NZ620914B2 - Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (cetp) inhibitors - Google Patents

Abstract

Disclosed herein are cycloalkylpyridin-2-amines of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof. 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 protein (CETP) inhibitors. The present application further relates to pharmaceutical compositions comprising compounds of formula (I) or stereoisomers thereof or pharmaceutically acceptable salts thereof. Particular examples of the compounds of formula I include 3-(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin-2-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine and 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-amine. cholesteryl ester-transfer protein (CETP) inhibitors. The present application further relates to pharmaceutical compositions comprising compounds of formula (I) or stereoisomers thereof or pharmaceutically acceptable salts thereof. Particular examples of the compounds of formula I include 3-(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin-2-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine and 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-amine.

Description

W0 2013I024358 SUBSTITUTED HETEROCYCLIC AMINE COMPOUNDS AS CHOLESTERYL ESTER- TRANSFER PROTEIN (CETP) INHIBITORS TECHNICAL FIELD The present application relates to cycloalkylpyridin-Z-amines derivates of formula (I) or stereoisomers thereof or pharmaceutically acceptable salts thereof.

BACKGROUND Cholesteryl ester-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 teryl ester from HDL to apolipoprotein B—containing oteins. This transfer is accompanied by transfer of cerides in the opposite direction. Thus, a decrease in CETP ty 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 density lipoprotein (LDL). CETP can therefore simultaneously affect the trations of herogenic (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%. r, iological 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., Circulation, 79, pp. 8-15, 1989; Despres et (11., 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 disease (CI-ID) risk, a magnitude comparable to that for low density otein (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 reverse cholesterol transport. HDL could protect against atherosclerosis by several other mechanisms. For example, several studies have shown that HDL to have idant and anti- inflammatory s. Oxidative products of lipid metabolism induce inflammatory cell tment in vascular cells. HDL particles carry enzymes that retard LDL oxidation, including paraoxonase, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase.

These enzymes e pro-inflammatory, oxidized phospholipids, limiting their accumulation in LDL. In on, 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 lipopolysaccharide (LPS) thus regulating the inflammatory effects of LPS. In animal models of endotoxic 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 ofHDL by CETP inhibition has been described in the art.

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

Accordingly, the present application relates to cycloamylpyridin-Z—amine derivatives of the general formula (I): (Raf 2 p NR R“ (I) wherein, HN/< C Rd\N [\AN ii mir“ sents U;N ‘, “‘1‘” or I ; R1 and R2 are ndently selected from en, acyl, haloalkyl, -(CHRe)qR3, an optionally substituted group ed from alkyl or cycloalkyl, wherein optional substituent, in each occurrence, is independently selected from halogen, cyano, hydroxyl, an alkyl, a haloalkyl or an alkoxy; R3 is a group selected from alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with a group selected from halogen, cyano, yl, alkyl, haloalkyl or alkoxy; Ra, in each occurrence, is independently selected from cyano, hydroxy, alkyl, haloalkyl or alkoxy; Rb, in each occurrence, is independently selected from halogen, alkyl, kyl, hydroxy, alkoxy or haloalkoxy; Rc is independently selected from hydrogen, cyano, halogen, —C(=O)- Rf, -CONRth, -C(=O)—CH=CH—NRiRj, an optionally substituted group ed from cycloalkyl, aryl, aryl or heterocyclyl ring, wherein the optional substituent, in each occurrence, is selected independently from hydrogen, n, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, alkoxyalkyl or koxy; Rd is selected from hydrogen or alkyl; Re, in each ence, is independently selected from hydrogen, alkyl or alkoxy; Rf is selected from hydrogen or alkyl; Rg, Rh, Ri and R, independently ents hydrogen or alkyl; m is 0, 1 or 2; nisO,1,20r3; p is 1 or 2; and qisO, 1,2,3,4or5.

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

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

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

ED DESCRIPTION The present application will be described in more detail below: WO 2013024358 ‘Alkyl’ group refers to a linear or branched alkyl group with 1 to 10 carbon atoms.

Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like.

‘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, t—butoxy, and the like. Unless otherwise specified, an alkoxy group has from 1 to 10 carbon atoms. yalkyl’ refers to an alkoxy tuted 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. ary alkoxyalkyl groups include, but are not limited to, ethoxymethyl, propoxyethyl, ethoxybutyl and the like.

‘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.

‘Aryl’ is a monocyclic or polycyclic aromatic ring system. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and the like. Unless otherwise specified, an aryl group typically has from 6 to about 14 carbon atoms.

‘Cycloalkyl’ 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, cycloheptyl, 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 d to tyl, noradamantyl, bicyclo[l .1.0]butanyl, norbornyl(bicyclo[2.2. l ]heptanyl), norbornenyl (bicyclo[2.2.1]heptanyl), norbornadienyl(bicyclo[2.2.1]heptadienyl), bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.l]octadienyl, o[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[2.2.2]octadienyl, bicyclo[5.2.0]nonanyl, bicyclo[4.3.2]undecanyl, lo[5.3.1.l]dodecanyl and the like.

‘Halogen or Halo’ ents fluorine, chlorine, bromine, or iodine.

‘Haloalkyl’ means at least one halogen atom is substituted on an alkyl group. Both halogen and alkyl have the meaning as defined above. Representative es of haloalkyl groups include, but are not limited to, ethyl, chloromcthyl, fluoroethyl, chloroethyl, difluoromethyl, trifluoromethyl, dichloroethyl, trichloroethyl and the like. Unless otherwise specified, a haloalkyl group typically has from 1 to 10 carbon atoms‘ ‘Haloalkoxy’ means at least one n atom is substituted on an alkoxy group, wherein alkoxy and n groups are as defined above. Exemplary haloalkoxy groups include, but not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trichloroethoxy, fluoroethoxy, chloroethoxy, trifloroethoxy, perfluoroethoxy (-OCF2CF3), trifluoro—t—butoxy, hexafluoro—t— butoxy, ro—t—butoxy (—OC(CF3)3), and the like. Unless otherwise specified, an haloalkoxy group typically has from 1 to 10 carbon atoms.

‘Heterocyclyl’ is a saturated or a mono- or poly—unsaturated, non-aromatic monocyclic or polycyclic ling system of 3 to 10 members having at least one heteroatom or heterogroup selected from —O-, -N—, —S-, —802, or —CO. Exemplary heterocyclyl groups include, but not limited to, azetidinyl, oxazolidinyl, oxazolidinonly, isoxazolidinyl, imidazolidin-Z—onyl, pyrrolidinyl, pyrrolidin—Z—onyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine—1,1—dioxide, thiazolidinyl, 1,3-dioxolanyl, l,4—dioxanyl, cyclopenta[b]pyridinyl, cyclopenta[d]py1imidinyl and the like. Unless otherwise specified, a heterocyclyl group typically has from 3 to about 10 carbon atoms.

‘Heteroaryl’ is an ic clic or polycyclic ring system of 3 to 10 members having at least one heteroatom or heterogroup selected from ~O—, -N—, -S-, -802, or —CO.

Exemplary heteroaryl groups include, but not d to, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrrolyl, pyrimidinyl, thiazinyl, pyrazinyl, pyrazolyl, tetrazolyl, imidazothiazolyl, indolizidinyl, l, quinolinyl, quinoxalinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzodioxolyl, benzotriazolyl, indazolyl, quinoxalinyl, imidazolyl, quinolin—2(1H)—onyl, and the like. Unless otherwise specified, a heteroaryl group lly has from 3 to about 10 carbon atoms.

‘(Cl-C10)alcohol’ represents ‘(C1-C10)alkyl—OH’, wherein alkyl group is as defined above. ary (C1-C10)alcohol includes methanol, ethanol, propanol, isopropanol, butanol, anol and the like.

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

‘Optionally substituted’ means that the substitution is optional and therefore it is le 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 ens on the atom are replaced and when the tution is fluoro, then one en 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 indicates 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 acceptable solvates, or any complex of the compound that, when administered to a recipient, is capable of providing (directly or indirectly) a compound as described herein. It should be appreciated, however, that salts that are not ceutically acceptable also lie within the scope of the application. The preparation of salts can be d out using known methods.

For example, pharmaceutically acceptable salts of compounds contemplated herein may be synthesized by conventional al methods using a parent nd containing an acid residue. Generally, such salts may be prepared, for example, by making free base of the compounds and reacting with a stoichiometric quantity of the appropriate acid and vice—versa in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, l, isopropanol or acetonitrile may be utilized. Examples of acid on salts include, but are not limited to, l acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, ate, and organic acid addition salts such as acetate, e, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate. Also included in present application are the isomeric forms and tautomers and the pharmaceutically-acceptable salts of compounds of formula (I). Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, onic, maleic, c, pyruvic, aspartic, glutamic, benzoic, nilic, mesylic, stearic, salicylic, p- 012/002056 hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, henic, toluenesulfonic, oxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, B—hydroxybutyric, galactaric, and galacturonic acids.

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. lly it includes mirror image isomers that are usually formed due to at least one asymmetric center (enantiomers).

Where the compounds according to the t application s one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, reomeric mixtures and individual diastereomers. Also n individual molecules may exist as geometric isomers (cis/trans). rly, 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 isomers and es thereof in any proportion are encompassed within the scope of the present application.

For any particular nd disclosed herein, any general ure presented 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 s, such as humans and other animals, including horses, dogs, cats, rats, mice, sheep, pigs, etc. In exemplary embodiments, the subject may include subjects for which treatment and/or prevention of the conditions described herein would be beneficial.

For ease of reference, in this application it will be described in terms of stration to human subjects. 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 obtaining a desired clinical outcome in the treatment of a specific disease.

The terms ing' or 'to treat' means to alleviate symptoms, eliminate the causation either on a temporary 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 W0 20132024358 es or disorders described above. Besides being useful for human treatment, these combinations are also useful for treatment of other s, including horses, dogs, cats, rats, mice, sheep, pigs, etc.

