Field of the Invention
Provided Ne novel pyrido-pyrimidine derivatives, which can be used as anti-inflammatory agents. Also provided Ne phNmaceutical compositions comprising one or more pyrido-pyrimidine derivatives, as well as methods of treating autoimmune diseases, inflammation or associated pathologies, including for example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection and psoriasis, comprising administering such compounds or phNmaceutical compositions comprising them.
Background of the Invention
During the last decade, numerous studies have focused on the roles played by cytokines, a unique class of intercellulN regulatory proteins, in the pathogenesis of many diseases. Cytokines play a crucial role in initiating, maintaining, and regulating immunological and inflammatory processes. Advances in our understanding of their role in immune and inflammatory disorders have led to the development of cytokine-based therapies, i.e., therapies that aim to inhibit or restore the activity of specific cytokines. Today, drugs that block inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), Ne among the most successful agents being introduced to the mNket.
Elevated levels of proinflammatory cytokines viz TNF-α and IL-lαNe associated with the pathogenesis of many immune mediated inflammatory disorders, for example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection or psoriasis. Inflammation is regulated by a lNge number of pro- and anti-inflammatory mediators, which include cytokines, eicosanoids, nitric oxide, and reactive oxygen species. The central role of these inflammatory mediators in the pathogenesis of both chronic and acute inflammatory diseases is well documented. Until a few yeNs ago, inflammatory disorders were treated primNily with relatively non-selective anti-inflammatory agents, such as corticosteroids and vNious non-steroidal anti-inflammatory drugs. In recent yeNs, novel therapies have been developed that specifically interfere with the action of selected pro-inflammatory mediators, such as TNFα and PGE2. These specific anti-inflammatory therapies have already proven to be very successful in treating rheumatoid Nthritis, inflammatory bowel disease, and several other inflammatory diseases.
The development of protein-based therapies that inhibit the activities of tumour-necrosis factor-a (TNF-α), including etanercept (Enbrel; Amgen/Wyeth), infliximab

(Remicade; Centocor), and adalimumab (Humira; Abbott), has been an important advancement in treating autoimmune diseases such as rheumatoid Nthritis. The approval ot KINERET, an interleukin-1 (IL-1) receptor antagonist, further indicates the clinical activity of protein-based therapies that regulate cytokine activities. However, current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heNt failure. Studies in rodent models have provided evidence that tNgeting specific pathways involved in TNF-α activities Ne effective approaches to interrupting the pro-inflammatory process. Oral small molecules that regulate these pathways should be the next significant advancement in treating chronic inflammatory diseases when used either as a monotherapy or in combination with the current injectables.
Numerous studies have now established that the pathogenesis of inflammatory diseases require cytokine-mediated communication between endothelial cells, infiltrating leukocytes, resident macrophages, mast cells, epithelial cells and osteoclasts. The p38 mitogen activated protein kinase (p38MAPK) regulates cytokine levels and therefore plays a central role in both the cellulN infiltration and activation responses associated with inflammatory diseases.
The p38 MAPK is a member of a lNge family of MAPK's whose signaling pathways also include the extracellulN regulated kinases (ERK) & the c-jun N terminal kinases (JNK). MAP kinases Ne serine threonine kinases that transduce environmental stimuli to the nucleus and they themselves Ne activated by upstream MAPK kinases by phosphorylation on both tyrosine and threonine residues. The MAPK pathways Ne involved in alterations in cell physiology resulting from a vNiety of stimuli and control cell death, cell cycle machinery, gene transcription and protein translation. p38a MAPK was first identified as a tyrosine phosphorylated protein in LPS (LipopolysacchNide) stimulated macrophages. The human p38a MAPK was identified as the tNget of pyridinyl imidazole compounds (cytokine suppressive anti-inflammatory drugs) that were known to block TNF-α and IL-1 release from LPS stimulated monocytes. After the cloning of first p38MAPK (p38a), additional members of the p38MAPK family were cloned by homology, including the p38a, p38p and p38y.
The p38 pathway controls the activity of multiple transcription factors and the expression of many genes. There is ample evidence implicating a pivotal role for p38 in inflammatory processes mediated by IL-1 and TNF-α. p38 inhibitors have been shown to effectively block both TNFa and IL-1 biosynthesis by LPS stimulated human monocytes.

In addition, p38MAPK also plays a role in the production of 1L-4, IL-6,1L-8 and IL-12. p38MAPK is also critical for cell response to certain cytokines. Treatment of human neutrophils with GM-CSF, TNF-α or TGF-a results in p38 activation. GM-CSF and TNF-α Ne potent enhancers of neutrophil respiratory activity suggesting a role for p38MAPK in respiratory burst.
p38 has also been implicated in the induction of cyclooxygenase-2 (COX-2) in LPS induced monocytes. COX-2 enzyme is the key enzyme in the production of prostaglandins from Nachidonic acid. Inhibitors of p38MAP kinase Ne also expected to inhibit COX-2 expression. Accordingly inhibitors of cytokine synthesis would be expected to be effective in disorders currently treated with NSAID's. These disorders include acute and chronic pain as well as symptoms of inflammation and cNdiovasculN disease.
Compounds, which modulate release of one or more of the aforementioned inflammatory cytokines, can be useful in treating diseases associated with the release of these cytokines.
WO03/057165 discloses a composition and method for preventing and treating amyloid-beta-peptide related disorders. WO03/093290 discloses nucleoside derivatives for treating hepatitis C virus infection. WO02/18380 and WO02/18379 disclose 7-oxopyridopyrimidines as inhibitors of cellulN proliferation. EP1364950 discloses pyridopyrimidine or naphthyridine derivatives. WO02/064594 discloses 6-substituted pyrido-pyrimidines as p-38 Kinase inhibitors. US5,945,422 discloses jV-oxide of amino containing pyrido [2,3-d] pyrimidines. WO98/33798 discloses pyrido [2,3-c/] pyrimidines and 4-aminopyridines as inhibitors of cellulN proliferation. US5,733,914 and WO 96/34867 disclose pyrido[2,3-d]pyrimidines for inhibiting protein tyrosine kinase mediated cellulN proliferation. US2004/0019210 discloses cyclin dependent kinase and tyrosine kinase inhibitors. WO02/03997 discloses nucleoside analogs as cell growth inhibitors. WO03/062236 discloses 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. WO 2004/014907 discloses-6-alkoxy-pyrido-pyrimidines as p38-MAP kinase inhibitors.
In view of the above, however, there remains a need for novel anti-inflammatory agents and in pNticulN, novel pyridopyrimidine derivatives that can act as anti-inflammatory agents.
SummNy of the Invention
Generally provided Ne novel pyridopyrimidine derivatives, which can be used for inhibiting or preventing autoimmune diseases, inflammation or associated pathologies, for

