NZ622698B2 - 5-benzylaminomethyl-6-aminopyrazolo[3,4-b]pyridine derivatives as cholesteryl ester-transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis - Google Patents

Abstract

Disclosed are pyra-zolopyridin-6-amines having the general formula (I), including their stereoisomers and/or their pharmaceutically acceptable salts. Wherein R, R1, R2, Ra, Raa, Rb and n are as defined herein. Also disclosed are pharmaceutical compositions comprising compounds of formula (I). The compounds of this application are useful as CETP inhibitors for increasing HDL cholesterol and decreasing LDL cholesterol in a patient. mpounds of this application are useful as CETP inhibitors for increasing HDL cholesterol and decreasing LDL cholesterol in a patient.

Description

-BENZYLAMINOMETHYLAMINOPYRAZOLO[3,4-B]PYRIDINE DERIVATIVES AS CHOLESTERYL ESTER-TRANSFER PROTEIN (CETP) INHIBITORS USEFUL FOR THE TREATMENT OF ATHEROSCLEROSIS TECHNICAL FIELD The present application s to substituted lopyridinamines of formula (I) or stereoisomers thereof or pharmaceutically acceptable salts thereof.

BACKGROUND Cholesteryl transfer protein (CETP) is an important player in metabolism of lipoproteins such as, for example, a high density lipoprotein (HDL). CETP is a 70 kDa plasma glycoprotein that is physically associated with HDL particles. It facilitates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. This transfer is accompanied by transfer of triglycerides in the opposite direction. Thus, a decrease in CETP actiVity can result in an increase in the level of HDL cholesterol and a decrease in the level of very low density lipoprotein (VLDL) and low y lipoprotein (LDL). CETP can therefore simultaneously affect the concentrations of pro-atherogenic (e.g., LDL) and anti-atherogenic (e.g., HDL) lipoproteins.

Clinical studies in humans have shown that inhibitors of CETP can be effective in elevating HDL levels by 30-110%. Further, epidemiological studies have shown that low high- density lipoprotein cholesterol (HDL-C) levels is a powerful risk factor for coronary artery disease (CAD). See generally, Gordon et al., ation, 79, pp. 8—15, 1989; Despres et al., Atherosclerosis 153: 263-272, 2000. Elevating HDL-C has been shown to decrease this risk and it is estimated that each 1 mg/dl (0.02 mmol/l) elevation of HDL-C is associated with a 2— 3% reduction in coronary heart e (CHD) risk, a magnitude comparable to that for low density lipoprotein (LDL) lowering.

It is believed that the anti-atherogenic role of HDL is in part due to its ability to promote the efflux of free terol from cells and to transport it to the liver, a process termed e cholesterol transport. HDL could protect against atherosclerosis by several other mechanisms. For example, l studies have shown that HDL to have antioxidant and anti- inflammatory effects. Oxidative products of lipid metabolism induce inflammatory cell recruitment in vascular cells. HDL particles carry enzymes that retard LDL oxidation, including paraoxonase, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase.

These enzymes degrade pro-inflammatory, oxidized phospholipids, limiting their accumulation in LDL. In addition, apoA-I can bind oxidized lipids and remove them from LDL. Further, HDL also can act as a carrier vehicle for small molecules, including bacterial lysaccharide (LPS) thus regulating the inflammatory effects of LPS. In animal models of xic shock, HDL attenuates organ injury and adhesion molecule expression. Thus elevating HDL is not only anti-atherogenic but it could also potentially be anti-inflammatory.

Elevation of HDL by CETP tion has been described in the art.

However, no CETP tors are currently being marketed. r, other existing therapies such as, for example, HDL-elevating therapies and anti-atherosclerosis therapies have limitations ing serious tolerance issues. Thus, there is a present need to find alternative therapies including methods of preventing or treating conditions or diseases associated With lipoprotein metabolism such as, for example, atherosclerosis.

SUMMARY Accordingly, the t ation relates to substituted pyrazolopyridinamines having the general formula (1): NA©7<R )n/ Rs \ b N\ l 2 N \N N’R Ra R1 (1) wherein, (RC?/‘\x R represents hydrogen or (NA;N X represents —CH or —N; R1 and R2 are independently of each other selected from hydrogen, acyl, alkyl or -(CH2)p-cycloalkyl; R81 and Raa are independently of each other selected from hydrogen or alkyl; Rb, in each occurrence, is ndently ed from halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; RC, in each occurrence, is independently selected from hydrogen, cyano, halogen, alkyl, alkoxy, koxy, -COORd, -C(=O)-Re, -CONRth, -C(=O)-CH=CH-NRiRj, -NHCORt, an ally substituted group selected from cycloalkyl, aryl, heteroaryl or heterocycle ring, wherein the optional substituent, in each occurrence, is selected independently from hydrogen, halogen, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, alkyl or haloalkoxy; Rd, Re, Rg, Rh, Ri and R], in each occurrence, independently of each other represents hydrogen or alkyl; Rt is selected from hydrogen, alkyl or cycloalkyl; nisO, 1,2or3; p is 0,1, or 2; and q is l or 2.

The present application also relates to the process for the preparation of compounds of formula (I).

The present application further describes the compounds of formula (I) as cholesteryl ester-transfer n (CETP) inhibitors.

The present application further relates to pharmaceutical compositions comprising compounds of a (I) or stereoisomers thereof or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION As used herein, the expression ‘Alkyl’ group refers to a linear or branched alkyl group with l to 10 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, opyl, n-butyl, tyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like.

As used herein, the expression ‘Alkoxy’ group refers to an —O-(alkyl) group, wherein alkyl group is as defined above. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, xy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 10 carbon atoms.

As used herein, the expression ‘Alkoxyalkyl’ refers to an alkoxy substituted alkyl group, wherein alkoxy and alkyl groups are as defined above. Typically, the alkoxy group can have from 1 to 10 carbon atoms, and the alkyl group can have from 1 to 10 carbon atoms.

Exemplary alkoxyalkyl groups include, but are not d to, ethoxymethyl, propoxyethyl, ethoxybutyl and the like.

As used herein, the expression ‘Acyl’ group refers to alkyl-CO- group, wherein alkyl group is as defined above. Acyl group refers to an alkyl-linker moiety bonded to the CO group.

Examples of acyl groups include, but are not limited to, acetyl, propionyl and the like. Acyl group includes formyl group also.

As used herein, the expression ‘aryl’ means substituted or unsubstituted phenyl or naphthyl. Specific examples of substituted phenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3- 2-methylnaphthyl, or “substituted , 1,4-xylyl, ylnaphthyl, etc. “Substituted phenyl” yl” also include any of the possible substituents as r defined herein or one known in the art. Derived expression, “arylsulfonyl,” is to be construed accordingly.

As used herein, the expression alkyl’ group refers to a cyclic alkyl group which may be mono, bicyclic, polycyclic, or a fused/bridged ring system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, cyclooctyl, and the like. Unless otherwise specified, a cycloalkyl group typically has from 3 to about 10 carbon atoms. Typical bridged cycloalkyl groups include, but are not limited to adamantyl, noradamantyl, bicyclo[l.l.0]butanyl, norbornyl(bicyclo[2.2.l]heptanyl), norbomenyl (bicyclo[2 .2. l ]heptanyl), nadienyl(bicyclo [2.2. l ]heptadienyl), o[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.1]octadienyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[2.2.2]octadienyl, bicyclo[5.2.0]nonanyl, bicyclo[4.3.2]undecanyl, tricyclo[5.3.1.1]dodecanyl and the like.

As used herein, the sion ‘halogen or halo’ represents fluorine, chlorine, bromine, or iodine.

As used herein, the expression ‘haloalkyl’ means at least one n atom is substituted on an alkyl group. Both halogen and alkyl have the meaning as defined above.

Representative examples of haloalkyl groups include, but are not limited to, fiuoromethyl, chloromethyl, fiuoroethyl, chloroethyl, difiuoromethyl, trifiuoromethyl, dichloroethyl, trichloroethyl and the like. Unless otherwise specified, a haloalkyl group typically has from 1 to 10 carbon atoms.

As used herein, the sion ‘haloalkoxy’ means at least one halogen atom is substituted on an alkoxy group, wherein alkoxy and halogen groups are as defined above.

Exemplary haloalkoxy groups include, but not limited to, fiuoromethoxy, chloromethoxy, trifiuoromethoxy, trichloroethoxy, fiuoroethoxy, chloroethoxy, trifiuoroethoxy, perfiuoroethoxy (-OCF2CF3), trifiuoro-t—butoxy, hexafiuoro-t—butoxy, perfiuoro-t-butoxy (-OC(CF3)3), and the like. Unless otherwise specified, a haloalkoxy group typically has from 1 to 10 carbon atoms.

As used herein, the expression ‘heterocycle’ or ‘heterocyclyl’ or ‘heterocyclic’ is a saturated monocyclic or polycyclic ring system of 3 to 10 members haVing at least one heteroatom or group ed from -O-, -N-, -S-, -802, or -CO. Exemplary cyclyl groups include, but not limited to, inyl, oxazolidinyl, oxazolidinonyl, isoxazolidinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-l,l-dioxide, thiazolidinyl, l,3-dioxolanyl, 1,4-dioxanyl, and the like. Unless otherwise specified, a heterocyclyl group typically has from 3 to about 10 carbon atoms.

