BR112017026088B1 - COMPOUND, USE OF A COMPOUND AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

SUBSTITUTED HETEROCYCLYL DERIVATIVES AS CDK INHIBITORS. The present invention provides substituted heterocyclyl derivatives of formula (I) which are therapeutically useful, particularly as inhibitors of selective transcriptional CDKs including CDK7, CDK9, CDK12, CDK13 and CDK18, more particularly CDK7 transcriptional inhibitors. These compounds are useful in the treatment and prevention of diseases and/or disorders associated with selective transcriptional CDKs in mammals. The present invention also provides the preparation of compounds and pharmaceutical formulations comprising at least one of the substituted heterocyclyl derivatives of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

Description

[001] This patent application claims the benefit of Indian provisional patent application number 2803/CHE/2015, filed on June 4, 2015 and 6214/CHE/2015, filed on November 18, 2015; the specifications thereof are incorporated herein in their entirety by reference.

FIELD OF INVENTION

[002] The present invention relates to compounds that inhibit the activity of selective transcriptional cyclin-dependent kinases (CDKs) including CDK7, CDK9, CDK12, CDK13 and CDK18, more particularly transcriptional cyclin-dependent kinase-7 (CDK7). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorders associated with selective transcriptional CDKs.

BACKGROUND OF THE INVENTION

[003] One of the most important and fundamental processes in biology is cell division mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. This is a highly regulated phenomenon that responds to a complex array of cellular signals within the cell and from external sources. A complex network of tumor-promoting and tumor-suppressor gene products are fundamental components of this cellular signaling process. Overexpression of tumor-promoting components or subsequent loss of tumor-suppressing products will lead to unregulated cell proliferation and tumor formation (Pardee, Science 246:603-608, 1989).

[004] Kinases are important cellular enzymes that perform essential cellular functions such as regulating cell division and proliferation, and they also appear to play a critical role in many disease states that are characterized by uncontrolled cell proliferation and differentiation. These disease states encompass a variety of cell types and diseases such as cancer, atherosclerosis, restenosis, and other proliferative disorders (Kris MG et al., JAMA 290 (16): 2149-58, 2003).

[005] Cyclin-dependent kinases (CDKs) are relatively small proteins, with molecular weights in the range of 34 to 40 kDa, and contain little more than the kinase domain. CDK binds the regulatory protein called cyclin. Without cyclin, CDK has little kinase activity; only the CDK-cyclin complex is an active kinase. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases (Morgan, D. O., Cell Division, 2:27, 2007).

[006] Members of the cyclin-dependent kinase (CDK) family play key regulatory roles in cell proliferation. Twenty mammalian CDKs are currently known. While CDK7-13 and 18 have been linked to transcription, only CDK1, 2, 4, and 6 exhibit demonstrable association with the cell cycle. Unique among mammalian CDKs, CDK7 has consolidated kinase activities, regulating both the cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is believed to function as a CDK1/2-activating kinase (CAK), where phosphorylation of conserved residues on CDK1/2 by CDK7 is required for full catalytic CDK activity and cell cycle progression (Desai et al., Mol. Cell Biol. 15, 345-350, 1995).

[007] CDK7, which complexes with cyclin H and MAT1, phosphorylates cell cycle CDKs upon T-loop activation to promote their activities (Fisher et al., Cell., Aug 26;78(4):713-24, 1994). As such, it has been proposed that inhibiting CDK7 would provide a potent means of inhibiting cell cycle progression, which may be especially relevant considering that there is compelling evidence from gene knockout studies in mice for a lack of a fundamental requirement for CDK2, CDK4, and CDK6 for the cell cycle, at least in most cell types (Malumbres et al., Nature Cell Biology,11, 1275 - 1276, 2009), while different tumors appear to require some, but be independent of other interphase CDKs (CDK2, CDK4, CDK6). Recently performed biochemical and genetic studies have confirmed the importance of CDK7 for cell cycle progression (Larochelle et al., Mol Cell., Mar 23;25(6):839-50. 2007; Ganuza et al., EMBO J., May 30; 31(11): 2498-510, 2012).

[008] Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general Transcription Factor II Human (TFIIH). CDK7 also plays a key role in transcription and possibly DNA repair. The trimeric Cak complex CDK7/CyclinH/MAT1 is also a component of TFIIH, the general transcription factor IIH/DNA repair factor (Morgan, D. O., Annu. Rev. Cell Dev. Biol. 13, 261-91, 1997). As a subunit of TFIIH, CDK7 phosphorylates the CTD (Carboxy-Terminal Domain) of the large subunit of RNA polymerase II (pol II). The CTD of mammalian pol II consists of 52 heptad repeats with the consensus sequence 1YSPTSPS7, and the phosphorylation state of Ser residues at positions 2 and 5 has been shown to be important for RNAP-II activation, indicating that it likely plays a crucial role in CTD function. CDK7, which primarily phosphorylates Ser-5 (PS5) of RNAP-II at the promoter as part of transcriptional initiation (Gomes et al., Genes Dev. 2006 Mar 1; 20(5):601-12, 2006), is in contrast to CDK9, which phosphorylates Ser-2 and Ser-5 of the heptad CTD (Pinhero et al., Eur. J. Biochem., 271, pp. 1004-1014, 2004).

[009] In addition to CDK7, other CDKs have been reported to phosphorylate and regulate RNA pol(II) CTD. The other CDKs include, Cdk9/Cyclin T1 or T2 which constitute the active form of the positive transcription elongation factor (P-TEFb) (Peterlin and Price, Mol Cell., Aug 4;23(3):297-305,2006) and Cdk12/Cyclin K and Cdk13/Cyclin K as the most recent members of RNAPII CTD kinases (Bartkowiak et al., Genes Dev., Oct 15;24(20):2303-16, 2010; Blazek et al., Genes Dev. Oct 15;25(20):2158-72, 2011).

[010] Disruption of RNAP II CTD phosphorylation has been shown to preferentially influence proteins with short half-lives, including those of the antiapoptotic BCL-2 family. (Konig et al., Blood, 1, 4307-4312, 1997; The nonselective cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and downregulation of Mcl-1; (Gojo et al., Clin. Cancer Res. 8, 3527-3538, 2002).

[011] This suggests that CDK7 enzyme complexes are involved in multiple functions in the cell: cell cycle control, transcriptional regulation, and DNA repair. It is surprising to find a kinase involved in such diverse cellular processes, some of which are even mutually exclusive. It is also surprising that multiple attempts to find cell cycle-dependent changes in CDK7 kinase activity have remained unsuccessful. This is unexpected since the activity and phosphorylation state of its substrate, CDC2, fluctuates during the cell cycle. Indeed, cdk7 activity has been shown to be required for the activation of the Cdc2/Cyclin A and Cdc2/Cyclin B complexes, and for cell division. (Larochelle, S. et al. Genes Dev 12,370-81, 1998). Indeed, flavopiridol, a nonselective pan-CDK inhibitor that targets CTD kinases, has demonstrated efficacy in the treatment of chronic lymphocytic leukemia (CLL), but presents a weak toxicity profile (Lin et al., J. Clin. Oncol. 27, 6012-6018, 2009; Christian et al., Clin. Lymphoma Myeloma, 9, Suppl. 3, S179-S185, 2009).

[012] In-vitro studies revealed substrate preferences for the different CDK7 complexes, indicating that CDK7 can form different complexes with different substrate specificity and presumably different in-vivo functions (Frit, P. et al., Biochimie 81, 27-38, 1999; Schutz, P. et al. Cell 102, 599-607, 2000).

[013] Thus, given the transcriptional role that CDKs play in regulating the cell cycle, there is a need for compounds to treat diseases and/or dysfunctions associated with selective transcriptional CDKs including CDK7, CDK9, CDK12, CDK13 and CDK18; more particularly CDK7. Accordingly, it is an object of this invention to provide compounds useful in the treatment and/or prevention or amelioration of such diseases and/or dysfunctions.

SUMMARY OF THE INVENTION

[014] Provided herein are substituted heterocyclyl derivatives and pharmaceutical compositions thereof, which are capable of suppressing and/or inhibiting the cyclin-dependent kinase-7 signaling pathway.

[015] In one aspect the present invention comprises compounds of formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof; wherein, ring A is cycloalkyl, aryl, heteroaryl, or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl, or absent; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl, or cycloalkyl; R3 is hydrogen, alkyl, or heteroaryl; alternatively, R2 together with R1 or R3 together with the ring atoms to which they are attached form a 5-7 membered ring;

[016] R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl; m where R5' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or – (CH2)1-3–NRaRb; R5” is H or alkyl;

[017] Ra and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

[018] R6 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

[019] L1 is *-CRcRd-C(O)-, *-NReC(O)- or absent; where * is the point of attachment with ring A;

[020] Rc and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, Rc and Rd together with the carbon to which they are attached form a cycloalkyl ring;

[021] Re is hydrogen or alkyl;

[022] L2 is -C(O)NH-, -C(O)O- or absent;

[023] m is 0, 1 or 2;

[024] p is either 0 or 1; and

[025] q is 0 to 3.

[026] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

[027] In yet another aspect, the present invention relates to the preparation of components of formula (I).

[028] In yet another aspect of the present invention, substituted heterocyclyl derivatives of formula (I) are provided herein which are capable of inhibiting CDK7 and the therapeutic use thereof.

DETAILED DESCRIPTION OF THE INVENTION

[029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein pertains. As used in the specification and appended claims, unless otherwise specified, the following terms have the meaning indicated to facilitate understanding of the present invention.

[030] As used herein, unless otherwise defined the term “alkyl” alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including linear C1-C10 or branched C3-C10 alkyl groups. Examples of “alkyl” include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.

[031] As used herein, the term “halo” or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

[032] As used herein, the term “haloalkyl” means alkyl substituted by one or more halogen atoms, wherein the alkyl groups are as defined above. The term “halo” is used interchangeably herein with the term “halogen” and means F, Cl, Br, or I. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

[033] As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s) means -OH.

[034] As used herein, the term “alkoxy” refers to the group alkyl-O- or -O-alkyl, wherein alkyl groups are defined as above. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy, and the like. An alkoxy group may be unsubstituted or substituted by one or more suitable groups.

[035] As used herein, the term “alkoxyalkyl” refers to the group alkyl-O-alkyl, wherein the alkyl and alkoxy groups are as defined above. Exemplary alkoxyalkyl groups include but are not limited to methoxymethyl, ethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

[036] As used herein, the term “cyano” refers to -CN; and the term “cyanoalkyl” refers to alkyl substituted with -CN; wherein the alkyl groups are as defined above.

[037] As used herein, the term “amino” refers to -NH2;

[038] As used herein, the term “nitro” refers to -NO2;

[039] As used herein, the term “acyl” refers to the group -C(O)-alkyl, wherein alkyl groups are as defined above. Exemplary alkoxy groups include but are not limited to acetyl, propanoyl, and acrylyl. An alkoxy group may be unsubstituted or substituted by one or more suitable groups.

[040] As used herein the term “cycloalkyl” alone or in combination with other term(s) means a C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, typically containing 3 to 7 carbon ring atoms. Examples of single ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include spirocyclic, bridged and fused cycloalkyls and the like.

[041] As used herein, the term “aryl” is the optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C6-C14 aryl group include, but are not limited to, phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. The aryl group may be substituted or unsubstituted by one or more suitable groups.

[042] The term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms. Examples of “Heterocycloalkyl” include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, azepanyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent may occur via a carbon atom or a heteroatom. A heterocycloalkyl group may be optionally substituted by one or more suitable groups mentioned above.

[043] As used herein, the term “heteroaryl” alone or in combination with other term(s) means a fully unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from a group consisting of carbon, oxygen, nitrogen, or sulfur. A heteroaryl can be a single (monocyclic) ring system or a polycyclic ring system. Examples of “heteroaryl” include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl, and the like.