example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection or psoriasis.
PhNmaceutically acceptable salts, phNmaceutically acceptable solvates, enantiomers, diastereomers or TV-oxides of these compounds having the same type of activity Ne also provided.
Also provided Ne phNmaceutical compositions comprising one or more compounds described herein and optionally one or more phNmaceutically acceptable cNriers, excipients or diluents.
Compounds or phNmaceutical compositions described herein can be used for treating or preventing inflammatory, autoimmune diseases or associated pathologies, for example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection or psoriasis.
Detailed Description of the Invention In one aspect, provided Ne compounds having the structure of Formula I:
(Formula Removed)
and phNmaceutically acceptable salts, phNmaceutically acceptable solvates, esters, enantiomers, diastereomers, ./V-oxides, polymorphs or metabolites thereof, wherein RI can be alkyl, alkenyl, alkynyl, cycloalkyl, Nyl, Nalkyl, heteroNyl, heterocyclyl,
heteroNylalkyl or heterocyclylalkyl;
R2 can be oxygen, sulphur -NH, -N-acyl, -N(CN), -N(NO2), -C(R3)2 or -CH(NO2); z^2 represents a single bond or a double bond; R3 can be hydrogen, alkyl, cycloalkyl, Nyl, heterocyclyl, heteroNyl, Nalkyl,
heteroNylalkyl or heterocyclylalkyl; R.4 can be cycloalkyl or heterocyclyl; and Het can be heterocyclyl.
In other aspects, provided Ne methods for treating autoimmune diseases, inflammation or associated pathologies, including for example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection or psoriasis.

In another aspect, provided Ne phNmaceutical compositions comprising one or more compounds described herein and optionally one or more phNmaceutically acceptable cNriers, excipients or diluents. Such phNmaceutical compositions can be used for treating autoimmune diseases, inflammation or associated pathologies, for example, sepsis, rheumatoid Nthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonNy disorder, organ transplant rejection or psoriasis.
In other aspects, provided Ne processes for prepNing compounds disclosed herein.
Definitions:
The term "alkyl," unless specified otherwise, refers to a monoradical branched or unbranched saturated hydrocNbon chain having from 1 to 20 cNbon atoms. This term is exemplified by groups, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl or tetradecyl, and the like. Alkyl groups may further be substituted with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocNbonyl, cNboxy, -COORe (wherein R&is alkyl, cycloalkyl, Nyl, Nalkyl, heteroNylalkyl or heterocyclylalkyl), Nylthio, thiol, alkylthio, Nyloxy, alkoxyamino, -NRxRy {wherein Rx and Ry Ne independently selected from hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, -SOiR? (wherein R? is alkyl, cycloalkyl, -NRpRq (wherein Rp and Rq Ne independently selected from hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl; Rp and Rq may also together join to form a heterocyclyl ring), Nyl, Nalkyl, heteroNyl, heterocyclyl, heterocyclylalkyl or heteroNylalkyl), heteroNyl, heterocyclyl, heteroNylalkyl or heterocyclylalkyl}, -C(=O)NRxRy, -OC(=O)NRxRy, -NHC(=K)NRxRy (wherein K is oxygen, sulphur or nitrogen; Rx and Ry Ne the same as defined eNlier), nitro, -S(O)nR.s (wherein R.s is the same as defined eNlier and n is 0, 1 or 2). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents selected from alkyl, cNboxy, -COOR6 (wherein Rf, is the same as defined eNlier), -NRxRy, -C'(=O)NRxRy, -OC(=O)NRxRy, -NHC(=K)NRxRy (wherein K is the same as defined eNlier), -NHC(=O)OR6 (wherein Rx and Ry Ne the same as defined eNlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)nRs (wherein n and R5 Ne the same as defined eNlier). Alkyl groups may also be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur and -NRa (wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, Nyl).

The term "alkenyl," unless specified otherwise, refers to a monoradical of a branched or unbranched unsaturated hydrocNbon group preferably having from 2 to 20 cNbon atoms with cis or trans geometry. Preferred alkenyl groups include ethenyl or vinyl, 1-propylene or allyl, iso-propylene, bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may further be substituted with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy, -NHC(=K.)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier), alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocNbonyl, cNboxy, -COOR(, (wherein R6 is the same as defined eNlier), Nylthio, thiol, alkylthio, Nyl, alkNyl, Nyloxy, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, alkoxyamino, nitro, -S(O)nR? (wherein n and R? Ne the same as defined eNlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, cNboxy, -COOR6 (wherein R& is the same as defined eNlier), hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry Ne the same as defined eNlier) and -S(O)nRs (wherein R.s and n Ne the same as defined eNlier).
The term "alkynyl," unless specified otherwise, refers to a monoradical of an unsaturated hydrocNbon, preferably having from 2 to 20 cNbon atoms. Preferred alkynyl groups include ethynyl, propNgyl or propynyl, and the like. In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. It may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, alkoxyamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocNbonyl, cNboxy, -COORe (wherein R6 is the same as defined eNlier), Nylthio, thiol, alkylthio, Nyl, Nalkyl, Nyloxy, nitro, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy, -C(=K)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier), -S(O)nR.s (wherein n and R.s Ne the same as defined eNlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, cNboxy, -COOR(, (wherein R6 is the same as defined eNlier), hydroxy, alkoxy, halogen, Cp3, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry Ne the same as defined eNlier), cyano and -S(O)nRs (wherein Rs and n Ne the same as defined eNlier).
The term '"cycloalkyl," unless specified otherwise, refers to cyclic alkyl groups of from 3 to 20 cNbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the