As used herein, the expression ‘heteroaryl’ is an unsaturated, ic or non-aromatic, monocyclic or polycyclic ring system of 3 to 10 members haVing at least one heteroatom or heterogroup ed from -O-, -N-, -S-, -802, or -CO. Exemplary heteroaryl groups include, but not d to, yl, isoxazolyl, thiazolyl, pyridinyl, pyrrolyl, pyrimidinyl, thiazinyl, pyrazinyl, pyrazolyl, tetrazolyl, imidazothiazolyl, indolizidinyl, indolyl, quinolinyl, quinoxalinyl, benzoxazolyl, benzoisoxazolyl, hiazolyl, benzodioxolyl, benzotriazolyl, indazolyl, quinoxalinyl, imidazolyl, pyrazolopyridinyl, and the like. Unless otherwise specified, a heteroaryl group typically has from 3 to about 10 carbon atoms.

As used herein, the expression ‘5-7 membered heterocyclic or heteroaryl group’ represents a cyclic or heteroaryl group as defined above haVing 5-7 ring atoms. ary 5-7 membered heterocyclic or heteroaryl groups include, but not limited to, pyrazolyl, olyl, isoxazolyl, oxazolyl, tetrazolyl, morpholinyl, oxazolidinonyl, and the like.

As used herein, the expression ‘OH’ represents a hydroxy group.

As used herein, the sion ‘CN’ represents a cyano group.

The cholesteryl ester-transfer protein (CETP) may be an animal or a non-mammalian or a mammalian protein, such as a human protein.

As used herein, the expression ‘optionally tuted’ means that the substitution is optional and therefore it is possible for the designated atom or molecule to be unsubstituted. In the event a substitution is desired, then such substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. For example, in formula (I) when a substituent is oxo (i.e., :0), then two hydrogens on the atom are ed and when the substitution is fluoro, then one hydrogen on the atom is replaced and the like.

As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly tes otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

One or more compounds of formula (I) can be supplied in the form of a therapeutic composition that is within the scope of the present application.

‘Salts’ refer to any acid or base salt, pharmaceutically able solvates, or any complex of the compound that, when administered to a recipient, is capable of ing (directly or indirectly) a compound as bed herein. It should be appreciated, however, that salts that are not pharmaceutically acceptable also lie within the scope of the application. The preparation of salts can be carried out using known methods.

For example, pharmaceutically acceptable salts of compounds contemplated herein may be synthesized by conventional chemical s using a parent compound containing either an acid or base functional group. Generally, such salts may be prepared, for example for nds having the basic functional group, by reacting the free base with a stoichiometric quantity of the appropriate acid in the presence of a suitable solvent such as water or in an organic solvent, or in a e of the two. Generally, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile may be utilized. Examples of acid on salts include, but are not d to, l acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate. Also included in present application are the isomeric forms and ers and the pharmaceutically-acceptable salts of compounds of a (I). rative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, , malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruVic, aspartic, glutamic, benzoic, anthranilic, c, stearic, lic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, esulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, c, B-hydroxybutyric, galactaric, and galacturonic acids. Similarly, Where the compounds carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; ne earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. In such situations the compound ng an acidic moiety is reacted with suitable base such as an , alkaline earth hydroxide or carbonate or organic amine in the presence of a suitable t such as water or organic solvents as described herein to prepare the alkali, alkaline earth metal or ammonium salt of the compound.

The term ‘stereoisomers’ is a general term used for all isomers of the indiVidual molecules that differ only in the orientation of their atoms in space. Typically it es mirror image isomers that are usually formed due to at least one asymmetric center (enantiomers). Where the compounds according to the present application possess one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric es and indiVidual diastereomers. Also certain indiVidual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this application may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such feasible isomers and mixtures thereof in any proportion are encompassed Within the scope of the present ation.

For any particular compound disclosed herein, any general structure ted also encompasses all conformational isomers, regioisomers and tautomers that may arise from a particular set of substituents.

As used herein, the term 'subject' or ‘patient’ means mammals, such as humans and other animals, including horses, dogs, cats, rats, mice, sheep, pigs, etc. In ary embodiments, the subject may include subjects for which treatment and/or tion of the conditions described herein would be beneficial.

For ease of reference, in this application it will be described in terms of administration to human ts. It will be understood, however, that such descriptions are not limited to administration to humans, but will also include administration to other animals unless explicitly stated otherwise.

A ‘therapeutically effective amount’ is the amount of compound that is effective in ing a desired clinical outcome in the treatment of a specific disease.

The terms 'treating' or 'to treat' means to alleviate symptoms, eliminate the causation either on a ary or permanent basis, or to prevent or slow the appearance of symptoms.

The term 'treatment' includes alleviation, elimination of causation of or prevention of any of the diseases or disorders described above. Besides being useful for human treatment, these combinations are also useful for treatment of other mammals, including , dogs, cats, rats, mice, sheep, pigs, etc.

Terms such as ," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, "comprising" means the elements recited, or their lent in structure or function, plus any other t or elements which are not recited. The terms "having," "including," and "comprised of“ are also to be construed as open ended unless the context suggests otherwise.

The nds described herein are typically administered in admixture with one or more pharmaceutically acceptable excipients or carriers in the form of a pharmaceutical ition. A 'composition' may contain one compound or a mixture of compounds. A 'pharmaceutical composition' is any composition useful or potentially useful in ing at least one physiological response in a t to which such pharmaceutical composition is administered.

Reference will now be made in detail to the embodiments of the application, one or more examples of which are set forth below. Each example is provided by way of explanation of the present application, and not by way of limitation of the present application. In fact, it will be apparent to those skilled in the art that various modification and ions can be made in the t application without ing from the scope or spirit of the present application.

For instance, features illustrated or described as part of one embodiment can be used on another embodiment to yield a still further embodiment. Thus it is intended that the present application cover such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present application are disclosed in, or are s from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of ary ments only, and is not to be construed as limiting the broader aspects of the present application.

The present application provides a compound of formula (I), or stereoisomers thereof or pharmaceutically acceptable salts thereof: fg )n/ R, \ b N. | 2 h“ \N W Ra R‘ (1) wherein, (Ref/‘\x R represents hydrogen or N ,5, X represents —CH or —N; R1 and R2 are independently of each other selected from hydrogen, acyl, alkyl or -(CH2)p-cycloalkyl; R81 and Raa are independently of each other selected from en or alkyl; Rb, in each occurrence, is independently ed from halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; RC, in each occurrence, is independently selected from hydrogen, cyano, halogen, alkyl, alkoxy, haloalkoxy, -COORd, -C(=O)-Re, -CONRth, -C(=O)-CH=CH-NRiRj, t, an optionally substituted group selected from lkyl, aryl, heteroaryl or heterocycle ring, n the optional substituent, in each occurrence, is selected independently from hydrogen, halogen, cyano, yl, alkyl, haloalkyl, , alkoxyalkyl or haloalkoxy; Rd, Re, Rg, Rh, Ri and R], in each occurrence, independently of each other represents hydrogen or alkyl; Rt is selected from hydrogen, alkyl or cycloalkyl; nis0,l,20r3; p is 0,1, or 2; and q is l or 2.

In r embodiment, there is provided a compound of formula (Ia), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; N | CF \ ,R2 3 4” N N R R1 (Ia) wherein, R, R1, R2, Ra and RM are as defined above.

In another embodiment, the present application provides a compound of formula (lb), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: aa \N NAQ R / / N\ I CFs N N NW (1b) Wherein Ra, Rae1 and RC are as defined above.

In another embodiment, there is provided a compound of formula (Ic), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: (10) wherein, Ra, Rafi, and RC are as defined above.

In another embodiment there is provided a compound of formula (I), (Ia), (lb) or (Ic), n RC represents a 5-7 ed heterocyclic or heteroaryl group.