[044] As used herein, the term “heterocyclyl” alone or in combination with other term(s) includes “heterocycloalkyl” and “heteroaryl” groups which are as defined above.

[045] The term “heteroatom” as used herein means an atom of sulfur, nitrogen or oxygen.

[046] As used in the above definitions, the term “optionally substituted” or “substituted” or “optionally substituted by suitable groups” refers to the replacement of one or more hydrogen radicals in a given structure by a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, and heteroaryl. It is understood that the substituent may also be substituted.

[047] As used herein, the term “compound(s)” encompasses the compounds disclosed in the present invention.

[048] As used herein, the term “comprises” or “comprising” is generally used in the sense of including, i.e., allowing for the presence of one or more features or components.

[049] As used herein, the term “or” means “and/or” unless otherwise indicated.

[050] As used herein, the term “including” as well as other forms such as “include,” “includes,” and “included” are not limiting.

[051] As used herein, the term “composition” is intended to cover a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts. “Pharmaceutically acceptable” means the carrier, diluent or excipient which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[052] As used herein, the terms “treat,” “treating,” and “treatment” refer to a method that alleviates or eliminates a disease and/or its accompanying symptoms.

[053] As used herein, the terms “prevent,” “preventing,” and “prevention” refer to a method of preventing the onset of a disease and/or its accompanying symptoms or preventing an individual from contracting a disease. As used herein, the terms “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and/or its accompanying symptoms and reducing the risk of an individual contracting a disease.

[054] As used herein, the term “therapeutically effective amount” refers to that amount of the compound being administered that is sufficient to prevent the development of or alleviate to some extent one or more symptoms of the condition or disorder being treated.

[055] “Pharmaceutically acceptable” means that a component is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, biologically or otherwise undesirable and includes that such component is acceptable for veterinary as well as human pharmaceutical use.

[056] The term “stereoisomers” refers to any enantiomers, diastereoisomers, or geometric isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG), whenever these are chiral or when they bear one or more double bonds. When the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) are chiral, they may exist in racemic form or in optically active form. It is to be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers and mixtures thereof. Stereoisomers of individual compounds can be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Furthermore, the compounds of the present invention can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers as well as suitable mixtures thereof.

[057] The present invention provides substituted heterocyclyl derivatives of formula (I) which are useful for the inhibition of CDK7.

[058] The present invention further provides pharmaceutical compositions comprising said heterocyclyl compounds of formula (I) and their derivatives as therapeutic agents.

[059] In the first embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof; wherein, ring A is cycloalkyl, aryl, heteroaryl, or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl, or absent; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl, or cycloalkyl; R3 is hydrogen, alkyl, or heteroaryl; alternatively, R2 together with R1 or R3 together with the ring atoms to which they are attached form a 5-7 membered ring;

[060] R4 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl; where R5' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or – (CH2)1-3–NRaRb; R5” is H or alkyl;

[061] Ra and Rb are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl;

[062] R6 at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl;

[063] L1 is *-CRcRd-C(O)-, *-NReC(O)- or is absent; where * is the point of attachment to ring A;

[064] Rc and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, Rc and Rd together with the carbon to which they are attached form a cycloalkyl ring;

[065] Re is hydrogen or alkyl; L2 is -C(O)NH-, -C(O)O-, or absent; m is 0, 1, or 2; p is 0 or 1; and q is 0 to 3.

[066] In another embodiment of the present invention, there is provided compounds of formula (IA), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring A is cycloalkyl, aryl, heteroaryl, or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl, or is absent; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl, or cycloalkyl; R3 is hydrogen, alkyl, or heteroaryl; alternatively, R2 together with R1 or R3 together with the ring atoms to which they are attached form a 5-7 membered ring;

[067] R4 in each occurrence is halo, alkyl, hydroxy or alkoxy; where R5' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or –(CH2)1-3–NRaRb; R5” is H or alkyl;

[068] Ra and Rb are each independently hydrogen or alkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, alkyl, hydroxy, haloalkyl or alkoxy;

[069] Li is *-CRcRd-C(O)-, *-NReC(O)- or absent; where * is the point of attachment to ring A;

[070] Rc and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, Rc and Rd together with the carbon to which they are attached form a cycloalkyl ring;

[071] Re is hydrogen or alkyl;

[072] L2 is -C(O)NH-, -C(O)O- or absent;

[073] m is 0, 1 or 2; and

[074] p is either 0 or 1.

[075] In another embodiment of the present invention, there is provided compounds of formula (IA) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring B is aryl, cycloalkyl, heterocyclyl or is absent; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl or cycloalkyl; R3 is hydrogen, alkyl or heteroaryl; alternatively, R2 together with R1 or R3 together with the ring atoms to which they are attached form a 5-7 membered ring;

[076] R4 in each occurrence is halo, alkyl, hydroxy or alkoxy;

[077] R5 is -(NH)pS(O)2-CH=CH2, -NH-CH2-CH=CH-C(O)-NRaRb, O R5" where R5' is hydrogen, halo, alkyl, alkoxyalkyl or –CH2-NRaRb; R5”is H or alkyl;

[078] Ra and Rb are each independently hydrogen or alkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, alkyl, hydroxy, haloalkyl or alkoxy;

[079] Li is *-CRcRd-C(O)-, *-NReC(O)- or absent; where * is the point of attachment with ring A;

[080] Rc and Rd independently are hydrogen, alkyl or haloalkyl; alternatively, Rc and Rd together with the carbon to which they are attached form a cycloalkyl ring;

[081] Re is hydrogen or alkyl;

[082] L2 is -C(O)NH-, -C(O)O- or absent;

[083] m is 0, 1 or 2; and

[084] p is either 0 or 1.

[085] In another embodiment of the present invention, it provides compounds of formula (IB), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring B, L1, L2, R2, R3, R4, R5, R6, m and q are the same as defined in the compounds of formula (I).

[086] In yet another embodiment of the present invention, there is provided compounds of formula (IC), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring A, ring B, L1, R2, R3, R4, R5, R6, m and q are the same as defined in the compounds of formula (I).

[087] In yet another embodiment of the present invention, it provides compounds of formula (ID), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring B, L1, R2, R3, R4, R5, R6, m and q are the same as defined in the compounds of formula (I).

[088] In yet another embodiment of the present invention, it provides compounds of formula (IE), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, Li is *-CRcRd-C(O)- or *-NReC(O)-;wherein * is the point of attachment with phenyl; R3, R4, R5 and m are the same as defined in the compounds of formula (I).

[089] In yet another form compounds of the formula (IF), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, Li is *-CRcRd-C(O)- or *-NReC(O)-;wherein * is the point of attachment with phenyl; R3, R4, R5 and m are the same as defined in the compounds of formula (I).

[090] In yet another embodiment of the present invention, it provides compounds of formula (IG), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, ring A, L1, R2, R3, R4, R5 and m are the same as defined in the compounds of formula (I).

[091] The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

[092] According to one embodiment, there are specifically provided compounds of formula (I), wherein ring A is aryl; preferably said aryl is phenyl.

[093] According to another embodiment, there are specifically provided compounds of formula (I), wherein ring B is aryl; preferably said aryl is phenyl.

[094] According to yet another embodiment, there are specifically provided compounds of formula (I), wherein ring B is heterocyclyl; preferably said heterocyclyl is piperidinyl, pyridinyl, piperazinyl, pyrazolyl, morpholinyl, indoninyl or pyrrolidinyl.

[095] According to yet another embodiment, specifically provided are compounds of formula (I) wherein ring B is absent.

[096] According to yet another embodiment, specifically provided are compounds of formula (I) wherein ring B and L2 are absent so that R5 is directly attached to ring A.

[097] According to yet another embodiment, specifically provided are compounds of formula (I) wherein Li is *-CRcRd-C(O) - wherein * is the point of attachment with ring A.

[098] According to the preceding embodiment, specifically provided are compounds of formula (I) wherein Rc and Rd are independently hydrogen or alkyl, wherein said alkyl is methyl, ethyl or isopropyl.

[099] According to yet another embodiment, specifically provided are compounds of formula (I), wherein L2 is *-C(O)NH-, *-C(O)O-, or is absent; wherein * is the point of attachment with ring B.

[100] According to yet another embodiment, specifically provided are compounds of formula (I), wherein L1 is present, L2 is absent.

[101] According to yet another embodiment, specifically provided are compounds of formula (I) wherein R2 is alkyl or cycloalkyl; preferably said alkyl is ethyl and said cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

[102] According to yet another embodiment, there are specifically provided compounds of formula (I), wherein R3 is hydrogen and alkyl; wherein said alkyl is methyl.

[103] According to yet another embodiment, specifically provided are compounds of formula (I) wherein R4 is halo; preferably said halo is fluorine.

[104] According to yet another embodiment, specifically provided are compounds of formula (I), wherein m is 0 or 1.

[105] According to yet another embodiment, there are specifically provided compounds of formula (I), wherein R5 is ; where R5' is hydrogen or –CH2-NRaRb.

[106] According to yet another embodiment, there are specifically provided compounds of formula (I), wherein R5 is when R5 is fixed to the hetero atom of ring B; R5' is hydrogen or –CH2-NRaRb.

[107] According to the two preceding embodiments, there are specifically provided compounds of formula (I), wherein Ra and Rb are each independently hydrogen or alkyl, preferably said alkyl is methyl.

[108] According to the preceding embodiment, there are specifically provided compounds of formula (I), wherein said Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, hydroxy, haloalkyl or alkoxy;

[109] According to yet another embodiment, specifically provided are compounds of formula (I), wherein n is 1 or 2.

[110] In certain embodiments of formula (I), ring A is aryl or heteroaryl; in another embodiment, said aryl is phenyl.

[111] In certain embodiments of formula (I), ring A is meta-substituted with respect to L1 and L2.

[112] In certain embodiments of formula (I), ring B is monocyclic or bicyclic cycloalkyl, aryl, heterocycloalkyl or heteroaryl.

[113] In certain embodiments of formula (I), ring B is heterocyclyl; in another embodiment said heterocyclyl is piperidinyl, pridinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, pyrazinyl, pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl.

[114] In certain embodiments of formula (I), ring B is absent.

[115] In certain embodiments of formula (I), wherein ring B and L2 are absent so that R5 is directly attached to ring A.

[116] In certain embodiments of formula (I), R2 is cycloalkyl; in any other embodiment, said cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.

[117] In certain embodiments of formula (I), R2 and R1 together with the atoms to which they are attached form a 5- or 6-membered ring.

[118] In certain embodiments of formula (I), R2 and R3 together with the atoms to which they are attached form a 5- or 6-membered ring.

[119] In certain embodiments of formula (I), R2 and R3 together with the atoms to which they are attached form a 6-membered aromatic ring.

[120] In certain embodiments of formula (I), R5 is, ; where R5' and R5” are as defined in formula (I).

[121] In certain embodiments of formula (I), R5 is, ; where R5' and R5” are as defined in formula (I).

[122] In certain embodiments of formula (I), R5 is ; where R5' and R5” are as defined in the formula

[123] In certain embodiments of formula (I), R5 is ; where R5' is hydrogen, halo, alkyl, alkoxy or alkoxyalkyl; and R5” is H or alkyl.

[124] In certain embodiments of formula (I), R5 is ; where R5' is –CH2–NRaRb; R5” is H or alkyl; Ra and Rb are each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl.

[125] In certain embodiments of formula (I), R5 is ; wherein R5' is –CH2–NRaRb; R5” is H or alkyl; Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted 4-7 membered heterocyclyl ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or –COO-alkyl.

[126] In certain embodiments of formula (I), R5 is where p, Ra and Rb are as defined in formula (I).

[127] In certain embodiments of formula (I), R5 is in which is an attachment point.

[128] In certain embodiments of formula (I), R5’ is –(CH2)1-3–NRaRb; wherein Ra and Rb are as defined in formula (I).

