OA16316A - Oxadiazole inhibitors of leukotriene production - Google Patents

Abstract

The present invention relates to compound of formula (I) :

Description

OXADIAZOLE INHIBITORS OF LEUKOTRIENE PRODUCTION

FIELD OF THE INVENTION

This invention relates to oxadiazoles that are useful as inhibitors of five lipoxygenase activating protein (FLAP) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of leukotrienes including asthma, allergy, rheumatoid arthritis, multiple sclerosis, inflammatory pain, acute chest syndrome and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

BACKGROUND OF THE INVENTION

Leukotrienes (LTs) and the bîosynthetic pathway from arachidonic acid leading to their production hâve been the targets of drug discovery efforts for over twenty years. LTs are produced by several cell types including neutrophils, mast cells, eosinophils, basophîls monocytes and macrophages. The first committed step in the întracellular synthesis of LTs involves oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to LTA4, a process requiring the presence of the 18 kD intégral membrane protein 5-lipoxygenase-activating protein (FLAP) (D.K. Miller et al., Nature, 1990, 343, 278-281; R.A.F. Dixon et al., Nature, 1990, 343, 282-284). Subséquent metabolism of LTA₄ leads to LTB₄, and the cysteînyl LTs- LTC₄, LTD₄ and LTE₄ (B. Samuelsson, Science, 1983, 220, 568-575). The cysteînyl LTs hâve potent smooth muscle constrictîng and bronchoconstricting effects and they stimulate mucous sécrétion and vascular leakage. LTB₄ is a potent chemotactîc agent for leukocytes, and stimulâtes adhesion, aggregation and enzyme release. A

Much of the early drug discovery effort in the LT area was directed towards the treatment of allergy, asthma and other inflammatory conditions. Research efforts hâve been directed towards numerous targets in the pathway including antagonîsts of LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, as well as inhibîtors of 5-lipoxygenase (55 LO), LTA4 hydrolase and inhibîtors of 5-lipoxygenase activating protein (FLAP) (R.W.

Friesen and D. Riendeau, Leukotriene Biosynthesis Inhibîtors, Ann. Rep. Med. Chem., 2005, 40, 199-214). Years of effort in the above areas hâve yielded a few marketed products for the treatment of asthma including a 5-LO inhibitor, zileuton, and LT antagonîsts, montelukast, pranlukast and zafirlukast.

More recent work has împlicated LTs in cardiovascular disease, including myocardial infarction, stroke and atherosclerosis (G. Riccioni et al., J. Leukoc. Biol., 2008, 13741378). FLAP and 5-LO were among the components of the 5-LO and LT cascade found in atherosclerotic lésions, suggesting their involvement in atherogenesis (R. Spanbroek et 15 al., Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 1238-1243). Pharmacological inhibition of

FLAP has been reported to decrease atherosclerotic lésion size in animal models. In one study, oral dosing of the FLAP inhibitor MK-886 to apoE/LDL-R double knockout mice fed a high-fat diet from 2 months of âge to 6 months led to a 56% decrease in plaque coverage in the aorta and a 43% decrease in the aortic root (J. Jawien et al., Eur. J. Clin.

Invest., 2006, 36, 141-146). This plaque effect was coupled with a decrease in plaquemacrophage content and a concomitant increase in collagen and smooth muscle content which suggests a conversion to a more stable plaque phenotype. In another study, it was reported that administration of MK-886 via infusion to ApoE xCD4dnT[3RII mice (apoE KO mice expressing a dominant-negative TGF-beta receptor which effectively removes ali TGF-beta from the system) resulted in about a 40% decrease in plaque area in the aortic root (M. Back et al., Cire. Res., 2007, 100, 946-949). The mice were only treated for four weeks after plaque growth was already somewhat mature (12 weeks) thus raising the possîbility of therapeutically treating atherosclerosis via this mechanism. In a study examining human atherosclerotic lésions, it was found that the expression of FLAP,

5-LO and LT A4 hydrolase was significantly increased compared to healthy controls (H.

Qiu et al., Proc. Natl. Acad. Sci. U.S.A., 103, 21, 8161-8166). Similar studies suggest that inhibition of the LT pathway, for example by inhibition of FLAP, would be useful for the treatment of atherosclerosis (for reviews, see M. Back Curr. Athero. Reports, 2008 10,244-251 and Curr. Pharm. Des., 2009, 15,3116-3132).

In addition to the work cited above, many other studies hâve been directed towards understandîng the biological actions of LTs and the rôle of LTs in disease. These studies hâve implicated LTs as having a possible rôle in numerous diseases or conditions (for a review, see M. Peters-Golden and W.R. Henderson, Jr., M.D., N. Engl. J. Med., 2007, 357,1841-1854). In addition to the spécifie diseases cited above, LTs hâve been implicated as having a possible rôle in numerous allergie, pulmonary, fibrotic, inflammatory and cardiovascular diseases, as well as cancer. Inhibition of FLAP is also reported to be useful for treating rénal diseases such as diabetes-induced proteinuria (see for example J. M. Valdivieso et al., Journal of Nephrology, 2003, 16, 85-94 and A Montera et al., Journal of Nephrology, 2003, 16, 682-690).

A number of FLAP inhîbitors hâve been reported in the scientific literature (see for example J.F. Evans et al., Trends in Pharmacological Sciences, 2008, 72-78) and in U.S. patents. Some hâve been evaluated in clinîcal trials for asthma, including MK-886, MK591, and BAY X1005, also known as DG-031. More recently, the FLAP inhibitor AM103 (J.H. Hutchînson et al., J. Med. Chem. 52, 5803-5815) has been evaluated in clinîcal trials, based on its anti-inflammatory properties (D.S. Lorrain et al., J. Pharm. Exp. Ther., 2009, DOI: 10.1124/jpet. 109.158089). Subsequently, it was replaced by the back-up compound AM-803 (GSK-2190915) for the treatment of respiratory diseases. DG-031 has also been in clinîcal trials to evaluate its effect on biomarkers for myocardial infarction risk and showed a dose-dependent suppression of several biomarkers for the disease (H. Hakonarson et al., JAMA, 2005, 293, 2245-2256). MK.-591 was shown in a clinîcal trial to reduce proteinuria in human glomerulonephritis (see for example A. Guash et al., Kidney International, 1999, 56, 291-267).

However, to date, no FLAP inhibitor has been approved as a marketed drug. S

BRIEF SUMMARY OF THE INVENTION

The présent invention provides novel compounds which inhibit 5-lipoxygenase activating protein (FLAP) and are thus useful for treating a variety of dîseases and disorders that are mediated or sustained through the activity of leukotrienes, including allergie, pulmonary, fîbrotic, inflammatory and cardiovascular dîseases and cancer. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various dîseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

DETAILED DESCRIPTION OF THE INVENTION

In its first broadest embodiment, the présent invention relates to a cornpound of formula

I:

I wherein:

R¹ and R² are each independently hydrogen, Ci.7 alkyl or Cj.io carbocycle, with the proviso that both R¹ and R² are not hydrogen;

R³isa5-ll membered heteroaryl ring containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, wherein the heteroaryl ring is optionally independently substituted with one to three groups selected from C|.s alkyl optionally substituted with one to three halogen atoms, Ci_s alkoxy, C1.3 hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C3.6 carbocycle, C|.6 alkylamino and C1-3 dialkylamino; —

R⁴ is hydrogen, Cp₃ alkyl, halogen or nitrile;

R⁵ is C].₆ alkyl, C₃ -jo carbocycle, 3-11 membered heterocycle, aryl, 5-11 membered heteroaryl, -C(O)-R⁶, hydroxy or —NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

R⁶ is C₃.g heterocycle or -NH-5-6 membered heterocycle, each optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹ ;

R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with CT ₆ alkyl, C₃_i₀ carbocycle optionally substituted with hydroxy or CT-r, alkyl;

R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) Ci-ealkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , 3-6 membered heterocycle, Ci-ôalkoxy, Ci-ealkoxy-O- Ci^alkyl, -CO2R¹², -C(O)N(R¹²)(R¹³) or -S(O)nCi^aIkyl, (g) C_!6alkoxy, (h) -N(R¹²)(R¹³), (i) -StOjnCr^alkyl, (j) -C0₂R¹², (k) -C(O)N(R^I2)(R¹³), (l) -S(O)₂N(R^,2)(Rⁱ³), (m) a 3-10 membered heterocyclic group optionally substituted with one to three Ci_6 alkyl groups, (n’) oxo, X (o)-C(O)-Ci-, alkyl;

R¹² and R¹³ are each independently selected from-H, -Cj^alkyl, C(O)C| 6^alkyh and a 36 membered heterocyclic group, each of which is optionally independently substituted with one to three C^alkyl groups, -OH, Ci^alkoxy, -C(O)N(R¹⁴)(R¹⁵), -S(O)_nC_;_/,alkyl, CN, a 3-6 membered heterocyclic group, -OCj^alkyl, CF₃, or;

R and R taken together with the nitrogen ring to which they are attached form a heterocyclyl ring optionally substituted with one to three -OH, CN, -OCi_6alkyl or oxo;

R¹⁴ and R¹⁵ are each independently selected from -H and -Ci-^alkyl;

n is 0,1 or 2;

or a pharmaceutically acceptable sait thereof.

In a second embodiment, the présent invention relates to a compound as described in the broadest embodiment above, wherein:

R^l and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cylohexyl, with the proviso that both R¹ and R² are not hydrogen;

R³ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thienyl, furanyl or thiazolyl, wherein each heteroaryl ring is optionally independently substituted with one to three groups selected from Ci_₃ alkyl optionally substituted with one to three halogen atoms, C[.₃ alkoxy, C|.< hydroxy, halogen, hydroxy, -O-benzyk oxo, cyano, amino, -NHC₃_6 carbocycle, Cj 6 alkylamino and Ci_₃ dialkylamino;

or

R³ is pyridooxazinyl, dihydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl or pyrrolopyrazinyl, wherein each heteroaryl ring is optionally independently substituted with one to three groups selected from Cj.₃ alkyl optionally substituted with one to three halogen atoms, Ci_₃ alkoxy, Ci_₃ hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amîno, -NH-C₃.₆ carbocycle, C1.3 alkylamino and Ci-₃ dialkylamino;

R⁴ is hydrogen, methyl or fluoro;

R⁵ is methyl, ethyl, propyl, isopropyl, butyl, îsobutyl, /eri-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, piperidînyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, pyrrolyl, thienyl, fiiranyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, îndolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, -C(O)-R⁶, hydroxy or NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

R⁶ is piperidînyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or -NHpîperadinyl each optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with methyl, C ^, carbocycle optionally substituted with hydroxy, or C1.5 alkyl;

R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e) -CF_3î (f) Ci^alkyl optionally substituted with one to three -OH, -N(R¹²)(R^1!) , 3-6 membered heterocycle, Ci-6alkoxy , Ci.6alkoxy-O- Ci.6alkyl, -CO2R , -C(O)N(R¹²)(R¹³) or -S(O)„Ci 6alkyl.

(g) Ci^alkoxy, S (h) -N(Rⁱ²)(R¹³), (i) -S(O)_nC^alkyl, (j) CO₂R¹², (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) a 3-8 membered heterocyclic group optionally substituted with one to three Ci_6 alkyl groups, (n’) oxo, (oJ-CÎO^î alkyl;

R¹² and R¹³ are each independently selected from -H, -Ci^alkyl, C(O)Ci <>alkyl, and a 3- membered heterocyclic group, each of which is optionally independently substituted with one to three Ci^alkyl groups, -OH, C| alkoxy, -C(O)N(R¹⁴)(R¹⁵), -S(O)_nCi-6alkyl, CN, a 3-6 membered heterocyclic group, -OC_t /,alkyl. CF3; or,

R¹² and R¹³ taken together with the nitrogen ring to which they are attached can form a heterocyclyl ring optionally substituted with one to three -OH, CN, -0Cj_6alkyl or oxo;

R¹⁴ and R¹⁵ are each independently selected from -H and -Cj^alkyl;

n is 1 or 2;

or a pharmaceutically acceptable sait thereof.

In a third embodiment, the présent invention relates to a compound as described în any of the preceding embodiments above, wherein:

R¹ and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, terf-butyl, cyclopropyl or cyclobutyl, with the proviso that both R and R are not hydrogen; or a pharmaceutically acceptable sait thereof.

In a fourth embodiment there is provided a compound of formula (I) as described in any of the preceding embodiments above, wherein:

R³ is pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with one to two groups selected from Ci.3 alkyl optionally substituted with one to three halogen atoms, C1.3 alkoxy, C1.3 hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C3.6 carbocycle, C].$ alkylamino and C1.3 dialkylamino; or

R³ is pyridooxazinyl, dîhydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl or pyrrolopyrazinyl;

or a pharmaceutically acceptable sait thereof.

In a fifth embodiment there is provided a compound as described in any of the preceding embodiments above, wherein:

R⁵ is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, oxazolyl, îsoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C(O)-piperizinyl, -C(O)piperidinyl, -C(O)-morpholînyl, -C(O)-NH-piperidinyl, hydroxy or -NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with methyl, C3.6 carbocycle optionally substituted with hydroxy or C1-C5 alkyl;

R⁹, R^lo and Rⁿ are independently selected from (a) -H, (b) -oh, y (c) halogen, (d) -CN, (e) -CF₃, (f) Ci^alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , morpholînyl, piperazinyl, C| _f>alkoxy, Ci.₃alkoxy-O- Ci.₃alkyl, -CO₂R¹² or -C(O)N(R^I3)(R¹³), (g) Ci_₃alkoxy, (h) -N(R¹²)(R¹³), (i) -SiOKCj.ôalkyl, (j) -CO₂R¹², (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) morpholînyl, piperazinyl, piperidinyl or oxetanyl each optionally substituted with a methyl group, (n’) oxo, (o) -C(O)-CH₃;

R¹² and R¹³ are each independently selected from -H and alkyl, wherein the alkyl group îs optionally substituted with one to three -OH, Ci-galkoxy, -C(O)N(R¹⁴)(R¹⁵) or S(O)_nCi.₆alkyl;

R¹⁴ and R^l5are each independently selected from -H and -C,^alkykn is 2;

or a pharmaceutically acceptable sait thereof.

In a sixth embodiment there is provided a compound of formula (I) as described in the second embodiment above, wherein:

R¹ and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, im-butyl. cyclopropyl or cyclobutyl, with the proviso that both R¹ and R² are not hydrogen;

R³ is pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with one to two groups selected from methyl, methoxy,-CH₂OH, trifluoromethyl, bromo, chloro, fiuoro, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C₃^ carbocycle, Cw alkylamino and Ci.₃ dialkylamino; or R³ is pyridooxazinyl, dihydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl or pyrrolopyrazînyl;

R⁴ is hydrogen;

R⁵ is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidînyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quînolinyl, isoquinolinyl, -C(O)-piperazinyl, -C(0)-morpholinyl, -C(O)-NHpiperidinyl, hydroxy or NRR*. wherein each R^s is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

R⁷and R⁸ are each independently hydrogen, piperidinyl optionally substituted with a methyl group, cyclohexyl optionally substituted with a hydroxy group, methyl or ethyl;

R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) Ci-₍₎alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , morpholinyl, piperazinyl, Ci.₃alkoxy, Ci_₃alkoxy-O- C].₃alkyl, -CO₂H or -C(O)N(R¹²)(R¹³), (g) Cr₃alkoxy, (h) -N(R^I2)(R^!3), (i) -S(O)₂Ci_₂alkyl, (i)CO₂R'\ (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R^l2)(R¹³), y (m) morpholinyl, piperazinyl, or oxetanyl each optionally substituted with a methyl group, (n’) oxo, (o) -C(O)-CH₃;

R¹² and R¹³ are each independently selected from -H and C].(,alkyl, wherein the alkyl group is optionally independently substituted with one to three -OH, Ci^alkoxy, C(O)N(R¹⁴)(R¹⁵), or -S(O)2C^alkyl;

R¹⁴ and R¹⁵are each independently selected from -H and -Ci ,;alkyl;

or a pharmaceutically acceptable sait thereof.

In a seventh embodiment there is provided a compound as described in the embodiment immediately above, wherein:

R¹ is methyl,

R² is selected from methyl, ethyl, isopropyl, ier/-butyl, cyclopropyl and cyclobutyl; or a pharmaceutically acceptable sait thereof.

In an eighth embodiment there is provided a compound as described in the sixth embodiment above, wherein:

R³ is selected from

or a pharmaceutically acceptable sait thereof.

In a ninth embodiment there îs provided a compound as described in the sixth embodiment above, wherein:

R⁵ is pyrazolyl optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹ ;

or a pharmaceutically acceptable sait thereof.

In a tenth embodiment there is provided a compound as described in the sixth embodiment above, wherein:

R¹ is methyl,

R² is selected from methyl, ethyl, îsopropyl, tert-butyl, cyclopropyl and cyclobutyl;

R³ is selected from

R⁴ is hydrogen,

R⁵ is selected from

or a pharmaceutically acceptable sait thereof.

In an eleventh embodiment there is provided a compound as described in the tenth embodiment above, wherein:

R² is cyclopropyl or cyclobutyl;

or a pharmaceutically acceptable sait thereof.

In a twelfth embodiment there is provided a compound as described in the tenth embodiment above, wherein:

R² is selected from methyl, ethyl, îsopropyl and tert-butyl;

or a pharmaceutically acceptable sait thereof.

In a thirteenth embodiment there is provided a compound as described in the sixth embodiment above, wherein:

R³ is selected from

H

or a pharmaceutically acceptable sait thereof.

In a fourteenth embodiment there is provided a compound as described in the sixth embodiment above, wherein:

R³ is selected from

or a pharmaceutically acceptable sait thereof.

In a fîfteenth embodiment there is provided a compound as described in the tenth embodiment above, wherein:

R¹ is methyl,

R² is cyclopropyl;

R³ is selected from

R⁴ is hydrogen,

or a pharmaceutically acceptable sait thereof.

In a sixteenth embodiment there is provided a compound of formula I, wherein

R¹ is methyl,

R² is cyclopropyl;

R³ îs selected from

R⁴ is hydrogen, a'

R⁵ is selected from

or a pharmaceutically acceptable sait thereof.

The following are représentative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art.

Table 1

Example	Structure	Name
1	1 /° o	2-(3-{2-[4-(5-methoxypyridin-3- yl)phenyl]-3-methylbutan-2-yl} - 1,2,4-oxadiazol-5-yl)pyrazine
2	<ννΝ' 1 T i 0	5-{4-[3-methyl-2-(5-phenyl-l,2,4oxadiazol-3-yl)butan-2yljphenyl} pyrimidin-2-amine
3	MU M N — Λ h2n'^n'X \Λ	5-(4-{3-methyl-2-[5-(pyridin-3-yl)- 1,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine

4	γ ηϊν^χ'νχ \Ύ Ν=/	5-(4- {3-methyl-2-[5-(6methylpyridin-3-yl)-1,2,4- oxadîazol-3-yl]butan-2- yl} phenyl)pyrimidin-2-ainine
5	Jk. ,.Ν jfjl > AV N=k H2N^rT —\~\ N=k	5-(4-{3-methyl-2-[5-(2- methylpyridin-3-yl)-l,2,4- oxadiazol-3-yi]butan-2- yl} phenyl)pyrimidin-2-amine
6	ίΐΊΓ χθ Ίπ h2n n \ / N=k	[2-amino-5-(4-{3-methyl-2-[5(pyridin-3-yl)-l,2,4-oxadiazol-3yl]butan-2-yl} phenyl)pyridin-3 yljmethanol
7	,<ÿ\ ,-N Av0 N'k_ H,kJ A N=k Cl	5-(4-{2-[5-(6-chloropyridin-3-yl)l,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimidin-2-amine
8	z\ k/N fYA kk A N=/ o—	5-(4-{2-[5-(6-methoxypyridin-3yl)-l,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimidin-2-amine

9	1 II i s° n^AJ *=7 h2n^^n^ \3 N-< o	5-(3- {2- [4-(2-aminopyrimldin- 5- yl)phenyl]-3-methylbutan-2-yl}l,2,4-oxadiazol-5-yl)pyridin-2(lH)one
10	HCA h2n^M °λ3 N=/	5-(4- [2-[5-(2-methoxypyridin-3- yl)-l ,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimidin-2-amine
11	rïr r a Q),	5-(4-{2-[5-(4-methoxypyridin-3yl)-l,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimidin-2-amine
12	aX^n'' A Ύ h2n^n °=\ \ N—Z	3-(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl}- 1,2,4-oxadîazol-5-yl)pyridin-2( 1H)- one
13	rîi r s° n^AJ nA Λ J /A hX n \ n —-o	5-(4- [2-[5-(5-methoxypyridin-3yl)-l,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimîdin-2-amine

14	nA/ Λ J h2n n	u	x 1 ° N^/ A N /	5-(4- [3-methyl-2-[5-( 1 -methyl-1Hpyrazol-3-yl)-1,2,4-oxadiazoi-3yl]butan-2-yl}phenyl)pyrimidin-2amine
				5-(4- (3-methyl-2-[5-( 1 -methyl-1 H-
				pyrazol-4-yl)-1,2,4-oxadiazol-3-
		AA
		f T	o l /	yl]butan-2-yl} 1 phenyl)pyrimidin-2-
15		AA	n=7
	A J h2n n		h VN 1	amine
				5-(4-{(2R)-3-methyl-2-[5-(l-
			N	methyl-1 H-pyrazol-3-yl)-1,2,4-
		A/
		1 1	T 0	oxadiazol-3-yl]butan-2-
16	N'A/	AA	N==/	yl} phenyl)pyrimidin-2-amine
	b		O N /
	h2n n
		J		5-(4-{(2S)-3-methyl-2-[5-(l-
				methyl-1 H-pyrazol-3-yl)-1,2,4-
		AAA	A?’'»
		0 T	1 °	oxadiazol-3-yl]butan-2-
17	aJ h2n n	AA	n=A -O	yl} phenyl)pyrimidin-2-amine
			N /
				5-(4-{3-methyl-2-[5-(l-rnethyl-lH-
		AA/	Αχ \	pyrazol-5-yl)-1,2,4-oxadiazol-3-
18	n^A<	A	I O n=a	yl]butan-2-yl} phenyl)pyrimidin-2amine
	h2n n		—N\ A
			a

19	Γ J T ,° h2n'/^'n/ hnCI3 rr	5-(4-{3-methyl-2-[5-(lH-pyrazol-5- yl)-1,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine
20	aaa\ 1 o NzyU =/ A J Q h2n n hn \	5-(4-{2-[5-(lH-imidazol-2-yl)- l,2,4-oxadiazol-3-yl]-3methylbutan-2yl} phenyl)pyrimidin-2-amine
21	aaAam rT r x° JJ f N H	5-(4-{l-cyclopropyl-l-[5-(lHpyrazol-4-yl)-l,2,4-oxadiazol-3yl]ethyl}phenyl)pyrimidin-2-amine
22	AA AA A 'A A \ 1 o n/AU -A η/Ά O N !	5-(4- {1-cyclopropyl-1 -[5-( 1 methyl- lH-pyrazol-4-yl)-1,2,4oxadîazol-3yljethyl} phenyl)pyrimidin-2-amine
23	nA Η,Ν'^ΝΓ HnQ t*T	5-(4-{(2R)-3-methyl-2-[5-(lHpyrazol-5-yl)-1,2,4-oxadiazol-3yl]butan-2-yI} phenyl)pyrimîdin-2amine

24	Λ J HjN N	A.. γγ	C I 0 NiJ HN J N	5-(4- {(2S)-3 -methyl-2-[5-(lH- pyrazol-5-yl)-l,2,4-oxadiazol-3yl]butan-2-yl}phenyl)pyrimidin-2amine
					5-(4-(1 -cyclopropyl-1 - [ 5 - ( 1 H-
			Mît		pyrazol-3 -yl)-1,2,4-oxadiazol-3 -
25	N'’	Ύ	AJ	l u nM	yI]ethyl}phenyl)pyrimidin-2-amine
	II	Y N		-o N H
					5-(4- {1 -cyclopropyl-1 -[5-( 1 methyl- lH-pyrazol-3-yl)-1,2,4-
			Mr	N i 0	oxadiazol-3-
26	n' Λ h2n	ίτ	•AJ	N=J b N /	yl]ethyl}phenyl)pyrimidin-2-amine
					5-(4- {1-cyclopropyl-1-(5-(1methyl-l H-pyrazol-5-yl)-1,2,4-
27	NX	γ-		x 1 0 Νχ/	oxadiazol-3 - yljethyl} phenyI)pyrimidin-2-amine
	h2n^^	Y N		-O N

28	I 0 HlNXX 7j tr I	5-(4- {1 -cyclopropyl-1 -[5-( 1 methyl- lH-imidazol-4-yl)-1,2,4oxadiazol-3yl]ethyl} phenyl)pyrimidm-2-amîne
29	XÇ\ .tox AJ N=^/ H^N^^hT (S \ N=Z	5-(4-{l-cyclopropyl-l-[5-(6methylpyridîn-3-yl)-l,2,4oxadiazol-3yljethyl} phenyl)pyrimidin-2-amine
30	r¥r xo N‘b A7^ b N ^0	5- [4-( 1 -cyclopropyl-1 - {5 - [ 1 -(2methoxyethyl)-1 H-pyrazol-4-yl]l,2,4-oxadiazol-3yl} ethyl)phenyl]pyrimidin-2-amine
31	—\A ΓΓ	5-(4- {(2R)-3-methyl-2-[5-( 1 methyl-lH-pyrazol-5-yl)-l,2,4oxadiazol-3 -yl]butan-2- yl} phenyl)pyrimidin-2-amine

32	Az ιΓΥν Νκ° Ν^/ Η^Ν'^'Ν^ --Ν\<3 hF	5-(4-{(2S)-3-methyl-2-[5-(l- methyl-1 H-pyrazol-5-yl)-1,2,4oxadîazol-3-yl]butan-2yl}phenyl)pyrimidin-2-amine
33	A AJ η2ν ν	Ί	/-Ν ' 'γΑ' X \ ° Ν==Ζ Ο VN !	5-(4- {1 -cyclobutyl- l-[5-(l -methyl- 1 H-pyrazol-4-yl)-1,2,4-oxadiazol- 3-yl]ethyi)phenyl)pyrimidin-2amine
34	Α A J η2ν ν	J	ΖΖ Ν 0 Ν==Ζ Ο VN Η	5-(4- {1 -cyclobutyl-1-[5-( 1Hpyrazol-4-yl)-1,2,4-oxadiazol-3yl]ethyl }phenyl)pyrimidîn-2-amine
35	xJ η2ν ν	J	ζγ,-ΐγ f' Y Υ__^Ν Ν k ΗΟ	1- {[5-(3-{ l-[4-(2-aminopyriniidin- 5-yl)phenyl]-l-cyclobutylethyl}- 1,2,4-oxadiazol-5-yl)pyrazin-2yljamino} -2-methylpropan-2-ol

36	Γγυν'ο A J /Λ H,N N N K N //NH —0	5- {4-[ 1 -cyclobutyl-1 -(5- {5-[(2methoxyethyl)amino]pyrazin-2-yl] l,2,4-oxadiazol-3yl)ethyl]phenyl}pyrimidin-2-amine
37	| T i o Ju q	5-(4-{2-[5-(6-methylpyiïdm-3-yl)l,2,4-oxadiazol-3-yl]propan-2yl} phenyl)pyrimidin-2-amine
38	^î\ AA r il A Η,Ν^Ν^ ζ^~\ n—/ N—. HA 0 \	5- [4-[ 1-cyclopropyl-l -(5- {6-[(2methoxyethyl)amino]pyridin-3-yl}- 1,2,4-oxadiazol-3yl)ethyl]phenyl} pyrimidin-2-amine
39	AA ^-n fY'O’ Ν^γ ++ N>—. H2N'^X'N<^ N—A 9Ί< HO	1- {[5-(3-{ l-[4-(2-ammopyrimidin5-yl)phenyl]-l -cyclopropylethyl} - 1,2,4-oxadiazol-5-yl)pyridin-2- yl]amîno}-2-methylpropan-2-ol

40	. , Ν \ lî N~( η-,ν'^’Ά N—Z N—, H \ HO	1- {[5-(3- {l-[4-(2-aminopyrimidin5-yl)phenyl]-1 -cyclopropylethyl} - 1,2,4-oxadiazol-5-yl)pyridin-2yl]amino}propan-2-ol
41	JA. /N ^jO^XL/0 ηχ^α N—7 N—. h¥ V o\	5-(4- {1 -cyclopropyl-1 -[5-(6- {[2(methylsulfonyl)ethyl] amino} pyridi n-3-yl)-l,2,4-oxadiazol-3yl]ethyl} phenyl )pyrimidin-2-amine
42	a¥¥n- i T 1 0 K nQ H \ λ	5- {4-[ 1 -cyclopropyl-1 -(5- {5-[(2methoxyethyl)amino]pyrazin-2-yl} l,2,4-oxadiazol-3yl)ethyl]phenyl} pyrimidin-2-amine

43	AA γιΓ v 'ο Jp b. N	5-(4-( l-cyclopropyl-1- [5-[ 1- (oxetan-3-yl)-lH-pyrazol-4-ylJ- l,2,4-oxadiazol-3- yl}ethyl)phenyl]pyrimidin-2-amine
44	rAAL·' ^XJ y0 Η,Ν-'Μ -θ «Λ —-T—OH	l-{[5-(3-(l-[4-(2-aminopyrimidin- 5-yl)phenyl]-1 -cyclopropyl ethyl} - 1,2,4-oxadiazol-5-yl)pyrazin-2- yl]amîno}-2-methylpropan-2-ol
45	Γ T T o n^A> Η,Ν'^'Ν^ f/ X y OH	2- {[5-(3 - {l-[4-(2-ammopyrimidin- 5-yl)phenyl]-l -cyclopropylethyl} l,2,4-oxadiazol-5-yl)pyrazin-2yl]amino} -2-methylpropan-1 -ol
46	crVo N^JU -y Λ A K h2n n A H N /	5-(4-{(2R)-3-methyl-2-[5-(l- methyl-1 H-pyrazol-4-yl)-1,2,4oxadiazol-3-yl]butan-2- yl}phenyl)pyrimidin-2-amine

47	Xz A h N I	5-(4-{(2S)-3-methyl-2-[5-(l- methyl-1 H-pyrazol-4-yl)-1,2,4oxadiazol-3-yl]butan-2yl} phenyl)pyriinidin-2-amine
48	iAîYn'o Jd h N H	5-(4-{(lR)-l-cyclopropyl-l-[5-(lHpyrazol-4-yl)-1,2,4-oxadiazoI-3yljethyl} phenyl)pyrimidin-2-amine
49	A/ JX h N H	5-(4- {( l S)-1 -cyclopropyl-1 -[5-( 1Hpyrazol-4-yl)-1,2,4-oxadiazol-3yl]ethyl} phenyl)pyrimidin-2-amine
50	Ki N zAO h2n n V p N=/ NH Æ	l-{[5-(3-{(lR)-1-(4-(2aminopyrimidin-5-yl)phenyl]-1 cyclopropylethyl} -1,2,4-oxadiazol5-yl)pyrazin-2-yl]amino} -2methylpropan-2-ol

51	4., (ΓΥυΝθ Ju Ίπ Ν==/ ΝΗ /ν0Η	l-{[5-(3-{(lS)-l-[4-(2- aminopyriniidin-5-yl)pheiiyl]-1 cyclopropylethyl)-l,2,4-oxadiazol5-yl)pyrazîn-2-yl]amino} -2methylpropan-2-ol
52		5- [4-[( 1 R)-1 -cyclopropyl-1-{5-[1(2-methoxyethyl)-1 H-pyrazol-4yl]-1,2,4-oxadiazol-3yl}ethyl]phenyl}pyrimidin-2-amine
53	4, fl ν 0 Ν=/ η2ν^ν^ Ç}^ °	5- {4-[( 1 S)-1 -cyclopropyl-1 - [5-[ 1 (2-methoxyethyl)-1 H-pyrazol-4yl]-l,2,4-oxadiazol-3yl)ethyl]phenyl}pyrimidin-2-amine
54	fAo wA A J 4 HîN Ν 4,'	5- [4-[( 1 R)-1-cyclopropyl-1 - {5-[ 1 (oxetan-3-yl)-lH-pyrazol-4-yl]1,2,4-oxadiazol-3 yl}ethyl]phenyl}pyrimidin-2-amme