In an embodiment, specific compounds of formula (I) without any limitation are enumerated as follows: N—(2-(((6-(bis(cyclopropylmethyl)amino)- l -(tert-butyl)-3 -methyl- 1 H-pyrazolo[3 ,4-b]pyridin- ethyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)isobutyramide, -(((3 ,5 -bis(trifluoromethyl)benzyl)(5-cyclopropylpyridin-Z-yl)amino)methyl)- l -(tert-butyl)- N,N—bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine, N—(2-(((6-(bis(cyclopropylmethyl)amino)- l -(tert-butyl)-3 -methyl- 1 H-pyrazolo[3 ,4-b]pyridin- -yl)methyl)(3 (trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)cyclopropane carboxamide, l-(2-(((6-(bis(cyclopropylmethyl)amino)-l ,3-dimethyl- l zolo [3 ,4-b]pyridin hyl)(3 ,5 rifluoromethyl)benzyl)amino)pyrimidin-5 -yl)ethanone, l-(2-(((6-(bis(cyclopropylmethyl)amino)- l -(tert-butyl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin- -yl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)ethanone, (E)- l -(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- l H-pyrazolo [3 ,4- b]pyridinyl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)-3 - (dimethylamino)propenone, -(((3 ,5 -bis(trifluoromethy1)benzyl)(5-(isoxazoly1)pyrimidiny1)amin0)methy1)-N,N— c10pr0pylmethyl)-1 ,3-dimethy1— 1 H-pyrazolo [3 ,4-b]pyridinamine, -(((5-(1H-pyrazol-3 -y1)pyrimidiny1)(3 (trifluoromethyl)benzy1)amin0)methy1) (tert-butyl)-N,N—bis(cyclopropylmethy1)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin amine, -(((3 ,5 -bis(triflu0romethy1)benzyl)(5-(1 -methy1—1H-pyrazol-3 -y1)pyrimidin yl)amin0)methy1)(tert-butyl)-N,N—bis(cyc10pr0pylmethyl)methy1— 1H- pyrazolo [3 ,4-b]pyridinamine, 2-(((6-(bis(cyc10pr0pylmethyl)amin0)(tert-buty1)methy1—1H-pyrazolo[3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 -bis(trifluor0methy1)benzyl)amino)pyrimidine-5 -carb0nitrile, 2-(((6-(bis(cyc10pr0pylmethyl)amin0)(tert-buty1)methy1—1H-pyrazolo[3 ,4-b]pyridin-5 - yl)methyl)(3,5-bis(trifluor0methy1)benzyl)amin0)pyrimidinecarb0xamide, 2-(((6-(bis(cyc10pr0pylmethyl)amin0)(tert-buty1)methy1—1H-pyrazolo[3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)-N,N-dimethy1pyrimidine carboxamide, 3-(2-(((6-(bis(cyclopropy1methyl)amin0)- 1-(tert-buty1)-3 -methyl- 1 H-pyrazolo [3 yridin- -y1)methy1)(3 ,5 rifluor0methyl)benzyl)amino)pyrimidiny1)0xazolidinone, -(((3 ,5 -bis(trifluoromethyl)benzyl)(5 -m0rph01in0pyrimidiny1)amino)methyl)(tert- butyl)-N,N-bis(cyc10pr0pylmethy1)methyl- 1 H-pyrazo10 [3 ,4-b]pyridinamine, 5-(((3 ,5 -bis(trifluoromethyl)benzyl)(5 -m0rph0linopyrimidin-Z-yl)amino)methyl)-N,N— bis(cyc10pr0pylmethyl)-1 ,3-dimethy1— 1 zolo [3 ,4-b]pyridinamine, 1-(2-(((6-(bis(cyc10pr0py1methyl)amin0)(tert-buty1)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin- -y1)methy1)(3 ,5 -bis(trifluor0methy1)benzyl)amino)pyrimidin-5 -y1)pyrrolidin0ne, 2-(((6-(bis(cyclopropylmethyl)amino)(tert-buty1)-3 -methyl- 1 H-pyrazo10 [3 ,4-b] pyridin-5 thyl)(3 ,5-bis(triflu0r0methy1)benzyl)amino)methylpyrimidine-5 - carboxylate, 2-(((6-(bis(cyc10pr0pylmethyl)amin0)(tert-buty1)methy1—1H-pyrazolo[3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 -bis(trifluoromethy1)benzyl)amino)methylpyrimidinecarb0xylic acid, Ethyl(((6-(bis(cyclopropylmethyl)amino)(tert-buty1)-3 -methyl- 1 H-pyrazo10 [3 ,4-b] pyridin-5 -yl)methyl)(3 ,5-bis(triflu0r0methy1)benzyl)amino)pyrimidine-5 -carb0xylate, WO 46045 2-(((6-(bis(cyclopropylmethyl)amino)butyl)-3 -methyl- 1 zolo [3 ,4- b]pyridinyl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidine-5 xylic acid, -(((3 ,5 rifluoromethyl)benzyl)amino)methyl)- l -(tert-butyl)-N,N—bis(cyclopropylmethyl) hyl- l H-pyrazolo [3 ,4-b]pyridinamine, and -(((3 ,5 -bis(trifluoromethyl)benzyl)(5 -bromopyrimidinyl)amino) methyl)(tert-butyl)- N,N—bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine, or stereoisomers thereof or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are also a part of this application.

The compounds of formula (I) may exist in the form of stereoisomers. Such stereoisomers are also a part of this application.

The compounds of formula (I) may also exist in the form of stereoisomers and/or their pharmaceutically acceptable salts. Such stereoisomers and/or their pharmaceutically acceptable salts are part of this application.

In another embodiment, the present ation provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more nds of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt f.

In another embodiment, there is provided compounds of formula (I) or stereoisomers thereof or pharmaceutically acceptable salt thereof, as CETP tors.

In another embodiment, there is provided a method of administering CETP inhibitors in a subject (i.e., a patient), which comprises administering to said subject (i.e., a patient) a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. As used herein the term “subject” and “patient” can be the same and can be used interchangeably.

In another embodiment, there is provided a method of increasing the level of HDL cholesterol and/or a decreasing the level of very low density otein (VLDL) and low density lipoprotein (LDL) and/or increasing the ratio of HDL-C to LDL-C, which comprises administering to said subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment, there is ed a method for treating or reducing the risk of ping a disease or ion that may be treated or prevented by inhibition of CETP in a patient in need of such a treatment comprising the administration of a therapeutically ive amount of a compound of a (I) or a isomer thereof or a pharmaceutically acceptable salt f to said patient.

In another embodiment, there is provided a method of binding CETP in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof to said patient.

In another embodiment, there is provided a method of increasing the level of HDL cholesterol in a patient in need of such a ent comprising the administration of a therapeutically ive amount of the compound of formula (I), or a stereoisomer thereof or a ceutically acceptable salt thereof to said patient.

In another embodiment, there is provided a method of lowering LDL cholesterol in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof to said patient.

In another embodiment, there is provided a method of raising the ratio of increasing HDL cholesterol to LDL cholesterol in a patient in need of such a treatment comprising the stration of a therapeutically effective amount of the compound of the formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof to said patient.

In another embodiment, there is provided a method of treating or preventing atherosclerosis in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt f to said patient.

The pharmaceutical composition of a compound of formula (I) may be administered enterally and/or parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.

Enteral administration includes solution, tablets, sustained e capsules, enteric coated capsules, , beverages, foods, and other ional supplements. When administered, the present pharmaceutical compositions may be at or near body temperature. In some embodiments, the present pharmaceutical compositions may be below body atures. In other embodiments, the present ceutical compositions may be above body temperatures.

The compounds of the t application may be administered in a wide variety of different dosage forms. For example, they may be combined with various pharmaceutically acceptable inert carriers in the form of, but not limited to, tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers may include solid ts or flllers, sterile aqueous media, and various nontoxic organic solvents, etc. Moreover, oral ceutical compositions may be sweetened and/or flavored.

In general, the compounds of the present ation may be present in such dosage forms at concentration levels ranging from about 0.1 % to about 90% by weight.

In general, compounds of the present application for treatment may be administered to a subject in a le effective dose in the range of from about 0.01 to about 100 mg per kilogram of body weight of recipient per day, in some embodiments, in the range of from about 0.5 to about 50 mg per kilogram body weight of recipient per day, in still other embodiments, in the range of from about 0.1 to about 20 mg per kilogram body weight of recipient per day.

The exemplary dose may be suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, may be administered at appropriate intervals through the day, or on other appropriate schedules.

An embodiment of the present application provides the preparation of compounds of formula (I) according to the procedures of the following examples, using appropriate materials.

Those skilled in the art will understand that known variations of the conditions and ses of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in , one of ordinary skill in the art can prepare additional compounds of the present application claimed herein. All temperatures are in degrees Celsius (C) unless otherwise noted.

The following acronyms, abbreviations, terms and definitions have been used throughout the reaction scheme and mental section.

CDC13 rated chloroform), Cs2C03 (cesium carbonate), CuI us iodide), CuCN r(I) cyanide), DCM (dichloromethane), DMF (N,N-dimethylformamide), DMF-DMA (N,N—dimethylformamide-dimethyl acetal), DME (dimethoxyethane), DMSO (dimethyl sulfoxide), EtOH (ethanol), EtOAC (ethyl acetate), HCl (hydrochloric acid), MeOH (methanol), K2C03 (potassium ate), KOH (potassium hydroxide), KOBut (potassium utoxide), KCN (potassium cyanide), K3PO4 (tripotassium phosphate), LiOH (lithium hydroxide), Pd (palladium), Pd(OAc)2 (palladium (II) acetate), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)), NaHC03 (sodium bicarbonate), Na2C03 (sodium carbonate), NaCN (sodium cyanide), NaOH (sodium hydroxide), Na(CN)BH3 (sodium cyanoborohydride), NaOtBu m tert-butoxide), NaH (sodium hydride), Na2804 m sulfate), NaBH4 (sodium borohydride), Na(OAc)3BH (sodium toxyborohydride), Ti(i- Pro)4 (titanium(IV) isopropoxide), THF (tetrahydrofilran), Zn(CN)2 (zinc cyanide), EDTA (Ethylenediaminetetraacetic acid), h (hour), min (minute), MS (mass spectroscopy), NMR (nuclear magnetic resonance), Mp/mp (melting point), aq (aqueous), 0C (degree Celsius), psi (pounds per square inch).

NMR abbreviations: MHz (Megahertz), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), m plet), bs (broad singlet).

