative compounds of formula I

Example 1:

4-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-l-ethyl-7-methyl- lH-indole-6-carboxamide

To a solution of 4-bromo-l-ethyl-7-methyl-lH-indole-6-carboxylic acid (Intermediate 1-14, 150 mg, 0.532 mmol) in DMF (2 mL) was added HATU (303 mg, 0.797 mmol) and the reaction mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (105 mg, 0.691 mmol) and TEA (0.148 mL, 1.063 mmol) and the resulting reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, was added water, the solid precipitated was filtered, washed with water, dried and further purified by column chromatography using 1-2 % MeOH in chloroform to yield 125 mg (55 ) of the title compound. ^J H NMR (DMSO-de, 500 MHz) δ ppm: 11.48 (s, 1H), 8.15 (t, J=4.5 Hz, 1H), 7.50 (d, J=3 Hz, 1H), 7.06 (s, 1H), 6.37 (d, J=3 Hz, 1H), 5.86 (s, 1H), 4.42 (q, J=7 Hz, 2H), 4.28 (d, J=4.5 Hz, 2H), 2.59 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.32 (t, J=7 Hz, 3H). MS (ESI+): 417.9 [M+H] ⁺ .

The compound of example 2 was prepared analogous to the compound of example 1 by reaction of the Intermediate 1-14 with appropriate amine or amine salt.

Example 2:

4-Bromo- 1 -ethyl-7-methyl-N- ((6-methyl-2-oxo-4-propyl- 1 ,2-dihy dropyridin-3- yl)methyl)-lH-indole-6-carboxamide H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 11.50 (s, 1H), 8.12 (t, J=5 Hz, 1H), 7.51 (d, J=3 Hz, 1H), 7.06 (s, 1H), 6.38 (d, J=3 Hz, 1H), 5.89 (s, 1H), 4.43 (q, J=2.5 Hz, 2H), 4.30 (d, J=7.5 Hz, 2H), 2.60 (s, 3H), 2.53 (s, 2H), 2.12 (s, 3H), 1.54 (m, 2H), 1.32 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz, 3H). MS (ESI+): 444.7 [M+H] ⁺ .

Example 3:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-eth yl-7-methyl-4-(4- (morpholinomethyl)phenyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-l-ethyl-7-methyl-lH-indole-6-carboxamide (compound of example 1, 90 mg, 0.216 mmol) in 1,4-dioxane (10 mL) and water (5.00 mL) were added 4-(4-(4,4,5,5- tetramemyl-l,3,2-dioxaborolan-2-yl)benzyl)morpholine (79 mg, 0.259 mmol) and 2.0 M solution of Na ₂ C(¾ (0.324 mL, 0.649 mmol). Argon was bubbled through the mixture for 10 minutes at room temperature. To this PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (17.65 mg, 0.022 mmol) was added and the reaction mixture was heated at 80 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite and concentrated. Water was added and extracted with ethyl acetate and concentrated. The compound obtained was purified by column chromatography using 2-5 % MeOH in chloroform to yield a solid compound. The solid was dissolved in MeOH and ether was added. The solid precipitated was filtered and dried to yield 58 mg (51 ) of the title compound. ^J H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 11.46 (s, 1H), 8.08 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.43 (d, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 6.94 (s, 1H), 6.50 (d, J=3 Hz, 1H), 5.86 (s, 1H), 4.45 (q, J=7 Hz, 2H), 4.31 (d, J=5 Hz, 2H), 3.59 (s, 4H), 3.51 (s, 2H), 2.67 (s, 3H), 2.39 (s, 4H), 2.22 (s, 3H), 2.10 (s, 3H), 1.34 (t, J=7 Hz, 3H). MS (ESI+): 513.5 [M+H]+.

The compounds of examples 4 and 5 were prepared analogous to the compound of example 3 by reaction of 4-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-l-ethyl-3,7-dimethyl-lH-indole-6-carboxamide (prepared analogous to the compound of example 1) and compound of example 2 with appropriate reagent D, 4-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)mo holine and l-methyl-4-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)pi perazine respectively.

Example 4:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-eth yl-3,7-dimethyl-4-(4- (morpholinomethyl)phenyl)-lH-indole-6-carboxamide H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 11.44 (s, 1H), 7.99 (m, 1H), 7.31-7.34 (dd, J=8Hz, 2H), 7.24-7.27 (dd, J=8 Hz, 2H), 7.07 (d, J=3 Hz, 1H), 6.66 (s, 1H), 5.84 (s,lH), 4.34-4.36 (q, J=7 Hz, 2H), 4.26-4.28 (d, J=5 Hz, 2H), 3.55-3.58 (m, 4H), 3.32 (s, 2H), 2.64 (s, 3H), 2.28-2.37 (m, 4H), 2.08 (s, 3H), 2.08 (s, 3H), 1.67 (s, 3H) 1.29 (t, J=7 Hz, 3H). MS (ESI+): 527.5 [M+H]+.

Example 5:

l-Ethyl-7-methyl-N-((6-methyl-2-oxo-4^ropyl-l,2-dihydropy ridin-3-yl)methyl)-4-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamid e

^J H NMR (DMSO-de, 500 MHz) δ ppm: 11.49 (s, 1H), 8.34 (s, 1H), 8.05 (s, 1H), 7.76 (d, J=9 Hz, 1H), 7.42 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.89 (s, 1H), 6.47 (d, J=2.5 Hz, 1H), 5.89 (s, 1H), 4.45 (q, J=2.5 Hz, 2H), 4.32 (d, J=4 Hz, 2H), 3.53 (s, 4H), 2.67 (s, 3H), 2.53 (t, J=8 Hz, 2H), 2.42 (s, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1.55 (m, 2H), 1.33 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz, 3H). MS (ESI+): 541.4 [M+H] ⁺ .

Example 6:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l- ethyl-7-methyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide

To a solution of l-ethyl-7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)- lH- indole-6-carboxylic acid (Intermediate 1-15, 70 mg, 0.185 mmol) in DMF (2 mL) was added HATU (105 mg, 0.277 mmol) and stirred at room temperature for 5 minutes. To the reaction mixture was added 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one hydrochloride (52.3 mg, 0.277 mmol), TEA (0.038 mL, 0.277 mmol) and stirred at 70 °C for 5 hours. After completion of the reaction, the reaction mixture was quenched with water. The solid precipitated was filtered, washed with water and dried. The compound obtained was purified by column using 1-2 % MeOH in chloroform to yield 20 mg (21 ) of the title compound.

^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 8.33 (s, 1H), 8.06 (s, 1H), 7.77(d, J=8.1 Hz, 1H), 7.40(s, 1H), 6.94(d, J=9 Hz, 1H), 6.88(s, 1H), 6.45 (s, 1H), 5.85 (s, 1H), 4.44 (q, J=6.9 Hz, 2H), 4.28 (s, 2H), 3.51 (s, 4H), 2.64 (s, 3H), 2.40 (s, 4H), 2.21 (s, 6H), 2.09 (s, 3H), 1.34 (t, J=6.6 Hz, 3H). MS (ESI+): 513 [M+H] ⁺ .

The compounds of examples 7-20 were prepared analogous to the compound of example 6 by reaction of the intermediates 1-15 to 1-20 with suitable amine or amine salt. Example 7:

l-Ethyl-7-methyl-N-((6-methyl-2-oxo-4-(trifluoromethyl)-l ,2-dihydropyridin-3-yl) methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole -6-carboxamide

^J H NMR (DMSO-de, 300 MHz) δ ppm: 12.33 (s, IH), 8.50 (d, J=8.4Hz, IH), 8.10 (s, IH), 7.822 (dd, J=8.7Hz, IH), 7.43 (d, J=3.3Hz, IH), 7.02 (d , J=6.9Hz, IH), 6.46 (d, J=3Hz, IH), 6.27 (s, IH), 4.45 (d, J=6.6Hz, 2H), 4.37 (bs, 2H), 3.68 (bs, 4H), 2.90 (bs, 4H), 2.66 (s, 3H), 2.57 (s, 3H), 2.23 (s, 3H), 1.34 (t, J=6.9Hz, 3H). MS (ESI-): 566[M+H] ⁺ .

Example 8:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carbo xamide

^J H NMR (CDC1 ₃ , 300 MHz) δ ppm: 11.48 (s, IH), 8.33 (s, IH), 8.02 (s, IH), 7.77 (d, J=8.7Hz, IH), 7.61 (d, J=3Hz, IH), 6.94 (d, J=9Hz, IH), 6.87 (d, J=3.3Hz, IH), 6.52 (d, J=3Hz, IH), 5.88 (s, IH), 5.22 (m, IH), 4.32(d, J=4.5Hz, 2H), 3.52 (bs, 4H), 2.65 (s, 3H), 2.54 (m, 2H), 2.41 (s, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.56 (m, 2H), 1.46 (d, J=6.3 Hz, 6H), 0.952 (t, J=6.2Hz, 3H). MS (ESI+): 555[M+H] ⁺ .

Example 9:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-iso propyl-7-methyl-4-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamid e

^J H NMR (CDCI3, 300 MHz) δ ppm: 11.46 (s, IH), 8.33 (s, IH), 8.05 (s, IH), 7.77 (d, J=8.7Hz, IH), 7.61 (d, J=3.3Hz, IH), 6.94 (d, J=8.7Hz, IH), 6.87 (s, IH), 6.52 (d, J=3Hz, IH), 5.85 (s, IH), 5.24 (m, IH), 4.30 (d, J=4.8Hz, 2H), 3.52 (s, 4H), 2.65 (s, 3H), 2.41 (s, 4H), 2.22 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.46 (d, J=6.3 Hz, 6H). MS (ESI+): 527[M+H] ⁺ .

Example 10:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3 -yl)methyl)-4-(6-(4- methyl piperazin- 1 -yl)pyridin-3-yl)- 1 -propyl- 1 H-indole-6-carboxamide

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 11.48 (s, IH), 8.32 (s, IH), 8.05 (s, IH), 7.77 (d, J=8.7Hz, IH), 7.41 (d, J=3Hz, IH), 6.95 (d, J=8.7Hz, IH), 6.88 (s, IH), 6.45 (d, J=3.3Hz, IH), 5.88 (s, IH), 4.31 (m, 4H), 3.53 (bs, 4H), 2.63 (s, 3H), 2.49 (m, 2H), 2.43 (bs, 4H), 2.23 (s, 3H), 2.10 (s, 3H), 1.72 (m, 2H), 1.56 (m, 2H), 0.949 (d, J=7.2Hz, 3H), 0.868 (t, J=7.2Hz, 3H). MS (ESI+): 555 [M+H] ⁺ . Example 11:

l,7-Dimethyl-N-((6-methyl-2-oxo-4^ropyl-l,2-dihydropyridi n-3-yl)methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide

^J H NMR (DMSO-de, 500 MHz) δ ppm: 11.47 (s, IH), 8.38 (s, IH), 7.99 (bs,lH), 7.84 (d, J=8.5Hz, IH), 7.34 (s, IH), 7.05 (d, J=9 Hz, IH), 6.89 (s, IH), 6.41 (s, IH), 5.89 (s, IH), 4.32 (d, J=4Hz, 2H), 4.09 (s, 3H), 3.75 (bs, 4H), 3.08 (bs, 4H), 2.72 (s, 3H), 2.69 (s, 3H), 2.54 (m, 2H), 2.12 (s, 3H), 1.58 (m, 2H), 0.94 (m, 3H). MS (ESI-): 527[M+H] ⁺ .

Example 12:

l-Isobutyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihyd ropyridin-3-yl)methyl)-4- (6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxa mide

^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 11.47 (s, IH), 8.37 (s, IH), 8.05 (s, IH), 7.83 (d, J=9.0Hz, IH), 7.39 (d, J=2.7Hz, IH), 7.03 (d, J=9Hz, IH), 6.90 (s, IH), 6.44 (d, J=2.7Hz, IH), 5.89 (s, IH), 4.30 (d, J=6.9Hz, 2H), 4.17 (d, J=6.9 Hz, 2H), 3.71 (bs, 4H), 3.04 (bs, 4H), 2.67 (s, 3H), 2.62 (s, 3H), 2.11 (s, 3H), 1.97 (m, IH), 1.55 (m, 2H), 1.31 (m, 2H), 0.92 (t, J=7.2Hz, 3H), 0.82 (d, J=6.3 Hz, 6H). MS (ESI+): 569.4 [M+H] ⁺ .

Example 13:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-eth yl-3,7-dimethyl-4-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamid e

^J H NMR (DMSO-d ₆ , 500 MHz) δ ppm: 11.46 (s, IH), 8.08 (d, J=8Hz, IH), 8.00 (s, IH) 7.47-7.50 (dd, J=8 Hz, 3Hz, IH), 7.14 (d, J=3Hz, IH), 6.84-6.87 (d, J=8Hz, 2H), 6.64 (s, IH), 5.84 (s, IH), 4.33-4.36 (q, J=7 Hz, 2H), 4.26-4.28 (d, J=5Hz, 2H), 3.50 (s, 4H), 2.63 (s, 2H), 2.41 (m, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.77 (s, 3H), 1.26-1.28 (m, 3H), 0.82-0.85 (m, 3H). MS (ESI+): 527.5 [M+H]+.

Example 14:

l-Ethyl-7-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydro isoquinolin-4-yl)methyl)- 4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carbo xamide

^J H NMR (DMSO-de, 300 MHz) δ ppm: 11.485 (bs, IH), 8.33 (s, IH), 8.03 (s, IH), 7.77 (d, J=7.8Hz, IH), 7.42 (s, IH), 6.94 (d, J=9Hz, IH), 6.88 (s, IH), 6.46 (s, IH), 4.44 (q, J=6.6Hz, 2H), 4.33 (s, 2H), 3.52 ( s, 4H), 2.76 (bs, 2H), 2.66 (s, 3H), 2.41 (s, 6H), 2.22 (s, 3H), 2.09 (s, 3H), 1.63 (bs, 4H), 1.34 (t, 3H). MS (ESI+): 553 [M+H] ⁺ .

Example 15:

l-Ethyl-7-methyl-N-((l-methyl-3-oxo-3,5,6,7-tetrahydro-2H -cyclopenta[c]pyridin-4- yl) methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole -6-carboxamide H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 11.26 (s, IH), 8.33 (s, IH), 7.77 (d, J=8.4Hz, IH), 7.42 (s, IH), 6.94 (m, 2H), 6.46 (s , IH), 4.44 (bs, J=6.6Hz, 2H), 4.34 (bs, IH), 4.25 (bs, IH), 3.25 (bs, 4H), 2.65 (s, 3H), 2.41 (bs, 4H), 2.22 (s,3H), 2.08 (s, 3H), 1.95 (m, 4H), 1.35 (m, 5H). MS (ESI-): 539[M+H] ⁺ .