[129] In certain embodiments of formula (I), Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having 0-2 additional heteroatoms selected from O, S or N; wherein the optional substituent is one or more halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl.

[130] In certain embodiments of formula (I), Li is *-CRcRd-C(O)-; wherein * is the point of attachment with ring A; and Rc and Rd are defined in accordance with claim 1.

[131] In certain embodiments of formula (I), L2 is -C(O)NH- or -C(O)O-.

[132] In certain embodiments of formula (I), L2 is *-C(O)NH- or *-C(O)O-; where * is the point of attachment with ring B.

[133] In certain embodiments of formula (I), when Li is -CRcRd-C(O)- or -NReC(O)-, L2 is absent.

[134] In certain embodiments, the present invention provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

[135] In certain embodiments, the present invention provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

[136] In certain embodiments, when R1 is hydrogen, the compounds of the present invention are known to rapidly equilibrate, in solution, as mixtures of both tautomers:

[137] Accordingly, in the present invention, where only one tautomer is indicated for the compounds of formula (I), it is also within the scope of the present invention, unless specifically indicated otherwise.

[138] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof as described herein, and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent) or be diluted by a carrier, or contained within a carrier which may be in the form of a capsule, sachet, paper or other container.

[139] In yet another embodiment, the compounds of the present invention are kinase inhibitors. In certain embodiments, the compounds of the present invention are selective CDK inhibitors (e.g., being more active in inhibiting a CDK than a non-CDK kinase). In certain embodiments, the compounds of the present invention are selective CDK7 inhibitors (e.g., being more active in inhibiting CDK7 than a non-CDK7 kinase).

[140] In another embodiment, the present invention provides a pharmaceutical composition for use in the treatment and/or prevention of a disease and/or dysfunction associated with aberrant activity of selective transcriptional CDKs.

[141] In another embodiment, the present invention provides a pharmaceutical composition for use in treating a subject suffering from a disease and/or dysfunction associated with aberrant activity of selective transcriptional CDKs.

[142] In another embodiment, the present invention provides a method of inhibiting selective transcriptional CDKs, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[143] In another embodiment, the present invention provides a method of treating diseases and/or dysfunction mediated by selective transcriptional CDKs in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention.

[144] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula (I), for use in the treatment of a subject suffering from a disease or condition associated with aberrant activity of selective transcriptional CDKs. In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula (I), for use in the treatment of a subject suffering from diseases and/or dysfunction associated with aberrant activity of transcriptional CDK9, CDK12, CDK13 or CDK18.

[145] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula (I), for use in the treatment of a subject suffering from diseases and/or dysfunction associated with aberrant CDK7 transcriptional activity.

[146] In another embodiment, the present invention provides a method of treating selective transcriptional CDK (CDK9, CDK12, CDK13 or CDK18)-mediated disorders and/or diseases or conditions in a subject comprising administering a therapeutically effective amount of a compound of the present invention.

[147] In yet another embodiment, the present invention provides a method of treating CDK7 transcriptional dysfunctions and/or diseases or conditions in a subject comprising administering a therapeutically effective amount of a compound of the present invention.

[148] In yet another embodiment, the present invention provides a method of inhibiting selective transcriptional CDKs. In yet another embodiment, the present invention provides a method of particularly inhibiting transcriptional CDK7, CDK9, CDK12, CDK13 or CDK18; more particularly CDK7, in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor/kinase.

[149] In another aspect, the present invention relates to methods of inhibiting the activity of a kinase in a biological sample or subject. In certain embodiments, the kinase is a transcriptionally selective CDK. In another embodiment, the transcriptionally selective CDK is CDK9, CDK12, CDK13, or CDK18. In yet another embodiment, the transcriptionally selective CDK is particularly CDK7.

[150] In certain embodiments, inhibition of kinase activity is irreversible. In other embodiments, inhibition of kinase activity is reversible.

[151] In certain embodiments, the present invention provides compounds of formula (I) as covalent inhibitors of selective transcriptional CDKs. In yet another embodiment, the present invention provides compounds of formula (I) as covalent inhibitors of selective transcriptional CDK9, CDK12, CDK13 or CDK18. In yet another embodiment, the present invention provides compounds of formula (I) as covalent inhibitors of transcriptional CDK7.

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

[153] The pharmaceutical composition may be administered orally, parenterally or by inhalation. Examples of parenteral administration include injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.

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

[155] The pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweetening agents, flavorings, coloring agents or any combinations of the foregoing.

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

[157] Administration of the compounds of the invention, in pure form or in a suitable pharmaceutical composition, may be accomplished using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any of the routes that effectively transport the active compound of the present invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

[158] Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or granulated form), lozenges.

[159] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids such as suspensions or solutions.

[160] Topical dosage forms include ointments, pastes, creams, lotions, powders, solutions, eye and ear drops, impregnated patches, and may contain appropriate conventional additives such as preservatives, solvents to aid in penetration of the drug.

[161] The pharmaceutical compositions of the present invention can be prepared by means of conventional techniques known in the literature.

[162] Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the art. Therapeutic doses are generally identified through a human dose study based on preliminary evidence derived from animal studies. Doses must be sufficient to result in a therapeutic benefit without causing undesirable side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are contemplated within the scope of the present invention.

[163] In one embodiment, the compounds as disclosed in the present invention are formulated for pharmaceutical administration.

[164] Yet another embodiment of the present invention provides the use of the compounds as disclosed in the present invention in the treatment and prevention of diseases and/or disorders associated with aberrant activity of selective transcriptional CDKs, particularly the selective transcriptional CDK CDK is CDK7, CDK9, CDK12, CDK13 or CDK18; more particularly CDK7.

[165] Yet another embodiment of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof, in the treatment and/or prevention of a disease for which the symptoms thereof are treated, ameliorated, reduced and/or prevented by inhibition of selective transcriptional CDKs, particularly the selective transcriptional CDK is CDK7, CDK9, CDK12, CDK13 or CDK18; more particularly CDK7.

[166] According to yet another embodiment, the selective transcriptional CDK-mediated dysfunction and/or disease or condition is a proliferative disease or dysfunction or condition.

[167] In yet another embodiment, the diseases and/or disorders mediated by selective transcriptional CDKs are selected from, but are not limited to, the group consisting of a cancer, an inflammatory disorder, an autoinflammatory disorder, or an infectious disease.

[168] In other embodiments, the proliferative disease to be treated or prevented using the compounds of formula (I) will typically be associated with aberrant activity of CDKs, more particularly with CDK7, CDK9, CDK12, CDK13 or 18. Aberrant activity of CDK7, CDK9, CDK12, CDK13 or CDK18 may be elevated activity and/or inappropriate (e.g., abnormal) activity of CDK7, CDK9, CDK12, CDK13 or CDK18. In certain embodiments, CDK7, CDK9, CDK12, CDK13 or CDK18 are not overexpressed, and the activity of CDK7, CDK9, CDK12, CDK13 or CDK18 is elevated and/or inappropriate. In other certain embodiments, CDK7, CDK9, CDK12, CDK13 or CDK18 are overexpressed, and the activity of CDK7, CDK9, CDK12, CDK13 or CDK18 is elevated and/or inappropriate. The compounds of formula (I), and pharmaceutically acceptable salts or stereoisomers, and compositions thereof, inhibit the activity of CDK7, CDK9, CDK12, CDK13 or CDK18 and have been useful in the treatment and/or prevention of proliferative diseases.

[169] According to yet another embodiment, the compounds of the present invention are expected to be useful in the therapy of proliferative diseases such as viral diseases, fungal diseases, neurological/neurodegenerative disorders, autoimmune, inflammation, arthritis, antiproliferative diseases (e.g., ocular retinopathy), neuronal, alopecia, and cardiovascular.

[170] According to yet another embodiment, the compounds of the present invention are useful in the treatment of a variety of cancers, including but not limited to carcinoma, including that of the breast, liver, lung, colon, kidney, bladder, including small cell lung cancer, non-small cell lung cancer, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell leukemia, myeloma, mantle cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including chronic and acute myeloid leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of masenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xenoderoma pigmentosum, follicular thyroid cancer, and Kaposi's sarcoma.

[171] According to yet another embodiment, the individual is a mammal including a human.

[172] According to yet another embodiment, the present invention provides compounds or pharmaceutically acceptable salts or stereoisomers thereof, for use as a medicament.

[173] According to yet another embodiment, the invention provides the use of the compounds of the present invention in the manufacture of a pharmaceutical.

[174] According to yet another embodiment, the present invention provides compounds or pharmaceutically acceptable salts or stereoisomers thereof, for use in the treatment of cancer.

[175] According to yet another embodiment, the invention provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of diseases and/or dysfunction associated with the aberrant activity of selective transcriptional CDKs.

[176] In yet another embodiment, the invention provides the use of the compounds of the present invention in the manufacture of a pharmaceutical for the treatment of cancer.

[177] According to yet another embodiment, the present invention provides compounds for use as a medicament for the treatment of a subject suffering from diseases and/or disorders associated with aberrant activity of selective transcriptional CDKs.

[178] According to yet another embodiment, the present invention comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention together with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesic agents.

[179] The method(s) of treatment of the present invention comprise administering an effective and safe amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient (in particular, a human) in need thereof.

[180] The compounds of the invention are indicated in the therapeutic and/or prophylactic treatment of the conditions referred to above. For the therapeutic uses referred to above the dosage administered will, of course, vary with the compound employed, mode of administration, desired treatment and the dysfunction or disease indicated.

[181] The compounds of the present invention can be used as a single medicament or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

[182] According to one embodiment, the compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the present invention also includes isotopically labeled variants of the present invention that are identical to those referred to herein, but for the fact that one or more atoms of the compound are replaced by an atom having an atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds of the present invention may generally be prepared following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[183] The following abbreviations refer respectively to definitions included herein: LDA (lithium diisopropylamide); K2CO3 (potassium carbonate); KOAc (potassium acetate); EtOH (ethanol); NH3 solution (ammonia solution); TLC Prep (preparative thin layer chromatography); tr (retention time); RT (room temperature); DMF (dimethylformamide); h (hour); NaOH (sodium hydroxide); HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate); LC-MS (liquid chromatography-mass spectroscopy); HCl (hydrochloric acid); THF (tetrahydrofuran); DCM (dichloromethane); TFA (trifluoroacetic acid); TLC (Thin layer chromatography); DIPEA (Diisopropylethylamine); Na2SO4 (Sodium sulfate); ACN/CH3CN (Acetonitrile); PdCl2(dppf)-DCM (1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex); Bpin2 (Bis(pinacolato)diboron); DMSO-d6 (Dimethyl sulfoxide-d); Boc2O (Di- tert-butyl dicarbonate); HPLC (High pressure liquid chromatography); NaHCO3 (Sodium bicarbonate); Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0)); TEA (triethylamine), Cs2CO3 (Cesium carbonate); MHz (mega hertz); s (singlet); m (multiplet); and d (doublet).

General preparation procedures:

[184] The following general guidelines apply to all experimental procedures described herein. Until otherwise indicated, experiments are performed under positive nitrogen pressure, the temperature described is outside temperature (i.e. oil bath temperature). Reagents and solvents received from suppliers are used as is without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate since they have not been verified by means of a previous titration as a standard. All reactions are stirred on a magnetic stir bar. Cooling to negative temperatures was done by means of acetone/dry ice or crushed ice/salts. Magnesium sulfate and sodium sulfate were used as solvent drying agents after reaction work-up and are interchangeable. Removal of solvents under reduced pressure or under vacuum means distilling solvents in a rotary evaporator.

[185] The compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is to be understood that the order of the steps in the processes may be varied, that the reagents, solvents and reaction conditions may be substituted for those specifically disclosed, and that vulnerable moieties may be protected and deprotected as required.