Terms such as "about," "substantially," and the like are to be ued as modifying a term or value such that it is not an absolute. Such terms will be defined by the stances 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 equivalent in structure or function, plus any other element 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 compounds described herein are typically administered in ure with one or more pharmaceutically acceptable excipients or rs in the form of a pharmaceutical composition. A 'composition' may contain one compound or a mixture of compounds. A 'pharmaceutical composition' is any composition useful or potentially useful in producing at least one physiological response in a subject to which such pharmaceutical composition is stered.

Reference will now be made in detail to the embodiments of the present application, one or more examples of which are set forth below. Each e is ed by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modification and variations can be made in the present application without departing from the scope or spirit of the invention. 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 lents. Other objects, features, and s of the present application are disclosed in, or are obvious from, the ing detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary ments only, and is not to be construed as limiting the broader aspects of the present application.

Thus in accordance of this application there is provided compounds of formula (I), or stereoisomers thereof or pharmaceutically acceptable salts thereof: Ndo\/(Rb)\ n (Ra):CIT\N N’R2 R (I) wherein, HN"/< RC Rd\N N M M\A ’ ‘u R represents N :1, w . or A.“ ; R1 and R2 are independently selected from hydrogen, acyl, haloalkyl, -(CHRe)qR3, an optionally tuted group selected from alkyl or cycloalkyl, wherein optional substituent, in each occurrence, is independently selected from halogen, cyano, hydroxyl, an alkyl, a haloalkyl or an alkoxy; R3 is a group selected from , koxy, cycloalkyl, aiyl, heterocyclyl or heteroaryl, wherein R3 is optionally substituted with a group selected from halogen, cyano, hydroxyl, alkyl, haloalkyl or alkoxy; Ra, in each occurrence, is independently selected from cyano, hydroxy, alkyl, haloalkyl or alkoxy; Rb, in each occurrence, is independently selected from halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy; RC is independently selected from hydrogen, cyano, halogen, —C(=O)— Rf, -CONRth, -C(=O)—CH=CH—NRiRj, an optionally tuted group selected from cycloalkyl, aryl, heteroaryl or heterocyclyl ring, wherein the optional substituent, in each occurrence, is selected independently from hydrogen, halogen, cyano, yl, alkyl, haloalkyl, alkoxy, alkyl or haloalkoxy; R“1 is selected from hydrogen or alkyl; Re, in each occurrence, is independently selected from en, alkyl or ; Rf is selected from hydrogen or alkyl; Rg, Rh, Ri and R independently represents hydrogen or alkyl; m is O, 1 or 2; nisO,1,2or3; p is 1 or 2; and qisO, l,2,3,4or5.

In one embodiment, there is provided a compound having the a (I), or a stereoisomer f or a pharmaceutically acceptable salt thereof: R‘N \/(Rb)n (Rafi p\N NR2 R‘ (I) wherein, L/\‘\ N R represents Nif, R1 and R2 are -(CHRe)qR3; R3 is cycloalkyl; Ra, in each ence, is independently selected from alkyl; Rb, in each occurrence, is independently selected from halogen, alkyl, haloalkyl, and hydroxy; RC is independently selected from hydrogen, cyano, halogen, -C(=O)- Rf, h, —C(=O)-CH=CH~NRiR3 and an optionally substituted , group selected from heteroaryl and heterocyclyl ring, wherein the al substituent, in each occurrence, is selected independently from hydrogen, halogen, and hydroxyl; R6, in each occurrence, is independently selected from hydrogen and alkyl; Rf is hydrogen or alkyl; Rg, Rh, Ri and Rj each independently represent hydrogen or alkyl; In is 1 or 2; n is 1, 2 or 3; p is l or 2; and qisO,1,2,3,4or5.

In another embodiment, there is provided a compound of formula (la), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: REAIN \N/kNAGleh,/ (Rafi{If\ [R2 p N1 R (Ia) wherein, R1, R2, Ra, Rb, Rc, p, m, n are as defined above.

In another embodiment, there is provided a compound of a (lb), or a stereoisomer f or a pharmaceutically acceptable salt thereof; mAN/qcF3 (1b) wherein, 1 and R2 are independently selected from en or -(CHRe)qR3, wherein R3 represents cycloalkyl, aiyl, heterocyclyl or heteroaryl; Rc ents optionally substituted ring selected from 55»: KCNQ 0 N \l O 1:2?!” N O / NH \ 312%"!\ .._..

' Egg [N/ g 1/1; or ? wherein the optional substituent is selected from halogen, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, alkoxyalkyl or haloalkoxy; q represents 1, 2 or 3; and Ra, Re and p are as defined above.

In another embodiment, there is provided a compound of formula (10), or a isomer thereof or a pharmaceutically acceptable salt thereof: (10) wherein, RC ents 0 N E j (—7?O C?“/ NH (éN/ Q N , y JJI‘N or «\fo l Ra and m are as defined above.

In another embodiment, there is provided a compound of formula (Id), or a stereoisomer thereof or a pharmaceutically acceptable salt f: ,N=N Rd-N‘NXNAQCF3 (Ra)? CF3 \N A? (1d) wherein, Rd, R8 and m are as defined above.

In yet another embodiment there is provided a compound of formula (1e), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: HNJ{ off £0: (Raln N/\Vg (1e) wherein, R8 and m are as defined in the above description of formula (I).

In another embodiment, specific compounds of formula (1) without any limitation are enumerated as follows: 3 —(((3 5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin-Z-yl)amino)methyl)-N,N-bis (cyclopropylmethyl)—7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin—2-amine; 1-(2-(((2-(bis(cyclopropylmethyl)amino)—7,7—dimethyl«6,7-dihydro—5H—cyclopenta[b] pyridin—3 —yl)methy1)(3 , 5—bis(t1ifluoromethyl)benzyl)amino)pyrimidin—5—y1) pyrrolidin-Z-one; 3-(((3 5-bis(t1iflu01'omethyl)benzy1)(5—morpholinopyrimidiny1)amino)methyl)-N,N—bis (cyclopropylmethy1)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridinamine; ((2—(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro-5H—cyclopenta[b] pyridine—3 thyl)(3 ,5—bis(trifluoromethyl)benzyl)amino)pyrimidin—5-yl) ethanone; (E)(2-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro—5H—cyclopenta[b] pyridine—3 —yl)methyl)(3 ,5—bis(trifluoromethyl)benzyl)amino)pyrimidin~5—yl)—3 — (dimethylamino)prop~2—en— 1 —one; 3 ( lH—pyrazol-3—y1)pyrimidin-2—yl)(3 trifluoromethyl)benzyl) , amino)methyl)— N,N—bis(cyclopropylmethyl)-7,7-dimethyl—6,7-dihydro-5H-cyclopenta[b]pyridin- 2-amine; 3 -(((3 5—bis(trifluoromethyl)benzyl)(5~(isoxazol—3 —yl)pyrimidin—2-yl)amino)methyl)—N,N~ bis(cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]py1idin amine; (followed by page 13a) 2-(((2—(bis(cyc10propylmethyl)amino)—7,7-dimethyl-6,7—dihydro-5H—cyclopenta[b] pyn'dinyl)methyl)(3,5-bis(trifluoromethyl)benzy1)amino)pyrimidine itrile; 2—(((2—(bis(cyclopropylmethyl)amino)-7,7-dimethy1—6,7—dihydro—5H—cyclopenta[b] pyfidin-3 -y1)methy1)(3,5—bis(trifluoromethy1)benzyl)amin0)pyrimidine—5— carboxamide; 3—(((3,5-bis(trifluoromethyl)benzyl)(5—morpholinopyrimidiny1)amin0)methy1)-N,N- bis(cyclopropylmethyl)methy1—6,7—dihydro—5H—cyclopenta[b]pyfidin—2-amine; 3-(((3,5—bis(triflu0romethy1)benzyl)(5~morpholinopyrimidinyl)amino)methy1)-N,N— bis(cyclopropy1methyl)~8-methy1-5,6,7,8-tetrahydroquinolin—2—amine; 3-(((3,5-bis(trifluor0methyl)benzyl)(2H—tetrazol—5-y1)amino)methyI)—N,N-bis (cyclopropylmethyl)—7,7—dimethyl-6,7—dihydro—5H—cyclopenta[b]pyridin—2—amine (followed by page 14) W0 20131024358 PCT/1132012/002056 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl—2H—tetrazo1yl)amino)methyl)—N,N-bis propylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin amine; 3—(((3,5~bis(trifluoromethyl)benzyl)(2—isopropyl-2H-tetrazo1-5—yl)amino)methyl)-N,N— bis (cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin amine; 3~(((3,5—bis(trifluoromethyl)benzyl)(2-isobutyl-2H—tetrazo1-5—yl)amino)methyl)—N,N-bis (cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin~2- amine; 3—(((3,5—bis(trifluoromethyl)benzy1)(2-methyl-2H-tetrazol—5~yl)amino)methyl)~N,N—bis (cyclo propylmethyl)—8,8—dimethyl-5,6,7,8~tetrahydroquinolin-Z-amine; 6-(((2-(bis(cyclopropy1methyl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b] pyridin-3 -yl)methyl)(3 ,5-bis(trifluoromethyl)benzyl)amino)benzo [d] oxazol— 2(3H)-one; ,5-bis(trifluoromethy1)benzy1)(2-methyl—2H—tetrazolyl)amino)methyl)—N,N-bis (cyclopropylmethyl)methyl-6,7-dihydro-5H-cyclopenta[b]pyridinamine; or stereoisomers thereof or pharmaceutically acceptable salts thereof.

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

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

In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of a (I) or a stereoisomer f or a pharmaceutically acceptable salt thereof.

One aspect of the above embodiment provides a pharmaceutical composition sing one or more compounds selected from formula (Ia), (Ib), (10), (Id) or (1e).

PCT/IBZOIZ/002056 In another embodiment, there is provided compounds of formula (I) or stereoisomers thereof or pharmaceutically acceptable salt thereof, as CETP inhibitors.

In r 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 ceutical composition comprising a eutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. As used herein the term ct” 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 lipoprotein (VLDL) and low density lipoprotein (LDL) and/0r increasing the ratio of HDL~C to LDL~C, which comprises administering to said t a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a isomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a method for treating or reducing the risk of developing a e 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 effective amount of a 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 binding CETP in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the nd of formula (I), or a isomer 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 treatment sing the administration of a therapeutically effective amount of the nd 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 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 ceutically acceptable salt thereof to said patient.