definition. Cycloalkyl groups may optionally contain 1-3 heteroatoms selected from O, N and S and include, for example, oxazoline, isoxazoline, thiazoline, and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused with an Nyl group, for example indane or tetrahydro-naphthalene and the like. Cycloalkyl groupsjnay further be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, alkoxyamino, acyloxy, alkoxycNbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocNbonyl, cNboxy, -COOR6 (wherein R6 is the same as defined eNlier), Nylthio, thiol, alkylthio, Nyl, Nalkyl, Nyloxy, -NRxRy, -NHC(=K)NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier), nitro, heterocyclyl, heteroNyl, heterocyclylalkyl, heteroNylalkyl, -S(O)nR5 (wherein RS and n Ne the same as defined eNlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, cNboxy, hydroxy, alkoxy, halogen, -CF3, -NRxRy, -C(=O)NRxRy, -NHC(=K)NRxRy, -OC(=0)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier), cyano, and-S(O)nRs (wherein R.s and n Ne the same as defined eNlier).
The term "alkoxy," unless specified otherwise, refers to the group O-alkyl wherein alkyl is the same as defined above.
The term "Nalkyl," unless specified otherwise, refers to Nyl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains cNbon atoms from 1-6 and Nyl is as defined below.
The term "Nyl," unless specified otherwise, refers to a cNbocyclic Nomatic group, (for example, phenyl, biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, acylamino, alkoxyamino, alkynyl, alkoxycNbonylamino, cycloalkyl, alkoxy, acyl, Nyloxy, cyano, nitro, -NRxRy, -C(=0)NRxRy, -NHC(=K)NRxRy, -OC(=O)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier), cNboxy, -S(O)nRs (wherein R5 and n Ne the same as defined eNlier), -COOR6 (wherein R6 is the same as defined eNlier), heterocyclyl, heteroNyl, heterocyclylalkyl or heteroNylalkyl.
The term "cNboxy," unless specified otherwise, herein refers to -C(=O)OH.
The term "heteroNyl," unless specified otherwise, refers to monocyclic Nomatic ring structure containing 5 or 6 cNbon atoms, a bicyclic or a tricyclic Nomatic group having 8 to 10 cNbon atoms, with one or more heteroatom(s) independently selected from N, O and S

optionally substituted with 1 to 3 substituent(s) selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, acylamino, alkoxyamino, alkoxycNbonylamino, cycloalkyl, acyl, cNboxy, -S(O)nR5 (wherein R? and n Ne the same as defined eNlier), -COOR6 (wherein R6 is the same as defined eNlier), Nyl, alkoxy, Nalkyl, cyano, nitro, aminocNbonylamino, -NRxRy, -C(=O)NRxRy and -OC(=O)NRxRy (wherein Rx and Ry Ne the same as defined eNlier).Examples of heteroNyl groups Ne pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, xanthene, benzoxazolyl, and the like.
The term 'heterocyclyl," unless specified otherwise, refers to a non Nomatic monocyclic, bicyclic (fused, bridged, or spiro) or tricyclic cycloalkyl group having 5 to 10 atoms in which 1 to 3 cNbon atoms in a ring Ne replaced by heteroatoms selected from the group comprising of O, S and N, and Ne optionally benzofused or fused heteroNyl of 5-6 ring members and the said heterocyclyl group is optionally substituted wherein the substituents Ne selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, Nyl, alkoxy, Nalkyl, cyano, alkoxyamino, acylamino, alkoxycNbonylamino, nitro, oxo, cNboxy, -S(O)nRs (wherein Rs and n Ne the same as defined eNlier), -COOR6 (wherein R& is the same as defined eNlier), -NHC(=K)NRXRV NHC(=K)R6, -C(=O)NRxRy, -OC(=O)NRxRy (wherein K, Rx and Ry Ne the same as defined eNlier). Examples of heterocyclyl groups Ne tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyridinyl, piperidinyl, morpholine, piperazinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, and the like.
The term "heteroNylalkyl," unless specified otherwise, refers to heteroNyl (wherein heteroNyl is same as defined eNlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains cNbon atoms from 1-6.
The term "heterocyclylalkyl," unless specified otherwise, refers to heterocyclyl (wherein heterocyclyl is same as defined eNlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains cNbon atoms from 1-6.
The term "acyl," unless specified otherwise, refers to -C(=O)R" wherein R" is selected from the group hydrogen, alkyl, cycloalkyl, Nyl, Nalkyl, heteroNyl, heterocyclyl, heteroNylalkyl or heterocyclylalkyl.
The term "leaving group" generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily sepNated from synthetic products under defined conditions. Examples of such leaving

groups includes but not limited to halogen (F, Cl, Br, I), Inflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
The term "protecting groups" refers to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the pNticulN chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, cNboxy and example of such groups Ne found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Edn. John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the cNboxylic protecting groups, amino protecting groups or hydroxy protecting group employed is not critical so long as the derivatised moiety/moieties is/Ne stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
The term "phNmaceutically acceptable salts" refers to salts of the free acids, which possess the desired phNmacological activity of the free acid and which Ne neither biologically nor otherwise undesirable. Examples of such salts include phNmacologically acceptable salts such as inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (for example, acetate, tNtNate, citrate, fumNate, maleate, tolounesulphonate and methanesulphonate). Suitable inorganic base addition salts include, but Ne not limited to aluminium, calcium, lithium, magnesium, potassium, sodium and zinc salts. Suitable organic base addition salts include, but Ne not limited to primNy, secondNy and tertiNy amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine and procaine salts. The phNmaceutically acceptable salts may be prepNed by the conventional methods known in the prior Nt.
Compounds described herein may be prepNed by techniques well known in the Nt and familiN to a practitioner skilled in Nt of this invention. In addition, compounds described herein may be prepNed by processes described herein, such processes Ne not the only means by which the compounds described may be synthesized. Further, vNious synthetic steps described herein may be performed in any alternate sequence to form the tNgeted compounds.
(Formula Removed)
Compounds of Formulae XI4a, XI5a, XI6a, VIII7b, VIII8b, VIII9b and Xlla may be prepNed by following the reaction sequence as depicted in Scheme I. Thus a compound of Formula II (wherein hal is halogen (Cl, Br or I)) can be reacted with a compound of Formula 111 (wherein Q is hydrogen or het (wherein het is heterocyclyl)) to form a compound of Formula IV. The compound of Formula IV can be reduced to form a compound of Formula V. The compound of Formula V can be oxidized to form a compound of Formula VI. The compound of Formula VI can be reacted with an ester of Formula VII (wherein R' is alkyl and RI is the same as defined eNlier) to form a compound of Formula VIII. The compound of
Formula VIII can be oxidized to form a compound of Formula IX (wherein is a bond
connected to a chiral or achiral center). The compound of Formula VIII can be reacted with a compound of Formula Villa (wherein the said compound of Formula Villa is racemic or optically active isomer and het is the same as defined eNlier) to form a compound of Formula VHIb. The compound of Formula VHIb can be oxidized to form a compound of Formula IX. The compound of Formula IX can be reacted with an amine of Formula X (wherein the said compound of Formula X is racemic or optically active isomer, T is cycloalkyl, heterocyclyl
or (Formula Removed)
(wherein X is cNbon or nitrogen; Y is cNbon or Yw (wherein Yw is -NC(=O)OC(CH3)3 or -NC(=O)OC(CH3)2CHBr2, -NC(=O)OC(CH3)2CC13, -N-Nalkyl, -N-
methylsulphonyl, -N-tolylsulphonyl or -N-alkyl)) to form a compound of Formula XI. The
(Formula Removed)
\ compound of Formula XI can be deprotected (wherein T is (Formula Removed)
and Y is Yw) to form a
compound of Formula XII. The compound of Formula XI and XII can be deprotected
(wherein het is ^- ) to form a compound of Formula XIa and Xlla, respectively. The compound of Formula XIa can be reacted with a compound of Formula Rjj-hal (wherein Rjj is -S(O)nRs (wherein R5 and n Ne the same as defined eNlier), -CONRxRy, acyl and hal is the same as defined eNlier) or with a compound of Formula XV (wherein K and NRX Ne the same as define eNlier) to form a compound of Formula XIaa (wherein Rj is -S(O)nR5, -C(=K)NHRX, -CONRxRy or acyl). The compound of Formula XIaa can be deprotected
(wherein T is —f and Y is Yw) to form a compound of Formula XIaaa. The compound of Formula XIaaa can be reacted with a compound of Formula Ym (wherein Ym is the same as defined above) to form a compound of Formula X14a (wherein K.2 is -CO or a bond and K| is R(1. The compound of Formula XIaaa can be reacted with a compound of Formula R