55	A . CrV-o h2n n ' N Ao	5-{4-[(lS)-l-cyclopropyl-l-[5-[l- (oxetan-3-yl)-1 H-pyrazol-4-yl]l,2,4-oxadiazol-3yl} ethyljphenyl} pyrimidin-2-amine
56	.Aa As A N=A NH A 0„	2-{[5-(3-{(lR)-l-[4-(2aminopyrimidin-5-yl)phenyl]-1 cyclopropylethyl} -1,2,4-oxadiazol5-yl)pyrazin-2-yl]amino} -2methylpropan-1 -ol
57	A\ ,n îi ί r o n=z AA A NH Χ,Η	2-{[5-(3-{(lS)-l-[4-(2ammopyrimidin-5-yl)phenyl]-lcyclopropylethyl} -1,2,4-oxadiazol5-yl)pyrazîn-2-yl]amino}-2methylpropan-1 -ol
58	ΠτΛ „YJ NA A J A h2n n < n N /	5-(4- (2,2-diinethyl-1 -[5-( 1 -methyl- 1 H-pyrazol-4-yl)-1,2,4-oxadiazol- 3 -yl]propyl} plienyl)pyrimidin-2amine

59	i T I ο + H2N N , CJn / N- 0	2-(4-(3- {l-(4-(2-aminopyrimidin-5yl)phenyl]-l -cyclopropylethyl} 1,2,4-oxadiazol-5-yl)-1 H-pyrazol- 1 -yl]-N,N-dimethylacetamide
60	JA. ,N fïr 'o JM b H « Y 0	2-(4-(3- {1 -(4-(2-aminopyrimidin-5yl)phenyl]-1 -cyclopropylethyl} 1,2,4-oxadiazol-5-yi)-1 H-pyrazoll-yl]-N-methylacetamide
61	-jO0° h N /	5-(4-{(lR)-l-cyclopropyl-l-[5-(lmethyl- lH-pyrazol-4-yl)-1,2,4oxadiazol-3yl]ethyl}phenyl)pyrimidin-2-amine
62	4./ <ννΝ' 1 T i ° AJ +1 Η,Ν N < « N /	5-(4- {( 1 S)-1 -cyclopropyl-1-(5-(1methyl-1 H-pyrazol-4-yl)-1,2,4oxadiazol-3yljethyl} phenyl)pyrimidin-2-amine
63		5-{4-[(2R)-2-{5-(l-(2- methoxyethyl)-lH-pyrazol-4-yl]- 1 l,2,4-oxadiazol-3-yl}-3-

	n X, v xJU -A h.nAt <fjj, N S °\	methylbutan-2- yljphenyl} pyrimidin-2-amine
64	A, [TYr% N^JU h2n^n^ N / ^0	5-{4-[(2S)-2-{5-[l-(2- methoxyethyl)-1 H-pyrazol-4-yI] l,2,4-oxadiazol-3-yl}-3methylbutan-2yljphenyl} pyrimidin-2-aniine
65	fil'/’ nx^A> X aJ K h2n N < H /	5-(4-{(lR)-2,2-dimethyl-l-[5-(l- methyl-1 H-pyrazol-4-yl)-1,2,4oxadiazol-3yl]propyl} phenyl)pyrimidin-2amine
66	-4/ iiTr sa h N /	5-(4- {(1 S)-2,2-dimethyl-1 -[5-( 1 methyl- lH-pyrazol-4-yl)-1,2,4oxadiazol-3yljpropyl} phenyl)pyrimidin-2amine
67		5-(4-{2-methyl-l-[5-(l-inethyl-lH- pyrazol-4-yl)-l,2,4-oxadiazol-3-

	I o pJU Π2Ν H <fl N I	yl]propyl}phenyl)pyrimidin-2- amine
68	zOrZx AI k AX b N /	5-(4- {2-[5-( l -methyl-1 H-pyrazol-4- yl)-1,2,4-oxadîazol-3-yl]propan-2yl}phenyl)pyrimidm-2-amine
69	a4a n/QU »=/ h/V 0| N H	5-(4-{2-[5-(lH-pyrazol-4-yl)-l,2,4oxadîazol-3-yl]propan-2yl]phenyl)pyrimidin-2-amme
70	XfX0 —/ «χΎΥ NH V HO X	1 - {[5-(3 - (2-[4-(2-aminopyrimidin5-yl)phenyl]propan-2-yl} -1,2,4oxadiazol-5-yl)pyridin-2yljamino} -2-methylpropan-2-ol

71	AC .--ν Γ II κ° Α>^ ο Ν=Κ ΝΗ 0=/ Λ 0 χ	5-(4-{2-[5-(6-{[2- (methylsulfonyl)ethyl] amino} pyridi n-3-yl)-l,2,4-oxadiazol-3yl]propan-2-yl}phenyl)pyrimidin2-amine
72	AC --Ν λ° KjA^hT ξ Ν=/ ΝΗ ΗΟ	2-{[5-(3-{2-[4-(2-aminopyriimdin- 5-yl)phenyl]propan-2-yl} -1,2,4oxadiazol-5-yl)pyridin-2yljamino} -2-methylpropan-1 -ol
73	.^aGa ο n^aj < Α> A Ν—22/ ΝΗ κ ΗΟ λ	1 -{[S-^-P-^-^-aminopyrimidinS-yljphenylJpropan^-yl} -1,2,4oxadiazol-5-yl)pyrazin-2 yl]amino}-2-methylpropan-2-ol
74	AC _--ν γΥγα ^Α^Α ν;Α γ\ Ν=/ ΝΗ ΗΟ	2-{[5-(3-{2-[4-(2-aminopyrimidin- 5-yI)phenyl]propan-2-yl} -1,2,4oxadiazol-5-yl)pyrazin-2yljamino} -2-methylpropan-1 -ol

75	dd -N ΓιΓΤο N y HO	1 -[4-(3 - {2-[4-(2-aminopyrimidin-5yl)phenyl]propan-2-yl}-1,2,4oxadiazol-5-yl)-lH-pyrazol-l-yl]2-methylpropan-2-ol
76	dd ^'N ί<^ 7Γ x [ ] I o N^ÂJ ”=( X^'f /J, N ..-.o	5-[4-(2-{5-[l-(2-methoxyethyl)- 1 H-pyrazol-4-yl]-l ,2,4-oxadiazol- 3-yl}propan-2- yl)phenyl]pyrimidin-2-amine
77	Ν^,ΧΧ -=? η,ν^ν'' ^3, N H	5-(4- { (2 R)-3-methyl-2-[5-( 1Hpyrazol-4-yl)-1,2,4-oxadiazol-3yl]butan-2-yl} phenyl)pyrîmidin-2amine
78	dd Ml rf x [ l o A <1 N H	5-(4-{(2S)-3-methyl-2-[5-(lH- pyrazol-4-yl)-l ,2,4-oxadiazol-3yl]butan-2-yl} phenyl)pyrimidin-2amine

79	AC 11° ^yU -y »vZnx N V' _^-NH	2-[4-(3-{2-[4-(2-aminopyrimidin-5yi)phenyl]propan-2-yl] -1,2,4oxadîazol-5-yl)-1 H-pyrazol-1 -yl]N-methylacetamide
80	ΜΑΜΆ h î t ïy-\ A J H?N N	2-[(3-{2-[4-(2-aminopyrimidin-5- yl)phenyl]-3-methylbutan-2-yl} l,2,4-oxadiazol-5-yl)amino]ethanol
81	LA u ΓΎΎ yA XyLL A J h2n n	5-[4-(2-{5-[(2- methoxyethyl)amino]-1,2,4oxadiazol-3-yl}-3-methylbutan-2yl)phenyl]pyrimidin-2-amine
82	yXï>M u HZN N	l-[(3-{2-[4-(2-aminopyrimidin-5- yI)phenyl]-3-methylbutan-2-yl} - 1,2,4-oxadiazol-5-yl)amino]-2- methylpropan-2-ol
83	ΑΖΑί r \ N—/ A—> N A ~ ° A J Η,Ν N	5-(4-{3-methyl-2-[5-(piperazin-l - yl)-l,2,4-oxadiazol-3-yl]butan-2- yl} phenyl)pyrimidm-2-amine

84	AAAn lliv ° N^UU -a A J A κχ N /--N N-—' H	(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl}1,2,4-oxadiazol-5-yl)(piperazin-1 yl)methanone
85	AC {jO H2N^^A \_, ho—Ά 0	4-(3-{2-[4-(2-aminopyrimidin-5- yl)phenyl]-3-methylbutan-2-yl}- 1,2,4-oxadiazol-5-yl)-2,2dîmethylbutanoic acid
86	.uSuA-ca JA	N-(l -acetylpiperidin-4-yl)-3- {2-[4(2-aminopyrimidin-5-yl)phenyl]-3methylbutan-2-yl} -1,2,4oxadiazole-5-carboxamide
87	AC m jfyi yA xAU A .z/	5-{4-[3-methyI-2-(5-{[2- (methylsulfonyl)ethyl]amino} 1,2,4-oxadiazol-3-yl)butan-2yljphenyl} pyrimidm-2-amine
88	/O. JAC A AA A> x ^Jj M° A C oh h2n n	3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl} l,2,4-oxadiazol-5-ol

89	ΑΠΑ A J HjN N	5-(4-{3-methyl-2-[5-(morpholin-4- yl)-1,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyriinidin-2-amine
90	ΠΑΜ0 N-X '—'0	(3-{2-[4-(2-aniinopyrimidni-5yl)phenyl]-3-methylbutan-2-yl} l,2,4-oxadiazol-5-yl)(morpholin-4yl)methanone
91	/A À\ A ifYr 'o AU A A J A h2n n /N n-A	(3- [2-[4-(2-aminopyrimidin-5yl)phenyl]-3-inethylbutan-2-yl}- 1,2,4-oxadiazol-5-yl)(4methylpîperazin-1 -yl)methanone
92	^AX a A TA, oz	3-(3- {2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2~yl} l,2,4-oxadiazol-5-yl)-3methylbutanoic acid
93	ifAAAAN\ A4 HjN N \ Γ™ O	3-(3-{2-[4-(2-ammopyrimidin-5yl)phenyl]-3-methylbutan-2-yl}- 1,2>4-oxadiazol-5-yl)-2,2- dimethylpropanoîc acid

94	A x 0 nA //—0H oz	3-(3-{2-[4-(2-amînopyrimidîn-5- yl)phenyl]-3-methylbutan-2-yl} - 1,2,4-oxadiazol-5-yI)propanoic acid
95	/7^ AA A iT \ i T I o fK Y 0	l-(3-{2-[4-(2-aminopyrimîdin-5- yl)phenyl]-3-methylbutan-2-yl} - 1,2,4-oxadiazol-S- yl)cyclopropanecarboxylic acid
96	KC A ijl > fJA/V n=A Il J N—, H,N N / '—N \	5-(4-{3-methyI-2-[5-(4- methylpiperazin-1 -yl)-1.2.4- oxadîazol-3-yl]butan-2yl}phenyl)pyrimidin-2-amine
97	aXa l o Aaaa NZA” JF h N Y -Y	2-(4-(3- {l-[4-(2-ammopyrimidîn-5yl)phenyl]-l-cyclobutylethyl}- 1,2,4-oxadîazol-5-yl)-1 H-pyrazol- 1 -yl]-N,N-dimethylacetainide

					2-[4-(3- {l -[4-(2-amînopyrimidin-5-
		A	A\ ,N I 0	yl)phenyl]-l-cyclobutyl ethyl}-
98	N'Y'	Y	N^=/	1,2,4-oxadiazol-5-yl)- lH-pyrazol-
AL b h2n n		<Ί N Y NH	1 -yl]-N-methylaceÎamide
					5-[4-(l -cyclobutyl-1 - {5-[ 1 -(oxetan-
				3-yl)-1 H-pyrazol-4-yl]-1,2,4-
99		-O	T ° N=y	oxadiazol-3-
A J h2n n		b N ύ	yl}ethyl)phenyl]pyrimidin-2-amine
					5-{4-[(lR)-l-cyclobutyl-l-{5-[l-
ιοο	A J h2n n	jO	N .'' JA l 0 nA p \ ^N N A	(2-methoxyethyl)-1 H-pyrazol-4- yl]-l ,2,4-oxadiazol-3yl}ethyl]phenyl}pyrimidîn-2-amine
				5- {4-[( 1 S)-1 -cyclobutyl-1 - {5-[ 1 -(2-
		A	/ ><> X I 0	methoxyethyl)-1 H-pyrazol-4-yl]-
		Ab	N=Y	l,2,4-oxadiazol-3-
ΙΟΙ	JL <J h2n n		b X N rJ ....-O	yl}ethyl]phenyl}pyrimîdin-2-ainine

102	Γϊ i o /z>A^A wA AA^ b N />	5-{4-[(lR)-l-cyclobutyl-l-{5-[l- (oxetan-3-yl)-1 H-pyrazol-4-yl]- 1,2,4-oxadiazol-3- yl}ethyl]phenyl}pyrimidin-2-amine
103	Π xz\b\,N Tr J' x 1 T 1 o n^AJ n=Z H^n θ N ύ	5- {4-[( 1 S)-1 -cyclobutyl-1 - {5-[ 1 (oxetan-3-yl)-1 H-pyrazol-4-yl]l,2,4-oxadiazol-3- yl} ethyl jphenyl} pyrimidin-2-amine
104	AAiA^ ° /z^AJ nA JJ h N V	2-[4-(3-{(lR)-l-[4-(2- aminopyrimidin-5-yl)phenyl]-1 cyclobutyl ethyl}-1 f2,4-oxadiazol-5yl)-1 H-pyrazol-1 -yl]-N,Ndimethylacetamide
105	R, AA N V	2-[4-(3-{(lS)-l-[4-(2- aminopyrimidin-5-yl)phenyl]-lcyclobutylethyl}-1,2,4-oxadiazol-5yl)-1 H-pyrazoi-1 -yl]-N,Ndimethylacetamide

Z

106	Η!Α9 Q tT V	2-[4-(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methyibutan-2-yl} l,2,4-oxadiazoI-5-yl)- ΙΗ-pyrazoll-yl]-N,N-dimethylacetamide
107	QÜ’Y'.n /-n ιΓΎυ OAk JL 2 ''OH η2ν ν	l-[4-(3-{(2R)-2-[4-(2aminopyrimidin-5 -yl)phenyl]-3methylbutan-2-yl}-l,2,4-oxadiazol5-yl)-lH-pyrazol-l -yl]-2methylpropan-2-ol
108	«ΑΧ Λ J Λη Η,Ν Ν	1-(4-(3-{^Sj^-JA-P- aminopyrimîdin-S-yljphenylJ-Smethylbutan-2-yl} -1,2,4-oxadiazol5-yl)-1 H-pyrazol-1 -yl]-2methylpropan-2-ol
109	/¾. XC AV Q h-	tert-butyl 4-(3-(2-(4-(2amînopyrimidin-5-yl)phenyl]-3methylbutan-2-yl}-1,2,4-0 xadiazol5-yl)piperidine-l-carboxylate

no	'—N \ H	5-(4-{3-methyl-2-[5-(piperidin-4- yl)-1,2,4-oxadiazol-3 -yl]butan-2- yl] phenyl)pyrimidin-2-amine
lll	1 ι ° N^JU =/ η,ζύ Ού° A	tert-butyl 3-(3-{2-[4-(2aminopyrimidin-5-yl)phenyl]-3 methylbutan-2-yl} ~ 1,2,4-oxadiazol5-yl)pîperidine-l-carboxylate
112	X, ,N ΙΓΊΓ'^ /° °\ N:::< z>/ JJ θ J	tert-butyl 2-(3-{2-[4-(2aminopyrimidin-5 -yl)phenyl] -3 methylbutan-2-yl} -1,2,4-oxadiazol5-yl)piperidine-l-carboxylate
113	lixV'° jQ^A Y H2N N ξ NH	5-(4- {3 -methyl-2-[5-(piperidin-3 yl)-l,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine
114	Η,,Ν^Ύ^ Y	5-(4-{3-methyl-2-[5-(pîperidin-2- yl)-1,2,4-oxadiazol-3-yl]butan-2yl}phenyl)pyrimidin-2-amine

115	A/0 HïfAA θ N 1	2-[4-(3-{(lR)-l-[4-(2- aminopyrimidin-5-yi)phenyl]-l cyclopropylethyl}-l,2,4-oxadiazol5-yl)-l H-pyrazol-1 -yl]-N,Ndimethylacetamide
ll6	4 AA fjr > η,ν^Α <0 N 1 cArjA	2-[4-(3-{(lS)-l-[4-(2- aminopyrimidîn-5-yl)phenyl]-1 cyclopropylethyl]-l,2,4-oxadiazol5-yl)-1 H-pyrazol-1 -yl]-N,Ndimethylacetamide
ll7	<JJ k A <5	5-(4-{3-methyl-2-[5-(lmethylcyclopentyl)-1,2,4- oxadiazol-3-yl]butan-2- yl} phenyl)pyrimîdin-2-amine
118	lYy H2N N	5-(4- {3-methyl-2-[5-( 1 - methylcyclopropyl)-1,2,4- oxadiazol-3-yl]butan-2- yl} phenyl )pyrimidin-2-amine
119	A\ .^n 1 T 1 o n^aa a AA (X	5- {4-[2-(5-cyclohexyl-1,2,4oxadiazol-3-yl)-3-methylbutan-2yljphenyl} pyrimidin-2-amine

120		5-(4'{3-methyI-2-[5-(lmethylcyclohexyl)-1,2,4-oxadiazol3-yl]butan-2-yl} phenyl)pyrimidin2-amîne
121	ΓμΑ N^/ h.A7^ h N 1	5-(4- {(1 R)-l -cyclobutyl-1 -[5-( 1 methyl-1 H-pyrazol-4-yl)-1,2,4oxadiazol-3- yl] ethyl} phenyl)pyrimidin-2-amine
122	X\ _X ΓΪΓ x o χχχ/ n;A a7^ h N 1	5-(4- {( 1 S)-1 -cyclobutyl-1 -[5-(lmethyl- lH-pyrazol-4-yl)-1,2,4oxadiazol-3yljethyl} phenyl)pyrimidîn-2-amine
123	rA/V' 11° NA JA 0 NH O \	5-{4-[(2R)-2-(5-{5-[(2methoxyethyl)amino]pyrazîn-2-yl}- 1,2,4-oxadiazol-3 - y 1) - 3 methylbutan-2yl]phenyl} pyrimidin-2-amine

x

124	HzNZ^N/ N=/ NH °\	5-{4-[(2S)-2-(5-{5-[(2- methoxyethyl)amino]pyrazin-2-yl} l,2,4-oxadiazol-3-yl)-3methylbutan-2yl]phenyl} pyrimîdin-2-amine
125	A J h2n n	5-(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl}1,2,4-oxadîazol-5-yl)pyridine-2carboxamide
126	rrVyQ joa HjN N	5-(4- {2-[5-( 1 H-imidazol-4-yl)- 1,2,4-oxadiazol-3-yl]-3methylbutan-2yl}phenyl)pyrimidin-2-amine
127	“o'VX aJ w h2n n	5-(4- {2-[5-(îsoquinolin-4-yl)-1,2,4oxadiazol-3-yl]-3-methylbutan-2yl} phenyl)pyrîmidm-2-amine
128	aJ h2n n	5-(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl} 1 f2,4-oxadiazol-5-yl)pyridine-2carbonitrile

129	N-o	5-(4- {3-methyl-2-[5-(pyrimidin-5- yl)-1,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-ainine
130	Aîyo Η,Ν'^^γΧ	5-(4-{3-methyl-2-[5-(l,3-thiazol-5- yl)-1,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine
131	mUk N-o N - Λ J h2n n	5-(4-{3-methyl-2-[5-(4-methyl-l,3thiazol-2-yl)-1,2,4-oxadiazol-3 yl]butan-2-yl} phenyl)pyrîmidin-2amine
132	ffiVO /'χχ/Α'.ζ ζ O Λ J H,N n	5-(4-{3-methyl-2-[5-(l,3-oxazol-5- yl)-1,2,4-oxadiazol-3-yl]butan-2yl} phenyI)pyrimidin-2-amine
133	zxzXzn Λ^’ΐ «γΟΧγ Η2Ν'·^ΧκΧ	5-(4- {2-(5-(3,5-dim ethyl-1Hpyrazol-4-yl)-l,2,4-oxadiazol-3-yl]3-methylbutan-2- yl} phenyl)pyrimidÎn-2-amine
134	/OxA H f η Ύ y-\ Ν^γΑ> — H/l	5-(4-{2-[5-(ethylamino)-1,2,4oxadiazol-3-yl]-3-methylbutan-2yl}phenyl)pyrimidin-2-amine

135	_dYv€><-> jj	5-[4-(3-methyl-2-[5-[6-(moipholin- 4-yl)pyridin-3-yl]-l,2,4-oxadiazol- 3-yl}butan-2-yl)phenyl]pyrimidin- 2-amine
136	/Aa A F A J HZN N	5-[4-(3-methyl-2-{5-[6(trifluoromethyl)pyridin-3-yl]l,2,4-oxadiazol-3-yl}butan-2yl)phenyl]pyrimidîn-2 -amine
137	Αύ-ο N^0 Z N vf A J h2n n	5-(4-{3-methyl-2-[5-(pyrazin-2-yl)l,2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine
138	nVyO ν^α> n~° vA J h2n n	5-(4-{3-methyl-2-[5-(tetrahydro2H-pyran-4-yl)-1,2,4-oxadiazol-3yl]butan-2-yl} phenyl)pyr imidin-2amine
139	rorvù æJU nA n	5-(4-{3-methyl-2-[5-(l,3-thîazol-2- yl)-1 f2,4-oxadiazol-3-yl]butan-2yl} phenyl)pyrimidin-2-amine
140	,aA Η2Ν'·'Χ·|'Γ	5-(4- {3-methyl-2-[5-(4-methyl-l ,3oxazol-5-yl)-1,2,4-oxadiazol-3yl]butan-2-yl} phenyl)pyrimidin-2amine

141	Αχχ(Αν Κν ffiH J XJ X 8 A J h2n n	5-(4- {3-methyl-2-[5-(4-methyl-1,3thiazol-5-yl)-1,2,4-oxadiazol-3 yl]butan-2-yl} phenyl )pyrimidin-2amîne
142	Λ J HaN N	2-(4-(3- {2-(4-(2-aminop yrimidin-5 yl)phenyl]-3-methylbutan-2-yl}- 1,2,4-oxadiazol-5-yl)-1 H-pyrazol- l-yl]-N-methylacetamide
143	zK\/An /=N nAaC<x A J h2n n	5-(4-{2-[5-(6-methyIpyridin-3-yl)- l,2,4-oxadiazol-3-yl]butan-2- yl} phenyl)pyrimidin-2-amine
144	/ A JAKAaC Ix Η,Ν N	5-{4-[3-methyl-2-(5-{l-(2- (morpholin-4-yl)ethylJ-1 H-pyrazol- 4-yl} -1,2,4-oxadiazol-3-yl)butan-2yljphenyl }pyrimidin-2-ainine
145	__/ o \/ V—OH AVA XJ X <) A J h2n n	l-(3-{2-[4-(2-aminopyrimidin-5- yl)phenyl]-3-methylbutan-2-yl} - 1,2,4-oxadiazol-5 yl)cyclohexanecarboxylic acid
146	zr\ AC -N /=?N Aj ocaJ h2n n	5-(4-{3-methyl-2-[5-(lH-pyrazol-4- yl)-1,2,4-oxadiazol-3-yl]butan-2yl}phenyl)pyrimidin-2-amine
147		5-(4-{3-methyl-2-[5-(pyridazin-4- yl)-1,2,4-oxadiazol-3-yl]butan-2- yl] phenyl)pyrimidin-2-amine

x

	n
148	ytW AJ Η,Ν N	5-[4-(3-methyl-2-{5-[3- (methylsulfonyl)phenyl]-1,2,4- oxadiazol-3-yl}butan-2- yl)phenyl]pyrimidin-2-amine
149	\S^° aJ η2ν n	5-[4-(3-methyl-2-{5-[2- (methylsulfonyl)phenylj-1,2,4- oxadiazol-3-yl} butan-2- yl)phenyl]pyrimidin-2-amine
150	_cArO A J h2n n	5-(4-{3-methyI-2-[5-(l- methylpiperidin-4-yl)-1,2,4- oxadiazol-3-yl]butan-2- yI}phenyi)pyrimidin-2-amine
151	.uAiKr-' A J HjN N	5-(4-{2-[5-(6-aminopyridin-3-yl)l,2,4-oxadiazol-3-yi]-3methylbutan-2- yl} phenyl )pyrimidin-2-amine
152	L> Z=N ΓΥ» aCA aj^ h2n n	5-(4- {3-methyl-2-[5-(2- methylpyrimidin-5-yl)-l,2,4- oxadiazol-3-yl]butan-2- yl}phenyl)pyrimidin-2-amine

153	XL) ' HtH N	5-(4- {2-[5-(2,4-dim ethyl-1,3thiazoI-5-yl)-1,2,4-oxadiazol-3-yl]3-methylbutan-2- yl} phenyl)pyrimîdin-2-amine
154	,-AU -A aJ h2n n	5-(3- {2-[4-(2-aminopyrimidin-5yl)phenyl]-3 -methylbutan-2-yl} 1 ,,2,4-oxadiazol-5-yl)pyrimidin2(lH)-one
155	îïWa pA> A ^- h2n tA	5-(4-{2-[5-(2-methoxypyrimidin-5yl)-l,2,4-oxadiazol-3-yl]-3methylbutan-2- yl} phenyl)pyrimidin-2-amine
156	rpry-A N-o aJ HjN N	5- {4-[2-(5-cyclopropyl-1,2,4oxadiazoi-3-yl)-3-methylbutan-2- yljphenyl} pyrimidin-2-amine
157	/ no jaVa-CX Z%% ri η,ιΥΆ	3-(3-{2-[4-(2-aminopyrimidin-5- yl)phenyl]-3-methylbutan-2-yl] 1,2,4-oxadiazol-5-yi)-6methylpyridin-2-ol

158	ΑχΑό A O c°x	5-[4-(2- {5-[ 1 -(2-methoxyethyl)- 1 H-pyrazol-4-yl]-l ,2,4-oxadiazol- 3-yl} -3 -methylbutan-2- yl)phenyI]pyrimidîn-2-amine
159	.jW A J H2N N	1 -[4-(3-{2-[4-(2-amînopyrimidin-5yl)phenyl]-3 -methylbutan-2-yi} - 1,2,4-oxadiazol-5-yl)-1 H-pyrazol- 1 -yl]-2-methylpropan-2-ol
160	NpAJ «v n·^' vA O’^'OH	2-[4-(3-{2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl} 1,2,4-oxadiazol-5 -yl)-1 H-pyrazoIl-yl]-2-methylpropanoîc acid
161	{44Γ”” a~44\^ n^AM -oz v\o A 4 v HZN N	5-[4-(3-methyl-2-{5-[l-(oxetan-3yl)-1 H-pyrazol-4-yl]-1,2,4oxadiazol-3 -yl} butan-2yl)phenyl]pyrimidin-2-amîne

162	II A0 h2n^A fA N=/ N—. H \ ^-o \	5-{4-[2-(5-{5-[(2- methoxyethyl)amino]pyrazin-2-yl} - 1,2,4-oxadiazol-3-yl)-3methylbutan-2yljphenyl }pyrimidin-2-ainine
163	.Ai H.N \ Q \	5-[4-(3-methyl-2- {5-[5-(4methylpiperazîn-1 -yl)pyrazin-2-yl]l,2,4-oxadiazol-3-yl}butan-2yl)phenyl]pyrimidin-2-amine
164	X d / N. o „A- ---L/-» h°A	3 -[4-(3 - [2-[4-(2-aminopyrimidin-5 yl)phenyl]-3-methylbutan-2-yl}- 1,2,4-oxadiazol-5-yl)- lH-pyrazol- l-yl]-2,2-dimethylpropanoic acid
165	îAvA A*	6-(3- {2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl} l,2,4-oxadiazol-5-yl)-lmethylpyridin-2( 1 H)-one
166	jCt^VA) nAV /Ao aJ H;N N	6-(3- [2-[4-(2-aminopyrimidin-5yl)phenyl]-3 -methylbutan-2-yl} - 1,2,4-oxadiazol-5-yl)-1 - methylpiperidin-2-one

167	m-o ETA AJ h2n n	6-(3- [2-[4-(2-aminopyrimidin-5yl)phenyl]-3-methylbutan-2-yl} l,2,4-oxadiazol-5-yl)piperidm-2one
168	LA i|*| \ ΝΧγΥζ N— JL J /Ά h2n n / \ r° o	5-(4- {1 -[5-( 1,1 -Dioxo-1 lambdaôthiomorpholin-4-yl)- [1,2,4]oxadiazol-3-yl]-1,2dimethyl-propyl) -phenyl)pyrimidin-2-ylamine
169	MM H fYY \ A y AJ /M hX n f \ N y0	1 -[4-(3- {1 -[4-(2-Amino-pyrimidin5-yl)-phenyl]-1,2-dimethylpropyl} -[ 1,2,4]oxadiazol-5-yl)pîperazin-1 -yl]-ethanone
170	,χΑ C '---N \ «r 0	5-(4- {l-[5-(4-Methanesulfonylpiperazin-1 -yl)-[ 1,2,4]oxadiazol-3yl]-1,2-dimethyl-propyl} -phenyl)pyrimidin-2-ylamine
171	x^JLa h n t y-\ M-OZ \ Ax r	N-(3- {l-[4-(2-Amino-pyrimidm-5yl)-phenyl]-1,2-dimethyl-propyl} [l,2,4]oxadiazol-5-yl)-N',N'diinethyl-ethane-1,2-diamine

172	γΧΧ Η2Ν Ν Ν ' A	2-[4-(3-{(R)-I-(4-(6-Amino- pyridin-3-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5 -yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
173	H3N n X '^Τ^ΟΗ	1 -(4-(3- {(R)-1 -[4-(6-Amino- pyridin-3-yl)-phenyl]-1 cyclopropyl-ethyl}- [1,2,4]oxadiazol-5-yl)-pyrazol-1 - yl]-2-methyl-propan-2-ol
174	ιΧΧ ηΧ ν' A Ν ” X	1 -(4-(3- {(R)-1 -[4-(2-Amino- pyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 - yl]-2-methyl-propan-2-ol
175	^-Ν ΛΠ, Ν Ί ^ΟΗ	1-(4-(3-{(R)-1-[4-(5-Amino- pyrazîn-2-yl)-phenyl]-1 cyclopropyl-ethyl} - [1,2,4]oxadiazol-5-yl)-pyrazol-1 - yl]-2-methyl-propan-2-ol
176	Η/1 N V?N Ν 1 <Α/ 1	2-(4-(3- {(R)-1 -(4-(5-Aminopyrazin-2-yl)-phenyl]-1 cyclopropyl-ethyl}[l,2,4]oxadiazol-5-yl)-pyrazol-lyl]-N,N-dimethyl-acetamide

177	xr7 b N 1 1	2-[4-(3-{(R)-l-[4-(5-Amino-6- methyl-pyrazin-2-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 - yl]-N,N-dimethyl-acetamide
178	fl X° xA A N 1 X'-.''	2-(4-(3-{(R)-1-(4-(6-Amino-5methyl-pyridin-3 -yl)-phenyl]-1 cyclopropyl-ethyl}- [ 1,2,4]oxadiazol-5-yl)-pyrazol-1- yl]-N,N-dimethyl-acetamîde
179	7<\ bb < V γΥ x l o AA H’N N X Y N 1	^OH	1 -(4-(3- {(R)-1 -[4-(6-Amino-5methyl-pyridin-3 -yl)-phenyl]-1 cyclopropyl-ethyl} [l,2,4]oxadiazol-5-yl)-pyrazol-lyl]-2-methyl-propan-2-ol
180	bb N Ί	^OH	1-(4-(3-( (R)-1-(4-(5-Amino-6- methyl-pyrazin-2-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 - yI]-2-methyl-propan-2-ol
181	xbr Y x χ°Υ h5n N X ,r>r N	5-(4- {(R)-1 -Cyclopropyl-1 -(5-(1 methyl-1 H-pyrazol-4-yl)[ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-pyridin-2-ylamine

182	AA AU uz A b C 1	5-[4-((R)-1 -Cyclopropyl-1 - {5-[ 1 (2-dimethylamino-ethyl)-1Hpyrazol-4-yl]-[l,2,4]oxadiazol-3yl} -ethyl)-phenyl]-pyrimidin-2ylamine
183	f^TT Ύ=^ x f 11 i o /AU “Æ N 4- x X	5-[4-((R)-l -Cyclopropyl-1 - [5-[ 1 (2-methoxy-ethyi)-1 H-pyrazol-4yl]-[ 1,2,4]oxadiazol-3-yl} -ethyl)phenyl]-pyridin-2-ylamine
184	Xb h2n n K;. N	5-(4- {(R)-1 -Cyclopropyl-1 -[5-( 1 methyl-lH-pyrazol-4-yl)[ 1 ^/IJoxadiazol-S-ylJ-ethyl} phenyl)-pyrazin-2-ylamine
185	i^iïT x° A A H2N N N	5-(4- {(R)-1 -Cyclopropyl-1 -[5-( 1 methyl-lH-pyrazol-4-yl)[ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-3-methyl-pyridin-2ylamine
186	XC N T A T'A \ pïJVA Ab /A h,n n / \ '----N ? OH	2-[4-(3- {1 -[4-(2-Amino-pyrimidin5-yl)-phenyl]-1,2-dîmethylpropyl} -[ 1,2,4]oxadiazol-5-yl)piperazin-l-yl]-ethanol