In another ment, there is provided a method of g the ratio of sing HDL terol 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 thereof to said patient.

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

Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, syrups, beverages, foods, and other nutritional ments. When administered, the present pharmaceutical itions may be at or near body temperature. In some embodiments, the present pharmaceutical compositions may be below body temperatures. In other embodiments, the present pharmaceutical compositions may be above body temperatures.

The compounds of the present application may be administered in a Wide variety of different dosage forms. For e, they may be combined with various pharmaceutically acceptable inert carriers in the form of, but not limited to, tablets, capsules, lozenges, s, 2O 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 diluents or fillers, sterile aqueous media, and various nontoxic organic ts, etc. Moreover, oral pharmaceutical compositions may be sweetened and/or flavored.

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

In general, compounds ofthe present application for ent may be administered to a subject in a suitable ive dose in the range of from about 0.01 to about 100 mg per kilogram ofbody 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 WO 2013024358 2012/002056 sub-doses, may be stered at appropriate als h the day, or on other appropriate schedules.

An embodiment of the present application provides the preparation of compounds of formula (1) according to the procedures of the ing examples, using appropriate materials.

Those skilled in the art will tand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional nds of the t ation claimed herein. All atures are in degrees Celsius (°C) unless otherwise noted.

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

DIBAL (Diisobutylaluminium hydride), CDC13 (Deuterated form), CuI (Cuprous Iodide), CNBr (Cynogen bromide), DCM oromethane), DMF (N,N- dimethylformamide), DMF—DMA (MN-dimethylformamide dimethyl acetal), DMSO (Dimethyl sulfoxide), HCI (hydrochloric acid), H202 (Hydrogen peroxide), AcOH (Acetic acid), MeOH (Methanol), NaOMe (Sodium methoxide), LDA um Diisopropylamide), LAH (Lithium aluminium hydride), NHZNH2.H20 (Hydrazine hydrate), NHZOHHCl (hydroxylamine hloride), K2C03 (Potassium Carbonate), KOH (Potassium hydroxide), KCN (Potassium cyanide), Pd (Palladium), Pd(OAc)2 (Palladium (II) acetate), Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0)), CNBr (Cyanogen bromide), POC13 (Phosphorus oxychloride), PC15 (Phosphorus pentachloride), PdClz (Palladium (II) chloride), Pd(PPh3)4 (Tetrakis(triphenylphosphine)palladium(0)), NaCN (Sodium cyanide), Na2C03 (Sodium Carbonate), NaOH (Sodium hydroxide), NaCl (Sodium chloride), Na(CN)BH3 (Sodium cyanoborohydride), Na2804 (Sodium Sulfate), NaOBut (sodium t-butoxide), NaBH4 (Sodium borohydride), )3BH (Sodium triacetoxyborohydride), NaN3 (Sodium azide), SnClz (Tin (II) chloride), Ti(i-Pro)4 (Titanium(IV)isopropoxide), SOC12 (Thionyl chloride), H20 (Water), ZnBrz (Zinc bromide), Zn(CN)2 (Zinc cyanide), H2 (Hydrogen gas), H2804 (Sulfilric acid), EDTA (Ethylenediaminetetraacetic acid).

Another embodiment of the present application provides a process for the preparation of compounds of formulae (10) & (11), both of which represent respectively a sub-group of a PCT/132012/002056 compound of formula (I), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-l.

Scheme l (R)/mC; d%9m“;m(/mp\0 /pN/OH /pN/C| (1))m ()mQ) (Ra)m (Ralm GflR)“/ , b) mgH:G(Rb) C“ (R/ N W:a/m plN/N’R2 (3)R R1 Cl (9) m m l (Rb)—-> PI/ (Rm /pN/ n \ ,R2 \ /pN/ ,R2 (Ra) N (Ra)m N1 m R‘ R (10) Ni (11a) CN /\CONH2 ATSTAO N1 R1()11b R (11c) ally substituted cycloalkanone of a (1), wherein Ra, m and p are as defined in the description of formula (I), is reacted with a formate ester, such as ethyl forrnate in the presence of sodium metal, NaOMe, and the like to obtain an optionally substituted 2- oxocyclolkanone carbaldehyde of formula (2). The compound (2) can be further condensed W0 2013I024358 with cyanoacetamide in the presence of a base, such as dine—acetate to obtain a compound of formula (3).

Amino substitutions on the ring of the compound of formula (5) can be obtained by first converting compound of formula (3) to compound of formula (4) using suitable reagents, such as SOClz, PC15 and the like; followed by using common nucleophilic tution reactions known in the art to obtain a compound of formula (5).

A compound of formula (6) can be obtained by reduction of the cyano group of compound (5) to aldehyde using reagents, such as DIBAL, SnClg-HCI, m imethyl nediaminoaluminium e, or by reduction of nitrile in presence of Hz—Raney Nickle or LAH or sodium borohydride and the like, followed by in—situ hydrolysis of the intermediate imine.

A compound of formula (8) can be obtained by sing a compound of formula (6) with an optionally substituted benzylamine of formula (7) in the presence of a suitable reagent such as sodium cyanoborohydride, sodium triacetoxyborohydride, Ti(z'-Pr0)4 and NaBH4, pyridine-borane complex and the like in a suitable solvent. Ra, Rb, m, n and p are as defined in the description of formula (I).

A compound of formula (10) can be ed by reacting the secondary amino group of compound of formula (8) with a 2—chloro—bromopyrimidine of formula (9), in the presence of a base such as potassium carbonate, sodium ate, potassium acetate, cesium carbonate and the like, in a solvent such as such as anhydrous DMF, l,4~dioxane, DMSO, itrile and the like.

Compound of formula (lla), wherein RC represents an optionally substituted group selected from cycloalkyl, aryl, aryl or heterocyclyl ring as defined in formula (I), can be obtained by nucleophilic substitutions on the pyrimidine ring of formula (10), by using a base such as potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate, sodium t- butoxide and the like, in the presence of a solvent such as anhydrous toluene, DMF, 1,4- dioxane, DMSO, acetonitrile and the like. Some nds of formula (I) can be prepared by using ium catalysts like Pd(OAc)2, Pd2(dba)3, PdClz in the presence of a ligand selected from biphenyl di-z-butylphosphine, triphenylphosphine, 2-(dicyclohexylphosphino)biphenyl, xanthphos and the like. For example a compound of formula (1 lb) can be obtained by palladium catalysed cyanation of compound of a (8) using Zn(CN)2, KCN and the like.

PCT/IBZOlZ/002056 Some compounds of the formula (I) can be prepared through Cul mediated Buchwald Coupling in the ce of a variety of ligands used for such purposes, which include for example trans- 1,2-diaminocyclohexane, quinolin-S-ol, bis-(2-aminoethy1)amine, and the like.

Further a compound of a (1 lc) can be obtained by hydrolyzing the e group in compound of formula (1 lb) using methods known in the art such as acid catalyzed hydrolysis in the presence of HCl, H2804 and other inorganic acids or base catalyzed hydrolysis in the presence of H202 and K2C03 or KOH.

In another embodiment there is ed a process for the preparation of a compound of formulae (13), (14), (15) & (16), all of which represent respectively a oup of a nd of formula (I), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-2.

Scheme 2: R1 . (8) R1 (13) R )nb _ / \ o / N l / N/ \N’ I \ \ l I a__ T , (Ra)/ R N/ N’R2 l ' " 1 n ( )m / \ p Ra N NIR2 m N/ R2 ét P (Ra) m p by [Q1 R1 (15) (14) (16) A compound of formula (13) can be obtained by reacting the secondary amino group of compound of formula (8) with a compound of a (12), in the presence of a base such as potassium carbonate, sodium carbonate, potassium acetate, cesium carbonate, and the like, in a solvent such as anhydrous DMF, 1,4—dioxane, DMSO, acetonitrile, and the like.

W0 2013I024358 A compound of formula (13) can be converted to a compound of formula (14) in the ce of an riate reagent such as ethylformamide dimethylacetal, in the presence of a solvent such as toluene, DCM, 1,2-dichloroethane, 1,4-dioxane, and the like.

A compound of formula (14) can be converted to a compound of formula (15) in the presence of an appropriate t such as NHzNHzflzo, in the presence of a t such as ethanol, methanol, isopropanol, n-butanol, and the like.

A compound of formula (14) can be converted to a compound of formula (16) in the ce of an appropriate reagent such as NHZOHHCl, in the presence of a solvent such as ethanol, methanol, isopropyl alcohol, n-butanol, and the like.

In another embodiment there is provided a process for the preparation of compounds of formulae (17), (18) &(19), all of which represent tively 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—3: Scheme 3: I /t:bln\- (Ram fill—m \ l\ / :—:<Rb)n__> \ N N O (Ram/1°l /—-<I R p b)n MR \ Ev N (8) (17) é1 (18) A compound of formula (8) is converted to a compound of formula (17) in the presence of a reagent, such as CNBr, NaCN, and the like, in a suitable solvent such as dimethylformamide, acetonitrile, a (Ci-Clo) alcohol, or the like, along with a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and the like. The temperature of the on is generally maintained from about °C to about 55°C, and the duration of the reaction typically can range from about 20 minutes to about 5 hours.

A compound of a (17) is ted to a compound of formula (18) by ng with sodium azide or potassium azide, in the presence of a zinc salt such as ZnBrz. Suitable solvent for this reaction can be selected from N,N—dimethylformamide, acetonitrile, (Cl—Clo) alcohols, and the like.

A compound of formula (l8) can be converted into a compound of formula (19) by reacting with an alkylating reagent such as alkyl halide or l sulphate, in the presence of a base such as sodium hydroxide, potassium hydroxide, ium carbonate, sodium hydride, ium hydride, and the like, along with a phase—transfer catalyst such as tetraalkylammoniumhalide or tetraarylammoiumhalide, in a solvent medium such as water, dimethylformamide, acetonitrile, and the like.