[186] The specifics of the process for preparing compounds of the present invention are detailed in the experiment section.

[187] The present invention shall be illustrated by means of some examples, which are not to be construed as limiting the scope of the invention.

EXPERIMENT

[188] Unless otherwise indicated, work includes distribution of the reaction mixture between organic and aqueous phases, separation of layers and drying of the organic layer with anhydrous sodium sulfate, filtration and evaporation of the solvent. Purification, unless otherwise indicated, includes purification by means of silica gel chromatographic techniques, usually using an ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.

[189] The analysis of the compounds of the present invention, unless otherwise noted, has been conducted by general methods well known to one skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.

[190] It will be apparent to those skilled in the art that many modifications, in materials and methods, can be practiced without departing from the scope of the invention. Some of the intermediates were taken to the next step based on TLC results, without further characterization, unless otherwise specified.

INTERMEDIARIES SYNTHESIS Scheme-1:

[191] Synthesis of 2-(3-bromophenyl)propionic acid 2-(3-Bromophenyl)acetic acid (3 g, 13.95 mmol) in THF (15 mL) was added to a solution of 2 M LDA (22 mL, 41.8 mmol) at −78 °C over a period of 10 min. The reaction mass was stirred for 1 h at −78 °C followed by the dropwise addition of iodomethane (6.3 g, 44.6 mmol) over a period of 10 min. The reaction mass was stirred at room temperature overnight. The reaction mass was quenched with 2 N HCl and concentrated under reduced pressure to remove excess THF. The residue was diluted with ether, washed twice with 2 N HCl, and the ether layer was extracted with 10% NaOH. The combined NaOH layer was acidified with 6 N HCl, and the compound was extracted into ether. The ether layer was washed with water followed by brine, dried, and concentrated under reduced pressure to afford the crude compound (2.5 g, 78%). LCMS: m/z = 229.1 (M+H)+.

Scheme-2:

[192] Syntheses of 5-cyclopropyl-1-methyl-1H-pyrazol-3-amine

[193] Methylhydrazine (1 mL) was added to a solution of 3-cyclopropyl-3-oxopropanenitrile (1 g, 9.17 mmol) in ethanol (15 mL). The resulting reaction mass was heated to reflux for 12 h. The reaction mass was quenched with ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (1.1 g, 97%) LCMS: m/z = 138 (M+H)+.

Scheme-3:

[194] Synthesis of (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide

[195] Step-i: (E)-4-Bromobut-2-enoic acid (4.5 g, 27.7 mmol) was added to DCM (30 mL) with catalytic amount of DMF followed by addition of oxalyl chloride (5 mL). The reaction mass was allowed to stir for 1.5 h at RT, and solvent was evaporated under vacuum. The residue was dissolved in DCM and added to pre-cooled solution of 5-bromopyridin-2-amine (3.0 g, 17.34 mmol) in acetonitrile (50 mL) and DIPEA (11.0 mL, 69.36 mmol) at 0 °C. The resulting reaction mixture was stirred for 2 h, water was added and extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with 10% methanol in DCM to afford (E)-4-bromo-N-(5-bromopyridin-2-yl)but-2-enamide (1.25 g, 40%), LCMS: m/z = 320.9 (M+H)+.

[196] Step-ii: To a stirred solution of (E)-4-bromo-N-(5-bromopyridin-2-yl)but-2-enamide (1.0g, 3.13mmol) in acetonitrile (20mL) was added potassium carbonate (1.0g, 7.83mmol) and morpholine (0.39g, 4.7mmol) at room temperature. The reaction mixture was heated to 60oC for about 2h, and the reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography on neutral alumina using 10% methanol in DCM to afford the title compound (0.8g, 60%), LCMS: m/z = 326.1 (M+H)+.

Scheme-4:

[197] Synthesis of 4-acrylamidobenzoic acid

[198] A solution of 4-aminobenzoic acid (1.40 g, 10 mmol) in DMF (10 mL) and pyridine (0.5 mL) was cooled to 0°C. To this solution was added acryloyl chloride (0.94 g, 10 mmol) and the resulting mixture was stirred for 3 h at RT. The mixture was poured into 200 mL of water and the white solid obtained was filtered, washed with water and ether, dried to afford the title compound which was used in the next step without purification (1.8 g) LCMS: m/z = 192.1 (M+H)+. Scheme-5: Synthesis of N-(5-bromopyridin-2-yl)acrylamide.

[199] To a solution of 5-bromopyridin-2-amine (0.5 g, 2.92 mmol) in ACN (20 mL) was added water (2 mL), DIPEA (0.75 g, 5.84 mmol), and acryloyl chloride (0.26 g, 2.92 mmol) at 0 °C. After 30 min, the reaction mixture was quenched with ice-water and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc (2x25 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column eluting with 10%-30% hexane-ethyl acetate system to afford the title compound (0.3 g, 48%), LCMS: m/z = 227.8 (M+H)+.

Scheme-6:

[200] Synthesis of 1-(5-bromoindolin-1-yl)prop-2-en-1-one.

[201] To a solution of 5-bromoindoline (0.5 g, 2.51 mmol) in DCM (5 mL) was added TEA (0.63 mL, 5.02 mmol) and acryloyl chloride (0.23 g, 2.51 mmol) at 0 °C. After 30 min, the reaction mixture was quenched with ice-water and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc (2x25 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified via silica gel column eluting with 10%-30% hexane-ethyl acetate system to afford the title compound (0.4 g, 63%), LCMS: m/z = 253.8 (M+H)+.

Scheme-7:

[202] Synthesis of N-((5-bromopyridin-2-yl)methyl)acrylamide.

[203] To a solution of (5-bromopyridin-2-yl)methanamine (0.5 g, 2.7 mmol) in ACN (20 mL) was added water (2 mL), DIPEA (0.94 mL, 5.4 mmol), and acryloyl chloride (0.24 g, 2.7 mmol) at 0 °C. After 30 min, the reaction mixture was quenched with ice-water and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc (2x25 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography eluting with 0-5% MeOH-DCM to afford the title compound (0.3g, 46%) LCMS: m/z = 240.9 (M+H)+. EXAMPLES General Synthetic Scheme Scheme-8: wherein, ring A, ring B, R1, R2, R3, R4, L1 and m are as defined in formula (I);

[204] Some compounds of the present invention can be generally synthesized using the process outlined in Scheme-8. Commercially available or synthesized intermediate-b was converted to the corresponding acid chloride in the presence of suitable reagents and solvents (DCM, DMF catalyst, oxalyl chloride, at RT, for 1.5h) which upon reaction with intermediate-a in the presence of suitable reagents and solvents (pyridine, 0°C-RT, 12h; or DCM, TEA, 0°C-RT, 12h) afforded intermediate-c. Treatment of intermediate-c with intermediate-d (boronic acid or boronate ester) by Suzuki coupling conditions in the presence of suitable catalysts such as Pd(dppf)Cl2.DCM or PdCl2(PPh3)2, suitable base such as potassium carbonate or cesium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water gives intermediate-e. This intermediate-e upon reaction with the corresponding acid chloride of intermediate-f for 1 h at room temperature followed by reaction with 2M N,N-dimethylamine in THF in the presence of DIPEA and suitable solvent such as ACN afforded the product of interest.

[205] The present invention is further exemplified, but not limited, by the following examples illustrating the preparation of compounds according to the invention. Example-1: Synthesis of (E)-N-(3'-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Compound-1)

[206] Step-i: Synthesis of tert-butyl 3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazol-1-carboxylate

[207] 2-(3-Bromophenyl)propionic acid (1 g, 4.36 mmol) was added into DCM at 0 °C with catalyst amount of DMF and oxalyl chloride (1.1 g, 8.7 mmol) was added. The reaction mass was stirred at room temperature for 1.5 h. The reaction mass was concentrated under reduced pressure. The residue was redissolved in DCM and added to the cooled solution of tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.876 g, 3.93 mmol) (synthesis performed as described in reference Tetrahedron Letters, 2005, vol. 46, #6 p. 933-935) in pyridine (20 mL) at 0 °C. The resulting reaction mass was stirred at room temperature for 12 h. The reaction mass was concentrated under reduced pressure and the residue was dissolved in DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and the crude product was purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.5 g, 26.45%) LCMS: m/z = 336.1 (M-Boc+3).

[208] Step-ii: Synthesis of 2-(4’-amino-[1,1’-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide

[209] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.5 g, 1.15 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.378 g, 1.72 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added Cs2CO3 (1.12 g, 3.44 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. and PdCl2(dppf).DCM (0.046 g, 0.057 mmol) was added. The reaction mass was heated for 12 h at 110 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.2 g, 50%), LCMS: m/z = 347.2 (M+H)+.

[210] Step-iii: Synthesis of (E)-N-(3'-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1 ,1'-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide

[211] (E)-4-Bromobut-2-enoic acid (0.14 g, 0.86 mmol) was added to DCM (5 mL) with catalytic amount of DMF followed by addition of oxalyl chloride (0.121 g, 0.95 mmol). The reaction mass was stirred for 1.5 h, and the reaction mass was evaporated under reduced pressure to obtain the residue. The reaction mass was redissolved in DCM (2 mL) and was added at 0 °C to a mixture of 2-(4´-amino-[1,1´-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide (0.15 g, 0.43 mmol) in acetonitrile (10 mL) and DIPEA (0.4 mL, 2.16 mmol). The resulting reaction mixture was stirred for 10 min at 0 °C and after completion of the reaction, a solution of N,N-dimethylamine (2M in THF, 1 mL, 2.16 mmol) was added and then allowed to stir at room temperature for 12 h. The reaction mixture was quenched with a saturated NaHCO3 solution and diluted with DCM. The aqueous layer was separated and extracted with DCM (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified with silica gel column chromatography eluting with 10% methanol-DCM to afford the title compound (0.015 g, 7.57%). 1HNMR (DMSO-d6, 400MHz) d, 1H), 6.13 (s, 1H), 3.89 (dd, 1H), 3.56-3.58 (m, 2H), 2.70 (s, 6H), 1.77-1.84 (m, 1H), 1.41 (d, 2H), 1.25-1.28 (m, 1H), 0.87 (d, 2H), 0.60 (d, 2H); LCMS: m/z = 458.3 (M+H)+; HPLC: 98.15%, rt: 6.54min.

[212] (E)-N-(3’-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1’-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (0.1g, Compound-1) was separated using chiral prep HPLC column. (Method: Column: Lux 5 μ Cellulose- 4(10.0x250 mm), Elution: isocratic (95:5), A=ACN, B= 0.1% DEA in EtOH ) to afford pure Isomer-1 (0.04g) and Isomer-2 (0.04g).

[213] Isomer-1 (Compound-2): 1HNMR (DMSO-d6, 400MHz): δ 12.0 (brs, 1H), 10.42 (s, 1H), 10.17 (s, 1H), 7.75 (d, 2H), 7.58-7.64 (m, 3H), 7.48 (d, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 6.72-6.76 (m, 1H), 6.28 (d, 1H), 6.12 (s, 1H), 3.87-3.89 (m, 1H), 3.05 (d, 2H), 2.17 (s, 6H), 1.80 (brs, 1H), 1.40 (d, 3H), 0.87 (dd, 2H), 0.60 (d, 2H). LCMS: m/z = 458.35 (M+H)+; HPLC: 97.98%, rt: 6.06 min.; Chiral HPLC: 97.67%, RT: 6.88 min.

[214] Isomer-2 (Compound-3): 1HNMR (DMSO-d6, 400MHz): δ 12.0 (brs, 1H), 10.42 (s, 1H), 10.17 (s, 1H), 7.75 (d, 2H), 7.58-7.64 (m, 3H), 7.48 (d, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 6.72-6.76 (m, 1H), 6.28 (d, 1H), 6.12 (s, 1H), 3.87-3.89 (m, 1H), 3.05 (d, 2H), 2.17 (s, 6H), 1.80 (brs, 1H), 1.40 (d, 3H), 0.87 (dd, 2H), 0.60 (d, 2H). LCMS: m/z = 458.35 (M+H)+; HPLC: 96.64%, rt: 6.05 min.; Chiral HPLC: 98.74%, RT: 10.16 min.