Another embodiment of the present application provides a process for the preparation of nds of formulae (ll), (12), (l3), (14), (15) & (16) which represent a sub-group of a compound of formula (I), wherein all symbols/variables are as defined earlier unless ise stated. The process is represented by Scheme-l: 2012/002435 (II) H2N RRR R33 ZfRa Ra'--NHNH2. HCI ::j\. NN‘ #N CN Stepl NHz Stepll Ra Steplll W0N N/ CI (1) <3) R(4) Step IV 2(5) Rae (Rb) R / \ E/\0\ b % n N I R)“ H2N l/ (7) / \ \O IN N NrR1 / N\ I / R1 Ra . StepV N N; Y (Rb) n Raa NYX Step VIII N/ \ N I |% N l N1 |\ (Rb) IN N’ N”R1 / ‘IN N/ N’R / n Ra ['22 Ra '2 R (14) Step IX (13) 0 NRh 22R(15) Step I A compound of formula (2) can be ed by reacting an 0t,B-unsaturated nitrile of a (1) with a tuted hydrazine of formula (1i) in ce of a base such as triethylamine, K2C03, Cs2C03 and the like in a suitable solvent such as methanol, ethanol, THF, DMF and the like. Ra and Raw1 independently represent an alkyl group.

Step II An amine compound of formula (2) can be reacted with acetylating agent such as acetic anhydride, acetyl chloride, at a temperature of about 20-350C for a sufficient duration, which can range from about 1 to 2 h or more to obtain a compound of formula (3).

Step III A compound of formula (3) can be treated with a suitable reagent such as phosphoryl trichloride, l chloride, phosphorous pentachloride and the like in a suitable solvent, e.g., DMF, DME, DMSO to obtain a compound of formula (4).

Step IV A compound of formula (4) can be reacted with an amine of formula (5) in presence of a base such as K2C03, NaHC03, Na2C03, Cs2C03, KOBut and the like, in a solvent such as toluene, DMF, DMSO, itrile, t-butanol and the like to obtain a compound of formula (6), n R1 and R2 are as defined in formula (I).

Step V Reductive ion of compound of formula (6) with a compound of formula (7) can be carried out for example in presence of a reducing agent such as Na(CN)BH3, Na(OAc)3BH, NaBH4 and the like, in a (Cl-Clo) l solvent such as , Ti(i-PrO)4, pyridine-borane complex methanol, ethanol, propanol, isopropanol, and the like, or a chlorinated t such as dichloromethane, chloroform, l,2-dichloroethane, and the like, along with an acid such as acetic acid or diluted hydrochloric acid. The temperature of the reaction could be maintained from about 25°C to about 35°C, and the duration of the reaction typically could range from about 30 minutes to about 5 hours. Ra, Rafi, R1, R2, Rb and n are as defined in formula (I).

Step VI A compound of formula (11) can be obtained by reacting a compound of formula (8) with a compound of formula (9) in presence of a base such as potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate, ylamine, disiopropylethylamine and the like, in a solvent such as anhydrous DMF, 1,4-dioxane, DMSO, acetonitrile, and the like, under suitable reaction conditions.

Step VII A compound of formula (13) can be obtained by cyanation of a compound of formula (11) using a suitable cyanating agent such as CuCN, Zn(CN)2, NaCN, KCN and the like in a solvent such as DMF, toluene, DMSO, and the like, under suitable reaction conditions.

Step VIII Base catalyzed hydrolysis of the cyano group in the compound of formula (13) in presence of a base such as KOH, NaOH, LiOH and the like in a solvent such as ethanol, ol, nol, utanol and the like can yield a carboxamide of formula (14).

Step IX A compound of a (15) can be obtained by N—alkylation of the alkali salt of the carboxamide compound of formula (14). The amide compound can be converted to its salt using metallic , NaH, K2C03 and the like. N—alkylation can be done by using alkylating agents such as alkyl halide and the like under suitable reaction conditions. Rg and Rh are as defined in the description of formula (I).

Step X A compound of formula (16) can be obtained by performing s substitution reactions on the compound of formula (11) wherein R represents n, alkyl, alkoxy, haloalkoxy, -NHCORt and the like, wherein Rt is as defined in compound of formula (I).

Step XI A compound of a (12) can be obtained by reacting a compound of formula (8) with a compound of formula (10) in the presence of a base such as K2C03, Na2C03, CszC03 2012/002435 and the like under suitable on conditions. X, Ra, Rafi, R1, R2, Rb, q and n are as defined herein for the compound of formula (1).

Another embodiment of the present application provides a process for the ation of various nds from compound of formula (12), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-II: O ORn O OH (7 e r? T T MN ““1“ (I) (ll) Ra‘ / N\N I /\ fi\| NI(:fi a, —> —> R NYX ”V” X NYC. w MN I (12) (III) (IV) (V) Various substituents of RIn containing compounds of formula (12) can be prepared either by using a suitable precursor compound of formula (12) in step X1 or by further (Rm)q fictionalization of “Y” . For example a compound of formula (12) with RIn as an acetyl group (III) or an ester group (I) can be obtained by using precursors having the respective substitutions. The ester group can be further hydrolysed for e by a base or acid catalyzed hydrolysis, to obtain a carboxyl group (11). Also when RIn is an acetyl group, it could further be converted to a group as shown in (IV) by reacting it with a suitable reagent such as DMF-DMA and the like. This 3-dimethylamino-propenonyl moiety can be further converted to RC (V), wherein RC represents a heterocycle, heteroaryl group; by reacting it with suitable reagents known in the art. For example, reaction with hydroxylamine hydrochloride under suitable reaction conditions would yield an isoxazolyl group. Reaction with ine hydrate would yield lyl moiety. Such heterocycles and heteroaryl groups could be further substituted by groups such as alkyl, halogen, cyano, hydroxyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy and the like using suitable reagents and tic methods known in the art.

EXAMPLES Example 1 ((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl-1H-pyrazolo [3 ,4-b]pyridin- -yl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl) isobutyramide Nw/UY“/ \ N N N K K CF3 Step (i): Preparation of 1-(tert-Butyl)methyl-1H-pyrazolamine To a mixture of 3-aminobutenenitrile (60 g, 731 mmol) and tert-butylhydrazine (96 g, 731.1 mmol) in ethanol (35 ml), ylamine (220 ml, 2195 mmol) was added. The mixture was refluxed for 12-16 h. The reaction mixture was then concentrated under reduced pressure.

The concentrate was extracted with water (100 ml) and ethylacetate (700 ml). The c layer was washed with brine and dried over Na2804 and concentrated under reduced pressure to obtain the title product. 1H NMR (400 MHz, CDC13) 5 5.37 (s, 1H), 3.51 (bs, 2H), 2.14 (s, 3H), 1.61 (s, 9H).

MS (m/z): 154 (M++1, 100%).

Step (ii): Preparation of N—(1-(tert-Butyl)methyl-1H-pyrazol-S-yl)acetamide Nd O \N NJJ\ To 1-(tert-butyl)methyl-1H-pyrazolamine (110 g, 0.71 mol), acetic anhydride (73 ml, 0.71 mol) was added dropwise with stirring. The reaction e was stirred for 1-2 h at -35 0C. fter the reaction mixture was washed with excess of hexane and filtered to obtain the title compound as a yellow solid. MP: 118-120°C. 1H NMR (400 MHz, CDClg) 5 7.27,(bs, 1H), 6.003 (s, 1H), 2.17 (s, 3H), 1.62 (s, 9H).

MS (m/z): 196 (M++1, 70%).

Step (iii): Preparation of 1-(tert-Butyl)chloromethyl-1H-pyrazolo[3,4-b]pyridine carbaldehyde Phosphorus oxychloride (62 g, 407 mmol) was added to 1-(tert-butyl)chloro -1H-pyrazolo[3,4-b]pyridinecarbaldehyde (15 g, 8.8 mmol) and the mixture was heated while stirring at 90-95 CC for 3 h. Thereafter, anhydrous DMF (18 g, 246 mmol) was added slowly over the period of 30 min while ining the temperature of the mixture at 90- 95 CC. After stirring for an additional 2 h, the reaction mixture was cooled to 20-35 0C and poured over crushed ice (100 g). The precipitated solid was filtered off, washed with water and dried under reduced pressure.

The yellowish solid product was subsequently dissolved in methylene chloride (200 mL), washed with water, dried over sodium sulfate, and the solvent was ated under reduced pressure to give the desired product as a light yellow solid. MS (m/z): 251 (M++1).

Step (iv): Preparation of 6-(Bis(cyclopropylmethyl)amino)(tert-butyl)methyl-1H- pyrazolo[3 ,4-b]pyridinecarbaldehyde Potassium carbonate (8.2 g, 57 mmol) was added to a solution of 1-(tert-butyl) chloromethyl-1H-pyrazolo[3,4-b]pyridinecarbaldehyde (5 g, 29 mmol) and bis- cyclopropylmethyl amine—(3.7 ml, 1.5 mmol) (prepared following the ture method disclosed in U. S. Patent No. 3,546,295) in DMSO (50 mL) under nitrogen. After stirring for 0.5 h at 20-35°C, the reaction mixture was heated for 14 h at 80 CC.