Example 16:

l-Isopropyl-7-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexah ydroisoquinolin-4- yl)methyl) -4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carb oxamide

^J H NMR (CDC1 ₃ , 300 MHz) δ ppm: 11.49 (s, IH), 8.33 (s, IH), 8.02 (s, IH), 7.77 (d, J=8.4Hz, IH), 7.61 (s, IH), 6.94 (d, J=9Hz, IH), 6.87 (s, IH), 6.52 (s, IH), 5.23 (m, IH), 4.33 (m, 2H), 3.52 (s, 4H), 2.75 (m, 2H), 2.66 (s, 3H), 2.41 (bs, 6H), 2.22 (s, 3H), 2.09 (s, 3H), 1.63 (s, 4H), 1.46 (d, J=6.6Hz, 6H). MS (ESI+): 567 [M+H] ⁺ .

Example 17:

1, 7-Dimethyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinol in-4-yl)methyl)-4-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamid e

JH NMR (DMSO-de, 300 MHz) δ ppm: 11.54 (bs, IH), 8.45 (d, J=8.4 Hz, IH), 8.35 (s, IH), 8.01 (s, IH), 7.80 (d, J=8.7Hz, IH), 7.33 (d, J=3Hz, IH), 6.98(d, J=9Hz, IH), 6.40(d, J=3.9Hz, IH), 4.32 (d, J=4.5Hz, 2H), 4.08 (s, 3H), 3.60 (bs, 4H), 3.16 (s, 3H), 2.71 (bs, 4H), 2.68 (bs, 2H), 2.41 (s, 3H), 2.36 (bs, 2H), 2.11 (s, 3H), 1.22 (bs, 4H). MS (ESI-): 539 [M+H] ⁺ .

Example 18:

l-Isobutyl-7-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahy droisoquinolin-4- yl)methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-ind ole-6-carboxamide

^J H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 11.53 (s, IH), 8.35 (s, IH), 8.05 (s, IH), 7.79 (d, J=8.4Hz, IH), 7.46 (s, IH), 7.0 (d, J=8.4Hz, IH), 6.89 (s, IH), 6.44 (s, IH), 4.32 (d, J=6.9Hz, 2H), 4.16 (d, J=6.9Hz, 2H), 3.63 (s, 4H), 2.9 (m, 2H), 2.76 (m, 4H), 2.62 (s, 3H), 2.37 (bs, 3H), 2.09 (s, 3H), 1.97 (s, IH), 1.64 (s, 4H), 1.38 (m, 2H), 0.82 (d, J=6.0Hz, 6H). MS (ESI+): 581.4 [M+H] ⁺ .

Example 19:

l-Ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydrop yridin-3-yl)methyl)-4-(6- morpholinopyridin-3-yl)-lH-indole-6-carboxamide

^J H NMR (DMSO-de, 300 MHz) δ ppm: 11.49 (s, IH), 8.35 (s, IH), 8.05 (s, IH), 7.80 (d, J=8.4Hz, IH), 7.43 (s, IH), 6.96 (d, J=9Hz, IH), 6.89 (s, IH), 6.46 (s, IH), 5.49 (s, IH), 4.45 (q, J=6.9Hz, 2H), 4.30 (s, 2H), 3.72 (s, 4H), 3.48 (s, 4H), 2.72 (s, 3H), 2.61 (m, 2H), 2.11 (s, 3H), 1.56 (m, 2H), 1.34 (t, J=6.6Hz, 3H), 0.951 (t, J=6.9Hz, 3H). MS (ESI+): 528

[M+H] ⁺ .

Example 20:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(6-morpholinopyridin-3-yl)-lH-indole-6-carboxamide

^J H NMR (CDCI ₃ , 300 MHz) δ ppm: 11.48 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.79 (d, J=6.6Hz, 1H), 7.61 (d, J=3.3Hz, 1H), 6.96 (d, J=9Hz, 1H), 6.88 (s, 1H), 6.52 (d, J=3.3Hz, 1H), 5.88 (s, 1H), 5.22 (m, 1H), 4.32 (d, J=4.8Hz, 2H), 3.72 (s, 4H), 3.48 (s, 4H), 2.66 (s, 3H), 2.54 (m, 2H), 2.11 (s, 3H), 1.56 (m, 2H), 1.46 (d, J=6.3 Hz, 6H), 0.95 l(t, J=7.2Hz, 3H). MS (ESI+): 542 [M+H] ⁺ .

Example 21:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-eth yl-7-methyl-4-(4- (morpholinomethyl)phenyl)indoline-6-carboxamide

To a solution of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-l-eth yl- 7-methyl-4-(4-(mo holinomethyl)phenyl)-lH-indole-6-carboxamide (Example 3, 25 mg, 0.049 mmol) in acetic acid (2 mL) was added sodium cyanoborohydride (12.26 mg, 0.195 mmol) and stirred at room temperature for 8 hours. After completion of the reaction, the solvent was removed, and added saturated solution of NaHCC>3. The solid obtained was filtered, washed with water and dried to yield 17 mg (64 %) of title compound.

JH NMR (DMSO-de, 500 MHz) δ ppm: 11.46 (s, 1H), 8.06 (s, 1H), 7.39 (d, J=6Hz, 2H), 7.35 (d, J=6Hz, 2H), 6.67 (s, 1H), 5.85 (s, 1H), 4.25 (d, J=2.5Hz, 2H), 3.58 (s, 4H), 3.48 (s, 2H), 3.34 (s, 2H), 3.19 (d, J=5.5Hz, 2H), 2.97 (q, 2H), 2.37 (s, 4H), 2.22 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.07 (s, 3H). MS (ESI+): 515.3 [M+H] ⁺ .

Example 22:

4-Bromo-l-ethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropy ridin-3-yl)methyl)-lH- indole-6-carboxamide

To a solution of 4-bromo-l-ethyl-lH-indole-6-carboxylic acid (1-24, 210 mg, 0.783 mmol) in DMF (2 mL) was added HATU (447 mg, 1.175 mmol) and stirred at RT for 10 minutes. 3-(Aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one (184 mg, 1.018 mmol) and triethyl amine (0.218 mL, 1.567 mmol) was added and stirred the reaction mass at 40 °C for 16 h. After completion of the reaction, water was added and the solid obtained was filtered, washed with water and dried which was further purified by column chromatography (silica gel, 0.5-1 % MeOH in chloroform) to obtain the compound. Yield 185 mg (54 ); H NMR (DMSO-d ₆ ; 300 MHz): δ 11.51 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 2.7 Hz, 1H), 6.42 (s, 1H), 5.89 (s, 1H), 4.35 (d, J= 3.9 Hz, 2H), 4.26 (q, J= 7.2 Hz, 2H), 2.49 (m, 2H), 2.12 (s, 3H), 1.47-1.49 (m 2H), 1.36 (t, J=

6.9 Hz, 3H), 0.85 (t, J= 6.9 Hz, 3H); MS (ESI+): 431.8 [M+H] ⁺ ; HPLC purity: 97.89 %. Example 23:

l-Ethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl)-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-ethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyrid in-3- yl)methyl)-lH-indole-6-carboxamide (Example 22, 125 mg, 0.290 mmol) and l-methyl-4- (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl )piperazine (114 mg, 0.378 mmol) in 1,4-dioxane (2 mL) was added 2 M solution of Na ₂ C0 ₃ (0.436 mL, 0.871 mmol) and stirred at RT for 15 minutes with argon bubbling. PdCi ₂ (dppf)-CH ₂ Ci ₂ adduct (23.72 mg, 0.029 mmol) was added and stirred at 85 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to RT and filtered through celite, water was added and extracted with ethyl acetate. The organic layer was washed with water and concentrated which was further purified by column chromatography (5-10 % MeOH in chloroform) to obtain the title compound.

Yield: 68 mg (43 ); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.51 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.86 (d, J = 9 Hz, 1H), 7.57 (s, 2H), 6.96 (d, J= 8.7 Hz, 1H), 6.54 (d, J= 3 Hz, 1H), 5.89 (s, 1H), 4.38 (d, J= 4.5 Hz, 2H), 4.28 (q, J= 6.9 Hz, 2H), 3.54 (s, 4H), 2.49 (m, 2H), 2.41 (s, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.46-1.53 (m 2H), 1.38 (t, J= 7.2 Hz, 3H), 0.86 (t, J= 7.2 Hz, 3H); MS (ESI+): 527.5 [M+H] ⁺ ; HPLC purity: 96.98 %.

Example 24:

l-Ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydrop yridin-3-yl)methyl)-4-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamid e hydrochloride salt.

To a solution of l-ethyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyri din-3- yl)methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-ind ole-6-carboxamide

(Example 5, 20 mg, 0.037 mmol) in THF (2 mL) was added 2 N hydrogen chloride (0.074 mL, 0.148 mmol) in diethyl ether and stirred at RT for 1 h and the solid obtained was separated and dried to obtain the title compound.

Yield: 15 mg; ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.56 (s, 1H), 10.80 (s, 1H), 8.35 (s, 1H),

8.10 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.19 (d, J= 9 Hz, 1H), 6.93 (s, 1H), 6.45 (d, J= 3 Hz, 1H), 5.92 (s, 1H), 4.45-4.50 (m, 2H), 4.32 (s, 2H), 3.51 (d, J= 11.4 Hz, 4H), 3.36 (t, J= 13.2 Hz, 2H), 3.13 (m 2H), 2.81 (d, J= 3.6 Hz, 2H), 2.67 (s, 3H), 2.49 (m, 2H), 2.12 (s, 3H), 1.53-1.56 (m 2H), 1.32 (t, J= 6.3 Hz, 3H), 0.92 (t, J= 7.2 Hz, 3H); HPLC purity: 97.74 %.

Example 25:

4-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)me thyl)-7-methyl-lH- indole-6-carboxamide

To a solution of 4-bromo-7-methyl-lH-indole-6-carboxylic acid (1-24, 325 mg, 1.279 mmol) in DMF (15 mL) was added HATU (730 mg, 1.919 mmol) and stirred at RT for 10 minutes. 3-(Aminomethyl)-4,6-dimethylpyridin-2(lH)-one (253 mg, 1.663 mmol) and TEA (0.357 mL, 2.56 mmol) were added and stirred at 45 °C for 16 h. After completion of the reaction, water was added, the solid obtained was filtered and purified by column chromatography (silica gel, 2-5 % MeOH in chloroform) to obtain the title compound. Yield 380 mg (76 ); ^J H NMR (DMSO-de; 300 MHz): δ 11.59 (s, 1H), 11.49 (s, 1H), 8.31(s, 1H), 7.52 (t, J= 2.7 Hz, 1H), 7.14 (s, 1H), 6.39 (s, 1H), 5.86 (s, 1H), 4.26 (d, J= 4.8 Hz, 2H), 2.45 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H); MS (ESI+): 388.2 [M+H] ⁺ ; HPLC purity 99.37 %.

Example 26:

4-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-7-methyl indoline- 6-carboxamide

To a solution of 4-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-7- methyl-lH-indole-6-carboxamide (Example 25, 150 mg, 0.386 mmol) in acetic Acid (2 mL) was added sodium cyanoborohydride (243 mg, 3.86 mmol) and stirred at RT for 16 h. After completion of the reaction, solvent was removed, NaHC(¾ solution was added and extracted with ethyl acetate. The organic layer was purified using column chromatography (silica gel, 5-20% ethyl acetate in pet ether) to obtain the title compound.

Yield: 50 mg (27 %); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.47 (s, 1H), 8.04 (s, 1H), 6.56 (s, 1H), 5.84 (s, 1H), 5.72 (s, 1H), 4.20 (d, J= 4.8 Hz, 2H), 3.49 (t, J= 8.1 Hz, 2H), 2.92 (t, J= 8.1 Hz, 2H), 2.17 (t, J= 5.7 Hz, 1H), 2.16 (s, 3H), 2.10 (s, 3H), 1.94 (s, 3H); MS (ESI+): 391.2 [M+H] ⁺ ; HPLC purity: 80.93 %.

Example 27:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(6-(4-methyl piperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide To a solution of 4-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-7- methyl-lH-indole-6-carboxamide (Example 25, 125 mg, 0.322 mmol) and l-methyl-4-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)pi perazine (127 mg, 0.419 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was added 2M Na ₂ C0 ₃ (0.483 mL, 0.966 mmol) and argon was bubbled at RT for 10 minutes and added PdCl2(dppf)-CH2Ci2 Adduct (26.3 mg, 0.032 mmol) catalyst and stirred the reaction mixture at 80 °C for 5 h. After completion of the reaction, cooled the reaction mixture to RT, filtered through celite, water was added, extracted with ethyl acetate and concentrated to obtain the crude product. The crude product obtained was stirred in ethyl acetate and filtered to obtain the title compound.

Yield: 70 mg (43 %); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.48 (s, 1H), 11.33 (s, 1H), 8.41 (s, 1H), 8.05 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 6.53 (s, 1H), 5.86 (s, 1H), 4.30 (d, J= 4.8 Hz, 2H), 3.52 (s, 4H), 2.52 (s, 3H), 2.41 (s, 4H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H); MS (ESI+): 485.2 [M+H] ⁺ ; HPLC purity: 96.29 %.

Example 28:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(6-(4- methyl piperazin-l-yl)pyridin-3-yl)-l-((tetrahydro-2H-pyran-4-yl)me thyl)-lH-indole- 6-carboxamide

To a solution of 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l-((tetr ahydro-2H- pyran-4-yl)methyl)-lH-indole-6-carboxylic acid (1-28, 80 mg, 0.178 mmol) in DMF (8 mL) was added HATU (102 mg, 0.268 mmol) and stirred at RT for 10 minutes. 3- (Aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one hydrochloride (50.2 mg, 0.232 mmol) and TEA (0.050 mL, 0.357 mmol) were added and stirred the reaction mass at 65- 70 °C for 16 h. After completion of the reaction, solvent was removed and the residue was purified by column chromatography (silica gel, 5-10% MeOH in chloroform) to obtain the title compound.