[215] The compounds listed in table-1 below were prepared by a procedure similar to that described in Example-1 with appropriate variations in reagents, amounts of reagents, protections, deprotections, solvents and reaction conditions. The characterization data of the compounds are also summarized herein in table-1. Table-1: General Synthetic Scheme Scheme-9: wherein, ring A, ring B, R1, R2, R3, R4, R5, L1 and m are as defined in formula (I);

[216] Some compounds of the present invention can be generally synthesized using the process outlined in this scheme. Commercially available or synthesized intermediate-b was converted to corresponding acid chloride in the presence of suitable reagents and solvents (DCM, DMF catalyst, oxalyl chloride, RT, ~1.5h) which upon reaction with intermediate-a in the presence of suitable reagents and solvents (pyridine, 0°C-RT, 12h; or DCM, TEA, 0°C-RT, 12h) afforded intermediate-c. Treatment of intermediate-c with intermediate-g (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)) under suitable conditions and reagents (1,4-Dioxane, potassium acetate, Pd(dppf)Cl2.DCM or PdCl2(PPh3)2, 12 h, 100 °C) gives intermediate-h. Treatment of intermediate-h with intermediate-i via Suzuki coupling conditions in the presence of suitable catalyst such as Pd(dppf)Cl2.DCM or PdCl2(PPh3)2, suitable base such as potassium carbonate or cesium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water afforded the product of interest. Example-2: Synthesis of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Compound-10) Step-i: Synthesis of tert-butyl 5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazol-1-carboxylate

[217] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate (5.0 g, 11.52 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (3.5 g, 13.8 mmol) in 1,4-dioxane (50 mL) was added potassium acetate (3.3 g, 34.5 mmol). The reaction mass was allowed to stir for 10 min with degassing at RT and the DCM PdCl2(dppf) complex (0.046 g, 0.057 mmol) was added. The reaction mass was heated for 12 h at 100 °C in a sealed tube, cooled and diluted with water and ethyl acetate. The aqueous layer was separated and re-extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 20% hexane-ethyl acetate to afford the title compound (4.0 g, 60%), LCMS: m/z = 482.2 (M+H)+. Step-ii: Synthesis of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide

[218] To a degassed solution of tert-butyl-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate (0.5 g, 1.04 mmol) and (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide (0.27 g, 0.83 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added Cs2CO3 (0.84 g, 2.6 mmol). The reaction mass was allowed to stir for 10 min with degasser and DCM PdCl2(dppf) complex (0.06 g, 0.07 mmol) was added, the reaction mass was heated for 12 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The aqueous layer was separated and re-extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10% methanol in DCM, and further purified with preparative HPLC (Method: Column: Gemini NX C18 (21.2mm X 150mm, 5 microns), Mobile phase: 0.01% NH4OH in Water, Acetonitrile: Methanol (1:1)) to afford the title compound (0.2g, 40%). 1HNMR (DMSO-d6, 400MHz) .42-7.34 (m, 2H), 6.82-6.75 (m, 1H), 6.47 (d, 1H), 6.12 (s, 1H), 3.91-3.86 (m, 1H), 3.60-3.58 (m, 4H), 3.13 (d, 2H), 2.37 (s, 4H), 1.83-1.76 (m, 1H), 1.41 (d, 3H), 0.87-0.85 (d, 2H), 0.60-0.59 (m, 2H); LCMS: m/z = 501.10 (M+H)+; HPLC: 97.63%, rt: 4.27 min.

[219] Racemic (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide was separated using chiral preparative HPLC column (Method: Column: Chiral Pak IA(20mmX250 mm, 5 micron), Elution: isocratic (50:50), A=ACN, B=MeOH, Flow rate: 20mL/min ) to afford pure Isomer-1 and Isomer-2.

[220] Isomer-1 (Compound-11): 1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.77 (s, 1H), 10.43 (s, 1H), 8.62-8.61 (m, 1H ), 8.27 (d, 1H), 8.06 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.43-7.34 (m, 2H), 6.82-6.75 (m, 1H), 6.47 ( d, 1H), 6.11 (s, 1H), 3.86 (m, 1H), 3.60-3.58 (m, 4H), 3.12 (d, 2H), 2.38 (s, 4H), 1.83-1.76 (m, 1H), 1.41 (d, 3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 501.3 (M+H)+; HPLC: 99.26%, rt: 3.45 Min.; Chiral HPLC: 97.58%, RT: 7.54 min.

[221] Isomer-2 (Compound-12): 1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.75 (s, 1H), 10.41 (s, 1H), 8.61-8.60 (m, 1H ), 8.27-8.20 (m, 1H), 8.05 (d, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.42-7.33 (m, 2H), 6.81-6.74 (m, 1H), 6.47 (d, 1H), 6.10 (s, 1H), 3.89-3.87 (m, 1H), 3.59-3.57 (m, 4H), 3.10 (d, 2H), 2.31 (s, 4H), 1.81-1.77 (m, 1H), 1.40 (d, 3H), 0.87-0.85 (m, 2H), 0.61-0.57 (m, 2H); LCMS: m/z = 501.2 (M+H)+; HPLC: 99.04%, rt: 3.44 Min.; Chiral HPLC: 95.42%, rt: 9.07 min.

[222] The compounds listed in table-2 below were prepared by a procedure similar to that described in Example-2 with appropriate variations in reagents, amounts of reagents, protections and deprotections, solvents and reaction conditions. The characterization data of the compounds are also summarized herein in table-2. Table-2: Example-3: Synthesis of 4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)-benzamide.(Compound-83) Step-i: Synthesis of tert-butyl 5-ethyl-3-((3-nitrophenyl)amino)-1H-pyrazol-1-carboxylate.

[223] To a degassed solution of tert-butyl 3-amino-5-ethyl-1H-pyrazole-1-carboxylate (synthesized similarly to intermediate-1-A) (0.5 g, 2.36 mmol) and 1-bromo-3-nitrobenzene (0.571 g, 2.84 mmol) in 1,4-dioxane (20 mL) was added Cs2CO3 (1.91 g, 5.92 mmol), the reaction mass was stirred for 10 min at RT and further degassed for 10 min, and Xantphos (0.136 g, 0.236 mmol) and Pd2(dba)3 (0.108 g, 0.118 mmol) were added. The reaction mass was heated for 4 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2x20mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.2g, 35%). LCMS: m/z = 333.10 (M+H)+.

Step-ii: Synthesis of tert-butyl 3-((3-aminophenyl)amino)-5-ethyl-1H-pyrazol-1-carboxylate.

[224] tert-Butyl-5-ethyl-3-((3-nitrophenyl)amino)-1H-pyrazole-1-carboxylate (0.2g, 0.60mmol) was added to ethanol, 10% Pd/C (0.05g) was added and the reaction mass was stirred at RT under H2 pressure (40Psi) for 4h on a Parr type shaker. The reaction mixture was filtered through a celite pad, washed with ethanol and the filtrate was concentrated in vacuo to obtain the title compound. (0.13g, 49%) LCMS: m/z = 302.8 (M+H)+.

Step-iii: Synthesis of tert-butyl 3-((3-(4-acrylamidobenzamido)phenyl)amino)-5-ethyl-1H-pyrazol-1-carboxylate

[225] To a solution of 4-acrylamidobenzoic acid (0.098 g (intermediate-11), 0.52 mmol) in DMF (4 mL), HATU (0.245 g, 0.64 mmol) was added followed by DIPEA (0.2 mL, 1.05 mmol) and finally tert-butyl 3-((3-aminophenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate (0.13 g, 0.430 mmol) was added. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. (0.13g, 90%). LCMS: m/z = 476.2 (M+H)+.

Step-iv: Synthesis of 4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)benzamide

[226] To a solution of tert-butyl-3-((3-(4-acrylamidobenzamido)phenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate (0.13 g, 0.33 mmol) in DCM (3 mL), TFA (1 mL) was added at 0 °C. The reaction mass was stirred at room temperature for 2 h. The reaction mass was concentrated in vacuo to afford the crude compound. The crude compound was purified by silica gel column chromatography eluting with 10% methanol-DCM, and was further purified with Preparative HPLC (Method: Column: X-BRIDGE PREP C18 5 MICRON OBD (19mmX150 mm), Mobile phase: 0.01% NH4OH: Acetonitrile) to afford the title compound (0.030 g, 25%). 1HNMR (DMSO-d6, 400MHz): δ 11.5 (s, 1H), 10.38 (s, 1H), 9.93 (s, 3H), 8.23 (s, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.64 (s, 1H), 7.05-6.98 (m, 3H), 6.46-6.40 (m, 1H), 6.29-6.24 (d, 1H), 5.78 (d, 1H), 5.62 (s, 1H), 2.52-2.50 (m, 2H), 1.16-1.12 (t, 3H); LCMS: m/z = 376.10 (M+H)+; HPLC: 92.00%, rt: 3.28 min. Example-4: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)-but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide (Compound-84)

Step-i: Synthesis of tert-butyl 4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine1 (2H)-carboxylate

[227] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.45 g, 1.03 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.42 g, 1.37 mmol) in 1,4-dioxane (20 mL) and water (1 mL) was added K2CO3 (0.45 g, 3.26 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. and PdCl2(dppf).DCM (0.044 g, 0.05 mmol) was added. The reaction mass was heated for 5 h at 100 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the compound was purified by combiflash column eluting with 70% hexane-ethyl acetate system to afford the title compound (0.3 g, 66%) LCMS: m/z = 437.2 (M+H)+.

Step-ii: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide

[228] TFA (1 mL) was slowly added to a stirred solution of tert-butyl 4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.1 g, 0.22 mmol) in dry DCM (10 mL) under argon atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, excess solvents were removed under reduced pressure to dryness to afford the title compound (0.13 g of title compound as TFA salt). LCMS: m/z = 337.1 (M+H)+.

Step-iii: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1,2 ,3,6-tetrahydropyridin-4-yl)phenyl)propanamide

[229] To a solution of (E)-4-(dimethylamino)but-2-enoic acid (0.063 g, 0.37 mmol) in DMF (5 mL) was added HATU (0.21 g, 0.55 mmol) at 0 °C followed by DIPEA (0.14 mL, 1.11 mmol) and finally N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide (0.17 g, 0.37 mmol) was added. The reaction mass was stirred for 1 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and further purified by preparative HPLC condition (Column: X-bridge prep C18 5u OBD (19*150mm), Mobile phase: Ammonia-water) to afford the title compound as free base (0.02g, 12%); 1HNMR (DMSO-d6, 400MHz) ), 3.81-3.83 (d, 2H), 3.73-3.74 (m, 2H), 3.4 (s, 1H), 3.03 (s, 2H), 2.14 (s, 6H), 1.79-1.2 (m, 1H), 1.36 (d, 3H), 0.87 (d, 2H), 0.6 (d, 2H). LCMS: m/z = 448.2 (M+H)+; HPLC: 98.28%, RT: 5.92 min. Example-5: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)-but-2-enoyl)piperidin-4-yl)phenyl)propanamide (Compound-85)

Step-i: Synthesis of tert-butyl 4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine -1-carboxylate

[230] 10% Pd/C was added to a degassed solution of tert-butyl 4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.12 g, 0.28 mmol) in methanol (10 mL). The reaction mixture was hydrogenated on a Parr 45Psi shaker for 40 min. The reaction mass was filtered through celite base and the celite base was washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound (0.11 g, 87%). LCMS: m/z = 439.1 (M+H)+.