Thereafter, the on was cooled to 20-35°C, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was ted from the mixture. The organic t was washed with brine, dried over sodium sulfate and the solvent was removed using a rotary evaporator under vacuum. The residue was purified by chromatography using silica gel (60- 120 mesh) and eluted with 5% eluent to afford the title compound as a yellow solid.

MS (m/z): 341 (M++1, 100%).

Step (v): Preparation of 5-(((3,5-Bis(trifluoromethyl)benzyl)amino)methyl)(tert-butyl)-N,N- bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine Acetic acid (2.82 g, 46 mmol) was added to a mixture of 6- (bis(cyclopropylmethyl)amino)(tert-butyl)-3 -methyl- 1H-pyrazolo [3 yridine-5 - carbaldehyde (8 g, 23 mmol) and (3,5-bis(trifluoromethyl)phenyl)methanamine (5.7 g, 23 mmol) in methanol at 0°C. The resulting mixture was stirred continuously for 20 min. Sodium cyanoborohydride (4.5 g, 70 mmol) was added portion wise to the on mixture at 0 0C and WO 46045 the mixture was stirred for l h. After which the mixture was quenched with water, organic layer was separated, washed with brine, dried and evaporated to obtain the title compound. 1H NMR (400 MHz, CDC13) 8 7.71-7.81 (m, 4H), 3.91 (s, 2H), 3.83 (s, 2H), 3.11-3.13 (m, 4H), 2.49 (s, 3H), 1.76 (s, 9H), 09-095 (m, 2H), 0.33-0.37(m, 4H), 0008-007 (m, 4H); MS (m/z): 568 (M++1, 100%).

Step (Vi): Preparation of 5-(((3,5-Bis(trifluoromethyl)benzyl)(5-bromopyrimidinyl)amino) methyl)butyl)-N,N—bis(cyclopropylmethyl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin amine 2N IN/ 6?CF3 Potassium carbonate (0.43 g, 3 mmol) was added to a mixture of -(((3 ,5-bis(trifluoromethyl)benzyl)amino)methyl)- l -(tert-butyl)-N,N—bis(cyclopropylmethyl)- 3-methyl-lH-pyrazolo[3,4-b]pyridinamine (0.6 g, 1 mmol) and 5-bromochloropyrimidine (0.6 g, 3 mmol) in DMF. The resultant mixture was stirred at 100 0C for 12-16 h. The on mixture was treated with water and extracted with ethylacetate (100 ml). The organic layer was washed with brine and dried over Na2804, concentrated under reduced pressure to obtain the crude product. This product was further purified by column tography using silica gel (60-120 mesh) and 5% ethyl acetate in petroleum ether as eluent. 1H NMR (400 MHz, CDClg) 5 8.69 (s, 2H), 7.69-7.72(m, 3H), 5.035 (s, 2H), 4.80 (s, 2H), 3.07- 3.15 (m, 4H), 2.40 (s, 3H), 1.79 (s, 9H), 0.89-0.86(m, 2H), 0.31-0.36 (m, 4H), 0015-007 (m, 4H) MS (m/z): 726 (M++1, 30%).

Step (Vii): Preparation of N—(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- 1H-pyrazolo [3 yridin-5 -yl)methyl)(3 ,5-bis(trifiuoromethyl)benzyl)amino)pyrimidinyl) isobutyramide -(((3 ,5 -Bis(trifiuoromethyl)benzyl)(5-bromopyrimidinyl)amino)methyl)(tert- butyl)-N,N-bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine (150 mg, 0.207 mmol) and isobutyramide (0.018 g, 0.207 mmol) were dissolved in oxane (5ml) in a sealed tube to which 1,2-transdiaminocyclohexane (0.007 g, 0.062 mmol), and Cul (0.007 g, 0.078 mmol) were added. The reaction mixture was de-gassed for 15 min with argon. K2C03 (0.057 g, 0.414 mmol) was added to the reaction mixture and it was further degassed with argon for 15 min. The reaction mixture was then stirred at 80°C for 3 days. Thereafter the on mixture was diluted with DCM-MeOH (3:1) mixture (10ml), filtered through celite.

The filtrate was concentrated under reduced pressure; purified by column chromatography using 60-120 silica gel and 25% EtOAc in petroleum ether as the eluent to obtain the title 1H NMR (400 MHz, CDClg) 5 8.53 (s, 2H), 7.75 (s, 3H), 7.70 (s, 1H), 6.91 (s, 1H), 5.05 (s, 2H), 4.82 (s, 2H), 3.09 (d, J: 6.8 Hz, 4H), 2.39 (s, 3H), 1.78 (s, 9H), 1.28 (d, J: 6.8 Hz, 6H), 0.92-0.88 (m, 3H), 0.84 (q, J: 1.6 Hz, 4H), 0.07-0.008 (m, 4H). MS (m/z): 731 (M++1, 100%).

Example 2 -(((3 (trifiuoromethyl)benzyl)(5 -cyclopropylpyridinyl)amino)methyl)butyl)- N,N-bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine iii/Nmififl Step (i): Preparation of 5-(((3,5-Bis(trifiuoromethyl)benzyl)(5-bromopyridinyl)amino) methyl)(tert-butyl)-N,N-bis(cyclopropylmethyl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin amine WO 46045 The title compound was prepared by following the procedures ntially same as set forth in step (Vi) of Example-1 and by ing appropriate starting materials.

Step (ii): Preparation of 5-(((3 ,5-Bis(trifluoromethyl)benzyl)(5-cyclopropylpyridin yl)amino)methyl)(tert-butyl)-N,N-bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4- b]pyridinamine -(((3 ,5 -bis(trifluoromethyl)benzyl)(5 -bromopyridinyl)amino)methyl)(tert-butyl)- N,N—bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridinamine (0.05 g, 0.069 mmol) as prepared above, cyclopropyl boronic acid (0.007 g were dissolved in , mol) toluene (10 ml). To this tricyclohexylphosphine (0.002 g, 0.0069mmol), Pd(OAc)2 (0.0007 g, 0.0034 mmol), K3PO4 (0.051 g, 0.241 mmol) were added. The mixture was stirred at 100 0C for 16 hr. The reaction mixture was diluted with water, extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2804, and concentrated under reduced pressure. The crude product thus obtained, was purified by column chromatography using silica gel 60-120 mesh, 10% EtOAc in petroleum ether as the eluent to obtain the title compound. 1H NMR (400 MHz, CDClg) 5 8.20 (s, 2H), 7.69 (m, 3H), 7.60 (s, 1H), 5.03 (s, 2H), 4.81 (s, 2H), 3.09-3.07 (m, 4H), 2.38 (s, 3H), 1.77 (s, 9H), 0.96-0.91 (m, 4H), 0.66-0.65 (m, 2H), 0008-0003 (m, 8H). MS (m/z): 686 (M++1, 100%).

Example 3 N—(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)-3 -methyl- 1 H-pyrazolo [3 yridin-5 - yl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl)cyclopropanecarboxamide 2012/002435 The title compound was synthesized using procedures substantially same as set forth in Example 1 and by using cyclopropane amide instead of isobutyramide in step (Vii). 1H NMR (400 MHz,CDC13)5 8.53 (s, 2H), 7.70 (s, 3H), 7.62 (s, 1H), 5.05 (s, 2H), 4.81 (s, 2H), 3.08 (d, J: 6.8 Hz, 4H), 2.39 (s, 3H), 1.78 (s, 9H), 1.57-0.88 (m, 6H), 0.33 (q, J: 1.6 Hz, 4H), 0.027-0.001 (m, 4H). MS (m/z): 729 (M++1, 100%).

Example 4 l-(2-(((6-(bis(cyclopropylmethyl)amino)-l ,3-dimethyl- l H-pyrazolo [3 ,4-b]pyridin yl)methyl)(3 ,5 rifluoromethyl)benzyl)amino)pyrimidinyl)ethanone N NW % Step (i): Preparation of 5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-N,N- bis(cyclopropylmethyl)-l ,3-dimethyl- l H-pyrazolo [3 ,4-b]pyridinamine / \ N /N N ”W k CF3 The title compound was synthesized using procedures substantially same as set forth in step (V) of e 1 and using appropriate starting materials.

Step (ii): Preparation of l-(2-(((6-(bis(cyclopropylmethyl)amino)-l ,3-dimethyl-1H- pyrazolo [3 ,4-b]pyridinyl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidin yl)ethanone -(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-N,N-bis (cyclopropylmethyl)-l ,3- dimethyl-lH-pyrazolo[3,4-b]pyridinamine (0.761 mmol, 0.400 g) in DMF was d withl-(2-chloropyrimidinyl)ethanone (0.761 mmol, 0.119 g) and K2C03 (2.283 mmol, 0.315 g). The reaction mixture was stirred at 60-70 0C for 12-16 h. The reaction e was then extracted with EtOAc. The combined organic layer was washed with water and brine solution, dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography using silica gel and 50% EtOAc in petroleum ether as eluent to get the title 1H NMR (400 MHz, CDC13) 5 8.9 (s, 1H), 7.70 (s, 1H), 7.60 (s, 2H), 7.50 (s, 1H), 5.10 (s, 2H), 4.80 (s, 2H), 3.90 (s, 3H), 3.10 (d, J: 6.0 Hz, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 0.90 (m, 2H), 0.40 (m, 4H), 0.10 (m, 4H). MS (m/z): 646 (M++1, 50%).