Yield 10 mg (8 %); ^J H NMR (CDC1 ₃ ; 300 MHz): δ 11.47 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.40 (s, 1H), 7.02 (d, J= 9 Hz, 1H), 6.89 (s, 1H), 6.42 (s, 1H), 5.88 (s, 1H), 4.27-4.30 (m, 4H), 3.60-.377 (m, 4H), 2.87-3.04 (m, 8H), 2.64 (s, 3H), 2.10 (s, 3H), 1.85-1.92 (m, 4H), 1.53-1.55 (m, 4H), 1.21 (s, 4H), 0.91 (t, J= 7.2 Hz, 3H); MS (ESI+): 611.2 [M+H] ⁺ ; HPLC purity: 91.20 %. Example 29:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(6-(4-methyl piperazin-l-yl)pyridin-3-yl)-l-((tetrahydro-2H-pyran-4-yl)me thyl)-lH-indole-6- carboxamide

To a solution of 7-methyl-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-l-((tetr ahydro-2H- pyran-4-yl)methyl)-lH-indole-6-carboxylic acid (1-28, 80 mg, 0.178 mmol) in DMF (8 mL) was added 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethy lisouronium, hexafluoro phosphate(V) salt (102 mg, 0.268 mmol) and stirred at RT for 5 minutes. 3- (Aminomethyl)-4,6-dimethylpyridin-2(lH)-one hydrochloride (43.7 mg, 0.232 mmol) and triethylamine (27.1 mg, 0.268 mmol) were added and stirred the reaction mixture at 65-70 °C for 16 h. After completion of the reaction, solvent was removed and the residue was purified by column chromatography (silica gel, 5-10% MeOH in chloroform) to obtain the title compound.

Yield: 52 mg (44 %); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.46 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.80 (d, J= 6.6 Hz, 1H), 7.39 (d, J= 3 Hz, 1H), 6.99 (d, J= 8.7 Hz, 1H), 6.89 (s, 1H), 6.42 (d, J= 3 Hz, 1H), 5.85 (s, 1H), 4.24-4.30 (m, 5H), 3.80 (d, J= 11.1 Hz, 2H), 3.67 (s, 4H), 3.10-3.20 (m, 4H), 2.83 (s, 4H), 2.63 (s, 3H), 2.20 (s, 3H), 2.09 (s, 3H), 1.85-1.95 (m, 1H), 1.28 (s, 4H); MS (ESI+): 583.2 [M+H] ⁺ ; HPLC purity: 89.97 %.

Example 30:

4-Bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl- l,2-dihydro pyridin-3- yl) methyl) - lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-lH-indole-6-carboxylic acid (3 g, 10.13 mmol) in DMF (15 mL) was added HATU (5.78 g, 15.19 mmol) and stirred at RT for 30 minutes and added 3-(aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one (2.374 g, 13.17 mmol) and DIPEA (3.54 mL, 20.26 mmol) and stirred the reaction mixture at 65 °C for 16 h. After completion of the reaction, water was added and the solid obtained was filtered, dried and further purified by column chromatography (silica gel, 1% MeOH in chloroform) to obtain the title compound.

Yield: 3.3 g (62 %); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.49 (s, 1H), 8.10 (s, 1H), 7.68 (d, J= 10 Hz, 1H), 7.03 (s, 1H), 6.42 (d, J= 3 Hz, 1H), 5.88 (s, 1H), 5.13-5.18 (m, 1H), 4.27 (d, J= 4.5 Hz, 2H), 2.58 (s, 3H), 2.48-2.52 (m, 2H), 2.10 (s, 3H), 1.49-1.56 (m, 2H), 1.43 (d, J= 6.6 Hz, 6H), 0.92 (t, J= 7.2 Hz, 3H); MS (ESI+): 459.2 [M+H] ⁺ ; HPLC purity: 99.00 %. Example 31:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(pyrido[2,3-b]pyrazin-7-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 125 mg, 0.273 mmol) and 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrido[2,3-b]py razine (91 mg, 0.355 mmol) in 1,4-dioxane (5 mL) added water (2.500 mL) and 2 M solution of Na ₂ C0 ₃ (0.409 mL, 0.818 mmol) and bubbled argon gas for 30 minutes. To the reaction mixture, PdCl ₂ (dppf)- CH ₂ C1 ₂ adduct (22.27 mg, 0.027 mmol) was added and stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 45 mg (31 ); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.49 (s, 1H), 9.45 (s, 1H), 9.14 (s, 1H), 9.10 (s, 1H), 8.67 (d, J= 3 Hz, 1H), 8.17 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 7.22 (s, 1H), 6.68 (d, J= 3.3 Hz, 1H), 5.88 (s, 1H), 5.27-5.28 (m, 1H), 4.33 (d, J= 4.5 Hz, 2H), 2.73 (s, 3H), 2.48-2.52 (m, 2H), 2.10 (s, 3H), 1.53-1.56 (m, 2H), 1.49 (d, J= 6.6 Hz, 6H), 0.91 (t, J= 7.2 Hz, 3H); MS (ESI+): 509.3 [M+H] ⁺ ; HPLC purity: 95.40 %.

Example 32:

4-(2-(Benzyloxy)-5-chloropyridin-3-yl)-l-isopropyl-7-methyl- N-((6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxami de

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 125 mg, 0.273 mmol) and (2-(benzyloxy)-5-chloropyridin-3-yl)boronic acid (144 mg, 0.545 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and 2 M solution of Na ₂ C0 ₃ (0.409 mL, 0.818 mmol) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)CH ₂ Cl ₂ adduct (66.8 mg, 0.082 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 3 % MeOH in chloroform) to obtain the title compound.

Yield: 42 mg (25 ); ^J H NMR (DMSO-d ₆ ; 500 MHz): δ 11.48 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.22-7.25 (m, 5H), 6.98 (s, 1H), 6.28 (d, J= 3 Hz, 1H), 5.88 (s, 1H), 5.32 (s, 2H), 5.21-5.23 (m, 1H), 4.32 (d, J= 4.5 Hz, 2H), 2.68 (s, 3H), 2.50- 2.53 (m 2H), 2.10 (s, 3H), 1.52-1.56 (m, 2H), 1.46 (d, J= 7.5 Hz, 6H), 0.91 (t, J= 7.5 Hz, 3H); MS (ESI+): 597.3 [M+H] ⁺ ; HPLC purity: 95.70 %.

Example 33:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(2-morpholinopyridin-3-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 125 mg, 0.273 mmol) and 4- (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl )mo holine (103 mg, 0.355 mmol) in 1,4-dioxane (5 mL), was added water (2.500 mL) and 2 M Na ₂ C0 ₃ (0.409 mL, 0.818 mmol) solution and bubbled argon gas for 30 minutes. To the reaction mixture, was added PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (22.27 mg, 0.027 mmol) and stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 0.1-3 % MeOH in chloroform) to obtain the title compound.

Yield: 65 mg (41 ); ^J H NMR (DMSO-d ₆ ; 500 MHz): δ 11.49 (s, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.50-7058 (m, 2H), 7.03 (s, 1H), 6.97 (d, /= 4.8 Hz, 1H), 6.30 (s, 1H), 5.88 (s, 1H), 5.21 (m, 1H), 4.48 (s, 1H), 4.32 (s, 2H), 4.20 (s, 1H), 3.32 (s, 4H), 2.92 (s, 4H), 2.67 (s, 3H), 2.50-2.53 (m 2H), 2.10 (s, 3H), 1.52-1.55 (m, 2H), 1.46 (d, J= 6.6 Hz, 6H), 0.91 (t, J= 7.2 Hz, 3H); MS (ESI+): 542.4 [M+H] ⁺ ; HPLC purity: 92.84 %.

Example 34:

tert-Butyl 4-(5-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-lH-indol-4-yl)pyridin- 2-yl)piperazine-l- carboxylate

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and tert-butyl 4- (5- (4,4,5 , 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)pyridin-2-yl)piperazine- 1 - carboxylate (357 mg, 0.916 mmol) in 1,4-dioxane (5 mL), was added water (2.500 mL) and bubbled Argon gas for 30 minutes. To the reaction mixture, PdCl ₂ (dppf)-CH ₂ Ci ₂ adduct (53.4 mg, 0.065 mmol) was added and stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound. Yield: 280 mg (66 ); H NMR (DMSO-de; 300 MHz): δ 11.48 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.78 (d, /= 8.7 Hz, 1H), 7.61 (d, /= 3.3 Hz, 1H), 6.95 (d, J= 9 Hz, 1H), 6.87 (s, 1H), 6.51 (d, J= 3.3 Hz, 1H), 5.88 (s, 1H), 5.19-5.24 (m, 1H), 4.31 (d, J= 4.5 Hz, 2H), 3.53 (s, 4H), 3.44 (s, 4H), 2.65 (s, 3H), 2.49-2.50 (m, 2H), 2.10 (s, 3H), 1.50-1.63 (m, 2H), 1.42-1.46 (s, 15H), 0.92 (t, /=7.2 Hz, 3H); MS (ESI+): 641.5 [M+H] ⁺ ; HPLC purity: 98.33 %.

Example 35:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(6-(piperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide hydrochloride

To a solution of tert-butyl 4-(5-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-lH-indol-4-yl)pyridin- 2-yl)piperazine-l- carboxylate (Example 34, 150 mg, 0.234 mmol) in MeOH (2 mL) was added IN hydrogen chloride (2.341 mL, 2.341 mmol) in diethyl ether and stirred at RT for 16 h. After completion of the reaction, the solvent was removed, added diethyl ether, the solid obtained was filtered, washed with ether and dried to obtain the title compound.

Yield: 100 mg (70 ); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.65 (s, 1H), 9.52 (s, 1H), 8.28 (s, 1H), 8.16 (d, /= 5.4 Hz, 1H), 8.11 (s, 1H), 7.78 (d, J= 3 Hz, 1H), 7.33 (d, J= 9 Hz, 1H), 6.95 (s, 1H), 6.50 (d, /= 3 Hz, 1H), 5.94 (s, 1H), 5.21-5.25 (m, 1H), 4.32 (d, J= 4.5 Hz, 2H), 3.94 (s, 4H), 3.38 (s, 4H), 2.67 (s, 3H), 2.49-2.50 (m, 2H), 2.12 (s, 3H), 1.51-1.58 (m, 2H), 1.45 (d, J= 6.3 Hz, 6H), 0.92 (t, /=7.2 Hz, 3H); MS (ESI+): 541.5 [M+H] ⁺ ; HPLC purity: 98.19 %.

Example 36:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(6-(piperazin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide

To a solution of l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3- yl)memyl)-4-(6-(piperazin-l-yl)pyridin-3-yl)-lH-indole-6-car boxarnide hydrochloride (Example 35, 50 mg) in water, NaHCC>3 solution was added and the solid obtained was filtered, washed with water and dried to obtain the title compound.

Yield: 45 mg (97 ); ^J H NMR (DMSO-d ₆ ; 300 MHz): δ 11.48 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 6.87 (s, 2H), 6.51 (s, 1H), 5.88 (s, 1H), 5.21 (s, 1H), 4.31 (m, 2H), 3.44 (s, 4H), 2.79 (s, 4H), 2.65 (s, 3H), 2.49-2.50 (m, 2H), 2.10 (s, 3H), 1.53 (s, 2H), 1.45 (s, 6H), 0.92 (s, 3H); MS (ESI+): 541.5 [M+H] ⁺ ; HPLC purity: 97.48 %. Example 37:

4-(2-Fluoro-[l,l'-biphenyl]-4-yl)-l-isopropyl-7-methyl-N-((6 -methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2-fluoro-[l,l'-biphenyl]-4-yl)boronic acid (198 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. To the reaction mixture, PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and stirred at 80- 85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 182 mg (33 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 7.2 Hz, 2H), 7.66 (m, 4H), 7.49 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 6.31 (s, 1H), 5.87 (s, 1H), 5.22 (m, 1H), 4.30 (d, J = 6.9 Hz, 2H), 2.68 (s, 3H), 2.09 (s, 3H), 1.52 (m, 3H), 1.47 (d, J = 6.6 Hz, 5H), 0.91 (d, J = 7.2 Hz, 3H); MS (ESI+): 550.4 [M+H] ⁺ ; HPLC purity: 92.67 %.

Example 38:

4-(4-Cyclohexylphenyl)-l-isopropyl-7-methyl-N-((6-methyl-2-o xo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (4-cyclohexylphenyl)boronic acid (186 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mixture was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 274 mg (51 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, 1H), 8.02 (m, 1H), 7.60 (d, / = 3.3 Hz, 1H), 7.50 (d, / = 7.8 Hz, 2H), 7.31 (d, / = 7.8 Hz, 2H), 6.89 (s, 1H), 6.54 (d, / = 3.0 Hz, 1H), 5.87 (s, 1H), 5.21 (m, 1H), 4.31 (d, / = 4.5 Hz, 2H), 3.32 (s, 3H), 2.65 (s, 3H), 2.53 (m, 2H), 2.09 (s, 3H), 1.72 (m, 4H), 1.55 (m, 2H), 1.50 (m, 7H), 1.39 (m, 3H), 0.91 (d, / = 7.2 Hz, 3H); MS (ESI+): 538.5 [M+H] ⁺ ; HPLC purity: 97.02 %. Example 39:

4-(4-(l,l,l,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)-l- isopropyl-7-methyl-N- ((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-lH -indole-6- carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (4-(l,l, l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)boronic acid (264 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Ci ₂ adduct (53.4 mg, 0.065 mmol) was added and reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (5 % MeOH in chloroform) to obtain the title compound.

Yield: 248 mg (40 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, 1H), 8.76 (s, 1H), 8.22 (s, 1H), 7.76 (s, 4H), 7.66 (m, 1H), 6.98 (s, 1H), 6.58 (d, J = 3.3 Hz, 1H), 5.88 (s, 1H), 5.24 (m, 1H), 4.21 (d, J = 4.5 Hz, 2H), 2.68 (s, 3H), 2.53 (m, 2H), 2.10 (s, 3H), 1.53 (m, 3H), 1.45 (d, J = 6.3 Hz, 5H), 0.92 (d, J = 7.2 Hz, 3H); MS (ESI+): 622.3 [M+H] ⁺ ; HPLC purity: 92.31 %.

Example 40:

4-(3,5-Dimethylisoxazol-4-yl)-l-isopropyl-7-methyl-N-((6-met hyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (129 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound. Yield: 223 mg (47 ); H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 5.88 (s, 1H), 5.21 (m, 1H), 4.30 (d, J = 4.5 Hz, 2H), 2.66 (s, 3H), 2.25 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.52 (m, 5H), 1.45 (d, J = 6.3 Hz, 5H), 0.91 (m, 3H); MS (ESI+): 475.4 [M+H] ⁺ ; HPLC purity: 93.01 %.