(wherein hal and R6 Ne the same as defined eNlier) to form a compound of Formula XI5a. The compound of Formula XIaaa can be reacted with a compound of Formula XV (wherein K and Rx Ne the same as defines eNlier) to form a compound of Formula XI6a. The
(Formula Removed)
compound of Formula VHIb can be deprotected (wherein het is ' ) to form a compound of Formula VIII2b. The compound of Formula VlII2b can be reacted with a compound of Formula Ym (wherein Ym is the same as defined eNlier) to form a compound of Formula VIII3b (wherein K2 and KI Ne the same as defined eNlier). The compound of Formula VIIBb can be oxidized to form a compound of Formula VIII4b. The compound of Formula VIII4b can be reacted with a compound of Formula X (wherein T is the same as defined
eNlier) to form a compound of Formula VIII5b. The compound of Formula VIII5b can be
(Formula Removed)
_ deprotected (wherein T is
(Formula Removed)
and Y is Yw) to form a compound of Formula VIII6b. The
compound of Formula VIII6b can be reacted with a compound of Formula XV, R6-S02hal or Ym to form a compound of Formula VIII7b. Formula VIII8b and Formula VIII9b, respectively.
The reaction of a compound of Formula II with a compound of Formula III to form a compound of Formula IV can be cNried out in one or more organic solvents, for example tetrahydrofuran, dimethylformamide, dioxane or diethyl ether in the presence of one or more bases, for example, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, pyridine or mixtures thereof.
The compound of Formula IV can be reduced to form a compound of Formula V in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or mixtures thereof. The reaction can also be cNried out in the presence of one or more reducing agents, for example, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, sodium borohydride or mixtures thereof.
The oxidation of a compound of Formula V to form a compound of Formula VI can be cNried out in one or more organic solvents, for example, dichloromethane, dichloroethane, cNbon tetrachloride, chloroform or mixtures thereof. The reaction can also be cNried out in the presence of one or more oxidizing agents, for example, manganese dioxide, potassium permanganate, Dess MNtin periodinane (DMP), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), chromic anhydride or mixtures thereof. Other known oxidation methods can also be employed (see, for example. Advanced Organic Chemistry, 4th Edn., Merck, John Wiley & Sons, 1992).
The reaction of a compound of Formula VI with a compound of Formula VII to form a compound of Formula VIII can be cNried out in one or more organic solvents, for example, /V-methylpyrrolidinone, dimethylformamide, tetrahydrofuran, diethylether, dioxane or mixtures thereof. The reaction can also be cNried out in the presence of one or more bases, for example, potassium cNbonate, sodium cNbonate, lithium cNbonate, potassium cNbonate, lithium cNbonate, sodium cNbonate or mixtures thereof.
The oxidation of a compound of Formula VIII to form a compound of Formula IX can be cNried out with one or more reagents selected from m-chloroperbenzoic acid, oxone (KHSO?) or mixtures thereof. The reaction can also be cNried out in one or more organic solvents, for example, chloroform, cNbon tetrachloride, dichloromethane, ethanol, tetrahydrofuran or mixtures thereof.
The reaction of a compound of Formula VIII with a compound of Formula Villa to
form a compound of Formula VHIb can be cNried out in one or more organic solvents, for
example, tetrahydrofuran, diethylether, dioxane, toluene, benzene, dimethylformamide or
mixtures thereof. The reaction can also be cNried out in the presence of a redox couple.
Suitable redox couple agents may be any known to a person skilled in the Nt. The oxidizing
pNt of the redox couple can be selected from diisopropylazodicNboxylate (DIAD),
diethylazodicNboxylate (DEAD), N,N,N'N'-tetramethylazodicNboxamide (TMAD), 1,1'-
(azodicNbonyl)dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP), 4,7-
dimethyl-3,5,7-hexahydro-l ,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N'N'-
tetraisopropylazodicNboxamide (TIPA) or mixtures thereof. The reduction pNt of the redox couple can be a phosphine selected from trialkylphosphine (such as tributylphosphine), triNylphosphine (such as triphenylphosphine), tricycloalkylphosphine (such as tricyclohexylphosphine), triheteroNylphosphine or mixtures thereof. The phosphine reagent having one or more Nyl, alkyl or heteroNyl substituents may also be used (such as diphenylpyridylphosphine).
The oxidation of a compound of Formula VUIb to form a compound of Formula IX can be cNried out with m-chloroperbenzoic acid, oxone (KHSOs) or mixtures thereof. The reaction can also be cNried out in one or more organic solvents, for example, chloroform, cNbon tetrachloride, dichloromethane, ethanol, tetrahydrofuran or mixtures thereof.
The reaction of a compound of Formula IX with a compound of Formula X to form a compound of Formula XI can be cNried in the presence of one or more bases, for example, pyridine, A'-methylmorpholine, jV-ethyldiisopropylamine, triethylamine or mixtures thereof. The reaction can also be cNried out in one or more organic solvents, for example, ethyl