187	x/A N '	5-(4- {(R)-1-Cyclopropyl-1 -(5-( 1 methyl-1 H-pyrazol-4-yl)[ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-3-methyl-pyrazin-2ylamine
188	xr14 “ \ 0 \	5-[4-((R)-l-Cyclopropyl-l-(5-(1(2-methoxy-ethyl)-1 H-pyrazol-4yl]-[l,2,4]oxadiazol-3-yl}-ethyl)phenyl]-3 -methyl-pyridin-2yl amine
189	x4 % \ O	5-(4-( (R)-1 -Cyclopropyl-1-(5-(1(2-methoxy-ethyl)-lH-pyrazol-4yl]-[ 1,2,4]oxadiazol-3-yl} -ethyl)phenyl]-3 -methyl-pyrazin-2ylamine
190	xvvN^ 1 T 1 o η,νΆα /A ΚΓ NH,	5-[4-((R)-1 - (5-[ 1 -(2-Amino-ethyl)lII-pyrazol-4-yl]-[l,2,4]oxadiazol3-yl}-l-cyclopropyl-ethyl)-phenyl]pyrimidin-2-ylamine
191	h2n N 5¾. .N. V 1 \	5-[4-((R)-l-Cyclopropyl-1-(5-(1(2-methoxy-ethyl)-1 H-pyrazol-4yl]-[ 1,2,4]oxadiazol-3-yl} -ethyl)phenyl]-pyrazîn-2-ylamine

192	A «=( '---N nh; 0	4-(3-(1 -[4-(2-Amino-pynmidin-5yl)-phenyl]-1,2-dimethyl-propyl} [l,2,4]oxadiazol-5-yl)-piperazine- 1 -carboxylic acid amide
193	<>AJ «-</ \_j y-\ AJ N	2-(4-(3- {l-^-^-Amino-pyrimidin- S-ylj-phenyl]- 1,2-dimethylpropyl}-[1,2,4]oxadiazol-5-yl)piperazin-1 -yl]-N,N-dimethyIacetamide
194	aj o tr V Λ 0 !	2-(4-(3- {(R)-1 -[4-(2-Aminopyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} [l,2,4]oxadiazol-5-yl)-pyrazol-lyl]-N-(2-methoxy-ethyl)-N-methylacetamide
195	i) O '---N H	5-(4-{(R)-l-Cyclopropyl-l-[5(3,4,5,6-tetrahydro-2H[ 1,2']bipyrazinyl-5'-yl)- [ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-pyrazin-2-ylamine

196	aJ H;N N	G	A ^-N ><x x T /° y N----< o ---N H	5-(4- {(R)-1 -Cyclopropyl-1 -[5(3,4,5,6-tetrahydro-2H[ 1,2’]bipyrazinyl-5'-yl)- [ 1,2,4]oxadîazol-3-yl]-ethyl} phenyl)-pyrimidin-2-ylamine
			1 A AC - N	2-(4-(3-{(R)-l-[4-(2-Amino-6-oxo-
	0		X >X \
		f	1 o	1,6-dihydro-pyrimidin-5-yl)-
		/Y/	J N=X
197	HtX AJ h2m n		h	phenyl]-1 -cyclopropyl-ethyl} - [1,2,4]oxadiazol-5-yl)-pyrazol-1 -
			1 f Ÿ o	yl]-N,N-dimethyl-acetamide
		(AV		2-[l-(3-{l-[4-(2-Amino-pyrimidin-
198		JU		5-yl)-phenyl]-1,2-dimethyl-
AJ		A	propyl] -[ 1,2,4]oxadiazol-5-yl)-
			C z OH	piperidin-4-yl]-propan-2-ol
				4-(3- {1 -[4-(2-Amino-pyrimîdin-5-
		ιίΎ	\x x 1 0	yl)-phenyl]-1,2-dimethyl-propyl] -
199		AA		[ 1,2,4]oxadiazol-5-yI)-piperazîn-2-
	A\ HZN N		CA k---N H	one

200	Γίϊ Νχ° Η2Ν'Χ^'ν’/ ΟΗ	1 -(3 - {1 - [4-(2-Amino-pyrimidin-5 yl)-phenyl]-1,2-dimethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-azetidin-3-ol
201	ΑΑ _-Ν ίι χ° II νη „ΑΑ	5-(4-( 1,2-DimethyI-l-{5[(tetrahydro-pyran-4-ylmethyl)amino]-[ 1,2,4]oxadiazol-3-yl} propyl)-phenyl] -pyrimidin-2ylamine
202	ρ<γ\ A J ζΝ~\ η£ν ν <	4-(3 - {1 - [4-(2-Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-1 -methylpiperazin-2-one
203	^Αγ-Vz Η,Ν^Ν^ Ο Λοη	l-(3-{l-[4-(2-Amino-pyrimidîn-5yl)-phenyl]-1,2-dîmethyl-propyl} [l,2,4]oxadiazol-5-yl)-3-methylazetidin-3-ol
204	AC Αύ \ ^JU Αο Λ J Ν---, N Q	5- {4-[ 1 -Cyclopropyl-1 -(5pyrrolidin-l-yl-[l,2,4]oxadiazol-3yl)-ethyl]-phenyl} -pyrimidîn-2ylamîne

205	TA x Λ j -X H2N^ Y / A OH	1 -(3- {1 -[4-(2-Amino-pyrimîdin-5yl)-phenyl]-1 -cyclopropyl-ethyl] [l,2,4]oxadiazol-5-yl)-pîperidin-4ol
206	aOK p° «2νΆ b N	5-(4-{l-Cyclopropyl-l-[5-(3oxetan-3-yl-3H-imidazol-4-yl)- [l,2,4]oxadiazol-3-yl]-ethyl}- phenyl)-pyrimidin-2-ylamîne
207	rrVo naAJ Λ J A HjAl C JJ N fi	5-(4- {1 -Cyclopropyl-1 -[5-( 1 oxetan-3-yl-1 H-imidazol-4-yl)- [ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-pyrimidin-2-ylamine
208	l o .^yU =( h,Y Q /r 0 0	5-(4- {1 -[5-(4-Methanesulfonylpiperidin-l-yl)-[l,2,4]oxadiazol-3yl]-l ,2-dimethyl-propyl] -phenyl)pyrimidin-2-ylainine
209	HO	[ 1 -(3- {1 -[4-(2-Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl] [ 1,2,4]oxadiazol-5-yl)-pîperidin-4yl]-methanol

210	χΎ3- N^/ O '---N H	5-(4-{(R)-l-Cyclopropyl-l-[5- (3,4,5,6-tetrahydro-2H- [ 1,2']bipyrazinyl-5'-yl)- [ 1,2,4]oxadiazol-3-yl]-ethyI} - phenyl)-pyridin-2-ylamine
211	Πο-νΑ» yj y Η,Ν N	1 -[4-(3- {l-[4-(2-Amino-pyrimidin- 5-yl)-phenyl]-1,2-dimethylpropyl) -[ 1,2,4]oxadiazol-5-yl)piperazin-1 -yl]-2-methyl-propan-2ol
212	(Γίγ'ο J *=( /Λ H2N N < \ 1 OH	2-[ 1 -(3- {1 -[4-(2-Amîno-pyrimidin5-yl)-phenyl]~ 1,2-dim ethylpropyl}-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]-ethanoi
213	h2n	1 -(3- {1 -[4-(2-Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-piperidine-4carboxylic acid amide

214	A il 'Ί 1' A Ύ k'j ύ o '-----N H	5-(4- {(S)-1-Cyclopropyl-1-[5(3,4,5,6-tetrahydro-2H[ 1,2']bipyrazinyl-5'-yl)- [l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyrazin-2-ylamine
215	„VJ -A V o N r~^ o	5-[4-((R)-1 -Cyclopropyl-1 - {5-[ 1 (2-pyrrolîdin-1 -yl-ethyl)- 1Hpyrazol-4-yl]-[ 1,2,4]oxadiazol-3yl)-ethyl)-phenyl]-pyrimidîn-2ylamine
216		1 -(3-{ l-[4-(2-Amino-pyrimidin-5yl)-phenyl]-l,2-dîmethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-4-methylpiperidin-4-ol
217	~Y 1 N-----1 v. y / v h2n n î \ NH /	5-(4- {1,2-Dîmethyl-1 -[5-(4methylamino-piperidin-1 -yl)[ 1,2,4]oxadiazol-3-yl]-propyl} phenyl)-pyrimidin-2-ylamîne

218	Α^Α y	Q	l ° Q N-- /	5-(4- {l-[5-(4-Dimethylaminopiperidin-l-yl)-[l,2,4]oxadiazol-3yl]-l,2-dimethyl-propyl} -phenyl)pyrimidin-2-ylamîne
		AAx		l -(3- {l -(4-(2-Amino-pyrimidin-5-
219	nAAi aJ	U	XA O	yl)-phenyl]-1,2-dimethyl-propyl} - [l,2,4]oxadiazol-5-yl)-piperidine-4-
	H:N N		A °h o	carboxylic acid
		n	''K rX^\ o	2-(4-(3-{(R)-1-(4-(2-Amino-
	AA/ aJ H,N N	AJ		pyrimidm-5-yl)-phenyl]-1 -
		<A	cyclopropyl-ethyl} -
220			\ N N 0 /	[ 1,2,4]oxadiazol-5-yl)-pyrazol-1 -
			r	yl]-1 -((R)-3-methoxy-pyrrolidin-1 -
			-N P	yl)-ethanone
			0 \

221	n^zCj -Z H.H'Z'' N V ...0 0 \	2-(4-(3- {(R)-1 -[4-(2-Amino- pyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl}- [1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]~ 1 ~((S)-3-methoxy-pyrrolidin-1 yl)-ethanone
222	q nh2	5-(4- {1 -[5-(4-Animo-piperidin-1 yl)-[ 1,2,4]oxadiazoI-3 -yl]-1,2dimethyl-propyl} -phenyl)pyrimidin-2-ylamine
223	ZZ (j a z ^ZaZa n’ < Λ J ”~A H2N N / A OH	l-(3-{(R)-l-[4-(2-Amino- pyrimidin-5-yl)-phenyl]-1,2dimethyl-propyl}-[l,2,4]oxadiazol5-yl)-piperidin-4-ol
224	Z. Z ZZ zZ x° N— θ OH	1-(3-{(S)-1-(4-(2-Amino- pyrimidin-5-yl)-phenyl]-1,2dimethyl-propyl}-(l,2,4]oxadiazol5-yl)-piperidin-4-ol

225	ΑΧ l o K^AA A/ OH	1 -(3- {1 -[4-(2-Ainino-pyrimidin-5yl)-phenyl]-l,2-dimethyl-propyl} - [ 1,2,4]oxadiazol-5-yl)-2-methylpropan-2-ol
226	Xï Y' a AX^ çv 0Ay	2-[4-(3-{(R)-l-Cyclopropyl-l-[4- (2-methylamino-pyrimîdin-5-yl)phenyl]-ethyl}-[l,2,4]oxadîazol-5- yl)-pyrazol-1 -yl]-N,N-dîmethylacetamide
227	x ]^OH	1 -(3- {(R)-1 -[4-(2-Aminopyrimidin-5-yl)-phenyl]-l ,2dimethyl-propyl}-[l,2,4]oxadiazol5-yl)-4-methyl-piperidin-4-ol
228	π x° [i n—\ H;m A CZ/> T	l-(3-{(S)-l-[4-(2-Amino- pyrimidin-5-yl)-phenyl]-1,2dimethyl-propyl}-[l,2,4]oxadiazol- 5-yl)-4-methyl-piperidin-4-ol

229	\ ιΓ aJ > η2ν ν /°	5-(4- {I -(5-(2-Methoxy- ethoxymethyl)-[ 1,2,4]oxadiazol-3yl]-l,2-dimethyl-propyl}-phenyl)pyrimidin-2-ylamine
230	ΓγνΝ'ο ν-^ΑΑ -4 Ο Ν V ΝΗ	2-(4-(3- {(R)-1 -[4-(2-Aminopyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl}- ( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N-methyl-acetamide
231	<ι fijr ο N^JU ~4 ηΑΑ Ο Ν V ΝΗ	2-(4-(3- {(S)-1 -[4-(2-Aminopyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl}( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yiJ-N-inethyl-acetamide
232	/ÿ\ Α \ rîir χθ Ν-χγ-Μ -Α aJ > η2ν ν < 0 /	5-(4- {l-[5-(2-Methoxy-ethyl)- [ 1,2,4]oxadiazol-3-yl]-1,2dimethyl-propyl} -phenyl )pyrimidin-2-ylamine

233	O pJJ Y Q OH	l-(3-{(R)-l-[4-(2-Aminopyrimidin-5-yi)-phenyl]-1 cyclopropyl-ethyl} [ 1,2î4]oxadiazol-5-yi)-piperidin-4ol
234	4 zQ X/° Λ J X h2n n / \ OH	l-(3-{(S)-l-[4-(2-Aminopyrimidm-5-yl)-phenyl]-lcyclopropyl-ethyl} [ 1,2)4]oxadiazol-5-yl)-piperidin-4ol
235	A A /j. H/J N X OH	8-(3- {l-[4-(2-Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl} [l,2,4]oxadiazol-5-yl)-8-azabicyclo[3.2.1 ]octan-3-ol
236	if Z 0 \ 0 .,/Qf γ J| J NH Η,Ν'^^Ν’^ / Ç N--Z Z	5-(4- {1,2-Dimethyl-1 -[5-(l -methylpiperidîn-4-ylamino)[l,2,4]oxadiazol-3-yl]-propyl}phenyl)-pyrimidin-2-ylamine

237	/J. A\ -N zyU A NH ' 0 HO	4-(3- {l -[4-(2-Amino-pyrimidin-5yl)-phenyl]-l,2-dimethyl-propyl}[ l ,2,4]oxadiazol-5-ylamino)cyclohexanol
238	Ας, ΓθΗ	] -(3- {1 -(4-(2-Amino-pyrimidin-5yl)-phenyl]-1 -cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-4-methylpiperidin-4-ol
239	œAj K Ί	2-(4-(3- {1 -Cyclopropyl-1 - [4-(3,4dihydro-2H-pyrido[3,2- b][l ,4]oxazin-7-yl)-phenyl]-ethyl} ( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
240	i /VV“' .LU 4 JA h 0Xr	2-(4-(3- {l-[4-(2-Amino-4-methylpyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} - ( 1,2,4]oxadîazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide

241	ΓΊίΟ5 çcA U “ 1 y·'»''	2-(4-(3- {1 -Cyclopropyl-1 -(4-(2,3 dihydro-1 H-pyrrolo[2,3-b]pyridin- 5-yl)-phenyl]-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-l - yl]-N,N-dimethyl-acetamide
242	Γ ιΓ χ° ATM À Η A Q 1	2-(4-(3- {1-Cyclopropyl-1 -[4-( 1Hpyrrolo[2,3-b]pyridin-5-yl)phenyl]-ethyl} -( 1,2,4]oxadiazol-5yl)-pyrazol-l-yl]-N,N-dimethylacetamide
243	μΑ η3ν ν 1 Ν1 °^ϊ	2-(4-(3- {1 -[4-(6-Amino-5-fluoropyridin-3-yl)-phenyl]-1cyclopropyl-ethyl}- [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yI]-N,N-dimethyl-acetamide
244	LA ^-ν ΜίΓ'ο χτΜ Η;Ν Ν ' Ν 1	2-(4-(3-( 1-(4-( 6- Amîno-2-methylpyridin-3-yl)-phenyl]-1 cyclopropyl-ethyl} - ( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
245	gyJg. Γ II ' /° Μ 1 Ν A A 1 0	2-(4-(3-(l-[4-(5-Amino-3-methylpyrazîn-2-yl)-phenyl]-lcyclopropyl-ethyl} - ( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide

246	/A A A AAA ΛΑ à Η,Ν Z 4 A 1 Zs	2-(4-(3-(1 -(4-(6-Amino-5- trifluoromethyl-pyridin-3-yl)- phenyl]-1 -cyclopropyl-ethyl] [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
247	N 1 OAnx- 1	2-(4-(3-(1-Cyclopropyl-l-[4-(5H- pyirolo[2,3-b]pyrazin-2-yl)phenyl]-ethyl]-[1,2,4]oxadiazol-5yl)-pyrazol- l-yl]-N,N-dimethylacetamide
248	'/a HSN N / \ OH	1 -(3- {1 -(4-(6-Amino-pyridin-3-yl)phenyl]-1 -cyclopropyl-ethyl] - [ 1,2,4]oxadiazol-5-yl)-piperidin-4ol
249	Ax H VA 0Az 1	2-(4-(3- {1 -Cyclopropyl-1-(4-(2ethylamino-pyrimidin-5-yl)phenyl]-ethyl] -( 1,2,4]oxadiazol-5- yl)-pyrazol-1 -yl]-N,N-dim ethyl acetamide
250	A \V H V N 1	2-(4-(3-{1-Cycloprop yl-1-(4-(2cyclopropylamino-pyrimidin-5-yl)phenyl]-ethyl]-[l,2,4]oxadiazol-5- yl)-pyrazol-l-yl]-N,N-dimethylacetamide

251	Hbi I		.N I 0 nA A 1 oAZ 1	2-[4-(3- {1 -Cyclopropyl-1 -(4-(6methylamîno-pyridin-3 -yl)phenyl]-ethyl}-[lf2,4]oxadiazol-5yl)-pyrazol-l-yl]-N,N-dîmethylacetamide
rx N	XX
			rXY	JA ' X' \	2-(4-(3- {1 -(4-(2-Amino-pyrimidin-
252		O N	x)	l /° N^/ 0 ? OH	5-yl)-phenyl]-1 -cyclopropyl-ethyl) - ( 1,2,4]oxadiazol-5-yl)-piperazin-1- yl]-ethanol
					5-(4- {1 -Cyclopropyl-1-(5-( 1 -
253			rAr	' '(C X 1 °	methyl-1 H-pyrazol-4-yl)-
A		aj	n=a	( 1,2,4]oxadiazol-3-yl]-ethyl) -
	N H	AJ N		A	phenyl)-lH-pyrrolo[2,3-b]pyridme
					2-(4-(3- {(R)-1-Cyclopropyl-1 -(4-
			XY'	Lx	(3,4-dîhydro-2H-pyrido[3,2-
254	C	XJ		y	b]( 1,4]oxazîn-7-yl)-phenyl]-ethyl} -
	r/ H			4 A N 1 1	[ 1,2,4]oxadiazol-5-yl)-pyrazol-1 -
				yl]-N,N-dimethyl-acetamide
					2-(4-(3- {(S)-1 -Cyclopropyl-1 -[4-
			χγ	L/	(3,4-dihydro-2H-pyrido(3,2-
255	C	XJ		A	b]( l,4]oxazin-7-yl)-phenyl]-ethyl) -
	H			4 A N 1 «A/ 1	( 1,2,4]oxadiazol-5-yl)-pyrazol-1 -
				yl]-N,N-dimethyl-acetamide

256	ça	5-(4- {1 -Cyclopropyl-1 -[5-( 1 methyl-1 H-pyrazol-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-2,3 -dihydro-1Hpyrrolo [2,3 -bjpyridine
257	. r; γΧ χ YU Α/ Xk b Ar	2-[4-(3-{(R)-l-[4-(2-Amiïio-4- rnethyl-pyrirnidin-5-yl)-phenyl]-1 cyclopropyl-ethyl}- [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
258	A ,Α^Ο'Ο’ ^A»'' AA 1 1	2-[4-(3-{(S)-l-[4-(2-Amino-4- methyl-pyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} [l,2,4]oxadiazol-5-yl)-pyrazol-lyl]-N,N-dimethyl-acetamide
259	l O K^AA ~=< H.AA q °=T~ o	5-(4- {1 -Cyclopropyl-1 -[ 5-(4methanesulfonyl-piperidin-1 -yl)- [ 1,2,4]oxadiazol-3-yl]-ethyl} phenyl)-pyrimidin-2-ylamine
260	2 '----N \	N-(3-{ l-[4-(2-Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl} [l,2,4]oxadiazol-5-yl)-N,N’,N’trimethyl-ethane-1,2-diamine

261	A A /—\ h2n n / \ '---N λ	5-(4- {1 -[5-(4-tert-Butyl-piperazinl-yl)-[l ,2,4]oxadiazol-3-yl]-l ,2dimethyl-propyl} -phenyl)pyrimidin-2-ylamine
262	JA Ay x° nAJ a A A N—λ OH	1-(3-(1 -[4-(2-Amino-pyrimidin-5 yl)-phenyl]-1,2-dimethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-piperidin-4ol
263	A/ ><N'· AA H?i N '/VA V°	5-(4- {(R)-1 -Cyclopropyl-1 -[5-( 1 oxetan-3-yl-lH-pyrazol-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyridin-2-ylamine
264	JA _-N ÎiJ^ X° N'Y/ 'Y N \ A J A HjN N / \ '---N A	5-(4- (1 -[5-(4-Isopropyl-piperazin1 -y l)-[ 1,2,4]oxadiazol-3-yl]-1,2dimethyl-propyl}-phenyl)pyrimidin-2-ylamine
265	A\ /À Afr /Y Y Η,Ν N νΑΛ v°	5-(4-{(R)-l-Cyclopropyl-l-[5-(loxetan-3-yl-lH-pyrazoI-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyrazin-2-ylamine; compound with trifluoro-acetic acid

/

266	b «a AA A X---N K	5-(4- {1 -[5-(4-Cyclopropylpiperazin-1 -yl)-[ 1,2,4]oxadiazol-3yl]-1,2-dimethyl-propyl} -phenyl)pyrimidm-2-ylamine
267	4 f'A’ ,,^AJ a AU -h Ν==/ O '---N H	5-(4-{(S)-l-Cyclopropyl-l-[5(3,4,5,6-tetrahydro-2H[l,2’]bipyrazinyl-5'-yl)- [ 1,2,4]oxadiazol-3-yl]-ethyi} - phenyl)-pyrimidin-2-ylamine
268	A rA/AV I II l o JA À A C > O x---N H	5-(4-{(S)-l-Cyclopropyl-l-[5(3,4,5,6-tetrahydro-2H[ 1,2’]bipyrazinyl-5'-yl)- [l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyridin-2-ylamîne
269	.Λ. A A ίΎΥχ° n^A4 -a AU /-} K	4-(3-( 1 -[4-(2- Amino-pyrimidin-5yl)-phenyl]-1,2-dimethyl-propyl} [ 1,2,4]oxadiazol-5-yl)-pîperazine- 1-carboxylic acid dimethylamide

270	„aA c o---	5-(4- {1 -[5-(4-Methoxy-piperidin-1 yl)-[ 1,2,4 Joxadiazol-3-yl]-1,2dimethyl-propyl} -phenyl)pyrimidin-2-ylamine
271	x .X ίτ γΧ λ o AU À N Z	5-(4- {(R)-l -Cyclopropyl-1 -[5-(l cyclopropyl-1 H-pyrazol-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyrimidin-2-ylamine
272	aJ Η,Ν N	[4-(3- {1 -[4-(2-Amino-pyrimidm-5yl)-phenyl]-l,2-diniethyl-propyl] [ 1,2,4]oxadiazol-5-yl)-piperazin-1 yl]-acetic acid
273	X \	2-(4- {1 -Cyclopropyl- l-[5-(lmethyl-1H-pyrazol -4-y ) ) - [ 1,2,4]oxadiazol-3-yl]-ethyl}phenyl)-5H-pyrrolo[2,3 -bjpyrazine
274	ζ^Α\γΝ χ ta c OH	1 -(3- {1 -[4-(2- Amino-pyrimidin-5yl)-phenyl]-1 -cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-azetidin-3-ol

275	t Aa „w γ A çî, ^0	2-[4-(3- {l -[4-(2-Amino-4-fluoropyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
276	h2 AA^^γ [Y	1-(3-(1- [4-(2-Amino-pyrimidin-5yl)-phenyl]-l-cyclopropyl-ethyl}[l,2,4]oxadiazol-5-yl)-3-methylazetidin-3-ol
277	cxJ À < N NH2 <Yn	2-[4-(3- {1 -[4-(2-Amino-6-fluoropyridin-3-yl)-phenyl]-lcyclopropyl-ethyl}- [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
278	A7’! H=N N F <( « N V -A	2-[4-(3-{l-[4-(6-Amino-2-fluoropyridin-3-yl)-phenyl]-lcyclopropyl-ethyl} - [1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide idin-3-yl)-phenyl]-1 -cyclopropyl-et hyl}-[l,2,4]oxadiazol-5-yl)-pyrazol -1 -yl]-N,N-dimethyl-acetamide

279	aAV H V ^-N N1 1	2-[4-(3- {(R)-1 -Cyclopropyl-1 -[4(2-isopropylamino-pyrimîdin-5-yl)phenyl]-ethyl} -[ 1,2,4]oxadiazol-5yl)-pyrazol-l-yl]-N,N-dimethylacetamide
280	iVVN' V Ί N X À 1 A oA	2-[4-(3-{(R)-l-Cyclopropyl-l-[4- (6-methylamino-pyridin-3-yl)phenyl]-ethyl}-[l,2,4]oxadiazol-5yl)-pyrazol-l-yl]-N,N-dimethylacetamide
281	i / i l 1 o ArA x 1 o<=X	2-[4-(3- {(R)-1 -[4-(6-Amino-5tri fluorom ethyl-pyridîn-3 -yl)phenyl]-1 -cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N.,N-dimethyl-acetamide
282	x I l 1 o pAJ 4 A J /v h2n n / \ OH	1 -(3- {(R)-1 - [4-(6-Amino-pyridin3-yl)-phenyl]-l-cyclopropyl-ethyl}[ 1,2,4]oxadiazoi-5-yl)-piperidin-4ol

/

283	4 I l o pXJ y A J Λ H2N N / \ OH	1 -(3 - {(S)-1 -[4-(6-Amino-pyridin-3 yl)-phenyl]-1 -cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-piperidin-4ol
284	’v. N 1 1	2-[4-(3- {(R)-1 -Cyclopropyl-1 - [4(2,3-dihydro-1 H-pyrrolo[2,3b]pyridin-5-yl)-phenyl]-ethyl}[ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
285	AL N 1 f444 1	2-[4-(3-{(R)-l-[4-(5-Amino-3methyl-pyrazin-2-yl)-phenyl] -1 cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yI)-pyrazol-1 yl]-N,N-dîmethyl-acetamide
286	Zr/A N A A N \	3-(4- {1 -Cyclopropyl-1 -[5-( 1 methyl-1 H-pyrazol-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-5 -methoxy-pyridine
287	^-N Îl x° Νζζζχ^ΑΑ J Il n—i h’n z 0 HO*	(R)-l-(3-{l-[4-(2-Amino- pyrimidin-5-yl)-phenyl]-1cyclopropyl-ethyl}- [ 1,2,4]oxadiazol-5-yl)-piperidin-3ol

288	ifXv Νχ° Il N----\ X θ ho'	(S)-1-(3-( l-[4-(2-Aminopyrimidin-5-yl)-phenyl]-1 cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-piperidîn-3ol
289	î/f XyU A H/< H Fl 1	2-(4-(3-{l-[4-(5-Amino-6- trifluoromethyl-pyrazin-2-yl)- phenyl]-1 -cyclopropyl-ethyl} [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
290	F fiXo V h. N A	3-Benzyloxy-5-(4- {1 -cyclopropyl- 1 -[5-(l -methyl-1 H-pyrazol-4-yl)[l,2,4]oxadiazol-3-yl]-ethyl}phenyl)-pyridîne
291	/X AA < Af \ 1 o Y î H=N N X N1 AKA' 1	2-(4-(3-{(R)-l-[4-(6-Amino-5- fluoiO-pyridin-3-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-l - yl]-N,N-dimethyl-acetamide
292	Ay JFJ ..N [ I o jxJ $ N 1 A	2-(4-(3-{(R)-1-[4-(6-Amino-2- methyl-pyridin-3-yl)-phenyl]-lcyclopropyl-ethyl} - [1,2,4]oxadiazol-5-yl)-pyrazol-1 - yll-NjN-dimethyl-acetamide

293	i Æv nAA> -A h,An1 Π N	2-(4-(3-{(R)-1-(4-(2-Amino-4fluoro-pyrimidin-5-yl)-phenyl] -1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
294	Γ]^Νο Y\/U Nk h/AL <T»n Ço	2-(4-(3- {(R)-1-(4-(5-Amino-6cyano-pyrazin-2-yl)-phenyl]-1 cyclopropyl-ethyl} - ( 1,2,4]oxadiazol-5-yl)-pyrazol-l - yl]-N,N-dimethyl-acetamide
295	A- F ç -x	2-(4-(3- {1-(4-(5-Amino-3-cyanopyrazin-2-yl)-phenyl]-1 cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamide
296	Av. vc j h2n n^n	2-(4-(3 - {1 -(4-(6-Amino-2-cyanopyridin-3 -yl)-phenyl] -1 cyclopropyl-ethyl}- ( 1,2,4]oxadiazol-5-yl)-pyrazol-1 yl]-N,N-dimethyl-acetamîde
297	AA V\ V ,^,ίΓΧί’ JJ /~O-“ H,N N \---/	4-[(3- {1-(4-(2-Amîno-pyrimîdin-5yl)-phenyl]-1-cyclopropyl-ethyl} - [ 1,2,4]oxadiazol-5-yl)-methylamino]-cyclohexanol

298

2-[4-(3-{(R)-1 -[4-(2-Amino-4fluoro-6-methyl-pyrimidin-5 -yl)phenyl]-l -cyclopropyl-ethyl} [ l ,2,4]oxadiazol-5-yl)-pyrazol-lyl]-N,N-dimethyl-acetamide

In one embodiment, the invention relates to any of the compounds depicted in Table 1 above or pharmaceutically acceptable salts thereof.

Représentative compounds of the invention show activity in the FLAP binding assay, described in the assessment of biological properties section, as shown in Table 2.