Example 41:

4-(3,5-Dimethyl-lH-pyrazol-4-yl)-l-isopropyl-7-methyl-N-((6- methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 - dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (3,5-dimethyl-lH-pyrazol-4-yl)boronic acid (128 mg, 0.916 mmol) in 1,4- dioxane (5 mL), was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mixture was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (5 % MeOH in chloroform) to obtain the title compound.

Yield: 166 mg (35 ); ^J H NMR (DMSO-de, 300 MHz): δ 12.23 (s, 1H), 11.47 (s, 1H), 7.91 (s, 1H), 7.53 (s, 2H), 6.65 (s, 1H), 6.12 (d, J = 3.0 Hz, 1H), 5.87 (s, 1H), 5.19 (m, 1H), 4.30 (d, J = 4.8 Hz, 2H), 2.64 (s, 3H), 2.10 (s, 3H), 2.10 (s, 3H), 2.02 (s, 5H), 1.55 (m, 1H), 1.46 (s, 3H), 1,44 (s, 3H), 0.91 (m, 3H); MS (ESI+): 474.8 [M+H] ⁺ ; HPLC purity: 96.08 %.

Example 42:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(naphthalen-l-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 - dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and naphthalen-l-ylboronic acid (286 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound. Yield: 192 mg (38 ); H NMR (DMSO-d ₆ , 500 MHz): δ 11.45 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.53 (m, 2H), 7.48 (m, 1H), 7.39 (m, 1H), 6.90 (s, 1H), 5.86 (s, 1H), 5.27 (m, 1H), 4.32 (d, J = 4.5 Hz, 2H), 2.74 (s, 3H), 2.09 (s, 3H), 1.55 (m, 6H), 1.46 (d, J = 6.0 Hz, 5H), 0.89 (t, J = 7.0 Hz, 3H); MS (ESI+): 506.5 [M+H] ⁺ ; HPLC purity: 95.07 %.

Example 43:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-lH-indole-6-carb oxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and

(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)boronic acid (203 mg, 0.916 mmol) in 1,4- dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes.

PdCi2(dppf)-CH2Cl2 adduct (53.4 mg, 0.065 mmol) and the reaction mass was stirred at

80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 261 mg (47 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 6.90 (d, J = 6.6 Hz, 2H), 6.51 (s, 1H), 5.86 (s, 1H), 5.23 (m, 2H), 4.31 (d, J = 4.2 Hz, 2H), 3.89 (m, 2H), 3.50 (t, J = 9.9 Hz, 2H), 2.67 (s, 3H), 2.54 (m, 2H), 2.10 (s, 3H), 2.05 (m, 2H), 1.66 (m, 4H), 1.46 (m, 7H), 0.92 (d, J = 7.2 Hz, 3H); MS (ESI+): 557.7 [M+H] ⁺ ; HPLC purity: 98.89 %.

Example 44:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(5,6,7,8-tetrahydronaphthalen-2-yl)-lH-indole-6-carboxamid e

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (161 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi2(dppf)CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (5 % MeOH in chloroform) to obtain the title compound.

Yield: 183 mg (36 ); ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.46 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 7.15 (m, 1H), 7.09 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 5.98 (s, 1H), 5.88 (s, 1H), 5.22 (m, 1H), 4.31 (d, J = 4.5 Hz, 2H), 2.81 (d, J = 5.0 Hz, 1H), 2.68 (s, 3H), 2.37 (d, J = 5.0 Hz, 1H), 2.10 (s, 3H), 1.71 (m, 2H), 1.58 (m, 4H), 1.52 (m, 3H), 1.50 (m, 3H), 1.24 (m, 4H), 0.92 (d, J = 7.2 Hz, 3H); MS (ESI+): 510.4 [M+H] ⁺ ; HPLC purity: 97.67 %.

Example 45:

4-(3-Fluoro-[l,l'-biphenyl]-4-yl)-l-isopropyl-7-methyl-N- ((6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (3-fluoro-[l,l'-biphenyl]-4-yl)boronic acid (198 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield 127 mg (23 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.67 (m, 3H), 7.50 (m, 3H), 6.94 (s, 1H), 6.32 (s, 1H), 5.88 (s, 1H), 5.23 (m, 1H), 4.30 (d, J = 6.9 Hz, 2H), 2.69 (s, 3H), 2.54 (m, 2H), 2.10 (s, 3H), 1.52 (m, 3H), 1.48 (d, J = 6.6 Hz, 5H), 0.92 (d, J = 7.2 Hz, 3H); MS (ESI+): 550.6 [M+H] ⁺ ; HPLC purity: 96.11 .

Example 46:

4-(4-(5-Amino-l,3,4-thiadiazol-2-yl)phenyl)-l-isopropyl-7-me thyl-N-((6-methyl-2- oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-car boxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (5-amino-l,3,4-thiadiazol-2-yl)boronic acid(133 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (5 % MeOH in chloroform) to obtain the title compound.

Yield: 95 mg (17 ); ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.47 (s, 1H), 8.15 (t, J = 5.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 3.0 Hz, 1H), 7.40 (s, 2H), 7.00 (s, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.90(s, 1H), 5.25 (m, 1H), 4.34 (d, J = 5.0 Hz, 2H), 2.69 (s, 3H), 2.55 (m, 2H), 2.12 (s, 3H), 1.60 (m, 2H), 1.48 (d, J = 6.5 Hz, 6H), 0.94 (d, J = 7.0 Hz, 3H); MS (ESI+): 555.5 [M+H] ⁺ ; HPLC purity: 96.80 %.

Example 47:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 1H, 1 Ή- [4,5 ' -biindole] -6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (lH-indol-5-yl)boronic acid (148 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Ci2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 32 %. ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.47 (s, 1H), 11.17 (s, 1H), 8.04 (s, 1H), 7.56 (s, 1H), 7.40 (m, 2H), 7.14 (m, 2H), 7.03 (s, 1H), 6.36 (m, 2H), 5.87 (s, 1H), 5.26 (m, 1H), 4.32 (d, 2H, J=4.2Hz), 2.69 (s, 3H), 2.49 (m, 2H), 2.09 (s, 3H), 1.57 (m, 2H), 1.48 (d, 6H, J=6.3Hz), 0.93 (m, 3H) ; MS (ESI+): m/z 494 (M+) ⁺ ; HPLC purity: 97.43 %. Example 48:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 1H, 1 Ή- [4,4' -biindole] -6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (lH-indol-4-yl)boronic acid (148 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi2(dppf)-CH2Ci2 adduct (53.4 mg, 0.065 mmol) and stirred reaction mass at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water and extracted with ethyl acetate, concentrated and purified by column (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 30 ; ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.47 (s, 1H), 11.13 (s, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.47 (m, 1H), 7.37 (m, 2H), 6.92 (s, 1H), 6.57 (s, 1H), 6.46 (s, 1H), 5.88 (s, 1H), 5.26 (m, 1H), 4.33 (d, 2H, J=4.5Hz), 2.66 (s, 3H), 2.10 (m, 2H), 2.07 (s, 3H), 1.56 (m, 2H), 1.47 (d, 6H, J=6.3Hz), 0.95 (t, J=7.2Hz, 3H) ; MS (ESI+): m/z 494 (M+) ⁺ ; HPLC purity: 98.61 %.

Example 49:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-lH-indole-6 -carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (lH-indol-5-yl)boronic acid(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)boronic acid (178 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdChidppft-CtbCb adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (5 % MeOH in chloroform) to obtain the title compound.

Yield: 211 mg (40 ); ^J H NMR (CDCI3, 300 MHz): δ 11.49 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.05 (s, 1H), 6.44 (s, 1H), 5.89 (s, 2H), 5.26 (m, 1H), 4.29 (m, 2H), 2.62 (m, 2H), 2.60 (s, 3H), 2.50 (s, 3H), 2.12 (s, 3H), 1.56 (m, 2H), 1.46 (d, 6H, J=3.6Hz), 0.94 (m, 3H); MS (ESI+): m/z 528 (M+l) ⁺ ; HPLC purity: 94.28 %.

Example 50:

4-(lH-Indazol-4-yl)-l-isopropyl-7-methyl-N-((6-methyl-2-o xo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (lH-indazol-4-yl)boronic acid (148 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Ci2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 194 mg (39 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 13.15 (s, 1H), 11.47 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.44 (m, 1H), 7.26 (s, 1H), 6.41 (s, 1H), 5.88 (s, 1H), 5.27 (m, 1H), 4.34 (s, 2H), 2.72 (s, 3H), 2.11 (m, 2H), 2.09 (s, 3H), 1.57 (m, 2H), 1.54 (d, 6H, J=4.5Hz), 0.95 (m, 3H); MS (ESI+): m/z 496 (M+l) ⁺ ; HPLC purity: 99.36 %.

Example 51:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole-6-carbo xamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (lH-indazol-4-yl) boronic acid(6-(4-methylpiperazin-l-yl)pyridin-3-yl)boronic acid (202 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 444 mg (80 ); ^J H NMR (CDCI3, 300 MHz): δ 11.48 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 6.95 (s, 1H), 6.88 (s, 1H), 6.52 (s, 1H), 5.89 (s, 1H), 5.23 (m, 1H), 4.32 (s, 2H), 3.53 (s, 4H), 2.66 (s, 3H), 2.42 (s, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.56 (m, 2H), 1.47 (d, 6H, J=3.6Hz), 0.95 (m, 3H); MS (ESI+): m/z 555 (M+l) ⁺ ; HPLC purity: 98.81 %.

Example 52:

4-(2,4-Dimethoxypyrimidin-5-yl)-l-isopropyl-7-methyl-N-((6-m ethyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2,4-dimethoxy pyrimidin-5-yl)boronic acid (169 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 207 mg (40 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 6.85 (s, 1H), 6.20 (s, 1H), 5.89 (s, 1H), 5.22 (m, 1H), 4.31 (s, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 2.67 (s, 3H), 2.11 (m, 2H), 2.09 (s, 3H), 1.57 (m, 2H), 1.55 (d, 6H, J=4.2Hz), 0.95 (m, 3H); MS (ESI+): m/z 518 (M+l) ⁺ ; HPLC purity 90.58 %.

Example 53:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(et hyl(tetrahydro-2H- pyran-4-yl)amino)-5-(3-fluorooxetan-3-yl)-2-methylbenzamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2,6-dimethoxy pyridin-3-yl)boronic acid (167 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 274 mg (53 ); ^J H NMR (CDCI3, 300 MHz): δ 11.48 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 6.83 (s, 1H), 6.48 (s, 1H), 6.16 (s, 1H), 5.92 (s, 1H), 5.22 (m, 1H), 4.31 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 2.66 (s, 3H), 2.11 (m, 2H), 2.09 (m, 3H), 1.57 (m, 2H), 1.55 (d, 6H, J=4.5Hz), 0.95 (m, 3H); MS (ESI+): m/z 518 (M+l) ⁺ ; HPLC purity: 93.53 %. Example 54:

l-Isopropyl-7-methyl-4-(4-(5-methyl-l,3,4-oxadiazol-2-yl) phenyl)-N-((6-methyl-2- oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-car boxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (4-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl)boronic acid (187 mg, 0.916 mmol) in 1,4- dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 231 mg (43 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.11 (m, 3H), 7.84 (s, 2H), 7.69 (s, 1H), 7.03 (s, 1H), 6.62 (s, 1H), 5.90 (s, 1H), 5.27 (m, 1H), 4.34 (s, 2H), 2.70 (s, 3H), 2.61 (m, 2H), 2.55 (s, 3H), 2.12 (s, 3H), 1.58 (m, 2H), 1.49 (d, 6H, J=6.9Hz), 0.90 (m, 3H); MS (ESI+): m/z 538 (M+l) ⁺ ; HPLC purity: 93.47 %.

Example 55:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(2-(4-methylpiperazin-l-yl)pyridin-4-yl)-lH-indole-6-carbo xamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2-(piperazin-l-yl)pyridin-4-yl)boronic acid (190 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 338 mg (61 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.47 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 6.99 (s, 1H), 6.90 (m, 2H), 6.85 (s, 1H), 5.88 (s, 1H), 5.22 (m, 1H), 4.32 (s, 2H), 3.50 (bs, 4H), 2.67 (s, 3H), 2.49 (m, 2H), 2.40 (bs, 4H), 2.21 (s, 3H), 2.10 (s, 3H), 1.54 (m, 2H), 1.46 (d, 6H, J=6.3Hz), 0.95 (t, 3H,J=6.9Hz); MS (ESI+): m/z 555 (M+l) ⁺ ; HPLC purity: 93.59 %.

Example 56:

4-(3-Fluoro-4-morpholinophenyl)-l-isopropyl-7-methyl-N-(( 6-methyl-2-oxo-4-propyl- l,2-dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (3-fluoro-4-morpholinophenyl)boronic acid (206 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL). PdCl2(dppf)-CH ₂ Ci2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 157 mg (28 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 7.37 (m, 2H), 7.55 (m, 1H), 7.09 (s, 1H), 6.56 (s, 1H), 5.88 (s, 1H), 5.22 (m, 1H), 4.32 (s, 2H), 3.56 (bs, 4H), 3.05 (bs, 4H), 2.66 (s, 3H), 2.49 (s, 2H), 2.10 (s, 3H), 1.56 (m, 2H), 1.46 (d, 6H, J=6.3Hz), 0.95 (m, 3H); MS (ESI+): m/z 559 (M+l) ⁺ ; HPLC purity: 97.66 %.

Example 57:

tert-Butyl 4-(3-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydro pyridin-3-yl)methyl)carbamoyl)-lH-indol-4-yl)pyridin-2-yl)pi perazine-l-carboxylate

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2-(4-(tert-butoxy carbonyl)piperazin-l-yl)pyridin-3-yl)boronic acid (281 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi2(dppf)-CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield 148 mg (23 ); ^J H NMR (CDCI3, 300 MHz): δ 11.47 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.58 (m, 2H), 7.03 (s, 1H), 6.97 (m, 1H), 6.27 (s, 1H), 5.87 (s, 1H), 5.22 (m, 1H), 4.30 (s, 2H), 2.99 (bs, 4H), 2.91 (bs, 4H), 2.68 (s, 3H), 2.49 (m, 2H), 2.10 (s, 3H), 1.40 (m, 2H), 1.46 (d, 6H, J=6.3Hz), 1.32 (s, 9H), 0.93 (m, 3H); MS (ESI+): m/z 641 (M+l) ⁺ ; HPLC purity: 97.78 %.