In another embodiment there is provided a process for the preparation of a compound of formula (20), which represents a sub—group of a compound of formula (I), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme—4.

Scheme 4: /tab)n\‘ (Ra)m N’CN (Ra)m o NH2 WH/GRb)n\ N / iFR”3) \ \ \ 7: / I b N ,R2 ————> 1 “-> I —.—(R)n P N / ,R2 / \ '1 p N N N ’R2 R P 1 I}! (8) R (17) R1 (20) A nd of formula (8) can be converted to a compound of formula (17) by a procedure as defined above.

PCT/IBZOlZ/002056 A compound of formula (17) can be hydrolyzed in the presence of a base such as KOH, NaOH, and the like, along with a catalytic amount of H202, lly at a temperature in the range from about 25 to about 100°C for a period of time from about 30 minutes to about 6 hours, to yield a compound of formula (20).

In another embodiment there is provided a process for the preparation of a compound of formula (24), which represents a sub-group of a compound of formula (I), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-5.

Scheme 5: 3L H HN NYC (Ra)m (Ra)m i CHO I (21)NH2 / \ ____.______, | (24) Reductive ion of a compound of formula (6) with a compound of formula (21) can be d out in the presence of a reducing agent, such as Na(CN)BH3, Na(OAc)3BH, NaBH4 and the like, in (Ci—Clo) l t medium such as ethanol, propanol, isopropanol, and the like, along with an acid, such as acetic acid or diluted hydrochloric acid, could yield a nd of formula (22). The temperature of the reaction may be maintained from about 25°C to about 35°C, and the duration of the reaction typically can range from about minutes to about 5 hours.

A compound of formula (22) can be reacted with a compound of formula (23) wherein X1 is a leaving group such as halogen, mesyloxy, tosyl, and the like, to obtain a compound of formula (24), in the presence of a base like sodium hydride or potassium hydride. The reaction can be carried in a solvent such as methylformamide, acetonitrile, tetrahydrofuran, toluene, and the like. The ature of the reaction may be maintained from about 25°C to about 55°C, and the duration of the reaction typically can range from about 20 minutes to about hours.

As used in the examples and preparations that follow, the terms used therein shall have the meanings indicated: refers to grams, "mg" refers to milligrams, "ug" refers to micrograms, "mol" refers togmoles, "mmol" refers to millimoles, "L" refers to liters, "mL" or ml" refers to milliliters, "uL" refers to microliters, "nm” refers to nanometers, "cone." refers to concentrated, "M" refers to molar, "mM" refers to millimolar, "uM" refers to olar, “rim” or "nM" refers to nanomolar, "TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, “min” refers to minute or minutes, “h” or “hr” refers to hour or hours; “S)9 refers to singlet, “(1” refers to doublet, “t” refers to triplet, (Cq)3 refers to quartet, “m” refers to multiplet, “dd” refers to “doublet of doublets”, “br” refers to broad, “LC” refers to liquid chromatograph, “MS” refers to mass spectroscopy, “ESI” refers to ospray tion, “CI” refers to chemical ionization, “M” refers to molecular ion, “NMR” refers to nuclear magnetic nce spectroscopy, “MHZ” refers to megahertz.

EXAMPLES Example 1 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(5~bromopyrimidin—2-y1)amino)methyl)-N,N— bis(cyclopropylmethyl)—7,7~dimethy1-6,7-dihydro-5H~cyclopenta[b] pyridin-Z—amine W0 20131024358 : Synthesis of 2, 2-dimethylcyclopentanone A solution of cyclopentanone (5 g, 59 mmol) in toluene (50 mL) was added to a suspension of sodium t—pentoxide (13 g, 118 mmol) in toluene (20 mL). yl e (14.8 g, 118 mmol) was added drop Wise to the mixture thus obtained at a temperature of 5°C. The mixture was warmed to a temperature of about 20-35°C and was stirred for about 28 h. The reaction mixture was treated with saturated sodium bisulfite (NaH803) on and was ted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the desired t as a brown liquid (5.2 g). MS (EST): 111 (M—1)+.

Step-2: Synthesis of 2-hydroxy-7,7-dimethy1—6,7-dihydro-5H-cyclopenta[b]pyridine carbonitrile N OH Sodium metal (0.854 g, 0.8 mol) was added portion wise to diethyl ether (20 mL) with continuous stirring until a clear suspension was formed. To this suspension, 2,2- dimethylcyclopentanone (5.2 g, 46.4 mmol), ethyl formate (4.1 g, 55.7 mmol) were added drop wise and the reaction e was stirred at a temperature of about 20-350C for about 28 h. The mixture was treated with methanol and filtered. The filtrate was trated under reduced pressure and the residue, 3,3-dimethyloxocyclopentanecarbaldehyde sodium salt, was directly used in the next step.

To a solution of 3,3-dimethyloxocyclopentanecarbaldehyde sodium salt (5 g, 30.9 mmol) in water (10 mL) was added cyanoacetamide (2.5 g, 30.9 mmol), piperidine (2.6 g, 30.9 mmol in 10 mL water) and acetic acid (1 mL) in that order. The reaction mixture was stirred at 100°C for about 26 h and then cooled to a temperature of about 20-35°C. The reaction mass was adjusted to pH value of about 6 and was then filtered off to obtain a crude product. The crude product was purified by column chromatography (60-120 mesh silica gel) with 10% ethyl acetate in petroleum ether as the eluent to obtain the desired product as a brown liquid (0.8 g). 1H NMR (400 MHz, CDC13)Z 5 13.6 (bs, 1H), 7.75 (s, 1H), 2.73 (t, J = 8.0 Hz, 2H), 2.02 (t, J = 8.0 Hz, 2H), 1.40 (s, 6H). MS (E81): 189 (M+l)+.

Step-3: Synthesis of 2-(bis(cyclopropy1methy1)amino)-7,7-dimethyl-6,7-dihydro-5H- cyclopenta[b]pyridinecarbonitrile Phosphorous oride (1.9 mL, 24 mmol) was added to 2-hydroxy-7,7-dimethyl-6,7- dihydro—5H-cyclopenta[b]pyridine-3~carbonitrile (0.8 g, 4.3 mmol), obtained in step-1, at 0°C over a period of about 10 min. The mixture was warmed to a temperature of about 20—35°C and was heated further to about 80°C. The mixture was stirred at about 80°C for about 18 h. The on mixture was cooled to a temperature of about 20—35°C and then was poured into d ice. The solid which separated out was filtered off and dried under reduced pressure to get 2-chloro—7,7—dimethyl-6,7—dihydro—5H-cyclopenta[b]pyridinecarbonitrile (0.7 g). 1H NMR (400 MHz, CDCl3)Z5 7.74 (s, 1H), 2.89 (t, J= 7.2 Hz, 2H), 2.05 (t, J= 7.6 Hz, 2H), 1.30 (s, 6H). MS (ESI): 207 (M+l)+. 2-Chloro—7,7-dimethyl-6,7—dihydr0-5H-cyclopenta[b]pyridine—3-carbonitrile (0.7 g, 3.4 mmol) obtained in the previous step, and bis (cyclopropylrnethyl)amine were heated with stirring at 100°C for about 20 h. The reaction mixture was cooled to a temperature of about 20— °C and was purified by column chromatography (60-120 mesh silica gel) using about 10% ethyl acetate in petroleum ether as eluent to obtain the desired t as a pale yellow liquid (0.7 g). 1H NMR (400 MHZ, CDC13)25 7.48 (s, 1H), 3.63 (d, J = 7.2 Hz, 2H), 1.92 (t, J = 6.8 Hz, 2H), 1.20 (s, 6H), .48 (m, 4H), 0.30-0.27 (m, 4H). MS (E81): 296 (M+1)+.

Step-4: Synthesis of 2-(bis(cyclopropylmethyl)amino)—7,7-dimethyl-6,7-dihydro-5H- cyclopenta[b]pyridinecarbaldehyde N/ NW R7 PCT/IBZOlZ/002056 2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine- 3-carbonitrile (2.1 g, 7.2 mmol), ed in step-3, was dissolved in dry romethane (10 mL) was added drop wise to 1M solution of DIBAL in toluene (4.2 mL, 14 mol) at about - 78°C. The reaction mixture was stirred at the same temperature for about 2 h. The reaction mixture was warmed to 0°C, and was adjusted to a pH value of about 6 with diluted HCl. The aqueous mass was extracted with ethyl acetate (3x200 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure.

The crude product was purified by column chromatography using silica gel (60—120 mesh) and about 5% ethyl acetate in dichloromethane as eluent to obtain the product as a pale yellow liquid (1 g). 1H NMR (400 MHZ, CDC13)26 10.11 (s, 1H), 7.79 (s, 1H), 3.38 (d, J = 6.8 Hz, 4H), 2.78 (t, J = 7.6 Hz, 2H), 1.95 (t, J = 7.2 Hz, 2H), 1.24 (s, 6H), 1.20-1.08 (m, 2H), 0.50-0.40 (m, 4H), 0.17-0.13 (m, 4H). MS (E81): 299 (M+1)+.

Step-5: Synthesis of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)—N,N- bis(cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro—5H—cyclopenta[b]pyridin~2-amine $8ng3 To a on of 2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl—6,7—dihydro-5H— cyclopenta[b]pyridine-3—carbaldehyde (1.2 g, 4 mmol), ed in step—4, and bis(trifluoromethyl)benzylamine (7.1 g, 29.4 mmol) in methanol (10 mL), was added glacial acetic acid (0.3 mL) and the resulting mixture was stirred for about 15 min at a temperature of about 20-35°C. Sodium cyanoborohydride (0.257 g, 4 mmol) was added portion wise to this reaction e and the on e was stirred for about 3 h.

After concentrating the mixture under reduced pressure, it was extracted with water (30 mL) and dichloromethane (2x30 mL). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced re to get the crude product.