Table 2

Example	FLAP binding IC50 (nM)	Human Whole Blood IC50 (nM)
1	57
2	5.1	680
3	1.7	94
4	1.6	310
5	1.6	150
6	1.1	70
7	3.1	560
8	3.8	530
9	2.9	210
10	4.3
11	1.9	89
12	3.3	290
13	3.6	460

14	4.6	140
15	2.0	46
16	2.5	110
17	24	510
18	3.3	320
19	5.8	260
20	10	3200
21	5.5	87
22	4.2	46
23	6.9	170
24	19	410
25	6.0	170
26	9.1	160
27	12	330
28	26	320
29	5.3	190
30	5.0	60
31	1.6	200
32	18	2500
33	6.6	210
34	3.7	160
35	3.2	360
36	3.2	170
37	7.4	250
38	2.2	97
39	2.1	110
40	2.3	100
41	2.2	170
42	1.5	25
43	2.5	30

44	2.2	150
45	3.1	140
46	1.6	33
47	7.7	360
48	6.8	190
49	19	680
50	1.3	95
51	3.9	140
52	2.4	26
53	27	450
54	2.6	27
55	11	200
56	2.4	79
57	6.8	150
58	11	190
59	1.1	76
60	4.0	140
61	1.3	15
62	18	350
63	1.1	14
64	16	410
65	75	1500
66	11	330
67	6.2	190
68	6.7	93
69	7.7	120
70	7.1	590
71	17	900
72	12	440
73	28	990

74	17	640
75	23	260
76	35	270
77	1.7	36
78	1.3	240
79	150	2200
80	23	350
81	11	180
82	13	220
83	26	1100
84	120	1700
85	48	>5000
86	190	>5000
87	41	970
88	51%inh@1000nM	>5000
89	13	270
90	63	1500
91	54	1300
92	110	>5000
93	240	>5000
94	350	>5000
95	130	>5000
96	7.5	150
97	8.8	170
98	12	570
99	3.9	200
100	2.3	110
101	280	>5000
102	1.6	51
103	130	2700

104	6.1	130
105	490	>5000
106	4.8	76
107	0.86	17
108	8.7	320
109	46	1500
110	190	2800
111	15	2900
112	190	>5000
113	66	3100
114	21	1100
115	1.9	58
116	150	2000
117	31	1200
118	9.9	820
119	9.2	900
120	40	2100
121	2.6	91
122	140	3200
123	1.7	42
124	2.3	31
125	1.5	290
126	4.6	260
127	2.9	650
128	1.6	240
129	2	180
130	1.4	180
131	8.7
132	2.8	330
133	1.6	190

134	8.3	190
135	1.4	250
136	5.4	320
137	2.8	77
138	15	760
139	4.4
140	4.1	710
141	1.5	530
142	1.1	59
143	4.1	360
144	3.1	26
145	17	2500
146	1.3	46
147	2.7	86
148	14	610
149	58
150	330	1800
151	2.3	100
152	3.3	270
153	4.6	180
154	3,3
155	1.9	81
156	15
157	3.3	760
158	3.4	55
159	4.6	83
160	9.0	>5000
161	2.0	36
162	2.3	41
163	0.74	30

164	1.4	2700
165	2.1	89
166	26	2400
167	46	4300
168	21	390
169	14	370
170	14	310
171	220	1900
172	1.1	66
173	2.4	31
174	1.2	19
175	2.2	39
176	1.2	73
177	8.9	66
178	2.2	180
179	4.6	49
180	2.9	29
181	3.3	51
182	3.1	14
183	5.5	39
184	2.0	23
185	1.9	28
186	20	150
187	17	23
188	48	51
189	13	49
190	5.9	230
191	5.9	17
192	23	740
193	18	230

194	6.0	96
195	4.6	280
196	2.2	180
197	16	>5000
198	7.5	280
199	32	690
200	15	250
201	13	200
202	46	350
203	15	130
204	13	150
205	11	68
206	23	310
207	92	700
208	13	250
209	8.2	100
210	4.4	190
211	12	230
212	12	86
213	14	330
214	12	450
215	3.6	28
216	7.7	34
217	90	1200
218	130	920
219	39	>5000
220	8.5	210
221	6.2	150
222	130	1700
223	7.3	55

224	80	760
225	16	350
226	2.0	30
227	3.1	21
228	54	550
229	99	550
230	3.8	160
231	120	700
232	37	370
233	5.2	37
234	230	1000
235	29	780
236	89	1300
237	26	470
238	5.0	29
239	4.1	290
240	15	190
241	3.4	170
242	5.7	310
243	12	170
244	25	270
245	28	310
246	19	430
247	5.9	300
248	10	80
249	370	>5000
250	470	>5000
251	9.1	130
252	15	220
253	3.8	120

254	2.8	210
255	15	1800
256	4.5	51
257	7.3	150
258	430	2300
259	16	270
260	94	900
261	11	190
262	11	84
263	3.5	21
264	11	120
265	5.1	22
266	16	170
267	12	390
268	9.3	600
269	24	230
270	9.8	96
271	4.9	51
272	280	>5000
273	6.1	56
274	40	200
275	11	220
276	28	260
277	64	>5000
278	5.0	150
279	76	>5000
280	3.0	35
281	5.0	160
282	6.5	44
283	16	920

284	4.7	200
285	7.0	190
286	16	2100
287	7.0	150
288	2.5	200
289	22	1000
290	22	2000
291	4.5	89
292	8.5	150
293	3.5	110
294	7.0	200
295	7.5	150
296	12	230
297	8.5	79
298	10	130

i i

i i

The invention also relates to pharmaceutical préparations, containing as active substance one or more compounds of the invention, or the pharmaceutically acceptable dérivatives thereof, optionally combined with conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelled forms. An isotopically-labelled form of an active agent of a combination of the présent invention is îdentical to said active agent but for the fact that one or more atoms of said active agent 10 have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature. Examples of isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the présent invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, 15 phosphorous, fluorine and chiorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ^,5N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. An active agent of a combination of the présent invention, a / prodrug thereof, or a pharmaceutically acceptable sait of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the présent invention.

The invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. Ail such isomeric forms of these compounds are expressly included in the présent invention. Each stereogenîc carbon may be in the R or S configuration, or a combination of configurations.

Some of the compounds of the invention can exist in more than one tautomeric form.

The invention includes methods using ail such tautomers.

Ail terms as used herein in this spécification, unless otherwise stated, shall be understood in their ordînary meaning as known in the art. For example, “C_if) alkoxy” is a Ci-6 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. Ail alkyl, alkenyl, and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more spécifie définitions are as follows:

The term “alkyl” refers to both branched and unbranched alkyl groups. It should be understood that any combination term using an “alk” or “alkyl” prefix refers to analogs according to the above définition of “alkyl”. For example, terms such as “alkoxy”, “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom. “Alkanoyl” refers to an alkyl group linked to a carbonyl group (C=O).

In ail alkyl groups or carbon chains, one or more carbon atoms can be optionally replaced by heteroatoms such as O, S or N. It shall be understood that if N is not substituted then it îs NH. It shall also be understood that the heteroatoms may replace either terminal carbon atoms or internai carbon atoms within a branched or unbranched carbon chain. X

Such groups can be substituted as herein above described by groups such as oxo to resuit in définitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.

As used herein, “nitrogen” and “sulfur” include any oxidîzed form of nitrogen and sulfur and the quatemized form of any basic nitrogen. For example, for a -S-Cj_₆ alkyl radical, unless otherwise specified, shall be understood to include -S(O)-Ci_6 alkyl and -S(O)₂-C_M alkyl.

The term C1.3hydroxy also means -Ci^alkyl-hydroxy or -C'i ;alkyl-OH.

The term “C3_to carbocycle” refers to a nonaromatic 3 to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, or spirocyclîc carbocyclic radical. The C3.10 carbocycle may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the création of a stable structure. Non-limiting examples of 3 to 10-membcred monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6 to 10-membered fused bicyclic carbocyclic radicale include bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalcnyl). Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicale include bicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl. Non-limiting examples of 6 to 10-membered spirocyclîc carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.

The term “Cé-io aryl” or “aryl” refers to aromatic hydrocarbon rings containing from six to ten carbon ring atoms. The term C^io aryl includes monocyclic rings and bicyclic rings where at least one of the rings îs aromatic. Non-limiting examples of C^jq aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl. X

The term “5 to 11 -membered heterocycle” refers to a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be either saturated or partially unsaturated. Non-limitîng examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1dioxo-A-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non10 limiting examples of nonaromatic 6 to 11-membered fiised bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to 11-membered bridged bicyclic radicals include 2azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to 11-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spîro[3,4]octanyl, and 7-azaspiro[3,4]octanyl.

The term “5 to 11-membered heteroaryl” shall be understood to mean an aromatic 5 to 6membered monocyclic heteroaryl or an aromatic 7 to 11-membered heteroaryl bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazînyl, and purinyl. Non-limiting examples of 7 to 1125 membered heteroaryl bicyclic heteroaryl rings include benzîmidazolyl, quinolinyl, dihydro-2//-quino[iny!, isoquinoiinyl, quinazoiinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, pyridooxazinyl, dîhydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrroiopyridinyl, pyrrolopyrazinyl, and benzothiazolyl.

It will be understood that one to three carbon ring moieties in the each of the C₃_io carbocyclic rings, the 5 to 11-membered heterocyclic rings, the nonaromatic portion of the bicyclic aryl rings, and the nonaromatic portion of the bicyclic heteroaryl rings can independently be replaced with a carbonyl, thiocarbonyl, or iminyl moiety, i.e., -C(=O)-, -C(=S)- and -C(=NR⁸)-, respectively, where R⁸ is as defined above.

The term “heteroatom” as used herein shall be understood to mean atoms other than carbon such as O, N, and S.

The term “halogen” as used in the présent spécification shall be understood to mean bromine, chlorine, fluorine or iodine. The définitions “halogenated”, “partially or fully halogenated”; partially or fully fluorinated; “substituted by one or more halogen atoms”, includes for example, mono, dî or tri halo dérivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH₂CHF₂, -CF₃ etc.

Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogs thereof, described herein shall be understood to be optionally partially or fully halogenated.

The compounds of the invention are only those which are contemplated to be ‘chemîcally stable’ as will be appreciated by those skilled in the art. For example, a compound which would hâve a ‘dangling valency’, or a ‘carbanion’ are not compounds contemplated by the inventive methods disclosed herein.

The invention includes pharmaceutically acceptable dérivatives of compounds of formula (I). A pharmaceutically acceptable dérivative refers to any pharmaceutically acceptable sait or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active métabolite or pharmacologically active residue thereof. A pharmacologically active métabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemîcally. This includes, for example, hydroxylated or oxidîzed dérivative compounds of the invention.

Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfiiric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartane, acetic, citric, methanesulfonic, formic, benzoîc, malonîc, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the préparation of salts usefol as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali métal (e.g., sodium), alkaline earth métal (e.g., magnésium), ammonium and N-(C |-C^ alkyl)4⁺ salts.

In addition, within the scope of the invention is use of prodrugs of compounds of the invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysîs, oxidation and réduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula I may be made using the general synthetic methods described below, which also constitute part of the invention.

GENERAL SYNTHETIC METHODS

The invention also provides processes for making compounds of Formula (I). In all Schemes, unless specified otherwise, R¹, R², R³, R^{4 an}^ R⁵ in the Formulas below shall hâve the meaning of R¹, R², R³, R⁴ and R^s in Formula (I) of the invention described herein above.

Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, températures, pressures, and other reaction conditions may be readily selected by one of ordinary skill în the art. Spécifie procedures are provided in the Synthetic Examples section. Typicalîy, reaction progress ^z may be monitored by thin layer chromatography (TLC) or LC-MS, if desired, and intermediates and products may be purified by chromatography on silica gel, recrystallization and/or préparative HPLC.

The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue expérimentation, Starting materials and intermediates used, in the Schemes below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.

The compounds of Formula (I) may be synthesized according to Scheme 1:

Scheme 1

As illustrated in scheme 1, reaction of a compound of formula II with a boronic acid or the corresponding boronic acid ester shown in the above scheme, in a suitable solvent, în the presence of a suitable catalyst, provides a compound of formula (I). Ra and Rb are hydrogen or Ra and Rb together with the oxygen atoms to which they are attached form a 5-6 membered ring optionally substituted with 2-4 methyl groups.

Alternatively, reaction of a compound of formula II with a diborane, under standard reaction conditions, provides a compound of formula III. Coupling the intermediate of z' formula III with a halide or triflate R³X, in a suitable solvent, in the presence of a suitable catalyst, provides a compound of formula (I). X is chloro,bromo, triflate, or iodo.

The compounds of Formula (I) may be prepared according to Scheme 2:

R⁵COCI or

R5COOH

Scheme 2

As illustrated in scheme 2, réaction of a compound of formula IV with an acid chloride

R⁵COC1, in a suitable solvent, in the presence of a suitable base, provides a compound of formula (I).

Altematively, reaction of a compound of formula IV with an acid R⁵COOH, in a suitable solvent, in the presence of carbonyl diimidazole, or other suitable amide coupling reagent, provides a compound of formula (I).

The intermediate of formula Π may be synthesized as outlined in Scheme 3 : S

Scheme 3

As illustrated in scheme 3, reaction of a nitrile of formula V with a halide R*X, in a suîtable solvent, in the presence of a suîtable base such as sodium hydride or potassium tbutoxide, provides a substituted nitrile of formula VI, Further reaction of the intennediate of formula VI with a halide R²X, in a suîtable solvent, in the presence of a suîtable base, provides the corresponding disubstituted nitrile of formula VII. X is chloro, bromo, or iodo. Reaction of the compound of formula VII with hydroxylamîne, under standard reaction conditions, provides a compound of formula VIII. Réaction of the compound of formula VIII with an acid chloride R⁵COC1, in a suîtable solvent, in the presence of a suîtable base, provides a compound of formula II. Alternative!y, reaction of a compound of formula VIII with an acid R⁵COOH, in a suîtable solvent, in the presence of carbonyl diimidazole, or other suîtable amide coupiing reagent, provides a compound of formula 15 II.

Aitematively, reaction of a compound of formula VIII with a reagent such as carbonyldiimidazole provides a compound of formula II wherein R^s îs -OH. Further tranformation of this -OH may be carried out by procedures known in the art, to provide additional compounds of formula II.

100

Nitrile intermediate of formula VII may also be resolved via resolution techniques, known to one skilled in the art, to provide the enantiomers VIIA and VIIA’. Each of these enantiomers may be further converted to a compound of formula I by the reaction sequence shown above in scheme 3.

The intermediate of formula II may also be synthesized as shown in Scheme 4:

Scheme 4

As shown în scheme 4, réaction of a carbonyl compound of formula IX with a grignard reagent R²MgX, in a suitable solvent, provides a hydroxy compound of formula X. Conversion of the hydroxyl group in compound of formula X to a cyano group, using 15 standard procedures, provides a compound of formula VII. The compound of formula

VII is converted to the intermediate of formula II by the reactions shown in scheme 3. X in R²MgX is chloro, bromo or iodo.

The intermediate of formula IV may be synthesized according to Scheme 5:

As illustrated above in scheme 5, reaction of a nitrile of formula VII with a boronic acid or the corresponding boronic acid ester shown in the above scheme, in a suitable solvent, /

101 in the presence of a suitable catalyst, provides a compound of formula XI. Ra and Rb are hydrogen or Ra and Rb together with the oxygen atoms to which they are attached form a 5-6 membered ring optionally substituted with 2-4 methyl groups. Reaction of a compound of formula XI with hydroxylamine, under standard reaction conditions, provides a compound of formula IV.

The nitrile intermediate of formula VII may be synthesized according to Scheme 6:

Scheme 6

As illustrated în scheme 6, reaction of a ketone of formula XIII with methylating agent in the presence of a suitable base, in a suitable solvent, provides an enolether of formula XIV. Reaction of the enolether XIV with an oxidizing agent such as ozone, under suitable conditions, provides an ester of formula XV. Hydrolysis of the ester of formula XV, in a suitable solvent, in the presence of a suitable base, provides an acid of formula XII. This racemic acid may be resolved to provide the enantiomers XiïA and XIIA’. Altematively, the acid XII may be reacted with an organic base such as a primary or secondary amine, în a suitable solvent, to provide the corresponding sait. /

102

Reaction of a carboxylic acid of XII with a reagent such as ammonia, in a suitable solvent, provides an amide of formula XVII. Reaction of the amide of formula XVII with a suitable dehydrating agent, în a suitable solvent, provides a nitrile of formula VII. Non-limiting examples of bases useful in step (a) include potassium t-butoxide, sodium tbutoxide, lithium ΐ-butoxide, sodium hydride, potassium hydride, lithium hydride, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, LD A, n-butyllithium, sec-butyllithium or t-butyllithium. Nonlimiting examples of solvents useful for step (a) include dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropylmethyl ether. Non-limiting examples of alkylating agents useful in step (a) include dimethyl sulfate, dimethyl carbonate, bromomethane, methyl trifluoromethanesulfonate and iodomethane. Non-limiting examples of silylating agents useful in step (a) include trimethylchlorosilane, tertbutyldimethylchlorosilane, triphenylchlorosilane, and triisopropylchlorosilane, triethylchlorosilane.

Non-limiting examples of solvents useful in step (b) include dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropylmethyl ether. Non-limiting examples of bases useful in step (b) include l,8-diazabicycloundec-7-ene (DBU), triethylamine, pyridîne, 4methylmorpholine, diisopropylethylamine and dimethylamine. Non-limiting examples of dehydrating agents usefiil in step (b) include acetic anhydride, methanesulfonyl chloride, trifluoroacetic anhydride, toluenesulfonyl chloride, sodium hypochlorite, calcium hypochlorite and tert-butyl hypochlorite.

Non-limiting examplcs of bases useful in step (c) include potassium hydroxide, sodium hydroxide, lithium hydroxide and césium hydroxide. Non-limiting examples of solvents usefiil in step (c) include methanol, methanol-water mixture, dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropylmethyl ether. /

103

The resolution of the racemic acid of formula ΧΠ described in optional step d) can be carried out using methods known in the art including, for example, fractional crystallization and chiral chromatography.

In one embodiment, the invention relates to a process of making intermediate acids XII, XII A or XIIA’ according to scheme 6 above. In another embodiment the invention relates to an intermediate acid of formula XII, XIIA or XIIA’

Compounds of formula I as well as întermediates prepared by the above methods may be further converted to additional întermediates or compounds of formula I by methods known in the art and exemplîfied in the Synthetic Examples section below.

SYNTHETIC EXAMPLES

The following are représentative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art.

LCMS rétention time and observed m/z data for the compounds below is obtained by one of the following methods:

LC-MS Method A

Column	Agilent Zorbax Eclipse XDB-C8 5pm 4.6x150mm Ambient temperatur
Mobile phase	A = Formic acid (aq) 0.1% B = Formic acid (acetonitrile) 0.1%
Flow rate	1.5 ml/min
Injection volume	7uL
Detector	200-600 nm
Gradient	Time (mins)	%B
	0	1

104

I ί J i

2	20
7	95
9	95
9.3	1
10	1

LC-MS Method B

Column	Agilent Zorbax C18 SB 3.5pm, 4.6x30mm Ambient température
Mobile phase	A = Formic acid (aq) 0.1 % B = Formic acid (acetonitrile) 0.1%
Flow rate	2.5 ml/min
Injection volume	7pL
Detector	200-600 nm
Gradient	Time (mins)	%B
	0	5
1.7	95
2	95
2.1	5
2.3	5

LC-MS Method C

Column	Agilent SB-C18 l.Spm, 3x50mm Ambient température
Mobile phase	A - Formic acid (aq) 0.1% B = Formic acid (acetonitrile) 0.1%
Flow rate	1.5 ml/min
Injection volume	3gL

105 ί

Detector	220 and 254 nm
Gradient	Time (mins)	%B
	0	5
3.8	90
4.5	100

LC-MS Method D

Column	Agilent SB-C18 l.Spm, 3x50mm column Ambient température
Mobile phase	A = Formic acid (aq) 0.1% B = Formic acid (acetonitrile) 0.1%
Flow rate	1.5 ml/min
Injection volume	3pL
Detector	220 and 254 nm
Gradient	Time (mins)	%B
	0	12
0.25	30
0.3	40
1.19	95
1.75	100

LC-MS Method E

Column	Agilent SB-AQ Ι.δμιη, 3x50mm Ambient température
Mobile phase	A = Formic acid (aq) 0.1 % B — Formic acid (acetonitrile) 0.1%
Flow rate	1.5 ml/min
Injection volume	3pL

106

Detector	220 and 254 nm
Gradient	Time (mins)	%B
	0	5
0.25	50
0.3	70
1.3	90
1.7	100

LC-MS Method F

Column	Waters Atlantis dC18 100 x 2.1mm, 3pm column 40 °C
Mobile phase	A - 0.1% Formic acid (water) B - 0.1% Formic acid (acetonitrile)
Flow rate	0.6 ml/min
Injection volume	3pL
Detector	215nm (nominal)
Gradient	Time (mins)	%B
	0	5
5	100
5.4	100
5.42	5

Synthetic Methods

The compounds of the invention may be prepared by the methods described below. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, températures, pressures and other

107 reaction conditions may be readily selected by one of ordinary skill in the art. Spécifie procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, 5 recrystallization and/or reverse phase HPLC. HPLC purification methods used anywhere from 0-100% acetonitrile in water and may contain 0.1% formîc acid, 0.1% TFA or 0.2% ammonium hydroxide and used one of the following columns:

a) Waters Sunfire OBD Cl8 5 μΜ 30x150 mm column

b) Waters XBridge OBD C18 5 μΜ 30x150 mm column

c) Waters ODB C8 5 μΜ 19x150 mm column.

d) Waters Atlantis ODB C18 5 μΜ 19x50 mm column.

e) Waters Atlantis T3 OBD 5 μΜ 30x100 mm column

f) Phenomenex Gemini Axia C18 5 μΜ 30x100 mm column

g) Waters SunFire C18 Prep OBD 5um 19 x 100 mm

h) Waters XBridge Prep C18 5 um 19 x 100 mm

Starting materials and reagents are either commercially avaîlable or may be prepared by one skilled in the art using methods described in the chemical lîterature.

Synthesis of Nitrile Intermediates:

Synthesis of 2-(4-bromo-phenyl)-2,3-dijnethylbutyronitrile X

108

To a solution of R-l (20.0 g, 0.102 mol) in DMF (300 mL) at 0 °C is added NaH (60% in oil suspension, 4.28 g, 0.107 mol) slowly. The mixture is then stirred for a further 15 minutes and 2-bromopropane (9.60 mL, 0.107 mol) is added. The reaction mixture is allowed to warm to room température, stirring contînued for 2 hours and then concentrated in vacuo. The residue is partitioned between CH₂C1₂ and brine. The combined organics are dried with Na₂SO₄, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 0-15% EtOAc in heptane) to give 1-1 (21.3 g); m/z 238.3, 240.2 [M/M+2H]

1-1 (21.3 g, 89.6 mmol) is dissolved in DMF (300 mL). The mixture is cooled to 0 °C and NaH (60% in oil suspension, 3.76 g, 94.1 mmol) is added slowly. The mixture is then stirred for a further 15 minutes and methyl iodide (5.9 mL, 94.1 mmol) is added. The reaction mixture is stirred at 0 °C to room température for 2 hours and then concentrated m vacuo. The residue is partitioned between methylene chloride and brine. The combined organics are dried with Na₂SC>4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 0-15% EtOAc in hepatne) to give the tîtle intermediate (21.7 g); m/z 252.3, 254.3 [M/M+2H].

The following intermediates are synthesîzed in similar fashion from the approprîate reagents:

Intermediate	Structure
1-3	.Y

Synthesis of 2-(4-bronio-phenyl)-2-cydopropylpropionitrile S

109

To a solution of R-2 (5.00 g, 22 mmol) in THF (30 mL) is added a solution of MeMgBr (l.OM in butyl ether, 27.0 mL). The solution is stirred for 30 min then treated with saturated aqueous NaHCO₃. The mixture is partîoned between CH2CI2 and brine then organics are collected, dried with MgSO₄, filtered, and concentrated to give R-3 (5.35 g).

To a solution of R-3 (5.35 g, 22.2 mmol) in CH2CI2 (100 mL) is added TMSCN (5.9 mL, mmol) and InBr₃ (790 mg, 2.22 mmol). The reaction is stirred ovemîght then poured into 20% aqueous Na2CO₃. The mixture is extracted with CH2CI2, dried with MgSO₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography 10 (SiO2, 0-15% EtOAc in heptane) to give the title intermediate (3.82 g); ’H-NMR, 400

MHz, DMSO-iZdppm: 7.65 (2H)(d: J=12 Hz); 7.52 (2H)(d: J-12 Hz); 1.69 (3H) (s); 1.41 (IH) (m); 0.68 (IH) (m); 0.58 (2H)(m); 0.41 (IH) (m).

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
1-5	.X	265.2

2-(4-Bromo-phenyl)-2-cyclopropylpropionitrile can also be prepared in the following manner:

To a solution of R-2 (309 g, 1.37 mol) in THF (3.0 L) îs added dropwise MeMgBr (3M in Et₂O 1.37 L, 4.12 mol) at -78 °C. The mixture is stirred at -78 °C for 10 min and then at room température for 2 h. The reaction mixture is quenched with saturated aqueous '

110

NH4CI and extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Ni^SO-, and concentrated to afford the crude compound R-3 (330

g) which is used in the next step without further purification.

To a solution ofR-3 (330 g, 1.37 mol) in CH₂C1₂ (2.4 L) is added dropwise BF₃.EtO₂ (198 g, 1.37 mol) at -78 °C. The mixture is stirred at the same température for 30 min. TMSCN (272 g, 2.74 mol) is added drop-wise at -78 °C. After addition, the mixture is allowed to stir at room température for 2 h. The reaction mixture is quenched with chilled water and the organic layer is separated. The aqueous phase is extracted with CH₂C1₂. The organic layer is washed with brine, dried over anhydrus NajSCL and concentrated. The residue is purified by chromatography on silica gel with petroleum ether/EtOAc (50:1) to give the title intermediate (160 g).

Préparation of (R)-2-(4-bromo-phenyl)-2-cyclopropylpropionitrile (1-6) and (5)-2-(4 bromo-phenyI)-2-cyclopropylpropiomtriie (1-7)

Enantiomers 1-6 and 1-7 are prepared by resolution of 1-4 (150 g) on a ChiralPak AY-H 300x20mm SFC column (eluting 85:15 SF CO₂:ethanol, 80 mL/min flow rate). The faster eluting isomer is determined to be 1-7; ¹ H-NMR, 400 MHz, CDC13-ri6 ppm: 7.547.50 (2H)(m); 7.41-7.37 (2H)(m); 1.73 (3H) (s); 1.26-1.19 (1H) (m); 0.74-0.50 (4H) (m); the slower eluting isomer is 1-6; ’H-NMR, 400 MHz, CDC13-riô ppm: 7.54-7.50 (2H)(m); 7.41-7.37 (2H)(m); 1.73 (3H) (s); 1.26-1.19 (1H) (m); 0.74-0.50 (4H) (m).

Synthesis of 2-(4-hroino-phenyl)-3,3-dimethylbutyronitrile S

111

H

R-4 t-BuMgBr

To a solution of t-BuMgBr (l 10 mL, 1.0 M in THF) is added a solution of R-4 (10 g, 54 mmol) in THF (50 mL). The solution is stirred for 10 min then treated with saturated aqueous NaHCth. The mixture is partioned between methylene chloride and brine, the 5 organics are collected, dried with MgSOi, filtered, and concentrated. Purification of the crude by flash chromatography (SiO₂, Heptane to 15% EtOAc in Heptane) gives a yellow solid that is further purified by slurrying in heptane to give after filtration R-5 (4.67 g).

To a solution of R-5 (4.63 g, 19.0 mmol) in CH₃CN (100 mL) is added imîdazole (3.89 g, 57.1 mmol) followed by PhTBr? (24.1 g, 57.1 mmol). The mixture is heated at 40 °C for 10 6 h then cooled to 23 °C and partioned between EtOAc and satuared aquoues NalICO-,.

The organics are collected, washed with water, dried with MgSÛ4, filtered, and concentrated in vacuo. The residue is slurried in hepatane and resulting solid is filtered.

The filtrate is collected and volatiles are removed in vacuo. The residue is dissolved in DMSO (100 mL) and treated with NaCN (1.11 g, 22.7 mmol). The mixture is heated at 15 140 °C for 3h then cooled to 23 °C. The mixture is partioned between Et₂O and water.

The organics are washed with water, dried with MgSO4, filtered, and concentrated. Purification of the crude by flash chromatography (SiO₂, Hep to 15%EtOAc in Hep) yields the title intermediate (2.37 g) ’H-NMR, 400 MHz, CDC1₃ ppm: 7.59 (2H)(d: J-12 Hz); 7.33 (2H)(d: J-12 Hz); 4.26 (lH)(brs); 1.35 (9H)(s).

Synthesis of Carboxamidine Intermediates

Synthesis of 2-(4-bronio-pheny])-A-hydroxy-2.3-dimethylbutyraniidine

112

A solution of 1-2 (10.0 g, 40 mmol) în EtOH (50 mL) is treated with 50% aqueous hydroxylamine (50 mL). The reaction is heated at 80 °C overnight then concentrated in vacuo. The solid is filtered and washed with water then heptane. The solid is collected and triturated with EtOAc then filtered, collected, and dried to afford the title intermediate (10.4 g); m/z 285.4;287.2 [M/M+2H]

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z IM/M+2H]
1-15	rxvSiNH2 Br'Xz	Not available
1-16	XXz Br OH	283.0/285.0
1-17	Br-XX N'OH	283.1/285.0
1-19	A, /A\/nh 2 JU 1 BT OH	283.1/285.0

Synthesis of 2-[4-(2-aminopyrimidin-5-yI)phenyl]-iV-hydroxy-2,3-dimethyl butanimidamide

113 i

A solution of 1-2 (2.00 g, 7.93 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (2.63 g, 11.9 mmol), and tetrakis(triphenylphosphîne)palladium(0) (459 mg, 0.397 mmol) in THF (20 mL) and saturated aqueous NibCCL (10 mL) is heated at 80 °C for 3 h. The 5 mixture is cooled to 23 °C then partioned between EtOAc and brine. The organics are collected, dried with MgSO4, filtered, and concentrated to give a residue that is purified by flash chromatography (SiOi, CH2CI2 to 3%MeOH in CH2CI2) to afford 1-20 (m/z 267.5 [M+H]).

The following intermediates were synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
I-20A	h2n^4	264.0
I-20B	JÎjX Λ J H2N N	265.1
I-20C	JJ J A Λ J h2n n	267.0

114

I-20D	jfj^N	253.1
I-20E	N A J H2N N	Not available
I-20F	,0,pJU	281.7

1-20 îs dissolved in EtOH (30 mL) and treated with 50% aqueous hydroxylamine (12 mL). The reaction is heated at 80 °C for 48 h then cooied to 23 ’C and filtered through 5 Celite. The filtrate is partioned between EtOAc and water. The organics are collected, dried with MgSOt, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (S1O2, CH2CI2 to 10%MeOH in CH₂C1₂) provides the title intermediate (1.56 g); m/z: 300.4 [M+H]

The following intermediates were synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
1-22	n-oh h2n^nx	312.4

115

1-23	AA %h h2n^n^	298.4
1-24	ν.οη Λ J h2n N	Not available
1-25	pX™, AYX·' n oh h2n^A	286.2
1-26	pANH, ν'Ύχ·;; n-oh Λ J h2n n	272.1
1-27	fAA -CA/J %„	Not available

Synthesis of: (R)-2-]4-(2-amino-pyrimidin-5-yl)-phenyl)-2-cyclopropyl-N-hvdroxypropionamidine

To a mixture of 1-6 (18.5 g, 0.074 mol) in THF (300 mL) are added 5-(4,4,5,5tetramethyI-[l,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (19.6 g, 0.089 mol), tetrakis A

116 (triphenylphosphine)palladium (0) (8.5 g, 0.007 mol) and 2M Nî^COj (74 mL, 0.148 mol). The mixture is heated to 80 °C for 24 hours. The solution is cooled down to room température and is extracted with EtOAc and water. The combined organic layer is dried with \lgSO4 and is filtered. The filtrate is concentrated and the residue is re-suspended in CH₂Ci₂. The solid that precipitated out from the solution is collected by filtration. The solid is dried and is confirmed to be 1-28 (14.8 g); m/z 265.4 [M+H].

A suspension of 1-28 (14.8 g, 0.056 mol), KOH (15.7 g, 0.28 mol), and hydroxylamine solution in H₂O (50% by weight) (34 mL, 0.56 mol) is stirred at 85 °C for 48 hours. The mixture is cooled and the solid is filtered and is dried to afford the title intermediate (12.5

g); m/z 298.4 [M+H], phenyl] -p ropionamidine

Synthesis of (R)-2-Cvclopropyl-N-hydroxv-2-|4-(2-methylainino-pyrimidin-5-yl)-

H__ \/ /

In a 5 ml microwave reaction vessel are combined 5-bromo-2-(methylamino)pyrimidine (451 mg, 2.39 mmol) and hexamethyldistannane (0.456 ml, 2.19 mmol) in toluène (5 ml). The mixture is degassed using argon after which tetrakis(triphenylphosphine) palladium (0) (115mg, 0.10 mmol) is added. The reaction is degassed once more, capped and warmed to 115°C for lh. Upon cooling to ambient température, 1-6 (500 mg, 1.99 mmol) is introduced along with tetrakis(triphenylphosphine) palladium (0) (115 mg, 0.10 mmol). The vessel is capped and warmed to 115°C over night. After this time the reaction is cooled and concentrated. The resulting solid is purifîed via flash chromatography (silica gel, 0-100% EtOAc/heptanes) to afford I-29bis (134 mg); m/z 279.4 [M+H].

To a suspension of I-29bis (134 mg, 0.481 mmol) in EtOH (3.2 ml) is added hydroxylamine solution in H₂O (50% by weight) (1.18 mL, 19.24 mmol) is stirred at 85 °C for 72 hours. The mixture is cooled and concentrated, and diluted with water and λ'

117 ethyl acetate. White solid is filtered and is dried, organic is purified by flash chromatography and combined with solid to afford the tîtle intermediate, (110 mg); m/z 312.4 [M+H].

Synthesis of Aryl Bromide Intermediates

Synthesis of 3-[2-(4-bromophenyl)-3-methylbutan-2-yl]-5-cyclopropyl-l,2,4oxadiazole

Pyridine

A mixture of 1-14 (150 mg, 0.53 mmol) and cyclopropylcarbonyl chloride (60 mg, 0.58 mmol) in pyridine (2 mL) îs stirred at room température for 15 minutes before heating at 110 °C for 18 h. The réaction mixture is concentrated in vacuo, then partitîoned between CH2CI2 and saturated aqueous NaHCO₃. The organics are dried with NiibSO.j, filtered and concentrated in vacuo to give the title intermediate (167 mg); m/z 336.0 [M+H].