Example 58:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(2-(4-methylpiperazin-l-yl)pyrimidin-5-yl)-lH-indole-6-car boxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2-(4-methyl piperazin-l-yl)pyrimidin-5-yl)boronic acid (204 mg, 0.916 mmol) in 1,4- dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: (19 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 6.89 (s, 1H), 6.53 (s, 1H), 5.88 (s, 1H), 5.20 (m, 1H), 4.30 (s, 2H), 3.76 (bs, 4H), 2.60 (s, 3H), 2.49 (m, 2H), 2.36 (bs, 4H), 2.22 (s, 3H), 2.10 (s, 3H), 1.53 (m, 2H), 1.46 (d, 6H, J=6.6Hz), 0.94 (m, 3H); MS (ESI+): m/z 556 (M+l) ⁺ ; HPLC purity: 93.52 %.

Example 59:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(2-methyl-2H-indazol-6-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (2-methyl-2H-indazol-6-yl)boronic acid (161 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Cl2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 148 mg (29 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.78 (d, 1H, J=8.7Hz), 7.71 (s, 1H), 7.62 (s, 1H), 7.29 (d, 1H, J=8.7Hz), 6.98 (s, 1H), 6.55 (s, 1H), 5.88 (s, 1H), 5.20 (m, 1H), 4.31 (s, 2H), 4.18 (s, 3H), 2.68 (s, 3H), 2.10 (s, 3H), 2.03 (m, 2H), 1.54 (m, 2H), 1.48 (d, 6H, J=6.6Hz), 0.95 (t, 3H, J=4.2 Hz); MS (ESI+): m/z 511 (M+l) ⁺ ; HPLC purity: 88.88 %.

Example 60:

tert-Butyl 4-(5-(l-isopropyl-7-methyl-6-(((6-methyl-2-oxo-4-propyl-l,2- dihydro pyridin-3-yl)methyl)carbamoyl)-lH-indol-4-yl)-3-methylpyridi n-2-yl) piperazine-1- carboxylate To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4- propyl- 1,2-dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (6-(4-(tert-butoxy carbonyl)piperazin-l-yl)-5-methylpyridin-3- yl)boronic acid (294 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Ci ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield (36 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.47 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 6.53 (s, 1H), 5.88 (s, 1H), 5.22 (s, 1H), 4.30 (s, 2H), 3.48 (bs, 4H), 3.06 (bs, 4H), 2.66 (s, 3H), 2.49 (m, 2H), 2.32 (s, 3H), 2.10 (s, 3H), 1.53 (m, 2H), 1.46 (d, 6H, J=6.6Hz), 1.42 (s, 9H), 0.95 (m, 3H); MS (ESI+): m/z 654 (M- 1) ⁺ ; HPLC purity 97.48 %.

Example 61:

4-(4-Acetyl-3-fluorophenyl)-l-isopropyl-7-methyl-N-((6-methy l-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (4-acetyl-3-fluorophenyl)boronic acid(167 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)-CH2Ci2 adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 129 mg (25 ); ^J H NMR (CDCI3, 300 MHz): δ 11.48 (s, 1H), 8.11 (s, 1H), 7.95 (t, 1H, J=7.8Hz), 7.70 (d, 1H, J=3.3Hz), 7.59 (m, 2H), 7.04 (s, 1H), 6.61 (s, 1H), 5.89 (s, 1H), 5.24 (m, 1H), 4.32 (d, 2H, J=4.5Hz), 2.69 (s, 3H), 2.62 (s, 3H), 2.49 (m, 2H), 2.10 (s, 3H), 1.56 (m, 2H), 1.47 (d, 6H, J=6.6Hz), 0.95 (t, 3H, J=7.2Hz) ; MS (ESI+) m/z 516 (M+l) ⁺ , HPLC=96.69

Example 62:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(5-methyl-6-morpholinopyridin-3-yl)-lH-indole-6-carboxamid e

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (5-methyl-6-mo holinopyridin-3-yl)boronic acid (203 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl2(dppf)- CH ₂ CI ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80- 85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 122 mg (22 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.47 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 6.90 (s, 1H), 6.54 (s, 1H), 5.88 (s, 1H), 5.22 (m, 1H), 4.31 (s, 2H), 3.75 (bs, 4H), 3.10 (bs, 4H), 2.66 (s, 3H), 2.49 (s, 2H), 2.31 (s, 3H), 2.10 (s, 3H), 1.56 (m, 2H), 1.46 (d, 6H, J=6.3Hz), 0.95 (m, 3H); MS (ESI+): m/z 556 (M+l) ⁺ ; HPLC purity: 91.68 %.

Example 63:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(6-(piperidin-l-yl)pyridin-3-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (6-(piperidin-l-yl) pyridin-3-yl)boronic acid (189 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield 129 mg (24 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.72 (m, 1H), 7.59 (s, 1H), 6.91 (m, 2H), 6.50 (s, 1H), 5.88 (s, 1H), 5.21 (s, 1H), 4.29 (s, 2H), 3.55 (bs, 4H), 2.64 (s, 3H), 2.48 (m, 2H), 2.10 (s, 3H), 1.55 (bs, 8H), 1.45 (d, 6H, J=6.3Hz), 0.94 (t, 3H, J=7.2Hz); MS (ESI+): m/z 540 (M+l) ⁺ ; HPLC purity: 94.90 %. Example 64:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl) methyl)- 4-(quinolin-3-yl)-lH-indole-6-carboxamide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and quinolin-3-ylboronic acid (158 mg, 0.916 mmol) in 1,4-dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Ci ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 182 mg (36 ); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 9.14 (s, 1H), 8.54 (s, 1H), 8.12 (m, 3H), 7.77 (m, 3H), 7.12 (s, 1H), 6.64 (s, 1H), 5.88 (s, 1H), 5.26 (s, 1H), 4.32 (s, 2H), 2.70 (s, 3H), 2.48 (m, 2H), 2.09 (s, 3H), 1.53 (m, 2H), 1.48 (d, 6H, J=6Hz), 0.94 (t, 3H, J=6.6Hz); MS (ESI+): m/z 507 (M+l) ⁺ ; HPLC purity: 98.32 %.

Example 65:

l-Isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 4-(5-(piperidin-l-ylmethyl)thiophen-2-yl)-lH-indole-6-carbox amide

To a solution of 4-bromo-l-isopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)-lH-indole-6-carboxamide (Example 30, 300 mg, 0.654 mmol) and (5-(piperidin-l-yl methyl)thiophen-2-yl)boronic acid (231 mg, 0.916 mmol) in 1,4- dioxane (5 mL) was added water (2.500 mL) and bubbled argon gas for 30 minutes. PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (53.4 mg, 0.065 mmol) was added and the reaction mass was stirred at 80-85 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, filtered through celite, added water, extracted with ethyl acetate, concentrated and purified by column chromatography (silica gel, 5 % MeOH in chloroform) to obtain the title compound.

Yield: 40 mg (31%); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.48 (s, 1H), 8.07 (s, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 6.80 (s, 1H), 5.89 (s, 1H), 5.23 (s, 1H), 4.32 (s, 2H), 3.64 (s, 2H), 2.72 (s, 3H), 2.49 (m, 2H), 2.26 (bs, 2H), 2.11 (s, 3H), 1.70 (m, 8H), 1.57 (d, 6H, J=7.8Hz), 0.97 (m, 3H); MS (ESI+): m/z 540 (M+l) ⁺ ; HPLC purity: 94.90 %. Example 66:

4-Bromo-l-cyclopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l ,2-dihydro pyridin- 3-yl)methyl)-lH-indole-6-carboxamide

The title compound was prepared as per the process described in the preparation of compound of example 22 using appropriate reagents.

Yield: 60 mg (21.21 %); ^J H NMR (CDC1 ₃ , 300 MHz): δ 11.49 (s, 1H), 8.10 (s, 1H), 7.44 (s, 1H), 7.05 (s, 1H), 6.27 (s, 1H), 5.88 (s, 1H), 4.27 (s, 2H), 3.82 (m, 1H), 2.76 (s, 3H), 2.48 (m, 2H), 2.11 (s, 3H), 1.52 (m, 2H), 1.09 (m, 4H), 0.95 (t, 3H, J=7.2Hz); MS (ESI+): m/z 455 (M-l) ⁺ ; HPLC purity: 98.72 %. Example 67:

l-Cyclopropyl-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-di hydropyridin-3-yl) methyl)-4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indole -6-carboxamide

The title compound was prepared as per the process described in the preparation of compound of example 23 using appropriate reagents.

Yield: 20 mg (31.6 ); ^J H NMR (CDCI ₃ , 300 MHz): δ 11.48 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.52 (m, 1H), 7.36 (s, 1H), 6.94 (m, 2H), 6.37 (s, 1H), 5.88 (s, 1H), 4.32 (s, 2H), 3.82 (m, 1H), 3.51 (bs, 4H), 2.71 (s, 3H), 2.40 (bs, 4H), 2.21 (s, 3H), 2.11 (s, 3H), 2.08 (m, 2H), 1.56 (m, 2H), 1.10 (m, 4H), 0.95 (m, 3H); MS (ESI+): m/z 553 (M+l) ⁺ ; HPLC purity: 95.72 %.

Example 68:

4-Bromo-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyri din-3-yl) methyl)-l- (2,2,2-trifluoroethyl)-lH-indole-6-carboxamide

To a solution of 4-bromo-7-methyl-l-(2,2,2-trifluoroethyl)-lH-indole-6-carbox ylic acid (1-30, 300 mg, 0.893mmol) in DMF (12 mL) was added HATU (509 mg, 1.339 mmol) and the reaction mixture was stirred at RT for 5 minutes. 3-(Aminomethyl)-6-methyl-4- propylpyridin-2(lH)-one hydrochloride (271 mg, 1.250 mmol) followed by DIPEA (0.312 mL, 1.785 mmol) were added and stirred at 70 °C for 5 h. After completion of the reaction, the solvent was removed, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated to obtain crude. The crude mass was purified by column chromatography (silica gel, 5-10 % methanol in chloroform) to obtain the title compound.

Yield: 360 mg (81 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.81 (s, 1H), 11.52 (s, 1H), 7.54 (m, 2H), 6.54 (d, J = 3.5 Hz, 1H), 5.90 (s, 1H), 5.38 (q, J = 6.9 Hz, 2H), 4.30 (d, J = 5.0 Hz, 2H), 2.56 (s, 3H), 2.53 (m, 2H), 2.12 (s, 3H), 1.95 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 498.1 [M+H] ⁺ ; HPLC purity: 98.16 %.

Example 69:

4-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-7-methyl-l-(2,2,2- trifluoroethyl)-lH-indole-6-carboxamide

The title compound was prepared as per the process described in the preparation of compound of example 68 by using appropriate reagents.

Yield: 95 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.78 (s, 1H), 11.48 (s, 1H), 8.74 (s, 1H), 8.53 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 5.840 (s, 1H), 5.36 (q, J = 6.9 Hz, 2H), 4.24 (d, J = 5.0 Hz, 2H), 2.53 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H); MS (ESI+): m/z 470.1 [M+H] ⁺ ; HPLC purity: 99.41 %.

Example 70:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(6-(4- methyl piperazin-l-yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-ind ole-6-carboxamide

To a solution of 4-bromo-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyri din-3-yl) methyl)- l-(2,2,2-trifluoroethyl)-lH-indole-6-carboxamide (Example 68, 50 mg, 0.100 mmol) in dioxane (2 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine (42.6 mg, 0.140 mmol) and PdCl2(dppf)- CH2CI2 adduct (2.458 mg, 3.01μπιο1) under nitrogen atmosphere and stirred at RT for 10 minutes. 2 M Na2CC>3 solution (0.151 mL, 0.301 mmol) was added and the reaction mixture was heated to 90 °C for 4 h. After completion of the reaction, reaction mixture was cooled to RT, filtered through celite, the filtrate was concentrated, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain crude. The crude was purified by flash chromatography using 1 :9 MeOH:CHCl ₃ to obtain the title compound.

Yield: 26 mg (43 ); ^J H NMR (DMSO-de, 300 MHz): δ 11.47 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.43 (s, 1H), 6.93 (m, 3H), 6.59 (s, 1H), 5.87 (s, 1H), 5.37 (m, 1H), 4.30 (d, J = 3.9 Hz, 2H), 3.51 (bs, 4H), 2.60 (s, 3H), 2.52 (m, 2H), 2.39 (bs, 4H), 2.20 (s, 3H), 2.09 (s, 3H), 1.54 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI+): 595.3 [M+H] ⁺ ; HPLC purity: 97.87 %.

The compounds of examples 71-78 were prepared analogous to the process described in the compound of example 70 using appropriate intermediates.

Example 71:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3 -yl)methyl)-4-(6- morpholinopyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indole-6 -carboxamide

Yield: 38 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.47 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 7.79 (d, / = 8.4 Hz, 1H), 7.44 (s, 1H), 6.94 (m, 2H), 6.58 (s, 1H), 5.87 (s, 1H), 5.37 (m, 2H), 4.29 (d, / = 3.9 Hz, 2H), 3.70 (bs, 4H), 3.48 (s, 4H), 2.60 (s, 3H), 2.53 (m, 2H), 2.09 (s, 3H), 1.51 (m, 2H), 0.90 (t, / = 7.2 Hz, 3H); MS (ESI+): m/z 582.3 [M+H] ⁺ .

Example 72:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(l-(2- morpholinoethyl)-lH-pyrazol-4-yl)-l-(2,2,2-trifluoroethyl)-l H-indole-6-carboxamide Yield: 41 ; H NMR (DMSO-de, 300 MHz): δ 11.47 (s, IH), 8.19 (s, IH), 8.07 (s, IH), 7.80 (s, IH), 7.44 (s, IH), 7.06 (s, IH), 6.79 (s, IH), 6.58 (s, IH), 5.87 (s, IH), 5.34 (m, 2H), 4.29 (m, 4H), 4.02 (m, IH), 3.52 (bs, 4H), 2.73 (s, 2H), 2.56 (s, 3H), 2.40 (s, 4H), 2.09 (s, 3H), 1.55 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 599.4 [M+H] ⁺ ; HPLC purity: 98.40 %.