Example 5 l -(2-(((6-(bis(cyclopropylmethyl)amino)- l -(tert-butyl)methyl- lH-pyrazolo [3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 rifluoromethyl)benzyl)amino)pyrimidinyl)ethanone The title compound was obtained following the procedures substantially same as set forth in Example 4 and using 5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-l-(tert-butyl)- N,N-bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridinamine, obtained in step (v) of e 1 as a ng material. 1H NMR (400 MHz, CDCl 3) d 8.90 (d, 2H), 7.80 (m, 3H), 7.60 (s, 1H), 5.10 (s, 2H), 4.90 (s, 2H), 3.10 (d, J = 6.0 Hz, 4H), 2.54 (s, 3H), 2.39 (s, 3H), 1.20 (s, 9H), 0.30 (m, 4H), 0.01 (m, 4H). MS (m/z): 688 (M++1, 100%).

Example 6 (E)(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl-1H-pyrazolo[3,4-b]pyridin- -yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl)(dimethyl amino)prop enone 1-(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl-1H-pyrazolo[3,4-b] pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl)ethanone, obtained in Example 5, (0.1 g, 0.14 mmol) and DMF-DMA (0.02 mL) was taken in e (2 mL) and refluxed the reaction mixture for 48 h. Water was added to the cooled (to 20-35oC) reaction mass and was extracted it with ethyl acetate. The organic layer was dried over sodium sulfate, solvent was evaporated to get the crude product which was purified by column chromatography using 60-120 mesh silica gel and eluted the desired product with 20% ethyl acetate in petroleum ether. MS (m/z): 743 (M++1, 100%).

Example 7 -(((3,5-bis(trifluoromethyl)benzyl)(5-(isoxazolyl)pyrimidinyl)amino)methyl)(tertbutyl )-N,N-bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridinamine To a mixture of (E)(((6-(bis(cyclopropylmethyl)amino)-l-(tert-butyl)methyl-1H- pyrazolo[3,4-b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)-N-((dimethyl amino)methylene)pyrimidinecarboxamide, ed in Example 6, (0.100 g, 0.130 mmol) in methanol, hydroxylamine hloride (0.03 ml, 0.80 mmol) was added. The resultant mixture was refluxed for 1-2 h. Thereafter the reaction e was treated with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product which was further purified by column chromatography using 100-200 mesh silica gel and 5% EtOAc as eluent. 1H NMR (400 MHz, CDClg) 5 8.81 (s, 2H), 8.30 (d, J: 1.9 Hz, 1H), 7.74 (s, 3H), 7.62 (s, 3H), 6.45 (d, J: 1.9 Hz, 1H), 5.30 (s, 1H), 5.14 (s, 2H), 4.90 (s, 1H), 3.105 (d, J: 6.6 Hz, 4H), 2.39 (s, 3H), 1.28 (s, 9H), 0.94-0.86 (m, 2H), 0.37-0.33 (m, 4H), 0.07-0.03 (m, 4H).

MS (m/z): 713 (M++1, 100%).

Example 8 5-(((5 -( l H-pyrazol-3 -yl)pyrimidinyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino) methyl) butyl)-N,N—bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine 2012/002435 (2-(((6-(bis(cyclopropylmethyl)amino)- l -(tert-butyl)methyl- l H-pyrazolo [3 ,4- b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl)(dimethyl acrylamide, obtained in Example 6, (0.100 g, 0.13 mmol) and hydrazine hydrate (0.04 ml, 0.8 mmol) were taken in ethanol. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure, extracted with EtOAC. The organic layer was washed with brine, dried over Na2804, and concentrated under reduced pressure to get the crude product which was purified with column chromatography using 100-200 silica gel and % EtOAc in eum ether as eluent. 1H NMR (400 MHz, CDC13) 5 8.82 (s, 2H), 7.74-7.72 (m, 4H), 7.64 (s, 2H), 6.58 (d, J: 2.2 Hz, 1H), 5.11 (s, 2H), 4.88 (s, 2H), 3.10 (d, J: 6.6 Hz, 4H), 2.38 (s, 3H), 1.78 (s, 9H), 0.96- 0.86 (m, 2H), 0.37-0.33 (m, 4H), 0.016-0.008 (m, 4H). MS (m/z): 712 (M+1, 100%).

Example 9 -(((3 ,5-Bis(trifluoromethyl)benzyl)(5 -( 1 -methyl- 1 H-pyrazol-3 -yl)pyrimidin no)methyl)- l -(tert-butyl)-N,N—bis(cyclopropylmethyl)methyl- l H-pyrazolo [3 ,4-b] pyridinamine Sodium hydride (0.008g, 0.21 mmol) in DMF (2 ml) was added se with stirring to 5-(((5 -( l H-pyrazol-3 -yl)pyrimidinyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)methyl)- l - (tert-butyl)-N,N-bis(cyclopropylmethyl)methyl- l H-pyrazolo [3 ,4-b]pyridinamine, obtained in Example 8 (0.03 g, 0.042 mmol). The reaction mixture was stirred for 20 min at 0°C. CH3I was added at this temperature and the mixture was stirred for an hour at 20-35 0C.

The reaction e was then treated with water and the mixture was extracted three times with ethyl acetate (50 ml). The combined organic layer was washed with brine, dried over 2012/002435 Na2804 and concentrated under reduced pressure to get the crude product. The crude product was further ed by column chromatography using 60-120 silica gel and 35% EtOAc in petroleum ether as eluent to afford the title compound. 1H NMR (400 MHz,CDC13)5 8.01 (s, 2H), 7.74 (m, 4H), 6.50 (s, 1H), 5.17 (s, 2H), 4.49 (s, 2H), 3.95 (s, 4H), 2.40 (s, 3H), 1.39 (s, 9H), 0.91-0.88 (m, 2H), 0.39-0.35 (m, 4H), 0.015-0.001 (m, 4H). MS (m/z): 726 (M++1, 60%).

Example 10 2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- l H-pyrazolo [3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 rifluoromethyl)benzyl)amino)pyrimidine-5 -carbonitrile \ CF3 N N/ N 0% -(((3 ,5 -bis(trifluoromethyl)benzyl)(5 -bromopyrimidinyl)amino)methyl)- l -(tertbutyl )-N,N—bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridinamine, obtained in step (Vi) of Example 1, (0.69 mmol, 0.500 g) was d with CuCN (0.0.69 mmol, 0.06 g).

DMF (5 ml) was added to this reaction mixture and the mixture was heated at 160 0C for 12-16 h. The mixture was then poured into crushed ice g precipitation of a solid. The precipitate was filtered and purified by column chromatography using 15% EtOAc in petroleum ether as eluent. 1H NMR (400 MHz,CDC13)5 8.65 (d, J: 10.0 Hz, 2H), 7.75 (s, 1H), 7.70 (s, 2H), 7.50 (s, 1H), 5.10 (s, 2H), 4.80 (s, 2H), 3.10 (d, J: 6.4 Hz, 4H), 2.40 (s, 3H), 1.70 (s, 9H), 0.80 (m, 2H), 0.36 (m, 4H), 0.00 (m, 4H). MS (m/z): 671 (M++1, 100%).

Example 1 l 2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- l H-pyrazolo [3 ,4-b]pyridin-5 - yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidinecarboxamide / Z \ | 1 N/ QC. 2-(((6-(Bis(cyclopropylmethyl)amino)- l -butyl)methyl- l H-pyrazolo [3 ,4- b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinecarbonitrile obtained in e 10, (0.000074 mmol, 0.050 g) in ethanol was treated with 1% solution of KOH (5 ml) and tic amount of hydrogen peroxide. The reaction mixture was heated at 40°C for 30 min. The reaction mixture was then concentrated under reduced pressure, treated with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated under reduced re, and purified by column chromatography using silica gel and 40% EtOAc in petroleum ether as eluent to obtain the title compound. 1H NMR (400 MHz, CDC13) 5 8.87 (s, 2H), 7.90 (s, 2H), 7.77 (s, 2H), 7.65 (s, 1H), 5.09 (s, 2H), 5.01 (s, 2H), 3.00 (d, J: 6.4 Hz, 4H), 2.28 (s, 3H), 1.67 (s, 9H), 0.80 (m, 2H), 0.27 (m, 4H), 0.00 (m, 4H). MS (m/z): 689 (M++1, 100%).

Example 12 2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- l H-pyrazolo [3 ,4-b] pyridin yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)-N,N-dimethylpyrimidinecarboxamide 0 N’ N N ‘N N/ N k W 2-(((6-(Bis(cyclopropylmethyl)amino)(tert-butyl)-3 -methyl- 1 H-pyrazolo [3 ,4- b]pyridinyl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidinecarboxamide, obtained in Example 11, (0.0000072 mmol, 0.005 g) in DMF (ml) was treated with sodium hydride (0.000014 mmol, 0.0003 g) and methyl iodide (0.000014 mmol, 0.002 g). The reaction mixture was stirred at 20-35 0C for 1 h. The reaction e was then treated with water, ted with ethyl acetate, dried over sodium sulphate, concentrated under reduced pressure and purified with column chromatography using 20% EtOAc in petroleum ether as eluent to get the title compound. 1H NMR (400 MHz, CDC13) 5 8.57 (s, 2H), 7.72 (s, 3H), 7.61 (s, 1H), 5.10 (s, 2H), 4.80 (s, 2H), 3.10 (s, 6H), 3.00 (d, J: 6.0 Hz, 4H), 2.40 (s, 3H), 1.78 (s, 9H), 0.40 (m, 4H), 0.00 (m, 4H). MS (m/z): 717 (M++1, 100%).