Step-ii: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(piperidin-4-yl)phenyl)-propanamide

[231] TFA (1 mL) was slowly added to a stirred solution of tert-butyl 4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)piperidine-1-carboxylate (0.11 g, 0.25 mmol) in dry DCM (10 mL) under argon atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, excess solvents were removed under reduced pressure to dryness to afford the title compound (0.12 g of title compound as TFA salt). LCMS: m/z = 339.25 (M+H)+.

Step-iii: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4- il)phenyl)propanamide

[232] To a solution of (E)-4-(dimethylamino)but-2-enoic acid (0.063 g, 0.37 mmol) in DMF (5 mL) was added HATU (0.21 g, 0.55 mmol) at 0 °C followed by DIPEA (0.14 mL, 1.11 mmol) and finally N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(piperidin-4-yl)phenyl)propanamide (0.17 g, 0.37 mmol) was added. The reaction mass was stirred for 1 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by prep HPLC (X bridge C18 (21.2*150mm), aqueous ammonium hydroxide/water–acetonitrile) to afford the title compound (0.021g, 9.3%). 1HNMR (DMSO-d6, 400MHz): δ 11.98 (s, 1H), 10.33 (s, 1H), 7.13–7.21 (m, 3H), 7.05 (d, 1H), 6.51–6.62 (m, 2H), 6.09 (s, 1H), 4.53 (d, 1H), 4.11 (d, 1H), 3.75 (d, 1H), 3.09 (t, 1H), 2.98 (d, 2H), 2.63-2.75 (m, 2H), 2.11 (s, 6H), 1.75-1.77 (m, 3H), 1.44-1.47 (m, 2H), 1.30 (d, 3H), 0.84 (d, 2H), 0.57 (d, 2H); LCMS: m/z = 450.0 (M+H)+; HPLC: 98.00%, rt: 6.44 min. Example-6: Synthesis of N-(3'-(2-((5-Methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1'-biphenyl]-4-yl)acrylamide (Compound-86)

Step i: Synthesis of tert-butyl 3-amino-5-methyl-1H-pyrazol-1-carboxylate

[233] 60% NaH (0.5 g, 20.6 mmol) was added to a stirred solution of 5-methyl-1H-pyrazol-3-amine (2 g, 20.6 mmol) in THF (50 mL) at 0 °C over a period of 10 min followed by the addition of Boc anhydride (4.5 mL, 20.6 mmol). The reaction mass was stirred at room temperature for a period of 2 h. The reaction mass was diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified via combiflash eluting with 30% hexane-ethyl acetate system to afford the title compound (1.8 g, 80%) LCMS: m/z = 198.0 (M+H)+.

Step-ii: Synthesis of tert-butyl 3-(2-(3-bromophenyl)acetamido)-5-methyl-1H-pyrazol-1-carboxylate

[234] To a solution of 2-(3-bromophenyl)acetic acid (0.5 g, 2.32 mmol) in DCM (20 mL) was added EDCI (0.88 g, 0.4.65 mmol) at 0 °C followed by DIPEA (1.12 mL, 6.97 mmol) and finally tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (0.4 g, 2.09 mmol) was added. The reaction mass was stirred for 12 h at room temperature. The reaction mixture was quenched with ice-water and diluted with DCM. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified eluting with 20% hexane-ethyl acetate in combiflash to afford the title compound (0.3 g, 60%). LCMS: m/z = 395.9 (M+H)+.

Step-iii: Synthesis of N-(3’-(2-((5-Methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1’-biphenyl]-4-yl)acrylamide

[235] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)acetamido)-5-methyl-1H-pyrazole-1-carboxylate (0.2 g, 0.5 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (0.166 g, 0.6 mmol) in DMF (2.5 mL) and water (0.5 mL) was added K2CO3 (0.12 g, 0.81 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. and Bis(triphenylphosphine)palladium(II) dichloride (0.017 g, 0.025 mmol) was added. The reaction mass was heated for 5 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure and purified by preparative HPLC (Condition: Kinetex Evo, A: 0.1% formic acid in H2O, B: Acetonitrile-methanol) to afford the title compound (0.018 g, 20%). 1HNMR (DMSO-d6, 400MHz): δ 11.78 (s, 1H), 10.14 (s, 1H), 10.04 (s, 1H),7.811 (d, 2H), 7.789 (t, 3H), 7.55 (d, 1H), 6.53-6.47 (m, 1H), 6.34 (d, 1H), 6.29 (s, 1H), 5.80 (d, 1H), 3.71 (s, 2H), 2.22 (s, 3H); LCMS: m/z = 361.1 (M+H)+; HPLC: 96.04%, rt: 3.39 min.

[236] The compounds listed in table-3 below were prepared by a procedure similar to that described in Example-6 with appropriate variations in reagents, amounts of reagents, protections, deprotections, solvents and reaction conditions. The characterization data of the compounds are also summarized herein in table-3. Table-3: Example-7: Synthesis of (E)-N-(3-((1H-Indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)-but-2-enamido)benzamide (Compound-89)

Step-i: Synthesis of 3-bromo-1H-indazole

[237] Bromine (1.5 g, 9.4 mmol) in a 2 M NaOH solution (10 mL) was added dropwise to a suspension of indazole (1.5 g, 12.7 mmol) and a 2 M NaOH solution (23 mL) at room temperature. The reaction mass was stirred for 3 h at room temperature and sodium bisulfate (0.05 g) was added followed by the addition of 2N HCl. The solid precipitate was filtered and washed with water, dried by suction followed by Rotavap under reduced pressure to afford the title compound (2 g, 80%). LCMS: m/z = 197.1 (M+H)+.

Step-ii: Synthesis of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[238] 3,4-Dihydro-2H-pyran (042 g, 5 mmol) was added to a solution of 3-bromo-1H-indazole (0.5 g, 2.5 mmol) in ethyl acetate (10 mL) with catalytic amount of PTSA (0.05 g). The resulting reaction mass was stirred and heated to reflux for 5 h. The reaction mass was neutralized with aqueous ammonia and diluted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 5% hexane-ethyl acetate to afford the title compound (0.4 g, 51%) LCMS: m/z = 283 (M+3).

Step-iii: Synthesis of N1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)benzene-1,3-diamine

[239] Benzene-1,3-diamine (0.02 g, 0.21 mmol) and 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.05 g, 0.17 mmol) were added to toluene (15 mL) in a sealed tube at room temperature and argon gas was purged for 5-10 min. Then sodium tert-butoxide (0.032 g, 0.34 mmol) and BINAP (0.01 g, 0.017 mmol) were added and the resulting reaction mixture was purged with argon gas for 5 min followed by the addition of Pd2(dba)3 (0.003 g, 0.003 mmol). Argon gas purging was continued for an additional 15 min before sealing the reaction tube. The reaction mixture was heated at 110 °C for 8 h. After completion of the reaction by TLC, the reaction mass was filtered through celite and the filtrate was evaporated, the residue was purified by combiflash eluting with -40% hexane-ethyl acetate system to afford the desired compound (0.025 g, 56%) LCMS: m/z = 309.2 (M+H)+.

Step-iv: Synthesis of 4-amino-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide

[240] To a solution of 4-aminobenzoic acid (0.052 g, 0.78 mmol) in DMF (10 mL) was added HATU (0.15 g, 0.41 mmol) at 0 °C followed by DIPEA (0.12 mL, 0.96 mmol) and finally N1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)benzene-1,3-diamine (0.1 g, 0.32 mmol) added. The reaction mass was stirred for 12 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, and dried over Na2SO4, filtered and concentrated under reduced pressure and purified with silica gel column chromatography eluting with 40% hexane-ethyl acetate to afford the title compound (0.07 g, 50%). LCMS: m/z = 428.2 (M+H)+.

Step-v: Synthesis of (E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 3-yl)amino)phenyl)benzamide

[241] (E)-4-Bromobut-2-enoic acid (0.32 g, 1.99 mmol) was added to DCM (20 mL) with catalytic amount of DMF followed by addition of oxalyl chloride (0.27 g, 2.17 mmol). The reaction mass was stirred for 2 h, and was concentrated under reduced pressure to obtain the residue. The residue was redissolved in DCM (2 mL) and was added at -5 °C to a mixture of 4-amino-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide (0.42 g, 0.99 mmol) in acetonitrile (10 mL) and DIPEA (0.7 mL, 3.96 mmol). The resulting reaction mixture was stirred for 10 min at -5 °C and after completion of the reaction, a solution of N,N-dimethylamine (2M in THF, 1.5 mL, 2.97 mmol) was added and then allowed to stir at room temperature for 12 h. The reaction mixture was quenched with a saturated NaHCO3 solution and diluted with DCM. The aqueous layer was separated and extracted with DCM (2x25 mL). The combined organic phase was washed with brine, and dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified with silica gel column chromatography eluting with 10% methanol-DCM to afford the title compound (0.12 g, 20%). LCMS: m/z = 539.3 (M+H)+.

Step-vi: Synthesis of (E)-N-(3-((1H-indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

[242] Methanolic HCl (0.3 mL) was added to a solution of (E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide (0.12 g, 0.20 mmol) in DCM (4 mL) at room temperature and stirred for 2 h, and the reaction mass was concentrated under reduced pressure. The residue was dissolved in DCM and basified with a NaHCO3 solution. The separated organic phase was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure and further purified using prep TLC. eluting with 10% methanol-DCM and the resulting compound was triturated with ether to afford the title compound (0.012 g, 16%). 1HNMR (DMSO-d6, 400MHz): δ 11.98 (s, 1H), 10.34 (s, 1H), 10.04 (s, 1H), 8.86 (s, 1H), 8.11 (s, 1H), 7.97 (t, 3H), 7.78 (d, 2H), 7.47 (d, 1H), 7.32-7.38 (m, 2H), 7.19 (t, 1H), 7.11 (d, 1H), 7.02 (t, 1H), 6.76-6.80 (m, 1H), 6.30-6.34 (m, 1H), 3.12-3.14 (m, 2H), 2.08 (s, 6H); LCMS: m/z = 455.3 (M+H)+; HPLC: 95.93%, rt: 6.14 min. Example-8: Synthesis of N-(3'-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide (Compound-90)

Step-i: Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine

[243] NaH (0.89 g, 22.3 mmol) was added dropwise to a stirred solution of 3-aminoindazole (2.5 g, 18.6 mmol) in DMF at 0 °C, the reaction mass was stirred for 15 min followed by the addition of SEM chloride. The reaction mass was stirred at room temperature for 2 h and was quenched with ethyl acetate and ice-water. The ethyl acetate layer was separated, washed with water followed by brine, dried and concentrated under reduced pressure, and the crude product was purified by combiflash to afford the desired title compound (2.5 g, 50%) LCMS: m/z = 264.1 (M+H)+.

Step-ii: Synthesis of 2-(3-bromophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide

[244] To a solution of 2-(3-bromophenyl)propionic acid (1.2 g, 5.2 mmol) in DCM (15 mL) was added oxalyl chloride (1.1 mL, 13.1 mmol) dropwise at 0 °C followed by the addition of one drop of DMF. The reaction mass was stirred for 1 h and concentrated under reduced pressure. The resulting crude residue was dissolved in DCM (5 mL) and added to a stirred solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine (1.38 g, 5.2 mmol) in pyridine (15 mL) and DCM (15 mL) at 0 °C. The resulting reaction mass was stirred at room temperature for 1 h. The reaction mass was diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by combiflash eluting with 20% hexane-ethyl acetate system to afford the title compound (1.3 g, 54%) LCMS: m/z = 474.4 (M+H)+.