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure
1-31	CH Q V-N 0 π Ύ H A V/
1-32	BrJU

118

Synthesis of

5-{3-[2-(4-bromophenyl)-3-methylbutan-2-yl]-l,2,4-oxadiazol-5yl}pyrimidine

To a solution of pyrimidine-5-carboxyiic acid (200 mg, 0.70 mmol) in pyridine (l.O mL) is added thionyl chloride (61 uL, 0.84 mmol). The mixture is stirred at room température for 15 minutes before 1-14 (91 mg, 0.74 mmol) is added. The resulting mixture is heated at 110 °C for 18 h then concentrated in vacuo. The residue îs partitîoned between EtOAc and saturated aqueous NalICOj, washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo to give the title compound (236 mg); m/z 373.0, 375.0 [Μ, M+2H]

The following intermediates were synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z
1-36	iX h n JxJ Ν-χ Br	361.0/363.0 [M/M+2H]

X

119

1-37	w	422.0/424.0 [M/M+2H]
1-38	xAy+x Br	397.0/399.0 [M/M+2H]
1-39	£ Tl HJ< N-o	380.0 [M+2H]
1-40	il T yO JL AA N-o N ' Br u	392.0/394.0 [M/M+2H]
1-41	T/AvA _ A/ N-0	362.0/364.0 [M/M+2H]
1-42	jrjjf aa^nh ΒγΑ<> N-o γ	389.0/391.0 [M/M+2H]
1-43	âHwi ΒγΛΡ n-o a n	Not available
1-44	z°~Ï1 os >-Vn Brx> N-° r	Not available
1-45	AT><An /-n os H? Br--^.O «-o S	Not available

120

1-46	Br	cr	X.-N ii yN-o	/=N ib	372.0/374.0 [M/M+2H]
1-47	Br	o	AXn « > N-o	ΛΝ A-nh	361.0/363.0 [M/M+2H]
1-48	Br	jO	AAn N-o	r=N Ab	374.0 [M+H]
1-49	Br'	n	Ύ y N-q	°a Ό	450.0 [M+H]
1-50	Br'	.o	AL o A<An u A N-o	y° Ab	Not avaîlable
1-51	Br''	cr	<L-N T y- N-O	_/ N	393.0 [M+H]
1-52	i Br	b	\.N Y y- N-O	cy	388.0 [M+H]
1-53	Br		XJn h y N-o	Ar	388.0 [M+H]
1-54	BX	O	?Cn T x) N-o	/Y A-N	407.0 [M+H]

I2l

1-55	AX	M	390.0 [M+H]
1-56		N-ci	404.0 [M+H]
1-57	a	HO Sytr	403.0 [M+H]
1-58	a		372.4/374.5 [M/M+2H]

Synthesis of 3-[l-(4-bromo-phenyl)-l-cycIopropyI-ethyl]-5-(lH-pyrazol-4-yl)-[l,2,4] oxadiazole

1,1'-Carbonyldiimidazoie (4.9 g, 30.7 mmol) is added to a mixture of lH-pyrazole-4carboxylic acid (3.4 g, 30.7 mmol) in 1,4-dioxane (150 ml). The mixture is stirred at 50°C for 30 minutes, 1-16 is added and the reaction mixture is heated at 85°C for 48 hours. The reaction mixture is cooled to room température, poored into a solution of saturated NalICOi and extracted with EtOAc. The organic layers are dried over MgSO4, 10 filtered and concentrated to afford the crude product that is purified via flash chromatography (SiO₂, 0-6% MeOH/CH₂C12) to afford the title intermediate (6.9 g); m/z 359,361 [Μ, M+2H]. z

122

The following întermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z
1-60	r il r θ N W A. Xi H N N-N H	388.4 [M+H]

Synthesis of 3- [(R)-l-(4-bromo-phenyl)- 1-cyclopropyl-ethyl]-5-(l H-pyrazoi-4-yl)[ 1,2,4]oxadiazole

To a sealed tube is added lH-pyrazole-4-carboxylic acid (484 mg, 4.2 mmol) in 1,4dioxane (8 ml), followed by the addition of Ι,Γ-carbonyldiimidazole (679 mg, 4.2 mmol). The reaction mixture is stirred at 55 °C for 30 minutes. Then 1-17 (1.1 g, 4.0 mmol) in 1,4-dioxane (5 ml) is added to the above mixture. The reaction mixture is 15 stirred at 120 °C for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried under anhy. Na2SO4, filtered and

123 concentrated. The residue is purified by flash chromatography (SiO₂, 0-5%

MeOH/CH₂Cl2) to afford the title intermediate (1.3 g); m/z 359.0, 361.0 [M, M+2HJ.

Synthesîs of 2-(4-{3-[l-(4-bromo-phenyI)-l-cyclopropyl-ethyl]-[1,2,4]oxadiazol-5-yl} pyrazol-l-yl)-N,N-dimethyl-acetamide

To a solution of 1-59 (6.9 g, 19 mmol) in DMF (80 mL) are added K2CO3 (5.3 g, 38 mmol) and 2-chloro-N,N-dimethylacetamide (2.9 g, 28 mmol) at room température. The mixture is stirred at the same température for 24 hours. Water (200 mL) is added and the mixture is extacted with EtOAc (300 mL). The combined organic layer is dried with MgSO* and filtered. The filtrate is concentrated and the remaining residue was purified via silica gel flash column chromatography with 8% MeOH in CH₂C1₂ as the eluent to afford the tîtle intermediate (8.3 g); m/z 444.2, 446.2 [M, M+2J.

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate

Structure m/z [M/M+2H]

124

1-63	nrV'o AJ B< Ά , Z x 0	444.2/446.2
I-64a	J VN V OH	431.2/433.2
I-65b	P /—z VA CD	415.1/417.1

a) The reaction mixtures îs stirred at 80°C for 48 hours

b) The reaction is run startîng from the corresponding iodide and the mixture is stirred at

80°C ovemîght

Synthesis of 3-[(R)-l-(4-bromo-phenyI)-l-cyclopropyl-ethyl]-5-(l-methyl-lH5 pyrazol-4-yl)-[l,2,4]oxadiazole z

125

To a vial îs added 1-61 (550 mg, 1.531 mmol), iodomethane (0.191 mL, 3.062 mmol) and K2CO3 (423 mg, 3.062 mmol) in 6 ml of DMF. The reation mixture is stirred at room température for 2 hrs, then poured into water and brine, and extracted with EtOAc (4x25ml). The combined organic fractions are dried with sodium sulfate, filtered, and concentrated in vacuo to afford the title intermediate (516 mgs); m/z 374.0, 376.0 [M/M+2]

The following intermediates are synthesîzed in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
1-68	/Y J NA/0 Br Ά b r' ^-0	417.2/419.2

Synthesis of 2-[4-(3-{l-cyclopropyl-l-(4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2· ν1)-ρΗ6ΐιν1|-εΐ1ινΙ}-|1,2,41οχαάΪΜζ.ο1-5-ν1)-ργΓίΐζο1-1-ν1|-Ν,Ν-0ΐηΐ6ί1ιν1-3€€ΐ3ΐηΐά€ /

126

To a solution of 1-62 (2.6 g, 5.9 mmol) in 1,4-dioxane (20 mL) in a pressure vial are added bis(pinacolato)diboron (2.2 g, 8.8 mmol), KOAc (2.3 g, 23 mmol) and tetrakis (triphenylphosphine)palladium (0) (481 mg, 0.6 mmol). The reaction mixture is stirred 5 under Ar at 100°C for 4 hours. The mixture is cooled down and is concentrated in vacuo.

The residue is diluted with EtOAc (100 mL) and is passed through a plug of Celite and is rinsed thoroughly with EtOAc (20 mL). The filtrate is dried with magnésium sulfate and is filtere to afford the title intermediate (1.9 g); m/z 492.3 (M+H)

The following intermediates were synthesîzed in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
I-70a	[i ï 1 ° FJ I / vn o	492.4

127

I-71a	γχχ i vn T	479.5
I-72a	A^x yN	421.5
I-73b	crv-o yX y Vl	463.3
I-74b	ίχΧχ y V V—.o<	465.3
I-75b	.Αν AJ X,	421.3

a) l,r-bis(diphenylphosphino) ferrocenedichlaropalladium(II) dichloromethane S

128 is used instead

b) l,r-bis(dîphenylphosphino) ferrocenedichloropalladium(II) dichloromethane is used instead and the reaction mixture is stirred at 100°C ovemight

Synthesis of Boc-piperidine intermediates.

Synthesis of 5'-(3-{l-[4-(2-amino-pvrin)idin-5-yl)-phenyl|-i cyclopropyl-ethyl}[l,2,4|oxadiazol-5-yl)-2,3,5,6-tetrahydr()-|1,2^,|bipyrazinyl-4-carboxylic acid tertbutyl ester

A 250ml RB flask is charged with R-7 (5.4 g, 28.99 mmol) in 100 mL of NMP. R-8 (5.00 g, 28.99 mmol) is added followed by triethylamine (4.85 ml, 34.79 mmol). The reaction is heated to 60 °C under nitrogen ovemight. The reaction is cooled to room température, Z

129 poured into ice water and the precipitated 1-76 (8.60 g) is isolated by filtration; m/z 323.4 [M+H]

To a stirred suspension of 1-76 (8,60 g, 26.68 mmol) in éthanol (250 ml) is added 5M NaOH (26.68 ml, 133.39 mmol) at room température. The mixture becomes homogenous before a persisting precipitate forms and becomes a solid mass. Water (200 ml) is added and the mixture is stirred for 4 h after which time the reaction appears complété. The light brown sludge is poured into a beaker and treated with water. AcOH îs added to reach acidic pH and the product is extracted into DCM (2x). The combined organics are dried over anhydrous MgSO₄, filtered and concentrated to give the product as a solid which is suspended in heptanes. The solid is collected via filtration and washed with heptanes to give 1-77 (7.90 g); m/z 309.4 [M+H].

To a suspension of 1-77 (3.0 g, 9.71 mmol) in THF (40 ml) is added 1,1'carbonyldiimidazole (1.6 g, 9.71 mmol) at room température. The mixture is stirred at 50° C for 30 minutes. After this time 1-16 (2.5 g, 8.83 mmol) is added and the resultîng mixture is heated at 80°C for 3 hours. The mixture is cooled down and treated with AcOH (8ml). The mixture is warmed to 80°C and stirred over nîght. Upon cooling toroom température, the reaction îs concentrated and diiuted with water. The product is extracted into DCM (2x). The combined organics are washed with brine and dried over anhydrous MgSO4. The mixture is filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford 1-78 (2.2 g). In a microwave reaction vessel îs added 1-78 (0.50 g, 0.90 mmol) în 15ml of DMF, followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (0.30 g, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.09 mmol) and aq. Ni^CCf (2.0M, 1.8 ml). The reaction mixture is stirred at 85 °C for 16 hours. After this time the reaction mixture is poured into brine and extracted with EtOAc (3x). The combined organic fractions are dried over anhydrous MgSO₄, filtered, then concentrated in vacuo to give the crude material. Purification via flash chromatography (silica gel, 0-5% MeOH/DCM) affords the title intermediate (150 mg); m/z 570.4 [M+H] /

130

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
1-80	N j N=^ O '—N T0./ 0 A	569.4
1-81	A, /yU A AJ c > O K ° A	569.4
1-82	sa A N=Z O	570.4

131

Synthesis of 5'-(3-{(S)-l-[4-(5-amino-pyrazin-2-yl)-phenyl]-l-cyclopropyl-ethyl}]l,2,4|oxadiazol-5-yl)-2,3,5,6-ietrahydro-|1.2'|bipyraziny]-4-carboxylic acid tertbutyl ester

To a suspension of 1-77 (1.0 g, 3.53 mmol) in THF (20 ml) is added 1,1*carbonyldiimidazole (0.63 g, 3.88 mmol) at room température. The mixture is stirred at 50° C for 30 minutes. After this time 1-19 (1.2 g, 3.88 mmol) is added as a THF solution

132 ( 15 ml) and the resulting mixture is heated at 80°C for 3 hours. The mixture is cooled and treated with AcOH (8 ml) then warmed to 80°C and stirred over night. After this time the reaction is cooled to room température, concentrated and diluted with water. Extracted the product into DCM (2x). The combined organics are washed with brine and dried (MgSO₄). Filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford 1-84 (1.2 g).

In a 5 ml microwave reaction vessel are combined 5-amino-2-bromopyrazine (60 mg, 0.34 mmol) and hexamethyldîstannane (120 mg, 0.38 mmol) în toluene (2 ml). The mixture is degassed using argon after which tetrakîs(triphenylphosphine) palladium (0) (40 mg, 0.03 mmol) is added. The reaction is degassed once more, capped and warmed to 115°C for lh. Upon cooling to ambient température, 1-84 (270 mg, 0.48 mmol) is introduced along with teÎrakis(triphenylphosphine) palladium (0) (30 mg, 0.05 mmol). The vessel is capped and warmed to 115°C over night. After this time the reaction is cooled and concentrated. The crude îs suspended in DCM/MeOH, treated with silica gel and concentrated. The resulting solid is purified via flash chromatography (silica gel, 010% MeOH/DCM) to afford the title intermediate (100 mg).

Synthesîs of 4-fluoro-pyrimidin-2-ylamine

To a suspension of R-9 (100 mg, 0.77 mmol) in CH₃CN (10 mL) is added HF in Et₃N (0.26 mL, 1.5 mmol) at room température. The solution is heated to 80 °C for 48 hours. The solution is cooled down and water (10 mL) is added. The solution is extracted with EtOAc (20 mL) and H₂O (5 mL). The combined organic layer is dried with MgSO₄ and is filtered. The filtrate is concentrated to afford 1-86 (25 mg); m/z 113.9 [M+H].

133

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
I-86bis	nv+Q F	127.9

Synthesis of 5-bromo-4-fluoro-pyrimidin-2-yIamine

To a solution of 1-86 (280 mg, 2.5 mmol) in ClfCN (20 mL) is addedN10 bromosuccinimide (881 mg, 4.9 mmol) at room température. The solution is stirred at the same température for 12 hours. The solid that precipiates out from the solution is collected and is dried to afford the title intermediate (250 mg); m/z 191.9, 193.9 [M, M+2H]

The following intermediates are synthesized în similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2+H]
I-87bis	A H2N—(Z V- Br N=( F	205.9/207.9

134

Synthesis of 5-bronio-3-trifluoroinethyl-pyridin-2-ylainine

NBS

To a stirred solution of R-IO (2.70 g, 16.66 mmol) in DMF (15 ml) is added Nbromosuccinimide (3.00 g, 16.85 mmol) as a DMF solution (15 ml, dropwise). After 4 h the réaction is poured onto ice. The resulting precipitate is collected via filtration to give the product as an off-white solid. Dissolved into DCM and washed with brine. The layers are separated and the organic phase is dried (MgSO₄), filtered and concentrated to give the title intermediate (3.8 g); m/z 241.2/243.2 [M/M+2H].

Synthesis of 5-bromo-3-fluoro-pyridin-2-ylamine

NBS

To a round bottom flask is added R-l 1 (500 mg, 4.46 mmol) in CH₃CN (120 ml) at 0 °C, followed by the addition of N-bromosuccinimide (397 mg, 2.23 mmol). The réaction mixture is stirred (protected from light) vigorously for 15 minutes, then at room température for 1 hour. The additional portion of N-bromosuccinimide (397 mg, 2.23 mmol) is added at 0 °C, then the reaction mixture is stirred at room température for 2 hours. The réaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with sat Na?S₂O₃ (20 ml), brine, dried over anhy. Na₂SO.i. filtered and concentrated. The residue is purifîed by flash chromatography (S1O2, 0-20% EtOAc/heptane) to afford the title intermediate (772 mg); m/z 190.89/192.86 [M/M+2HJ. Z

135

The following intermediates are synthesîzed in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
1-90	C( 1 Ar h/J	207.9/209.9

Synthesis of (5-bromo-pyrimidin-2-yl)-tert-butyl-amine

Λ7 - R-12

/Br H 1-91

To a vîal is added R-12 (200 mg, 1.13 mmol) in DMF (5 ml), followed by the addition of

K₂CO₃ (312 mg, 2.26 mmol) and isopropylamine (134 mg, 2.27 mmol). The reaction mixture is stirred at 70 °C for 3 hours. The reaction mixture îs concentrated in vacuo. The residue is dissolved in EtOAc, washed with water, brine, dried under anhy. Na₂SO4, fitered and concentrated to afford the title intermediate (221 mg); m/z 216.0/218.0 [M/M+2HJ.

The following intermediates are synthesîzed in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
1-92	N^YBr H	202.2/204.2

136

Synthesis of 3-BenzyIoxy-5-bromo-pyridine

I-94

To a vîal is added 3-bromo-5-hydroxypyridine (200 mg, 1.15 mmol), benzyl alcohol (137 mg, 1.27 mmol) and triphenylphosphine (332 mg, 1.27 mmol) in THF (5 ml) at 0 °C, followed by the addition of dîisopropyl azodicarboxylate (256 mg, 1.27 mmol). The reaction mixture is stirred at room température for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with sat NaHCOj, water, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is purified 10 by flash chromatography (S1O2, 0-5% MeOH/C^CL) to afford title compound (97 mg);

m/z 264.0, 266.0 [Μ, M+2H]

Synthesis of 5-Bromo-3-trifluoromethyl-pyrazin-2-ylamine

To a solution of 2-amino-5-bromopyrazine (174 mg, 1 mmol) in DMSO (3ml) stirring under Ar is added ferrocene (56 mg, 0.3 mmol) and degassed for 5 minutes with Ar. 2ml '

137 of IN H2SO4 in DMSO is added, followed by CF3I (0.276 ml, 3 mmol) in DMSO (2 ml), giving a slight yellow solution. 0.2ml of 30% H₂O₂ is added slowly, causing the reaction to go from yellow to dark green in color. The reaction was heated to 50 °C for 2 hours under Ar. After cooling to room température, the reaction mixture is poured into brine, and product is extracted with EtOAc (4x20ml). The combined organic fractions are dried with magnésium sulfate, filtered, then concentrated in vacuo. The crude material was purified by flash chromatography (SiO₂, Biotage SNAP 10g, 0-50% EtOAc/hept) which yields 70 mg of title compound; m/z 242.0, 244.0 (Μ, M+2H)

Synthesis of 4-benzyIoxy-5-bronio-pyrÎmidin-2-y)amine

1-96

1-90

A 20 ml microwave reaction vessel îs charged with benzyl alcohol (7.0 ml) and sodium (145 mg, 6.33 mmol). The vessel is capped and stirred at ambient température until the sodium is consumed. After this time, 1-90 (1.10 g, 5.28 mmol) is added and the reaction is warmed to 130°C for 2h. Upon cooling to room température the reaction mixture is concentrated to low volume. The remaining residue is diluted with water. The water is decanted and the remaining oil is treated with méthanol. The precipîtated solid is collected via filtration and washed with méthanol to give the title intennedîate (0.86 g); m/z 282.0 [M+H].

Synthesis of (5-bromo-pyridin-2-yl)-methyl-amine

138

H l-96bis

A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33% solution in éthanol, 84.43 mmol) and warmed to 80°C for 3 days. After this time the reaction is concentrated and the remaining solid is treated with IM HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using IN NaOH (to pH-11). The product was extracted into DCM (2x) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). lH-NMR (400MHz, DMSOd6): 2.75 ppm (d, 3H), 6.44 ppm (d, IH), 6.72 ppm (bs, IH), 7.51 ppm (dd, IH), 8.05 ppm (s, 1 H)

Synthesis of 2-[4-(3-Î(R)-l-[4-(2-AmÎno-4-benzyIoxy-pyrimidin-5-yl)-phenylJ-l-cyclo propybethvlHL2,4|oxadiazoI-5-yl)-pyrazol-l-yl|-N,N-dimethyl-acetamide

1-97 is prepared following Method 26 (using Palladium tetrakis, 2M Na₂CO_Î5 and DMF at 85°C for 16h); m/z 565.0 [M+H].

Synthesis of 2-{2-[4-(3-{(R)-l-[4-(2-Amino-pyriïnidin-5-yl)-phenyl]-l-cyclopropyl-et hyI}-[l,2,41oxadiazol-5-yl)-pyrazoH-ylJ-ethyI}-isoindole-l,3-dione /

139

Example 48 (100 mg, 0.266 mmol) is treated with DMF (2.5 mL), 2-(2-Bromo-ethyl)isoindole-l,3-dione (101 mg, 0.399 mmol), and CS2CO3 (83.0 mg, 0.599 mmol) and the reaction is stirred ovemight. The resulting mixture is diluted with water and ethyl acetate and the phases separated. The organic phase is washed with water and brine, dried over Na₂SO4, filtered, and concentrated in vacuo. The resulting residue is purified by flash chromatography over silica eluting 0-10% methanol/CH₂Cl₂ to give 1-98 (120 mg).

Synthesis of Final Compounds

Method 1

Synthesis of 2-(3-{2-[4-(5-methoxypyridin-3-yl)phenyl]-3-methylbutan-2-yI}-l,2,4oxadiazoI-5-yl)pyrazine (Example 1, table 1)

Hunig’s base

DMF

To a solution of 1-27 (200 mg, 0.64 mmol) in DMF (5 mL) is added Hunig’s base (0.3 mL, 1.6 mmol) followed by pyrazine-2-carbonyl chloride (110 mg, 0.80 mmol). The reaction mixture is heated at 120 ’C for 2 h then volatiles are removed in vacuo. The residue is purified by flash chromatography (SiO₂, heptane to 60% EtOAc in heptane) to give the title compound (165 mg). Z

140

The following compounds were synthesized in similar fashîon from the appropriate intermediates:

Examples 2-5, table 1

Example 7, table 1

Examples 117-118, table 1

Example 120, tablel

Method 2

Synthesis of [2-amino-5-(4-[3-methyi-2-[5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl]butan

2-yl}phenyl)pyridin-3-yl] methanol (Example 6, table 1)

1-58 1-99

Example 6

1-58 (0.450 g, 1.21 mmol) is suspended in 1,4-dioxane (3.0 mL). Bis(pinacolato)diborane (0.364 g, 1.43 mmol), potassium acetate (0.500 g, 5.09 mmol) and 1,1'bis(diphenylphosphino)ferrocenedichloropalladium(ll) dichloromethane complex (0.100 g, 0.122 mmol) is added. This reaction mixture is de-gassed and heated under argon at 100 °C for 4 h. The mixtue is cooled to room température then diluted with EtOAc and washed with water. The organics are collected and concentrated in vacuo to afford a residue that is purifed by flash chromatography (SiO₂, hexane to 30% EtOAc in hexane) to give 1-99 (0.362 g); m/z 420.61 [M+1]

1-99 (0.100 g, 0.238 mmol) is dissolved in DMF (2.0 mL) and treated with 2-amino-5bormo-3(hydroxymethyl)pyridine (0.051 g, 0.25 mmol),

141 tetrakis(triiphenylphosphine)palladium(0) (0.029 g, 0.025 mmol), and aqueous Na₂CO3 (2.0 Μ, l .0 mL, 1.0 mmol). This reaction mixture is de-gassed and heated under argon at 100 °C for 4 h. The mixtue is cooled to room température then diluted with EtOAc and washed with water. The organics are collected and concentrated in vacuo to afford a residue that is purifed by flash chromatography (SiO₂, 0-10% MeOH in CH₂C1₂) to give the title compound (0.025g).

Method 3

Synthesis of 5-(4-(2- [5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3-yl]-3-methylbutan-

2-yl}phenyl)pyrimidin-2-amine (Example 8, table 1)

Example 7 (35 mg, 0.083 mmol) is dissoved in MeOH (2.0 mL). A 25% (w/w) NaOMe solution in MeOH (50 pL) is added. The reaction mixture is heated at 70 °C for 6 h then volatiles are removed in vacuo. The residue is purified by flash chromatography (SiO₂, 0-10% MeOH in CH₂C1₂) to give the title compound (26 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 9, table 1

Method 4

Synthesis of 3-(3-{2-[4-(2-aminopyrimidin-5-yl)phenyl]-3-methylbutan-2-yl}-l,2,4oxadiazol-5-yl)pyridin-2(lH)-one (Example 12, table 1) χ

142

Cl

1-21 (100 mg, 0.255 mmol) îs dissoved in l-methyl-2-pyirolidinone (1 mL). Ethyldiisopropylamine (0.3 mL, 1.6 mmol) is added followed by 2 chloro-nîcotinyl chloride (62 mg, 0.35 mmol). The reaction mixture is heated at 120 °C for 1 h then cooled to room température and partioned between CH2CI2 and water. The organics are collected and volatiles are removed in vacuo. The residue is purified by flash chromatogrophy (S1O2, 0-100% ethyl aceatate in heptane) to afford 1-100 (78 mg); m/z 421.48 [M+1]

1-100 (35 mg, 0.083 mmol) is dissoved in 1,4-dioxane (2.0 mL). A 10% (w/w) aqueous LiOH solution (50 pL) is added. The reaction mixture is heated at 70 °C for 2 h. The solvent is removed in vacuo and the residue is suspended in water (2.0 mL). The precipetate is collected by filtration, washed with water, and air-dried. The solid is furhter purified by flash chromatography (S1O2, 0-10%MeOH in CH2CI2) to give the title compound (28 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 10, table 1

Method 5 ^z

143

Synthesis of 5-(4-{2-[5-(4-methoxypyridin-3-yl)-l,2,4-oxadiazol-3-yl]-3-methylbutan-

2-yl}phenyl)pyrimidin-2-amine (Example 11, table 1)

4-Methoxy-nicotînic acid (54 mg, 0.35 mmol) is dissoved in l-methyl-2-pyrrolidinone (1 mL) and carbonyldiimidazole (57 mg, 0.35 mmol) is added. The mixuture is stirred for 15 minutes then 1-21 (100 mg, 0.255 mmol) is added. This reaction mixture îs heated at 120 °C for 1 h then cooled to room température and diluted with water. The solid is collected by filtration and purified by flash chromatogrophy (S1O2, 0-100% EtOAc in heptane) to give the title compound (19 mg).

The following compounds were synthesized in similar fashion from the appropriate intermediates:

Examples 13-15, table 1

Examples 18-22, table 1

Examples 25-29, table 1

Examples 33-34, table l

Example 37, table 1

Example 58, table 1

Examples 67-69, table 1

Example 119, table 1

Synthesis of 5-(4-{(R)-l-cyel{>propyl-l-|5-(lll-pvrazoL4-yl)-|L2,4]oxadiazol-3-vl]ethyl}-phenyI)-pyrimidin-2-yIamme (Example 48, Table 1)

144

To a suspension of IH-pyrazole-4-carboxylic acid (7.1 g, 0.063 mol) in THF (200 mL) is added Ι,Γ-carbonyldfimidazole (10.2 g, 0.063 mol) at room température. The mixture is stirred at 50 °C for 30 minutes. A suspension of 1-29 (12.5 g, 0.042 mol) in THF (100 5 mL) is added to the above mixture and the resulting mixture is heated under reflux for 24 hours. The mixture is cooled down and the solid is collected by means of filtration. The solid is then suspended in AcOH (150 mL) at room température. The mixture is heated to 90 °C for 2 hours. The solution is cooled down and is concentrated under vaccuum.

The residue is dissolved in EtOAc (100 mL) and the solution is washed with H₂O (200 10 mL) and saturated NaHCO₃ solution (200 mL). The organic layer is concentrated to afford the title compound (14.7 g, 0.040 mol).

Method 6

Synthesis of 4-(3-{l-[4-(2-Amino-pyrimidin-5-yI)-phenyl]-l,2-dimethyl-propyl}- l,2,4-oxadiazol-5-yI)-piperidine-l-carboxylic acid tert-butyl ester (Example 109, table 1) and 5-(4-{3-methyl-2-[5-(piperidin-4-yl)-l,2,4-oxadiazol-3-yI]butan-2- yl}phenyl)pyrimidin-2-amine (Example 110, table 1) s

145

To a suspension of 7V-Boc-isonipocotic acid (115 mg, 0.50 mmol) in THF (1 mL) is added carbonyldiimîdazole (81 mg, 0.50 mmol). The mixture is heated at 55 °C for 20 min then treated with 1-21 (100 mg, 0.33 mmol). The reaction mixture is heated at 55 ’C for 17 h then heated in microwave at 150 °C for 20 min. The mixture is cooled to room température then directly purified by flash chromatography (SiCh, 15-100% EtOAc in heptane) to give Example 109 (89 mg).

Example 109 (83 mg, 0.17 mmol) is dissolved in CH2CI2 (1 mL) and treated with a solution of HCl in 1,4-dioxane (4.0 M, 0.4 mL). The mixture is stirred at room température for 3.5 h then resulting solid is filtered, washed with CH2CI2, collected, and dried to afford the title compound (63 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Examples 111-114, table 1

Method 7

Synthesîs of 5-(4-{3-methyl-2-[5-(lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl]butan-2yl}phenyl)pyrimidin-2-amîne (Example 146, table 1)

146

PdCI₂(PPh₃)_z

2M aq Na₂CO₃

DMF

A mixture of 1-47 (70 mg, 0.19 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (51 mg, 0.23 mmol) and 2M aqueous Na₂CO₃ (0.2 mL) in DMF (1 mL) is degassed under N₂ for 5 minutes. To this mixture is added PdCl₂(PPhs)₂ (14 mg, 0.02 mmol). The mixture is stirred at 80 °C for 18 h then partitioned between EtOAc and water. The organics are washed with water, dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by préparative HPLC to give the title compound (13 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Examples 125, table 1 - upon reaction of 1-38 with -aminopyrimîdine-5-boronic acid , PdCl₂dppf (0.05eq) and dppf (0.05eq) only Example 125 is formed instead of Example 128

Example 126-133, table 1

Example 139, table 1

Example 143, table 1

Examples 146-157, table 1

Method 8

Synthesis of 5-[4-(3-methyl-2-Î5-[6-(trifluoromethyl)pyridin-3-yl]-l,2,4-oxadiazol-3yl}butan-2-yl)phenyl]pyrimidm-2-amine (Example 136, table 1)

147

OH _Ν·^γ-^ΒΟΗ

H,

PdCI₂(dppf)

Na₂CO₃ EtOH: toluene (4:1)

To a suspension of 1-33 (156 mg, 0.35 mmol), 2-ammopyrimîdine-5-boronic acid (58 mg,

0.42 mmol) and 2M aqueous NaiCOj (0.53 mL) in ethanol:toluene (4:1, 2 ml) in a pressure tube is added [l,r-bis(diphenylphosphino)-ferrocene]dichloro palladium (II) 5 (25 mg, 0.030mmol) and l,r-bis(diphenylphosphino)fenOcene (15 mg, 0.02 mmol). The reaction mixture is stirred at 90 °C for 2 h. The reaction mixture îs filtered through a pad of Celite, washed with EtOAc and CH2CI2. The collected filtrate is concentrated in vacuo. Purification by préparative HPLC gives the title compound (72 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 135-138, table 1

Examples 140-141, table 1

Method 9

Synthesis of 2-[4-(3-( l-[4-(2-aminopyrimidin-5-yl)phenyl]-l-cyclopropylethyl}-l,2,4oxadiazol-5-yl)-lH-pyrazol-l-yl]-N,N-dimethylacetamide (Example 59, table 1)

-N^A-^CI I

K._?CO, DMF

148

To a solution of example 21 (350 mg, 0.94 mmol) in DMF (1 mL) is added K-CO; (260 mg, 1.9 mmol) and 2-chior<)-.V,/V-dimethylacetamidu (0.19 mL, 1.9 mmol). The reaction mixture is stirred for 20 h at room température then directly purified by prepartive HPLC (10-60% CH₃CN in water containing 0.1%TFA) to give the title compound (200 mg).

The following intermédiares are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
I-100bisa	AA A+ Ao'	446.4

a) The reaction mixture is heated at 50°C

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 30, table 1

Example 43, table 1

Example 60, table lExample 75-76, table 1

Example 79, table 1

Examples 97-99, table 1

Example 106, table 1

Example 271, table 1 - the reaction is performed at 130^l’C for 48 hours starting from the corresponding bromide /

149

Synthesis of 2—[4-(3-{(R)-l-[4-(2-amino-pyriniidin-5-yl)-phenyl]-l-cyclopropylethyl}-[l,2,4]oxadiazol-5-yl)-pyrazol-l-yl]-N,N-dimethyl-acetamide (Example 115. table 1)

To a solution of Example 48 (14.7 g, 0.040 mol) in DMF (150 mL) are added 2-chloroN,N-dimethylacetamide (6.1 mL, 0.059 mol) and K-CO3 (10.9 g, 0.079 mol) at room température. The mixture is stirred at the same température for 2 hours. Water (100 mL) is added and the mixture is extacted with EtOAc (200 mL). The combined organic layer is dried with VlgSO₄ (20 g) and is filtered. The filtrate is concentrated and the remaining solid is re-suspended in small amount of acetonitrile (30 mL) for 10 minutes. The solid is collected by filtration and is washed with cold acetonitrile. The resulting solid is dried under vaccuum and is confirmed to be the title compound (10 g).

The title compound îs further purified, if desired, by recrystallization from éthanol, methanol or THF. Alternatively, the title compound is converted to its hydrochloride sait by dissolving the free base in éthanol or isopropyl alcohol followed by addition of aqueous hydrochloric acid to the solution.