The crude product was purified by column chromatography using silica gel (60-120 mesh) and eluted with 50% eum ether in ethyl acetate to obtain the pure product as a pale yellow liquid (0.7 g). 1H NMR (400 MHz, CDC13):8 7.83 (s, 2H), 7.75 (s, 2H), 7.30 (s, 1H), 3.87 (s, 2H), 3.80 (s, 2H), 2.98 (d, J = 7.2 Hz, 4H), 2.79 (t, J = 6.8 Hz, 2H), 1.95 (t, J = 7.6 Hz, 2H), .78 (m, 2H), .28 (m, 4H), -0.01 (m, 4H). MS (EST): 526 (M+1)+.

Step-6: Synthesis of 3—(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyrimidin—2- yl)amino)methyl)—N,N—bis(cyclopropylmethyl)—7,7-dimethyl—6,7-dihydro—5H—cyclopenta[b] pyridinamine To a mixture of 3—(((3,5—bis(trifluoromethyl)benzyl)(4-bromophenyl)amino)methyl)- N,N-bis(cyclopropylmethyl)—7,7-dimethyl—6,7-dihydro-5H-cyclopenta[b]pyridinamine (1.0 g, 1.9 mmol), obtained in step-5, and 2-chlorobromopyrimidine (0.735 g, 3.8 mmol) in anhydrous dimethylformamide, potassium carbonate (0.525 g, 3.8 mmol) was added. The reaction mixture was heated with stirring at 100°C for about 18 h. Thereafter, the reaction mixture was allowed to cool to a temperature of about 20—35°C. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3X50 mL). The ed organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by chromatography using silica gel (100- 200 mesh) and about 10% ethyl acetate in petroleum ether as eluent to obtain the pure product as a brown Viscous liquid (0.3 g). 1H NMR (400 MHz, CDC13):5 8.69 (s, 3H), 8.35 (s, 2H), 7.70-7.66 (m, 2H), 7.17 (s, 1H), 4.99 (s, 2H), 4.79 (s, 2H), 2.69 (t, J = 6.8 Hz, 2H), 1.21 (s, 6H), .81 (m, 2H), 0.30- 0.26 (m, 4H), -0.00 (m, 4H). MS (E81): 684 (M+2)+, 682 (M+1)+.

Example 2 W0 20131’024358 Synthesis of ((2-(bis(cyclopropylmethyl)amino)—7,7-dimethyl-6,7-dihydro—SH— cyclopenta[b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl) pyrrolidinone “mgr To a mixture of 3-(((3,5-bis(trifluoromethyl)benzyl)(4—bromophenyl)amino)methyl)~ N,N—bis(cyclopropylmethyl)-7,7-dimethyl-6,7-dihydro~5H-cyclopenta[b]pyridinamine, obtained in step-6 of Example 1, (0.15 g, 0.2 mmol), oxazolidin—Z—one (0.037 g, 0.4 mmol) and anhydrous 1,4-dioxane (10 mL) was added potassium carbonate (0.06 g, 0.4 mmol), Cul (0.008 g, 0.04 mmol) and trans-1,2-diaminocyclohexane (0.07 g, 0.06 mmol) sequentially. The reaction mixture was degassed for about 10 min with argon and heated at 100°C with stirring for about 70 h.

The reaction mixture was cooled to a temperature of about 20-35°C, filtered off through celite. The filtrate was trated under reduced re to get the crude product which was purified by column chromatography using silica gel (100-200 mesh) and about 10% ethyl acetate in petroleum ether as eluent to yield the desired t as a white solid (0.02 g, 13%). 1H NMR (400 MHz, CDCl3)25 8.61 (s, 2H), 7.71 (s, 3H), 7.20 (s, 1H), 5.02 (s, 2H), 4.82 (s, 2H), 3.82 (t, J = 6.8 Hz, 2H), 2.96 (d, J = 6.8 Hz, 4H), 2.69 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.26-2.18 (m, 2H), 1.91 (t, J = 7.2 Hz, 2H), 1.21 (s, 6H), 0.88-0.70 (m, 2H), 0.29— 0.27 (m, 4H). MS (E81): 681 (M+1)+ Example 3 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(5—morpholinopyrimidin-Z-yl)amino)methyl)- N,N-bis(cyclopropylmethyl)—7,7-dimethyl—6,7-dihydro-5H-cyclopenta [b]pyridinamine N NAG N N/Q A mixture of 3-(((3,5-bis(trifluoromethyl)benzyl)(4-bromophenyl)amino)methyl)~N,N— bis(cyclopropylmethyl)—7,7-dimethy1—6,7-dihydro-5H—cyclopenta[b]pyridinamine, obtained in step-6 of example-1, (0.500 g, 0.7 mmol), morpholine (0.013 g, 2 mmol) and Pd2(dba)3 (0.114 g, 0.2 mmol), biphenyl di-t—butylphosphine (0.025 g, 0.08 mmol) and sodium l-butoxide (0.105 g, 1.05 mmol) in toluene (10 mL) was heated with stirring at 100°C for about 2 h under argon atmosphere.

The reaction mixture was cooled to a temperature of 20-35°C, water (10 mL) was added to it and the aqueous mass thus obtained was then extracted with ethyl acetate (3x15 mL). The combined c layer was dried over sodium sulfate and concentrated under reduced re to get the crude product. The crude product was purified by column tography using silica gel (100—200 mesh) and about 10% ethyl acetate in petroleum ether as eluent to yield the desired product as a white solid (0.120 g). 1H NMR (400 MHz, DMSO~d5):8 8.14 (s, 2H), 7.70 (s, 3H), 7.19 (s, 1H), 4.98 (s, 2H), 4.79 (s, 2H), 3.87 (d, J = 9.6 Hz, 4H), 3.06-3.04 (m, 4H), 2.96-2.94 (m, 4H), 2.68 (t, J = 6.8 Hz, 2H), 1.90 (t, J = 6.8 Hz, 2H), 1.21 (s, 6H), 0.80-0.78 (m, 2H), 0.30-0.28 (m, 4H), ~0.013 (m, 4H). MS (ESI): 689 (M+1)+ Example 4 Synthesis of 1-(2-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl—6,7-dihydro-5H-cyclopenta [b]pyridin—3-yl)methyl)(3,5-bis(trifluor0methy1)benzyl)amino)pyrimidinyl)ethanone *chy $06wN N To 3-((3,5—bis(trifluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-7,7— dimethy1-6,7-dihydro—SH-cyclopenta[b]pyridin~2~amine, ed in step-5 of example 1, (0.5 g, 0.9 mmol) in DMF (10 mL) were added 1~(2-chloropyrimidinyl)ethanone (0.14 g, 0.0009 mmol), potassium carbonate (0.39 g, 2.7 mmol). The reaction mixture was heated with stirring at about 70°C for about 2 h. The reaction mixture was cooled to a temperature of about 20- °C, diluted with water (20 mL) and the aqueous mass was then extracted with ethyl acetate (3x40 mL). The combined organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The title compound was then isolated by preparative TLC using romethane (0.36 g) as an eluent. 1H NMR (400 MHZ, DMSO‘dfi):8 8.93-8.91 (m, 3H), 7.75 (s, 3H), 5.10 (s, 2H), 4.9 (s, 2H), 2.97 (d, J = 6.6 Hz, 4H), 2.71-2.67 (m, 2H), 2.52 (s, 3H), 1.96-1.94 (m, 2H), .81 (m, 2H), 0.32-0.28 (m, 4H), 0.07 (s, 6H), 0.04-0.01 (m, 4H). MS (E81): 646 (M+1)+.

Example 5 Synthesis (E)(2~(((2~(bis(cyclopropylmethy1)amino)-7,7~dimethy1-6,7-dihydro-5H— cyclopenta [b]pyridinyl)methy1)(3,5~bis(trifluoromethyl)benzy1)amino)pyrimidin-S-yl) hyl amino)propenone 2012/002056 1-(2—(((2—(bis(cyclopropylmethyl)amino)-7,7-dimethyl—6,7—dihydro-SH-cyclopenta[b] pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin—5-yl)ethanone (0.40 g, 0.6 mmol), obtained in Example 4, and MN—dimethylformamide dimethyl acetal (0.073 g, 0.6 mmol) were taken in toluene (20 mL) and this mixture was refluxed with stirring for 12 h. The reaction was cooled to a temperature of about 20-35°C, concentrated under reduced pressure and diluted with water (15 mL). The aqueous mass thus obtained was then extracted with ethyl acetate (3x25 mL). The combined organic layer was washed with brine, dried over sodium sulfate and was concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-120 mesh silica gel and about 30% ethyl acetate in petroleum ether as eluent to obtain the pure product as a yellow gum (0.2 g).

MS (E81): 701 (M+1)+ Example 6 Synthesis of 3-(((5~( l H-pyrazol-3—yl)pyrimidinyl)(3 ,5 —bis(trifluoromethyl)benzyl) amino)methyl)-N,N-bis(cyclopropylmethyl)-7,7-dimethy1-6,7—dihydro-5H- cyclopenta[b]pyridinamine HN~N // N CF3 WflI\ I CFa N N/\V A mixture of (2-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyI-6,7~dihydro- 5H-cyclopenta[b]pyridinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5~yl)— 3-(dimethylamino)propen—l-one (0.1 g, 0.1 mmol), obtained in Example 5, and hydrazine hydrate (0.03 g, 0.6 mmol) in ethanol (15 mL) was heated at about 70—75°C with stirring for about 2 h. The mixture was concentrated under d pressure, diluted with water (10 mL) and the aqueous mass thus obtained was extracted with ethyl e (3x15 mL). The ed organic layer was washed with brine, dried over sodium e and concentrated under d pressure to obtain the crude product. The crude product was purified by column WO 24358 PCT/IBZOIZ/OOZOSG chromatography using 60-120 mesh silica gel and 30% ethyl acetate in petroleum ether as eluent to obtain the pure product as a light yellow paste (0.04 g). 1H NMR (400 MHz, CDClg):8 8.79 (d, J= 4.7 Hz, 3H), 7.75—7.73 (dd, J= 8.8 Hz, 4H), 7.64 (d, J= 2.2 Hz, 1H), 6.57 (d, J= 2.2 Hz, 1H), 5.34 (s, 2H), 4.97 (s, 2H), 2.9 (d, J: 6.6 Hz, 4H), 2.70-2.67 (m, 2H), 0.89—0.82 (m, 2H), 0.32-0.27 (m, 4H),0.07-0.01 (m, 4H). MS (E81): 670 (M+l)+.