Step-iii: Synthesis of 2-(4’-amino-[1,1’-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-3-yl)propanamide

[245] To a degassed solution of 2-(3-bromophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide (1.3 g, 2.7 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (0.92 g, 4.1 mmol) in 1,4-dioxane (15 mL) and water (4 mL) was added Cs2CO3 (2.72 g, 8.3 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. and PdCl2(dppf)2.DCM (0.11 g, 0.13 mmol) was added. The reaction mass was heated for 12 h at 110 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the compound was purified by silica gel column chromatography eluting with 40% hexane-ethyl acetate system to afford the title compound (1 g, 78%) LCMS: m/z = 487.4 (M+H)+.

Step-iv: Synthesis of N-(3'-(1-oxo-1-((1-((2-(trimethylsily)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl )-[1,1'-biphenyl]-4-yl)acrylamide

[246] TEA (0.34mL, 2.4mmol) was added to a solution of 2-(4´-amino-[1,1´-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide (0.4g, 0.8mmol) in DCM (8mL) at 0 °C. The reaction mass was stirred for 5 min and acryloyl chloride (0.088g, 0.9mmol) in DCM (1mL) was added. The resulting reaction mass was stirred for 20 min at 0 °C, the reaction mass was quenched with ice-water and DCM. The separated organic layer was washed with water followed by brine, dried and concentrated under reduced pressure to afford the title compound (0.4g crude) LCMS: m/z = 541.2 (M+H)+.

Step-v: Synthesis of N-(3'-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl) acrylamide

[247] TFA (5 mL) was slowly added to a stirred solution of N-(3'-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide (0.4 g, 0.7 mmol) in dry DCM (5 mL) under an argon atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 h. After completion of the reaction, excess solvents were removed under reduced pressure. The resulting residue was stirred with aqueous NH3 solution (10 mL) for 1 h. The separated solid was filtered and washed with ether and hexane and further purified by preparative HPLC condition (Column: Zorbax C18 (21.2*150mm), Mobile phase: Acetonitrile-water) to afford the title compound as free base (0.04g, 13%). 1HNMR (DMSO-d6, 400MHz) 3H), 7.29 (t, 1H), 7.0 (t, 1H), 6.42-6.49 (m, 1H), 6.26 (dd, 1H), 5.77 (dd, 1H), 4.03 (dd, 1H), 1.50 (d, 3H). LCMS: m/z = 411.1 (M+H)+; HPLC: 98.43%, RT: 3.95 min. Example-9: Synthesis of (E)-N-(3'-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Compound-91)

Step-i: Synthesis of (E)-4-(dimethylamino)-N-(3'-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-indazol- 3-yl)amino)propan-2-yl)-[1,1'-biphenyl]-4-yl)but-2-enamide

[248] To a solution of (E)-4-bromobut-2-enoic acid (0.35g, 2.1mmol) in DCM (8mL) was added oxalyl chloride (0.27mL 2.3mmol) dropwise at 0 °C followed by the addition of one drop of DMF, the reaction mass was stirred for 1.5h and concentrated under reduced pressure. The resulting crude residue was redissolved in DCM (2 mL) and added to a stirred solution of 2-(4´-amino-[1,1´-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide (0.51 g, 1 mmol) in DIPEA (0.94 mL, 5.3 mmol) and acetonitrile (10 mL) at 0 °C for 20 min followed by the addition of 2 M N,N-dimethylamine solution in THF (1.3 mL) at 0 °C. The resulting reaction mass was stirred at room temperature for 12 h. The reaction mass was diluted with DCM and water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by combiflash eluting with 8% methanol-chloroform system to afford the title compound (0.3 g, 48 %). LCMS: m/z = 598.1 (M+H)+.

Step-ii: Synthesis of (E)-N-(3'-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]- 4-yl)-4-(dimethylamino)but-2-enamide

[249] TFA (5 mL) was slowly added to a stirred solution of (E)-4-(dimethylamino)-N-(3'-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1'H-indazol-3-yl)amino)propan-2-yl)-[1,1'-biphenyl]-4-yl)but-2-enamide (0.3 g, 0.5 mmol) in dry DCM (5 mL) under an argon atmosphere at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 h. After completion of the reaction, excess solvents were removed under reduced pressure. The crude product was purified by preparative HPLC condition (Column: Xbridge C18 (19*150mm), Mobile phase: Ammonium acetate-Acetonitrile-water) to afford the title compound as free base (0.01g, 4.2%). 1HNMR (DMSO-d6, 400MHz) 0 (t, 1H), 6.71-6.76 (m, 1H), 6.28 (d, 1H), 4.03 (d, 1H), 3.06 (d, 2H), 2.18 (s, 6H), 1.51 (d, 3H). LCMS: m/z = 468.1 (M+H)+; HPLC: 90.40%, rt: 6.25 min. Example-10: Synthesis of (E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Compound-92)

Step-: Synthesis of 2-(3-(6-aminopyrazin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide.

[250] To a degassed solution of tert-butyl 5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate (1.5 g, 3.11 mmol) and 6-chloropyrazin-2-amine (0.32 g, 2.49 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added Cs2CO3 (2.5 g, 7.69 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. and PdCl2(dppf).DCM (0.17 g, 0.218 mmol) was added. The reaction mass was heated for 12 h at 100 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with ethyl acetate and water. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (1 g, 50%), LCMS: m/z = 349.2 (M+H)+.

Step-ii: Synthesis of (E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin- 2-yl)-4-(pyrrolidin-1-yl)but-2-enamide.

[251] (E)-4-Bromobut-2-enoic acid (Intermediate-1d, 0.227g, 1.31mmol) was added to DCM (5mL) with catalytic amount of DMF followed by the addition of oxalyl chloride (0.121g, 0.95mmol). The reaction mass was stirred for 1.5h, and was concentrated under reduced pressure to obtain the residue. The reaction mass was redissolved in DCM (2mL) and was added at 0 °C to a mixture of 2-(3-(6-aminopyrazin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide (0.30g, 0.86mmol) in acetonitrile (5mL) and DIPEA (0.37mL, 2.16mmol). The resulting reaction mixture was stirred for 10 min at 0 °C and after completion of the reaction, a pyrrolidine solution (0.086 g, 1.2 mmol) was added and then it was left to stir at room temperature for 12 h. The reaction mixture was quenched with a saturated NaHCO3 solution and diluted with DCM. The aqueous layer was separated and extracted with DCM (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 10% methanol-DCM to afford the title compound (0.01 g, 10%). 1HNMR (DMSO- d6, 400MHz): δ 12.10 (s, 1H), 11.25 (s, 1H), 10.49 (s, 1H), 9.93 (s, 1H), 9.39 (s, 1H), 8.95 (m, 1H), 8.09 (s, 1H), 7.97-7.95 (d, 1H), 7.53-7.47 (m, 1H), 6.91-6.84 (m, 1H), 6.71-6.67 (d, 1H), 6.11 (s, 1H) .77 (m, 3H),1.44-1.43 (m, 3H), 0.88-0.85 (m, 2H), 0.64-0.62 (m, 2H), LCMS: m/z = 485.2 (M+H)+, HPLC: 95.04%, rt: 7.07 min. Example-11: Synthesis of (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Compound-93)

Step-i: Synthesis of tert-butyl (S)-3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazol-1-carboxylate

[252] (S)-2-(3-Bromophenyl)propionic acid (0.08 g, 0.34 mmol) (synthesis performed as described in reference WO2014/201073 A1) was added to 2 mL DCM at 0 °C with catalytic amount of DMF, and oxalyl chloride (0.42 g, 0.34 mmol) was added, the reaction mass was allowed to stir at room temperature for 1.5 h. The reaction mass was concentrated in vacuo, and the residue was dissolved in 2 mL dry DCM and added to a cooled solution of tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.078 g, 0.34 mmol) in 2 mL DCM and TEA (0.086 g, 0.1 mL) at 0 °C. The resulting reaction mass was stirred at room temperature for 1 h, after 1 h, the reaction mixture was diluted with DCM and then washed with saturated NaHCO3 solution followed by brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.1 g, 53 %) LCMS: m/z = 283 (M+3). LCMS: m/z = 436.1 (M+H)+.

Step-ii: Synthesis of tert-butyl (S)-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) propanamido)-1H-pyrazol-1-carboxylate.

[253] To a degassed solution of tert-butyl (S)-3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.1 g 0.23 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (0.087 g, 0.34 mmol) in 1,4-dioxane (5 mL) was added potassium acetate (0.045 g, 0.46 mmol). The reaction mass was allowed to stir for 10 min with degassing at RT and the DCM PdCl2(dppf) complex (0.010 g, 0.011 mmol) was added. The reaction mass was heated for 12 h at 100 °C in a sealed tube, cooled, and diluted with water and ethyl acetate. The aqueous layer was separated and re-extracted with ethyl acetate (2 × 25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane to afford the title compound (0.065 g, 58%), LCMS: m/z = 482.2 (M+H)+.

Step-iii: Synthesis of (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide.

[254] To a degassed solution of tert-butyl (S)-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate (0.065 g, 0.13 mmol) and (E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide (0.044 g, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.1 mL) was added Cs2CO3 (0.084 g, 0.26 mmol). The reaction mass was allowed to stir for 10 min with degasser and DCM PdCl2(dppf) complex (0.005 g, 0.007 mmol) was added, the reaction mass was heated for 12 h at 100 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The aqueous layer was separated and re-extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with 10% methanol in DCM (and further purified with Preparative HPLC (Column: GEMINI NX C18: 21.2mm*150mm, A: 0.01% Ammonia, B: ACN/MeOH) to afford the title compound (0.006g, 8%). 1HNMR (CD3OD-d6, 400MHz): δ 8.57-8.56 (d, 1H), 8.26-8.24 (d, 1H), 8.04-8.02 (m, 1H), 7.65 (s, 1H), 7.53-7.50 (m, 1H), 7.44-7.39 (m, 2H), 7.00-6.93 (m, 1H), 6.43-6.39 (d, 1H), 6.13 (s, 1H), 3.89-3.88 (m, 1H), 3.73-3.70 (m, 4H), 3.23-3.21 (m, 2H), 2.512.48 (m, 4H), 1.86-1.81 (m, 1H), 1.54-1.39 (d, 3H), 0.94-0.92 (m, 2H), 0.68-0.62 (m, 2H); LCMS: m/z = 501.1 (M+H)+; HPLC: 96.27%, rt: 5.88 min., Chiral HPLC: 90.84%, rt: 8.87 min. Example-12: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide(Compound-94)

Step-i: Synthesis of tert-butyl 3-(1-(3-bromophenyl)cyclopropane-1-carboxamido)-5-cyclopropyl-1H-pyrazol-1-carboxylate.

[255] To a solution of 1-(3-bromophenyl)cyclopropane-1-carboxylic acid (0.4 g, 1.66 mmol) (synthesis carried out as described in references EP1206446 B1; and WO2005/19161A1) in DMF (5 mL) was added HATU (0.94 g, 2.49 mmol) followed by DIPEA (0.86 mL, 4.98 mmol) at 0 °C and finally tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.37 g, 1.66 mmol) was added. The reaction mass was stirred for 15 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and the crude residue was purified by silica gel column chromatography to afford the desired title compound (0.4 g, 54%). LCMS: m/z = 448.0 (M+H)+.

Step-ii: Synthesis of tert-butyl 5-cyclopropyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1- carboxamido)-1H-pyrazol-1-carboxylate

[256] To a degassed solution of tert-butyl 3-(1-(3-bromophenyl)cyclopropane-1-carboxamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.2 g, 0.45 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’bi(1,3,2-dioxaborolane) (0.25 g, 0.54 mmol) in 1,4-dioxane (10 mL) was added KOAc (0.13 g, 1.35 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min with argon and PdCl2(dppf).DCM (0.036 g, 0.045 mmol) was added. The reaction mass was heated for 15 h at 110 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo and purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.2 g, crude product) LCMS: m/z = 494.2 (M+H)+.

Step-iii: Synthesis of (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido) pyridin-3-yl)phenyl)cyclopropane-1-carboxamide.