Example 1 3 3 -(2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- 1H-pyrazolo [3 yridin-5 - yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)oxazolidinone -(((3 ,5 -Bis(trifluoromethyl)benzyl)(5-bromopyrimidinyl)amino)methyl)(tert- butyl)-N,N—bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridinamine, ed in step (Vi) of Example 1 and oxazolidinone (0.15 g, 0.22 mmol) were taken in 1,4-dioxane (5 mL). To this CuI (0.004 g, 0.22 mmol), cyclohexylamine (0.005 g, 0.048 mmol) and K2C03 (0.06 g, 0.44 mmol) were added. The reaction mixture was degassed with Argon for 15 min.

Thereafter it was stirred at a temperature of 114 0C at 40-50 psi for 3 days. The reaction mixture was then filtered through celite, concentrated under reduced pressure, and purified h column chromatography using 60-120 mesh silica gel and 20% EtOAc in petroleum ether as eluent to obtain the title compound as white solid. 1H NMR (400 MHz, CDC13) 5 8.59 (s, 2H), 7.72-7.70 (m, 3H), 7.61 (s, 1H), 5.07 (s, 2H), 4.83 (s, 2H), 4.55 (t, J: 7.6 Hz, 2H), 4.04 (t, J: 8.0 Hz, 2H), 3.09 (d, J: 6.4 Hz, 4H), 2.40 (s, 3H), 1.78 (s, 9H), 0.92-0.88 (m, 2H), 0.39 (q, J: 8.4 Hz, 4H), 0.03-0.00 (m, 4H).

MS (m/z): 731 (M++1, 100%).

Example 14 -(((3,5-Bis(trifluoromethyl)benzyl)(5-morpholinopyrimidinyl)amino)methyl)(tertbutyl bis(cyclopropylmethyl)methyl- 1 H-pyrazolo [3 ,4-b]pyridinamine N N \ CF3 \N / Toluene was added to a mixture of 5-(((3,5-bis(trifluoromethyl)benzyl)(5- yrimidinyl)amino)methyl)(tert-butyl)-N,N-bis(cyclopropylmethyl)methyl- 1 H- pyrazolo[3,4-b]pyridinamine (0.25 g, 0.345 mmol), obtained in step (Vi) of Example 1, Pd2(dba)3 (0.053 g, 0.05 mmol), henyl)di-tert-butylphosphine (0.0012 g, 0.04 mmol), NaOtBu (0.05 g, 0.52 mmol) and morpholine (0.045 g, 0.52 mmol). The ant mixture was heated to reflux for 4 h. Thereafter the reaction mixture was cooled to 20-35 0C, treated with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography using 15% EtOAc in petroleum ether as eluent to obtain the title compound. 1H NMR (400 MHz, CDC13) 5 8.17 (s, 2H), 7.70 (s, 3H), 7.61 (s, 1H), 5.02 (s, 2H), 4.81 (s, 2H), 3.89-3.87 (m, 4H), 3.08-3.06 (m, 8H), 2.38 (s, 2H), 0.89-0.86 (m, 2H), 0.34-0.31 (m, 4H), 0.08-0.009 (m, 4H). MS (m/z): 731 (M++1, 100%).

Example 15 -(((3 ,5 -bis(trifluoromethyl)benzyl)(5-morpholinopyrimidinyl)amino)methyl)-N,N- clopropylmethyl)-1 ,3-dimethyl- 1 H-pyrazolo [3 ,4-b]pyridinamine j¢ CF \ 3 \N / Step (i): Preparation of 5-(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-1 ,3-dimethyl- 1 H-pyrazolo [3 ,4-b]pyridin amine The title compound was sized using a procedure substantially similar to that of step (Vi) of Example 1 and by using appropriate starting materials. 1H NMR (400 MHz, CDC13) 5 8.4 (s, 2H), 7.58 (s, 1H), 7.65 (s, 2H), 7.71(s, 1H), 5.03(s, 2H), 4.77(s, 2H), 3.96(s, 3H), 3.13(s, 2H), 3.11(s, 2H), 2.39 (s, 3H), 0.94-0.86(m, 2H), 0.39-0.35 (m, 4H), 0.08-0.04(m, 4H). MS (m/z): 684 (M++2, 100%).

Step (ii): Preparation of 5-(((3,5-bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin no)methyl)-N,N-bis(cyclopropylmethyl)-1 ethyl- 1 H-pyrazolo [3 ,4-b]pyridin amine The title compound was obtained by a procedure substantially similar to that of Example 14, by using 5-(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-l ,3-dimethyl- l H-pyrazolo [3 ,4-b]pyridin amine obtained from above step as the reactant. 1H NMR (400 MHz, CDC13) 5 8.19 (s, 2H), 7.68 (s, 1H), 7.61 (s, 1H), 7.60 (s, 2H), 5.03 (s, 2H), 4.79 (s, 2H), 3.97 (s, 3H), 3.91-3.87 (m, 4H), 3.09 (m, 4H), 2.38 (s, 3H), 0.93-0.88 (m, 2H), 0.37-0.35 (m, 4H), 0.14-0.01 (m, 4H). MS (m/z): 689 (M++1, 100%).

Example 1 6 l-(2-(((6-(Bis(cyclopropylmethyl)amino)- l -butyl)-3 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidin-5 -yl)pyrrolidinone 580N N N \ CF3 5-(((3 ,5 -Bis(trifluoromethyl)benzyl)(5-bromopyrimidinyl)amino)methyl)- l -(tertbutyl )-N,N-bis(cyclopropylmethyl)methyl-lH-pyrazolo[3,4-b]pyridinamine (0.2 g, 0.293 mmol), obtained in step (Vi) of Example 1, 2-pyrrolidinone (0.024 g, 0.293 mmol), Cul (0.005 mg, 0.029 mmol), trans-1,2-diaminocyclohexane (0.007 g, 0.064 mmol) were taken in a sealed tube in oxane (5 mL), which was degassed with argon for 15 min. K2C03 (0.08 g, 0.586 mmol) was added to it. The reaction mixture was stirred at 100 CC for 28 h. Thereafter the reaction mixture was filtered through celite, extracted with EtOAc. The combined organic layer was washed with water, dried over , concentrated under reduced re, and purified by column chromatography using EtOAc-petroleum ether as eluent to obtain the title compound. 1H NMR (400 MHz, CDClg) 5 8.66 (s, 2H), 7.71 (s, 3H), 7.61 (s, 1H), 5.06 (s, 2H), 4.83 (s, 2H), 3.84 (t, J: 6.8 Hz, 2H), 3.09 (d, J: 6.4 Hz, 4H), 2.61 (t, J: 8.0 Hz, 2H), 2.40 (s, 3H), 2.27—2.22 (m, 2H), 1.78 (s, 9H), .36 (m, 2H), 0.34 (q, J: 8.4 Hz, 4H), 0.03-0.00 (m, 4H).

MS (m/z): 729 (M++1, 100%).

Example 1 7 Ethyl(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)-3 -methyl- 1 H-pyrazolo [3 ,4- b]pyridin-5 -yl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)methylpyrimidine carboxylate COOEt N N ‘N N/ N K (V CF3 To 5 -(((3 ,5-bis(trifluoromethyl)benzyl)amino)methyl)- l -(tert-butyl)-N,N-bis (cyclopropyl )methyl-lH-pyrazolo[3,4-b]pyridinamine, obtained in step (V) of Example 1, (0.8 g, 1.4 mmol) was dissolved in DMF (8 ml), ethylchloromethyl pyrimidine-S-carboxylate (0.29 g, 1.4 mmol), filSCd ium carbonate (0.58 g, 2.8 mmol) were added to the above solution and the resultant mixture was heated at 70°C for 2 h. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulphate, trated under reduced pressure and purified by column chromatography using 60-120 silica gel and 5% EtOAc in eum ether as eluent to obtain the title compound (yield: 30%). 1H NMR (400 MHz,CDC13)5 8.90 (bs, 1H), 7.80-7.60 (m, 4H), 5.10 (s, 2H), 4.90 (s, 2H), 3.10 (m, 4H), 2.70 (s, 3H), 2.40 (s, 3H), 0.80 (m, 2H), 0.40 (m, 4H), 0.10 (m, 4H).

MS (m/z): 732 (M++1, 100%).