Example 7 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(5—(isoxazol—3—yl)pyrimidin-2~yl)amino) methyl)-N,N—bis(cyclopropylrnethyl)—7,7-dimethyl-6,7—dihydro-5H—cyclopenta[b]pyridin—2- amine 04p} / N CF3 “3N9 A e of (E)-l—(2-(((2-(bis(cyclopropylmethyl)amino)—7,7-dimethyl-6,7-dihydro- 5H—cyclopenta[b]pyridin—3—yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidinyl)— 3-(dimethylamino)propen-l-one (0.1 g, 0.1 mmol), obtained in Example 5 and ylamine hydrochloride (0.03 g, 0.6 mmol) in methanol (15 mL) was heated at about 70— 75°C with stirring for about 2 h. The reaction was cooled to a temperature of about 20-35°C, diluted with water (10 mL) and the aqueous mass thus obtained was extracted with ethyl acetate (3x15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography using 60-120 mesh silica gel and about 10% ethyl e in petroleum ether as eluent to obtain the pure product as a light yellow paste (0.03 g). 1H NMR (400 MHz, CDClg):8 8.66 (s, 2H), 8.03 (s, 1H), 7.73 (s, 1H), 7.26 (s, 1H), 6.65 (s, 1H), 5.36-5.34 (m, 2H), 5.08 (s, 2H), 4.86 (s, 2H), 2.97-2.96 (m, 4H), 2.69-2.67 (m, 2H), W0 2013I024358 1.93-1.89 (m, 2H), 1.29-1.22 (m, 6H), 0.94-0.80 (m, 2H), 0.31-0.27 (m, 4H), 0.01—0.04 (m, 4H).

MS (ESI): 671 (M+1)+.

Example 8 Synthesis of 2—(((2-(bis(cyclopropylmethyl)amino)—7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b] pyridin—3-yl)methyl)(3,5—bis(trifluoromethyl)benzyl)amino)pyrimidine-5—carbonitrile \\Ck / N CF3 N N | CF3 N NW Toluene (5 mL) was added to a e of 3-(((3,5—bis(trifluoromethyl)benzyl)(5- bromopyrimidinyl)amino)methyl)-N,N-bis(cyclopropy1methyl)-7,7-dimethyl-6,7-dihydro- 5H-cyclopenta[b]pyridinamine (0.02 g, 0.03 mmol), obtained in step 6 of Example 1, Zn(CN)2 (0.003 g, 0.03 mmol), Pd(PPh3)4 (0.01 g, 0.008 mmol) and K2C03 (0.008 g, 0.06 mmol) in a sealed tube. The above mixture was degassed with argon and heated to about 150°C. The mixture was stirred at the same temperature for about 2 days. The reaction mass was cooled to a temperature of about 20-35°C, water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced re to get the desired product. MS (ESI): 629 (M+1)Jr Example 9 Synthesis of —(bis(cyclopropylmethyl)amino)~7,7-dimethyl—6,7-dihydro-5H-cyclopenta [b]pyridin-3—yl)methy1)(3,5~bis(trifluoromethyl)benzyl)amino) pyrimidine carboxamide W0 20131024358 HZN / N CF3 A solution of potassium hydroxide (0.018 g, 0. 3 mmol) in water (1.0 mL) was added to 2-(((2-(bis(cyclopropylmethyl)amino)—7,7-dimethy1—6,7~dihydro-5H-cyclopenta[b]pyridin-3~yl) methyl)(3,5—bis(trifluoromethyl)benzyl)amino)pyrimidine-5—carbonitrile (0.02 g, 0.32 mmol, obtained in Example 8, in l (5 mL) followed by addition of hydrogen peroxide (0.02 mL) at about 20-35°C. The reaction mixture was heated to about 40°C and was d at the same temperature for about 2 h.

The reaction mixture was cooled to about 20-35°C, water was added to it and the aqueous mass was extracted with ethyl e (3 x 15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered off. The filtrated was trated under reduced pressure to obtain the crude product which was purified by column chromatography and eluted with 50% ethyl acetate in petroleum ether. 1H NMR (400 MHz, CDC13)25 8.80 (s, 2H), 7.74 (s, 3H), 7.18 (s, 1H), 5.09 (s, 2H), 4.88 (s, 2H), 2.97 (d, J = 6.6 Hz, 4H), 2.69 (t, J = 7.3 Hz, 2H), 1.92 (t, J = 6.4 Hz, 2H), 1.22 (s, 6H), 0.85-0.82 (m, 2H), 0.30-0.28 (in, 4H), 0.01-0.008 (m, 4H). MS (ESI): 647 (M+1)+.

Example 10 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(5~morpholinopyrimidin-Z—yl) amino)methyl)- N,N—bis(cyclopropy1methy1)-7~rnethyl-6,7-dihydro-5H—cyclopenta[b]pyridinamine at?1/:in W0 2013I024358 PCT/[82012/002056 3-(((3,5-bis(trifluoromethy1)benzyl)(5-morpholinopyrimidiny1)amino)methy1)-N,N- bis (cyclopropylmethy1)methy1-6,7-dihydro-5H—cyclopenta[b]pyridinamine was prepared from 2-methylcyclopentanone by following substantially r procedure as described in Example 3 and ing appropriate materials and reagents. 1H NMR (400 MHz, CDClg):6 8.15 (s, 2H), 7.70 (s, 2H), 7.69 (s, 2H), 7.21 (s, 1H), .08-4.72 (m, 4H), 3.88-3.86 (m, 4H), 3.13-3.04 (m, 4H), .67 (m, 2H), 2.36-2.28 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H), 0.86-0.81 (m, 2H), 0.33-0.27 (m, 4H), 0.01-0.005 (m, 4H). MS (ESI): 675 (M+1)+.

Example 11 Synthesis of 3—(((3,5—bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin-2—yl) amino)methyl)~ N,N—bis(cyclopropylmethyl)-8—methyl—5,6,7,8~tetrahydroquinolin-2—amine I}! /N CFs \ N N N CF3 3-(((3,5—bis(trifluoromethyl)benzyl)(5-morpholinopyrimidin-2—yl)amino)methy1)-N,N~ bis (cyclopropylmethyl)methy1—5,6,7,8-tetrahydroquinolin-Z-amine was prepared from 2- methylcyclohexanone by following ntially similar procedure as described in Example 3 and employing riate materials and reagents. 1H NMR (400 MHz, CDCI3)25 7.73 (s, 1H), 7.70 (s, 2H), 7.27 (s, 1H), 4.83 (s, 2H), 4.65 (s, 2H), 4.18 (s, 3H), 2.94 (d, J = 5.1 Hz, 4H), 2.70 (t, J = 6.4 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.56 (s, 6H), 0.79~0.75 (m, 2H), 0.29-0.25 (m, 4H), 002-0006 (m, 4H). MS (E81): 608 (M+1)+ Example 12 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(2H—tetrazol—5-yl)amino)methy1)~N,N- bis(cyclopropylmethy1)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridinamine HIN~{\1 CF3 N\\Rikki/Q l 01:3 \N N/\7 Step 1: Synthesis of N—((2—(bis(cyclopropylmethyl)amino)-7,7—dimethy1~6,7-dihydro-5H— cyclopenta[b]pyridin—3-yl)methyl)—N~(3,5-bis(trifluoromethyl)benzy1)cyanamide \ N [N/N/\V To 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N-bis(cyclopropylmethyl)-7,7- dimethyl-6,7—dihydro-5H-cyclopenta[b]pyn'din-2—amine (0.3 g, 0.57 mmol), obtained in step-5 of Example—1, in ol (8 ml) were added CNBr (0.074 g, 0.6 mmol) followed by addition of sodium hydrogen carbonate (0.1 g, 1.2 mmol). The reaction mixture was stirred at about 20—3 5°C for about 2 h. The reaction mixture was concentrated under d pressure and diluted the e with water (15 ml). The aqueous mass thus obtained was then ted with ethyl acetate (3X25 ml). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (0.3 g). MS (1381): 551 (M+1)+ Step 2: Synthesis of 3—(((3,5-bis(trifluoromethyl)benzyl)(2H—tetrazol—5—y1)amino)methyl)-N,N— bis(cyclopropylmethyl)—7,7—dimethyl-6,7—dihydro-5H—cyclopenta[b]pyridinamine HN“N W0 2013I024358 PCT/IBZOlZ/002056 To a on of N-((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro-5H— cyclopenta[b]pyridinyl)methyl)-N-(3,5-bis(trifluoromethyl)benzyl)cyanamide (0.3 g, 0.00054 mmol) obtained in step-l, in DMF (5 ml) were added NaN3 (0.18 g, 2.7 mmol) and ammonium chloride (0.15 g, 2.7 mmol) was heated at 100 °C with stirring for about 2 h.

The reaction mixture was cooled to about 20-35°C, water was added to it and the aqueous mass was extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered off. The filtrate was dried under vacuum to obtain the crude which was purified by column chromatography using 60—120 mesh silica gel and 40% ethyl acetate in petroleum ether as eluent to obtain the pure t (0.3 g). 1H NMR (400 MHz, CDClg):6 7.82 (s,1H),7.75(s,2H), 6.99 (s,1H), 5.04 (s,2H), 4.43 , 3.21 (d, J = 6.9 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.22 (s, 6H), 0.95-0.88 (m, 4H), 0.19-0.06 (m,4H). MS (E81): 594 (M+1)+ Example 13 Synthesis of 3-(((3,5-bis(trifluoromethy1)benzyl)(2—methyl-2H-tetrazolyl)amino)methy1)- N,N-bis(cyclopropy1methyl)-7,7-dimethy1-6,7-dihydro-5H-cyclopenta[b]pyridinamine N—N\\ N\ N 01:3 W683I To a suspension of 3-(((3,5—bis(trifluoromethyl)benzy1)(2H—tetrazolyl)amino) methyl)-N,N—bis(cyclopropylmethy)-7,7-dimethyl-6,7-dihydro-5H—cyclopenta[b]pyridinami ne (0.3 g, 0.44 mmol), obtained in Example 12, in DCMzHZO (5 ml; 4:1 ratio) were added NaOH (0.035 g, 8.7 mmol), TBAB (0.01 g, 2 mmol) and dimethyl sufate (0.06 ml, 5.3 mmol).