acetate, dichloromethane, dichloroethane, cNbon tetrachloride, chloroform or mixtures
thereof.
Alternatively, rather than using a compound of Formula IX, a compound of Formula VIII can be reacted directly with a compound of Formula X to form a compound of Formula
XI. (Formula Removed)
The deprotection of a compound of Formula XI (T is and Y is Yw (wherein
Yw is -NC(=O)OC(CH3)3 or -NC(=O)OC(CH3)2CHBr2)) to form a compound of Formula XII can be cNried out in one or more alcoholic or ethereal solutions of one or more acids (for example, hydrochloric acid solution of methanol, ethanol, propanol, isopropyl alcohol or ether) or trifluoroacetic acid neat or in dichloromethane.
The deprotection of a compound of Formula XI (T is (Formula Removed)
' and Y is Yw (wherein Yw is -NC(=O)OC(CH3)2CCb)) to form a compound of Formula XII can be cNried out by one or more supernucleophiles, such as, for example, lithium cobalt (I) phthalocyanine, zinc and acetic acid, cobalt phthalocyanine or mixtures thereof.
The deprotection of a compound of Formula XI (wherein T is (Formula Removed)
/ and Y is Yw (wherein Yw is -Af-Nalkyl)) to form a compound of Formula XII can be cNried out in an organic solvent (for example, ethyl acetate, methanol, ethanol, propanol or isopropyl alcohol) in the presence of a deprotecting agent (for example, palladium on cNbon in presence of hydrogen gas or palladium on cNbon with a source of hydrogen gas (for example, ammonium formate, cyclohexene or formic acid)).
The deprotection of a compound of Formula XI (wherein T is (Formula Removed)
and Y is Yw (wherein Yw is -/V-methylsulphonyl, -Af-tolylsulphonyl)) to form a compound of Formula XII can be cNried out in one or more organic solvents, for example, dimethylformamide, tetrahydrofuran or acetonitrile in the presence of one or more bases, for example, sodium hydride, potassium hydride, lithium hydride, potassium hydroxide, lithium hydroxide or sodium hydroxide (as described in T.W. Greene and P.G.M. Wuts. "Protective Groups in Organic Synthesis", 2nd Edn. John Wiley and Sons, New York, N.Y.)
The deprotection of a compound of Formula XI and a compound of Formula XII
(wherein het is (Formula Removed)
) to form a compound of Formula XIa and Xlla, respectively, can be cNried out in an organic solvent (for example, ethyl acetate, methanol, ethanol, propanol or isopropyl alcohol) in the presence of a deprotecting agent (for example, palladium on cNbon

in presence of hydrogen gas or palladium on cNbon with a source of hydrogen gas (for example, ammonium formate, cyclohexene or formic acid)).
The reaction of a compound of Formula Xla with a compound of Formula Ry-hal or with a compound of Formula XV to form a compound of Formula XIaa can be cNried out in an organic solvent, for example dichloromethane, tetrahydrofuran, dimethylformamide, dioxane or diethyl ether in the presence of one or more bases, for example, triethylamine, N-ethyldiisopropylamine, yV-methylmorpholine or pyridine.
The compound of Formula XIaa can be deprotected to form a compound of Formula
XIaaa (wherein T is (Formula Removed)
and Y is Yw (wherein Yw is -NC(=O)OC(CH3)3 or -NC(=O)OC(CH3)2CHBr2)) in one or more alcoholic or ethereal solutions of one or more acids (for example, hydrochloric acid solution of methanol, ethanol, propanol, isopropyl alcohol, ether or mixtures thereof) or trifluoroacetic acid neat or in dichloromethane.
The compound of Formula XIaa can be deprotected to form a compound of Formula
XIaaa (wherein T is(Formula Removed)
and Y is Yw (wherein Yw is -NC(=O)OC(CH3)2CC13)) by one or more supernucleophiles, such as, for example, lithium cobalt (I) phthalocyanine, zinc and acetic acid, cobalt phthalocyanine or mixtures thereof.
The compound of Formula XIaa can be deprotected to form a compound of Formula
XIaaa (wherein T is(Formula Removed)
and Y is Yw (wherein Yw is -NNalkyl)) in an organic solvent (for example, ethyl acetate, methanol, ethanol, propanol or isopropyl alcohol) in the presence of a deprotecting agent (for example, palladium on cNbon in presence of hydrogen gas or palladium on cNbon with a source of hydrogen gas (for example, ammonium formate, cyclohexene or formic acid)).
The compound of Formula XIaa can be deprotected to form a compound of Formula
XIaaa (wherein T is(Formula Removed)
and Y is Yw (wherein Yw is -N-methylsulphonyl, -N-tolylsulphonyl)) in one or more organic solvents, for example, dimethylformamide, letrahydrofuran or acetonitrile in the presence of one or more bases, for example, sodium hydride, potassium hydride, lithium hydride, potassium hydroxide, lithium hydroxide or sodium hydroxide (as described in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Edn. John Wiley and Sons, New York, N.Y.)
The compound of Formula XIaaa can be reacted with a compound of Formula Ym (wherein Ym is R6-hal, acetic anhydride or R6-COhal (wherein R6 and hal Ne the same as defined eNlier) to form a compound of Formula XI4a, XI5a and XI6a, respectively in an
organic solvent, for example dichloromethane, tetrahydrofuran, dimethylformamide, dioxane or diethyl ether in the presence of one or more bases, for example, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine or pyridine.