Example 73:

7-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-4-(4- morpholinophenyl)-l-(2,2,2-trifluoroethyl)-lH-indole-6-carbo xamide

Yield: 58 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, IH), 8.12 (s, IH), 7.53 (m, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.92 (s, IH), 6.61 (d, J = 2.7 Hz, IH), 5.87 (s, IH), 5.33 (m, 2H), 4.30 (d, J = 3.9 Hz, 2H), 3.74 (bs, 4H), 3.14 (s, 4H), 2.58 (s, 3H), 2.52 (m, 2H), 2.09 (s, 3H), 1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); MS (ESI+): 581.4 [M+H] ⁺ ; HPLC purity: 96.36 %.

Example 74:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7- methyl-4-(6-(4-methyl piperazin-l-yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-ind ole-6-carboxamide

Yield: 73 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.46 (s, IH), 8.32 (s, IH), 8.15 (s, IH), 7.76 (d, J = 8.7 Hz, IH), 7.43 (s, IH), 6.96 (m, 2H), 6.59 (d, J = 3.0 Hz, IH), 5.84 (s, IH), 5.37 (q, J = 8.7 Hz, 2H), 4.29 (d, J = 4.5 Hz, 2H), 3.51 (bs, 4H), 2.59 (s, 3H), 2.39 (s, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H); MS (ESI+): m/z 567.3 [M+H] ⁺ ; HPLC purity: 98.42 %.

Example 75:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(4-(morpholino methyl)phenyl)-l-(2,2,2-trifluoroethyl)-lH-indole-6-carboxam ide

Yield: 61 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.45 (s, IH), 8.17 (s, IH), 7.55 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 2.7 Hz, IH), 7.41 (d, J = 8.1 Hz, 2H), 6.98 (s, IH), 6.61 (d, J = 3.0 Hz, IH), 5.84 (s, IH), 5.38 (q, J = 8.7 Hz, 2H), 4.29 (d, J = 4.5 Hz, 2H), 3.57 (bs, 4H), 3.49 (s, 2H), 2.61 (s, 3H), 2.37 (s, 4H), 2.19 (s, 3H), 2.08 (s, 3H); MS (ESI+): m/z 567.3 [M+H] ⁺ ; HPLC purity: 98.51 %.

Example 76:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(6-morpholino pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indole-6-carboxami de Yield: 68 ; H NMR (DMSO-de, 300 MHz): δ 11.46 (s, IH), 8.34 (s, IH), 8.15 (s, IH), 7.80 (d, / = 8.7 Hz, 2H), 7.44 (s, IH), 6.94 (m, 2H), 6.58 (s, IH), 5.84 (s, IH), 5.37 (q, / = 8.7 Hz, 2H), 4.29 (d, / = 4.5 Hz, 2H), 3.70 (bs, 4H), 3.48 (bs, 4H), 2.60 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H); MS (ESI+): m/z 554.3 [M+H] ⁺ . HPLC purity: 95.90 %.

Example 77:

N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(l-(2-morpholino ethyl)-lH-pyrazol-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indole-6 -carboxamide

Yield: 49 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.46 (s, IH), 8.31 (s, IH), 8.19 (s, IH), 7.82 (s, IH), 7.44 (s, 2H), 7.07 (s, IH), 6.79 (s, IH), 5.84 (s, IH), 5.34 (m, 2H), 4.28 (m, 3H), 3.52 (bs, 4H), 2.73 (t, / = 5.7 Hz, 2H), 2.55 (s, 3H), 2.41 (s, 4H), 2.20 (s, 3H), 2.08 (s, 3H); MS (ESI+): m/z 571.3 [M+H] ⁺ ; HPLC purity: 94.26 %.

Example 78:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7-met hyl-4-(4-morpholino phenyl)-l-(2,2,2-trifluoroethyl)-lH-indole-6-carboxamide

Yield: 39 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.46 (s, IH), 8.15 (s, IH), 7.53 (m, IH), 7.47 (m, 2H), 7.05 (d, J = 8.4 Hz, IH), 6.92 (s, IH), 6.61 (d, J = 3.0 Hz, IH), 5.84 (s, IH), 5.36 (q, J = 8.7 Hz, 2H), 4.29 (d, J = 4.2 Hz, 2H), 3.74 (bs, 4H), 3.14 (bs, 4H), 2.59 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H); MS (ESI+): m/z 553.3 [M+H] ⁺ ; HPLC purity: 98.49 %. Example 79:

7-Bromo-3-(dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-m ethyl-2-oxo-4-propyl pyridin-3-yl)methyl)-4-methyl-lH-indene-5-carboxamide

To a solution of 7-bromo-3-(dimethylamino)-2,3-dihydro-4-methyl-lH-indene-5- carboxylic acid (1-41, 260 mg, 0.872 mmol) and HATU (497 mg, 1.308 mmol) in DMF (10 mL), the reaction mass was stirred for 45 minutes. 3-(Aminomethyl)-4,6- dimethylpyridin-2(lH)-one hydrochloride (230 mg, 1.221 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.304 mL, 1.744 mmol) were added and the reaction mass was heated at 50 °C for 16 h. On completion of reaction, added water to the reaction mass, extracted using diethyl ether, washed with brine, dried over sodium sulfate and concentrated to obtain the crude compound which was purified by column chromatography to obtain the title compound.

Yield: 150 mg (39.8 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.45 (s, IH), 8.19 (s, IH), 7.26 (s, IH), 5.89 (s, IH), 4.42 (bd, IH), 4.26 (bs, 2H), 2.81 (m, 2H), 2.27 (s, 3H), 2.20 (m, 1H), 2.12 (s, 3H), 2.05 (bs,7H), 1.82 (m, 1H), 1.55 (m, 3H), 0.93 (t, 3H); MS (ESI+): m/z 244 (M+H) ⁺ .

Example 80:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl) methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)- lH-indene-5- carboxamide

To a solution of 7-bromo-3-(dimethylamino)-4-methyl-N-((6-methyl-2-oxo-4-prop yl-l,2- dihydropyridin-3-yl)methyl)-2,3-dihydro-lH-indene-5-carboxam ide (Example 79, 20 mg, 0.043 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added l-methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (18.44 mg, 0.061 mmol) and 2 M solution of sodium carbonate (13.81 mg, 0.130 mmol) and argon gas was bubbled for 30 minutes at room temperature. PdCl ₂ (dppf) (3.18 mg, 4.34 μπιοΐ) was added and the reaction mass was heated to 80 °C for 16 h. After completion of reaction, the reaction mass was cooled to room temperature, filtered through celite, the filtrate was concentrated, added water, extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the title compound.

Yield: 12 mg (49.6 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.46 (s, 1H), 8.20 (s, 1H), 8.10 (bs, 1H), 7.66 (d, 1H, J=7.8 Hz), 7.09 (s,lH), 6.88 (d, 1H, J=9Hz), 5.87 (s, 1H), 4.27 (bs, 3H), 3.50 (bs, 4H), 2.97 (m, 1H), 2.73 (m, 1H), 2.40 (bs, 4H), 2.35 (s, 3H), 2.22 (s, 3H), 2.10 (bs, 8H), 1.71 (m, 1H), 1.51 (m, 2H), 1.32 (bs, 1H), 1.22 (bs, 3H), 0.92 (m, 3H); MS (ESI+): m/z 557 (M+H) ⁺ .

The compounds of examples 81-86 were prepared analogous to the process described in the compound of example 80.

Example 81:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2- oxo-4-propyl pyridin-3- yl) methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)- lH-indene-5- carboxamide

^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, 1H), 8.10 (s, 1H),7.32 (d, 2H, J=8.7 Hz), 7.09 (s,lH), 6.98 (d, 2H, J=8.4 Hz), 5.88 (s, 1H), 4.29 (bs, 3H), 3.17 (bs, 4H), 2.98 (m, 1H), 2.73 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 2.10 (bs, 8H), 1.69 (m, 1H), 1.54 (m, 2H), 1.35 (bs, 3H), 1.23 (bs, 5H), 0.93 (m, 3H); MS (ESI+): m/z 556 (M+H) ⁺ . Example 82:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl) methyl)-4-methyl-7-(2-(4-methylpiperazin-l-yl)pyrimidin-5-yl )-lH-indene-5- carboxamide

JH NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, IH), 8.49 (s, 2H), 8.10 (bs, IH), 7.13 (s, IH), 5.88 (s, IH), 4.27 (bs, 3H), 3.75 (bs, 4H), 2.98 (m, IH), 2.76 (m, IH), 2.36 (bs, 7H), 2.21 (s, 3H), 2.09 (bs, 8H), 1.72 (m, 1H),1.54 (m, 2H), 1.33 (bs, IH), 1.22 (bs, 3H), 0.93 (m, 3H). MS (ESI+): m/z 558 (M+H) ⁺ .

Example 83:

3-(Dimethylamino)-2, 3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo-4-propyl pyridin-3- yl) methyl)-4-methyl-7-(6-morpholinopyridin-3-yl)-lH-indene-5-ca rboxamide

^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, IH), 8.32 (s, IH), 8.11(bs, IH), 7.70 (d, IH, J=8.7 Hz), 7.10 (s, IH) , 6.89 (d, IH, J=8.7 Hz), 5.88 (s, IH), 4.29 (bs, 3H), 3.70 (bs, 4H), 3.46 (bs, 4H), 2.97 (m, IH), 2.74 (m, IH), 2.36 (bs, 3H), 2.10 (bs, 8H), 1.71 (m, IH), 1.54 (m, 2H), 1.33 (bs, IH), 1.22 (bs, 3H), 0.93 (m, 3H). MS (ESI+): m/z 544 (M+H) ⁺ .

Example 84:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl) methyl)-4-methyl-7-(4-(morpholinomethyl)phenyl)-lH-indene-5- carboxamide

^J H NMR (DMSO-de, 300 MHz): δ 11.47 (s, IH), 8.13 (s, IH), 7.42 (m, 4H), 7.13 (s, IH), 5.87 (s, IH) , 4.29 (bs, 3H), 3.57 (bs, 4H), 3.48 (s, 2H), 2.98 (m, IH), 2.75 (m, IH) , 2.37 (bs, 7H), 2.10 (bs, 8H), 1.71 (m, IH), 1.54 (m, 2H), 1.33 (bs, IH), 1.22 (bs, 3H), 0.93 (m, 3H); MS (ESI+): m/z 557 (M+H) ⁺ .

Example 85:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl) methyl)-4-methyl-7-(4-(l-morpholinoethyl)phenyl)-lH-indene-5 -carboxamide

^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.47 (s, IH), 8.12 (s, IH), 7.42 (m, 4H), 7.13 (s, IH), 5.87 (s, IH) , 4.27 ( bs, 3H), 3.55 (bs, 4H), 3.37 (s, 2H), 2.97 (m, IH), 2.76 (m, IH), 2.42 (s, 4H), 2.29 (m , 3H ), 2.10 (bs, 8H), 1.71 (m, IH), 1.54 (m, 2H), 1.30 (d, 3H), 1.23 (bs, 3H), 0.93 (m, 3H); MS (ESI+): m/z 571 (M+H) ⁺ .

Example 86:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-6-methyl-2-oxo -4-propyl pyridin-3- yl) methyl)-4-methyl-7-(4-(l-(piperidin-l-yl)ethyl)phenyl)-lH-in dene-5-carboxamide H NMR (DMSO-d ₆ , 300 MHz): δ 11.46 (s, IH), 8.12 (s, IH), 7.40 (m, 4H), 7.13 (s, IH), 5.87 (s, IH), 4.27 (bs, 3H), 3.44 (m, IH), 2.98 (m, IH), 2.77 (m, IH), 2.37 (m, 7H), 2.10 (bs, 8H), 1.71 (m, IH), 1.54 (m, 6H), 1.33 (m, 3H), 1.23 (m, 6H), 0.93 (m, 3H); MS (ESI+): m/z 569 (M+H) ⁺ .

Example 87:

7-Bromo-3-(dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-di methyl-2-oxopyridin- 3-yl)methyl)-4-methyl-lH-indene-5-carboxamide

To a solution of 7-bromo-3-(dimethylamino)-4-methyl-2,3-dihydro-lH-indene-5- carboxylic acid (1-41, 260 mg, 0.872 mmol) in DMF (10 mL) was added HATU (497 mg, 1.308 mmol) and the reaction mass was stirred for 45 minutes. 3-(Aminomethyl)-4,6- dimethylpyridin-2(lH)-one hydrochloride (230 mg, 1.221 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.304 mL, 1.744 mmol) were added and the reaction mass was heated at 50 °C for 16 h. On completion of reaction, added water to the reaction mass, extracted using diethyl ether, washed with brine, dried over sodium sulfate, and concentrated to obtain crude, which was purified by column chromatography to obtain the title compound.

Yield: 150 mg (39.8 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, IH), 8.21 (s, IH), 7.25 (s, IH), 5.85 (s, IH), 4.41 (d, IH), 4.22 (bs, 2H), 2.81 (m, 2H), 2.25 (bs, 3H), 2.17 (bs, 4H), 2.09 (bs, 3H), 2.03 (bs, 6H), 1.82 (m,lH); MS (ESI+): m/z 433 (M+H) ⁺ .

Example 88:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-dimethyl- 2-oxo pyridin-3-yl) methyl)-4-methyl-7-(4-(morpholinomethyl)phenyl)-lH-indene-5- carboxamide

To a solution of 7-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-3- (dimethylamino)-4-methyl-2,3-dihydro-lH-indene-5-carboxamide (Example 87, 70 mg, 0.162 mmol) in 1,4-dioxane (2 mL) and water (2 mL), 4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzyl)morpholine (68.7 mg, 0.227 mmol) and sodium carbonate (51.5 mg, 0.486 mmol) were added, the reaction mass was degassed for 30 minutes. PdCi ₂ (dppf)-CH ₂ Ci ₂ adduct (13.22 mg, 0.016 mmol) was added and degassed for 30 minutes. The reaction mass was heated at 110 °C for 16 h. On completion of reaction, the reaction was purified by column chromatography to obtain the title compound.

Yield: 20 mg (23.37 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.44 (s, IH), 8.13 (s, IH), 7.39 (m, 4H), 7.12 (s, IH), 5.84 (s, IH), 4.27 (bs, 2H), 3.57 (bs, 4H), 3.47 (bs, 2H), 2.96 (m, 1H), 2.71 (m, 1H), 2.36 (bs, 7H), 2.17 (m, 10H), 1.70 (m, 1H), 1.10 (t, 1H), 2.49 (bs, 3H); MS (ESI+): m/z 529 (M+H) ⁺ .

The compound of example 89 is prepared analogous to the process described in the compound of example 88.