The reaction mixture was stirred at about 20—35°C for about 30 min.

Water was added to it and the aqueous mass was extracted with ethyl acetate (3 x 15 mL). The ed c layer was washed with brine, dried over sodium e and filtered off. The filtrate was dried under reduced pressure to obtain the crude product which was W0 20132‘024358 PCT/IBZOIZ/002056 purified by column chromatography using 60-120 mesh silica gel and 5% ethyl acetate in petroleum ether as eluent to afford the pure product as a yellow gum (0.1 gram, 45%). 1H NMR (400 MHz, CDC13):8 7.73 (s, 1H), 7.70 (s, 2H), 7.27 (s, 1H), 4.83 (s, 2H), 4.65 (s, 2H), 4.18 (s, 3H), 2.94 (d, J = 5.1 Hz, 4H), 2.70 (t, J = 6.4 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.56 (s, 6H), .75 (m, 2H), 0.29-0.25 (m, 4H), 0.02-0.006 (m, 4H). MS (E81): 608 (M+1)+.

Example 14 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(2-isopropyl-ZH-tetrazol-5—yl)amino)methyl)- N,N—bis(cyclopropylmethyl)-7,7—dimethyl—6,7—dihydro-5H—cyclopenta [b]pyridin-2—amine N\ N gr“?N/ CF3 QCF3 To a stirred on ofNaH (0.002 g, 0.03 mmol) in DMF (5 mL) were added 3—(((3,5— bis(trifluoromethyl)benzy1)(2H—tetrazolyl)amino)methyl)-N,Nbis(cyclopropylmethyl)-7,7- dimethyl-6,7-dihydro—5H—cyclopenta[b]pyridin-2—amine (0.002 g, 0.03 mmol), obtained in Example 12, followed by the addition of 2-bromo propane (0.005 mg, 0.3 mol) at 0°C and continued ng at about 20-350C for about 12—16 h.

Ice cold water was added to it and the aqueous mass was extracted with ethyl acetate (3 x 15 mL). The combined c layer was washed with brine, dried over sodium sulfate and filtered off. The filtrate was dried under vacuum to obtain the crude product which was d by column chromatography using 100-200 mesh silica gel and about 10% acetone in petroleum ether as eluent to afford the pure product as a yellow gum (0.01 g). 1H NMR (400 MHZ, CDC13)I 8 7.74—7.73 (m, 3H), 7.32 (s, 1H), 4.84 (s, 2H), 4.63 (s, 2H), 2.96 (d, J = 6.6 Hz, 4H), 2.71 (t, J = 7.1 Hz, 2H), 2.30- 2.24 (m, 1H), 1.93 (t, 7.1 Hz, 2H), 1.60 (d, J = 7.0 Hz, 6H), 1.22 (s, 6H), 0.83-0.80 (m, 2H), 0.31-0.26 (m, 4H), 0.01-0.006 (m, 4H).

W0 2013/‘024358 MS (ESI): 636 (M+1)+.

Example 15 3—(((3,5—bis(trifluoromethyl)benzy1)(2-isobutyl—2H—tetrazolyl)amino)methyl)-N,N-bis (cyclo propylmethyl)~7,7—dimethyl-6,7—dihydro-SH-cyclopenta[b]pyridinamine To a d solution ofNaH (0.036 g, 0.15 mmol) in DMF (5 ml) were added 3-(((3,5- bis(trifluoromethyl)benzyl)(2H—tetrazolyl)amino)methyl)—N,Nbis(cyclopropylmethyl)-7,7— dimethyl—6,7-dihydro-5H-cyclopenta[b]pyridin—2-amine (0.09 g, 0.15 mmol), obtained in Example 12, ed by the addition of 1-bromomethylpropane (0.041 mg, 0.3 mol) at 0°C and continued stirring at about 20-35°C for about 12-16 h.

Ice cold water was added to it and the aqueous mass was extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered off. The filtrate was dried under vacuum to obtain the crude product which was purified by column chromatography using 100—200 mesh silica gel and 4% ethyl acetate in petroleum ether as eluent to obtain the pure product as a yellow gum (0.03 g). 1H NMR (400 MHz, I 8 7.72~7.7l (m, 3H), 7.30 (s, 1H), 4.84 (s, 2H), 4.65 (s, 2H), 4.94 (d, 6.3 HZ, 2H), 2.95 (d, J = 6.6 Hz, 4H), 2.70 (t, J = 7.1 Hz, 2H), 2.30—2.29 (m, 1H), 1.92 (t, J = 7.1 Hz, 2H), 1.22 (s, 6H), 0.94 (d, J = 6.6 Hz, 6H), 0.82—0.78 (m, 2H), 0.30-0.26 (m, 4H), 0.01-0.03 (m, 4H). MS (E81): 650 (M+1)+.

Example 16 Synthesis of ,5-bis(trifluoromethyl)benzyl)(2-methyl—2H—tetrazolyl)amino)methyl)- N,N-bis(cyclopropylmethyl)-8,8-dimethyl-5,6,7,8-tetrahydroquinolin-2—amine PCT/182012/002056 N—N.

“\(N CFa \ N N N CF3 3—(((3,5-bis(trifluoromethyl)benzy1)(2»methyl—2H~tetrazol—5-y1)amino)methyl)~N,N-bis (cyclopropylmethyl)-8,8-dimethy1—5,6,7,8-tetrahydroquinolin~2—amine was prepared from 2,2— dimethyleyclohexanone by substantially ing the ure as described in Example 13 and employing appropriate materials and reagents. 1H NMR (400 MHZ, CDC13)I 5 7.73(s, 1H), 7.70 (s, 2H), 7.09 (s, 1H), 4.77 (s, 2H), 4.66 (s, 2H), 4.18 (s, 3H), 2.93 (d, J = 6.6 Hz, 4H), 2.57 (t, J = 6.1 Hz, 2H ), 1.69-1.57 (m, 4H), 1.25 (s, 6H), 0.89-0.77 (m, 2H), 0.89-0.77 (m, 2H), 0.31-0.26 (m, 4H), 0.02-0.15 (m, 4H).

MS (E81): 622 (M+1)+.

Example 17 6-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethy1-6,7-dihydro—5H—cyclopenta[b] pyridin—3- yl)methyl)(3,5-bis(trifluoromethy1)benzyl)amino)benzo[d]oxazol-2(3H)-one Step 1 : 6—(((2-(bis(cyclopropylmethy1)amino)-7,7-dimethyl-6,7-dihydro—5H—cyclopenta[b] pyridine-3~y1)methyl)amino)benzo[d]oxazol-2(3H)—one Q55iO < Pg Nflffi To a solution of 2-(bis(cyclopropylmethyl)amino)—7,7—dimethyl—6,7—dihydro-5H— cyclopenta[b]pyridinecarbaldehyde (0.2 g, 0.671 mmol, obtained in step 4 of Example—1, and 6—aminobenzo[d]0xazol~2(3H)—one (0.1 g, 0. 671 mmol) in methanol (10 mL), was added glacial acetic acid (0.3 mL) and the resulting mixture was stirred for 15 min at a temperature of about —35°C. Sodium cyanoborohydride (0.042 g, 0.671 mmol) was added portion wise to this on e and the reaction mixture was stirred for about 3 h.

After evaporating solvent from the mixture under reduced pressure, it was ted with water (30 mL) and dichloromethane (2x30 mL). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using silica gel (60-120 mesh) and eluted with about 50% eum ether in ethyl e to obtain the pure product as a pale yellow liquid (0.15 g). MS (E81): 433 (M+1)+ Step—2: 6-(((2-(bis(cyclopropylmethyl)amino)—7,7-dilnethyl—6,7-dihydro—5H—cyclopenta[b] pyridine —3—yl)methyl)(3 ,5—bis(trifluoromethyl)benzyl)amino)benzo[d]oxazo1—2(3H)-one HNJ( To a solution of 6-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethyl-6,7-dihydro—5H- cyclopenta[b]pyridinyl)methyl)amino)benzo[d]oxazol-2(3H)-one (0.15 g, 0.346 mmol) obtained in the above step-1, in THF (10ml) were added 1-(bromomethyl)-3,5- W0 2013I024358 PCT/IBZOIZ/002056 bis(trifluoromethyl)benzene (0.106 g, 0.346 mmol), sodium hydrogen carbonate (0.043 g, 0.519 mmol) was stirred at about 20-35°C for about 14 h.

Water was added to it and the aqueous mass was extracted with ethyl e (3 x 15 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered off. The e was dried under vacuum to obtain the crude t which was purified by column chromatography using 60-120 mesh silica gel and 30% ethyl acetate in petroleum ether as eluent to achieve the pure product (0.06 g).

IHNMR (400 MHz, CDClg): 87.78 (s, 2H), 7.69 (s, 2H), 7.26 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J: 2.4 Hz, 1H), 4.72 (s, 2H), 4.68 (s, 2H), 2.96 (d, J= 6.8 Hz, 3H), 2.71 (t, J = 6.8 Hz, 2H), l.92 (t, J= 7.2 Hz, 2H), 1.22 (s, 9H), 0.88-0.83 (m, 2H), 0.34— 0.29 (m, 4H), 00034-00001 (m, 4H). MS (ESI): 659 (M+1)+.