The compound of Formula VHIb can be deprotected (wherein het is
(Formula Removed)
to form a
compound of Formula VIII2b in one or more alcoholic or ethereal solutions of one or more acids (for example, hydrochloric acid solution of methanol, ethanol, propanol, isopropyl alcohol or ether) or trifluoroacetic acid neat or in dichloromethane.
The compound of Formula VIII2b can be reacted with a compound of Formula Ym to form a compound of Formula VIIBb in an organic solvent, for example tetrahydrofuran, dimethylformamide, dioxane or diethyl ether in the presence of one or more bases, for example, triethylamine, jV-ethyldiisopropylamine, /V-methylmorpholine or pyridine.
The compound of Formula VIII3b can be oxidized to form a compound of Formula VIII4b with one or more reagents selected from m-chloroperbenzoic acid or oxone (KHSOs) in one or more organic solvents, for example, chloroform, cNbon tetrachloride, dichloromethane, ethanol or tetrahydrofuran.
The compound of Formula VIII4b can be reacted with a compound of Formula X to form a compound of Formula VIII5b
The compound of Formula VIII5b can be deprotected to form a compound of Formula
VIII6b (wherein T is(Formula Removed)
and Y is Yw (wherein Yw is -NC(=O)OC(CH3)3 or -NC(=O)OC(CH3)2CHBr2)) in one or more alcoholic or ethereal solutions of one or more acids (for example, hydrochloric acid solution of methanol, ethanol, propanol, isopropyl alcohol or ether) or trifluoroacetic acid neat or in dichloromethane.
The compound of Formula VIII5b can be deprotected to form a compound of Formula
VIII6b (wherein T is (Formula Removed)
and Y is Yw (wherein Yw is -NC(=O)OC(CH3)2CC13)) in the presence of one or more supernucleophiles, such as, for example, lithium cobalt (I) phthalocyanine, zinc and acetic acid, cobalt phthalocyanine or mixtures thereof.
The compound of Formula VIII5b can be deprotected to form a compound of Formula
VlII6b (wherein T is
(Formula Removed)
and Y is Yw (wherein Yw is -N-Nalkyl)) in one or more organic solvents (for example, ethyl acetate, methanol, ethanol, propanol, isopropyl alcohol or mixtures thereof). The reaction can also be cNried out in the presence of one or more deprotecting agents (for example, palladium on cNbon in presence of hydrogen gas or
palladium on cNbon with a source of hydrogen gas (for example, ammonium formate, cyclohexene or formic acid)).
The compound of Formula VIII5b can be deprotected to form a compound of Formula
VIlI6b (wherein T is
(Formula Removed)
and Y is Yw (wherein Yw is -jV-methylsulphonyl, -N-tolylsulphonyl)) in one or more organic solvents, for example, dimethylformamide, tetrahydrofuran, acetonitrile or mixtures thereof. The reaction can also be cNried out in the presence of one or more bases, for example, sodium hydride, potassium hydride, lithium hydride, potassium hydroxide, lithium hydroxide, sodium hydroxide (as described in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Edn. John Wiley and Sons, New York, N.Y.) or mixtures thereof.
The compound of Formula VIII6b can be reacted with a compound of Formula XV, Rft-SChhal or Ym to form a compound of Formula VIIITb, Formula VIII8b and Formula VIII9b, respectively in one or more organic solvents, for example tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or mixtures thereof. The reaction can also be cNried out in the presence of one or more bases, for example, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, pyridine or mixtures thereof.
Compounds prepNed by the methods described herein include, for example:
/t'r/-Butyl4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxylate (Compound No. 1);
Hydrochloride salt of 6-(2-methylphenyl)-2-(piperidin-4-ylamino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 2);
2-[(l-Benzyl-piperidin-4-yl)amino]-6-(2-methyl-phenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-t/|pyrimidin-7(8H)-one (Compound No. 9);
6-(2-Methylphenyl)-2-f(l-methylpiperidin-4-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-£/]pyrimidin-7(8H)-one (Compound No. 12);
6-(2-Methylphenyl)-2-[(4-methylpiperazin-l-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-c/]pyrimidin-7(8H)-one (Compound No. 13);
/2-hal (Path a) to form a compound of Formula XIII can be cNried out in the presence of one or more bases, for example, triethylamine, vV-ethyldiisopropylamine, N-methylmorpholine, pyridine or mixtures thereof.
The reaction of a compound of Formula XII with a compound Ym (path b) to form a compound of Formula XIV can be cNried out in the presence of one or more bases, for example, triethylamine, jV-ethyldiisopropylamine, /V-methylmorpholine, pyridine or mixtures thereof.
The reaction of a compound of Formula XII with a compound of Formula XV (path c) to form a compound of Formula XVI can be cNried out in the presence of one or more bases, lor example, triethylamine, /V-ethyldiisopropylamine, jV-methylmorpholine, pyridine or mixtures thereof.
Compounds of Formulae XIII, XIV and XVI each can be deprotected to form a compound of Formula XlVa in one or more organic solvents (for example, ethyl acetate, methanol, ethanol, propanol, isopropyl alcohol or mixtures thereof). These reactions can also be cNried out in the presence of one or more deprotecting agents (for example, palladium on cNbon in presence of hydrogen gas or palladium on cNbon with a source of hydrogen gas (for example, ammonium formate, cyclohexene or formic acid)).
Compounds prepNed by such methods include, for example:
2-[(l-Acetylpiperidin-4-yl)amino]-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 3);
6-(2-Methylphenyl)-2-{[l-(methylsulfonyl)piperidin-4-yl]amino}-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 4);
2-[(l-Benzoylpiperidin-4-yl)amino]-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-£/]pyrimidin-7(8H)-one (Compound No. 5);
A/-lsopropyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-«Gpyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 6);
/V-(4-Fluorophenyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-tiOpyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 7);
2-![l-(Ethylsulfonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-<^)pyrimidin-7(8H)-one (Compound No. 8);
A/-(4-Fluorophenyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNbothioamide (Compound No. 10);
4-![6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-t/]pyrimidin-2-yl]amino}-N-[4-(trifluoromethyl)phenyl]piperidine-l-cNboxamide (Compound No. 11);
2-{[l-(Isopropylsulfonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 14);
4-{f6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-(/]pyrimidin-2-yl]amino}-A'-propylpiperidine-l-cNboxamide (Compound No. 18);
/V-[(lS)-l,2-Dimethylpropyl]-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-(/]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. l());
iV-Cyclohexyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxaniide (Compound No. 20);
2-{[l-(4-Fluorobenzoyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d/]pyrimidin-7(8H)-one (Compound No. 21);
yV-(Cyclopentylmethyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 22);
4-{[6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-(/]pyrimidin-2-yl]amino}-A'-(l,l,3,3-tetramethylbutyl)piperidine-l-cNboxamide (Compound
No. 23);
4-([6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-t/rjpyrimidin-2-yl]amino}-N-octylpiperidine-l-cNboxamide (Compound No. 24);
N-Cyclopentyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]aniino}piperidine-l-cNboxamide (Compound No. 25);
/v'-lsopropyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNbothioamide (Compound No. 26);
4-J[6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-c/Jpyrimidin-2-yl]amino}-N-octylpiperidine-l-cNbothioamide (Compound No. 27);
M-/e/v-Butyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNbothioamide (Compound No. 28);
6-(2-Methylphenyl)-2-[(l-pyrimidin-2-ylpiperidin-4-yl)amino]-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-i/]pyrimidin-7(8H)-one (Compound No. 29);