[257] To a degassed solution of tert-butyl 5-cyclopropyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamido)-1H-pyrazole-1-carboxylate (0.2 g, 0.4 mmol) and (E)-N-(5-bromopyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (0.1 g, 0.33 mmol) (synthesized similarly to intermediate 3-B) in 1,4-dioxane (10 mL) and water (2 mL) was added Cs2CO3 (0.26 g, 0.81 mmol. The reaction mass was stirred for 10 min and further degassed for 10 min with argon and PdCl2(dppf).DCM(0.033 g, 0.04 mmol). Then the reaction mass was heated for 15 h at 110 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo and purified by silica gel column chromatography eluting with 0-5% MeOH-DCM and further purified by preparative HPLC (Method: A: 0.005% TFA in water, B: ACN-MeOH, Column: Kinetex 5 μ (150 mmX19.0 mm) to afford the title compound (0.02 g, 10%). 1HNMR (DMSO-d6, 400MHz) ), 7.67-7.65 (m, 1H), 7.50-7.42 (m, 2H), 6.88-6.81 (m, 1H), 6.49-6.45 (m, 1H), 6.05 (s, 1H), 3.21-3.18 (m, 2H), 2.55-2.45 (m, 4H), 1.82-1.70 (m, 1H), 1.70-1.68 (m, 4H), 1.45-1.42 (m, 2H), 1.16-1.12 (m, 2H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 497.3 (M+H)+; HPLC: 93.65%, rt: 4.52 min. Example-13: Synthesis of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Compound-95)

Step-i: Synthesis of tert-butyl 3-(2-(3-bromophenyl)-2-methylpropanamide)-5-cyclopropyl-1H-pyrazol-1-carboxylate.

[258] To a solution of 2-(3-bromophenyl)-2-methylpropanoic acid (0.4 g, 1.66 mmol) (the synthesis was carried out as described in reference US2008/194600A1) in DMF (5 mL) was added HATU (0.94 g, 2.49 mmol) followed by DIPEA (0.86 mL, 4.98 mmol) at 0 °C, and finally tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.37 g, 1.66 mmol) was added. The reaction mass was stirred for 15 h at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and the crude residue was purified by 100-200 silica gel column chromatography to afford the desired title compound (0.15 g, 20%). LCMS: m/z = 450.0 (M+H)+.

Step-ii: Synthesis of tert-butyl 5-cyclopropyl-3-(2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) propanamido)-1H-pyrazol-1-carboxylate

[259] To a degassed solution of tert-butyl 3-(2-(3-bromophenyl)-2-methylpropanamide)-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.15 g, 0.45 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (0.1 g, 0.4 mmol) in 1,4-dioxane (10 mL) was added KOAc (0.1 g, 1.0 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min with argon and PdCl2(dppf).DCM (0.027 g, 0.033 mmol) was added. The reaction mass was heated for 15 h at 110 °C in a sealed tube. The reaction mass was cooled and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo and purified by silica gel column chromatography eluting with 15% hexane-ethyl acetate to afford the title compound (0.15 g, 92%) LCMS: m/z = 496.3 (M+H)+.

Step-iii: Synthesis of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl) phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide.

[260] To a degassed solution of tert-butyl 5-cyclopropyl-3-(2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate (0.14 g, 0.28 mmol) and (E)-N-(5-bromopyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (0.09 g, 0.28 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Cs2CO3 (0.17 g, 0.56 mmol). The reaction mass was stirred for 10 min and further degassed for 10 min. with argon and PdCl2(dppf).DCM (0.023 g, 0.028 mmol) was added and then heated for 15 h at 110 °C in a sealed tube. The reaction mass was cooled to room temperature and diluted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-5% MeOH-DCM and further purified by preparative HPLC (Method: A: 0.005% TFA in water, B: ACN-MeOH, Column: Kinetex 5 μ (150 mmX19.0 mm) to afford the title compound (0.004 g, 2.85%). 1HNMR (DMSO-d6, 400MHz): δ 11.05 (s, 1H), 9.89 (brs, 1H), 9.49 (s, 1H), 8.68-8.67 (m, 1H), 8.28-8.26 (m, 1H), 8.15-8.12 (m, 1H), 7.65 (s, 1H), 7.659-7.57 (m, 1H), 7.46-7.42 (m, 1H), 7.34-7.32 (m, 1H), 6.85-6.79 (m, 1H), 6.66-6.62 (m, 1H), 6.12 (s, 1H), 3.07-3.05 (m, 2H), 2.5 (s, 4H), 2.00-1.80 (m, 5H), 1.60 (s, 6H), 0.90-0.87 (m, 2H), 0.64-0.60 (m, 2H); LCMS: m/z = 499.3 (M+H)+; HPLC: 95.03%, rt: 6.16 min.

[261] Although the present invention has been illustrated by certain foregoing examples, it should not be construed as being limited thereby; rather, the present invention covers the general field as disclosed above. Various modifications and embodiments may be made without departing from the spirit and scope thereof. For example, the compounds in Table-4 below which may be prepared by following similar procedures as described in the above Schemes/Examples with suitable modifications known to those of ordinary skill in the art are also included within the scope of the present invention: Table-4:

Biochemical assay for CDK7:

[262] The ability of the compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM CDK7/CycH/MNAT1 obtained from Invitrogen, USA. The tested compounds were pre-incubated with the kinase at room temperature for 60 min. After incubation, the substrate mixture [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 min of kinase reaction. 1 nM Eu-labeled anti-phospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by 1/3 serial dilutions of 10 mM DMSO stock solution of the test compound. All fluorescence measurements were made on a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to the sigmoid curve fitting equation using GraphPad Prism V5 software. To identify compounds that irreversibly inhibit CDK7, time-dependent inhibition studies were performed by preincubating the compound with the enzyme at three time points (20, 60, and 180 min) and performing the assay as described above.

[263] The compounds were analyzed through the above mentioned assay procedure. The % inhibition at 10 μM concentration and IC50 values of the compounds are summarized in table-5 below wherein “+++” refers to IC50 value less than 0.025 μM, “++” refers to IC50 value in the range of 0.025 μM to 0.1 μM and “+” refers to IC50 value greater than 0.1 μM. Table-5: % Inhibition and IC50 Values

Claims (28)

1. COMPOUND characterized by being represented by the formula (IB): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein: ring B is phenyl or 5-14 membered heterocyclyl; R2 is hydrogen, (C1-C10) alkyl or (C3-C10) cycloalkyl; R3 is hydrogen or (C1-C10) alkyl; alternatively, R2 together with R3 together with the ring atoms to which they are attached form a 5-7 membered ring; R4 in each occurrence is halo, (C1-C10) alkyl or halo(C1-C10) alkyl; ; wherein R5' is hydrogen, (C1-C10)alkyl, (C1-C10)alkoxyalkyl or -(CH2)i-3-NRaRb and R5” is H or, (C1-C10)alkyl; wherein the double bond of R5 is in the (E) configuration; Ra and Rb are each independently hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy or (C1-C10)alkoxyalkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted 5-6 membered ring containing 0-2 additional heteroatoms independently selected from N, O or S; wherein the optional substituent is one or more halo, (C1-C10)alkyl, cyano, cyano(C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxyalkyl, -COOH or -COO-(C1-C10)alkyl; R6 in each occurrence is halo, (C1-C10)alkyl, (C1-C10)alkoxy or halo(C1-C10)alkyl; Li is *-CRcRd-C(O)- or is absent; where * is the point of attachment to the phenyl ring; Rc and Rd independently are hydrogen or (C1-C10)alkyl; alternatively, Rc and Rd together with the carbon atom to which they are attached form a (C3-C10)cycloalkyl ring; L2 is -C(O)NH- or is absent; m is 0, 1 or 2; p is 1; eq is 0 to 3. 2. COMPOUND, according to claim 1, characterized by being represented by the formula (ID): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 3. COMPOUND, according to claim 1, characterized by being represented by the formula (IE): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein Li is *-CRcRd-C(O)-; wherein * is the point of attachment to the phenyl ring. 4. COMPOUND, according to claim 1, characterized by being represented by the formula (IF): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 5. COMPOUND according to any one of claims 1 to 2, characterized in that ring B is piperidinyl, pyridinyl, piperazinyl, pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl. 6. COMPOUND according to any one of claims 1 to 4, characterized in that R5 is 7. COMPOUND, according to claim 1, characterized in that L2 is *- C(O)NH-; in which * is the point of attachment to ring B. 8. COMPOUND, according to claim 1, characterized by being selected from: or a pharmaceutically acceptable salt or stereoisomer thereof. 9. COMPOUND, according to claim 1, characterized by being a (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide or a pharmaceutically acceptable salt or a stereoisomer thereof. 10. COMPOUND, according to claim 1, characterized by being an N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide or a pharmaceutically acceptable salt or a stereoisomer thereof. 11. COMPOUND, according to claim 1, characterized by being represented by the formula: or a pharmaceutically acceptable salt or stereoisomer thereof. 12. COMPOUND, according to claim 1, characterized by being a (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt or a stereoisomer thereof. 13. COMPOUND, according to claim 1, characterized by being a (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide or a pharmaceutically acceptable salt or a stereoisomer thereof. 14. COMPOUND, according to claim 1, characterized by being represented by the formula: or a pharmaceutically acceptable salt or stereoisomer thereof. 15. COMPOUND, according to claim 1, characterized by being represented by the formula: or a pharmaceutically acceptable salt or stereoisomer thereof. 16. COMPOUND, according to claim 1, characterized by being represented by the formula: or a pharmaceutically acceptable salt or stereoisomer thereof. 17. COMPOUND, according to claim 1, characterized by being represented by the formula: or a pharmaceutically acceptable salt or stereoisomer thereof. 18. COMPOUND, according to claim 1, characterized by being an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide. 19. COMPOUND, according to claim 1, characterized by being an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof. 20. USE of a compound, as defined in any one of claims 1 to 19, characterized in that it is for the manufacture of a medicament for the treatment of cancer. 21. PHARMACEUTICAL COMPOSITION comprising a compound as defined in any one of claims 1 to 19, characterized in that it is a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient. 22. PHARMACEUTICAL COMPOSITION, according to claim 21, characterized by being used in the treatment of diseases and/or dysfunctions associated with aberrant activity of selective transcriptional CDKs, in which said diseases and/or dysfunctions are selected from a group consisting of a cancer, an inflammatory dysfunction, an autoinflammatory dysfunction and an infectious disease. 23. PHARMACEUTICAL COMPOSITION, according to claim 22, characterized in that said diseases and/or dysfunctions are associated with aberrant CDK9, CDK12, CDK13 or CDK18 transcriptional activity. 24. PHARMACEUTICAL COMPOSITION, according to claim 22, characterized in that said diseases and/or dysfunctions are associated with aberrant CDK7 transcriptional activity. 25. USE of a compound as defined in any one of claims 1 to 19, characterized in that it is used in the preparation of a medicament for the treatment of diseases and/or dysfunctions mediated by selective transcriptional CDKs, in which said diseases and/or dysfunctions are selected from a group consisting of a cancer, an inflammatory dysfunction, an autoinflammatory dysfunction and an infectious disease. 26. USE of a compound according to claim 20, characterized in that the cancer is selected from the group consisting of a carcinoma, including that of the breast, liver, lung, colon, kidney, bladder, including small cell lung cancer, non-small cell lung cancer, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell leukemia, myeloma, mantle cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including chronic and acute myeloid leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xenoderma pigmentosum, follicular thyroid cancer, and Kaposi's sarcoma. 27. USE of a compound according to any one of claims 25 to 26, characterized in that said use is in conjunction with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants and analgesic agents. 28. USE of a compound according to claim 25, characterized in that the selective transcriptional CDKs are CDK7, CDK9, CDK12, CDK13 or CDK 18.