Example 18 Synthesis of 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol~5~yl)amino)methy1)— N,N—bis(cyclopropylmethy1)methyl-6,7-dihydro-5H-cyclopenta[b]pyridinamine I \\ N\ N mé§0% 3-(((3,5—bis(trifluoromethyl)benzyl)(2-methyl-2H~tetrazo1—5~y1)amino)methyl)-N,N—bis (cyclopropylmethyl)—7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2~amine was prepared from 2~methylcyclopentanone by following substantially similar procedure as described in Example 13 and employing appropriate materials and reagents. 1H NMR (400 MHz, CDCl3): 8 7.72 (s, 1H), 7.68 (s, 2H), 7.28 (s, 1H), 4.84 (s, 2H), 4.66 (s, 2H), 3.96 (s, 3H), .00 (m, 4H), 3.09-2.88 (m, 4H), 2.75-2.68 (m, 2H), 2.33-2.32 (m, 2H), 1.26 (d, J= 6.9 Hz, 3H), 0.89-0.79 (m, 4H), 03-028 (m, 4H). MS (ESl): 594 (M+l)+.

Example 19 Determination of in vitro activity using fluorometric technique WO 24358 An in vitro cholesteryl ester transfer protein inhibition (CETP) assay using a commercially available fiuorometric assay kit from ROAR Biomedicals, USA was used to measure the CETP inhibition activity of the nds 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 CETP enzyme. The CETP-mediated er of the fluorescent neutral lipid to the acceptor le results in an increase in fluorescence (Excitation: 492 nm; Emission: 516 nm).

A 20 mM stock on of compounds were prepared in 100% DMSO and further dilutions were made such that the final concentration of DMSO in the on mix was 1%.

The reactions were performed as suggested by the kit manufacturer as follows. The assay was performed in 96 well microplates and in each well, the reaction mixture contained 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 or particle, rCETP (50 ng) and 2 pl of test compound at varying final concentration of 0.1, l, 10, 100, 1000 & 10000 nM. Two control reactions were performed, one without test compound (positive control) and the other without the rCETP (negative 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; on: 516 nm).

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

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

Using this protocol, s compounds as described herein were found to exhibit inhibitory effect on CETP as follows: Example No. leo (nM) WO 2013024358 PCT/[32012/002056 Although the invention as disclosed in the t application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made t departing from the spirit and scope thereof.

Claims (17)

1. What is d is l. A compound having the formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: /(Rb)n (Rafi p\NCmNR2 R1 (I) wherein, /\‘\ N R represents EMA; R1 and R2 are -(CHRe)qR3; R3 is cycloalkyl; R“, in each occurrence, is independently ed from alkyl; Rb, in each occurrence, is independently selected from halogen, alkyl, haloalkyl, and hydroxy; Rc is independently selected from hydrogen, cyano, halogen, -C(=O)- Rf, —CONRth, —C(=O)-CH=CH—NRiRj and an , optionally substituted group selected from heteroaryl and heterocyclyl ring, wherein the optional substituent, in each occurrence, is selected independently from en, halogen, and hydroxyl; Re, in each occurrence, is independently ed from hydrogen and alkyl; Rf is hydrogen or alkyl; Rg, Rh, Ri and Rj each independently represent hydrogen or alkyl; m is 1 or 2; n is l, 2 or 3; p is 1 or 2; and qisO, 1,2, 3,4or5.
2. 2. The compound according to claim 1 having the formula (Ib): mXN/»\\‘:::;::;CF3 (1b) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are —(CHRe)qR3 R3 represents cycloalkyl; Rc represents optionally substituted ring selected from: 2&0 rec w”? n o KN), (MkO,K/N ’DIQF,Q\X£1aN o/ EQN O N O \ pug/NNH ,/‘.
3. W x, 33/ — . (page? N"‘5 N C) “Isa/forI N Egg/N , n the optional substituent is selected from n, cyano, hydroxyl, and alkyl; Ra, in each occurrence, is independently ed from alkyl; m is 1 or 2; q ents 1, 2 or 3; and p represents 1 or 2.
4. The compound according to claim 2, having the formula (10) \NANAQ/ I CF3 / CFS (10) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0 represents A nd which is selected from the group consisting of: 3—(((3,5—bis(trifluoromethy1)benzyl)(5-bromopyrimidin~2~yl)amino)methyl)—N,N—bis (cyclopropylmethy1)-7,7-dimethy1—6,7-dihydro—5H—cyciopenta[b]pyridin—2—amine; 1-(2-(((2-(bis(cyclopropylmethyl)amino)-7,7—dimethy1—6,7—dihydro—5H—cyclopenta [b]pyridin—3-y1)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin yl)pyrrolidin-2~one; 3—(((3,5—bis(trifluoromethyl)benzyl)(5—morpholinopyrimidin—2-yl)amino)methyl)~N,N—bis (cyclopropylmethyl)-7,7—dimethyl—6,7—dihydro-5H—cyclopenta[b]py1idin—2—amine; 1—(2-(((2-(bis(cyclopropylmethy1)amino)-7,7—dimethy1—6,7—dihydro—5H—cyclopenta [b]pyridin-3—yl)methyl)(3 ,5~bis(trifluoromethy1)benzyl)amino)pyrimidin-5—y1) ethanone; (E)(2-(((2-(bis(cyclopropylmethyl)amino)-7,7-dimethy1-6,7-dihydro-5H-cyclopenta[b] pyridine—3 —yl)methyl)(3 ,5—bis(trifluoromethyl)benzyl)amino)pyrimidinyl)-3 - hyl amino)propenone; 3-(((5—(1H—pyrazol-3—y1)pyrimidinyl)(3 ,5-bis(trifluoromethy1)benzyl) amino)methy1)- N,N—bis(cyclop1‘opy1methy1)-7,7—dimethy1-6,7—dihydro—5H-cyclopenta[b]pyridin— 2-amine; 3-(((3,5-bis(trifluoromethyl)benzyl)(5—(isoxazol-3—y1)pyrimidin—2-y1)amino)methyl)—N,N- bis(cyclopropyhnethyl)~7,7—dimethyl—6,7—dihydro-5H—cyc10penta[b]py1idin—2- amine; 2-(((2-(bis(cyclopropy1methyl)amino)-7,7-dimethyl—6,7—dihydro—5H—cyclopenta [b]pyridin—3-yl)methy1)(3,5—bis(trifluoromethyl)benzyl)amino)pyrimidine itrile; 2-(((2-(bis(cyclopropylmethy1)amino)-7,7—dimethyl—6,7—dihydro—5H—cyclopenta [b]pyridineyl)methy1)(3 ,5—bis(trifluoromethy1)benzyl)amino)pyfimidine carboxamide; 3-(((3,5—bis(trifluoromethyl)benzyl)(5-morpholinopyrimidinyl)amino)methyl)-N,N- bis(cyclopropy1methyl)-7—methy1—6,7-dihydro-5H-cyclopenta[b]pyridinamine; ,5-bis(trifluoromethyl)benzyl)(5-morpholinopyrimidiny1)amino)methyl)-N,N- bis(cyclopropylmethyl)-8—methy1-5,6,7,8-tetrahydroquinolin-Z-amine; 3—(((3,5-bis(trifluoromethyl)benzyl)(2H—tetrazol—5~y1)amino)methyl)—N,N-bis (cyclopropylmethy1)-7,7-dimethyl—6,7-dihydro—5H-cyclopenta[b]pyridin—2-amine; 3-(((3,5-bis(tn'fluoromethyl)benzyl)(2-methyl—2H—tetrazol-5—yl)amino)methyl)—N,N—bis (cyclopropylmethyl)-7,7-dimethyl—6,7-dihydro—5H—cyclopenta[b]pyridin—2-amine; 3—(((3,5—bis(trifluoromethyl)benzyl)(2~isopropyl—2H—tetrazolyl)amino)methyl)-N,N—bis (cyclopropylmethyl)-7,7~dimethyl~6,7—dihydro-5H—cyclopenta[b]pyridinamine; 3—(((3,5~bis(trifluoromethyl)benzyl)(2~isobuty1-2H—tetrazol—5-yl)amin0)methyl)-N,N—bis (cyclopropylmethyl)—7,7—dimethyl-6,7-dihydro~5H-cyclopenta[b]pyridin—2—amine; 3—(((3,5—bis(trifluoromethyl)benzyl)(2—methy1-2H—tetrazolyl)amino)methy1)—N,N—bis (cyclopropylmethyl)-8,8-dimethyl-5,6,7,8-tetrahydroquinolinamine; 6—(((2—(bis(cyclopropylmethyl)amino)-7,7—dimethyl-6,7-dihydro—5H—cyclopenta idinyl)methyl)(3,5-bis(trifluoromethyl)benzyl)a1nino)benzo[d]oxazol- 2(3H)-one; and 3—(((3,5-bis(trifluoromethyl)benzyl)(2—methyl—2H-tetrazol—5—yl)amino)methyl)—N,N- bis(cyclopropylmethyl)-7—methyl~6,7-dihydro—5H—cyclopenta[b]pyridin—2-amine; or a isomer thereof, or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition compn'sing at least one compound according to any one of claims 1 to 4 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
6. Use of a compound ing to any one of claims 1 to 4 in the manufacture of a medicament for ng, ting or inhibiting a disease which is mediated by cholesteryl ester—transfer protein (CETP).
7. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for increasing high density lipoprotein (HDL) cholesterol.
8. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for lowering low density lipoprotein (LDL) cholesterol.
9. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for g cholesteryl ester—transfer protein.
10. 10. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease which is mediated by cholesteryl ester-transfer protein (CETP).
11. 11. Use of a nd according to any one of claims 1 to 4 in the manufacture of a medicament for the treating and/or preventing a condition or disease associated with lipoprotein metabolism in a patient, whereby there is a decrease in levels of high density otein (HDL) cholesterol in the patient.
12. 12. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for treating and/or preventing a condition or e associated with lipoprotein metabolism in a patient, whereby there is an increase in levels of low density lipoprotein (LDL) terol in the patient.
13. 13. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of atherosclerosis.
14. 14. A pharmaceutical composition comprising at least one compound ing to any one of claims 1 to 4 and at least one pharmaceutically acceptable excipient, wherein the composition is in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, nts, aqueous suspensions, inj ectable solutions, elixirs or syrups.
15. 15. The compound according to any one of claims 1 to 4, substantially as herein described with nce to any one of the examples and/or figures.
16. 16. Use according to any one of claims 6 to 13, substantially as herein described with reference to any one of the examples and/or .
17. 17. The composition according to claim 5 or claim 14, substantially as herein described with reference to any one of the es and/or figures.