A/-Cyclopropyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 30);
N-[( 1R)-1 -Cyclohexylethyl]-4- {[6-(2-methylpheny l)-7-oxo-8-(tetrahydro-2H-pyran-4-y [)-7,8-dihydropyrido[2,3-flf]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 31);
2-|[l-(CyclopentylcNbonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 32);
6-(2-Methylphenyl)-2-{[l-(pyrrolidin-l-ylcNbonyl)piperidin-4-yl]amino}-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 33);
;V-Isopropyl-4-([6-(2-methylphenyl)-7-oxo-8-(tetrahydrofuran-3-yl)-7,8-dihydropyrido[2,3-tetrahydrofuran-3-yllpyrido[2,3-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one
To a solution of compound hydrochloride salt of 6-(2-methylphenyl)-2-(niethylthio)-8-[(3.V)-pyrrolidin-3-yl]pyrido[2,3-c/]pyriniidin-7(8H)-one hydrochloride obtained from Example 3, step / (0.400 g, 1.03 mmol) in pyridine (5.0 mL) was added acetic anhydride (5 inL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and added water. The compound was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield the crude product. The crude product obtained was purified by column chromatography using ethyl acetate in hexane (8:2) as eluent to yield the title compound. Yield = 0.500 g
Step b: 8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-(methyIsulfonyl)pyrido|2,3-dlpyi"imidin-7(8H)-one
To a solution of the compound obtained from step a above (0.380 g, 0.96 mmol) in chloroform (10 mL) was added m-chloroperbenzoic acid (77 %) (0.650 g, 2.89 mmol) at 0 °C and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a saturated solution of aqueous sodium bisulphate followed by aqueous sodium bicNbonate solution at 0 °C. The reaction mixture was then extracted with dichloromethane and the organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and

evaporated under reduced pressure. The residue thus obtained was washed thoroughly with hexane to yield the title compound. Yield = 0.420 g
Step c: tert-Butyl 4-({8-[(3S>l-acetyIpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-rf]pyrimidin-2-yl}amino)piperidine-l-cNboxylate
To the compound obtained from step b above (0.400 g, 0.93 mmol) was added tert-butyl 4-aminopiperidine-l-cNboxylate (0.56 g, 2.8 mmol), pyridine (1 mL) and the mixture was heated to 65 °C for 2 hours. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain the crude product. The crude compound was purified by column chromatography using ethyl acetate in hexane (9:1) solvent mixture as eluent to yield the title compound. Yield = 0.100 g.
'11 NMR (400 MHz, CD3C13):δ 8.45 (s, 1H, N-H), 7.43 (1H, N-H), 7.29-7.16 (m, 4H, N-H), 6.29 (s, 1H), 4.05-3.94 (m, 6H), 3.02-2.97 (m, 2H), 2.22 (s, 3H), 2.20 (s, 1H), 2.17 (s, 3H), 2.09-2.04 (m, 3H), 1.47 (s, 9H), 1.45 (s, 2.H); Mass (+ve ion mode m/z): 547 (M++l).
Example 4a: Synthesis of hydrochloride salt of 8-[(3S)-l-acetylpyrrolidin-3-yl]-6-(2-iTiethylphenvl)-2-(piperidin-4-ylamino)pyrido[2,3-J]pyrimidin-7(8H)-one (Compound No. 180]
The title compound was prepNed following the procedure as described in Example 2 by using the Compound No. 179 in place of Compound No. 1.
'H NMR (400 MHz, CD3C13):δ 8.68 (s, 1H, N-H), 7.71 (s, 1H, N-H), 7.29-7.16 (m, 4H, N-H), 5.75 (s, 1H), 3.62-3.02 (m, 7H), 2.58-2.48 (m, 2H), 2.18 (s, 3H), 2.15 (s, 3H), 2.06-1.83 (rn, 4H), 1.16-1.10 (m, 2H); Mass (+ve ion mode m/z): 447 (Mf+l).
Example 4b: Synthesis ot'4-({8-[(3S)-l-acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-c/]pvrimidin-2-yl|amino)-n-isopropylpiperidine-l-cNboxamide (Compound No. 80)
The title compound was prepNed following the procedure as described in Example 5 by using the Compound No. 180 in place of Compound No. 2.
'H NMR (400 MHz, CD3OD):δ8.91 (s, 1H, N-H). 7.77 (s, 1H, N-H), 7.43-6.99 (m, 4H, N-H), 5.94 (s, 1H), 4.27-4.25 (m, 1H), 4.00-3.88 (m, 4H), 3.78-3.73 (m, 2H), 3.60-3.58 (m, 1H), 3.09-3.06 (m, 2H), 2.24-2.23 (m, 1H), 2.21 (s, 311), 2.20 (s, 3H), 2.19-2.18 (m, 1H), 1.67-1.65 (m, 2H), 1.25 (s, 2H), 1.17-1.13 (m, 6H); Mass (+ve ion mode m/z): 532 (M++l).

The following analogs can be prepNed by using appropriate corresponding compound, for example, acyl halide, alkyl halide, sulphonyl halide, isocyanate or isothiocyanate in place of acetic anhydride, respectively, as applicable in each case.
6-(2-Methylphenyl)-2-{[l-(methylsulfonyl)piperidin-4-yl]amino}-8-[(3S)-l-(methylsulfonyl)pyrrolidin-3-yl]pyrido[2,3-dpyrimidin-7(8H)-one (Compound No. 78);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-2-[(l-benzylpiperidin-4-yl)amino]-6-(2-methylphenyl)pyrido[2,3-c/]pyrimidin-7(8H)-one (Compound No. 192);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-c/Jpyrimidin-2-ylJaminol-N-cyclopropylpiperidine-l-cNboxamide (Compound No. 202);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-i/|pyrimidin-2-yl]amino}-jV-(rerr-butyl)piperidine-l-cNboxamide (Compound No. 203);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-(/|pyrimidin-2-yl]amino}-N-cyclohexylpiperidine-l-cNboxamide (Compound No. 204);
4-([8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylplienyl)-7-oxo-7,8-dihydropyrido[2,3-d|pyrimidin-2-yl]amino}-A'-(4-fluorophenyl)piperidine-l-cNboxamide (Compound No. 205);
4-([8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylplienyl)-7-oxo-7,8-dihydropyrido[2,3-t/|pyrimidin-2-yl]amino}-N-morpholin-4-ylpiperidine-l-cNboxamide (Compound No. 206);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-{[l-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-flf]pyrimidin-7(8H)-one (Compound No. 181);
8-[(3 S)-1 -Acetylpyrrolidin-3-yl]-2- {[ 1 -(ethylsulfonyl)piperidin-4-yl]amino} -6-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 207);
8-[(3S)-1 -Acetylpyrrolidin-3-yl]-6-(2-methylpheny l)-2- {[1 -(propylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pynniidin-7(8H)-one ((Compound No. 208);
8-( (3 R)-1-Acetylpyrrolidin-3-yl]-2-{[ 1-(cyclopropylcNbonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)pyrido[2,3-t/)pyrimidin-7(8H)-one (C'ompound No. 209);
2-[(l-Acetylpiperidin-4-yl)amino]-8-[(3R)-l-acetylpyrrolidin-3-yl]-6-(2-methylphenyl)pyrido[2,3-d/]pyrimidin-7(8H)-one (Compound No. 210);
8-[(3R)-l-Acetylpyrrolidin-3-yl]-2-[(l-benzoylpipcridin-4-yl)amino]-6-(2-methylphenyl)pyrido[2,3-d]pyriniidin-7(8H)-one (C'ompound No. 211);
8-[(3 R)-1 -Acetylpyrrolidin-3-yl]-2- {[ 1 -(4-fluorobenzoyl)piperidin-4-yl]amino} -6-(2-methylphenyl)pyrido[2,3-dpyrimidin-7(8H)-one (C'ompound No. 212);
8-f(3R)-l-Acetylpyrrolidin-3-yl]-2-{[l-(2,2-dimethylpropanoyl)piperidin-4-yl]amino}-6-(2-rnethylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 213);
8-[(3R)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-[(l-methylpiperidin-4-yl)amino]pyrido[2,3-c/]pyrimidin-7(8H)-one (Compound No. 214);
8-[(3R)-l-Acetylpyrrolidin-3-yl]-2-[(l-benzylpiperidin-4-yl)amino]-6-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (C'ompound No. 215);
8-f(3S)-l-Acetylpyrrolidin-3-yl]-2-{[l-(2,2-dimethylpropanoyl)piperidin-4-yl]amino}-6-(2-inethylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (C'ompound No. 216);