Example 89:

3-(Dimethylamino)-2,3-dihydro-N-((l,2-dihydro-4,6-dimethyl- 2-oxo pyridin-3-yl) methyl)-4-methyl-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)- lH-indene-5- carboxamide

^J H NMR (DMSO-de, 300 MHz): δ 11.46 (s, 1H), 9.04 (s, 1H), 8.22 (s, 1H), 8.14 (bs, 1H), 7.68 (d, 1H, J=6.6 Hz), 7.12 (bs, 1H), 6.91 (d, 1H, J=8.7 Hz), 5.85 (s, 1H), 4.28 (m, 2H), 3.55 (m, 4 H) 2.73 (m, 1H), 2.50 (m, 1H), 2.36 (bs, 3H), 2.30 (bs, 3H), 2.18 (m, 10H), 1.70 (m, 1H), 1.35 (m, 3H), 1.22 (bs, 4H); MS (ESI+): m/z 529 (M+H) ⁺ .

Example 90:

3-(N-Ethyl-N-(tetrahydro-2H-pyran-4-yl)amino)-7-bromo-2,3-di hydro-N-((l,2- dihydro-6-methyl-2-oxo-4-propylpyridin-3-yl)methyl)-4-methyl -lH-indene-5- carboxamide

To a solution of 7-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-2, 3- dihydro-lH-indene-5-carboxylic acid (Intermediate 1-44, 80 mg, 0.209 mmol) in DMF was added N-ethyl-N-isopropylpropan-2-amine (109 μί _^ , 0.628 mmol) and stirred the reaction mass for 30 minutes. HATU (119 mg, 0.314 mmol) was added and stirred the reaction mass for 30 minutes. 3-(Aminomethyl)-6-methyl-4-propylpyridin-2(lH)-one hydrochloride (63.5 mg, 0.293 mmol) was added and stirred the reaction mass at 60 °C for 16 h. On completion of reaction, added water to reaction mass, extracted using ethyl acetate, the organic layer was washed with brine, dried on sodium sulfate and concentrated to obtain crude compound, which was purified to obtain the title compound.

Yield: 60 mg (52.7 ); ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, 1H), 8.18 (s, 1H), 7.23 (s, 1H), 5.87 (s, 1H), 4.72 (d, 1H), 4.25 (d, 2H), 3.86 (d, 2H), 3.28 (m, 2H), 2.86-2.67 (m, 5H), 2.29 (bs, 3H), 2.10 (bs, 4H), 2.03 (m, 2H), 1.76 (m, 2H), 1.52-1.41 (m, 5H), 0.93 (t, 3H), 0.77 (t, 3H); MS (ESI+): m/z 545(M+H) ⁺ .

Example 91:

3-(N-Ethyl-N-(tetrahydro-2H-pyran-4-yl)amino)-2,3-dihydro-N- ((l,2-dihydro-6- methyl-2-oxo-4-propylpyridin-3-yl)methyl)-4-methyl-7-(6-(4-m ethyl piperazin-1- yl)pyridin-3-yl)-lH-indene-5-carboxamide To a solution of 7-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N- ((6- methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-2,3-di hydro-lH-indene-5- carboxamide (Example 90, 45 mg, 0.083 mmol), (4-(l-(piperidin-l- yl)ethyl)phenyl)boronic acid (27.0 mg, 0.116 mmol), sodium carbonate (26.3 mg, 0.248 mmol) in 1,4-dioxane (8 mL) and water (2 mL) nitrogen gas was purged 30 minutes. PdCi ₂ (dppf)-CH ₂ Cl ₂ adduct (6.75 mg, 8.26 μπιοΐ) was added and degassed for 30 minutes. The reaction mass was heated at 110 °C for 16 h. On completion of reaction, the reaction mass was purified using column chromatography to obtain the title compound.

Yield: 12 mg, (22.24 ); ^J H NMR (DMSO-de, 300 MHz): δ 11.48 (s, 1H), 8.20 (s, 1H), 8.09 (bs, 1H), 7.66(d, 1H, J=8.7 Hz), 7.07 (s, 1H), 6.87 (d, 1H, J=8.7 Hz), 5.87 (s, 1H), 4.60 (bs, 1H), 4.27 (bs, 2H), 3.88 (bs, 2H), 3.49(bs, 4H), 3.27 (m, 2H), 3.01 (m, 1H), 2.76 (m, 2H), 2.39 (bs, 5H), 2.26 (m, 1H), 2.21 (bs, 3H),2.10 (bs, 3H), 1.98 (bs, 2H), 1.78 (bs, 2H), 1.53-1.50 (m, 4H),1.21 (bs, 4H), 0.92(t, 3H), 0.83(t, 3H); MS (ESI+): m/z 545(M+H) ⁺ .

Example 92:

7-Bromo-2-isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3- yl)methyl)benzo[d]thiazole-5-carboxamide

To a solution of 7-bromo-2-isopropyl-4-methylbenzo[d]thiazole-5-carboxylic acid (1-48, 300 mg, 0.955 mmol) in DMF (12 mL) was added HATU (545 mg, 1.432 mmol) and reaction mixture was stirred for 5 minutes at RT. 3-(Aminomethyl)-6-methyl-4- propylpyridin-2(lH)-one hydrochloride (290 mg, 1.337mmol) was added followed by DIPEA (0.334 mL, 1.910 mmol) and stirred at 70 °C for 5 h. After completion of reaction, the solvent was removed, water was and extracted with ethyl acetate. The organic layer was washed with brine, added water, dried over sodium sulfate and concentrated to obtain crude. The crude mass obtained was purified by column chromatography (silica gel, 1 :9 % methanohdichloromethane) to obtain the title compound.

Yield: 305 mg (67 ); ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.52 (s, 1H), 8.37 (s, 1H), 7.48 (s, 1H), 5.90 (s, 1H), 4.31 (d, J= 4.5 Hz, 2H), 3.45 (m, 2H), 2.61 (s, 4H), 2.13 (s, 3H), 1.55 (m, 2H), 1.42 (d, J = 6.5 Hz,6H), 0.93 (t, J = 7.0 Hz, 3H); MS (ESI+): m/z 477.1 [M+H] ⁺ .

The compounds of examples 93-96 were prepared analogous to the process described in the compound of example 92 using appropriate intermediates. Example 93:

7-Bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methy l)-2-isopropyl-4- methylbenzo[d]thiazole-5-carboxamide

Yield: 77 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.51 (s, 1H), 8.38 (t, J= 5.0 Hz, 1H), 7.49 (s, 1H), 5.87 (s, 1H), 4.30 (d, J= 5.0 Hz, 2H), 3.44 (m, 1H), 2.60 (s, 4H), 2.21 (s, 3H), 2.12 (s, 2H), 1.42 (d, J = 7.0 Hz, 6H); MS (ESI+): 448.1 m/z [M+H] ⁺ .

Example 94:

7-Bromo-2,4-dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl) benzo[d]thiazole-5-carboxamide

Yield: 70 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 13.79 (s, 1H), 11.49 (s, 1H), 8.35 (m, 1H), 7.43 (s, 1H), 5.87 (s, 1H), 4.28 (d, J = 4.5 Hz, 2H), 2.81 (m, 2H), 2.56 (s, 3H), 2.52 (m, 2H), 2.10 (s, 3H), 1.55 (m, 2H), 0.91 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 449.2 [M+H] ⁺ .

Example 95:

7-Bromo-2-(tert-butyl)-4-methyl-N-((6-methyl-2-oxo-4-prop yl-l,2-dihydropyridin-3- yl)methyl)benzo[d]thiazole-5-carboxamide

Yield: 75 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.52 (s, 1H), 8.35 (m, 1H), 7.47 (s, 1H), 5.89 (s, 1H), 4.30 (d, J = 4.5 Hz, 2H), 2.61 (s, 3H), 2.52 (m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.46 (s, 9H), 0.92 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 490.2 [M+H] ⁺ .

Example 96:

7-Bromo-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyri din-3-yl) methyl)-2- neopentylbenzo[d]thiazole-5-carboxamide

Yield: 82 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, 1H), 8.36 (m, 1H), 7.47 (s, 1H), 5.89 (s, 1H), 4.30 (d, J = 4.5 Hz, 2H), 3.02 (s, 2H), 2.68 (s, 3H), 2.53 (m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.03 (s, 9H), 0.93 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 504 [M+H] ⁺ . Example 97:

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)- 7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5 -carboxamide

To a solution of 7-bromo-2-isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2 -dihydro pyridin-3-yl)methyl)benzo[d]thiazole-5-carboxamide (Example 92, 70 mg, 0.147 mmol) in dioxane (2.8 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperazine (62.4 mg, 0.206 mmol), PdCl2(dppf)-CH ₂ Ci ₂ adduct (3.60 mg, 4.41 μπιοΐ) under nitrogen atmosphere and stirred at RT for 10 minutes. 2 M Na ₂ CC>3 solution (0.220 mL, 0.441 mmol) was added and reaction mixture was heated to 90 °C for 4 h. After completion of reaction, reaction mixture was cooled to RT, filtered through celite, filtrate was concentrated, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated to obtain crude and the crude obtained was purified by flash chromatography using 1 :9 methanohdichloromethane to obtain the title compound.

Yield: 62 mg (74 ); ^J H NMR (DMSO-de, 500 MHz): δ 11.51 (s, IH), 8.44 (s, IH), 8.32 (s, IH), 7.86 (d, J = 9.0 Hz, IH), 7.33 (s, IH), 6.99 (d, J = 9.0 Hz, IH), 5.90 (s, IH), 4.34 (d, J = 5.0 Hz, 2H), 3.57 (bs, 4H), 3.43 (m, IH), 2.69 (s, 3H), 2.55 (m, 2H), 2.42 (s, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1.56 (m, 2H), 1.42 (d, J = 7.2 Hz, 6H), 0.93 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 573.3 [M+H] ⁺ .

The compounds of examples 98-124 were prepared analogous to the process described in the compound of example 97 using appropriate intermediates.

Example 98:

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3-yl)methyl)- 7-(4-(morpholinomethyl)phenyl)benzo[d]thiazole-5-carboxamide

Yield: 60 ; ^J H NMR (DMSO-de, 500 MHz): δ 11.51 (s, IH), 8.36 (s, IH), 7.67 (s, 2H), 7.47 (s, 2H), 7.38 (s, IH), 5.90 (s, IH), 4.35 (d, / = 5.0 Hz, 2H), 3.60 (m, 5H), 3.44 (m, IH), 2.72 (s, 3H), 2.40 (m, 4H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (m, 2H), 1.42 (m, 6H), 0.93 (s, 3H); MS (ESI+): m/z 573.4 [M+H] ⁺ .

Example 99:

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)- 7-(4-morpholinophenyl)benzo[d]thiazole-5-carboxamide

Yield: 84 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.51 (s, IH), 8.33 (d, J = 4.5 Hz, IH), 7.58 (d, J = 8.5 Hz, 2H), 7.32 (s, IH), 7.10 (d, J = 8.5 Hz, 2H), 5.90 (s, IH), 4.34 (d, J = 4.5 Hz, 2H), 3.77 (m, 4H), 3.40 (m, IH), 3.19 (m, 4H), 2.69 (s, 3H), 2.54 (m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.41 (m, 6H), 0.93 (t, J = 7.0 Hz, 3H); MS (ESI+): m/z 559.3 [M+H] ⁺ . Example 100:

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)- 7-(6-morpholinopyridin-3-yl)benzo[d]thiazole-5-carboxamide

Yield: 68 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.51 (s, IH), 8.46 (d, J = 2.5 Hz, IH), 7.58 (t, J = 4.5 Hz, IH), 7.90 (d, J = 2.5 Hz, IH), 7.55 (m, IH), 7.34 (s, IH), 7.00 (d, J = 8.5 Hz, IH), 5.90 (s, IH), 4.34 (d, J = 5.0 Hz, 2H), 3.72(m, 4H), 3.53 (m, 3H), 3.41 (m, IH), 2.70 (s, 3H), 2.55 (m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.42 (m, 6H), 0.93 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 560.3 [M+H] ⁺ .

Example 101:

2-Isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)- 7-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5- carboxamide

Yield: 54 ; ^J H NMR (DMSO-de, 500 MHz): δ 11.51 (s, IH), 8.31 (s, IH), 8.27 (s, IH), 7.94 (s, IH), 7.50 (s, IH), 5.91 (s, IH), 4.34 (d, J = 4.0 Hz, 2H), 3.57 (m, 4H), 3.46 (m, 2H), 2.75 (m, 2H), 2.66 (s, 3H), 2.54 (m, 2H), 2.44 (m, 5H), 2.13 (s, 3H), 1.57 (m, 2H), 1.44 (m, 6H), 0.94 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 577.3 [M+H] ⁺ .

Example 102:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5-carb oxamide

Yield: 77 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.50 (s, IH), 8.44 (d, J = 2.0 Hz, IH), 8.33 (m, IH), 7.87 (d, J = 2.5 Hz, IH), 7.34 (s, IH), 6.99 (d, J = 9.0 Hz, IH), 5.87 (s, IH), 4.33 (d, J = 5.0 Hz, 2H), 3.57 (m, 4H), 3.43 (m, IH), 2.69 (s, 3H), 2.42 (m, 4H), 2.23 (s, 6H), 2.11 (s, 3H), 1.42 (m, 6H); MS (ESI+): m/z 545.3 [M+H] ⁺ .

Example 103:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5-carb oxamide

Yield: 57 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.50 (s, IH), 8.36 (s, IH), 7.67 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz,2H), 7.37 (s, IH), 5.87 (s, IH), 4.33 (d, J = 4.5 Hz, 2H), 3.59 (m, 4H), 3.53 (m, 2H), 3.43 (m, IH), 2.70 (s, 3H), 2.39 (m, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.41 (m, 6H); MS (ESI+): m/z 545.3 [M+H] ⁺ .

Example 104:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2- isopropyl-4-methyl-7-(6- (4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5-carb oxamide

Yield: 88 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.50 (s, IH), 8.47 (s, IH), 8.33 (m, IH), 7.90 (d, J = 8.5 Hz, IH), 7.35 (m, IH), 7.00 (d, J = 8.5 Hz, IH), 5.67 (s, IH), 4.32 (d, J = 5.0 Hz, 2H), 3.73 (m, 4H), 3.53 (m, 4H), 3.44 (m, IH), 2.69 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H), 1.42 (m, 6H), 0.93 (d, J = 7.5 Hz, 3H); MS (ESI+): m/z 532.3 [M+H] ⁺ .