Example 18 2-(((6-(Bis(cyclopropylmethyl)amino)(tert-butyl)methyl- lH-pyrazolo [3 ,4-b]pyridin-5 - yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)methylpyrimidinecarboxylic acid Ethyl 2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)-3 l- 1 H-pyrazolo [3 ,4- b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)methylpyrimidine carboxylate, obtained in Example 17, (0.120 g, 0.16mmol) was dissolved in EtOH (6 ml) and % NaOH (4 ml) was added to it. The reaction mixture was stirred at 20-35 0C for 3 h. The reaction mixture was then acidified with citric acid solution, extracted with EtOAc, washed with water, dried over sodium sulphate, and concentrated under reduced pressure to obtain the crude product. This product was further d by column chromatography using 60-120 silica gel and 20% EtOAc in petroleum ether as eluent to get the desired t (yield : 14%). 1H NMR (400 MHz,CDC13)5 8.90 (bs, 1H), 7.80-7.60 (m, 4H), 5.1 (s, 2H), 4.90 (s, 2H), 3.10 (m, 2H), 2.70 (s, 3H), 2.40 (s, 3H), 0.80 (m, 2H), 0.40 (m, 4H), 0.10 (m, 4H).

MS (m/z): 704 (M++1, 100%).

Example 1 9 Ethyl 2-(((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl- 1 H-pyrazolo [3 ,4- b]pyridin-5 thyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5 -carboxylate COOEt w¢ CF \ 3 \N / -(((3 ,5 -bis(trifluoromethyl)benzyl)amino)methyl)(tert-butyl)-N,N—bis(cyclopropyl methyl)methyl-1H-pyrazolo[3,4-b]pyridinamine, obtained in step (V) of Example 1, (0.8 g, 1.4 mmol) was dissolved in DMF (8 ml). Ethyl 2-chloropyrimidinecarboxylate (0.58 g, 1.4 mmol), fused potassium carbonate (0.58 g, 2.8 mmol) were added to the above solution and the resultant mixture was heated at 70°C for 2 h. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulphate, concentrated under d pressure and purified by column chromatography using 60-120 silica gel and 5% EtOAc in petroleum ether as eluent to obtain the title compound (yield 30%). 1H NMR (400 MHz, CDC13) 5 8.90 (bs, 1H), 7.80-7.60 (m, 4H), 5.10 (s, 2H), 4.90 (s, 2H), 4.30 (m, 2H), 3.10 (m, 4H), 2.70 (s, 3H), 2.40 (s, 3H), 1.40 (t, 3H), 0.80 (m, 2H), 0.40 (m, 4H), 0.10 (m, 4H). MS (m/z): 732 (M++1, 100%).

Example 20 -(Bis(cyclopropylmethyl)amino)(tert-butyl)methyl- lH-pyrazolo [3 yridin-5 - yl)methyl)(3 ,5 -bis(trifluoromethyl)benzyl)amino)pyrimidine-5 -carboxylic acid COOH N N \f CF \ 3 \N / The title nd was prepared by a procedure substantially similar to that used for Example 18 using ethyl 2-(((6-(bis(cyclopropylmethyl)amino)-l-(tert-butyl)methyl-1H- pyrazolo[3,4-b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine carboxylate, obtained in Example 19 as a starting material. 1H NMR (400 MHz,CDC13)5 13 (bs, 1H), 8.77 (s, 2H), 7.90 (s, 1H), 7.77 (s, 2H), 7.68 (s, 1H), .11 (s, 2H), 5.02 (s, 2H), 3.05 (d, J: 6, 4H), 2.28 (s, 3H), 1.67 (s, 9H), 0.8 (m, 2H), 0.27 (dd, J: 12.6, J: 5.18, 4H), 0.04 (dd, J=9.46, J: 4.8, 4H).

MS (m/z): 690 (M++1, 100%), 325 (50%).

Example 21 Determination of in vitro CETP actiVity using fluorometric technique An in vitro cholesteryl ester er protein inhibition (CETP) assay using a commercially ble fluorometric assay kit from ROAR Biomedicals, USA was used to measure the CETP tion activity of the compounds of this application. This assay kit uses a donor molecule containing a fluorescent self-quenched neutral lipid that is transferred to an acceptor molecule in the presence of recombinant CETP enzyme (rCETP). The CETP-mediated transfer of the fluorescent neutral lipid to the acceptor molecule results in an increase in fluorescence (Excitation: 492 nm; on: 516 nm). mM stock ons of compounds were prepared in 100% DMSO and further dilutions were made such that the final concentration of DMSO in the reaction mix was 1%.

The reactions were performed as suggested by the kit manufacturer as follows. The assay was med in 96 well microplates and in each well, the reaction mixture ned 190 pl of assay buffer (150 mM NaCl, 10 mM Tris and 2 mM EDTA, pH-7.4), 4 ul of donor particle, 4 ul of acceptor particle, rCETP (50 ng) and 2 ul of test compound at varying final concentration of 0.1, 1, 10, 100, 1000 & 10000 nM. Two control reactions were performed, one without test compound (positive control) and the other without the rCETP ive control). The reactions were incubated at 37°C for 90 minutes and the reaction plate was transferred to a PCR machine MX3005P and the fluorescence units (FLU) were quantified (Excitation: 492 nm; Emission: 516 nm).

The negative control values were subtracted from the positive control as well as all the test values to correct for ound fluorescence. The percentage inhibition of activity was calculated by using the following equation: % Inhibition of CETP activity = [100 - (100 X (FLU in test/FLU in positive l))].

The half maximal inhibitory concentration (IC50) was determined using the BIOGRAPH software (version no. 3.3).

Using this protocol, various compounds as described herein were found to exhibit inhibitory effect on CETP, as shown in the below table: —Example No. IC50 (nM) —1 64 —3 35 —4 5.7 41.5 7 9.4 8 27 9 100 1250 11 18 12 215 13 10 14 46 49 16 56 18 54 19 70 61 Example 22 Determination of qualitative and quantitative changes of HDL-C in the hamster model of dyslipidemia.

Male Golden Syrian hamsters (Mesocricetus auratus) were procured from local sources.

After acclimatization period of one week on high fat diet (10% coconut oil, 0.2% terol), s were bled and randomized into vehicle or drug treatment groups based on plasma HDL-C prior to ting drug therapy. The s were bled after 7 days of dosing, plasma total cholesterol, HDL-C, triglycerides were measured spectrophotometrically using commercially available kits. The percent elevation was calculated ing to the formula: [(TT/OT)/(TC/OC)]—1 X 100, percent reduction was calculated according to the formula: 1- T) / (TC/OC)] X 100, where TT is the test day treated, OT the zero day treated, TC the test day control and OC the zero day control. Statistical cance for differences between the groups was by one way analysis of variance (ANOVA), followed by Dunnett’s test. P<0.05 was considered cant. Significant difference for treatment group Vs vehicle group was determined by student’s . P<0.05 was considered significant. Pooled plasma samples from each treatment group after 7 days of dosing were also fractionated by FPLC using Superose 6 and Superdex 200 columns connected in tandem, into the major lipoprotein classes, VLDL, LDL, and HDL. Fractions for all samples were assayed for total cholesterol using the Amplex Red Cholesterol Assay kit (Molecular Probes, USA). It was found that the compounds as described herein showed remarkable effects in terms of their dose-dependent and significant effect on in Vivo HDL-C elevation accompanied by appearance of large size HDL-2 subclass, characteristic of in Vivo CETP inhibition.

Although the present application has been illustrated by certain of the preceding es, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. Various modifications and ments can be made Without departing from the spirit and scope thereof.

Claims (14)

What is claimed is

1. A compound selected from: ,5-bis(trifluoromethyl)benzyl)(5-(isoxazolyl)pyrimidinyl)amino)methyl) (tert-butyl)-N,N-bis(cyclopropylmethyl)methyl-1H-pyrazolo[3,4-b]pyridin amine, and ((6-(bis(cyclopropylmethyl)amino)(tert-butyl)methyl-1H-pyrazolo[3,4- b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin yl)oxazolidinone, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising at least one compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

3. Use of a compound according to claim 1 in the manufacture of a medicament for treating, preventing or inhibiting a disease which is ed by cholesteryl ester-transfer protein (CETP).

4. Use of a nd according to claim 1 in the manufacture of a medicament for increasing high y otein (HDL) cholesterol.

5. Use of a compound according to claim 1 in the manufacture of a medicament for lowering low density lipoprotein (LDL) cholesterol.

6. Use of a compound according to claim 1 in the manufacture of a medicament for g cholesteryl ester-transfer protein.

7. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease that is mediated by cholesteryl ester-transfer protein (CETP).

8. Use of a compound according to claim 1 in the manufacture of a medicament for the treating and/or preventing a condition or e associated with lipoprotein metabolism, whereby there is a decrease in levels of high density lipoprotein (HDL) cholesterol.

9. Use of a nd according to claims 1 in the manufacture of a medicament for treating and/or preventing a condition or disease associated with lipoprotein metabolism, whereby there is an increase in levels of low y lipoprotein (LDL) cholesterol.

10. Use of a compound ing to claim 1 in the manufacture of a medicament for the treatment of atherosclerosis.

11. A pharmaceutical ition comprising compound according to claim 1 and at least one pharmaceutically acceptable excipient, wherein the composition is formulated in the form of tablets, capsules, lozenges, troches, hard candies, powders, , creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, able solutions, elixirs or syrups.

12. The compound according to claim 1, substantially as herein described with reference to any one of the examples and/or figures.

13. Use according to any one of claims 3 to 10, substantially as herein described with reference to any one of the examples and/or figures.

14. The composition according to claim 2 or claim 11, substantially as herein described with nce to any one of the examples and/or figures.