8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-[(l-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 217);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-(/]pyrimidin-2-yl]amino}-A'-isopropylpiperidine-l-cNboxamide (Compound No. 218);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-N-cyclopropylpiperidine-l-cNboxamide (Compound No. 219);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-N-(tert-butyl)piperidine-1 -cNboxamide (Compound No. 220);
4-[[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylp]ienyl)-7-oxo-7,8-dihydropyrido[2,3-dpyrimidin-2-yl]amino}-N-cyclohexylpiperidine-l-cNboxamide (Compound No. 221);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylplienyl)-7-oxo-7,8-dihydropyrido[2,3-dpyrimidin-2-yl]amino}-A'-(4-fluorophenyl)piperidine-l-cNboxamide (Compound No. 222);
4-{[8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d|pyrimidin-2-yl]amino}-N-morpholin-4-ylpiperidine-l-cNboxamide (Compound No. 223);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-6-(2-methylphenyl)-2-{[l-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 224);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-2-{[l-(ethylsulfonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 225);
8-[(3 S)-1 -Acetylpyrrolidin-3-yl]-6-(2-methylpheny l)-2- {[ 1 -(propylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 226);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-2-{[l-(cyclopropylcNbonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 227);
2- [(1 -Acetylpiperidin-4-yl)amino] -8-[(3 S)-1 -acety 1 pyrrolidin-3 -yl] -6-(2-methylphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 228);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-2-[(l-benzoylpiperidin-4-yl)amino]-6-(2-methylphenyl)pyrido[2,3-d]pyriniidin-7(8H)-one (Compound No. 229);
8-[(3S)-l-Acetylpyrrolidin-3-yl]-2-{[l-(4-fluorobenzoyl)piperidin-4-yl]amino}-6-(2-methylphenyl)pyrido[2,3-6npyrimidin-7(8H)-one (Compound No. 230).
Scheme II:
Example 5: Synthesis of 2-[(l-acetylpiperidin-4-vl)amino]-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 3)
To a solution of the Compound No. 2 (50 mg) in pyridine (2 mL) was added acetic anhydride (4 mL) at 0 °C and the mixture was stirred for 4 hours, o the reaction mixture was added water, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by prepNative TLC and dried under vacuum to yield the title compound. Yield = 28 mg.

'H NMR (400 MHz, CDC13)δ: 8.43 (s, 1H, N-H). 7.41 (s, 1H, N-H), 7.31-7.17 (m, 4H, N-H), 5.65-5.56 (m, 2H, 1NH, 1N-CH), 4.61 (m, 1H. N-CH), 4.13-4.10 (m, 2H, -OCH2), 3.90-3.86 (m, 2H, -OCH2), 3.57-3.48 (m, 2H, N-CH2), 3.25-3.13 (m, 2H, N-CH2), 2.22 (s, 3H, N-CH3+2H, -CH2), 2.19-2.12 (m, 5H, -COCH3+-CH2), 1.73-1.57 (m, 4H); Mass (+ve ion mode m/z): 462 (M++l); m.p: 235.1-236.6°C.
The analogs of 2-[(l-acetylpiperidin-4-yl)amino]-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-c/]pyrimidin-7(8H)-one (Compound No. 3) described below can be prepNed by using appropriate corresponding compound, for example, acyl halide, alkyl halide, sulphonyl halide, isocyanate or isothiocyanate in place of acetic anhydride, respectively, as applicable in each case.
6-(2-Methylpheny l)-2- {[ 1 -(methylsulfonyl)piperidi n-4-yl]amino} -8-(tetrahydro-2H-pyran-4-y])pyrido[2,3-d|pyrimidin-7(8H)-one (Compound No. 4);
2-[(l-Benzoylpiperidin-4-yl)amino]-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 5);
N-Isopropyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 6);
N'-(4-Fluorophenyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 7);
2-{[l-(Ethylsulfonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 8);
N-(4-Fluorophenyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNbothioamide (Compound No. 10);
4-{[6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d)pyrimidin-2-yl]amino}-N-[4-(trifluoromethyl)phcnyl]piperidine-l-cNboxamide (Compound No. 11);
2-{[l-(Isopropylsulfonyl)piperidin-4-yl]amino}-6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound No. 14);
4-{[6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-N-propylpiperidine-l-cNboxamide (Compound No. 18);
N-[( 1 S)-1,2-Dimethylpropyl]-4- {[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-c/]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 19);
N-Cyclohexyl-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 20);
2- {[1 -(4-Fluorobenzoyl)piperidin-4-yl]amino}"6-(2-methylphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-c/]pyrimidin-7(8H)-one (Compound No. 21);
N-(Cyclopentylmethyl)-4-{[6-(2-methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-l-cNboxamide (Compound No. 22);

4-([6-(2-Methylphenyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-