Example 105:

N-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-iso propyl-4-methyl-7-(l- (2-morpholinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5-carbo xamide Yield: 24 ; H NMR (DMSO-d ₆ , 300 MHz): δ 11.48 (s, IH), 8.29 (m, 2H), 7.93 (s, IH), 7.48 (s, IH), 5.85 (s, IH), 4.29 (d, J = 4.5 Hz, 2H), 3.53 (m, 4H), 3.43 (m, 2H), 2.72 (m, 2H), 2.62 (s, 3H), 2.54 (m, 2H), 2.41 (m, 4H), 2.21 (s, 2H), 2.09 (s, 3H), 1.42 (m, 6H); MS (ESI+): m/z 549.3 [M+H] ⁺ .

Example 106:

7-Bromo-2-isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8- hexahydro isoquinolin- 4-yl)methyl)benzo[d]thiazole-5-carboxamide

Yield 56 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, IH), 8.31 (s IH), 7.45 (s, IH), 4.29 (d, J= 4.2 Hz, 2H), 3.41 (m, IH), 2.72 (s, IH), 2.58 (s, 3H), 2.35 (s, 2H), 2.08 (s, 3H), 1.62 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.21 (m, 2H); MS (ESI+): m/z 488.2 [M+H] ⁺ . Example 107:

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydr o isoquinolin-4-yl) methyl)-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d]th iazole-5-carboxamide

Yield 67 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.52 (s, IH), 8.43 (d, J = 2.4 Hz, IH), 8.29 (m, IH), 7.86 (d, J = 9.0 Hz, IH), 7.31 (s, IH), 6.98 (d, J = 9.0 Hz, IH), 4.34 (d, J = 4.5 Hz, 2H), 3.55 (m, 4H), 3.42 (m, IH), 2.74 (s, IH), 2.67 (s, 3H), 2.40 (m, 5H), 2.21 (s, 6H), 2.09 (s, 3H), 1.63 (s, 3H), 1.40 (m, 6H); MS (ESI+): m/z 585.3 [M+H] ⁺ .

Example 108:

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydr o isoquinolin-4-yl) methyl)-7-(4-(morpholinomethyl)phenyl)benzo[d]thiazole-5-car boxamide

Yield: 72 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.52 (s, IH), 8.31 (s, IH), 7.66 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.35 (s, IH), 4.32 (d, J = 4.5 Hz, 2H), 3.76 (m, 4H), 3.51 (s, 2H), 3.39 (m, IH), 2.74 (s, 2H), 2.69 (s, 3H), 2.37 (m, 6H), 2.08 (s, 3H), 1.62 (s, 4H), 1.40 (s, 3H), 1.38 (s, 3H); MS (ESI+): m/z 585.3 [M+H] ⁺ .

Example 109:

2-Isopropyl-4-methyl-N-((l-methyl-3-oxo-2,3,5,6,7,8-hexahydr o isoquinolin-4-yl) methyl)-7-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)benzo[d]thi azole-5-carboxamide

Yield: 41 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.52 (s, IH), 8.31 (s, IH), 8,24 (s, IH), 7.94 (s, IH), 7.50 (s, IH), 4.33 (m, 4H), 3.56 (m, 4H), 3.43 (m, 2H), 2.76 (s, 4H), 2.65 (s, 3H), 2.43 (m, 6H), 1.64 (s, 4H), 1.44 (s, 3H), 1.41 (s, 3H), 1.08 (t, J = 6.9 Hz, 2H); MS (ESI+): m/z 589.4 [M+H] ⁺ . Example 110:

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin- 3-yl) methyl)-7-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)benzo[d]thiazole-5-carboxa mide

Yield: 74 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.49 (s, IH), 8.42 (s, IH), 8.31 (s, IH), 7.85 (d, J = 8.7 Hz, IH), 7.31 (s, IH), 6.98 (d, J = 8.7 Hz, IH), 5.89 (s, IH), 4.33 (d, J = 5.0 Hz, 2H), 3.55 (bs, 4H), 2.81 (s, 3H), 2.67 (s, 3H), 2.53 (m, 2H), 2.40 (s, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.56 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 545.4 [M+H] ⁺ . Example 111:

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin- 3-yl) methyl)-7-(4- (morpholinomethyl)phenyl)benzo[d]thiazole-5-carboxamide

Yield: 72 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, IH), 8.34 (s, IH), 7.65 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.36 (s, IH), 5.89 (s, IH), 4.34 (d, J = 4.5 Hz, 2H), 3.58 (bs, 4H), 3.52 (s, 2H), 2.81 (s, 3H), 2.68 (s, 3H), 2.52 (m, 2H), 2.38 (s, 4H), 2.11 (s, 3H), 1.55 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 545.3 [M+H] ⁺ .

Example 112:

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin- 3-yl) methyl)-7-(6- morpholinopyridin-3-yl)benzo[d]thiazole-5-carboxamide

Yield: 88 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.50 (s, IH), 8.44 (s, IH), 8.32 (m, IH), 7.88 (d, J = 8.7 Hz, IH), 7.55 (m, 2H), 7.32 (s, IH), 6.99 (d, J = 8.7 Hz, IH ), 5.89 (s, IH), 4.34 (d, J = 4.5 Hz, 2H), 3.71 (bs, 4H), 3.52 (bs, 4H), 2.81 (s, 3H), 2.67 (s, 3H), 2.11 (s, 3H), 1.56 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 532.2 [M+H] ⁺ .

Example 113:

2,4-Dimethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin- 3-yl) methyl)-7-(l-(2- morpholinoethyl)-lH-pyrazol-4-yl)benzo[d]thiazole-5-carboxam ide

Yield: 46 ; ^J H NMR (DMSO-de, 500 MHz): δ 11.50 (s, IH), 8.26 (s, 2H), 7.92 (s, IH), 7.48 (s, IH), 5.89 (s, IH), 4.32 (m, 4H), 3.55 (m, 4H), 2.83 (s, 3H), 2.74 (m, 2H), 2.63 (s, 3H), 2.53 (m, 2H), 2.42 (m, 4H), 2.11 (s, 3H), 1.57 (m, 2H), 0.93 (t, / = 7.5 Hz, 3H); MS (ESI+): m/z 549.3 [M+H] ⁺ .

Example 114:

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-d ihydropyridin-3- yl)methyl)-7-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)benzo[d ]thiazole-5-carboxamide

Yield: 53 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.50 (s, IH), 8.47 (s, IH), 8.30 (s, IH), 7.93 (d, J = 8.7 Hz, IH), 7.33 (s, IH), 7.08 (d, J = 8.7 Hz, IH), 5.90 (s, IH), 4.34 (d, J = 4.5 Hz, 2H), 3.89 (bs, 4H), 3.03 (s, 4H), 2.69 (s, 3H), 2.64 (m, 2H), 2.23 (s, 3H), 2.11 (s, 3H), 1.56 (m, 2H), 1.46 (s, 9H), 0.92 (t, J = 7.5 Hz, 3H); MS (ESI+): m/z 587.2 [M+H] ⁺ . Example 115:

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3- yl)methyl)-7-(4-(morpholinomethyl)phenyl)benzo[d]thiazole-5- carboxamide

Yield: 90 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.50 (s, 1H), 8.34 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.36 (s, 1H), 5.89 (s, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.59 (bs, 4H), 3.52 (s, 2H), 2.71 (s, 3H), 2.55 (m, 2H), 2.38 (s, 4H), 2.11 (s, 3H), 1.55 (m, 2H), 1.46 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 587.2 [M+H] ⁺ .

Example 116:

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3- yl)methyl)-7-(6-morpholinopyridin-3-yl)benzo[d]thiazole-5-ca rboxamide

Yield: 92 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.50 (s, 1H), 8.46 (s, 1H), 8.31 (m, 1H),

7.90 (d, J = 8.7 Hz, 1H), 7.33 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.89 (s, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.72 (m, 4H), 3.54 (m, 4H), 2.70 (s, 3H), 2.56 (m, 2H), 2.11 (s, 3H), 1.56 (m, 2H), 1.46 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 574.2 [M+H] ⁺ .

Example 117:

2-(tert-Butyl)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihy dropyridin-3- yl)methyl)-7-(4-(l-(piperidin-l-yl)ethyl)phenyl)benzo[d]thia zole-5-carboxamide

Yield: 42 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, 1H), 8.33 (s, 1H), 7.81 (m, 2H), 7.70 (m, 2H), 7.40 (s, 1H), 5.90 (s, 1H), 4.57 (m, 1H), 4.33 (d, J = 4.5 Hz, 2H), 3.59 (bs, 4H), 2.81 (s, 3H), 2.72 (s, 3H), 2.52 (m, 2H), 2.11 (s, 3H), 1,72 (s, 2H), 1.68 (s, 4H), 1.56 (m, 2H), 1.42 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI-): m/z 597.2 [M-H]\

Example 118:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3 -yl)methyl)-7-(6-(4- methyl piperazin-l-yl)pyridin-3-yl)-2-neopentylbenzo[d]thiazole-5-c arboxamide

Yield: 94 ; ^J H NMR (DMSO-d ₆ , 500 MHz): δ 11.50 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.31 (t, J = 5.0 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J = 4.0 Hz, 1H), 5.90 (s, 1H), 4.34 (d, J = 5.0 Hz, 2H), 3.56 (bs, 4H), 3.01 (s, 2H), 2.69 (s, 3H), 2.54 (m, 2H), 2.41 (bs, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1.56 (m, 2H), 1.03 (s, 9H), 0.93 (t, J = 7.0 Hz, 3H); MS (ESI+): m/z 601.2 [M+H] ⁺ . Example 119:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(4- (morpholinomethyl)phenyl)-2-neopentylbenzo[d]thiazole-5-carb oxamide

Yield: 67 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.49 (s, 1H), 8.34 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.37 (s, 1H), 5.89 (s, 1H), 4.33 (d, J = 4.5 Hz, 2H), 3.59 (bs, 4H), 3.52 (s, 2H), 3.01 (s, 2H), 2.70 (s, 3H), 2.54 (m, 2H), 2.38 (s, 4H), 2.11 (s, 3H), 1.56 (m, 2H), 1.03 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 601.2 [M+H] ⁺ . Example 120:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(6- morpholinopyridin-3-yl)-2-neopentylbenzo[d]thiazole-5-carbox amide

Yield: 68 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.32 (m, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.89 (s, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.72 (m, 4H), 3.53 (m, 4H), 3.01 (s, 2H), 2.69 (s, 3H), 2.55 (m, 2H), 2.11 (s, 3H), 1.56 (m, 2H), 1.03 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 588.2 [M+H] ⁺ .

Example 121:

7-Bromo-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyri din-3-yl) methyl)-2- (tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-5-carboxamide

Yield: 65 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, 1H), 8.37 (m, 1H), 7.48 (s, 1H), 5.89 (s, 1H), 4.29 (d, J = 4.5 Hz, 2H), 3.93 (m, 2H), 3.45 (m, 3H), 2.60 (s, 3H), 2.12 (s, 3H), 2.02 (m, 3H), 1.82 (m, 3H), 1.52 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 519 [M+H] ⁺ .

Example 122:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(6-(4- methyl piperazin-l-yl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)ben zo[d] thiazole-5- carboxamide

Yield: 71 ; ^J H NMR (DMSO-de, 300 MHz): δ 11.50 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.90 (s, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.96 (m, 2H), 3.56 (bs, 4H), 3.03 (s, 4H), 2.69 (s, 3H), 2.54 (m, 2H), 2.41 (bs, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 2.02 (m, 1H), 1.83 (m, 2H), 1.53 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 615.2 [M+H] ⁺ . Example 123:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(4- (morpholinomethyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)benzo[ d]thiazole-5- carboxamide

Yield: 39 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, 1H), 8.36 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 5.89 (s, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.96 (m, 2H), 3.59 (bs, 4H), 3.52 (s, 2H), 3.46 (m, 3H), 2.71 (s, 3H), 2.54 (m, 2H), 2.38 (s, 4H), 2.11 (s, 3H), 2.02 (m, 2H), 1.82 (m, 2H), 1.56 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); MS (ESI+): m/z 615.3 [M+H] ⁺ .

Example 124:

4-Methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl )methyl)-7-(6- morpholinopyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzo[d] thiazole-5- carboxamide

Yield: 78 ; ^J H NMR (DMSO-d ₆ , 300 MHz): δ 11.51 (s, 1H), 8.46 (s, 1H), 8.33 (m, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.34 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 5.90 (s, 1H), 4.32 (d, J=4.5 Hz, 2H), 3.93 (m, 2H), 3.72 (m, 4H), 3.53 (m, 4H), 3.46 (m, 3H), 2.69 (s, 3H), 2.54 (m, 2H), 2.11 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.53 (m, 2H), 0.92 (t, J=7.5 Hz, 3H); MS (ESI+): m/z 602.2 [M+H] ⁺ . Biological Assays

Representative compounds of formula I of the present invention (referred to as test compounds) were tested for their EZH2 inhibitory activity using the assays and the methods described below:

EZH2 biochemical activity assay was performed to measure the rate of trimethylation of Histone H3 at lysine 27. Serial dilutions of the test compounds ranging from 0.1 nM to 10 μΜ were pre-incubated for 10 minutes with 50 ng EZH2 protein complex and enzymatic reactions were initiated by the addition of 100 nM Histone H3 peptide (ATKAARKSAPATGGVKKPHRYRP-GG-K) substrate and 10 μΜ SAM S-(5'- Adenosyl)-L-methionine chloride. The assay buffer used in every reaction contained 0.5 % DMSO in assay buffer containing 50 mM Tris-HCl pH 9.0, 50 mM NaCl, 1 mM dithiothreitol (DTT), 0.01 % Tween-20 and 0.01 % bovine serum albumin (BSA). Detection mixture containing 500 ng of anti trimethyl Histone H3 Lysine 27 Acceptor Bead conjugate (Perkin Elmer) and 500 ng of Straptavidin donor beads (Perkin Elmer) were added to each reaction mixture and plate was incubated for one hour at room temperature, 25-35 °C. Alpha counts were detected using Multilable Plate Reader. The IC5 ₀ values for the test compounds were determined by a four-parameter sigmoidal curve fit (Sigma plot or Graph pad).

The IC5 ₀ (nM) values of the compounds are presented in Table 1 wherein "++" refers to an IC5 ₀ value in range of 0.01 nM to 50.00 nM, "+" refers to IC5 ₀ value in range of 50.01 nM to 100.0 nM.

REFERENCES: Dillon SC, et al. 2005. Genome Biology 6:227.

Table 1 : In-vitro IC ₅₀ value

All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.