Method 10

Synthesis of 2-[(3-{2-f4-(2-aminopyriniidin-5-yl)phenyl]-3-niethyibutan-2-yl}-l,2,4oxadiazol-5-yl)amino] éthanol (Example 80, table 1) /

150

To a solution of I-2l (900 mg, 3.0 mmol) in toluene (35 mL) is added trichloroacetic anhydride (0.69 mL, 3.6 mmol). The reaction mixture is heated at reflux for 2.5 h then cooled to room température. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCXL, dried with Na-SCL, filtered and concentrated to afford 1-101 (1.25 g); m/z 426.31/428.22 [M/M+2H].

To a solution of 1-101 (80 mg, 0.19 mmol) and KOH (19 mg, 0.28 mmol) in DMSO (1 mL) is added ethanolamine (20 μL, 0.28 mmol). The reaction mixture is stirred at room température for 1 h then treated with water. The mixture is extracted with EtOAc, washed with brine, dried with Na?SO4, filtered, and concentrated. The residue is purifîed by flash chromatography (SiO₂, 0-10%MeOH in CH?CL) to yield the title compound (45 mg).

The following compounds are synthesized in simîlar fashion from the appropriate intermediates:

Examples 81-83, table 1

Example 84, table 1 - sideproduct isoiated from the reaction performed to form Example 83

Example 86, table 1 - the intended amine dérivative is not isoiated and the amide sideproduct is the only one that is isoiated

Example 87, table 1

Examples 89, table 1 x

151

Example 90, table l - sideproduct isolated from the reaction performed to form Example

Example 91, table 1 - the intended amine dérivative is not isolated and the amide sideproduct is the only one that is isolated

Example 134, table 1

Example 171, table 1

Method 11

Synthesis of l-{ [5-(3-(1-[4-(2-aminopy rimidin-5-yl)phenyl]-l-cyclopropylethyl}10 l,2,4-oxadiazol-5-yl)pyrazin-2-y]]amino}-2-methylpropan-2-ol (Example 44, table 1)

To a solution of 5-chIoro-pyrazine-2-carboxylic acid (490 mg, 3.1 mmol) in NMP (3 mL) is added carbonyldiimidazole (500 mg, 3.1 mmol). The mixture is stirred at 50 for 0.5 h then treated with 1-23 (830 mg, 2.8 mmol) and heated at 110 °C for 2 h. The mixture is 15 cooled to room température, treated with water, and stirred for 18 h. The resulting solid is filtered, dried, and collected to give 1-102 (1.0 g). 1H NMR (DMSO-J6) Ô ppm 9.40 (1H, s), 9.20 (1H, s), 8.75 (1H, s), 8.55 (2H, s), 8.10 (1H, s), 7.60 (2H, d), 7.40 (2H, d), 7.20 (1H, s), 6.75 (2H, s), 1.65-1.75 (1H, m), 1.55 (3H, s), 0.3-0.75 (4H, m).

1-102 (300 mg, 0.66 mmol) is dissolved in 1-amino-2-methyl-propan-2-ol (1.5 mL) and 20 heated at 80 °C for 4 h. The mixture is cooled to room température and treated with

152 water. The resulting solid îs filtered, collected, and further purified by recrystallization from CH₃CN to give the title compound (l 55 mg).

The following compounds are synthesized in similar fashion from the appropriate 5 intermediates:

Example 42, table 1

Example 45, table 1

Examples 35-36, table 1

Examples 73-74, table 1

Examples 162-163, table 1

Method 12

Synthesis of 5-{4-|l-cyc!opropyl-l-(5-{6-|(2-inethoxyethyl)amino]pyridin-3-yl [-1,2,4oxadiazol-3-yl)ethyi]phenyl}pyrimidin-2-amine (Example 38, table 1)

Example 38

To a solution of 6-chloronicotinîc acid (500 mg, 3.2 mmol) in NMP (7 mL) is added carbonyldiimidazole (520 mg, 2.9 mmol). The mixture is stirred at room température for 1 h then treated with 1-23 (860 mg, 2.8 mmol) and heated at 130 °C for 2 h. The mixture

153 îs cooled to room température and treated with water. The resulting solid is filtered, dried, and collected to give 1-103 (350 mg); m/z 419.33 [M+H]

1-103 (150 mg, 0.36 mmol) is dissolved in 2-methoxyethylamine (0.5 mL) and heated at 80 °C for 2 h. The mixture îs cooled to room température and treated with water to afford a residue. The water is decanted and the residue is purified by préparative HPLC (1060% CH-,CN în water containing 0.1%TFA) to give the title compound (98 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 39-41, table 1

Examples 70-72, table 1

Method 13

Synthesis of l-[4-(3-{2-[4-(2-aminopyrimidin-5-yl)phenyI]-3-methylbutan-2-yl}l,2,4-oxadiazoI-5-yl)-lH-pyrazol-l-yl]-2-methylpropan-2-ol (Example 159, table 1)

To a suspension of 1-47 (336 mg, 0.93 mmol) and potassium carbonate (154 mg, 1.12 mmol) în DMF (6 mL) is added l-chloro-2-methyl-propan-2-ol (100 pL, 0.98 mmol). The reaction mixture is stirred at 80 °C for 16 h then concentrated in vacuo. The residue îs extracted with CH₂C1₂, washed with saturated aqueous N'H.RT, dried with Na₂SCU, filtered and concentrated in vacuo to afford 1-104 (365 mg); m/z 434 [M+H].

The following intermediates are synthesized in similar fashion from the appropriate reagents: /

154

Intermediate	Structure	m/z [M/M+2H]
1-104 A	YVo BrAJ N< Ua- H	432.0/434.0
I-104B	ryV'o V	474.0/476.0
I-104C	ifjA)	419.0/421.0
I-104D	ryVo 'n'NVo	417.0/419.0

A mixture of 1-104 (365 mg, 0.84 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (279 mg, 1.26 mmol) and 2M aqueous Na₂COî (0,85 mL) in DMF (4 mL) is degassed under N₂ for 5 minutes. To this mixture is added bis(triphenylphosphine)palladium(II)chloride (59 mg, 0.08 mmol). The mixture is stirred /

155 i

î at 80 °C for 18 h then concentrated in vacuo. The residue is extracted with CH₂Cl₂, i

î washed with saturated aqueous NaHCOi, dried with filtered, and concentrated in vacuo. The residue îs purified by flash chromatography (S1O2, 0-5% MeOH in CH2CI2) to J give the title compound (268 mg).

_; The following compounds are synthesized in similar fashîon from the appropriate intermediates:

Example 142, table 1

Example 144, table 1

Example 158, table 1

Example 161, table 1

Method 14

Synthesis of l-(3-{2-[4-(2-aminopyrimidin-5-yl)phenyl]-3-methyJbutan-2-yl}-l,2,415 oxadiazol-5-yl)cyclopropanecarboxylic acid (Example 95, table 1)

1-21 1-105

Example 95

To a solution 1-21 (189 mg, 0.63 mmol) in DMF (1 mL) is added a solution of 1chlorocarbonyl-l-cyclopropanecarboxylic acid methyl ester (113 mg, 0.69 mmol) in 20 DMF (1 mL). The reaction mixture is stirred at room température for 15 min then heated at 120 °C for 2 h. The mixture is cooled then treated wîth water and extracted with

EtOAc, washed with brine, dried with Na₂SO4, filtered, and concentrated in vacuo. The

156 residue is purified by falsh chromatography (SiO₂, 0-10% MeOH în CH₂C1₂) to give I105 (30 mg); m/z 408 [M+H],

To a solution of 1-105 (30 mg, 0.074 mmol) in MeOH (0.5 mL·) is added an aqueous solution of NaOH (4.0M, 90 pL). The reaction mixture is stirred at room température for 1 h then concentrated in vacuo. The residue is partioned between EtOAc and water then the aqueos layer was acidified to pli -4 with 1 M aqueous HCL The aqueous mixture is extracted with EtOAc and concentrated in vacuo to afford a residue that is purified by préparative HPLC to afford the title compound (20 mg).

Method 15

Synthesis of l-(3-{2-[4-(2-aminopyriinidin-5-yl)phcnyi|-3-methylbutan-2-vl}-l,2,4oxadiazoI-5-yl)cycIohexanecarboxylic acid (Example 145, table 1)

1-107 Example 145

A mixture of cyclohexane-1,1-dicarboxylic acid monoethyl ester (142 mg, 0.50 mmol), HATU (199 mg, 0.52 mmol) and triethylamîne (80 pL, 0.55 mmol) in DMF (2.5 mL) is stirred for 5 min then 1-14 (100 mg, 0.50 mmol ) is added. The mixture is stirred at room température for 2 h then at 90 °C for 18 h then concentrated in vacuo. The résultant residue is partitioned between 1 M aqueous HCl and EtOAc. The organics are washed with brine, dried over MgSO₄, fîltered and concentrated in vacuo. The residue îs purified by flash chromatography (SiO₂, 15% EtOAc in cyclohexane) to give 1-106 (251 mg); m/z 449/451 [M/M+2H]. /

157

A mixture of 1-106 (223 mg, 0.50 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (121 mg, 0.55 mmol) and 2M aqueous Na_?C()₃ (1.9 mL) in DMF (5 mL) is degassed under N₂ for 5 minutes. To this mixture is added bis(triphenylphosphine)palladium(ll)chloride (35 mg, 0.05 mmol). The mixture is stirred at 80 °C for 1 h then concentrated in vacuo. The residue is extracted with EtOAc, washed with saturated aqueous NaHCXh, dried with Na₂SO4, filtered, and concentrated in vacuo. The residue îs purified by flash chromatography (SiO₂, 0-20% EtOAc in cyclohexane) to give 1-107 (182 mg); m/z 464 [M+H].

To a solution of 1-107 (175 mg, 0.38 mmol) in 1:1 THF:water (3 mL) is added LiOHH₂O (17 mg, 0.40 mmol). The reaction mixture is stirred at room température for 2 d then THF is removed in vacuo. The aqueous mixture is washed with EtOAc then acidified with saturated aqueous NH4CI. The aqueous mixture is extracted with EtOAc, washed with brine, dried with MgSÛ4, filtered, and concentrated in vacuo. The résultant solid is triturated with Et₂O then filtered, collected and dried to yield the title compound (88 mg).

Method 16

Synthesis of 3-[4-(3-{2-[4-(2-aminopyrîmidin-5-yI)phenyIl-3-methylbutan-2-yl}- l,2,4-oxadiazol-5-yl)-lH-pyraz.ol-l-yl|-2,2-dimethylpropanoic acid (Example 164,

O

table 1)

CSjCO,

TBAI

Example 164

To a mixture of 1-47 (407 mg, 1.13 mmol) and 3-chloro-2,2-dimethyl propionic acid ethyl ester (557 mg, 3.38 mmol) in DMF (8 mL) is added CS2CO3 (734 mg, 2.25 mmol) and

158 tetrabutylammonium iodide (832 mg, 2.25 mmol). The mixture is stirred at 80 °C for 36 h then concentrated in vacuo. The residue is partitioned between CH₂C1₂ and saturated aqueous NalICOj. The organics are dried with Na^SCU, filtered and concentrated in vacuo. The residue is purified by flash chromatography (S1O2, 10% EtOAc in cyclohexane) to give 1-108 (299 mg); m/z 489/491 [M/M+2HJ.

The following intermediate is synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+2H]
I-108bisa	AAAn /=n 0	463.0

a) The reaction is run at 80°C for 8 hours using K₂CO_;( in DMF

A mixture of 1-108 (290 mg, 0.46 mmol), 2-aminopyrimîdine-5-boronic acid pinacol ester (307 mg, 1.39 mmol) and 2M aqueous Na₂CO₃ (0.46 mL) in DMF (6 mL) is degassed under N₂ for 5 minutes. To this mixture is added bis(triphenylphosphine)palladium(H)chloride (65 mg, 0.09 mmol). The mixture is stirred at 80 °C for 3 h then concentrated in vacuo. The residue is extracted with EtOAc, washed with saturated aqueous NaHCO₃, dried withNa2SO₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (S1O2, 0-1% MeOH in CH2CI2) to give ΙΙΟ? (171 mg); m/z 504.90 [M+H].

The following intermediate is synthesized in similar fashion from the appropriate reagents:

Intermediate

Structure

m/z [M+H]

159

A mixture of 1-109 (171 mg, 0.282 mmol), LiOH.H₂O (12 mg, 0.286 mmol), methanol (2.5 mL), THF (2.5 mL) and water (1.3 mL) is heated at 40 °C for 8 h then concentrated in vacuo. The residue is purified by préparative HPLC to give the title compound (33 mg).

The following compound is synthesized in similar fashion from the appropriate intermediates:

Example 160, table 1

Method 17

Synthesis of 6-(3-{2-[4-(2-aminopyriinidin-5-yl)phcnyl|-.3-inethylbutan-2-yl}-l,2.4oxadiazoI-5-yl)-l-methyIpyridin-2(lH)-one (Example 165, table 1)

9¼

PdCl₂(PPh₃)₂

2M aq Na₂CO₃

DMF

To a solution of 2-carboxylic acid-6-oxo-pyridîne (161 mg, 1.16 mmol) in DMF (3 mL) is added carbonyldiimidazole (188 mg, 1.16 mmol). The mixture is stirred for 20 min at A

160 °C then treated with I-14 (300 mg, 1.05 mmol) and stirred at 110 “C for 3 h. The mixture is concentrated in vacuo and the residue is extracted with EtOAc, washed with saturated aqueous NaHCO₃, dried with MgSO₄, filtered, and concentrated. The residue is purifîed by flash chromatography (SiO₂, 2% MeOH in CH2CI2) to give 1-110 (223 mg); m/z 389.95 [M+1].

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
I-11 Obis	Ao 0	392.0/394.0

To a solution of 1-110 (223 mg, 0.41 mmol) in THF (3 mL) is added K₂CO₃ (68 mg, 0.49 mmol) and Meï (30 jiL. 0.49 mmol). The mixture is stirred at 40 °C for 20 h and is treated with additional Meï (30 pL, 0.49 mmol) at 3 h and 15 h. The mixture is treated with saturated aqueous ammonia and MeOH then volatiles are removed in vacuo. The residue is extracted with EtOAc, washed with saturated aqueous NaHCO₃, water, brine, dried with MgSO₄₎ filtered, and concentrated. Purification of the crude by flash chromatography (SiO₂, 0-10% EtOAc in cyclohexane) yields 1-111 (80 mg); m/z 403.85 [M+1].

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate

Structure

m/z [M/M+2H]

161

A mixture of I-l 11 (80 mg, 0.19 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (124 mg, 0.56 mmol) and 2M aqueous Na₂CO₃ (0.20 mL) in DMF (2 mL) îs degassed under N₂ for 5 minutes. To this mixture is added PdCl₂(PPh₃)₂ (26 mg, 0.094mmol). The mixture is stirred at 80 °C for 3 h then concentrated in vacuo. The residue is extracted with EtOAc, washed with saturated aqueous NaHCOj, dried wîth Na₂SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 0-1% MeOH în CH₂C1₂) to give the tîtle compound (30 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Example 166-167, table 1 — the reaction is run starting from a mixture of 1-1 lObis and I11 Ibis. Silica gel column chromatography affords Example 166 and 167.

Method 18

Synthesis of 2-[4-(3-{(lR)-l-[4-(2-aminopyrimidin-5-yI)phenyl]-l-cyclopropylethyl} l,2,4-oxadiazol-5-yI)-lH-pyrazol-l-yll-N,N-dimethyiacetamide (Example 115) and 2 [4-(3-{(lS)-l-f4-(2-aminopyriinidin-5-yl)phenyl]-l-cyclopropylethyl}-l,2,4oxadiazol-5-yI)-lH-pyrazol-l-yl]-N,N-dimethyIacetainide (Example 116, table 1)

162

Enantiomers 115 and 116 are prepared by resolution of example 59 (100 mg) on a Chiralpak® AD-H (avaîlable form Chiral Technologies, Inc., Exton, PA) semipreparative (250 x 20 mm) HPLC column (eluting with 95% EtOH in heptane containing 0.1%diethylamine). The faster eluting enantiomer 115 having a rétention time of ~ 35 min and the slower eluting enantiomer 116 having a rétention time of — 73 min. The eluants are concentrated to provide Example 115 (32 mg) and Example 116 (27 mg).

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Examples 23-24, table 1

Examples 31-32, table 1 - eluting with 70%EtOH with 0.1% diethylamine/heptane

Examples 61-62, table 1

Examples 65-66, table 1

Examples 77-78, table 1

Examples 102-103, table 1

Example 104-105, table 1 - 95% EtOH in heptanes +0.05% diethylamine at 8ml/min

40°C

Examples 107-108, table 1

Example 115-116, table 1 - 95% EtOH in heptanes +0.05% diethylamine at 55ml/min

Examples 121-122, table 1 - 95% EtOH in heptanes +0.4% diethylamine at 55ml/min

Examples 123-124, table 1

Example 227-228, table 1

Example 230-231, table 1

Example 233-234, table 1

Example 254-255, table 1

Example 257-258, table 1

Example 282-283, table 1 /

163

Method 19

Préparation of 5-(4-{(2R)-3-methyl-2-[5-(l-methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol· 3-yl]butan-2-yl}phenyI)pyrimidin-2-amine (Example 46) and 5-(4-{(2S)-3-methyl-2[5-(l-methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazoI-3-yl|butan-2-yl}phenyl)pyrimidin-2amine (Example 47, table 1)

Enantiomers 46 and 47 are prepared by resolution of example 15 (50 mg) on a Chiralpak® AD-H (available form Chiral Technologies, Inc., Exton, PA) semipreparative (250 x 30 mm) HPLC column (eluting with 70% MeOH in CO?) at 250 bar. The faster eluting enantiomer 46 having a rétention time of --5 min (Chiralpak® AD-H analytical HPLC column 4.6 x 100 mm) and the slower eluting enantiomer 47 having a rétention time of -13 min. The eluants are concentrated to provide Example 46 (12 mg) and Example 47 (15 mg).

The following compounds are resolved in similar fashion:

Examples 16-17, table 1

Examples 48-49, table 1

Method 20

Préparation of 2- {[5-(3- {(IR)- l-[4-(2-aminopyrimidiii-5-yl)phenyl] -1cyclopropylethyl}-l,2,4-oxadiazol-5-yl)pyrazin-2-yl]amino}-2-methylpropan-l-ol (Example 56, table 1) and 2-{[5-(3-{(lS)-l-[4-(2-aminopyrimidin-5-yl)phenyII-lcyclopropylethyI}-l,2,4-oxadiazoi-5-yi)pyrazin-2-yl]amîno}-2-methylpropan-l-oI (Example 57, table 1) z

164

Enantiomers 56 and 57 are prepared by resolution of Example 45 (89 mg) on a RegisPak (available form Chiral Technologies, Inc., Exton, PA) semi-preparative (250 x 30 mm) HPLC column (eluting with 70% MeOH in CO?) at 250 bar. The f'aster eluting enantîomer 56 having a rétention time of ~5 min (Chiralpak® AD-H analytical HPLC column 4.6 x 100 mm) and the slower eluting enantîomer 57 having a rétention time of —13 min. The eluants were concentrated to provide Example 56 (12 mg) and Example 57 (15 mg).

The following compounds are resolved in similar fashion:

Examples 50-51, table 1 - eluting with 55% MeOH in CO₂

Examples 52-53, table 1 - eluting with 45% of 3/1/0.1

MeOH/isopropanol/isopropylamine in CO₂

Examples 54-55, table 1 eluting with 55% EtOH in CO₂

Examples 56-57, table 1 - eluting with 45% 1/1 methanol/ispropanol

Example 100-101, table 1 - eluting with 40% co-solvent of 1:1 methanoliisopropanol with 0.5% isopropylamine at 150 bar

Example 63-64, table 1

Method 21

Synthesis of 5-(4-{3-methyI-2-[5-(4-methylpiperazin-l-yl)-l,2,4-oxadiazol-3yl]butan-2-yl}phenyl)pyrimidin-2-amine (Example 96, table 1) X

165

To a mixture of 1-14 (1.029 g, 3.61 mmol) and carbonyldiimidazole (702 mg, 7.33 mmol) is added acetonitrile (20 mL). The reaction mixture is heated at 75 °C for 18 hours. After this time, the reaction mixture is concentrated in vacuo and purified by flash 5 chromatography (SiO2, 12-100% EtOAc in heptane) to give 1-112 (373 mg); m/z 311.2/313.2 [M/M+2H].

To a solution of 1-112 (163 mg, 0.523 mmol) in pyridine (0.5 mL) is added POC1₃ (0.479 mL, 5.23 mmol). The reaction mixture is heated at 90 °C for 18 hours. The reaction mixture is cooled to room température and carefully poured into ice water and then 10 extracted with EtOAc twice. The organcis are combined and washed with brine, dried over NapSOi- filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO₂, 12-100% EtOAc in heptane) to give 1-113 (59 mg); IH- NMR (DMSO-ί/ό) Ô ppm 7.50 (2H, d), 7.35 (2H, d), 2.62 (IH, m), 1.60 (3H, s), 0.83 (3H, d), 0.6 (3H, d).

To a solution of 1-113 (44 mg, 0.133 mmol) in DMSO (1 mL) is added 1methylpiperazine (0.148 mL, 1.33 mmol) and the reaction mixture is stirred at room température for 1.5 hours. The reaction mixture is quenched with water and extracted with EtOAc twice. The organics are combined and washed with water then brine, dried over Na?SOi, filtered and concentrated in vacuo. The residue is purified by flash 20 chromatography (SiO₂, 10-100% MeOH in CH₂C1₂) to give 1-114 (45 mg); m/z 393.0/395.0 [M/M+2H]. Z

166

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
1-115b	rANo N-:( Ao O X	450.2/452.2
I-116a	Q	428.2/430.2
1-117a	fKc βΛ N«< D V 0	421.2/423.2
1-118b	A bA X O '—N ..s— oô	457.2/459.2
1-119a	fA bF'·^ n,:< O ? OH	423.2/425.2

167

I-I20b	pY B,A NX O '—N Ao h2n	422.2/424.2
I-I21b	ÂYo b/> Νχ HO	436.4/438.4
I-!22b	ίγΑ'ο bA NX Ν-χ < Ko H	393.2/395.4
I-I23b	ΓγΑο A Νχ OH	366.2/368.2
I-I24b	BrA> N==( NH S	408.4/410.4
I-125b	ryKo bA Νχ (A A \	407.1/409.1

168

I-126b	S Q .s00	456.2/458.2
I-127b	ÂVo q HO	408.2/410.2
I-128b	A BrXJ N.X 9 OH	422.3/424.2
I-I29b	A 0ΓΛ> N-( X. h2n	421.2/423.2
I-130b	0 N/	421.2/423.2
I-13lb	ΓγΑο V Ah o N—/ /	407.4/409.4

169

I-132b	00% N*< NH 0 HO	408.2/410.1
I-133b	00% xM N=( N-- S --N	395.4/397.4
I-134b	ίΥΛ O A	435.4/437.4
I-135b	00% bXX n=( Q OH	394.4/396.2
I-I36b	00% V	421.4/423.4
I-137c	00% O V	419.4/421.2

170

I-138b	A Br+X N=( D -N Y	450.4/452.4
I-139b	jA O z°	408.2/410.2
1-140	nbo BrAA N-=< N-Λ U OH	420.4/422.4
I-140bis	jCjbN'° Ν-λ Q P-+ -H A	507.3/509.3
I-140tris	ryXo ΒγΛΧ n-( Q hN~V H o	493.3/495.3

a) 1.2 equ. of amine and 1.2 equ. of diisopropylethylamine are used.

b) 1.2 equ. of amine (either as free base or hydrochloride sait) and 2.5 equ. of diisopropylethylamine are used. /

171 ί ί ί

c) 1.2 equ. of amine as di-hydrochloride sait and 5 equ. of diisopropylethylamine are used.

The mixture of 1-114 (45.000 mg, 0.114 mmol), 2-aminopyrîmidine-5-boronic acid pinacol ester ¢30.286 mg, 0.137 mmol) and tetrakis (triphenylphosphine)palladium (0) (13.173 mg, 0.011 mmol) in a vial is evacuated and back filled with Ar 3 times. Then THF (1 mL) and sat. Na^CO. aqueous solution are added and the mixture is heated to 65 °C for 18 hours. After this time, the reaction mixture is quenched with water and extracted with EtOAc twîce. The organcis are combined and washed with brine, dried over Na₂SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 12-100% EtOAc in heptane) to give Example 96 (12 mg).

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
I-141a	A II J Ν-Λ h-nA < ) o-4/H \ 0	522.4
I-142a	AzAn. (Ύ r o J! J hjAnJ < ) ( oZ H 0	508.4

172

I-143^a

465.4

a) The reaction has been performed in the microwave oven at 110°C for 45 minutes.

The following compounds are synthesized in similar fashion from the appropriate intermediates:

Examples 168, table 1

Example 169, table 1 - the last step has been performed in the microwave oven at 110°C for one hour

Example 170, table 1 - the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 186, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 192, table 1

Exemples 198-202, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 208-209, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 212-213, table 1 - the last step has been performed în the microwave oven at 110°C for 45 minutes

Examples 218, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Exampe 235, table 1 - the last step has been performed in the microwave oven at 100°C for two hours

Examples 236-237, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 260, table 1 S

173 f

Examples 261-262, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 264, table 1 - the last step has been performed in the microwave oven at 110°C 5 for 45 minutes

Exemples 266, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Examples 269-270, table 1- the last step has been performed in the microwave oven at 110°C for 45 minutes

Method 22

Synthesis of 4-(3-{2-|4-(2-aminopyrimidin-5-yI)plienyl|-3-metIiyIbutan-2-yI}-l,2.4oxadiazol-5-yl)-2,2-dimethylbutanoic acid (Example 85, tablel)

[.21 Example 85

To a solution of 1-21 (100 mg, 0.334 mmol) in DMF (1 mL) is added 2,2dimethylglutaric anhydride (52 mg, 0.367 mmol). The reaction mixture is heated to 120 °C for 2.5 hours. After this time, the reaction mixture is quenched with water and extracted with EtOAc twice. The organics are combined and washed with water then 20 brine, dried over Na₂SÛ4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 10-100% MeOH in CH₂C1₂) then triturated in hot MeOH to give Example 85 (40 mg).

The following compounds are synthesized in similar fashion from the appropriate 25 intermediates:

Example 92-94, Table 1 x

174

I s i

i i

Method 23

Synthesis of: 5-(4-{(R)-l-Cyclopropyl-l-[5-(3,4,5,6-tetrahydro-2H-[l,2’]bipyrazinyl5 *-yl)-[ 1,2,4] oxadiazoI-3-yl]-ethyl]-phenyl)-pyraziii-2-y lamine (Example 195, tablel)

To cold (0°C) méthanol (20 ml) is added 1 ml of acetyl chloride (dropwise). Upon 10 complété addition, 1-83 (350 mg, 0.61 mmol) is added as a méthanol solution (5 ml).

Allow to gradually warm to RT and stir over night. After this time the reaction is basified using 7N ammonia and concentrated to dryness. The remaining residue is purifîed via flash chromatography (silica gel, 0-10% MeOH/DCM) to give 1-135.

The following intermediates are synthesized in similar fashion from the appropriate 15 reagents:

Intermediate	Structure	m/z [M+H]
I-143tris	ΓγΑο A J AN HJsAbf f > N=( O H	Not available

175

I ί i r

I i

i

The following compounds are synthesized in a similar fashion from the appropriate intermedîates:

Example 214, Table I - the crude is purified via flash chromatography (silica gel, ΟΙ 00% MeOH/DCM)

Example 267, Table 1

Example 268, Table 1 - the crude is concentrated to dryness and purified the crude via flash chromatography (silica gel, 0-10% MeOH/DCM, with 0.5% NH4OH)

Step2:

I-I43bis

Example 195 Ά

176

Chiral resolution of 1-135 was performed using a ChiralPak® AD-H column (3.0 x 25.0 cm, available from Chiral Technologies, West Chester PA). Eluting with methanol/IPA (1:3) with 1% isopropylamîne at 150 bar afforded Example 195 (6 mg).

The following compounds are synthesized in a similar fashion from the appropriate intermediates:

Example 196, Table 1- the chiral resolution is performed at 125 psi

Example 210, Table 1- the chiral resolution is performed at 125 psi, with no ispropylamine in the eluent

Method 24

Synthesîs of 1-(3- (1-(4-(2- Amino-pyrimidin-5-yI)-phenyl]-l, 2-dimethyl-propyl}[l,2,4]oxadiazol-5-yl)-2-methyI-propan-2-ol (Example 225, table 1)

To a suspension of R-13 (118 mg, 1.0 mmol) in THF 10 ml) is added 1,1’carbonyldîimidazole (162 mg, 1.0 mmol) at room température. The mixture is stirred at 50 °C for 30 minutes. After this time 1-21 (200 mg, 0.67 mmol) is added and the resulting mixture is heated under reflux for 3 hours. After this time the reaction is cooled 20 to RT, treated with HOAc (1 ml) and warmed to 80°C. After stirring for 3 days the mixture is cooled to RT and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0-8% MeOH/DCM) to afford the title compound (80 mg).

The following compounds are synthesized in a similar fashion from the appropriate intermediates:

Example 229, Table 1- no AcOH is added in the reaction mixture s

177

Example 232, Table I- no AcOH is added in the reaction mixture

Method 25

Synthesis of 5-(4-{l-Cyclopropyl-l-[5-(3-oxetan-3-yl-3H-imidazol-4-yl)5 [l,2,4]oxadiazol-3-ylJ-ethyl}-pbenyl)-pyrimidin-2-ylaniÎne (Example 206, table 1)

Synthesis of 5-(4-{l-Cyclopropyl-l-[5-(l-oxetan-3-yl-lH-imidazol-4-yl)·

11,2,4]oxadiazol-3-yl|-ethyl}-ph<.’nyl)-pyriinidin-2-ylamine (Example 207, table 1)

Example 206 Example 207

To a suspension of l-trityl-lH-imidazole-4-carboxylic acid (893 mg, 2.5 mmol) in THF (10 mL) is added Ι,Γ-carbonyldiimidazole (409 mg, 2.5 mmol) at room température.

The mixture is stirred at 50 °C for 30 minutes. A suspension of 1-23 (500 mg, 1.7 mmol) in THF (5 mL) is added to the above mixture and the resulting mixture is heated at 130 °C in a microwave reactor for 2 hours. The mixture is cooled down and is concentrated under vaccuum. The residue is extracted with H2O (10 mL) and EtOAc (20 mL). The combined organic layer is dried with MgSO.1 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford 1-144 (150 mg); m/z 374 [M-trityl group].

To a solution of 1-144 (80 mg, 0.13 mmol) in CH2CI2 (10 mL) is added TFA (0.015 mL,

0.19 mmol) at room température. The solution is stirred at the same température for 24 /

178 hours. The solution is concentrated under vaccuum to afford 1-145 (48 mg); m/z 374 [M+H],

To a round bottom flask is added 1-145 (100 mg, 0.27 mmol), 3-iodooxetane (98 mg, 0.54 mmol) and K₂CO₃ (111 mg, 0.8 mmol) in DMF (10 mL). The reation mixture is stirred at 5 80 °C for 12 hours. The reaction is cooled down and water (10 mL) is added. The solution is extracted with EtOAc (20 mL) and H₂O (10 mL). The combined organic layer is dried with MgSO₄ and is filtered. The fïltrate is concentrated and the residue is purified by silica gel flash cloumn chromatography with 10% MeOH in TB ME as the elunet to afford the title compounds (Example 206: 8 mg; Example 207: 10 mg).

Method 26

Synthesis of 2-[4-(3-{l-[4-(2-Ammo-4-fluoro-pyrimidin-5-yl)-phenylJ-l-cyclopropylethyl}-[l,2,41oxadiazoI-5-yl)-pyrazol-l-yl]-N,N-dimethyl-acetamide (Example 275, table 1)

To a solution of 1-69 (300 mg, 0.6 mmol) in DMF (10 mL) are added 1-87 (140 mg, 0.7 mmol), tetrakis (triphenylphosphine)palladium (0) (70 mg, 0.06 mmol) and 2M Na₂CO₃ (1.5 mL, 3.0 mmol). The mixture is heated to 100 °C for 1 hour in a microwave reactor. The mixture is cooled down and is extracted with H₂O (20 mL) and EtOAc (30 mL). The 20 combined organic layer is dried with MgSO₄ and is filtered. The fïltrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH₂C1₂ as the eluent to afford the title compound (200 mg).

The following compounds are synthesized in a similar fashion from the appropriate intermediates: /

179

J i

t

Example 175, Table 1 - the reaction is run at 120°C

Example 176-180, Table 1 — the reaction is run at 120°C

Example 184-185, Table 1 — the reaction is run at I2O°C j Example 187-189, Table 1 - the reaction is run at 120°C

Example 191, Table 1 - the reaction is run at 120°C

Example 239-243, Table 1 - the reaction is run for 6 hours at 100°C in an oil bath

Example 244-246, Table 1

Example 247, Table 1 — the reaction is run for 6 hours at 100°C in an oil bath

Exemple 249-250, Table 1 — the reaction is run for 6 hours at 100°C in an oil bath

Example 251, Table 1- the reaction is run at 85°C overnight

Example 253, Table 1 - the reaction is run for 6 hours at 100°C in an oil bath

Example 256, Table 1 — the reaction is run for 6 hours at 100°C in an oil bath

Example 265, Table 1 - the reaction is run for 6 hours at 100°C in an oil bath

Example 273, Table l - the reaction is run for 6 hours at 100°C in an oil bath

Example 275, Table 1

Example 279, Table 1

Example 280-281, Table 1 - the reaction is run for 48 hours at 80°C

Example 284-286, Table 1

Example 289-291, Table 1

Example 292, Table 1- the reaction is run for 16 hours at 85^ÛC

Example 293-294, Table 1

Example 298, Table 1

Method 27

2-[4-(3-{(R)-l-[4-(6-Amino-pyridin-3-yI)-phenyl]-l-cyclopropyI-ethyI}- [l,2,4]oxadiazol-5-yl)-pyrazol-l-yl|-N,N-dimethyI-acetamide (Example 172, table 1) y

180

Το a micro wave vial is added 1-63 (lOOmg, 0.225 mmol) in DMF (2 ml), followed by the addition of 2-aminopyridine-5-boronic acid pinacol ester (55 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.023 mmol) and 2 M aq. Na₂CO₃ (0.4 5 ml, 0.8 mmol). The reaction mixture is stirred in microwave reactor at 120 °C for 1 hour.

The residue is diluted with EtOAc, washed with water, brine, dried under anhy. Na₂SO₄, filtered and concentrated. The residue is purified by flash chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂) to afford the title compound (39 mg).

The following compounds are synthesized in a similar fashion from the appropriate intermediates:

Example 173-174, Table 1

Example 181, Table 1

Example 183, Table 1

Example 263, Table 1 - the reaction is run at 80°C overnight

Method 28

Synthesis of5-(4-{l,2-Dimethyl-l-[5-(4-methylamÎno-piperidin-l-yl)- [l,2,4]oxadiazol-3-yI]-propyI}-phenyl)-pyrimidin-2-ylamine (Example 217, table 1)

181

1-141 (138 mg, 0.265 mmol) îs dissolved in DCM (2 mL) and 4N HCl in 1,4-dioxane (0.663 mL, 2.65 mmol) is added and the reaction mixture is stirred at room température for 3 hours. After this time, the reaction mixture is concentrated in vacuo and the residue is dissolved in MeOH and passed through a PL-HCOj MP-resin column to free base the product. The filtrate is concentrated in vacuo and the crude is purified by préparative TLC using 10% MeOH/DCM as solvent mixtures to afford the title compound (71 mg); m/z 422.4 [M+1].

The following compounds are synthesized in a similar fashion from the appropriate intermediates:

Example 222, Table 1

Method 29

Synthesis of 2-[4-(3-( 1-(4-(2-Amitio-pvrirnidin-5-yl)-phenvl|-l,2-diinetliyl-propyl}[l,2,4]oxadiazol-5-yI)-piperazin-l-yl]-N,N-dimethyl-acetamide (Example 193, table

182

Synthesis of 2-[4-(3-{l-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-l,2-dimethyl-propyl}- [l,2,4]oxadiazol-5-yI)-pîperazin-l-yl]-N,N-dimethyl-acetainide

Synthesis is performed in similar conditions used in Method 9 using the appropriate reagents.

The following intermedîates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M+H]
1-146	ί η r o NA JL J < ) Vf o-	466.0

The following compounds are synthesized in a similar fashion from the appropriate intermedîates:

Example 211, Table 1

Method 30

Synthesis of l-(3-{l-|4-(2-Amino-pyriinidin-5-yl)-phenyl]-l,2-diniethyl-propyl}- [l,2,4]oxadiazol-5-yl)-piperidine-4-carboxyIic acid (Example 219, table 1)

183 i

I

Synthesis is similar to conditions used in Method 14 Step 2 using the appropriate reagents; m/z 437.4 [M+1]. Compound is purified by trituation from hot MeOH.

The following compounds are synthesized in a similar fashion from the appropriate intermediates:

Example 272, Table 1

Method 31

Synthesis of l-(3-{l-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-l,2-dimethyl-propyl}10 [1,2,4] oxadiazol-5-yl)-3-methyl-azetidin-3-ol (Example 203, table 1)

Step!

MeMgCl THF

Step 2

Synthesis of l-{3-[l-(4-Bromo-phenyl)-l,2-diinethyl-propyI]-[l,2,4]oxadiazol-5-yl}azetidin-3-one

Synthesis is performed in similar conditions used in Method 21 Step 3 using the appropriate reagents; m/z 364 [M+H]. S

184

The following intermediates are synthesized în similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
I-147bis	Q O	392.2/394.2
I-147tris	.M» Q O	390.1/392.1
I-147quadris	.A 7 O	362.2/364.0

Synthesis of l-{3-[l-(4-Bromo-phenyl>l,2-dimethyl-propyi]-[l,2,4]oxadiazol-5-yl}-3methyl-azetidin-3-ol

To a cooled solution of 1-147 (132.6 mg, 0.364 mmol) in THF (1 mL) at -78°C is added 3M methyl magnésium chloride in THF (0.485 mL, 1.456 mmol). The reaction mixture is 10 stirred at -78°C for 10 minutes then at room température for 20 minutes. After this time, the reaction mixture is quenched with water and extracted with EtOAc twice. The organcis are combined and washed with brine, dried over NajSO.·, filtered and concentrated in vacuo to afford the title compound (122 mg); m/z 380 [M+H], Z

185

The following intermediates are synthesized in similar fashion from the appropriate reagents:

Intermediate	Structure	m/z [M/M+2H]
M48bis	A'S βΓΛ> N=( Q V°H	408.4/410.4
I-148tris	iWO X N=< V	406.1/408.1
I-148quadris	A-	378.2/380.2

Synthesis of l-(3-{l-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-l,2-diniethyl-propyl} [ 1,2,4] oxadiazoI-5-yi)-3-methyl-azetidin-3-oi

Synthesis is performed in similar conditions used in Method 21 Step 4 using the appropriate reagents.

The following compounds are synthesized in a similar fashion from the appropriate intermediates;

Example 216, Table 1

Example 238, Table l

Example 276, Table 1 /

186

Method 32

Synthesis of 2-[4-(3-{l-[4-(2-Amino-pyrimidin-5-yI)-phenyi]-l-cyclopropyl-ethyl}[l,2,4]oxadiazol-5-yI)-piperazin-l-yl]-ethanol (Exampie 252, tablel)

OH

Synthesis of 3-[l-(4-Bromo-phenyl)-l-cyclopropyl-ethyl]-[l,2,4]oxadiazol-5“Ol

Synthesis is performed in similar conditions used in Method 21, Step 1 using the appropriate reagents; m/z 307 [M+H].

Synthesis of 3-(l-(4-Bromo-phenyl)-l-cyclopropyl-ethyl]-5-chloro-Jl,2,4]oxadiazole To a solution of 1-149 (847 mg, 2.74 mmol) in DCM (8 mL) in a microwave vial is added POCI3 (0.401 mL, 4.384 mmol) andpyridine (1.107 mL, 13.7 mmol). The reaction mixture is heated in microwave oven at 120°C for 1 hour. After this time, the reaction mixture is quenched with water and extracted with CH2CI2 twice. The organcis are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂, 6-50% EA/Hep) to afford the title intermediate (694 mg). 1H-NMR: (DMSO-J6) Ô ppm 7.5 (2H, d), 7.3 (IH, d), 1.5 (IH, m), 1.4 (3H, s), 0.6 (IH, m), 0.5 (IH, m), 0.4 (IH, m), 0.3 (IH, m).

187

Synthesis of 2-(4-{3-[l-(4-Bromo-phenyl)-l-cyclopropy]-ethyl]-[l,2_}4]oxadiazol-5yl}-piperazin-l-yl)-ethanol

Synthesis is similar to conditions used in Method 21, Step 3 using the appropriate reagents; m/z 421/423[M/M+2H].

Synthesis of 2-[4-(3-{l-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-l-cyclopropyl-ethyl}- [1.2.4] oxadiazol-5-yl)-piperazin-l-yl]-ethanol

To a mixture of 1-151 (193 mg, 0.458 mmol) and Pd(PPh₃)4 (53 mg, 0.046 mmol) in a microwave vîai is added the DMF (5 mL) solution of 2-aminopyrimidine-5-boronic acid pinacol ester (121.6 mg, 0.55 mmol) and 2M Na₂CO₃ aqueous solution (0.92 mL). The reaction mixture is purged with Ar and then heated in microwave oven at 110°C for 45 minutes. After this time, the reaction mixture is quenched with water and extracted with EtOAc twice. The organics are combined and washed with brine, dried over Na>SOi, filtered and concentrated in vacuo. The crude is purified by flash chromatography (SiO₂,

1.2-10% MeOH/DCM) to afford the tîtle compound (83 mg).

The following compounds are synthesîzed in a similar fashion from the appropriate intermediates:

Example 204-205, Table 1

Example 248, Table 1

Example 252, Table 1 Example 259, Table 1 Example 274, Table 1 Example 287-288, Table 1 Example 297, table 1

Method 33

Synthesis of l-(3-{(R)-l-[4-(2-Ainino-pyriniidin-5-yl)-phenyl]-],2-dimethyl-propyl}- [1.2.4] oxadiazol-5-yI)-piperidin-4-ol (Example 223, table 1) and l-(3-{(S)-l-[4-(2Amino-pyrimidin-5-yl)-phenyl]-l,2-dimethyl-propyl}-[l,2,4]oxadiazol-5-yI)piperidin-4-oI (Example 224, table 1) y

188

Example 223 and Example 224 are prepared by resolution of Example 262 (90.3 mg) on a RegisPak (available from Regis Technologies, Morton Grove, IL) semi-preparative (30*250 mm) HPLC column (eluting with 35% 1:1 MeOH in Isopropanol containing 0.1% isopropylamine in CO2) at 100 bar. The faster eluting enantiomer Example 223 having a rétention time of 2.07 min (RegisPack 4.6* 100 mm, available from Regis Technologies, Morton Grove, IL) and the slower eluting enantiomer Example 224 having a rétention time of 2.68 min. The eluents are concentrated to provide Example 223 (36 mg) and Example 224 (34 mg).

Method 34:

Synthesis of 5-I4-((R)-l-Cyclopropyl-l-{5-[l-(2-dimethylamino-ethyl)-lH-pyrazol-4yl]-[l,2,41oxadiazol—yl}-ethyl)-phenyI]-pyrimidin-2-ylamine (Example 182, table 1)

N/

CIH

Example 48 (75.0 mg, 0.201 mmol) is treated with (2-Chloro-ethyl)-dimethyl-amine hydrochloride (43.4 mg, 0.301 mmol), Cs2CO₃(147 mg, 0.452 mmol), and DMF (1.5 mL) and the resulting mixture is stirred at 60 °C for 1 hour. At this time the mixture is treated with (2-Chloro-ethyl)-dimethyl-amine hydrochloride (14.5 mg, 0.100 mmol), Cs₂CO₃ (32.7 mg, 0.100 mmol) and stirred for 1 hour longer. The reaction is then purified directly by flash chromatography over C-18 silica eluting 10-60% s

189 acetonitrile/water/0.1% trîfluoroacetic acid. The resulting semi-pure material is treated with CH₂C1₂ and saturated aqueous NaHCOî and the phases are separated. The resulting aqueous phase is extracted 5 additional times with CH₂C1₂ and the combined organic phases are dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue that is further purified by préparative TLC eluting 8% methanol/ CH₂C1₂ to give the title compound (35.0 mg).

The following compound is synthesized in a similar fashion from the appropriate intermediates:

Example 215, table 1

Method 35:

Synthesis of2-[4-(3-{(R)-l-|4-(2-Ammo-pyrimidin-5-yl)-phenyl]-l-cyclopropylethyl}-[l,2,4]oxadiazoI-5-yl)-pyrazol-l-yl]-l-((R)-3-methoxy-pyrrolidin-l-yl)ethanone (Example 220, table 1).

o \

Synthesis of [4-(3-{(R>-1-(4-(2-Amino-pyrimidin-5-yl)-phenyl]-l-cyclopropyl-ethyl}- [l,2,4]oxadiazol-5-yl)-pyrazol-l-yl]-acetic acid ethyl ester

Example 48 is alkylated according to Method 9; m/z 460 [M+H].

190 i ι

Synthesis of [4-(3-{(R)-l-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-l-cyclopropyl-ethyl}[ 1,2,4]oxadiazol-5-yl)-pyrazol-l-yl]-acetic acid j

' 1-152 is hydrolyzed according to the final step of Method 16; m/z 432 [M+H].

1-153 (94.0 mg, 0.218 mmol) is treated with (R)-3-methoxy-pyrrolidine (33.1 mg, 0.327 mmol), HATU (125 mg, 0.327 mmol), DIEA (114 pL, 0.654 mmol), and DMF (1.50 mL) and the resulting mixture is stirred for 1 hour. The reaction is purified directly by reverse phase préparative HPLC eluting 30-70% acetonitriIe/water/0.1% formic acid to give the title compound (16.0 mg).

The following compounds aresynthesized in a similar fashion from the appropriate intermediates:

Example 194, table 1 Example 221, table 1

Method 36

Synthesis of 2-[4-(3-{(R)-l-[4-(2-amino-6-oxo-l,6-dihydro-pyrimidm-5-yl)-phenyI]l-cyclopropyl-ethyl}-[l,2,4]oxadiazol-5-yl)-pyrazoI-l-yl]-N,N-dimethyl-acetamide (Example 197, table 1)

1-97 (170 mg, 0.30 mmol) is dissolved in éthanol (10 ml) and treated with Pearlman's catalyst (Palladium hydroxîde, 35 mg, 50% wet, 0.12 mmol). The vessel is degassed and

191 placed under hydrogen (balloon). Upon complété conversion, the reaction is filtered through a pad of celite and the solids are washed with méthanol. The combined filtrâtes are concentrated and the remaining crude is purified via flash column chromatography (010% MeOH/DCM) to give the title compound (100 mg).

Method 37

Préparation of 5- [4-((R)-l-{5-1 l-(2-Amino-ethyl)-111-pvrazol-4-yl]-[ 1,2,4Joxadiazol-

3-yl}-l-cyclopropyI-ethyl)-phenyl|-pyrimidin-2-ylamine (Example 190, table 1).

Example 190

Intermédiare 1-98 (120 mg, 0.22 mmol) is treated with éthanol (2.7 mL) and THF (0.5 ml.) and hydrazîne (97 mg, 1.93 mmol) is then added. The resultingmixture is stirred at °C for 2 hours. The resulting mixture is filtered, rinsing with éthanol, diluted with ethyl acetate and water, and the phases separated. The organic phase is washed with brine dried over Na₂SO4, filtered, and concentrated in vacuo. The residue îs purified by reverse-phase préparative HPLC eluting 10-80% acetonitrile/water/trifluoroacetic acid to | give the title compound (33.0 mg).| r I

Method 38I

J

Synthèses of 2-[4-(3-{l-[4-(2-Amino-6-fluoro-pyridin-3-yl)-phenyl]-l-cyclopropyl-| ethyl}-[l,2,4]oxadiazoI-5-yl)-pyrazoi-l-yl]-N,N-dimethyl-acetaniide (Example 277,j table 1) and 2-[4-(3-{l-[4-(6-Amino-2-fluoro-pyridÎn-3-yI)-phenyl]-l-cyclopropyl- S[ t

192 ethyl}-[l,2,4]oxadiazol-5-yI)-pyrazol-l-yl]-N,N-dimethyl-acetamide (Example 278, table 1)

Example 277 Example 278

To a mixture of 1-69 (300 mg, 0.68 mmol) in 1,4-dioxane (10 mL) are added 2,6difluoropyridin-3-boronic acid (128 mg, 0.81 mmol), PdC12(PPh3)2 (47 mg, 0.068 mmol) and 2 M NîitCO;, solution (2M aqueous solution)(l mL, 02 mmol). The mixture is heated to 100 °C for 1 hour in a microwave reactor. The solution is cooled down and is extracted with H2O and EtOAc. The combined organic layer is dried with \lg2SO4 and is 10 filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford 1-154 (200 mg) (m/z:

479.2 [M^+H]).

1-154 (150 mg, 0.31 mmol) is dissolved in NH3 in MeOH (2M solution)(10 mL) and the solution is heated to 100 °C for 72 hours. The solution îs cooled down and is 15 concentrated. The residue is purified by préparative silica gel TLC to obtain the title compounds (example 277: 10 mg; example 278: 14 mg) X

193

Method 39

Synthesis of 2-[4-(3-{l-[4-(5-Amino-3-cyano-pyrazin-2-yl)-phenyl]-l-cyclopropylethyl}-[1,2,4] oxadiazoI-5-yl)-pyrazol-l-yl]-N,N-dimethyl-acetamide (Example 295, table 1)

1-155 Example 295

To a solution of 1-69 (100 mg, 0.2 mmol) in DMF are added 2-amino-5-bromo-6chloropyrazîne (51 mg, 0.24 mmol), Tetrakis (triphenylphosphine)palladium (0) (24 mg, 0.02 mmol) and 2M Na₂CO₃ solution (2M aqueous)(0.5 mL, 1 mmol). The mixture is heated to 100 °C for 1 hour in a microwave reactor. The mixture is cooled down and is extracted with H₂O and EtOAc. The combined organic layer is dried with MgSO₄ and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford 1-155 (86 mg) (m/z:

493.2 [M^+H]).

In a microwave reaction vessel is dissolved 1-155 (80 mg, 0.16 mmol) in DMF (8 mL). Zinc cyanide (23 mg, 0.19 mmol) and Pd(PPh₃)₄ (18 mg, 0.016 mmol) are added and the solution is heated to 120^oC in a microwave for 2 hours. The solution is cooled down and îs poured into water and extracted the product into EtOAc. The combined organics are dried with MgSO₄, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 10% MeOH in CH₂C1₂ as the eluent to afford the title compound (38 mg).

Method 40 /

194

Synthesis of 2- [4-(3-(1- [4-(6-Amino-2-cyano-pyridin-3-yl)-phenyl]-l-cyclopropylethyl}-l,2,4]oxadiazo]-5-yl)-pyrazol-l-yl]-N,N-dimethyl-acetamide (Example 296, table 1)

Example 296

To a solution of 2-bromo-6-aminopyridine (200 mg, 1.2 mmol) in DMF (10 mL) are added Zn(CN)2 (163 mg, 1.4 mmol) and Pd(PPh₃)4 (134 mg, 0.12 mmol) at room température. The solution is heated at 120 °C in a microwave reactor for 2 hours. The solution is cooled down and water is added. The solution îs extracted with EtOAc and the combined organic layer was dried with MgSO₄ and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford 1-156 (54 mg) (m/z: 119.9 [M⁺]).

To a solution of 1-156 (54 mg, 0.46 mmol) in CH3CN (10 mL) is added NBS (162 mg, 0.9 mmol) at room température. The solution is stirred at the same température for 12 hours. The solution is concentrated and the residue îs purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford 1-157 (35 mg) (m/z: 197.9 [M⁺]).

To a solution of 1-69 (50 mg, 0.1 mmol) in DMF (8 mL) are added 1-157 (24 mg, 0.12 mmol), Tetrakis (triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) and 2M Na2CO₃ (0.25 mL, 0.51 mmol). The mixture is heated to 100 °C for 1 hour in a microwave reactor. The mixture is cooled down and is extracted with H₂O and EtOAc. The Z

195 combined organic layer is dried with MgSO₄ and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2CI2 as the eluent to afford the title compound (26 mg).

Method 41:

Synthesis of 3-{l-[4-(2-Amino-pyrimidin-5-yl)-phenyil-l,2-dimethyl-propyl] [1,2,4] oxadîazol-5-ol (Example 88, table 1)

To a suspension of morpholine-4-carbonyl chloride (32.907 mg, 0.220 mmol) in DMF (1 ml) is added 1-21 (60.000 mg, 0.200 mmol). The reation mixture is stirred at room température for 20 mîns then Hunig’s base (0.038 mL, 0.22 mmol) is added and the reaction mixture is heated at 55°C for 1 hour then heated in microwave oven at 150°C for 30 mins. After this time, the reaction mixture is concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, 0-10% MeOH in DCM) then pre-TLC (10% MeOH in DCM) yields Example 88 (23 mg) as a white solid; m/z 326.0 [M+H].

Final Compounds; Table 3

Example

Structure

Method

Rétention time (min)

m/z [M+ H]+

LCMS meth od

196

l	dd 1 ifji > XX a N fj>	1	7.4	402.6	A
2	dd M* :.^XX n=/ «A \X	1	8.23	386.6	A
3	AA NpX^ =/ Η,Ν^Χ ^A N^/	1	7.32	387.6	A
4	ίΓ^τ^Γ^Νχ° d x N=/	1	7.66	401.2	A
5	îTaVnx η-λι^α —d x N=/	1	7.51	401.6	A

197

6	ΗΟ'^'Υ· Η/Γ	x y Ν	A	A Ν:=^/	2	6	416.6	A
			αα	Y -Ν y s ι 0
7	Ν'	Ύγ	AU	Ν=Υ	1	7.98	421.5	A
	II Η,ΓΤ	A Ν		Ο
				Ν-’-’/
				Cf
			AT	χ yy χ I °
8		Χγ''		N==V	3	8.04	417.6	A
	A Ν		ο
				Ν=/
				ο—
			ΓΤ	X. -Ν I /°
9	τΓ	γγ-	ΑΑ	Ν=/	3	6.55	403.5	A
	II ΗΖΝ	y) Ν		Ο
				ν—y Η V
				0
			Af
ΙΟ	ν'	γγ-	A	| ο Ν^Υ	4	7.82	417.6	A
	η3ν^	yfi Ν		Αι
				Ν=/

198

11	A J h2n n	o	Xi, y r X N=A °-b	5	6.75	417.6	A
12	17 h2n n	o	XX -N 'rp' x l ° °=Q N-JZ H	4	6.37	403.5	A
13	AV	o	XA^\ l ° nX	5	7.55	417.5	A
	AJ H2N N		0
			—o
14		A	AX r x 1 0 1 N=A	5	5.87	390.6	A
	H2N N		A N /
15	AV A J h2n n	Ό	XX^N X nX XA VN 1	5	5.74	390.6	A

199

16	Λ J η2ν ν	U	À-^N\ y P Ν-·=/ N /	19	1.6	390.7	B
17	Ν’ΧΑγχ AJ η2ν ν	J:. O	A^\ 1 0 N==/ o N /	19	1.6	390.7	B
18	Ν’Χ<Υτχ		A a A X 1 °	5	6.36	390.6	A
	Λ A η2ν ν		-A J N
19			A A X 1 0 N=/	5	5.46	376.6	A
	JL A η2ν N		HN\ <J w
20		XT	A ^-N A x [ 0 N^y	5	4.82	376.6	A
	Jj A h2n n		HN A

200

21	h2n'	n Λ	Tr	\A 1 0 Nx/ X \ /-N N H	5	5.03	374.6	A
'Tr A 'N	UxJ
				Tr	1 °
22		N I	Τγ	Λχ	A	5	5.37	388.6	A
	H2n'	II	A 'N		X VN 1
					χ
				AT
23		Nz II	Τγ	XJ	1 θ NA/'	18	5.48	376.6	A
	hX	II	A 'N		hn, u
					N'
				J.
				/4/	ζγ
24		N' [|	Τγ	XJ	l 0 «A	18	5.48	376.6	A
	hX	II	A 'N		HN J
					N
25		bT il	Τγ		\ /-N x 1 0	5	5.13	374.6	A
	hX	II	. A N		O N H

201

26	J HaN	7	-G	X. ,-N ><> I 0 n=x A N I	5	5.5	388.6	A
			Aï
27	Nx t	V	kj	I 0 nJ	5	5.98	388.6	A
	II h2n'^'	J 'N		---N [ \ J N
			Πτ	JC __-N \x x l 0
28	n'		VA	Μι/	5	4.8	388.6	A
	4 h2n			h N I
			JY	JC ^.n | 0
29	H		AA	N-J	5	5.78	399.6	A
	II	J ‘N		o
				N=J
			Hr	JC -N x I 0
30	J		Ά/	“k	9	2.32	432.2	B
h2n^^	J N		a N J
				/

202

203

36	yyJyo X S/NH —-o	11	2.61	473.4	C
37	aXa [ ΪΓ T p -u./Az NM N \ h2n'^^'n<^ ξ \	5	2.31	373.2	C
38	AifL N/yAJ h2nJ^X N—/ N—. L o \	12	5.42	458.4	A
39	yyyNY nay/x/ η,ν-AJ y N—/ N—Λ , Ύ HO	12	2.29	472.2	C

204

40	KnA N—y N—, H \ HO	12	2.15	458.2	C
41	/-N \ n 'o hX^X À N—7 N—. A °^ / X ο X	12	5.34	506.4	A
42	Η/Γ N vJ N—-, H λ X	11	2.33	459.4	C
43	.AA. N J	9	5.32	430.4	A

205

44	Αχ tyr νγ N—, OH	11	5.26	473.4	A
45	/AU U U h U 'OH	11	5.57	473.4	A
46	itA b h2n n < H N /	19	2.45	390.4	C
47	Χζ /xJ\U n^:< X~Jn N /	19	2.45	390.4	C
48	111° η2ν^Α θ N H	19	2.01	374.4	C

206

49	A. z n \ y A N Y< H,N \A \ A 2 X N N H	19	2.01	374.4	C
50	lÎlV'o b HjN'b'b N=/ NH A	20	5.26	473.4	A
51	A, _ rx°u NH Æ0H	20	5.26	473.4	A
52	fijr o *ύ η3ν^Α An NX I	20	5.55	432.4	A

207

53	4 , .νΑ Ç1	20	5.55	432.4	A
54	ΓΥ Ύ ο zX/ÎJ Μ;=/ n +q ν.	20	5.32	430.4	A
55	4, ιΓΥιΥ= Ν-yM Νΐ< hF+	20	5.32	430.4	A
56	/Χ,Α/Ν ιΤ +ύ ϊ+ s [il ] ο pAJ À Il A Λ—N Η,Ν'^'Ν'^ N==/ NH Aœ	20	5.57	473.5	A
57	4 . ryv> /xAJ N=/ il J YN H2N N \ y N=J NH A-o„	20	5.57	473.5	A

208

58	A Λ J HaN N	\^N yA x 1 0 N^=/ A A /	5	5.9	390.3	A
59	AA N/VJ y nK-V f çN Ar1 o	9	4.97	459.6	A
60	Αλ» n^VaJ y h.n^n'' <o H f O	9	4.74	445.5	A
61	11° Va A aJ K H.N N < J, N /	18	5.36	388.3	A

209

62	A ,	18	5.36	388.3	A
A J η2ν n	U	° N^/ \ _.-N N /
63	AJ η2ν n	--'x c> U	..N Ά l 0 N=s=/ X N <	20	5.91	434.4	A
			? °\
64	Ν^ΑΖ A J h2n n	Z cJ	\ A l ° N^/ <n VN J	20	5.91	434.4	A
			r
65	A J h2n n	u	1 ° n=A X VN /	18	5.89	390.3	A

210

66	Η2Ν·	V	A	18	5.89	390.3	A
Άγ A ’Ν	£	Ζ\χΝ ι ν' χ° J ν=Α VN !
				ΑΑ	Γ χ
67		Ν' I	Άγ	AJ	1 θ	5	2.27	376.4	C
	η2ν	II	Ν		Ρ VN 1
				η	\ | ο
68		ν' II	a	ΑζΑ	ν=Α	5	1.16	362.4	D
	η2ν'	II	A Ν		)α Αα I
				Π	ΑΑν^Ν\ ι Τ °
69		π	Αγ		t'A	5	1.08	346.4	D
	Η,Ν'	Η	A Ν		A
					Ν Η
				£ύ	ΑΓ Μ χΧ χ 1 /°
		Νι	a	Αα	Ν=7
70	η2ν^^	A Ν		Ο	12	1.19	446.4	D
					Ν=/
					ΝΗ 0
					A

211

71	,ΑγΖ -=Ζ «Y-b (Λ y 0=s οΑ	12	1.15	480.4	D
72	r ri ν'χ N/AU -Ζ Af θ ΝΗ X ΗΟ	12	1.24	446.4	D
73	fYpo νΑ Ν \ Η^Χ'-ΙΤ ξ Ν=/ ΝΗ V HO X	11	1.18	447.4	D
74	a N \__ ξ N=Z NH HO	11	1.22	447.4	D

212

75	ΑίΓγ^ο k /fl N y HO	9	1.17	420.4	D
76	A |J yyA/ nV H,rk^V \ 2 \ N	9	1.19	406.4	D
77	fi x 1 o NfJ =/ H/VZ θ N H	18	1.21	376.4	D
78	NV H N/Z^'N v^ Π2 M \ ^N N H	18	1.21	376.4	D

213

79	r 11 χο ζγ/Χζ νΑ η3ν'χ^Α x~^L 1 X ^Ν Ν Y ._--ΝΗ	9	1.06	419.4	D
80	/AXA Η ί ] Ύ V\ Ν^ΑΧΧ --Λ Λ J Η,Ν Ν	10	1.28	369.4	D
81	XX ΖΝ Η fYï Ά\ M-^yXX ν-ο \	10	1.4	383.4	D
82	jlj^Vvv Λ J HjN Ν	10	1.37	397.4	D
83	N^Otrv7H Λ J η2ν Ν	10	1.11	394.4	D
84	ΑΧΧν AU Χ° Λ J Χ° HjN Ν y--Ν Ν---ζ Η	10	1.12	422.4	D

214

85	Η-,νΆ^ ' HO— O	22	1.46	424.4	D
86	pVrO-f HJ1 N	10	1.37	478.5	D
87	i T I V\ n^VaAa n-o \ VJ Y	10	1.29	431.4	D
88	1 ï 1 o naJJ A A J °h h2n n	41	1.26	326.4	D
89	aAaA-n. f \ ffj\i An\7° Az^ N-— n ' n >r ° A J h2n n	10	1.59	395.4	D
90	Aj” v/A A n-X h2n'^xn^ \—o	10	1.43	423.4	D

215 ί I

I j i j

91	o a A J Ύ H2N N /--N N--'	10	1.12	436.4	D
92	AA A A A x N^AA »v A A>0H 0	22	1.43	410.4	D
93	<VvN'' ^OAa h2n n \ Y°H 0	22	1.43	410.4	D
94	ιτγγ\ Ν^γΜ nA Η,Ν^^Α ' \ 2—OH oz	22	1.32	382.4	D
95	rAA» nAa a H^'N^ H°~X\ O	14	1.39	394.4	D
96		21	0.64	408.4	D

216

217

I ,!

218

104	v v ' „γν- nX H00 * X N V -Nx	18	2.3	473.4	C
105	□ ^A'o /x/k/ NA jX 01 * X N V	18	2.3	473.4	C
106	/zzk/ N‘'r;-'/ fifi h ΙΨ V	9	2.24	461.4	C
107	/4Ax /=n XrA „.z7 Λη	18	1.29	448.4	D
108	z, A J Aoh H2N N	18	1.29	448.4	D

219

109	LA ^-N 1 Ο Y A ML Ο + '> 0 X	6	1.67	493.4	Ε
110	Αα ίΑ X η2ν ν ( \ '—Ν \ Η	6	1.09	393.4	Ε
111	/Μ/\Α MU 4 νΖ/Αθ Ο X	6	1.68	493.4	Ε
112	LA» Π I ι Ρ <λ Χμ ÀA HjN Ν \ / /	6	1.72	493.4	Ε
113	ΑαΑα 1 ι ο AJ X η2ν ν ( νη	6	1.13	393.4	Ε

220

ll4	α£	6	1.13	393.4	E
115	r; ίΑ o n/AA hAa a N 1 1	18	4.97	459.4	A
116	4 ,/¾. AC ^-N iï ν' xo m=a n Λ h2n h' 4 J N 1	18	4.97	459.4	A
117	.,a£	1	1.69	392.4	D
118	Ai	1	1.58	364.4	D

221

119	ιΤνν' I T ο jûi ν5α η2ν ν ( \	5	1.68	392.4	D
120	Π Τ Τ ° η2ν ν ( \	1	1.73	406.4	D
121	ζ^κ/kJ ΝΑ η£ν'/^ν^ \~3ν Ν !	18	2.5	402.4	C
122	□,. Xd -ν \ Ιι χ ο /Αν νΑ η2ν^Α 4~Λ Ν !	18	2.5	402.4	C

222

P ! i Ί .1 i i

123	y>^ JA. Λ (y Tr zvU A I J A hAA J N=/ NH <	18	1.33	461.4	D
124	na° A J A H2N N ξ 2 n-=7 NH $	18	1.33	461.4	D
125	yOiA>-CA Λ J HjN N	7	4.03	430.1	F
126	jXyA NyA/ nA n	7	3.47	376.1	F
127	îaXaO NyA> Y A\ A J V h2n n	7	4.92	437.1	F

223

128	Λ J H.N N	7	4.54	412.1	F
129	rAvO N-0 η2ν'^''Ά	7	4.02	388.1	F
130	Au N +γ	7	4.92	393.1	F
131	rruMX “X -''	7	4.6	407.1	F
132	n%-o N X	7	4.07	377.1	F
133	.A'yXX.- /Ύ ni « y^v«H N(/^a> “-v y	7	4.13	404.2	F
134	ί T IK- jCjJ h2n n	10	3.94	353.2	F

224

135	JT	8	4.65	472.1	F
136	îPjy J N-J F Aï	8	4.87	455	F
137	ήχο AÏ HjN N	8	3.74	388.1	F
138	rrVy-O xu «v AÏ k2n n	8	4.26	394.1	F
139	N A A J h2n n	7	4.36	393.1	F
140	Χχζχ /°1 r T Ύ y-O Xk -ο γ A J H;N M	8	4.3	391.1	F
141	iyVvb XyA/1 nA s	8	4.59	407.1	F

225

142	N^JU Α^Άτ aJ Η/Γ Ν	13	3.62	447.1	F
143	^\Αχγ-Ν /=Ν „ -γΜ ζΚ-Γ	7	4.85	387.1	F
144	/ JA /VN r ît τ v/ i '' / \<^n za >w N-o A J Η,Ν N	13	3.06	489.3	F
145	A/ A—oh ^-N / ΠτΥνΑ n/a JU n^o	15	4.35	436.2	F
146	Av n^az «g hAA	7	3.73	376.1	F
147	V-o JA	7	3.87	388.1	F
148	y fïVvO N	7	4.37	464.1	F

226

149		7	4.28	464.1	F
150	Υχ aJ HZN N	7	2.92	407.2	F
151	A) H.N N	7	3.57	402.2	F
152	nJy-O /yU < V N	7	4.23	402.2	F
153	aY AV	7	4.72	421.1	F
154	A'jFaCV0 AJ Ά A A J H,N n	7	3.02	404.1	F
155	iyJyCH jCj H,N N	7	4.33	418.1	F

227

156	fAz «n H2N'X^'A	7	4.41	350.2	F
157	/ HO A - A Λ J HZI< N	7	3.65	417.2	F
158	nrVo naJU h2n^Z C°x	13	5.91	434.4	A
159	/xJZ/N /SSN αΛ*Α A J Ah H2N N	13	4.06	448.3	F
160	A Tr x o Xîj à vu O'^'OH	16	3.93	462.2	F
161	ii+y-Cl.__ A -· l-ÇN N	13	3.91	432.2	F

228

162	ί-'''AsAAzj Γι τ>- ' Λ Π 1 Το ν^/ ηΧγΤ \\ ν=Α Ν—, Η \ ν~Ό \	11	4.06	461.3	F
163	ώ Nb ΗΖ \-χ Q \	11	3.12	486.3	F
164	Νζ/0 Λ J Y Η,Ν N Α. ι ' // ηΧΝ~Ν ηοΑο	16	4.04	476.2	F
165	rfYy-Q ° /Α Η2Ν'^ΧΝΧ	17	3.97	417.2	F
166	X/ r ° ΗΖΝ Ν	17	3.79	421.1	F

229

167	(Xybb N-y H,nA-nA	17	3.6	407.1	F
168	J! J A xV / Γ° 0	21	1.37	443.4	E
169	bb fYY \ «AJ γ —N yo	21	1.39	436.4	E
170	bX^ .XX j \ 0=r 0	21	1.42	472.4	E
171	Abx h γ ύ ύ y-\ n-oz x—-\ JA /'	10	1.1	396.4	E

230

172	XX HjN N	-U	X NX/ >		27	1.06	458.4	H
		ΧΎ	X. -N
173	XX HfN N	ÂJ	NA^/ A A-, A	X0H	27	0.66	445.3	G
174	Xb H?N N	£r	A CX A	'—'OH	27	0.82	446.4	G
175	ÎJ hLN N	XX	^XfAN\ U/ H N A	^OH	26	0.86	446.4	G
176	.N £ΐ HjN N	A	À A X K N Ί		26	0.78	459.4	G
			A- 0	r

23!

232

182	fl T i x° /V/\A N5=y V h N k<	34	1	445.4	H
183	A ?r A s 1 « 0 ' A 1	27	0.68	432.4	G
184	xkV HX N A ,.tJ_. N	26	0.85	389.5	G
185	z\ Xk /-N X Ar rri x Vf H,N N A N	26	0.69	401.6	G
186	vC V i|j \ /v h2n / \ ’N ? OH	21	1.1	438.4	E

233

187	1 ' 0 'γΝγ\ζ A N	26	0.9	403.4	G
188	JA Il ,,Xj o, Λ	26	0.74	445.1	G
189	\ 0 1	26	0.94	446.1	G
190	aXa AJ nX «Α~'Ζ N J^-nh2	37	0.98	417.4	H
191	ZX/V'1’ jCX j Hsrr n ,n. \ o 1	26	0.9	433.3	G

234

192	_-N ιίΥΥ 'ο n==/ h/AA '----N Anhj 0	21	1.31	437.4	E
193	jm A/V AJ HjN N	29	1.15	479.4	E
194	rA ZA y xJ h π2ν N < n N y '7 0 !	35	1.19	503.4	H
195	Aj1 /—z zH X	23	0.59	470.3	G

235

196	h2n		Af	A. A AA x T /° nA C N=^ <	N \\	23	1	470.4	D
A x N	A/
N- A	) N H
			0	P	/A M \ 'v	x P
		un''		JA,---	J Ni=:	(
197		H			y		36	0.59	475.3	G
	Η,Ν	AA N			( N	M
					V	J
					II 0
				ΓΎ	X A AA x 1 °
198			A'	A	N- C			21	1.49	451.4	E
	h2n		d N		γ>	V
					A^x 1 P
199		jiA	A/	JIJ	nsA			21	1.29	408.4	E
	h2n	A	A N		\ N— C	3 N H	~o

236

200	NX J	Αγ A 'N	Cr	Α,ν T ° t	OH	21	1.29	381.4	E
			Ay	A. ^-N Z-Z x
			1 I	1 o
201	NX II	Aj	££	NH /		21	1.42	423.4	E
		X>
	hjA	VN		é	) o
			A/	zz\
			T	1 0
202	rr	A		N===/		21	1.36	422.4	E
	„ A	A		/A
	Η2Ν	N		W	=0
				\
			ZA	Ά --n X x
			il 1	l °
203		Αγ-	££			31	1.34	395.4	E
	A	A		Λ	>
	h2n	'N		$	Ah
				A. ..n
			ZA
			1 I	T °
204	N	Αγ	W			32	1.43	377.4	E
		A		N-	-η
	H2N^	'N		<	3

237

205	λ. JA Υγ a χ o /AJ A A /nA HjN N / \ OH	32	1.3	407.4	E
206	na3*A p «z/ b N	25	1.4	430.4	D
207	ιγΑο ,A A A b N J	25	1.3	430.2	D
208	ζΥζΥ®Ν λ q 04~ ° o	21	0.8	471.3	G
209	HO	21	0.82	423.3	G

238 i

ί i

I !

i

210	x4 X X >r Ύ' x 1 o ( \) N^/ O '—N H	23	0.85	469.4	H
211	xOAVCxy- AJ N	29	0.63	466.4	G
212	N^Ay+Xz A^ /~\ H?N N ΐ \ OH	21	0.87	437.4	G
213	JC* HjN	21	0.75	436.3	G

239

214	A, z	23	0.68	470.3	G
1 HaN	.n. y w	A	Xx AA \ 1 P nA Q
				A
				V H
				L
			va	/À \ o
	N K	Ά	AA
215	11 Η,ΙΨ	x y> N		)a Vn /	34	0.7	471.4	J
				0
			VY	X. γ+ \ l z°
216	Ν'*	ύζ	Ab	nY	31	0.89	423.3	G
	J Η.8Γ	N		Q
				[Ah
			Ay h T	ZX yU \y x l 0
217	N' A H?N	'Άχ -A	Ab	Q	28	0.7	422.4	G
				NH /

240

218	II,M J— >>' ( ) N--- /	21	1.14	436.4	E
219	aaa /JU b „AJ q a°h o	30	1.39	437.4	E
220	\ H S° AJ A O N ν' n 0 \	35	1.17	515.4	F

241

221	h2Z	I	-0 N	O	%x* >Ax\ p	35	1.17	515.4	F
N^X C Y' ZN ...o O \	1
				ΓΤ	XX \ l 0
222		NX		Αχ	N=z^		28	0.69	408.4	G
	h2n''		X N		C	) hh2
					Ύν
				ΓΤ	Z. N XX \ l °
223		Z	XZ	Αχ			33	1.36	409.4	E
	HjN	[I	X n		N — Y	> OH
				J...,
				ιΓΥ	XA l 0
224		Z	Xz	Ax	NY/^		33	1.36	409.4	E
	h2n'	II	X N		N-— C	OH

242

243

229	AA AA -N \ Il xo AaA/ nF n Xf \ o /	24	1.32	398.4	D
230	ΓγΎο nAJ -A «AV o N Y NH	18	1.29	445.4	D
231	F< «Z nAA Λ h2An O Y ^-NH	18	1.29	445.4	D
232	z\zKa\ Γ iT ν' x° AxAU NF N AA \ h2n/^x‘n/ ξ 0 /	24	1.3	368.4	D

244

233	ίι ίΓ 'i Xz\j χ/ Λ J N-X G/ / V OH	18	1.3	407.4	E
234	a, vOa> A J J-a H;N'X*X'N / \ OH	18	1.3	407.4	E
235	[f^|ï N'o Q OH	21	0.87	435.3	G
236	X x X \ Il 1 l o N^JU X A J /H h2n n /r~~< N--' /	21	1.11	422.4	E

245

237	h2n'	aJ N	X	A A	AX -n ν' 19¾ c	\ 0 ( NH /	21	1.33	423.4	E
					/— HO
238	H A	N'UU xJ N	c		\A\ 1 ° ς	) OH	31	1.35	421.2	E
		f	Ά		O \
239	c N H	I XX N	A	N	V x-N\ Ί		26	0.67	500.3	G
					χΧ CT	W 1
240	H/i	1 i y J N	UX Y	X		26	0.72	473.3	G
					/	M

z

246

241	rA Η	ο Ν	0	A V 1 CV	Y	26	1.15	484	Η
			ΑΎ	>C Αί> 1 °
242	Ζ Ν— Η	Ο Ν	ΛΑ	ΝΑ? Η 4		26	1.98	482.3	Η
				A	1
			ιΓΎ	| ρ
243	1=	υ	ΛΑ	~χ		26	0.81	4763	G
	η/γ	A		ν\
				b	1
			ΑΧ	*C A 0
244		oc	ΑΑ	X		26	1.01	472.2	D
	Η/Γ			43 Ί
				X	1
			ΑΎ	___,Ν Ο
245	J	ΟΧ	Αα	X		26	1.16	473.4	D
	Η,Ν			VS
				b	Αγ 1

247 i l i j I

J

246	y fY ' '° N 1 OAZ	26	1.38	526.2	D
247	N-Q <cX 1	26	0.85	483.3	G
248	XX0 A X h2n n / \ OH	32	0.59	406.3	G
249	h H VNz	26	0.89	487.3	G
250	aXa -=/ ArAi CL X 1	26	0.87	499.3	G

248

251	ΗΓΓ 1		X Ν 1 1	26	0.62	472.3	D
ίΧ Ν	υ
			ίΧη	JX _/-Ν ' X
			I	Ο
			χ·'.....Α	Ν^γ/	32
252		ΛΑ		/-\	1.08	436.2	Ε
	η2ν			Q ;
				< ΟΗ
			υύ	ζΧ\
			I	[ ζ°
253	Λ	Ά	AJ		26	1.32	413.3	Η
	Ν' Η	Ν		ο
			τ	1 Ζ°
	X
254	L	A J		/X	18	0.66	500.1	G
	Η			4 Α Ν 1
			A
			UUA	\
			1 T	1 ο
		ΑΧ-	χχ	Ν^/
255	c	A a			18	0.66	500.3	G
	η' Η	'Ν''		“ 1 0^../

249

J

256	ΑΧ vk	26	1.32	413.3	H
257	/A n/LXJ «Y A CL 1 1	18	0.72	473.3	G
258	4 K ^-N’/ N 1 □>A 1	18	0.72	473.3	G
259	/ΤγΑγ/Πχ Ju S j <”ΤΤ O	32	1.32	469.2	E
260	UC XXlz XX^ /A η/γΆ / \ /	21	1.14	410.4	E

250

261	.,ΛΖ '---N Z	21	1.16	450.4	E
262	OH	21	1.37	409.4	E
263	A^f HSN N	27	1.34	429.3	H
264	zAa\/N\ aA Z '---N λ~	21	1.16	436.4	E
265	. Of HïN n VN-fX	26	0.8	430.3	G

251

266	A A2 / A J	21	0.63	434.4	G
267	A O '---N H	23	0.61	470.4	G
268	Pa jCa^ A\\ h2n n \ / N=/ O 1---N H	23	0.53	469.4	G
269	PP	21	0.82	465.4	G

252

				X
			ΆΑ^	γΧ X
		fi		l 0
270	Y					21	0.93	423.3	G
	A	A		/N-\
	Η,Ν N		o
				0—.
			Fy	1 .·'' XC X XX x
			[ T	1 0
271	N'' II	Ax		T		9	0.87	414.4	D
	II	X		F	1 X
	h2n	Ή		\ N 4
			AZ xn	Y-n
272		JO	y y	— N yN \	—OH	30	0.61	452.3	G
	ν-Ύ		N-o
				O
	H.N N
			AAA	A^n
			1 T	1 /°
273		-N\/	aJ	N=A		26	2.02	412.3	H
	FY			Y
	SA H			XN N
				X
				JA X XX x
			i I	1 °
274		Αχ	-S.x:J			32	1.23	379.4	E
	jl			χ
		X			7
	h2n	n		Y	( OH

253 ί I ί | !

275	vA-'J ç. ^γο	26	1.38	477.4	D
276	fÇV'o a η,ν^ν^ C? P OH	31	0.71	393.2	G
277	lirVo XV V F N NH2 < ,¾ ^γο -A	38	0.93	476.3	D
278	•aXa l ° JJ A ç>	38	0.88	476.3	D
279	Aq AAV h H V 1 ,Αγ	26	0.97	501.3	G

254

280	ί Ηϊ	Ύ- ’Ν	A	φ	26	0.63	472.3	D
U	A N ’ A
	ί F		|X	iï	< -h-N b^ x°
281	Γ I	X	A.	H	b		26	0.97	526.6	D
		A			4 A Ί
					cr	V 1
			if	xy	X, _^N yX x l /°
282		ιΡί		A	N^/		18	0.62	406.3	G
	Η,Ν^	A A N			C	> OH
				A
			if	γ	AA I o
283					N ^/		18	0.62	406.3	G
	η2ν^	A N			<:	OH
				j	I /°
284	Ν' Η	o N	A.		A N 1 A		26	1.28	484.3	H

255

285	vx N1	26	0.76	473.3	D
286	1 ' /° M2=< CX N \	26	0.89	402.2	G
287	j HO*	32	1.31	407.2	E
288	kVk'. o au a «A4 0 HO	32	1.31	407.2	E
289	v fFv> H,N^SZ ζ J N 1	26	2.35	527.2	H
290	N -	26	1.1	478.3	G

256

291	Ν1 1	26	0.79	476.3	G
292	ΖυΑ' Η,Ν Ν ' Ν 1 Αζ 1	26	0.64	472.3	D
293	f Γγν·ο „W V η2Α< AJj Ν' Ύ	26	0.83	477.3	D
294	π2ν n <Ç?N -Νχ	26	0.88	484.2	D

257 .ι i

J •f i ;

295	ArY/0 o r	39	0.83	484.2	D
296	xr N1 -X	40	0.85	483.3	D
297	ZX JA. /N ίΐΊΓ Z ïr /O» h2n n \---/	32	0.82	435.3	G
298	naaj a h2AAf a N £o X	26	0.85	491.3	D

Assessment of Biological Properties

1. Binding Assay

Compounds are assessed for the ability to bind to FLAP in a binding assay that measures compound-specific displacement of an iodinated (^,25I) FLAP inhibitor via a Scintillation

258

Proximity Assay format (adapted from S. Charleson et al., Mol. Pharmacol., 1992, 41, 873-879).

Cell pellets produced from sf9 insect cells expressing recombinant human FLAP protein are resuspended in buffer A [15 mM Tris-HCl (pH 7.5), 2 mM MgCl₂, 0.3 mM EDTA, 1 mM PMSF]. The cells are lysed with a Dounce homogenizer and the material is centrifuged at 10,000 x g for 10 minutes. The supematant is then collected and centrifuged at 100,000 x g for 60 minutes. To préparé membrane protein for an assay, an alîquot of the 100,000 x g pellet is resuspended in 1 ml of buffer A, Dounce homogenized, and finally subjected to polytron mixing (30 seconds). Membrane protein (25 μΐ, 5 pg) is mixed with WGA SPA beads (Amersham) and stirred for lh. To an assay plate (Perkin Elmer FlexiPlate) is added 25 μΐ of test compound prepared în Binding buffer [100 mM Tris (pH 7.5), 140 mM NaCl, 5% glycerol, 2 mM EDTA, 0.5 mM TCEP, 0.05% Tween 20], 25 μΐ of [¹²⁵I]L-691,831 (an iodinated analog of MK-591, Charleson étal. Mol, Pharmacol., 41, 873-879,1992) and finally 50 μΐ of the bead/protein mixture, (final concentrations: beads, 200 pg/well; protein, 5pg/well; [¹²⁵I] probe, 0 08 nM/well(17 nCi/well). The plates are shaken for 2h before reading on a Microbeta plate reader. Non-specific binding îs determined by the addition of 10 μΜ cold L-691,831 compound.

In general, the preferred potency range (IC50) of compounds in the above assay is between 0.1 nM to 10 μΜ, the more preferred potency range is 0.1 nM to 1 μΜ, and the most preferred potency range is 0.1 nM to 100 nM.

2. Whole Blood Assay:

Compounds are additionally tested in a human whole blood assay to détermine their abîlîty to inhibit the synthesis of LTB₄ in a cellular system. Compounds are combined with heparinized human whole blood and incubated for 15 minutes at 37°C. Calcimycin (20μΜ final, prepared in phosphate-buffered saline, pH 7.4) is then added and the mixture is incubated for another 30 minutes at 37°C. The samples are centrifuged for 5 S

259 min at low speed (1500 x g) and the plasma layer is removed. Plasma LTB₄ concentrations are then measured using an antibody-based homogenous time-resolved fluorescence method (CisBio, Bedford, MA).

METHOD OF USE

The compounds of the invention are effective inhibitors of 5-lipoxygenase activating protein (FLAP) and thus suggest they inhibit leukotriene production. Therefore, in one embodiment of the invention, there is provided methods of treating leukotriene-mediated disorders using compounds of the invention or their pharmaceutically acceptable salts thereof. In another embodiment, there is provided methods of treating cardiovascular, inflammatory, allergie, pulmonary and fibrotic diseases, rénal dîseases and cancer using compounds of the invention or their pharmaceutically acceptable salts thereof.

Without wishing to be bound by theory, by inhibitîng the activity of FLAP, the compounds of the invention block the production of LTs resulting from the oxidation of arachidonic acid by 5-LO and subséquent metabolism. Thus, the inhibition of FLAP activity îs an attractive means for preventing and treating a variety of diseases mediated byLTs. These include:

Cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis;

Allergie dîseases including asthma, allergie rhinitis, rhinosinusitis, atopie dermatitis and urticaria;

Fibrotic diseases including airway remodeling in asthma, idiopathic pulmonary fibrosis, scleroderma, asbestosis; /

260

Pulmonary syndromes including adult respiratory distress syndrome, viral bronchiolitis, obstructive sleep apnea, chronic obstructive pulmonary disease, cystic fibrosis, and bronchopulmonary dysplasia;

Inflammatory diseases including rheumatoid arthritis, osteoarthritis, goût, glomerulonephritis, interstitial cystitis, psoriasis, inflammatory bowel disease, inflammatory pain, multiple sclerosis, systemic lupus erythematosus, transplant rejection, inflammatory and allergie ocular diseases;

Cancer including solid tumors, leukemias and lymphomas; and

Rénal diseases such as glomerulonephritis.

For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage. For example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to détermine an optimal dosing level and pattern. The active ingrédient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other /

261 pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

Administration of the compounds of the invention, în pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topîcally, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aérosols, or the like, preferably in unit dosage forms suitable for simple administration of précisé dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other médicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), American Pharmaceutical Ass’n, 2000; H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms andDrug Delivery Systems, 5th ed., Lea and Febiger, 1990; each of which is încorporated herein by reference in their entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that are required for the formulation to be efficacious. P' *$ JAN 2013

262

CLA1MS

What is claîmed is:

Claims (16)

1. What is claîmed is:

   wherein:

   R*and R² are each independently hydrogen, C1.7 alkyl or C3.10 carbocycle, with the proviso that both R¹ and R² are not hydrogen;

   R³ is a 5-11 membered heteroaryl ring containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, wherein the heteroaryl ring is optionally independently substituted with one to three groups selected from C1-5 alkyl optionally substituted with one to three halogen atoms, C1.5 alkoxy, Ci.3 hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C₃.₆ carbocycle, Ci 6 alkylamino and C|<, dialkylamino;

   R⁴ îs hydrogen, C1.3 alkyl, halogen or nitrile;

   R⁵ is Ci_6 alkyl, C₃.io carbocycle, 3-11 membered heterocycle, aryl, 5-11 membered heteroaryl, -C(O)-R⁶, hydroxy or -NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R*';

   R⁶ is C₃_s heterocycle or NI 1-5-6 membered heterocycle, each optionally independently substituted with one to three groups selected from R⁹, Rⁱ⁰ and R¹¹ ; Z

   263

   R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with Ci_6 alkyl, C3.J0 carbocycle optionally substituted with hydroxy or Ci_₆ alkyl;

   R⁹, Rⁱ⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) Ci /,alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , 3-6 membered heterocycle, Ci^alkoxy, Cj^alkoxy-O- C| 6alkyl, -CO2R¹², -C(O)N(R¹²)(R¹³) or -S(O)nCi_₆alkyl.

   (g) C_{; 6}alkoxy, (h) -N(R¹²)(R¹³), (i) -SiO^Ct-ealkyl, (j) CO2R¹², (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) a 3-10 membered heterocyclic group optionally substituted with one to three Ci-e alkyl groups, (n’) oxo, (o) -C(O)-Ci_3 alkyl;

   R¹² and R¹³ are each independently selected from -H, -Ci^alkyl, C(O)Ci_6aIkyl, and a 36 membered heterocyclic group, each of which is optionally independently substituted with one to three Ci.·,alkyl groups, -OH, Cj_6alkoxy, -C(O)N(R¹⁴)(R¹⁵), -S(O)_nCi.6alkyl, CN, a 3-6 membered heterocyclic group, -OCi^alkyl, CF₃, or; X

   264

   R¹² and R¹³ taken together with the nitrogen ring to which they are attached form a heterocyclyl ring optionally substituted with one to three OH, CN, -OCi-6alkyl or oxo;

   R¹⁴ and R¹⁵ are each independently selected from -H and -Ci^alkyl;

   n is 0, 1 or 2;

   or a pharmaceutically acceptable sait thereof.
2. 2. A compound according to claim 1, wherein:

   R^l and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cylohexyl, with the proviso that both R¹ and R² are not hydrogen;

   R³is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thienyl, furanyl or thiazolyl, wherein each heteroaryl ring is optionally independently substituted with one to three groups selected from C1.3 alkyl optionally substituted with one to three halogen atoms, C1.3 alkoxy, Ci_₃ hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NHC₃^carbocycle, Ci/ alkylamino and C1.3 dialkylamino;

   or

   R³ is pyridooxazinyl, dihydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrrolopyrîdinyl, pyrrolopyrazinyl, wherein each heteroaryl ring is optionally independently substituted with one to three groups selected from C1-3 alkyl optionally substituted with one to three halogen atoms, Cj_₃ alkoxy, C].₃ hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C3^ carbocycle, C1.3 alkylamino and C1.3 dialkylamino;

   R⁴ is hydrogen, methyl or fluoro;

   R⁵ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, teri-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidînyl, X

   265 tetrahydropyranyl, pyrrolyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidînyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, -C(O)-R^S, hydroxy or NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

   R⁶ is piperidinyl, pîperazinyl, tetrahydropyranyl, morpholinyl, tliiomorpholiny! or -NHpiperadinyl each optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

   R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with methyl, CA, carbocycle optionally substituted with hydroxy, or C1-5 alkyl;

   R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) C i_<,alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , 3-6 membered heterocycle, C|.(, alkoxy, C,.,,alkoxy-O- Ci.&alkyl, -CO2R¹², -C(O)N(R^,2)(R¹³) or -S(O)nCi^alkyl, (g) Ci.₆alkoxy, (h) -N(R¹²)(R¹³), (i) -S(O)_nCr₆alkyI, (j) -CO₂R¹², (k) -C(O)N(R^,2)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) a 3-8 membered heterocyclic group optionally substituted with one to three C-i 6 alkyl groups, /

   266 ! ι ί I ί τ Î (η’) οχο, (ο) -C(O)-Ci_₃ alkyl;

   R¹² and R¹³ are each independently selected from -H, -Cj^alkyl, C(O)Ci-6alkyl, and a 3-

   6 membered heterocyclic group, each of which is optionally independently substituted with one to three Ci^alkyl groups, -OH, C|/alkoxy, -C(O)N(R^,4)(R¹⁵), -S(O)nCi.6alkyl, ·

   CN, a 3-6 membered heterocyclic group, -OCi^alkyl, CF_3; or,

   R¹² and R¹³ taken together with the nitrogen ring to which they are attached can form a heterocyclyl ring optionally substituted with one to three -OH, CN, -OC; alkyl or oxo;

   R¹⁴ and R¹⁵ are each independently selected from -H and C 1.4alkyl;

   n is 1 or 2;

   or a pharmaceutically acceptable sait thereof.
3. 3. A compound according to claim 1 or 2, wherein:

   R¹ and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,

   1 2 cyclopropyl or cyclobutyl, with the proviso that both R and R are not hydrogen;

   or a pharmaceutically acceptable sait thereof.
4. 4. A compound according to any of the claims 1-3 wherein:

   R³ is pyridînyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with one to two groups selected from Ci_₃ alkyl optionally substituted with one to three halogen atoms, Ci_₃ alkoxy, Ci.₃ hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C3.6 carbocycle, Ci.₅ alkylamino and Ci_₃ dîalkylamino; or /

   267

   R³ is pyridooxazinyl, dihydro-pyridooxazînyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl;

   or a pharmaceutically acceptable sait thereof.
5. 5. A compound according to any of the claims l-4, wherein:

   R⁵ is methyl, ethyl, propyl, îsopropyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thîazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C(O)-piperizinyl, -C(O)piperidinyl, -C(O)-morpholinyl,-C(O)-NH-piperidinyl, hydroxy or -NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

   R⁷and R⁸ are each independently hydrogen, 5-6 membered heterocycle optionally substituted with methyl, Cj.₆ carbocycle optionally substituted with hydroxy or C1-C5 alkyl;

   R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) Ci^alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , morpholinyl, piperazinyl, Cj^alkoxy, Ci.₃alkoxy-O- Ci_₃alkyl, -CO₂R¹² or -C(O)N(R¹²)(R¹³), (g) C[.₃alkoxy, (h) -N(R¹²)(R¹³), (i) -S(O)_nC_Malkyl, (l) C()_?R'², Z

   268 (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) morpholinyl, piperazinyl, piperidinyl or oxetanyl each optionally substituted with a methyl group, (n’) oxo, (o)-C(O)-CH₃;

   R¹² and R¹³ are each independently selected from -H and Ci alkyl, wherein the alkyl group is optionally substituted with one to three - OH, Ci^alkoxy, -C(O)N(R¹⁴)(R¹⁵) or S(O)_nC_[.₆alkyl;

   R¹⁴ and R¹⁵are each independently selected from -H and -Ci^alkyl;

   nis 2;

   or a pharmaceutically acceptable sait thereof.
6. 6. A compound according to claim 1 or 2, wherein:

   R¹ and R² are each independently hydrogen, methyl, ethyl, propyl, isopropyl, toY-butyl, cyclopropyl or cyclobutyl, with the proviso that both R¹ and R² are not hydrogen;

   R³ is pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with one to two groups selected from methyl, methoxy,-CH₂OH, trifluoromethyl, bromo, chloro, fluoro, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C 3-6 carbocycle, Cy alkylamino and C1-3 dialkylamîno; or R³ is pyridooxazinyl, dihydro-pyridooxazinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl;

   R⁴ is hydrogen;

   R⁵ is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, A

   269 pyridazinyl, quînolinyl, isoquinolinyl, -C(O)-piperazinyl, -C(O)-morpholiny], piperidinyl, hydroxy or -NR⁷R⁸, wherein each R⁵ is optionally independently substituted with one to three groups selected from R⁹, R¹⁰ and R¹¹;

   R⁷and R⁸ are each independently hydrogen, piperidinyl optionally substituted with a methyl group, cyclohexyl optionally substituted with a hydroxy group, methyl or ethyl;

   R⁹, R¹⁰ and R¹¹ are independently selected from (a)-H, (b)-OH, (c) halogen, (d)-CN, (e)-CF (f) Ci-₆alkyl optionally substituted with one to three -OH, -N(R¹²)(R¹³) , morpholinyl, piperazinyl, Ci^alkoxy, Ci-₃alkoxy-O- Ci_3alkyl, -CO₂H or -C(O)N(R¹²)(R¹³), (g) C i_3 alkoxy, (h) -N(R¹²)(R¹³), (i) -S(O)₂C_k2alkyl,

   0) CO_?R^)?, (k) -C(O)N(R¹²)(R¹³), (l) -S(O)₂N(R¹²)(R¹³), (m) morpholinyl, piperazinyl, or oxetanyl each optionally substituted with a methyl group, (n’) oxo, (o)-C(O)-CH₃;

   R¹² and R¹³ are each independently selected from -H and -Ci^alkyl, wherein the alkyl group is optionally independently substituted with one to three -OH, Ci.₆alkoxy, C(O)N(R¹⁴)(R¹⁵), or -SiOhCï-ealkyl;

   R¹⁴ and R¹⁵are each independently selected from —H and -Ci^alkyl;

   270 | or a pharmaceutically acceptable sait thereof.

   i

   I
7. 7. A compound according to claim 6 immediately above, wherein:

   R¹ is methyl, j 5 R² is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl;

   1 or a pharmaceutically acceptable sait thereof.

   i i
8. 8. A compound according to claim 6, wherein: R³ is selected from or a pharmaceutically acceptable sait thereof.
9. 9. A compound according to claim 6, wherein:

   R⁵ is pyrazolyl optionally independently substituted with one to three groups selected 15 from R⁹, R¹⁰ and R¹¹ ;

   or a pharmaceutically acceptable sait thereof.
10. 10. A compound according to claim 6, wherein:

    R¹ îs methyl,

    20 R² is selected from methyl, ethyl, isopropyl, terZ-butyl, cyclopropyl and cyclobutyl;

    R³ is selected from

    Η₂Ν h₂n ,and Z¹

    HO

    R⁴ is hydrogen,

    R⁵ is selected from

    271 or pharmaceutically acceptable salts thereof.
11. 11. A compound according to ciaim 10, wherein:

    R² is cyclopropyl or cyclobutyl;

    or a pharmaceutically acceptable sait thereof.
12. 12. A compound according to claim 10, wherein:

    R² îs selected from methyl, ethyl, isopropyl and /iAbulyl; or a pharmaceutically acceptable sait thereof.
13. 13. A compound according to claim 6, wherein:

    R³ is selected from or a pharmaceutically acceptable sait thereof.
14. 14. A compound according to claim 6, wherein: R³ is selected from /

    272 or a pharmaceutically acceptable sait thereof.

    5
15. 15. A compound according to claim 10, wherein:

    R¹ is methyl,

    R² îs cyclopropyl;

    R³ is selected from

    R⁴ is hydrogen,

    273 or a pharmaceutically acceptable sait thereof.
16. 16. A compound selected from a group consisting of: