ANTIBACTERIAL COMPOUNDS

Abstract

The present invention relates to the following compounds wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis.

##STR00001##

Claims

1. A compound of formula (Ia): ##STR00156## wherein: Q.sub.1 is ═N— or ═C(R.sup.4)—; A is a 5- or 6-membered ring, which is aromatic or non-aromatic, and optionally containing 1 or 2 heteroatoms selected from nitrogen or sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R.sup.1 is one or more optional substituents independently selected from halo, —R.sup.6a, —O—R.sup.6b, —C(═O)—R.sup.6c, —C(═O)—N(R.sup.7)(R.sup.8), —CN or —N(R.sup.7a)R.sup.7b; or any two R.sup.1 groups are taken together (when attached to adjacent atoms of the A ring) to form a 5- or 6-membered ring optionally containing one or two heteroatoms, and which ring is optionally substituted by one or two C.sub.1-3 alkyl substituents; R.sup.2 is —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo —OC.sub.1-3 alkyl; any two of R.sup.3, R.sup.3a, R.sup.4 and R.sup.4a are H, and the other two independently are a substituent selected from H, F, —C.sub.1-3 alkyl or —O—C.sub.1-3 alkyl; R.sup.5 is H, —R.sup.9a, —C(═O)—R.sup.9b, —SO.sub.2—R.sup.10 or Het.sup.1; either one of X and Y is —CR.sup.11a and the other is N or —CR.sup.11b; R.sup.6a and R.sup.6b independently represent are hydrogen or —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo —O—CH.sub.3 or phenyl; R.sup.6c is —C.sub.1-3 alkyl; R.sup.7 and R.sup.8 are independently selected from H or —C.sub.1-3 alkyl; R.sup.7a and R.sup.7b independently represent are H, C.sub.1-6 alkyl or R.sup.7a and R.sup.7b are linked together to form a 3- to 6-membered ring; R.sup.9a is —C.sub.1-4 alkyl, optionally substituted by one or more substituents selected from halo, —OC.sub.1-3 alkyl or Het.sup.2; R.sup.9b is hydrogen or —C.sub.1-3 alkyl optionally substituted by one or more fluoro atoms; R.sup.10 is —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo or —O—CH.sub.3; R.sup.11a and R.sup.11b independently represent are H, C.sub.1-4 alkyl (itself optionally substituted by one or more substituent(s) selected from fluoro, —CN, —R.sup.12a, —OR.sup.12b, —N(R.sup.12c)R.sup.12 or —C(O)N(R.sup.12e)R.sup.12f) or —O—C.sub.1-4 alkyl (itself optionally substituted by one or more substituent(s) selected from fluoro, —R.sup.12g, —OR.sup.12h/or —N(R.sup.12i)R.sup.12j); R.sup.12a, R.sup.12b, R.sup.12c, R.sup.12d, R.sup.12e, R.sup.12f, R.sup.12g, R.sup.12h, R.sup.12i and R.sup.12j independently represent are hydrogen or C.sub.1-3 alkyl optionally substituted by one or more fluoro atoms; Het.sup.1 and Het.sup.2 independently are a 5- or 6-membered aromatic ring containing one or two heteroatoms, optionally substituted by one or more substituents selected from halo or C.sub.1-3 alkyl (optionally substituted by one or more fluoro atoms, or a pharmaceutically-acceptable salt thereof.

2. A compound of formula (I): ##STR00157## wherein: A is a 5- or 6-membered ring, which is aromatic or non-aromatic, and optionally containing 1 or 2 heteroatoms selected from nitrogen or sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R.sup.1 is one or more optional substituents independently selected from halo —R.sup.6a, —O—R.sup.6b, —C(═O)—R.sup.6c, —C(═O)—N(R.sup.7)(R.sup.8), —CN or —N(R.sup.7a)R.sup.7b; R.sup.2 is —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo or —OC.sub.1-3 alkyl; any two of R.sup.3, R.sup.3a, R.sup.4 and R.sup.4a are H, and the other two independently are a substituent selected from H, F, —C.sub.1-3 alkyl or —O—C.sub.1-3 alkyl; R.sup.5 is H, —R.sup.9a, —C(═O)—R.sup.9b, —SO.sub.2—R.sup.10 or Het.sup.1; either one of X and Y is —CR.sup.11a and the other is N or —CR.sup.11b; R.sup.6a and R.sup.6b independently are —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo or —O—CH.sub.3; R.sup.6, is —C.sub.1-3 alkyl; R.sup.7 and R.sup.8 are independently selected from H or —C.sub.1-3 alkyl; R.sup.7a and R.sup.7b independently are H, C.sub.1-6 alkyl or R.sup.7a and R.sup.7b are linked together to form a 3- to 6-membered ring; R.sup.9a represents is —C.sub.1-4 alkyl, optionally substituted by one or more substituents selected from halo, —OC.sub.1-3 alkyl or Het.sup.2; R.sup.9b is hydrogen or —C.sub.1-3 alkyl optionally substituted by one or more fluoro atoms; R.sup.10 is —C.sub.1-4 alkyl optionally substituted by one or more substituents selected from halo or —O—CH.sub.3; R.sup.11a and R.sup.11b independently are H, C.sub.1-4 alkyl (itself optionally substituted by one or more substituent(s) selected from fluoro, —CN, —R.sup.12a, —OR.sup.12b, —N(R.sup.12c)R.sup.12d or —C(O)N(R.sup.12e)R.sup.12f) or —O—C.sub.1-4 alkyl (itself optionally substituted by one or more substituent(s) selected from fluoro, —R.sup.12g, —OR.sup.12h or —N(R.sup.12i)R.sup.12j); R.sup.12a, R.sup.12b, R.sup.12c, R.sup.12d, R.sup.12e, R.sup.12f, R.sup.12g, R.sup.12h, R.sup.12i, and R.sup.12j independently are hydrogen or C.sub.1-3 alkyl (optionally substituted by one or more fluoro atoms); Het.sup.1 and Het.sup.2 independently are a 5- or 6-membered aromatic ring containing one or two heteroatoms, optionally substituted by one or more substitutents substituents selected from halo or C.sub.1-3 alkyl (itself optionally substituted by one or more fluoro atoms, or a pharmaceutically-acceptable salt thereof.

3. The compound of claim 1, wherein: there are none, one or two R.sup.1 substituents present on ring A; R.sup.1 (when present) is one or two substituents independently selected from F, Cl, —R.sup.6a, —O—R.sup.6b, —C(═O)—R.sup.6c, —C(═O)—N(R.sup.7)(R.sup.8), —CN or —N(R.sup.7a)R.sup.7b; R.sup.6a is C.sub.1-3 alkyl optionally substituted by —O—C.sub.1-2 alkyl; R.sup.6b and R.sup.6c are C.sub.1-3 alkyl; R.sup.7 and R.sup.8 independently are hydrogen or C.sub.1-3 alkyl; R.sup.7a and R.sup.7b are linked together to form a 4-6 membered ring.

4. The compound of claim 1, wherein: Ring A is of formula (II), (III), (IV), (V), or (VI): ##STR00158##

5. The compound of claim 1, wherein: Ring B is of formula (VII) or (VIII) ##STR00159##

6. The compound of claim 1, wherein: the combined ring system, i.e. ring A and ring B, is of formula (IX), (X), (XI), (XII), or (XIII): ##STR00160##

7. The compound claim 1, wherein: R.sup.2 is linear —C.sub.1-4 alkyl optionally substituted by one or more substituents; any two of R.sup.3, R.sup.3a, R.sup.4 and R.sup.4a are H, and the other two independently are a substituent selected from H, F, —CH.sub.3 or —OCH.sub.3; R.sup.5 is H, —R.sup.9a, —C(═O)—R.sup.9b, —SO.sub.2—R.sup.10 or Het.sup.1; R.sup.9a is C.sub.1-3 alkyl unsubstituted or substituted with one substituent; R.sup.9b is H or C.sub.1-3 alkyl optionally substituted by one or more fluoro atoms (so forming a —CF.sub.3 group); R.sup.10 is C.sub.1-4 alkyl optionally substituted by one or more substituents selected from fluoro or —OC.sub.1-2 alkyl and hence R.sup.10 is —CF.sub.3, —CH.sub.3, i-propyl, —CH.sub.2C(H)(CH.sub.3).sub.2 (i-butyl), —CH.sub.2CH.sub.2—OCH.sub.3; and/or Het.sup.1 and Het.sup.2 independently are a 5- or 6-membered heteroaryl ring containing one or two heteroatoms selected from nitrogen or sulfur, which ring is unsubstituted or substituted by one or two substituent C.sub.1-3 alkyl (itself optionally substituted by one or more fluoro atoms, so forming a —CF.sub.3 group).

8. The compound as of claim 1, wherein: either one of X and Y is —CR.sup.11a and the other is N or —CR.sup.11b; when R.sup.11a or R.sup.11b represents is C.sub.1-4 alkyl, then it is unsubstituted or substituted with e.g. —CN, —OR.sup.12b and/or —N(R.sup.12c)R.sup.12d; R.sup.12b is H or C.sub.1-2 alkyl; R.sup.12c and R.sup.12d independently, are C.sub.1-2 alkyl; hence, when R.sup.11a or R.sup.11b is such a C.sub.1-4 alkyl group, then it is —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2—OH, —CH.sub.2CH.sub.2—OCH.sub.3, —C(H)(CH.sub.3).sub.2, —CH.sub.2—N(CH.sub.3).sub.2 or —CH.sub.2—CN; when R.sup.11a or R.sup.11b is —O—C.sub.1-4 alkyl.

9. (canceled)

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of claim 1.

11. (canceled)

12. (canceled)

13. A method of treating a mycobacterial infection (e.g. tuberculosis), comprising administering a therapeutically effective amount of a compound of claim 1.

14. A combination of (a) a compound of claim 1, and (b) one or more other anti-mycobacterial (e.g. anti-tuberculosis) agent.

15. A product containing (a) a compound of claim 1, and (b) one or more other anti-mycobacterial (e.g. anti-tuberculosis) agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

16. A process for preparing a compound of formula (I) of claim 2, comprising: (i) reacting a compound of formula (XIV); ##STR00161## with a compound of formula (XV); ##STR00162## (ii) coupling of a compound of formula (XVII); ##STR00163## wherein R.sup.12 is a suitable leaving group, with a compound of formula (XVI); ##STR00164## (iii) wherein when X is N reacting a compound of formula (XVIII); ##STR00165## with a compound of formula (XIX);
R.sup.11xC(OCH.sub.3).sub.3  (XIX) wherein R.sup.11x is R.sup.11a or R.sup.11b; (iv) wherein when X is N (and preferably R.sup.5 is H), reacting a compound of formula (XX); ##STR00166## with a compound of formula (XIX); and/or (v) wherein when R.sup.5 is —C(═O)—R.sup.9b, —S(O).sub.2—R.sup.10 or Het.sup.1, reacting a compound of formula (I) in which R.sup.5 is H, with a compound of formula (XXI);
LG.sup.1-Z  (XXI) wherein Z is —C(═O)—R.sup.9b, —S(O).sub.2—R.sup.10 or Het.sup.1, and LG.sup.1 is a suitable leaving group, and in the case of Het.sup.1, the LG.sup.1 is attached to an appropriate C atom of that heteroaromatic ring.

17. A process for preparing a compound of formula (I) of formula (Ia) of claim 1, comprising: (i) reacting a compound of formula (XIV): ##STR00167## with a compound of formula (XVA): ##STR00168## (ii) coupling a compound of formula (XVIIA): ##STR00169## wherein R.sup.12 is a suitable leaving group, with a compound of formula (XVI): ##STR00170## (iii) wherein when X is N, reacting a compound of formula (XVIIIA): ##STR00171## with a compound of formula (XIX):
R.sup.11xC(OCH.sub.3).sub.3  (XIX) wherein R.sup.11x is R.sup.11a or R.sup.11b; (iv) wherein when X is N, reacting a compound of formula (XXA): ##STR00172## with a compound of formula (XIX); and/or (v) wherein when R.sup.5 is —C(═O)—R.sup.9b, —S(O).sub.2—R.sup.10 or Het.sup.1, reacting a compound of formula (I) in which R.sup.5 is H, with a compound of formula (XXI):
LG.sup.1-Z  (XXI) wherein Z is —C(═O)—R.sup.9b, —S(O).sub.2—R.sup.10 or Het.sup.1, and LG.sup.1 is a suitable leaving group, and in the case of Het.sup.1, the LG.sup.1 is attached to an appropriate C atom of that heteroaromatic ring.

18. The compound of claim 1, wherein: R.sup.1 is one, two or three substituents; the halo in R.sup.1 is Cl or F; the halo in R.sup.6a and/or R.sup.6b is F; the halo in R.sup.10 is F; the C.sub.1-4 alkyl in R.sup.11a and/or R.sup.11b is substituted by one substituent; or the O—C.sub.1-4 alkyl in R.sup.11a and/or R.sup.11b is substituted by one substituent; or Het.sup.1 and Het.sup.2 independently are a 5- or 6-membered aromatic ring containing one or two heteroatoms selected from nitrogen or sulfur.

19. The compound of claim 3, wherein: R.sup.6a is methyl, ethyl, or n-propyl; or R.sup.6a is substituted by one substituent; or R.sup.6a is substituted by OCH.sub.3; or R.sup.6b and R.sup.6c are methyl; or R.sup.6b and R.sup.6c is unsubstituted methyl; or R.sup.7 and/or R.sup.8 are methyl; or R.sup.7 and/or R.sup.8 are unsubstituted methyl; or R.sup.7a and R.sup.7b are linked together to form a 5-membered ring.

20. The compound of claim 7, wherein: R.sup.2 is substituted by one substituent; or R.sup.2 is substituted by one or more —O—C.sub.1-2 alkyl; or R.sup.2 is substituted by one or more —OCH.sub.3; R.sup.9a is methyl; or R.sup.9a is substituted with one substituent; or R.sup.9a is substituted with one Het.sup.2; R.sup.9b methyl; R.sup.10 is C.sub.1-4 alkyl optionally substituted by one or more —OCH.sub.3; or Het.sup.1 and/or Het.sup.2 are thiazolyl; or Het.sup.1 and/or Het.sup.2 are 2-thiazolyl ring; or Het.sup.1 and/or Het.sup.2 are substituted by one substituent.

21. The compound of claim 8, wherein: X is N and Y is —CR.sup.11a; or R.sup.11a or R.sup.11b is C.sub.1-4 alkyl substituted one substituent; or R.sup.11a or R.sup.11b is C.sub.1-4 alkyl substituted one —CN, —OR.sup.12b and/or —N(R.sup.12c)R.sup.12d; R.sup.12b is methyl; R.sup.12c and/or R.sup.12d are methyl; and R.sup.11a or R.sup.11b is unsubstituted; or R.sup.11a or R.sup.11b is —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2—OH, —CH.sub.2CH.sub.2—OCH.sub.3, —C(H)(CH.sub.3).sub.2, —CH.sub.2—N(CH.sub.3).sub.2 or —CH.sub.2—CN; or R.sup.11a or R.sup.11b are —OCH.sub.3.

22. The process of claim 16, wherein R.sup.5 is H.

23. The method of claim 13, wherein the mycobacterial infection is tuberculosis.

24. The combination of claim 14, wherein the anti-mycobacterial agent is an anti-tuberculosis agent.

25. The product of claim 15, wherein the anti-mycobacterial agent is an anti-tuberculosis agent.

Description

EXAMPLES

1. General Information

[0220] Melting Points Melting points were recorded using a differential scanning calorimeter DSC 1 Mettler Toledo. Melting points were measured with a temperature gradient of 10° C. per min from 25 to 350° C. Values are peak values. Unless indicated, this method is used.

[0221] An alternative method is with open capilliary tubes on a Mettler Toledo MP50, which may be indicated at “MT”. With this method, melting points are measured with a temperature gradient of 10° C./minute. Maximum temperature is 300° C. The melting point data is read from a digital display and checked from a video recording system.

[0222] .sup.1H NMR

[0223] .sup.1H NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer or Bruker Advance III 400 spectrometer using internal deuterium lock and equipped with reverse double-resonance (.sup.1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for proton and 100 MHz for carbon and a Bruker Avance 500 MHz spectrometer equipped with a Bruker 5 mm BBFO probe head with z gradients and operating at 500 MHz for proton and 125 MHz for carbon.

[0224] NMR spectra were recorded at ambient temperature unless otherwise stated.

[0225] Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS (δ=0 ppm) on the scale, integration, multiplicity (s=singulet, d=doublet, t=triplet, q=quartet, quin=quintuplet, sex=sextuplet, m=multiplet, b=broad, or a combination of these), coupling constant(s) J in Hertz (Hz).

[0226] HPLC-LCMS

[0227] Analytical Methods

[0228] LCMS

[0229] The mass of some compounds was recorded with LCMS (liquid chromatography mass spectrometry). The methods used are described below.

[0230] General Procedure LCMS Methods A and B

[0231] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

[0232] Compounds are described by their experimental retention times (R.sub.t) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H].sup.+ (protonated molecule) and/or [M−H].sup.− (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]*, [M+HCOO].sup.−, etc. . . . ). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector, “MSD” Mass Selective Detector.

TABLE-US-00001 TABLE LCMS Method codes (Flow expressed in mL/min; column temperature (T) in ° C.; Run time in minutes). Method Flow Run code Instrument Column Mobile phase gradient Column T time A Waters: Waters: A: 95% 84.2% A for 0.49 0.343 6.2 Acquity BEH C18 CH.sub.3COONH.sub.4 min, to 10.5% A in 40 UPLC ®—DAD (1.7 μm, 7 mM/5% 2.18 min, held for and Quattro 2.1 × 100 CH.sub.3CN 1.94 min, back to Micro ™ mm) B: CH.sub.3CN 84.2% A in 0.73 min, held for 0.73 min. B Waters: Waters: A: 95% 84.2% A to 10.5% 0.343 6.1 Acquity ® BEH C18 CH.sub.3COONH.sub.4 A in 2.18 min, held 40 H-Class—DAD (1.7 μm, 7 mM/5% for 1.96 min, back and SQD2 ™ 2.1 × 100 CH.sub.3CN to 84.2% A in 0.73 mm) B: CH.sub.3CN min, held for 0.73 min. C Waters: Waters: A: 95% From 85% A to 0.35 6.1 Acquity BEH C18 CH.sub.3COONH.sub.4 10% A in 2.1 min, 40 UPLC ® (1.7 μm, 7 mM/5% held for 2 min, back H-Class—DAD 2.1 × 100 CH.sub.3CN, B: to 85% A in and QDa mm) CH.sub.3CN 0.8 min, held for 0.7 min. D Agilent YMC-pack A: 0.1% From 95% A to 5% 2.6 6.2 1100 HPLC ODS-AQ HCOOH in A in 4.8 min, held 35 DAD C18 (50 × H2O for 1.0 min, to 95% LC/MS 4.6 mm, B: CH3CN A in 0.2 min. G1956A 3 μm)

[0233] When a compound is a mixture of isomers which give different peaks in the LCMS method, only the retention time of the main component is given in the LCMS table.

2. Abbreviations (and formulae)

[0234] AcOH Acetic acid [0235] AcCl Acetyl chloride [0236] BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [0237] BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl [0238] BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate [0239] CBr.sub.4 Tetrabromomethane [0240] CbzCl Benzyl chloroformate [0241] CH.sub.3CN/ACN Acetonitrile [0242] Cs.sub.2CO.sub.3 Cesium carbonate [0243] CSA Camphor-O-sulfonic acid [0244] DCE Dichloroethane [0245] DCM or CH.sub.2Cl.sub.2 Dichloromethane [0246] DIPEA N,N-Diisopropylethylamine [0247] DMAP 4-(Dimethylamino)pyridine [0248] DME 1,2-Dimethoxyethane [0249] DMF Dimethylformamide [0250] DMF-DMA N,N-dimethylformamide dimethyl acetal [0251] DMSO Methyl sulfoxide [0252] EDCI.HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride [0253] Et.sub.2O Diethylether [0254] Et.sub.3N or TEA Triethylamine [0255] EtOAc Ethyl acetate [0256] EtOH Ethanol [0257] h hour [0258] H.sub.2 Dihydrogen gas [0259] HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium [0260] HCl Hydrochloric acid [0261] HFIP Hexafluoroisopropanol [0262] HOBT.H.sub.2O 1-Hydroxybenzotriazole hydrate [0263] i-PrOH Isopropyl alcohol [0264] K.sub.2CO.sub.3 Potassium carbonate [0265] KHSO.sub.4 Potassium bisulfate [0266] LiGH Lithium hydroxide [0267] LiHMDS Lithium bis(trimethylsilyl)amide [0268] MeOH Methanol [0269] MeTHF/2-MeTHF Methyltetrahydrofurane [0270] MgSO.sub.4 Magnesium sulfate [0271] min Minute [0272] N.sub.2 Nitrogen [0273] NaCl Sodium Chloride [0274] NaHCO.sub.3 Sodium Bicarbonate [0275] NaOH Sodium hydroxide [0276] NBS 1-bromopyrrolidine-2,5-dione [0277] NH.sub.3 Ammonia [0278] NH.sub.4Cl Ammonium, chloride [0279] NH.sub.4HCO.sub.3 Ammonium bicarbonate [0280] NMR Nuclear Magnetic Resonance [0281] Pd/C Palladium on carbon [0282] PdCl.sub.2(PPh.sub.3).sub.2 Dichlorobis(triphenylphosphine)palladium(II) [0283] Pd(OAc).sub.2 Palladium(II) acetate [0284] Pd.sub.2dba.sub.3 Tris(dibenzylideneacetone)dipalladium(O) [0285] Pd(PPh.sub.3).sub.4 Palladium-tetrakis(triphenylphosphine) [0286] PIDA (Diacetoxyiodo)benzene [0287] POCl.sub.3 Phosphorous Oxychloride [0288] Ra-Ni/Ni Raney Raney®-Nickel [0289] rt/RT Room temperature [0290] RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl [0291] RuPhos Pd G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate [0292] t-AmylOH tert-Amyl alcohol [0293] SiOH Silica Gel [0294] TBTU O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [0295] Tf.sub.2O Trifluoromethanesulfonic Anhydride [0296] TFA Trifluoroactetic acid [0297] THF Tetrahydrofuran [0298] TMSCl Trimethylsilyl chloride [0299] TsOH or PTSA p-Toluensulfonic acid [0300] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

3. Procedures

[0301] Synthesis of Compound 1

##STR00016##

[0302] Preparation of Intermediate A1

[0303] In an 1 L autoclave, a mixture of N-Boc-[2-[(4-cyanophenyl)amino]ethyl] [865788-36-9] (50.0 g, 191 mmol) and Raney Nickel (2.25 g, 38.2 mmol) in a 7M solution of NH.sub.3 in MeOH (600 mL) was hydrogenated at room temperature under 10 bars of H.sub.2 for 24 h. The reaction mixture was filtered through a pad of Celite® and washed with a mixture of DCM and MeOH (9/1). The filtrate was evaporated in vacuo to afford 50.2 g of intermediate A1 as a greenish oil (99%).

[0304] Preparation of Intermediate A2

[0305] A 2 L flask was charged with 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (15.0 g, 66.8 mmol), intermediate A1 (18.6 g, 70.1 mmol) and DIPEA (17.3 mL, 100 mmol) in DCM (600 mL) and Me-THF (100 mL). The reaction mixture was stirred for 10 min at room temperature, then HATU (27.9 g, 73.4 mmol) was added portionwise over 5 minutes and the reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with DCM (1 L) and water (800 mL). The organic layer was separated and washed with water (400 mL), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was solubilized in a minimum amount of warm EtOAc. The solution was cooled to room temperature, and then to 0° C. The suspension was collected by filtration and the solid was washed with cold EtOAc, then with Et.sub.2O before being dried under vacuum to afford 21.7 g of intermediate A2 as an off-white solid (69%).

[0306] Preparation of Intermediate A3

[0307] Intermediate A2 (5.00 g, 10.6 mmol) was solubilized at 40° C. in Me-THF (80 mL) and acetic acid (6.1 mL, 106 mmol). Isopentyl nitrite (7.12 mL, 53.0 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 3 h. The solution was diluted in EtOAc and water, washed with NaHCO.sub.3 (sat., aq.) (twice) and brine, dried over MgSO.sub.4 and evaporated in vacuo. The residue was triturated in Et.sub.2O. the product was collected by filtration, washed with Et.sub.2O and dried under vacuum to give 4.26 g of intermediate A3 as a beige solid (80%).

[0308] Preparation of Intermediate A4

[0309] A solution of intermediate A3 (5.00 g, 9.98 mmol) in THE (100 mL) and MeOH (65 mL) was treated with a NaOH (1M, aq., 100 mL). Formamidinesulfinic acid (5.40 g, 49.9 mmol) was added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted in DCM and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated. The aqueous phase was extracted with DCM and MeOH (95/5). The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo to give 4.67 g of intermediate A4 as a white solid (Quant.).

[0310] Preparation of Intermediate A5

[0311] To a solution of intermediate A4 (4.67 g, 9.59 mmol) in MeOH (96 mL) was added dropwise TMSCl (9.73 mL, 76.7 mmol). The reaction mixture was stirred at 40° C. for 1.5 h and at room temperature for another 17 h. The mixture was concentrated in vacuo. The residue was triturated in Et.sub.2O. the solid was collected by filtration, washed with Et.sub.2O, and dried under vacuum to afford 4.76 g of intermediate A5 as a pale yellow solid (Quant.).

[0312] Preparation of Intermediate A6

[0313] A mixture of intermediate A5 (4.76 g, 10.4 mmol) and trimethyl orthoformate (3.40 mL, 31.1 mmol) in acetic acid (52 mL) was stirred for 1 h at 100° C. The reaction mixture was concentrated in vacuo. The residue was diluted in DCM and K.sub.2CO.sub.3 (10%, aq.) was added. The aqueous layer was extracted with DCM and MeOH (95/5) twice. The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo to give 3.44 g of intermediate A6 as a beige solid (83%).

[0314] Preparation of Compound 1

[0315] A solution of intermediate A6 (80 mg, 0.202 mmol) in DCM (6 mL) and Me-THF (3 mL) was treated with Et.sub.3N (70 μL, 0.50 mmol). The mixture was cooled to 0° C. and a solution of Tf.sub.2O (1M in DCM, 302 μL, 0.302 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min. MeOH (0.3 mL) was added, followed by K.sub.2CO.sub.3 (10%, aq., 5 mL) and DCM. The layers were separated. The organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 70:30 to 0:100). The residue (62 mg) was dissolved in warm EtOAc (3 mL) and allowed to cool down to room temperature. The supernatent was removed. The solid was triturated in Et.sub.2O. The product was collected by filtration and dried under vacuum to afford 42 mg of compound 1 as a white solid (36%).

[0316] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (s, 1H), 8.47 (br s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.46 (br d, J=9.1 Hz, 1H), 7.30 (br d, J=8.1 Hz, 2H), 7.20 (br d, J=7.6 Hz, 2H), 4.49 (br d, J=5.1 Hz, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 3.39-3.31 (m, 1H), 2.98 (q, J=7.4 Hz, 2H), 2.63-2.58 (m, 2H), 2.34-2.29 (m, 2H), 1.26 (br t, J=7.3 Hz, 3H)

[0317] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.12 (s, 1H) 8.71 (m, 1H) 7.79 (d, J=9.4 Hz, 1H) 7.68 (d, J=8.8 Hz, 1H) 7.26-7.37 (m, 3H) 7.19 (d, J=8.7 Hz, 2H) 4.48 (d, J=5.9 Hz, 2H) 4.08 (t, J=4.5 Hz, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.01 (q, J=7.6 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H)

[0318] Synthesis of Compound 2

##STR00017##

[0319] Preparation of Intermediate A7

[0320] A mixture of intermediate A5 (300 mg, 0.652 mmol) and trimethyl orthopropionate (0.102 mL, 0.718 mmol) in acetic acid (6 mL) was stirred for 1 h at 100° C. Additional amount of trimethylorthopropionate (0.102 mL, 0.718 mmol) was added and the reaction mixture was stirred for at 100° C. for another 2 h. The reaction mixture was diluted in DCM and NaOH (3M, aq.). The layers were separated and the organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo to give 138 mg of intermediate A7 as a foam (50%).

[0321] Preparation of Compound 2

[0322] A solution of intermediate A7 (138 mg, 0.325 mmol) in DCM (4 mL) was treated with Et.sub.3N (113 μL, 0.812 mmol). The mixture was cooled to 0° C. and a solution of Tf.sub.2O in DCM (1M in DCM, 357 μL, 0.357 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min. The reaction was quenched with MeOH (0.2 mL) and pyridine (0.1 mL). Celite® was added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 70:30 to 0:100). A second purification was performed by reverse phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 40:60 to 10:90) to give 60 mg of compound 2 as a white solid (33%).

[0323] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (d, J=1.6 Hz, 1H) 8.43 (t, J=5.9 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.5, 2.1 Hz, 1H) 7.32 (d, J=8.7 Hz, 2H) 7.18 (d, J=8.8 Hz, 2H) 4.46 (d, J=5.9 Hz, 2H) 3.91-4.02 (m, 2H) 3.79-3.90 (m, 2H) 2.98 (q, J=7.5 Hz, 2H) 2.61 (q, J=7.3 Hz, 2H) 1.26 (t, J=7.5 Hz, 3H) 1.18 (t, J=7.3 Hz, 3H).

[0324] Synthesis of Compound 3

##STR00018##

[0325] In a pressure vessel reactor, a mixture of compound 1 (250 mg, 0.473 mmol) and Pd/C (54 mg, 50.5 μmol) in EtOH (15 mL) was stirred at room temperature under 5 bar of H.sub.2 for 20 h. The mixture was filtered over a pad of Celite®. The filtered cake was washed with EtOH and DCM, and the filtrate was evaporated in vacuo. The residue was combined with another batch to give 250 mg of a crude mixture. The residue was purified by reverse phase (Stationary phase: YMC-actus Triaroom temperature C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 55:45 to 30:70). The residue was triturated in Et.sub.2O, and the solvent was removed under reduced pressure to give 165 mg of compound 3 as a white solid (58%).

[0326] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.16 (t, J=6.1 Hz, 1H) 7.28 (s, 1H) 7.26 (d, J=8.6 Hz, 2H) 7.16 (d, J=8.6 Hz, 2H) 4.35 (d, J=6.1 Hz, 2H) 4.07 (t, J=4.6 Hz, 2H) 3.97 (t, J=5.7 Hz, 2H) 3.77-3.87 (m, 2H) 2.68-2.75 (t, J=6.4 Hz, 2H) 2.60 (q, J=7.5 Hz, 2H) 1.73-1.90 (m, 4H) 1.09 (t, J=7.5 Hz, 3H).

[0327] Synthesis of Compound 4

##STR00019##

[0328] Preparation of Intermediate B1

[0329] A flask (equipped with a findenser) was charged with 4-fluorobenzonitrile [1194-02-1](1.00 g, 8.26 mmol), DMSO (5.9 mL) and ethanolamine (0.757 g, 12.4 mmol). Et.sub.3N (1.72 mL, 12.4 mmol) was added and the reaction mixture was stirred at 120° C. for 17 h. The mixture was poured into brine. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine (3 times), dried over MgSO.sub.4, filtered and evaporated in vacuo to afford intermediate B1 as pale-yellow oil (Quant.).

[0330] Preparation of Intermediate B2

[0331] A solution of the intermediate B1 (2.00 g, 12.3 mmol) and triphenylphosphine (4.21 g, 16.0 mmol) in Me-THF (100 mL) was treated with CBr.sub.4 (5.32 g, 16.0 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was evaporated in vacuo. The residue was solubilized in EtOH (40 mL) and treated with methylhydrazine (5.19 mL, 98.6 mmol). The reaction mixture was stirred at 75° C. for 4 h and concentrated in vacuo. The residue was diluted with DCM and HCl (3M, aq.) was added. The layers were separated and the organic phase was washed with water.

[0332] The combined aqueous extracts were basified by the addition of K.sub.2CO.sub.3. The aqueous phase was extracted with DCM (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo to afford 2.54 g of compound B2 as an orange oil (Quant.).

[0333] Preparation of Intermediate B3

[0334] A solution of intermediate B2 (2.15 g, 11.3 mmol) and trimethyl orthoformate (3.71 mL, 33.9 mmol) in acetic acid (60 mL) was stirred at 60° C. for 17 h. The yellow solution was cooled to room temperature. Water (150 mL) and EtOAc (150 mL) were added. K.sub.2CO.sub.3 was added portionwise until basification of the aqueous layer. The organic layer was separated, washed with water, and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo to give 1.50 g of intermediate B3 as an orange solid (66%).

[0335] Preparation of Intermediate B4

[0336] In an autoclave, a mixture of intermediate B3 (1.5 g, 7.49 mmol) and Raney Nickel (440 mg, 7.49 mmol) in a 7M solution of NH.sub.3 in MeOH (64 mL) was hydrogenated at room temperature under 5 bars of H.sub.2 for 17 h. The reaction mixture was filtered through a pad of Celite®, and washed with a mixture of DCM and MeOH (9/1). The filtrate was evaporated in vacuo to afford 1.53 g of intermediate B4 as a grey solid (Quant.).

[0337] Preparation of Compound 4

[0338] 6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (600 mg, 2.67 mmol) was solubilized in Me-THF (30 mL), and DCM (15 mL) and DIPEA (0.736 mL, 4.27 mmol) was added. After complete solubilization, intermediate B4 (627 mg, 3.07 mmol) was added followed by HATU (1.17 g, 3.07 mmol). The reaction mixture was stirred for 3 h at 35° C. EtOAc and water was added. The organic layer was separated and washed with water, then brine. The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was solubilized in a minimum amount of warm EtOAc. The solution was cooled to room temperature and the suspension was filtered. The solid was washed with EtOAc, then with EtOH and Et.sub.2O. The solid was collected by filtration and dried under vacuum to afford 210 mg of an off-white solid. The solid was combined with the filtrate and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, mobile phase: DCM/(DCM/MeOH/NH.sub.3 aq., 18/20/2), gradient from 90:10 to 60:40). The residue was crystallized from EtOAc, washed with Et.sub.2O and dried under vacuum to afford 317 mg of compound 4.

[0339] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (d, J=1.47 Hz, 1H) 8.45 (t, J=5.81 Hz, 1H) 7.67 (d, J=9.66 Hz, 1H) 7.46 (dd, J=9.41, 2.08 Hz, 1H) 7.30-7.36 (m, 3H) 7.11 (d, J=8.56 Hz, 2H) 4.47 (d, J=5.87 Hz, 2H) 3.70 (t, J=5.01 Hz, 2H) 3.17 (d, J=5.14 Hz, 1H) 2.88-3.01 (m, 4H) 2.54-2.65 (m, 4H) 1.26 (t, J=7.52 Hz, 3H).

[0340] Synthesis of Compound 5

##STR00020##

[0341] Preparation of Intermediate B5

[0342] NBS (204 mg, 1.15 mmol) was added to a solution of Compound 1 (600 mg, 1.13 mmol) in MeCN (9.5 mL) and the reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with EtOAc and water. The layers were separated. The organic phase was washed NaHCO.sub.3 (sat., aq.), dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give 700 mg of intermediate B5 as a brown residue.

[0343] Preparation of Compound 5

[0344] A mixture of intermediate B5 (250 mg, 0.234 mmol), trimethylboroxine (131 μL, 0.938 mmol) and Cs.sub.2CO.sub.3 (229 mg, 0.703 mmol) in DME (3.6 mL) and water (3.6 mL) was purged with N.sub.2. PdCl.sub.2(PPh.sub.3).sub.2 (32.9 mg, 0.0469 mmol) was added and the mixture was purged again with N.sub.2. The reaction mixture was stirred at 100° C. for 16 h. Water and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4, filtered and evaporated to dryness in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: DCM/MeOH, gradient from 99:1 to 95:5). A second purification was performed via reverse phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30*150 mm, mobile phase NH.sub.4HCO.sub.3 (0.2% in water/MeCN, gradient from 55:45 to 35:65) to give 14 mg of a white residue which was solubilized in MeCN, extended with water and freeze-dried to give 12 mg of compound 5 as a white powder (7%).

[0345] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (d, J=1.34 Hz, 1H) 8.48 (t, J=5.99 Hz, 1H) 7.67 (d, J=9.41 Hz, 1H) 7.46 (dd, J=9.54, 2.08 Hz, 1H) 7.29 (s, 1H) 7.22 (s, 1H) 7.21 (d, J=7.74 Hz, 2H) 7.12-7.17 (m, 1H) 4.49 (d, J=6.11 Hz, 2H) 4.10 (br d, J=4.28 Hz, 2H) 3.38-3.54 (m, 4H) 3.00 (q, J=7.42 Hz, 2H) 2.67-2.69 (m, 1H) 2.52-2.56 (m, 5H) 2.33-2.45 (m, 2H) 2.25 (s, 3H) 1.19-1.33 (m, 3H).

[0346] Synthesis of Compound 6

##STR00021##

[0347] Preparation of Intermediate C1

[0348] In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol) and molecular sieves 3 Å in MeOH (4.3 mL) was stirred at room temperature for 10 min. Tetramethyl orthocarbonate (347 μL, 2.61 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Water and DCM were added. The layers were separated and the organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo to dryness. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 60:40 to 0:100) to give 77 mg of intermediate C1 as a white solid (24%).

[0349] Preparation of Compound 6

[0350] To a solution of intermediate C1 (48 mg, 0.112 mmol) in anhydrous DCM (1.3 mL) at room temperature was added Et.sub.3N (23.4 μL, 0.169 mmol) and the mixture was stirred at room temperature for 10 min. The mixture was cooled at 0° C. and a solution of Tf.sub.2O in DCM (1M in DCM, 112 μL, 0.112 mmol) was added dropwise. The mixture was stirred warming to room temperature for 1 h. A solution of Tf.sub.2O in DCM (1M in DCM, 112 μL, 0.112 mmol) was added and the mixture was stirred at room temperature for another 1 h. NaHCO.sub.3 (sat., aq.) and DCM were added. The layers were separated, and the organic phase was washed with NaHCO.sub.3 (twice) and brine. The combined organic extracts were dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 50:50 to 0:100). A second purification was performed via reverse phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 45:55 to 25:75) to give 33 mg of compound 6 as a white solid (37%).

[0351] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.07 (d, J=1.58 Hz, 1H) 8.39 (t, J=5.83 Hz, 1H) 7.66 (d, J=9.46 Hz, 1H) 7.44 (dd, J=9.46, 2.21 Hz, 1H) 7.29 (d, J=8.51 Hz, 2H) 7.15 (d, J=8.83 Hz, 2H) 4.46 (d, J=5.99 Hz, 2H) 4.06-4.14 (m, 2H) 3.85 (s, 3H) 3.71-3.77 (m, 2H) 3.32-3.46 (m, 2H) 3.17 (d, J=5.36 Hz, 1H) 2.97 (q, J=7.36 Hz, 2H) 2.52-2.58 (m, 6H) 1.26 (t, J=7.57 Hz, 3H).

[0352] Synthesis of Compound 7

##STR00022##

[0353] Preparation of Intermediate C.sub.2

[0354] To a solution of 2-amino-5-chloropyrimidine [428-89-7] (500 mg, 3.86 mmol) in Me-THF (40 mL) at 5° C. were added ethyl 3-cyclopropyl-3-oxopropanoate [24922-02-9](0.603 g, 3.86 mmol) and (diacetoxyiodo)benzene (1.24 g, 3.86 mmol). Boron trifluoride etherate (50 μL, 0.191 mmol) was added dropwise, and the reaction mixture was stirred at 5° C. for 30 min, then at room temperature for 1 h. Extra amounts of ethyl 3-cyclopropyl-3-oxopropanoate (0.301 g, 1.93 mmol) (diacetoxyiodo)benzene (0.622 g, 1.93 mmol) and boron trifluoride etherate (50 μL, 0.191 mmol) were added. The mixture was purged with N.sub.2 and stirred at room temperature for 1 h. Extra amounts of ethyl 3-cyclopropyl-3-oxopropanoate (0.301 g, 1.93 mmol), (diacetoxyiodo)benzene (0.622 g, 1.93 mmol) and boron trifluoride etherate (50 μL, 0.191 mmol) were added again. The mixture was purged with N.sub.2 and stirred at room temperature for another 1 h. EtOAc and water were added. The layers were separated, and the organic phase was dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, dry loading (Celite®), mobile phase: heptane/EtOAc, 80:20, 65:35). The residue was triturated in pentane. The solid was collected by filtration and dried under vacuum to give 598 mg of intermediate C2 as a white solid (58%).

[0355] Preparation of Intermediate C3

[0356] To a solution of the intermediate C2 (125 mg, 0.47 mmol) in EtOH (2.2 mL) and water (2.2 mL) was added K.sub.2CO.sub.3 (196 mg, 1.42 mmol). The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to room temperature and the reaction was quenched with HCl (1M in water) until pH-3. The mixture was evaporated in vacuo to afford 294 mg of intermediate C3 as a white solid. The crude product was used as such in the next step.

[0357] Preparation of Compound 7

[0358] To a solution of intermediate C3 (294 mg, 0.472 mmol) in DMF (4.5 mL) were added EDCI.HCl (110 mg, 0.574 mmol), HOBt.H.sub.2O (76 mg, 0.496 mmol), DIPEA (0.245 mL, 1.42 mmol) and intermediate E9 (185 mg, 0.516 mmol). The reaction mixture was stirred at room temperature for 16 h evaporated in vacuo. The residue was taken-up in EtOAc, washed with NaHCO.sub.3 (sat., aq.) and brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 24 g Buchi, dry loading (Celite®), mobile phase: heptane/(EtOAc/MeOH, 9:1), gradient from 90:10 to 40:60) to afford a light yellow solid. The solid was crystallized from EtOAc and sonicated in pentane. The solid was collected by filtration and dried under vacuum to obtain 121 mg of compound 7 as a white solid (47%).

[0359] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.40 (d, J=1.8 Hz, 1H) 8.58-8.75 (m, 2H) 7.34 (d, J=8.1 Hz, 2H) 7.29 (s, 1H) 7.19 (d, J=8.4 Hz, 2H) 4.50 (d, J=5.6 Hz, 2H) 4.08 (s, 2H) 3.83 (s, 2H) 2.38-2.46 (m, 1H) 1.03-1.13 (m, 4H).

[0360] Synthesis of Compound 8

##STR00023##

[0361] Preparation of Intermediate C.sub.4

[0362] To a solution of 2-amino-5-chloropyridine [1072-98-6] (3.00 g, 23.3 mmol) in Me-THF (100 mL) were added iodobenzene diacetate (7.50 g, 23.3 mmol) and ethyl-4-methoxy-3-oxobutanoate [66762-68-3] (6.00 g, 34.8 mmol). Then boron trifluoride etherate (0.30 mL, 1.15 mmol) was added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was warmed to room temperature and stirred for another 1 h. EtOAc and NaHCO.sub.3 (sat., aq.) were added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated to give a brown liquid. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 120 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 90:10 to 40:60) to afford 2.44 g of the intermediate C4 as a yellow solid (39%).

[0363] Preparation of Intermediate C5

[0364] To a solution of intermediate C4 (1.44 g, 5.36 mmol) in EtOH (11.5 mL) and water (11.5 mL) was added NaOH (650 mg, 16.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with HCl (3N in water) until pH˜3. The mixture was filtered to afford 996 mg of the intermediate C5 as an off-white solid (77%).

[0365] Preparation of Compound 8

[0366] To a mixture of intermediate C5 (125 mg, 0.519 mmol) and DIPEA (270 μL, 1.57 mmol) in DMF (5 mL) at room temperature were added EDCI.HCl (125 mg, 0.652 mmol) and HOBt.H.sub.2O (85 mg, 0.555 mmol). Intermediate E9 (205 mg, 0.571 mmol) was added and the resulting mixture was stirred for 16 h. NaHCO.sub.3 (1%, aq.) and EtOAc were added and the layers were separated. The organic layer was washed with brine (3 times), dried over MgSO.sub.4, filtered and concentrated in vacuo until dryness to give an orange solid which was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/(EtOAc/MeOH, 9:1), gradient from 75:20 to 30:70) to obtain a white solid. The residue was purified by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 60:40 to 0:100) to give 233 mg of compound 8 as a white solid (71%).

[0367] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ ppm 9.68 (dd, J=2.0, 0.8 Hz, 1H) 8.51 (t, J=4.7 Hz, 1H) 7.56 (d, J=9.4 Hz, 1H) 7.31-7.36 (m, 3H) 7.18 (d, J=7.9 Hz, 2H) 7.11 (s, 1H) 4.75 (s, 2H) 4.59 (d, J=5.5 Hz, 2H) 4.06 (t, J=4.7 Hz, 2H) 3.79 (t, J=4.7 Hz, 2H) 3.28 (s, 3H)

[0368] Synthesis of Compound 9

##STR00024## ##STR00025##

[0369] Preparation of Intermediate D1

[0370] A mixture of 3,4-difluorobenzonitrile [64248-62-0] (3.67 g, 26.4 mmol), N-Boc-1,2-diaminoethane (5.50 g, 34.3 mmol) and Et.sub.3N (14.7 mL, 105 mmol) in DMSO (47 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled down and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine (3 times), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 100:0 to 50:50) to give 5.02 g of intermediate D1 as a white solid (68%).

[0371] Preparation of Intermediate D2

[0372] In an autoclave, to a solution of intermediate D1 (2.00 g, 7.16 mmol) in a 7M solution of NH.sub.3 in MeOH (70 mL), purged with nitrogen, was added Raney-Nickel (3.39 g, 57.7 mmol). The reaction mixture was hydrogenated under 7 bars at room temperature for 2 h. The mixture was filtered through a pad of Celite® and rinsed with MeOH. The filtrate was concentrated in vacuo to give 2.11 g of the intermediate D2 as a white solid (Quant.).

[0373] Preparation of Intermediate D3

[0374] HATU (2.57 g, 6.77 mmol) was added to a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (1.52 g, 6.77 mmol) and DIPEA (4.7 mL, 27.1 mmol) in DCM (126 mL). The reaction mixture was stirred at room temperature for 10 min and then intermediate D2 (2.11 g, 7.45 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and water. The aqueous layer was extracted with DCM (twice). The combined organic layers were washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 120 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 50:50 to 0:100) to give 2.76 g of intermediate D3 as a pale brown solid (83%).

[0375] Preparation of Intermediate D4

[0376] Intermediate D3 (1.5 g, 3.06 mmol) was solubilized at 40° C. in Me-THF (23.2 mL) and AcOH (1.75 mL). Isopentyl nitrite (2.06 mL, 15.3 mmol) was added dropwise over 10 min and the reaction mixture was stirred at 40° C. for 1 h. The solution was diluted in EtOAc and NaHCO.sub.3 (sat., qa.). The layers were separated and the organic layer was washed with NaHCO.sub.3 (sat., aq.) (twice), and brine, dried over MgSO.sub.4 and evaporated in vacuo to give 1.74 g of intermediate D4 as a pale-yellow oil.

[0377] Preparation of Intermediate D5

[0378] A solution of intermediate D4 (1.59 g, 3.06 mmol) in THE (47 mL) and MeOH (32 mL) was treated with NaOH (1M, aq., 37 mL). Thisurea dioxide (formamidinesulfonic acid) (1.66 g, 15.3 mmol) was added and the reaction mixture was stirred at 50° C. for 1 h (using findeser equipment). The reaction mixture was diluted with DCM and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated, and the organic layer was dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give 1.44 g of intermediate D5 as a yellow oil.

[0379] Preparation of Intermediate D6

[0380] A solution of intermediate A5 (1.55 g, 3.06 mmol) in MeOH (34 mL) was treated with TMSCl (3.88 mL, 30.6 mmol) and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the resulting solid was triturated in Et.sub.2O. The solvent was evaporated to give 1.51 g of intermediate D6 as a pale-yellow solid (Quant.).

[0381] Preparation of Intermediate D7

[0382] Trimethyl orthoformate (0.618 mL, 5.65 mmol) was added to a suspension of intermediate D6 (900 mg, 1.88 mmol) in HFIP (18 mL) and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled down to room temperature, diluted with EtOAc and then basified with NaHCO.sub.3 (sat., aq.). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 90:10) to give 202 mg of the intermediate D7 as an off-white solid (33%).

[0383] Preparation of Compound 9

[0384] Et.sub.3N (0.169 mL, 1.22 mmol) was added to a solution of intermediate D7 (202 mg, 0.487 mmol) in DCM (9 mL) and 1,4-dioxane (6 mL). The solution was cooled to 5° C. and a solution of Tf.sub.2O in DCM (1M in DCM, 0.487 mL, 0.487 mmol) was added dropwise over 5 min. The reaction mixture was diluted with DCM and with NaHCO.sub.3 (sat., aq.). The layers were separated. The organic layer was washed with brine, dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 70:30 to 0:100) to give 183 mg of a yellow solid. The solid was triturated and sonicated in EtOAc. The suspension was filtered off. The solid and the filtrate were combined. The residue was triturated in Et.sub.2O and sonicated, filtered off, washed with Et.sub.2O and collected to give 125 mg of compound 9 as a white solid (47%).

[0385] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.09 (d, J=1.5 Hz, 1H) 8.48 (t, J=5.9 Hz, 1H) 7.67 (d, J=9.5 Hz, 1H) 7.47 (dd, J=9.5, 2.0 Hz, 1H) 7.30-7.41 (m, 2H) 7.16-7.30 (m, 2H) 4.50 (d, J=5.9 .sub.Hz, 2H) 4.10 (br t, J=4.2 Hz, 2H) 3.65 (t, J=4.6 Hz, 2H) 3.00 (q, J=7.5 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0386] Synthesis of Compound 10

##STR00026##

[0387] To a solution of 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid [1368682-64-7] (82 mg 0.393 mmol) in DMF (4.5 mL) were added EDCI.HCl (91 mg, 0.474 mmol), HOBt.H.sub.2O (63 mg, 0.415 mmol) and DIPEA (203 μL, 1.18 mmol). The mixture was stirred at room temperature for 15 min. Intermediate B9 (155 mg, 0.432 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (twice), dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). A second purification was performed by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 50:50 to 25:75). The residue was solubilized in MeCN and MeOH (50:50), extended with water and freeze-dried to give 44 mg of compound 10 as a white solid (22%).

[0388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.40 (dd, J=4.8, 2.9 Hz, 1H) 8.82 (d, J=3.1 Hz, 1H) 8.51 (t, J=5.7 Hz, 1H) 7.26-7.35 (m, 3H) 7.18 (d, J=8.7 Hz, 2H) 4.48 (d, J=5.7 Hz, 2H) 4.08 (t, J=4.6 Hz, 2H) 3.82 (t, J=4.8 Hz, 2H) 3.02 (q, J=7.5 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0389] Synthesis of Compound 11

##STR00027##

[0390] To a mixture of 2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [1403942-20-0](125 mg, 0.654 mmol) and DIPEA (228 μL, 1.32 mmol) in DMF (6.5 mL) at room temperature were added EDCI.HCl (150 mg, 0.782 mmol) and HOBt.H.sub.2O (105 mg, 0.686 mmol). Intermediate E9 (230 mg, 0.714 mmol) was added and the resulting mixture was stirred for 16 h. NaHCO.sub.3 (1%, aq.) and EtOAc were added. The layers were separated, and the organic layer was washed with brine (twice), dried over MgSO.sub.4, filtered and concentrated in vacuo until dryness. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/(EtOAc/MeOH, 9/1), gradient from 60:40 to 10:90). The residue was crystallized from EtOAc and collected by filtration to give 170 mg of compound 11 as a white solid (52%).

[0391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.30 (dd, J=7.0, 2.0 Hz, 1H) 8.61 (dd, J=4.2, 2.0 Hz, 1H) 8.48 (t, J=5.9 Hz, 1H) 7.27-7.35 (m, 3H) 7.13-7.21 (m, 3H) 4.47 (d, J=6.0 Hz, 2H) 4.05-4.11 (m, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.01 (q, J=7.5 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0392] Synthesis of Compound 12

##STR00028##

[0393] To a mixture of 6-ethyl-2-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [1131613-58-5] (150 mg, 0.608 mmol) and DIPEA (345 μL, 2.00 mmol) in DMF (6.5 mL) were added EDCI.HCl (140 mg, 0.730 mmol) and HOBt.H.sub.2O (100 mg, 0.653 mmol). The mixture was stirred at room temperature for 15 min. Then intermediate E9 (240 mg, 0.669 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was evaporated in vacuo. NaHCO.sub.3 (1%, aq.) and EtOAc were added and the layers were separated. The organic layer was washed with brine, dried over MgSO.sub.4 and concentrated to dryness. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/(EtOAc/MeOH, 9/1), gradient from 95:5 to 50:50). A second purification was performed by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 60:40 to 5:95) to give 206 mg of compound 12 as a white solid (66%).

[0394] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.05 (t, J=6.0 Hz, 1H) 7.87 (s, 1H) 7.24-7.30 (m, 3H) 7.17 (d, J=8.5 Hz, 2H) 4.41 (d, J=6.0 Hz, 2H) 4.04-4.10 (m, 2H) 3.81 (br t, J=4.7 Hz, 2H) 2.86 (q, J=7.6 Hz, 2H) 2.41 (s, 3H) 1.20 (t, J=7.6 Hz, 3H).

[0395] Synthesis of Compound 13 and Compound 14

##STR00029## ##STR00030##

[0396] Preparation of Intermediate E1

[0397] The reaction was performed on 2 batches. Herein is reported the procedure for one batch. Herein, where “Tf” is used, for avoidance of doubt, it represents —S(O).sub.2CH.sub.3. Further, Intermediate E9 may be prepared and/or employed as the HCl salt. A 1 L flask equipped with a findenser was charged with 4-fluorobenzonitrile [1194-02-1] (20 g, 165 mmol), DMSO (320 mL) and N-boc-1,2-diaminoethane (39.7 g, 248 mmol). Et.sub.3N (92 mL, 661 mmol) was added and the reaction mixture was stirred at 120° C. for 20 h. The two batches were combined and poured in a mixture of crushed ice and water (1 L). Brine (1 kg) was added and the mixture was stirred at room temperature for 30 min. EtOAc (1 L) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×1 L), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was triturated in pentane (500 mL). The solid was collected by filtration, washed with cold Et.sub.2O, and dried under vacuum to give 48.28 g of intermediate E1 as a white solid (46%, 92% purity).

[0398] Preparation of Intermediate E2

[0399] In an 1 L autoclave, a mixture of intermediate E1 (41.5 g, 159 mmol) and Raney-Nickel (4.66 g, 79.4 mmol) in a 7M solution of NH.sub.3 in MeOH (500 mL) was hydrogenated at room temperature under 6 bars of H.sub.2 for 12 h. The reaction mixture was filtered through a pad of Celite®, washed with a mixture of DCM and MeOH (9/1) and the filtrate was evaporated in vacuo to afford 41.8 g of intermediate E2 as a green oil (99%).

[0400] Preparation of Intermediate E3

[0401] Under N.sub.2 at 0° C., benzylchloroformate (0.592 mL, 4.15 mmol) was added dropwise to a mixture of intermediate E2 (1 g, 3.8 mmol) and DIPEA (0.78 mL, 4.52 mmol) in DCM (38 mL). The reaction mixture was stirred at room temperature for 16 h and diluted with DCM. The mixture was washed with NaHCO.sub.3 (sat., aq.), dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give 1.11 g of intermediate E3 as a white solid (74%).

[0402] Preparation of Intermediate E4

[0403] Intermediate E3 (1.11 g, 2.78 mmol) was solubilized at 40° C. in Me-THF (21 mL) and AcOH (1.6 mL). Isopentylnitrite (1.87 mL, 13.9 mmol) was added dropwise over 15 min and the reaction mixture was stirred at 40° C. for 1.5 h. The solution was diluted with EtOAc and NaHCO.sub.3 (sat., aq.). The layers were separated and the organic phase was washed with NaHCO.sub.3 (sat., aq., twice), brine, dried over MgSO.sub.4 and evaporated in vacuo to give 1.23 g of intermediate E4 as a pale-yellow solid (Quant.).

[0404] Preparation of Intermediate E5

[0405] A solution of intermediate E4 (1.24 g, 2.89 mmol) in THE (29 mL) and MeOH (19 mL) was treated with NaOH (1M, aq., 29 mL). Thiourea dioxide (formamidinesulfonic acid) (1.56 g, 14.5 mmol) was then added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted with DCM and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated. The aqueous layer was extracted with DCM and MeOH (95/5). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo to give 970 mg of intermediate E5 as a pale-yellow oil (81%).

[0406] Preparation of Intermediate E6

[0407] To a solution of intermediate E5 (970 mg, 2.34 mmol) in MeOH (23 mL) was added dropwise TMSCl (2.4 mL, 18.7 mmol). The reaction mixture was stirred at room temperature for 20 h and concentrated in vacuo to give 710 mg of intermediate E6 as a brown solid (78%).

[0408] Preparation of Intermediate E7

[0409] A mixture of intermediate E6 (0.71 g, 1.83 mmol) and trimethyl orthoformate (0.602 mL, 5.50 mmol) in AcOH (9.2 mL) was stirred for 50 min at 100° C. The reaction mixture was concentrated in vacuo. The residue was diluted in a solution of DCM and K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 40 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 90:10) to give 273 mg of intermediate E7 as a yellow residue (46%).

[0410] Preparation of Intermediate E8

[0411] Et.sub.3N (0.292 mL, 2.10 mmol) was added to a solution of intermediate E7 (273 mg, 0.842 mmol) in DCM (12 mL). The solution was then cooled to 5° C. and a solution of Tf.sub.2O (1M in DCM, 1.0 mL, 1.0 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 1 h and diluted with DCM and NaHCO.sub.3 (sat., aq.). The layers were separated. The aqueous layer was extracted with DCM (twice). The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 100:0 to 0:100) to give 105 mg of intermediate E8 as a white solid (27%).

[0412] Preparation of Intermediate E9

[0413] In a steal bomb, a mixture of intermediate E8 (85 mg, 0.186 mmol) and Pd(OH).sub.2 (21 mg, 0.075 mmol) in MeOH (8.5 mL) was hydrogenated at room temperature under 10 bars of H.sub.2 for 6 h. The mixture was filtered on a pad of Celite® and the filtrate was evaporated in vacuo to give 65 mg of intermediate E9 as a white residue (Quant.).

[0414] Preparation of Compound 13

[0415] To a mixture of 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (46 mg, 0.202 mmol) and DIPEA (0.070 mL, 0.403 mmol) in DCM (3 mL) and Me-THF (3 mL) were added EDCI.HCl (39 mg, 0.202 mmol), HOBt.H.sub.2O (31 mg, 0.202 mmol) and intermediate E9 (65 mg, 0.202 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and washed with NaHCO.sub.3 (sat., aq.). The organic layer was dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 90:10). The solid (70 mg) was triturated and sonicated in Et.sub.2O and the solvent was removed under reduced pressure. The residue (68 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 55:45 to 35:65) to give 42 mg of compound 13 as a white solid (39%).

[0416] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.40 (d, J=2.69 Hz, 1H) 8.68 (d, J=2.57 Hz, 1H) 8.55 (t, J=5.87 Hz, 1H) 7.32 (m, J=8.68 Hz, 2H) 7.28 (s, 1H) 7.19 (m, J=8.68 Hz, 2H) 4.47 (d, J=5.87 Hz, 2H) 4.08 (t, J=4.58 Hz, 2H) 3.83 (t, J=4.77 Hz, 2H) 3.01 (q, J=7.46 Hz, 2H) 1.29 (t, J=7.46 Hz, 3H).

[0417] Preparation of Compound 14

[0418] Compound 14 was prepared following the procedure reported for the synthesis of compound 13 starting from intermediate E9 and 5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [1352395-28-8] affording 32 mg as white fluffy solid (40%).

[0419] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.50 (d, J=7.46 Hz, 1H) 7.86 (t, J=5.99 Hz, 1H) 7.25-7.33 (m, 3H) 7.24 (d, J=2.69 Hz, 1H) 7.18 (d, J=8.68 Hz, 2H) 6.63 (dd, J=7.46, 2.81 Hz, 1H) 4.43 (d, J=5.99 Hz, 2H) 4.08 (t, J=4.59 Hz, 2H) 3.85 (s, 3H) 3.79-3.83 (m, 2H).

[0420] Synthesis of Compound 15

##STR00031## ##STR00032##

[0421] Preparation of Intermediate F1

[0422] A mixture of 4-fluorobenzonitrile [1194-02-1] (10.0 g, 82.6 mmol), N-boc-N-methylethylenediamine (20.2 mL, 116 mmol) and K.sub.2CO.sub.3 (13.7 g, 99.1 mmol) in anhydrous DMSO (40 mL) was heated at 120° C. for 6 h. The reaction mixture was poured in brine and EtOAc was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 90:10 to 30:70) to give 18.04 g of intermediate F1 as a colorless oil (80%).

[0423] Preparation of Intermediate F2

[0424] In a 1 L autoclave, a mixture of intermediate F1 (17.0 g, 61.7 mmol) and Raney-Nickel (14.5 g, 247 mmol) in MeOH (330 mL) was stirred at room temperature for 2 h under 6 bars of H.sub.2. The mixture was filtered on a pad of Celite®, washed with MeOH and the filtrate was evaporated in vacuo to give 17.25 g of intermediate F2 as a blue/green oil (Quant.).

[0425] Preparation of Intermediate F3

[0426] To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (2.35 g, 10.0 mmol), intermediate F2 (3.07 g, 11.0 mmol) and DIPEA (3.45 mL, 20.0 mmol) in DCM (70 mL) and Me-THF (70 mL) were added EDCI.HCl (2.30 g, 12.0 mmol) and HOBt.H.sub.2O (1.62 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 8 h. The mixture was evaporated and the crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 220 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 70:30 to EtOAc 0:100) to give 3.703 g of intermediate F3 as a brown foam (76%).

[0427] Preparation of Intermediate F4

[0428] Intermediate F3 (3.54 g, 7.28 mmol) was solubilized in Me-THF (62 mL) and AcOH (4.17 mL, 72.8 mmol). Isopentyl nitrite (4.89 mL, 36.4 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 1 h. The resulting solution was diluted in EtOAc. The organic layer was washed with K.sub.2CO.sub.3 (10%, aq.) (twice) and brine, dried over MgSO.sub.4 and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 50:50 to 0:100) to give 3.54 g of intermediate F4 as an orange paste (94%).

[0429] Preparation of Intermediate F5

[0430] A solution of intermediate F4 (1.13 g, 2.19 mmol) in THF (22 mL) and MeOH (14 mL) was treated with NaOH (1M aq., 22 mL, 22 mmol). Formamidinesulfonic acid (1.19 g, 11.0 mmol) was added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted in DCM and K.sub.2CO.sub.3 (10% aq.) was added. The aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo to give 970 mg of intermediate F5 as a yellow foam (91% purity, 80%).

[0431] Preparation of Intermediate F6

[0432] A solution of intermediate F5 (932 mg, 1.69 mmol) in MeOH (18 mL) was treated with TMSCl (2.15 mL, 16.9 mmol). The reaction mixture was stirred at room temperature for 20 h and evaporated in vacuo. The solid was triturated in Et.sub.2O. The supernatant was removed and the yellow powder was dried under vacuum to give 915 mg of intermediate F6 (Quant.).

[0433] Preparation of Compound 15

[0434] To a solution of intermediate F6 (270 mg, 0.570 mmol) in HFIP (4.86 mL) was added trimethyl orthoformate (187 μL, 1.71 mmol) and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc and quenched with K.sub.2CO.sub.3 (10%, aq.). The organic layer was washed with H.sub.2O (once) and brine (once), dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 80:20), gradient from 95:5 to 75:25). The residue was heated under reflux in EtOH for 20 min. The solution was cooled to room temperature and at 0° C. The mixture was filtered. The solid was rinsed with cold EtOH and dried under vacuum at 60° C. for 7 h to give 51 mg of compound 15 as a beige downy solid (22%).

[0435] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.03 (s, 1H) 8.40 (t, J=5.8 Hz, 1H) 7.66 (d, J=9.4 Hz, 1H) 7.45 (dd, J=9.5, 2.08 Hz, 1H) 7.18 (d, J=8.7 Hz, 2H) 7.10 (d, J=8.7 Hz, 2H) 6.70 (s, 1H) 4.42 (d, J=5.8 Hz, 2H) 3.51 (t, J=5.2 Hz, 2H) 3.34 (t, J=5.2 Hz, 2H) 2.96 (q, J=7.6 Hz, 2H) 2.83 (s, 3H) 1.25 (t, J=7.5 Hz, 3H).

[0436] Synthesis of Compound 16

##STR00033## ##STR00034##

[0437] Preparation of Intermediate G1

[0438] A flask was charged with 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (1.00 g, 4.45 mmol), 4-bromo-2-fluorobenzylamine [112734-22-2](0.954 g, 4.67 mmol), Me-THF (15 mL), DCM (15 mL) and DIPEA (1.23 mL, 7.12 mmol). HATU (1.86 g, 4.90 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was solubilized in warm EtOAc. The solution was cooled to room temperature and to 0° C. The suspension was filtered off and the solid was washed with cold EtOAc and then with Et.sub.2O. The solid was dried in vacuo to afford 773 mg of intermediate G1 as an off-white solid (42%).

[0439] Preparation of Intermediate G2

[0440] A mixture of intermediate G1 (740 mg, 1.80 mmol), N-boc-ethylenediamine (375 mg, 2.34 mmol) and Cs.sub.2CO.sub.3 (1.06 g, 3.24 mmol) in tert-Amyl alcohol (24 mL) and Me-THF (16 mL) was purged with N.sub.2. Brettphos Pd G3 (82 mg, 0.090 mmol) and Brettphos (97 mg, 0.18 mmol) were added. The reaction mixture was purged again with N.sub.2 and stirred for 17 h at 80° C. The reaction mixture was cooled to room temperature. Celite® was added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 40 g, mobile phase: heptane/EtOAc, gradient from 50:50 0:100) to give 444 mg of intermediate G2 as a pale-yellow foam (50%).

[0441] Preparation of Intermediate G3

[0442] Intermediate G3 was prepared following the synthesis reported for the synthesis of intermediate F4 starting from intermediate G2 and affording 408 mg as a yellow solid (87%).

[0443] Preparation of Intermediate G4

[0444] Intermediate G4 was prepared following the procedure reported for the synthesis of intermediate F5 starting from intermediate G3 and affording 362 mg as a beige solid (94%).

[0445] Preparation of Intermediate G5

[0446] Intermediate G5 was prepared following the procedure reported for the synthesis of intermediate F6 starting from intermediate G4 and affording 343 mg as a yellow powder (Quant.).

[0447] Preparation of Intermediate G6

[0448] A mixture of intermediate G5 (283 mg, 0.592 mmol) and trimethyl orthoformate (194 μL, 1.78 mmol) in anhydrous DMF (3.7 mL) was stirred for 23 h at 60° C. Additional amount of anhydrous DMF (3.7 mL) and trimethyl orthoformate (194 μL, 1.78 mmol) were added at room temperature and the reaction mixture was stirred at 60° C. for another 1.5 h. The reaction mixture was diluted with DCM and quenched with K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 80/20), gradient from 95:5 to 70:30) to give 156 mg of intermediate G6 as a white solid (63%).

[0449] Preparation of Compound 16

[0450] Under N.sub.2 atmosphere, a mixture of intermediate G6 (143 mg, 0.345 mmol) and Et.sub.3N (240 μL, 1.72 mmol) in anhydrous DCM (5 mL), anhydrous Me-THF (5 mL) and anhydrous 1,4-dioxane (5 mL) was heated at 40° C. The reaction mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.517 mL, 0.517 mmol) was added dropwise. The mixture was stirred at 0° C. for 20 min and diluted with DCM. A small quantity of MeOH was added and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 80:20), gradient from 100:0 to 80/20). The residue was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 55:45 to 25:75) to give 84 mg of compound 16 as a white solid (45%).

[0451] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.05 (s, 1H) 8.40 (t, J=5.8 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.5, 2.1 Hz, 1H) 7.36 (t, J=8.5 Hz, 1H) 7.02 (m, 2H) 7.32 (s, 1H) 4.50 (d, J=5.8 Hz, 2H) 4.07 (t, J=4.7 Hz, 2H) 3.86 (t, J=4.7 Hz, 2H) 2.96 (q, J=7.5 Hz, 2H) 1.25 (t, J=7.5 Hz, 3H).

[0452] Synthesis of Compound 17

##STR00035##

[0453] Preparation of Compound 17

[0454] Under N.sub.2 atmosphere, a mixture of intermediate A6 (180 mg, 0.454 mmol) and Et.sub.3N (315 μL, 2.27 mmol) in anhydrous Me-THF (7 mL), anhydrous 1,4-dioxane (7 mL) and anhydrous DCM (7 mL) was cooled to 0° C. Isobutanesulfonyl chloride (88.8 μL, 0.680 mmol) was added dropwise. The reaction mixture was stirred for 1 h at 0° C. and diluted with DCM and quenched with K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The solid was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM:MeOH, 80:20), gradient from 100:0 to 95:5) to give 124 mg of compound 17 as a slightly yellow solid (53%).

[0455] .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm 9.51-9.54 (m, 1H) 7.51-7.55 (m, 1H) 7.32 (d, J=8.7 Hz, 2H) 7.29 (dd, J=9.5, 2.0 Hz, 1H) 7.23 (s, 1H) 7.18 (d, J=8.7 Hz, 2H) 6.03 (br t, 1H) 3.71 (t, J=4.6 Hz, 2H) 3.00 (d, J=6.6 Hz, 2H) 2.95 (q, J=7.6, 2H) 2.32 (m, 1H) 1.39 (t, J=7.6 Hz, 3H) 1.15 (s, 3H) 1.14 (s, 3H).

[0456] Synthesis of Compound 18

##STR00036##

[0457] Under N.sub.2 atmosphere a mixture of intermediate A6 (300 mg, 0.756 mmol) and Et.sub.3N (0.525 mL, 3.78 mmol) in anhydrous DCM (11.5 mL), anhydrous Me-THF (11.5 mL) and anhydrous 1,4-dioxane (11.5 mL) was stirred for 2.5 h at 70° C. The mixture was cooled to room temperature and then to 0° C. Acetyl chloride (53.9 μL, 0.756 mmol) was added dropwise and the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was diluted with DCM and quenched with MeOH and K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 80/20), gradient from 95:5 to 85:15) to give 180 mg of compound 18 as a white solid (54%).

[0458] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm rotamers: 9.08 (d, J=1.3 Hz, 1H) 8.17 (br t, J=5.4 Hz, 1H) 7.62 (d, J=9.8 Hz, 1H) 7.58 (br s, 1H) 7.41 (dd, J=9.5, 2.2 Hz, 1H) 7.30 (d, J=8.8 Hz, 2H) 7.20 (d, J=8.5 Hz, 2H) 4.49 (d, J=6.0 Hz, 2H) 3.86 (br s, 2H) 3.66 (t, J=5.0 Hz, 2H) 2.99 (q, J=7.6 Hz, 2H) 2.25 (s, 3H) 1.28 (t, J=7.6 Hz, 3H).

[0459] Synthesis of Compound 19

##STR00037##

[0460] To a mixture of intermediate A6 (100 mg, 0.252 mmol) and Et.sub.3N (0.175 mL, 1.26 mmol) in anhydrous DCM (2.7 mL) and anhydrous Me-THF (2.7 mL) was added 2-methoxy-1-ethanesulfonyl chloride (88.3 μL, 0.756 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 15 min. The reaction was quenched with a small amount of MeOH and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with water (twice) and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtAOc, gradient from 55:45 to 0:100, then EtOAc/MeOH 99:1). The solid was triturated in MeCN, the supernatant was removed and the solid was dried under vacuum to give 53 mg of compound 19 as a white solid (41%).

[0461] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.06 (d, J=1.5 Hz, 1H) 8.43 (t, J=5.9 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.5, 2.1 Hz, 1H) 7.28 (d, J=8.7 Hz, 2H) 7.17 (d, J=8.7 Hz, 2H) 7.14 (s, 1H) 4.45 (d, J=5.9 Hz, 2H) 3.84 (t, J=4.3 Hz, 2H) 3.63-3.75 (m, 6H) 3.24 (s, 3H) 2.97 (q, J=7.5 Hz, 2H) 1.25 (t, J=7.5 Hz, 3H) 1.09 (t, J=7.0 Hz, 1H).

[0462] Synthesis of Compound 20

##STR00038##

[0463] A mixture of intermediate A6 (120 mg, 0.302 mmol) and Et.sub.3N (210 μL, 1.51 mmol) in anhydrous THE (6 mL) was cooled to 0° C. Methanesulfonyl chloride (46.8 μL, 0.605 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 15 min. Additional amount of methanesulfonyl chloride (23.4 μL, 0.302 mmol) was added dropwise at 0° C. and the reaction mixture was stirred for another 30 min at 0° C. The reaction mixture was diluted with DCM and quenched with a small amount of MeOH and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 30:70 to 0:100, then EtOAc/MeOH 99:1). The solid was triturated in EtOAc and the supernatant was removed to give 68 mg of compound 20 as a white solid (47%).

[0464] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.06 (d, J=1.6 Hz, 1H) 8.43 (t, J=5.8 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.4, 2.08 Hz, 1H) 7.28 (d, J=8.6 Hz, 2H) 7.19 (s, 1H) 7.17 (d, J=8.8 Hz, 2H) 4.46 (d, J=5.9 Hz, 2H) 3.86 (t, J=5.1 Hz, 2H) 3.70 (t, J=5.1 Hz, 2H) 3.27 (s, 3H) 2.97 (d, J=7.5 Hz, 2H) 1.99 (s, 1H) 1.25 (t, J=7.5 Hz, 3H).

[0465] Synthesis of Compound 21

##STR00039##

[0466] Preparation of Intermediate H6

[0467] A mixture of intermediate A5 (200 mg, 0.435 mmol) and trimethyl orthoacetate (166 μL, 1.31 mmol) in acetic acid (3.6 mL) was stirred for 3 h at 100° C. The reaction mixture was evaporated in vacuo. The residue was diluted with DCM and K.sub.2CO.sub.3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading, mobile phase: DCM/MeOH, gradient from 100:0 to 95:5) to give 132 mg of intermediate H6 as a yellow foam (77% purity, 57%).

[0468] Preparation of Compound 21

[0469] To a mixture of intermediate H6 (133 mg, 0.249 mmol) in anhydrous DCM (2.7 mL) and anhydrous Me-THF (2.5 mL) was added Et.sub.3N (0.17 mL, 1.3 mmol). The mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.75 mL, 0.75 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 min and quenched with a small amount of MeOH and K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtAOc, gradient from 80:20 to 0:100). A second purification was performed via reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: NH.sub.4HCO.sub.3 (0.2% in water)/MeCN, gradient from 40:60 to 10:90) to give 52 mg of compound 21 as an off-white solid (38%).

[0470] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.06 (d, J=1.6 Hz, 1H) 8.44 (s, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.6, 2.1 Hz, 1H) 7.30 (d, J=8.8 Hz, 2H) 7.16 (d, J=8.8 Hz, 2H) 4.46 (d, J=6.0 Hz, 2H) 4.00 (t, J=5.4 Hz, 2H) 3.82 (t, J=5.4 Hz, 2H) 2.97 (q, J=5.6 Hz, 2H) 2.26 (s, 3H) 1.25 (t, J=7.6 Hz, 3H).

[0471] Synthesis of Compound 22

##STR00040## ##STR00041##

[0472] Preparation of Intermediate I1

[0473] A mixture of 4-bromo-2-methoxybenzonitrile [330793-38-9] (1.55 g, 7.31 mmol), N-boc-ethylenediamine (1.76 g, 11.0 mmol) and Cs.sub.2CO.sub.3 (4.76 g, 14.6 mmol) in anhydrous tert-amyl alcohol (46 mL) was purged with N.sub.2. Brettphos Pd G3 (331 mg, 0.365 mmol) and Brettphos (392 mg, 0.731 mmol) were added and the reaction mixture was heated at 120° C. using a single mode microwave (Biotage Initiator60) for 1 h, and then for another 45 min. The two batches were filtered on a pad of Celite® and the filtrate was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 120 g, dry loading (Celite®), mobile phase: heptane/EtAOc, gradient from 90:10 to 0:100) to give 1.64 g of intermediate I1 (74%).

[0474] Preparation of Intermediate 12

[0475] Intermediate 12 was prepared following the procedure reported for the synthesis of intermediate F2 starting from intermediate I1 and affording 1.55 g of a grey oil (94%).

[0476] Preparation of Intermediate 13

[0477] Intermediate 13 was prepared following the procedure reported for the synthesis of intermediate F3 starting from intermediate 12 and affording 765 mg of a beige solid (62%).

[0478] Preparation of Intermediate 14

[0479] Intermediate 14 was prepared following the procedure reported for the synthesis of intermediate F4 starting from intermediate 13 and affording 724 mg of a yellow solid (90%).

[0480] Preparation of Intermediate 15

[0481] Intermediate 15 was prepared following the procedure reported for the synthesis of intermediate F5 starting from intermediate 14 and affording 692 mg of a beige foam (99%).

[0482] Preparation of Intermediate 16

[0483] Intermediate E6 was prepared following the procedure reported for the synthesis of intermediate F6 starting from intermediate 15 and affording 710 mg of a beige solid (Quant.).

[0484] Preparation of Intermediate 17

[0485] A solution of intermediate 16 (270 mg, 0.551 mmol) and N,N-dimethylformamide dimethyl acetal (73.8 μL, 0.551 mmol) in anhydrous DMF (3.4 mL) was stirred at room temperature for 4.5 h. The reaction mixture was diluted with DCM and quenched K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95/5) (twice). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM:MeOH, 80/20), gradient from 95:5 to 85:15) to give 100 mg of intermediate 17 as a white solid (42%).

[0486] Preparation of Compound 22

[0487] Under N.sub.2 atmosphere and at 0° C., to a mixture of intermediate 17 (92.0 mg, 0.216 mmol) and Et.sub.3N (150 μL, 1.08 mmol) in anhydrous DCM (3.1 mL), anhydrous Me-THE (3.1 mL) and anhydrous 1,4-dioxane (3.1 mL) was added dropwise trifluoromethanesulfonic anhydride (0.323 mL, 0.323 mmol). The reaction mixture was stirred at 0° C. for 10 min, and diluted with DCM and K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95/5) (twice). The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 95/5), gradient from 100:0 to 80/20). The solid was triturated in EtOAc. The supernatant was removed and the white solid was dried under vacuum for 1 h at 60° C. to give 28 mg of compound 22 (23%).

[0488] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.04 (d, J=1.5 Hz, 1H) 8.23 (t, J=5.7 Hz, 1H) 7.66 (d, J=9.7 Hz, 1H) 7.45 (dd, J=9.5, 2.1 Hz, 1H) 7.31 (s, 1H) 7.19 (d, J=8.3 Hz, 1H) 6.93 (d, J=2.0 Hz, 1H) 6.70 (dd, J=8.3, 2.0 Hz, 1H) 4.43 (d, J=5.7 Hz, 2H) 4.07 (br d, J=4.6 Hz, 2H) 3.86 (br d, J=5.3 Hz, 2H) 3.84 (s, 3H) 2.96 (d, J=7.5 Hz, 2H) 1.25 (t, J=7.5 Hz, 3H).

[0489] Synthesis of Compound 23

##STR00042##

[0490] Preparation of Intermediate J1

[0491] To a mixture of intermediate E7 (400 mg, 1.23 mmol) and Et.sub.3N (0.857 mL, 6.17 mmol) in anhydrous DCM (18 mL) was added isobutanesulfonyl chloride (0.161 mL, 1.23 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with NaHCO.sub.3 (sat., aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95/5) (twice). The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 100:0 to 0:100, then mobile phase EtOAc/MeOH, gradient from 100:0 to 95:5) to give 406 mg of intermediate J1 as a green solid (74%).

[0492] Preparation of Intermediate J2

[0493] A mixture of intermediate J1 (406 mg, 0.913 mmol) and Pd(OH).sub.2 (264 mg, 0.941 mmol) in MeOH (20 mL), EtOAc (20 mL) and THF (5 mL) was stirred at room temperature under 15 bar of H.sub.2 for 18 h. The reaction mixture was filtered off and rinsed with MeOH, EtOAc and THF. The filtrate was evaporated in vacuo to give 180 mg of intermediate J2 as a yellow solid (60%).

[0494] Preparation of Compound 23

[0495] A mixture of 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3carboxylic acid [2059140-68-8] (113 mg, 0.501 mmol), intermediate J2 (180 mg, 0.551 mmol), EDCI.HCl (96.0 mg, 0.501 mmol), HOBt.H.sub.2O (76.7 mg, 0.501 mmol) and DIPEA (431 μL, 2.50 mmol) in DCM (10 mL) and Me-THF (6 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and washed with water (twice) and brine. The organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtAOc, gradient from 90:10 to 0:100, then mobile phase: EtOAc/MeOH, gradient from 100:0 to 95:5) to give 101 mg of compound 23 as a slightly yellow solid (39%).

[0496] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.39 (d, J=2.8 Hz, 1H) 8.67 (d, J=2.6 Hz, 1H) 8.51 (t, J=6.0 Hz, 1H) 7.28 (d, J=8.7 Hz, 2H) 7.19 (s, 1H), 7.17 (d, J=8.8 Hz, 3H) 4.46 (d, J=6.0 Hz, 2H) 3.86 (t, J=4.8 Hz, 2H) 3.69 (t, J=4.9 Hz, 2H) 3.32 (d, J=6.6 Hz, 3H) 3.01 (q, J=7.5 Hz, 2H) 2.13 (m, 1H) 1.27 (t, J=7.6 Hz, 3H) 1.06 (s, 3H) 1.04 (s, 3H).

[0497] Synthesis of Compound 24

##STR00043##

[0498] Preparation of Intermediate K1

[0499] To a mixture of intermediate E7 (550 mg, 1.70 mmol) and Et.sub.3N (1.18 mL, 8.48 mmol) in anhydrous DCM (24 mL) at 0° C. was added acetyl chloride (0.145 mL, 2.04 mmol) dropwise. The reaction mixture was stirred at room temperature for 15 min, and the reaction was quenched with NaHCO.sub.3 (sat., aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95/5) (twice). The combined organic extracts were dried over MgSO.sub.4, filtered, and evaporated in vacuo. The residue was triturated in EtOAc and the solid was collected by filtration to afford 320 mg of intermediate K1 as a slightly yellow solid (52%).

[0500] Preparation of Intermediate K2

[0501] A mixture of intermediate K1 (256 mg, 0.698 mmol), Pd(OH).sub.2 (157 mg, 0.558 mmol) and HCl (1M in H.sub.2O, 0.698 mL, 0.698 mmol) in MeOH (6.4 mL) and EtOAc (6.4 mL) was stirred at room temperature under 5 bars of H.sub.2 for 1 h. The reaction mixture was filtered and rinsed with EtOAc and MeOH. The yellow solid was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase DCM/(DCM/MeOH/NH.sub.3 aq., 80/20/0.5), gradient from 100:0 to 70:30) to give 130 mg of intermediate K2 (75%).

[0502] Preparation of Compound 24

[0503] To a mixture of 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (98.5 mg, 0.436 mmol), intermediate K2 (129 mg, 0.480 mmol) and DIPEA (752 μL, 4.36 mmol) in DCM (8.8 mL) and Me-THF (5.2 mL) were added EDCI.HCl (83.7 mg, 0.436 mmol) and HOBt.H.sub.2O (66.8 mg, 0.436 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered and the solid was washed with DCM to give 114 mg of compound 24 as a slightly yellow downy solid (59%).

[0504] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.38 (d, J=2.2 Hz, 1H) 8.61 (d, J=2.5 Hz, 1H) 8.26 (br t, J=6.0 Hz, 1H) 7.56 (br s, 1H) 7.28 (br d, J=8.5 Hz, 2H) 7.18 (d, J=8.5 Hz, 2H) 4.47 (d, J=5.7 Hz, 2H) 3.84 (br s, 2H) 3.64 (t, J=5.0 Hz, 2H) 3.01 (q, J=7.6 Hz, 3H) 2.23 (br s, 3H) 1.28 (t, J=7.4 Hz, 3H).

[0505] Synthesis of Compound 25

##STR00044##

[0506] Preparation of Intermediate L1

[0507] To a mixture of 4-fluoro-3-methoxy-benzonitrile [243128-37-2] (4.88 g, 32.3 mmol) and N-boc-ethylenediamine (18.0 mL, 0.129 mol) in DMSO (58 mL) was added Et.sub.3N (6.65 mL, 42.0 mmol). The reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled down and poured in brine. EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a mixture of water and brine (1/1) (3 times), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 330 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 100:0 to 30:70) to give 5.23 g of intermediate L1 as a white solid (56%).

[0508] Preparation of Intermediate L2

[0509] Intermediate L2 was synthesized according to the procedure reported for the synthesis of intermediate F2 starting from intermediate L1 and affording 1.09 g of a green oil (Quant.).

[0510] Preparation of Intermediate L3

[0511] To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic [1216142-18-5](701 mg, 3.12 mmol), intermediate L2 (1.01 g, 3.43 mmol) and DIPEA (2.69 mL, 15.6 mmol) in DCM (60 mL) and Me-THF (40 mL) were added EDCI.HCl (598 mg, 3.12 mmol) and HOBt.H.sub.2O (478 mg, 3.12 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with DCM and water. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 60:40 0:100) to give 1.078 g of intermediate L3 as a yellow solid (69%).

[0512] Preparation of Intermediate L4

[0513] Intermediate L3 (1.08 g, 2.15 mmol) was solubilized in Me-THF (21 mL) and acetic acid (1.23 mL, 21.5 mmol). Isopentyl nitrite (1.44 mL, 10.7 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 1.5 h. The reaction mixture was diluted with EtOAc and NaHCO.sub.3 (sat., aq.). The layers were separated. The organic phase was washed with NaHCO.sub.3 (sat., aq.) (twice) and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was triturated in pentane and the supernatant was removed to give a yellow solid which was dried under vacuum to afford 1.127 g of intermediate L4 (99%).

[0514] Preparation of Intermediate L5

[0515] Intermediate L5 was prepared following the procedure reported for the synthesis of intermediate F5 starting from intermediate L4 and affording 1.07 g of an orange foam (97%).

[0516] Preparation of Intermediate L6

[0517] Intermediate L6 was prepared following the procedure reported for the synthesis of intermediate F6 starting from intermediate L5 and affording 1.10 g of a yellow powder (Quant.).

[0518] Preparation of Intermediate L7

[0519] A mixture of intermediate L6 (600 mg, 1.14 mmol) and trimethyl orthoformate (374 μL, 3.42 mmol) in HFIP (10.8 mL) was stirred at 60° C. for 1 h. The reaction mixture was diluted with EtOAc and quenched with K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the organic phase was washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 25 g, dry loading (Celite®), mobile phase: DCM/(DCM/MeOH, 80/20), gradient from 100:0 to 50:50) to give 290 mg of intermediate L7 as a slightly orange solid (60%).

[0520] Preparation of Compound 25

[0521] To a mixture of intermediate L7 (290 mg, 0.679 mmol) and Et.sub.3N (0.472 mL, 3.40 mmol) in anhydrous DCM (10 mL) and anhydrous Me-THF (10 mL) was added dropwise trifluoromethanesulfonic anhydride (0.815 mL, 0.815 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and diluted with DCM. A small amount of MeOH and K.sub.2CO.sub.3 (10%, aq.) were successively added. The layers were separated and the aqueous phase was extracted with DCM and MeOH (95/5) (twice). The combined organic extracts were washed with water and brine, dried over MgSO.sub.4, filtered and evaporated. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 25 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 70:30 to 0:100). The yellow solid was triturated in Et.sub.2O, sonicated and collected by filtration to give 135 mg of compound 25 as a beige solid (36%).

[0522] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.06 (d, J=1.6 Hz, 1H) 8.47 (br t, J=6.0 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.46 (dd, J=9.5, 2.2 Hz, 1H) 7.29 (s, 1H) 7.21 (d, J=7.9 Hz, 1H) 7.08 (s, 1H) 6.96 (d, J=7.9 Hz, 1H) 4.52 (d, J=6.0 Hz, 2H) 4.06 (br t, J=4.4 Hz, 2H) 3.82 (s, 3H) 3.55 (br t, J=4.7 Hz, 2H) 3.01 (d, J=7.6 Hz, 2H) 1.27 (t, J=7.6 Hz, 3H)

[0523] Synthesis of Compound 26

##STR00045## ##STR00046##

[0524] Preparation of Intermediate M1

[0525] To a mixture of 2-amino-5-methoxypyrimidine [13418-77-4] (4.75 g, 38.0 mmol), ethyl-3-oxovaleraethyl-3-oxovalerate [4949-44-4] (9.48 mL, 66.4 mmol) and (diacetoxyiodo)benzene (iodobenzenediacteate) (12.2 g, 38.0 mmol) in anhydrous Me-THF (150 mL) was added boron trifluoride etherate (0.993 mL, 3.80 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h. The two batches were combined and the mixture was diluted with EtOAc. NaHCO.sub.3 (sat., aq.) was added. The layers were separated and the organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 85:15 to 50:50) to give 4.94 g of intermediate M1 as a yellow solid (26%).

[0526] Preparation of Intermediate M2

[0527] To a solution of intermediate M1 (500 mg, 2.01 mmol) in THE (10 mL) was added a solution of LiOH.H.sub.2O (253 mg, 6.02 mmol) in water (5 mL). The reaction mixture was stirred for 2 h at 45° C., cooled to room temperature and HCl (1M, aq., 6 mL) was added followed by EtOAc. The layers were separated and the aqueous phase was extracted with DCM, then with a mixture of DCM and MeOH (95/5). The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo to afford 80 mg of intermediate M2 (18%).

[0528] Preparation of Compound 26

[0529] To a mixture of intermediate M2 (80 mg, 0.362 mmol) and intermediate E9 (117 mg, 0.362 mmol) in DMF (2.44 mL) were successively added DIPEA (0.156 mL, 0.904 mmol) and TBTU (128 mg, 0.398 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was poured in EtOAc. The organic phase was washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 50:50 to 0:100) to give 78 mg of compound 26 as a white solid (41%).

[0530] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.40 (d, J=2.57 Hz, 1H) 8.68 (d, J=2.69 Hz, 1H) 8.53 (t, J=5.87 Hz, 1H) 7.30 (d, J=8.68 Hz, 2H) 7.15 (d, J=8.68 Hz, 2H) 4.46 (d, J=5.87 Hz, 2H) 4.06-4.18 (m, 2H) 3.85 (s, 3H) 3.69-3.78 (m, 2H) 3.01 (q, J=7.54 Hz, 2H) 1.27 (t, J=7.52 Hz, 3H).

[0531] Synthesis of Compound 27

##STR00047##

[0532] Preparation of Intermediate Ni

[0533] A solution of intermediate E6 (3.00 g, 7.75 mmol) in acetic acid (30 mL) was treated with tetramethoxymethane (2.58 mL, 19.4 mmol) and stirred at room temperature for 2 h. The reaction mixture was poured in DCM and quenched with K.sub.2CO.sub.3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (98/2). The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 70:30 to 0:100) to give 1.09 g of intermediate Ni as an oil (40%).

[0534] Preparation of Intermediate N2

[0535] To a mixture of intermediate Ni (1.00 g, 2.82 mmol) and DIPEA (0.972 mL, 5.64 mmol) in DCM (15 mL) was added a solution of Tf.sub.2O in DCM (1M in DCM, 2.96 mL, 2.96 mmol) dropwise over 10 min. The reaction mixture was stirred at room temperature for 30 min and diluted with DCM. The mixture was washed with NaHCO.sub.3 (sat., aq.), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 40 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 80:20 to 40:60) to give 680 mg of intermediate N2 as a white solid (50%).

[0536] Preparation of Intermediate N3

[0537] In a steal bomb, a mixture of intermediate N2 (630 mg, 1.30 mmol), Pd(OH).sub.2 (132 mg, 0.470 mmol) and HCl (3M in H.sub.2O, 0.432 mL, 1.30 mmol) in MeOH (5 mL) and EtOAc (5 mL) was hydrogenated under 5 bars of H.sub.2 at room temperature for 2 h. The mixture was filtered on a pad of Celite® to give 503 mg of intermediate N3 as white solid (Quant.).

[0538] Preparation of Compound 27

[0539] A mixture of intermediate N3 (150 mg, 0.665 mmol), 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (284 mg, 0.731 mmol) and DIPEA (0.344 mL, 1.99 mmol) in DMF (4.5 mL) was treated with TBTU (235 mg, 0.731 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 80:20 to 20:80). The white solid solubilized in warm EtOAc and the solution was cooled to room temperature, then to 0° C. The suspension was filtered off, washed with Et.sub.2O, and dried under vacuum to give a solid (71 mg). The filtrate was evaporated in vacuo and combined with the solid. The residue was solubilized in warm i-PrOH, and cooled to room temperature. The suspension was slowly concentrated under vacuum (120 mbar) to obtain a thick solution. After filtration, the solid was washed with Et.sub.2O, and dried under vacuum to afford 135 mg of compound 27 as a white solid (36%).

[0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.94 (d, J=3.06 Hz, 1H) 8.51 (d, J=3.06 Hz, 1H) 8.40 (t, J=5.87 Hz, 1H) 7.32 (d, J=8.68 Hz, 2H) 7.28 (s, 1H) 7.19 (d, J=8.68 Hz, 2H) 4.48 (d, J=5.87 Hz, 2H) 4.08 (t, J=4.65 Hz, 2H) 3.86 (s, 3H) 3.79-3.84 (m, 2H) 2.99 (q, J=7.50 Hz, 2H) 1.25 (t, J=7.52 Hz, 3H).

[0541] Synthesis of Compound 28

##STR00048##

[0542] PTSA (108 mg, 567 μmol) was added to a suspension of compound 1 (300 mg, 567 mmol) in MeOH (7.8 mL). After sonication, the solution was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The residue was triturated in Et.sub.2O and the solvent was removed under reduced pressure (operation repeated twice) to give 406 mg of compound 28 as an off-white solid (Quant.).

[0543] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.14 (s, 1H) 8.80 (t, J=5.7 Hz, 1H) 7.74-7.89 (m, 2H) 7.47 (d, J=8.1 Hz, 2H) 7.27-7.37 (m, 3H) 7.19 (d, J=8.7 Hz, 2H) 7.11 (d, J=7.8 Hz, 2H) 4.49 (d, J=5.9 Hz, 3H) 4.08 (t, J=4.4 Hz, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.02 (q, J=7.5 Hz, 2H) 2.29 (s, 3H) 1.27 (t, J=7.5 Hz, 3H).

[0544] Synthesis of Compound 29

##STR00049##

[0545] A solution of MeSO.sub.3H in MeOH (9.1% v/v, 368 μL, 516 μmol) was added to a mixture of compound 1 (300 mg, 567 μmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 45 min and evaporated to dryness. The residue was triturated in Et.sub.2O and the solvent was removed under reduced pressure. The solid was dried under reduced pressure to give 355 mg of compound 29 as an off-white solid (Quant.).

[0546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.13 (s, 1H) 8.74 (t, J=5.3 Hz, 1H) 7.82 (d, J=9.4 Hz, 1H) 7.73 (d, J=9.4 Hz, 1H) 7.33 (m, J=8.7 Hz, 2H) 7.29 (s, 1H) 7.19 (m, J=8.7 Hz, 2H) 4.49 (d, J=5.9 Hz, 2H) 4.08 (t, J=4.6 Hz, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.02 (q, J=7.5 Hz, 2H) 2.32 (s, 3H) 1.27 (t, J=7.5 Hz, 3H).

[0547] Synthesis of Compound 30

##STR00050##

[0548] (1R)-(−)-Camphor-10-Sulfonic acid (110 mg, 473 μmol) was added to a solution of compound 1 (250 mg, 473 μmol) in anhydrous MeOH (5 mL). The reaction mixture was stirred at room temperature for 30 min and the solvent was removed under reduced pressure. The residue was triturated in Et.sub.2O and the solvent was removed under reduced pressure to give 359 mg of compound 30 as a white solid (Quant.).

[0549] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.12 (d, J=1.3 Hz, 1H) 8.69 (t, J=5.3 Hz, 1H) 7.80 (m, 1H) 7.69 (m, 1H) 7.33 (d, J=8.6 Hz, 2H) 7.28 (s, 1H) 7.19 (d, J=8.7 Hz, 2H) 4.48 (d, J=5.7 Hz, 3H) 4.08 (t, J=4.6 Hz, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.01 (q, J=7.6 Hz, 2H) 2.86 (d, J=14.7 Hz, 1H) 2.65-2.75 (m, 1H) 2.37 (d, J=14.7 Hz, 1H) 2.23 (dt, J=18.1, 3.9 Hz, 1H) 1.93 (t, J=4.5 Hz, 1H) 1.83-1.91 (m, 1H) 1.82 (s, 1H) 1.77 (s, 1H) 1.21-1.32 (m, 5H) 1.05 (s, 3H) 0.74 (s, 3H).

[0550] Synthesis of Compound 31

##STR00051##

[0551] A solution of HCl in EtOH (2.5M, 89 μL, 473 μmol) was added to a mixture of compound 1 (250 mg, 473 μmol) in MeOH (2.7 mL). The reaction mixture was stirred at room temperature for 30 min, then evaporated in vacuo to dryness. The residue was triturated in Et.sub.2O and the solvent was removed under reduced pressure to give 269 mg of compound 31 as a white solid (Quant.).

[0552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.12 (s, 1H) 8.71 (m, 1H) 7.79 (d, J=9.4 Hz, 1H) 7.68 (d, J=8.8 Hz, 1H) 7.26-7.37 (m, 3H) 7.19 (d, J=8.7 Hz, 2H) 4.48 (d, J=5.9 Hz, 2H) 4.08 (t, J=4.5 Hz, 2H) 3.83 (t, J=4.8 Hz, 2H) 3.01 (q, J=7.6 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0553] Synthesis of Compound 32

##STR00052##

[0554] H.sub.2SO.sub.4 (13 μL, 238 μmol) was added to a solution of compound 1 (252 mg, 476 μmol) in MeOH (4.2 mL). The reaction mixture was stirred at room temperature for 30 min, then evaporated to dryness. The residue was triturated in Et.sub.2O and the solvent was removed under reduced pressure. The white solid was dried at 60° C. for 6 h under vacuum to give 271 mg of compound 32 as a white solid (98%).

[0555] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.11 (s, 1H) 8.63 (t, J=5.5 Hz, 1H) 7.76 (d, J=9.5 Hz, 1H) 7.62 (d, J=9.8 Hz, 1H) 7.26-7.36 (m, 3H) 7.19 (d, J=8.7 Hz, 2H) 4.48 (d, J=5.9 Hz, 2H) 4.07 (t, J=4.7 Hz, 2H) 3.83 (t, J=4.7 Hz, 2H) 3.00 (q, J=7.5 Hz, 2H) 1.26 (t, J=7.5 Hz, 3H).

[0556] Synthesis of Compound 33

##STR00053##

[0557] Preparation of Intermediate 01

[0558] A 2 L round bottom flask equipped with a dropping funnel was charged at 5° C. with a solution of 2-amino-5-chloropyrimidine [5428-89-7] (10 g, 77 mmol) in Me-THF (350 L). Ethyl-3-oxovalerate [4949-44-4] (20 mL, 140 mmol) and (diacetoxyiodo)benzene (iodobenzene diacetate) (25 g, 78 mmol) were added. Boron trifluoride diethyl etherate (1 mL, 3.8 mmol) was added dropwise over 30 min and the solution was stirred at 5° C. for 2 h. The mixture was warmed to room temperature and stirred for 1 h. The mixture was filtered. EtOAc and NaHCO.sub.3 (sat., aq.) were added to the filtrate. The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 85:15 to 50:50) to give intermediate 01 (2.98 g, 15%).

[0559] Preparation of Intermediate 02

[0560] A solution of intermediate 01 (1.00 g; 3.94 mmol), potassium (methoxymethyl) trifluoroborate [910251-11-5] (1.80 g, 11.8 mmol) and Cs.sub.2CO.sub.3 (3.85 g, 11.8 mmol) in 1,4-dioxane (10 mL) and water (1.4 mL) was purged with nitrogen. RuPhos (184 mg, 0.394 mmol) and RuPhos Pd G3 (330 mg, 0.394 mmol) were added. The reaction mixture was purged again with nitrogen and stirred at 100° C. for 17 h. The reaction mixture was concentrated in vacuo and purified by preparative LC (irregular SiOH 15-40 μm, 40 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 75:25 to 0:100). The residue was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: (aq. NH.sub.4HCO.sub.3 0.2%)/MeCN, gradient from 70:30 to 30:70) to give intermediate O.sub.2 (212 mg, 20%) as a white solid.

[0561] Preparation of Intermediate 03

[0562] A mixture of intermediate 02 (130 mg, 0.494 mmol) and LiGH (14 mg, 0.585 mmol) in THE (2.3 mL) and water (2.3 mL) was stirred at room temperature for 36 h. The reaction mixture was evaporated in vacuo to afford 168 mg of intermediate 03 as a light-yellow gum. The crude product was used as such in next step.

[0563] Preparation of Compound 33

[0564] To a mixture of intermediate 03 (168 mg, 0.529 mmol) and DIPEA (0.275 mL, 1.59 mmol) in DMF (5 mL) were successively added HOBt.H.sub.2O (83.0 mg, 0.542 mmol), EDCI.HCl (102 mg, 0.533 mmol) and intermediate E9 (223 mg, 0.536 mmol). The reaction mixture was stirred at room temperature for 20 h. DCM and water were added.

[0565] The layers were separated and the organic layer was washed with NaHCO.sub.3 (sat., aq.) and brine (3 times), dried over MgSO.sub.4, filtered and evaporated. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 24 g, dry loading (Celite®), mobile phase: heptane/(EtOAc/MeOH, 9/1), gradient from 90:10 to 0:100). The residue (175 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry loading (Celite®), mobile phase: (aq. NH4HCO.sub.3 0.2%)/MeCN, gradient from 90:10 to 30:70). MeCN was evaporated and the product was extracted with DCM (twice). The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to afford 154 mg of a white solid. The product was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry loading (Celite®), mobile phase: (aq. NH.sub.4HCO.sub.3 0.2%)/MeCN, gradient from 60:40 to 45:55). MeCN was evaporated and the product was extracted with DCM (twice). The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo. The product was triturated in MeCN and EtOAc, filtered and dried under high vacuum at 50° C. for 16 h to afford compound 33 (119 mg, 42%) as a white solid.

[0566] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.27 (d, J=2.3 Hz, 1H) 8.60 (d, J=2.4 Hz, 1H) 8.50 (t, J=6.0 Hz, 1H) 7.27-7.34 (m, 3H) 7.19 (d, J=8.7 Hz, 2H) 4.53 (s, 2H) 4.47 (d, J=5.9 Hz, 2H) 4.03-4.12 (m, 2H) 3.79-3.86 (m, 2H) 3.34 (s, 3H) 3.00 (q, J=7.5 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0567] Synthesis of Compound 34

##STR00054##

[0568] To a mixture of the 5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [1352395-28-8] (80 mg, 0.39 mmol), intermediate N3 (151 mg, 0.39 mmol) and DIPEA (201 μL, 1.17 mmol) in DMF (5 mL) were added EDCI.HCl (74 mg, 0.39 mmol) and HOBt.H.sub.2O (59 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The residue was diluted in EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated. The residue (229 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm (30*150 mm), mobile phase: (aq. NH.sub.4HCO.sub.3 0.2%)/MeCN, gradient from 50:50 to 25:75) affording 118 mg of compound 34.

[0569] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.49 (d, J=7.5 Hz, 1H) 7.85 (t, J=5.9 Hz, 1H) 7.22-7.29 (m, 3H) 7.14 (d, J=8.7 Hz, 2H) 6.62 (dd, J=7.5, 2.8 Hz, 1H) 4.41 (d, J=6.0 Hz, 2H) 4.07-4.12 (m, 2H) 3.84 (d, J=2.3 Hz, 6H) 3.69-3.75 (m, 2H) 2.52 (s, 3H).

[0570] Synthesis of Compound 35

##STR00055## ##STR00056##

[0571] Preparation of Intermediate P1

[0572] In a round bottom flask, a solution of 3,4,5-trifluorobenzonitrile [134227-45-5] (5 g, 31.8 mmol), N-boc-1,2-diaminoethane [57260-73-8] (5.2 mL, 32.8 mmol) and Et.sub.3N (17.7 mL, 127 mmol) in anhydrous DMSO (57 mL) was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature and DMSO was evaporated with Genevac. EtOAc, water and NaCl were added. The layers were separated and the organic layer was washed with brine (3 times), dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude mixture was solubilized in EtOAc and SiOH was added. The dry loading was evaporated and washed with heptane (100 mL). The product was eluted with heptane/EtOAc (1:1, 3×100 mL). The filtrate was evaporated to afford 9.30 g of intermediate P1 as a colorless oil which crystallized on standing (98%).

[0573] Preparation of Intermediate P2

[0574] Intermediate P2 was prepared following the synthesis reported for intermediate E2, starting from intermediate P1 (31.3 mmol) and affording 9.3 g as a light blue gum (99%) which crystallized on standing.

[0575] Preparation of Intermediate P3

[0576] Intermediate P3 was prepared following the synthesis reported for intermediate E3, starting from intermediate P2 (6.64 mmol) and affording 1.63 g as a colorless oil (56%) which crystallized on standing.

[0577] Preparation of Intermediate P4

[0578] Intermediate P4 was prepared following the synthesis reported for intermediate E4, starting from intermediate P3 (3.74 mmol) and affording 1.91 g as a yellow oil (91%).

[0579] Preparation of Intermediate P5

[0580] Intermediate P5 was prepared following the synthesis reported for intermediate E5, starting from intermediate P4 (3.74 mmol) and affording 1.69 g as a yellow oil (100%) which crystallized on standing.

[0581] Preparation of Intermediate P6

[0582] A solution of intermediate P5 (1.69 g, 3.75 mmol) in anhydrous DCM (35 mL) was treated with TFA (3.5 mL, 45.7 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated in vacuo to give 3.42 g of intermediate P6 as an orange gum.

[0583] Preparation of Intermediate P7

[0584] Trimethylorthoformate (1.24 mL, 11.3 mmol) was added to a solution of intermediate P6 (3.42 g, 3.78 mmol) in HFIP (35 mL) and the mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and basified with NaHCO.sub.3 (sat., aq.). The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give 2.0 g of intermediate P7 as a yellow gum.

[0585] Preparation of Intermediate P8

[0586] Triethylamine (1 mL, 7.19 mmol) was added to a solution of intermediate P7 (1.5 g, 2.83 mmol) in DCM (28 mL). The solution was then cooled to 0° C. (ice/water bath) and Tf.sub.2O (1M in DCM, 3.4 mL, 3.4 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 0° C. for 30 min. The mixture was slowly warmed to room temperature and stirred for 2 h. DCM, water and NaHCO.sub.3 (10%, aq.) were added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and evaporated. The residue (1.61 g) was purified by preparative LC (irregular SiOH, 30 μm, 80 g, liquid injection (DCM), mobile phase: heptane/EtOAc, gradient from 95:5 to 50:550) to afford 317 mg of intermediate P8 as an orange gum (23% over 3 steps).

[0587] Preparation of Intermediate P9

[0588] In a steal bomb, a mixture of intermediate P8 (317 mg, 0.644 mmol), palladium hydroxide, Pd 20% on carbon, nominally 50% water (120 mg, 0.171 mmol) and HCl (1M, aq., 0.64 mL, 0.64 mmol) in EtOAc (3.2 mL) and MeOH (3.2 mL) was hydrogenated under 5 bars of H.sub.2 at room temperature for 4 h. The mixture was filtered. An extra amount of palladium hydroxide, Pd 20% on carbon, nominally 50% water (60 mg, 0.085 mmol) and HCl (1M, aq., 0.64 mL, 0.64 mmol) were added. The mixture was hydrogenated under 5 bars of H.sub.2 at room temperature for 1.5 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to afford 269 mg of intermediate P9 as an orange gum. The crude product was used as such in next step.

[0589] Preparation of Compound 35

[0590] To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylicacid [1216142-18-5] (80 mg, 0.356 mmol) and DIPEA (0.245 mL, 1.42 mmol) in DMF (3.5 mL) were successively added EDCI.HCl (72 mg, 0.376 mmol), HOBt.H.sub.2O (60 mg, 0.392 mmol) and intermediate P9 (270 mg, 0.356 mmol). The reaction mixture was stirred at room temperature for 20 h. The crude mixture was taken-up in DCM and NaHCO.sub.3 (sat., aq.) was added. The layers were separated and the organic layer was washed with brine (twice), dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue (409 mg) was purified by preparative LC (regular SiOH 30 μm, 24 g, mobile phase: heptane/(EtOAc/MeOH, 9/1), gradient from 80:20 to 20:80). A second purification was performed by reverse Phase (stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry loading (Celite®), mobile phase: (aq. NH.sub.4HCO.sub.3 0.2%)/MeCN, gradient from 65:35 to 25:75). The desired fractions were combined and MeCN was evaporated. The product was extracted with DCM (3 times) and the organic layer was dried over MgSO.sub.4, filtered and evaporated to give a colorless gum (81 mg). The product was triturated in pentane and Et.sub.2O (1/1), evaporated and dried under high vacuum at 50° C. for 5 h to afford 66 mg of compound 35 as a light-yellow solid (24%).

[0591] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.11 (m, 1H) 8.45-8.53 (m, 1H) 7.69 (d, J=9.4 Hz, 1H) 7.48 (dd, J=9.7, 1.8 Hz, 1H) 7.29 (s, 1H) 7.18 (d, J=9.5 Hz, 2H) 4.54 (d, J=5.6 Hz, 2H) 4.05-4.13 (m, 2H) 3.61-3.70 (m, 2H) 3.03 (q, J=7.4 Hz, 2H) 1.23-1.35 (t, J=7.4 Hz, 3H).

[0592] Synthesis of Compound 36

##STR00057##

[0593] Preparation of Intermediate 01

[0594] Carbone tetrabromide (16 g; 43.4 mmol) was added to a mixture of 2-amino-5-methoxypryridine [10167-97-2] (3 g, 24.2 mmol) and ethyl-3-oxovalerate[4949-44-4](5.2 mL, 36.6 mmol) in MeCN (50 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated to dryness.

[0595] The residue (20 g) was purified by preparative LC (regular SiOH 30 μm, 330 g, dry loading (SiOH), mobile phase: heptane/EtOAc, gradient from 80:20 to 0:100) to give 1.89 g of intermediate Q1 as a greenish solid (32%).

[0596] Preparation of Intermediate 02

[0597] To a solution of intermediate Q1 (1.89 g, 7.61 mmol) in water (20 mL) and EtOH (25 mL) was added NaOH (913 mg, 22.8 mmol). The reaction mixture was stirred at room temperature for 16 h. Additional quantity of NaOH (304 mg, 7.61 mmol) was added and the reaction mixture was stirred for 3 h. EtOH was concentrated. The mixture was acidified to pH 2-3 with HCl (1N). The white precipitate was filtered and washed with water and dried under high vacuum to give 750 mg of intermediate Q2 as a white solid (45%).

[0598] Preparation of Compound 36

[0599] To a mixture of intermediate Q2 (150 mg, 0.681 mmol) and DIPEA (0.48 mL, 2.79 mmol) in DMF (7 mL) were successively added EDCI.HCl (174 mg, 0.908 mmol), HOBt.H.sub.2O (144 mg, 0.94 mmol) and intermediate N3 (265 mg, 0.681 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The residue was taken-up in DCM and NaHCO.sub.3 (sat., aq.) was added. The layers were separated and the organic layer was washed with water and brine (twice), dried over MgSO.sub.4, filtered and evaporated. The crude mixture was purified by preparative LC (regular SiOH 30 μm, 24 g, liquid injection (DCM), mobile phase: heptane/(EtOAc/MeOH, 9/1), gradient from 80:20 to 20:80). The fractions containing product were combined and evaporated to afford a white solid (304 mg). The product was recrystallized from MeCN, filtered and dried under high vacuum at 50° C. for 3 h to afford 200 mg of compound 36 as a white solid (53%).

[0600] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.65 (d, J=2.2 Hz, 1H) 8.23-8.32 (m, 1H) 7.53 (d, J=9.5 Hz, 1H) 7.29 (d, J=8.7 Hz, 2H) 7.13-7.21 (m, 3H) 4.46 (d, J=5.9 Hz, 2H) 4.06-4.17 (m, 2H) 3.85 (s, 3H) 3.72-3.82 (m, 5H) 2.95 (q, J=7.5 Hz, 2H) 1.24 (t, J=7.5 Hz, 3H).

[0601] Synthesis of Compound 37

##STR00058## ##STR00059##

[0602] Preparation of Intermediate R1

[0603] Intermediate R1 was prepared following the synthesis reported for intermediate E3, starting from intermediate D2 (7.06 mmol) and affording 2.53 g as an off-white solid (86%).

[0604] Preparation of Intermediate R2

[0605] Intermediate R2 was prepared following the synthesis reported for intermediate E4, starting from intermediate R1 (6.06 mmol) and affording, 3.2 g as a yellow oil used as such for next step without purification.

[0606] Preparation of Intermediate R3

[0607] Intermediate R3 was prepared following the synthesis reported for intermediate E5, starting from intermediate R2 (6.06 mmol theorical) and affording 2.22 g as a yellow oil (87% over 2 steps).

[0608] Preparation of Intermediate R4

[0609] To a solution of intermediate R3 (2.22 g, 5.13 mmol) in MeOH (52 mL) was added dropwise TMSCl (5.2 mL, 41 mmol). The reaction mixture was stirred at room temperature for 20 h and concentrated in vacuo. Et.sub.2O was added to the residue and the gum was triturated. The solvent was removed under reduced pressure to give 2.06 g of intermediate R4 as a pale green solid (99%).

[0610] Preparation of Intermediate R5

[0611] A solution of intermediate R4 (1.00 g, 2.47 mmol) in acetic acid (25 mL) was treated with tetramethoxymethane (0.82 mL, 6.17 mmol) and stirred at room temperature for 1 h. Additional amount of tetramethoxymethane (0.82 mL, 6.17 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured in DCM and water. The mixture was basified with K.sub.2CO.sub.3 powder and the layers were separated. The aqueous layer was extracted with DCM (once) and the combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue (685 mg) was purified by preparative LC (irregular SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: DCM/MeOH, gradient from 100:0 to 85:15) to give 445 mg of intermediate R5 as a colorless oil (48%).

[0612] Preparation of Intermediate R6

[0613] Intermediate R6 was prepared following the synthesis reported for intermediate P8, starting from intermediate R5 (1.19 mmol) and affording 0.45 g as colorless oil (72%).

[0614] Preparation of Intermediate R7

[0615] Intermediate R7 was prepared following the synthesis reported for intermediate P9, starting from intermediate R6 (0.61 mmol) and affording 0.24 g as colorless oil (96%).

[0616] Preparation of Compound 37

[0617] To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (87.3 mg, 0.388 mmol), intermediate R7 (158 mg, 0.388 mmol) and DIPEA (0.335 mL, 1.94 mmol) in DMF (5.3 mL) were successively added EDCI.HCl (74.5 mg, 0.388 mmol) and HOBt.H.sub.2O (59.5 mg, 0.388 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 12 g, dry loading (Celite®), mobile phase: heptane/EtOAc, gradient from 80:20 to 30:70). The desired fractions were combined and evaporated under vacuum. The product (163 mg) was sonicated in Et.sub.2O and filtered to give 118 mg of compound 37 as a white solid (53%).

[0618] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.09 (d, J=1.6 Hz, 1H) 8.47 (t, J=5.9 Hz, 1H) 7.68 (d, J=9.5 Hz, 1H) 7.42-7.50 (m, 2H) 7.16-7.25 (m, 2H) 4.49 (d, J=5.9 Hz, 2H) 4.07-4.15 (m, 2H) 3.83 (s, 3H) 3.53-3.61 (m, 2H) 3.00 (q, J=7.5 Hz, 2H) 1.27 (t, J=7.5 Hz, 3H).

[0619] Synthesis of Compound 38

##STR00060##

[0620] Preparation of Intermediate S1

[0621] To a solution of DMF (103 μL, 1.33 mmol) in DCE (6.5 mL) at room temperature was added POCl.sub.3 (123 μL, 1.33 mmol) and the mixture was stirred at room temperature for 30 min. Then the mixture was cooled down to 0° C. and intermediate E7 (430 mg, 1.33 mmol) in DCE (6.5 mL) was added dropwise and the mixture was stirred at 0° C. for 2 hours. Water and DCM were added. The aqueous layer was slowly basified with NaHCO.sub.3 (s) to pH 8. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered off and evaporated to afford 421 mg of intermediate S1 as a yellow solid. The crude was used as such in next step.

[0622] Preparation of Intermediate S2

[0623] In a steal vessel, a mixture of intermediate S1 (421 mg, 1.20 mmol), palladium hydroxide (100 mg, 0.14 mmol) and HCl 1M in H.sub.2O (1.2 mL, 1.2 mmol) in MeOH (10.5 mL) and EtOAc (10.5 mL) was hydrogenated under 5 bar of H.sub.2 at room temperature for 3 hours. The mixture was filtered on a pad of Celite® to give 413 mg of intermediate S2 as a yellow solid. The crude was used as such in next step.

[0624] Preparation of Compound 38

[0625] To a solution of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylicacid (CAS [1216142-18-5], 240 mg, 1.07 mmol) and diisopropylethylamine (0.75 mL, 4.35 mmol) in DCM (11 mL) were added EDCI.HCl (210 mg, 1.10 mmol) and HOBt.H.sub.2O (170 mg, 1.11 mmol) then intermediate S2 (410 mg, 1.13 mmol) and the mixture was stirred at room temperature for 16 hours. DCM and water were added. The layers were separated, and the organic layer was washed with an aqueous saturated solution of NaHCO.sub.3 and brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated. The crude was purified by Reverse Phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry loading (on Celite®), mobile phase: Gradient from 80% (aq. NH.sub.4HCO.sub.3 0.2%), 20% MeCN to 40% (aq. NH.sub.4HCO.sub.3 0.2%), 60% MeCN). MeCN was evaporated and the product was extracted with DCM/MeOH (9:1) (3 times). The organic layer was dried over MgSO.sub.4, filtered and evaporated to afford 176 mg of a light-yellow solid. It was purified by Reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry loading (on Celite®), mobile phase: Gradient from 60% (aq. NH.sub.4HCO.sub.3 0.2%), 40% MeCN to 45% (aq. NH.sub.4HCO.sub.3 0.2%), 55% MeCN over 16 CV). All fractions were combined to obtain 139 mg as a yellow solid. It was purified by Reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, liquid loading (DMSO), Mobile phase: Gradient from 70% (aq. NH.sub.4HCO.sub.3 0.2%), 30% ACN to 50% (aq. NH.sub.4HCO.sub.3 0.2%), 50% ACN) to afford 39 mg as a white solid. It was solubilized in DCM/MeOH then combined with a previous fraction, evaporated and dried under high vacuum (50° C., 2 h) to afford 68 mg as an off-white solid. It was co-evaporated in MeOH (5 times), then dried under high vacuum (50° C., 6 h) to give 65 mg of compound 38 as an off-white solid (12%) Major rotamer (84%).sup.1H NMR (500 MHz, DMSO-d6, 350K) 6 ppm 9.07 (s, 1H), 8.57 (s, 1H), 8.15 (br t, J=5.2 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J=9.6, 2.0 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.47 (d, J=6.0 Hz, 2H), 3.78 (br t, J=4.7 Hz, 2H) 3.64 (br t, J=4.8 Hz, 2H), 2.97 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H). Minor rotamer (16%).sup.1H NMR (500 MHz, DMSO-d6, 350K) δ ppm 9.07 (s, 1H), 8.57 (s, 1H), 8.15 (br t, J=5.2 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J=9.6, 2.0 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.47 (d, J=6.0 Hz, 2H), 3.90 (m, 2H) 3.73 (m, 2H), 2.97 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).

[0626] Synthesis of Compound 39

##STR00061## ##STR00062##

[0627] Preparation of Intermediate T1

[0628] To a solution of 3-chloro-4-methoxypyridine-2-amine (CAS [1232431-05-8], 0.2 g, 1.26 mmol) in 2-MeTHF (6 mL) at 5° C. under N.sub.2 were added ethyl-3-oxovalerate (CAS [4949-44-4], 0.18 mL, 1.26 mmol) and iodobenzenediacetate ((diacetoxyiodo)benzene) (0.406 g, 1.26 mmol.), then borontrifluoride etherate (16.5 μL, 0.063 mmol) was added dropwise. The solution was stirred at the 5° C. for 30 min then warmed to room temperature and stirred for 2 hours. An extra amount of ethyl-3-oxovalerate (0.09 mL, 0.63 mmol), iodobenzenediacetate (0.203 g, 0.63 mmol) and borontrifluoride etherate (16.5 μL, 0.063 mmol) were added, the mixture was purged with N.sub.2 and stirred at rt for 1 hour. EtOAc and water were added. The layers were separated, and the organic layer was dried over MgSO.sub.4, filtered off and concentrated. The crude was purified by preparative LC (regular SiOH, 30 μm, 24 g liquid loading (DCM), mobile phase: Heptane 95%, EtOAc 5% isocratic for 3 CV then gradient to Heptane 60%, EtOAc 40% over 12 CV) to afford 295 mg of intermediate T1 as a white solid (83%).

[0629] Preparation of Intermediate T2

[0630] To a solution of intermediate T1 (270 mg, 0.96 mmol) in water (4.8 mL) and EtOH (4.8 mL) was added NaOH (115 mg, 2.88 mmol) and the mixture was stirred at room temperature for 4 days. The mixture was evaporated to afford 371 mg of intermediate T2 as a light-yellow solid (purity 71%). The crude was used as such in next step.

[0631] Preparation of Compound 39

[0632] To a solution of intermediate T2 (371 mg, 0.952 mmol) and diisopropyethylamine (0.50 mL, 2.90 mmol) in DMF (9.5 mL) were added HOBt.H.sub.2O (160 mg, 1.05 mmol) and EDCI.HCl (195 mg, 1.02 mmol) then intermediate E9 (400 mg, 0.959 mmol). The mixture was stirred at rt for 20 hours. The mixture was evaporated then taken-up in DCM and an aqueous saturated solution of NaHCO.sub.3 was added. The organic layer was separated and washed with brine, dried over MgSO.sub.4, filtered and evaporated to give an orange gum. The crude was purified by preparative LC (irregular SiOH, 15-40 μm, 50 g, liquid loading (in DCM), mobile phase gradient: from Heptane 75%, EtOAc/MeOH (9:1) 25% to Heptane 25%, EtOAc/MeOH (9:1) 75% over 12 CV). Clean fractions were combined and evaporated to afford 312 mg as a light-yellow solid. It was purified by Reverse Phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry loading (on Celite®), mobile phase: Gradient from 55% (aq. NH.sub.4HCO.sub.3 0.2%), 45% MeCN to 5% (aq. NH.sub.4HCO.sub.3 0.2%), 95% MeCN over 12 CV) to afford 286 mg as an off-white solid. It was sonicated in MeCN (suspension) then filtered off. The solid was dried under high vacuum (50° C., 6 h) to afford 230 mg of compound 39 as a white solid (43%).

[0633] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (d, J=7.7 Hz, 1H), 8.35 (t, J=5.9 Hz, 1H), 7.26-7.35 (m, 3H), 7.12-7.23 (m, 3H), 4.45 (br d, J=5.9 Hz, 2H), 4.07 (br d, J=4.4 Hz, 2H), 3.99 (s, 3H), 3.82 (t, J=4.6 Hz, 2H), 2.95 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H).

[0634] Synthesis of Compound 40 and Compound 41

##STR00063##

[0635] Preparation of Intermediate U1

[0636] A mixture of intermediate E6 (1.00 g, 2.58 mmol), ethyl-3-ethoxy-3-iminopropanoate hydrochloride (CAS [2318-25-4], 2.17 g, 7.75 mmol) and triethylamine (1.08 mL, 7.75 mmol) in NMP (14 mL) was stirred for 18 h at 150° C. in a sealed tube. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (×3). The combined organic phases were washed with NaCl sat., dried over MgSO.sub.4 and concentrated to give 1.85 g as a brown oil. It was diluted in EtOAc and washed with a diluted solution of NaCl. The organic layer was dried over MgSO.sub.4 and concentrated to give 1.03 g of intermediate U1. The crude product was used as such in the next step based on the theoretical quantity.

[0637] Preparation of Intermediate U2

[0638] At −78° C., to a solution of intermediate U1 (900 mg, 2.19 mmol) and triethylamine (914 μL, 6.58 mmol) in dry DCM (45 mL) was added dropwise Tf.sub.2O 1M in DCM (3.1 mL, 3.1 mmol) and the reaction mixture was stirred for 15 min. The reaction mixture was diluted with DCM and water. The organic phase was dried over MgSO.sub.4, filtered off and evaporated to give 1.0 g. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 40 g, liquid loading (DCM), mobile phase gradient: (EtOAc/MeOH (90:10)) in heptane from 0 to 50% over 5 CV then isocratic for 5 CV) to give 456 mg of intermediate U2 as an orange-brown oil (38%).

[0639] Preparation of Intermediate U3

[0640] Lithium borohydride (276 μL; 0.553 mmol) was added to a solution of intermediate U2 (150 mg; 0.276 mmol) in THE (5 mL) and the solution was stirred at room temperature for 15 hours. Further lithium borohydride (276 μL, 0.553 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted once again with EtOAc and the combined organic layers were washed with brine (3 times) dried over MgSO.sub.4, filtered and evaporated to dryness to give 132 mg of intermediate U3 (95%) as a yellow residue.

[0641] Preparation of Intermediate U4

[0642] Accordingly, intermediate U4 was prepared in the same way as intermediate S2 starting from intermediate U3 (0.132 g, 0.26 mmol) affording 0.11 g (quantitative).

[0643] Preparation of Compound 40

[0644] To a solution of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylicacid (CAS [1216142-18-5], 67 mg, 0.300 mmol), intermediate U4 (110 mg, 0.300 mmol), and diisopropylethylamine (155 μL, 0.901 mmol) in DMF (4 mL) were added EDCI.HCl (58 mg, 0.30 mmol) and HOBt.H.sub.2O (46 mg, 0.30 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue was taken up in EtOAc and water. The organic layer was washed with NaCl sat, dried over MgSO.sub.4, filtered off and concentrated to give 143 mg. The crude was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, liquid loading (DCM), mobile phase gradient: (EtOAc/MeOH (90:10)) in heptane from 0 to 50% over 5 CV then isocratic for 5 CV) to give 100 mg as white solid. It was purified by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: from 55% (aq. NH.sub.4HCO.sub.3 0.2%), 45% MeCN to 75% (aq. NH.sub.4HCO3 0.2%) MeCN) to give 19 mg and 59 mg of a residue which was co-evaporated with EtOH and MeCN affording 80 mg of compound 40 as a yellowish solid (combined yield: 57%).

[0645] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.03-9.13 (m, 1H) 8.41 (br t, J=6.0 Hz, 1H) 7.66 (d, J=9.5 Hz, 1H) 7.45 (dd, J=9.5, 1.9 Hz, 1H) 7.32 (d, J=8.5 Hz, 2H) 7.16 (d, J=8.5 Hz, 2H) 4.66 (t, J=5.7 Hz, 1H) 4.47 (d, J=6.0 Hz, 2H) 3.96 (br t, J=5.0 Hz, 2H) 3.84 (t, J=4.9 Hz, 2H) 3.73 (q, J=6.6 Hz, 2H) 2.98 (q, J=7.6 Hz, 2H) 2.74 (t, J=6.9 Hz, 2H) 1.26 (t, J=7.6 Hz, 3H)

[0646] Preparation of Compound 41

[0647] Accordingly, compound 41 was prepared in the same way as compound 40, starting from 6-chloro-2-ethyl-imidazo[1,2-a]-pyrimidine-3-carboxylic acid (CAS [2059140-68-8], 0.32 mmol) and intermediate U4 (0.32 mmol) affording 0.067 g (37%) as green-light solid.

[0648] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.39 (d, J=2.5 Hz, 1H) 8.68 (d, J=2.5 Hz, 1H) 8.55 (t, J=5.8 Hz, 1H) 7.31 (m, J=8.5 Hz, 2H) 7.15 (m, J=8.5 Hz, 2H) 4.70 (t, J=5.7 Hz, 1H) 4.47 (d, J=6.0 Hz, 2H) 3.95 (br t, J=4.9 Hz, 2H) 3.79-3.88 (m, 2H) 3.72 (q, J=6.6 Hz, 2H) 3.01 (q, J=7.4 Hz, 2H) 2.73 (t, J=6.8 Hz, 2H) 1.27 (t, J=7.6 Hz, 3H)

[0649] Synthesis of Compound 42

##STR00064##

[0650] To a solution of intermediate Q2 (125 mg, 0.568 mmol) in diisopropylethylamine (0.4 mL, 2.32 mmol) and DMF (6 mL) were added EDCI.HCl (145 mg, 0.756 mmol), HOBt.H.sub.2O (120 mg, 0.784 mmol) then intermediate E9 (205 mg, 0.571 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and taken-up in DCM and an aqueous saturated solution of NaHCO.sub.3. The layers were separated, and the organic layer was washed with water, brine (twice), dried over MgSO.sub.4, filtered and evaporated. The crude was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid loading (DCM), mobile phase gradient: from Heptane 80%, EtOAc/MeOH (9:1) 20% to Heptane 20%, EtOAc/MeOH (9:1) 80% over 12 CV) to afford 166 mg as a white solid. It was recrystallized form MeCN then filtered off and dried under high vacuum to afford 107 mg of compound 42 as a white solid (36%).

[0651] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=2.2 Hz, 1H), 8.30 (t, J=5.8 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.27-7.36 (m, 3H), 7.14-7.22 (m, 3H), 4.47 (d, J=5.9 Hz, 2H), 4.08 (br t, J=4.5 Hz, 2H), 3.83 (br t, J=4.5 Hz, 2H) 3.76 (s, 3H), 2.95 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H).

[0652] Synthesis of Compound 43

##STR00065##

[0653] Preparation of Intermediate V1

[0654] In a sealed tube, a suspension of imidazo[1,2-a]-pyridine-3-carboxylic acid, 6-bromo-2-ethyl-ethyl ester (CAS [1908481-13-9], 400 mg, 1.35 mmol), potassium (methoxymethyl)trifluoroborate (614 mg, 4.04 mmol) and cesium carbonate (1.32 g, 4.04 mmol) in 1,4-dioxane (3.44 mL) and water (0.49 mL) was purged with N.sub.2. RuPhos (62.8 mg, 0.135 mmol) and RuPhos Pd G3 (113 mg, 0.135 mmol) were added, the mixture was purged again with N.sub.2 then stirred at 100° C. overnight. The mixture was filtered off then the filtrate was evaporated. The crude was purified by preparative LC (regular SiOH, 30 μm, 50 g, dry loading (on Celite®), mobile phase gradient: from heptane 90%, EtOAc/MeOH (9:1) 10% to Heptane 50%, EtOAc/MeOH (9:1) 50% over 12 CV) to obtain 317 mg of intermediate V1 as a colorless gum which crystallized on standing (66%).

[0655] Preparation of Intermediate V2

[0656] To a solution of intermediate V1 (317 mg, 0.894 mmol) in water (4 mL) and EtOH (4 mL) was added NaOH (107 mg, 2.68 mmol) and the mixture was stirred at room temperature for 24 hours. The mixture was evaporated to afford 518 mg of intermediate V2 as a yellow gum. The crude was used as such in next step.

[0657] Preparation of Compound 43

[0658] Accordingly, compound 43 was prepared in the same way as compound 42, starting from intermediate V2 (0.9 mmol) and intermediate E9 (0.84 mmol) affording 0.113 g (22%) as a white solid.

[0659] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.93 (s, 1H), 8.38 (t, J=6.0 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.26-7.36 (m, 4H), 7.19 (d, J=8.5 Hz, 2H), 4.43-4.51 (m, 4H), 4.08 (br t, J=4.6 Hz, 2H), 3.83 (t, J=4.7 Hz, 2H), 3.30 (s, 3H), 2.96 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).

[0660] Synthesis of Compound 44

##STR00066##

[0661] Accordingly, compound 44 was prepared in the same way as compound 42, starting from 5-methoxy-2-methylpyrrazolo[1,5-a]-pyridine-3-carboxylic acid (CAS [1352395-28-8], 0.37 mmol) and intermediate N3 (0.37 mmol) affording 0.19 g (42%) as a white solid.

[0662] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.51 (d, J=7.6 Hz, 1H) 7.91 (t, J=6.0 Hz, 1H) 7.43 (t, J=8.7 Hz, 1H) 7.26 (d, J=2.8 Hz, 1H) 7.12-7.23 (m, 2H) 6.64 (dd, J=7.6, 2.8 Hz, 1H) 4.44 (d, J=5.7 Hz, 2H) 4.07-4.15 (m, 2H) 3.86 (s, 3H) 3.82 (s, 3H) 3.53-3.60 (m, 2H) 2.53 (s, 3H)

[0663] Synthesis of Compound 45

##STR00067##

[0664] Preparation of Intermediate W1

[0665] To a solution of 4-chloro-5-methoxypyridin-2-amine (CAS [867131-26-8], 500 mg, 3.15 mmol) in dry acetonitrile (7.5 mL) were added ethyl 3-oxovalerateethyl 3-oxovalerate (0.90 mL, 6.3 mmol), bromotrichloromethane (1.1 mL, 11 mmol) and potassium bicarbonate (947 mg, 9.46 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted in EtOAc and water. The organic layer was then washed with brine, dried over MgSO.sub.4, filtered off and evaporated. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 40 g, dry loading on Celite®, mobile phase gradient: Heptane/EtOAc 95/5 to Heptane/EtOAc 40/60 in 15 CV) to give 458 mg of intermediate W1 as a yellow solid (51% yield).

[0666] Preparation of Intermediate W2

[0667] A mixture of intermediate W1 (456 mg, 1.61 mmol) and NaOH (194 mg, 4.86 mmol) in water (8.1 mL), EtOH (8.1 mL) and MeOH (9.8 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated. The residue was solubilized with MeOH and acidified with a 3N aqueous solution of HCl. The solution was evaporated to give 726 mg of a yellow solid. DCM and MeOH were added to the yellow solid. The mixture was then filtered off and the filtrate was evaporated to give 443 mg of intermediate W2 as a beige solid (93% purity, quantitative).

[0668] Preparation of Compound 45

[0669] Accordingly, compound 45 was prepared in the same way as compound 42, starting from intermediate W2 (0.46 mmol) and intermediate N3 (0.46 mmol) affording 0.19 g (69%) as a beige solid.

[0670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.77 (s, 1H) 8.32 (t, J=5.8 Hz, 1H) 7.86 (s, 1H) 7.29 (d, J=8.6 Hz, 2H) 7.15 (d, J=8.7 Hz, 2H) 4.46 (br d, J=5.7 Hz, 2H) 4.10 (br t, J=4.8 Hz, 2H) 3.87 (s, 3H) 3.85 (s, 3H) 3.74 (br t, J=4.8 Hz, 2H) 2.95 (q, J=7.5 Hz, 2H) 1.24 (t, J=7.5 Hz, 3H)

[0671] Synthesis of Compound 46

##STR00068##

[0672] Preparation of Intermediate X1

[0673] Accordingly, intermediate X1 was prepared in the same way as intermediate T1 starting from 5-chloro-4-methoxypyridin-2-amine CAS [662117-63-7] (6.31 mmol) affording 1.23 g (69%) as a light-yellow solid.

[0674] Preparation of Intermediate X2

[0675] Accordingly, intermediate X2 was prepared in the same way as intermediate V2 starting from intermediate X1 (4.35 mmol) affording 0.83 g (75%) as a light-yellow solid.

[0676] Preparation of Compound 46

[0677] Accordingly, compound 46 was prepared in the same way as compound 42, starting from intermediate X2 (0.45 mmol) and intermediate R7 (0.43 mmol) affording 0.14 g (48%) as a white solid.

[0678] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 8.27 (br t, J=5.8 Hz, 1H), 7.44 (t, J=8.5 Hz, 1H), 7.16-7.25 (m, 3H), 4.47 (br d, J=5.7 Hz, 2H), 4.08-4.13 (m, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 3.54-3.59 (m, 2H), 2.96 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H)

[0679] Synthesis of Compound 47

##STR00069##

[0680] Accordingly, compound 47 was prepared in the same way as compound 42, starting from intermediate 6-Chloro-2-ethyl-imidazo[1,2-a]-pyrimidine-3-carboxylic acid CAS [2059140-68-8] (0.38 mmol) and intermediate P9 (0.31 mmol) affording 0.027 g (15%) as a white fluffy solid.

[0681] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.35 (d, J=2.7 Hz, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.52 (t, J=5.9 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=9.4 Hz, 2H), 4.46 (br d, J=5.7 Hz, 2H), 4.01 (br s, 2H), 3.57 (br t, J=4.3 Hz, 2H), 2.98 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H)

[0682] Synthesis of Compound 48

##STR00070##

[0683] Accordingly, compound 48 was prepared in the same way as compound 42, starting from intermediate Q2 (0.52 mmol) and intermediate R7 (0.51 mmol) affording 0.15 g (52%) as a white solid.

[0684] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (d, J=2.2 Hz, 1H), 8.31 (t, J=5.8 Hz, 1H), 7.54 (d, J=9.8 Hz, 1H), 7.45 (t, J=8.7 Hz, 1H), 7.15-7.25 (m, 3H), 4.49 (d, J=5.7 Hz, 2H), 4.07-4.14 (m, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.54-3.60 (m, 2H), 2.98 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H)

[0685] Synthesis of Compound 49

##STR00071##

[0686] Accordingly, compound 49 was prepared in the same way as compound 42, starting from intermediate W2 (0.44 mmol) and intermediate R7 (0.44 mmol) affording 0.164 g (62%) as a white solid.

[0687] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.80 (s, 1H) 8.36 (br t, J=5.8 Hz, 1H) 7.87 (s, 1H) 7.45 (t, J=8.5 Hz, 1H) 7.15-7.26 (m, 2H) 4.50 (br d, J=5.7 Hz, 2H) 4.10 (br t, J=5.0 Hz, 2H) 3.87 (s, 3H) 3.82 (s, 3H) 3.56 (br t, J=5.0 Hz, 2H) 2.98 (q, J=7.6 Hz, 2H) 1.26 (t, J=7.6 Hz, 3H)

[0688] Synthesis of Compound 50

##STR00072##

[0689] Preparation of Intermediate Y1

[0690] Accordingly, intermediate Y1 was prepared in the same way as intermediate X1 starting from 2-amino-5-methoxypyrimidine CAS [13418-77-4] (75.92 mmol) affording 4.94 g (26%) as a yellow solid.

[0691] Preparation of Intermediate Y2

[0692] To a solution of intermediate Y1 (150 mg, 0.602 mmol) in THF (3 mL) was added a solution of LiOH (75.8 mg, 1.81 mmol) in water (1.5 mL). The reaction mixture was stirred for 2 hours at 45° C. The mixture was evaporated to afford 218 mg of intermediate Y2 as a yellow solid. The crude was used as such in next step.

[0693] Preparation of Compound 50

[0694] Accordingly, compound 50 was prepared in the same way as compound 42, starting from intermediate Y2 (0.6 mmol) and intermediate R7 (0.55 mmol) affording 0.098 g (31%) as a white solid.

[0695] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, J=2.9 Hz, 1H), 8.52 (d, J=2.9 Hz, 1H), 8.41 (t, J=5.9 Hz, 1H), 7.45 (t, J=8.6 Hz, 1H), 7.15-7.26 (m, 2H), 4.50 (d, J=5.7 Hz, 2H), 4.08-4.14 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.53-3.59 (m, 2H), 3.02 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H)

[0696] Synthesis of Compound 51 and Compound 52

##STR00073##

[0697] Preparation of Compound 51

[0698] Accordingly, compound 51 was prepared in the same way as compound 42, starting from 2-ethyl-7-methoxyimidazo[1,2-a]-pyridine-3-carboxylic acid (CAS [1536994-62-3], 0.46 mmol) and intermediate E9 (0.46 mmol) affording 0.195 g (72%) as a white solid.

[0699] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.83 (d, J=7.6 Hz, 1H) 8.19 (t, J=5.9 Hz, 1H) 7.25-7.34 (m, 3H) 7.18 (d, J=8.7 Hz, 2H) 7.00 (d, J=2.4 Hz, 1H) 6.70 (dd, J=7.6, 2.6 Hz, 1H) 4.44 (d, J=5.9 Hz, 2H) 4.07 (br t, J=4.4 Hz, 2H) 3.78-3.88 (m, 5H) 2.92 (q, J=7.5 Hz, 2H) 1.24 (t, J=7.5 Hz, 3H)

[0700] Preparation of Compound 52

[0701] Accordingly, compound 52 was prepared in the same way as compound 42, starting from 2-ethyl-7-methoxyimidazo[1,2-a]-pyridine-3-carboxylic acid (CAS [1536994-62-3], 0.46 mmol) and intermediate N3 (0.46 mmol) affording 0.178 g (69%) as a white solid.

[0702] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.84 (d, J=7.6 Hz, 1H) 8.16 (t, J=6.0 Hz, 1H) 7.28 (d, J=8.7 Hz, 2H) 7.14 (d, J=8.7 Hz, 2H) 6.99 (d, J=2.5 Hz, 1H) 6.70 (dd, J=7.7, 2.7 Hz, 1H) 4.43 (d, J=5.7 Hz, 2H) 4.10 (br t, J=5.0 Hz, 2H) 3.84 (m, 6H) 3.73 (br t, J=5.0 Hz, 2H) 2.91 (q, J=7.6 Hz, 2H) 1.25 (t, J=7.6 Hz, 3H)

[0703] Synthesis of Compound 53

##STR00074##

[0704] Preparation of Intermediate Z1

[0705] Accordingly, intermediate Z1 was prepared in the same way as intermediate X1 starting from 4,5-dimethoxy-pyridin-2-ylamine CAS [1000843-61-7] (1.3 mmol) affording 0.135 g (37%) as a light-yellow solid

[0706] Preparation of Intermediate Z2

[0707] Accordingly, intermediate Z2 was prepared in the same way as intermediate X2 starting from intermediate Z1 (0.49 mmol) affording 0.209 g (63%) as a light-yellow solid.

[0708] Preparation of Compound 53

[0709] Accordingly, compound 53 was prepared in the same way as compound 42, starting intermediate Z2 (0.48 mmol) and intermediate R7 (0.4 mmol) affording 0.149 g (39% over last 2 steps) as a white solid.

[0710] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.11 (t, J=5.8 Hz, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.15-7.23 (m, 2H), 7.05 (s, 1H), 4.47 (d, J=5.7 Hz, 2H), 4.07-4.14 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H), 3.53-3.59 (m, 2H), 2.95 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H)

[0711] Synthesis of Compound 54

##STR00075##

[0712] A mixture of intermediate C1 (190 mg, 0.445 mmol), 2-bromothiazole (48.1 μL, 0.534 mmol) and sodium tert-butoxide (214 mg, 2.23 mmol) in dry 1,4-dioxane (5 mL) was purged with N.sub.2 (3 times). XantPhos (51.5 mg, 89.0 μmol) and Pd(OAc).sub.2 (9.99 mg, 44.5 μmol) were added and the mixture was purged with N.sub.2 (3 times). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted with EtOAc/MeOH (95/5) and water. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered off and evaporated to give a yellow solid. The solid was purified by preparative LC (regular SiOH 30 μm, 25 g, dry loading (Celite®), mobile phase gradient: DCM 100% to DCM/(DCM: MeOH 80:20) 90/10 in 15 CV). The fractions containing product were combined and evaporated under vacuum to give a pale-yellow solid. The solid was triturated in Et.sub.2O, filtered off, washed with Et.sub.2O and then dried under vacuum to give 153 mg of compound 54 as a white solid (67% yield).

[0713] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.08 (d, J=1.5 Hz, 1H) 8.42 (t, J=5.9 Hz, 1H) 7.66 (d, J=9.6 Hz, 1H) 7.45 (dd, J=9.5, 2.1 Hz, 1H) 7.40 (d, J=3.7 Hz, 1H) 7.27 (d, J=8.7 Hz, 2H) 7.22 (d, J=8.7 Hz, 2H) 7.17 (d, J=3.7 Hz, 1H) 4.46 (d, J=5.8 Hz, 2H) 4.20 (t, J=5.1 Hz, 2H) 3.92 (s, 3H) 3.67 (t, J=5.1 Hz, 2H) 2.98 (q, J=7.6 Hz, 2H) 1.26 (t, J=7.6 Hz, 3H)

[0714] Synthesis of Compound 55

##STR00076##

[0715] Preparation of Intermediate AA1

[0716] In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol), 3-methoxypropionimidic acid ethyl ester hydrochloride (328 mg, 1.96 mmol) and triethylamine (272 μL, 1.96 mmol) in 2-propanol (6 mL) was stirred for 1.5 h at 90° C. After cooling to room temperature, the reaction mixture was concentrated. The residue was taken up in EtOAc and aqueous solution of NaHCO.sub.3 (1%) was added. After separation, the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried over MgSO.sub.4, filtered off and concentrated to give 280 mg of intermediate AA1 as a light-yellow oil which crystallized on standing (94%).

[0717] Preparation of Compound 55

[0718] Triethylamine (0.281 mL, 2.02 mmol) was added to a solution of intermediate AA1 (230 mg, 0.506 mmol) in dry DCM (4.6 mL). The solution was then cooled at 0° C. (ice/water bath). A 1M solution of Tf.sub.2O (1.01 mL, 1.01 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. DCM and an aqueous solution of NaHCO.sub.3 (10%) were added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered off and evaporated to obtain a brown gum which was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid loading (DCM), mobile phase gradient: from Heptane 90%, EtOAc/MeOH (9:1) 10% to Heptane 25%, EtOAc/MeOH (9:1) 75% over 12 CV). Fractions containing product were combined and evaporated to give 208 mg as a yellow solid. It was purified by Reverse phase (Stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry loading (Celite®) Mobile phase: Gradient from 60% (aq. NH.sub.4HCO.sub.3 0.2%), 40% MeCN to 100% MeCN over 12 CV). Fractions containing product were combined and evaporated to afford 175 mg as a yellow solid. It was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid loading (DCM), mobile phase gradient: from Heptane 90%, EtOAc/MeOH (9:1) 10% to Heptane 25%, EtOAc/MeOH (9:1) 75% over 12 CV). Fractions containing product were combined and evaporated to give 146 mg as a white solid. This one was purified by Reverse phase (Stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry loading (Celite®) Mobile phase: Gradient from 60% (aq. NH.sub.4HCO.sub.3 0.2%), 40% MeCN/MeOH (1:1) to 15% (aq. NH.sub.4HCO.sub.3 0.2%), 85% MeCN/MeOH (1:1) over 14 CV). Fractions containing product were combined and evaporated to afford 129 mg as a white solid. It was purified by achiral SFC (Stationary phase: diethylaminopropyl 5 μm 150×21.2 mm, Mobile phase: 90% CO.sub.2, 10% MeOH). Fractions containing product were combined and evaporated to afford 94 mg as a white solid. This one was sonicated in MeCN (10 mL) and evaporated (3 times) then MeCN (5 mL) was added, the product was filtered and dried under high vacuum (50° C., 2 h) to afford 84 mg of compound 55 as a white solid (28%)

[0719] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (d, J=1.5 Hz, 1H), 8.44 (br t, J=5.7 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.45 (dd, J=9.4, 2.1 Hz, 1H), 7.32 (m, J=8.7 Hz, 2H), 7.16 (m, J=8.7 Hz, 2H), 4.47 (br d, J=5.9 Hz, 2H), 3.90-4.00 (m, 2H), 3.81-3.89 (m, 2H), 3.66 (t, J=6.7 Hz, 2H), 3.26-3.29 (m, 3H), 2.98 (q, J=7.5 Hz, 2H), 2.82 (t, J=6.7 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H)

[0720] The following compounds were prepared in accordance with the procedures described herein:

##STR00077## ##STR00078## ##STR00079## ##STR00080##

[0721] Synthesis of Compound 73

##STR00081##

[0722] Preparation of intermediate AB1

[0723] To a solution of 2-amino-5-cyanopyridine (CAS [4214-73-7]; 5 g, 42.0 mmol) in Me-THF (200 mL) at 5° C. were added iodobenzene diacetate (13.5 g, 41.9 mmol) and ethyl-3-oxovalerate (10 mL, 70.1 mmol). Then boron trifluoride etherate (550 μL, 2.10 mmol) was added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was warmed to room temperature and stirred for 2 hours. EtOAc and a sat. solution of NaHCO.sub.3 were added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (twice), dried over MgSO.sub.4, filtered off then evaporated to give 26 g of a brown liquid (which crystallized on standing). The crude product was purified by preparative LC (irregular SiOH, 15-40 μm, 330 g, Grace, dry loading (Celite®), mobile phase gradient: from heptane 85%, EtOAc 15% to heptane 30%, EtOAc 70%) to afford 3.14 g of the intermediate AB1 as a yellow solid (30%).

[0724] Preparation of Intermediate AB2

[0725] Under Nitrogen, NaH 60% (0.677 g; 16.9 mmol) was added to a solution of 2-(trimethylsilyl)ethanol (2.43 mL; 16.9 mmol) in dry toluene (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min then intermediate AB1 (0.823 g; 3.38 mmol) was added and the reaction mixture was stirred for 16 h warming to room temperature. The reaction mixture was hydrolyzed with a aqueous saturated solution of NH4C.sub.1 and extracted with EtOAc. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO.sub.4, filtered, evaporated to dryness and purified by preparative LC (Regular SiOH, 30-40 μm, 40 g, loading (DCM), mobile phase gradient: Heptane/EtOAc from 100:0 to 50:50). The fractions containing product were evaporated to give 559 mg of intermediate AB2 as a white solid (52%).

[0726] Preparation of Compound 73

[0727] Cesium fluoride (289 mg, 1.90 mmol) was added to a solution of intermediate AB2 (200 mg, 0.634 mmol) in F (8.4 mL) and the reaction mixture was stirred at 60° C. for 2 h. Then diisopropylethylamine (139 μL, 0.817 mmol) and HATU (267 mg, 0.701 mmol) were added and the reaction mixture was stirred at room temperature for 15 min (the reaction mixture turned to brown). Intermediate R7 (266 mg, 0.634 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours.

[0728] The reaction mixture was diluted with EtOAc, and the organic layer was washed with an aqueous solution of NaHCO3 1%, then with water and brine, dried over MgSO.sub.4, filtered off and concentrated. DCM and MeOH were added to the residue. The mixture was filtered. The precipitate was dried under vacuum at 50° C. to give 160 mg of a crude product as a white solid.

[0729] The crude product was heated to reflux with EtOAc (15 mL) for 20 min then slowly cooled down to room temperature for 18 hours with slowly stirring.

[0730] The solid was filtered, rinced with cooled EtOAc and dried under vacuum at 60° C. to give 128 mg of compound 73 as white solid (36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (s, 1H) 8.63 (t, J=5.9 Hz, 1H) 7.78 (d, J=9.3 Hz, 1H) 7.66 (dd, J=9.3, 1.7 Hz, 1H) 7.45 (t, J=8.6 Hz, 1H) 7.13-7.31 (m, 2H) 4.51 (d, J=5.87 Hz, 2H) 4.06-4.19 (m, 2H) 3.53-3.62 (m, 2H) 3.02 (q, J=7.50 Hz, 2H) 1.28 (t, J=7.46 Hz, 3H).

[0731] Synthesis of Compound 74

##STR00082##

[0732] Preparation of Intermediate AC1

[0733] A mixture of intermediate A5 (500 mg, 1.09 mmol), methyl-2,2-diethoxyacetimidate (526 mg, 3.26 mmol) and triethylamine (453 μL, 3.26 mmol) in iPrOH (9.4 mL) was stirred for 2 h at 90° C. After cooling to room temperature, the reaction mixture was concentrated. The residue was taken up in EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered off and concentrated. The residue was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, liquid loading (DCM), mobile phase gradient: EtOAc in heptane from 20 to 80% then isocratic). Fractions containing product were combined and evaporated to give 343 mg of intermediate AC1 as a white solid (63%).

[0734] Preparation of Intermediate AC2

[0735] Diisopropylethylamine (0.311 mL, 1.80 mmol) was added to a solution of intermediate AC1 (300 mg, 0.601 mmol) in DCM (5.5 mL). The solution was then cooled at 0° C. (ice/water bath). A 1M solution of Tf.sub.2O in DCM (0.721 mL, 1.2 eq., 0.721 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. An extra amount of a 1M solution of Tf.sub.2O in DCM (0.721 mL, 1.2 eq., 0.721 mmol) was added and the mixture was stirred at 0° C. for 1 hour. A saturated aqueous solution of NaHCO.sub.3 and DCM were added. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered off and evaporated to afford a brown gum. This crude product was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid loading (DCM), mobile phase gradient: from DCM 100% to DCM 85%, MeOH/AcOH (9:1) 15%) to afford 94 mg of intermediate AC2 as an orange gum.

[0736] Preparation of Compound 74

[0737] To a solution of intermediate AC2 (94 mg, 0.17 mmol) in AcOH (29 μL, 0.51 mmol) and DCM (1.5 mL) was added a 2M solution of dimethylamine in THE (0.25 mL, 0.51 mmol) and the mixture was stirred at room temperature for 6 hours. Then, sodium triacetoxyborohydride (71.5 mg, 0.34 mmol) was added and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of NaHCO.sub.3 was added carefully then the layers were separated. The aqueous layer was extracted with DCM (twice) then the combined organic layers were dried over MgSO.sub.4, filtered off and evaporated. The crude product was purified by preparative LC (regular SiOH, 30 μm, 12 g, liquid loading (DCM), mobile phase gradient: from heptane 80%, EtOAc/MeOH (9:1) 20% to Heptane 15%, EtOAc/MeOH (9:1) 85%). Fractions containing product were combined and evaporated to give 68 mg as a light-yellow oil which was purified by Reverse phase (Stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 12 g, dry loading (Celite®) Mobile phase: Gradient from 55% (aq. NH.sub.4HCO.sub.3 0.2%), 45% MeCN to 100% MeCN). Fractions containing product were combined and evaporated to afford a colorless oil which was triturated in Et.sub.2O, dried under high vacuum (50° C., 1 h) to afford 40 mg of compound 74 as a white solid (40%).

[0738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.06 (d, J=1.0 Hz, 1H) 8.44 (br t, J=5.8 Hz, 1H) 7.67 (d, J=9.7 Hz, 1H) 7.45 (dd, J=9.4, 1.8 Hz, 1H) 7.33 (br d, J=8.6 Hz, 2H) 7.19 (br d, J=8.6 Hz, 2H) 4.47 (br d, J=5.5 Hz, 2H) 3.90 (br dd, J=16.6, 4.2 Hz, 4H) 2.97 (q, J=7.5 Hz, 2H) 2.19 (s, 7H) 1.26 (t, J=7.5 Hz, 4H).

[0739] Synthesis of Compound 75

##STR00083##

[0740] Preparation of Intermediate AD1

[0741] Carbon tetrabromide (26.9 g, 81.0 mmol) was added to a solution of 2-amino-4-methoxypyridine [CAS:10201-73-7] (5.02 g, 40.4 mmol) and ethyl-3-oxovalerate (8.69 mL, 60.8 mmol) in MeCN (85 mL) and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was evaporated until dryness then purified by preparative LC (regular SiOH, 30 μm, 330 g, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc 95/5 to EtOAc) to give 669 mg of intermediate AD1(16%).

[0742] Preparation of Intermediate AD2

[0743] To a mixture of intermediate AD1 (1.55 g, 6.24 mmol) in water (20 mL) and EtOH (20 mL) was added NaOH (752 mg, 18.8 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to give 2.16 g of intermediate AD2 (Quant.)

[0744] Preparation of Compound 75

[0745] A mixture of intermediate AD2 (138 mg, 0.397 mmol), intermediate R7 (160 mg, 397 μmol), EDCI.HCl (99.1 mg, 0.517 mmol), HOBt (79.1 mg, 0.517 mmol) and diisopropylethylamine (205 μL, 1.19 mmol) in DMF (6 mL) was stirred at room temperature for 20 hours.

[0746] The residue was dissolved in EtOAc and water. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO.sub.4, filtered off and evaporated to give an orange oil. The oil was purified by preparative LC (regular SiOH 30 μm, 12 g, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc 70/30 to EtOAc 100%). The fractions containing product were combined and evaporated under vacuum to give a yellow solid which was triturated in Et.sub.2O. The supernatant was removed by pipette and the solid was dried under vacuum to give 124 mg of a white solid which was co-evaporated in Et.sub.2O (3 times) to give 120 mg of compound 75 as a white solid (46% yield).

[0747] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.86 (d, J=7.7 Hz, 1H) 8.21 (br t, J=5.8 Hz, 1H) 7.44 (t, J=8.5 Hz, 1H) 7.12-7.26 (m, 2H) 7.01 (d, J=2.3 Hz, 1H) 6.71 (dd, J=7.6, 2.5 Hz, 1H) 4.47 (br d, J=5.9 Hz, 2H) 4.07-4.15 (m, 2H) 3.84 (d, J=8.2 Hz, 6H) 3.52-3.61 (m, 2H) 2.94 (q, J=7.5 Hz, 2H) 1.26 (t, J=7.5 Hz, 3H).

[0748] Synthesis of Compound 76

##STR00084##

[0749] A mixture of intermediate A6 (30.0 mg, 75.6 μmol), 2-Bromothiazole (8.18 μL, 90.7 μmol) and NaOtBu (36.3 mg, 0.378 mmol) in dry 1,4-dioxane (1.3 mL) was purged with N.sub.2 (3 times). XanthPhos (8.7 mg, 15 μmol) and Palladium II acetate (1.7 mg, 7.6 μmol) were then added and the mixture was purged with N.sub.2 (3 times). The reaction mixture was stirred at 80° C. for 22 hours. The reaction mixture was diluted with EtOAc/MeOH and water. The aqueous layer was extracted with EtOAc (twice). The combined organic layer was washed with brine, dried over MgSO.sub.4, filtered off and evaporated to give a brown solid. The solid was purified by preparative LC (regular SiOH 30 μm, 12 g, dry loading (Celite®), mobile phase gradient: DCM 100% to DCM/(DCM: MeOH 80:20) 30/70). The fractions containing product were combined and evaporated under vacuum to give 17 mg of compound 76 as yellow solid (47% yield).

[0750] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.07 (d, J=1.4 Hz, 1H) 8.45 (t, J=5.9 Hz, 1H) 7.63-7.69 (m, 2H) 7.45 (dd, J=9.5, 2.0 Hz, 1H) 7.39 (d, J=3.5 Hz, 1H) 7.26 (dd, J=36.7, 8.7 Hz, 2H) 7.16 (d, J=3.5 Hz, 1H) 4.46 (d, J=5.6 Hz, 2H) 4.00 (t, J=5.0 Hz, 2H) 3.78 (t, J=5.0 Hz, 2H) 2.98 (q, J=7.5 Hz, 2H) 1.26 (t, J=7.5 Hz, 4H).

[0751] The following compound was also prepared in accordance with the procedures described herein:

##STR00085##

[0752] B. Further Procedures

[0753] Synthesis of Compound 127

##STR00086##

[0754] HATU (0.099 g, 0.26 mmol) was added to a solution of 2-(Trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [73221-19-9], 0.052 g, 0.23 mmol) and DIPEA (0.097 mL, 0.56 mmol) in dry Me-THF (1.52 mL) and DCM (0.51 mL) under N.sub.2. The solution was stirred at room temperature for 15 min. Then intermediate E9 (0.08 g, 0.25 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated then the residue was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO.sub.3, water then brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to give a yellow oil, 0.167 g. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording a colorless oil which crystallized on standing, 0.102 g. A purification was performed via Reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, Mobile phase: Gradient from 40% NH.sub.4HCO.sub.3 0.2%, 60% ACN to 10% NH.sub.4HCO.sub.3 0.2%, 90% ACN). Pure fractions were collected and evaporated affording 0.037 g as white foam. It was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. affording compound 127 as white powder, 0.032 g (26%).

[0755] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.23 (br s, 1H), 8.53 (br d, J=6.4 Hz, 1H), 7.79 (br d, J=8.9 Hz, 1H), 7.55 (br t, J=7.5 Hz, 1H), 7.25-7.37 (m, 3H), 7.20 (br d, J=8.1 Hz, 3H), 4.42-4.56 (m, 2H), 4.08 (br s, 2H), 3.84 (br s, 2H)

##STR00087##

[0756] Accordingly, compound 128 was prepared in the same way as compound 127 starting from 2-(Difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [2059954-47-9], 0.23 mmol) and intermediate E9 affording a white powder, 0.045 g (39%).

[0757] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.96 (br t, J=5.6 Hz, 1H), 8.79 (d, J=7.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.25-7.45 (m, 4H), 7.20 (d, J=8.7 Hz, 2H), 7.16 (td, J=6.9, 1.1 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 4.08 (br t, J=4.5 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H)

[0758] Synthesis of Compound 137

##STR00088##

[0759] HATU (0.093 g, 0.24 mmol) was added to a solution of 2-(Difluoromethyl)-5H,6H,7H,8H-imidazo[1,2-A]pyridine-3-carboxylic acid (0.046 g, 0.21 mmol) and DIPEA (0.091 mL, 0.53 mmol) in dry Me-THF (1.43 mL) and DCM (0.48 mL) under N.sub.2. The solution was stirred at room temperature for 15 min. Then intermediate R7 (0.095 g, 0.23 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated then the residue was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO.sub.3, water then brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to give a yellow oil, 0.271 g. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording 0.112 g as colourless oil which crystalized on standing. It was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. affording compound 137 as white powder, 0.096 g (79%).

[0760] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.77 (br t, J=5.6 Hz, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.10-7.19 (m, 2H), 6.95 (t, J=54.3 Hz, 1H), 4.40 (br d, J=5.8 Hz, 2H), 4.06-4.15 (m, 2H), 4.02 (br t, J=5.5 Hz, 2H), 3.83 (s, 3H), 3.54-3.60 (m, 2H), 2.78 (br t, J=6.3 Hz, 2H), 1.89 (br d, J=4.6 Hz, 2H), 1.83 (br d, J=5.5 Hz, 2H)

[0761] Synthesis of Compound 79

##STR00089##

[0762] Accordingly, compound 79 was prepared in the same way as compound 137 starting from 2-(Trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [73221-19-9], 0.21 mmol) and intermediate R-7 (0.23 mmol) affording a white powder, 0.09 g (70%).

[0763] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.27 (t, J=5.8 Hz, 1H), 8.57 (d, J=6.9 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.40-7.62 (m, 2H), 7.14-7.27 (m, 3H), 4.47-4.56 (m, 2H), 4.08-4.14 (m, 2H), 3.84 (s, 3H), 3.52-3.63 (m, 2H)

[0764] Synthesis of Compound 132

##STR00090##

[0765] Preparation of Intermediate AB-1

[0766] In a sealed tube, to a solution of 2-amino-5-chloropicoline (CAS [36936-27-3], 1.00 g, 7.01 mmol) in ACN (12 mL) were added Ethyl-ethyl 3-oxovalerate (CAS [4949-44-4], 2.00 mL, 14.0 mmol), bromotrichloromethane (2.40 mL, 24.4 mmol) and potassium bicarbonate (2.12 g, 21.2 mmol). The mixture was stirred at 80° C. for 16 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO.sub.4), evaporated and purified by preparative LC (irregular SiOH, 15-40 μm, 80 g, mobile phase gradient: from heptane/EtOAc 90:10 to 10:90) The fractions containing product were combined and evaporated to afford 0.95 g of intermediate AB-1 as an orange solid (51%).

[0767] Preparation of Intermediate AB-2

[0768] To a mixture of intermediate AB-1 (180 mg, 0.675 mmol) in water (2.2 mL) and EtOH (2.2 ml) was added NaOH (81 mg, 2.03 mmol) and the mixture was stirred at 40° C. for 18 h.

[0769] The reaction mixture was evaporated to give 270 mg g of intermediate AB-2 (Quant. purity 65%).

[0770] Preparation of Compound 132

[0771] A mixture of intermediate AB-2 (150 mg, 0,374 mmol, purity 65%), intermediate R7 (151 mg, 0,374 mmol), HATU (157 mg, 0.414 mmol), DIPEA (82 μL, 0.48 mmol) and DMF (2.3 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with an aqueous solution of NaHCO.sub.3 1%, then with water and brine, dried over MgSO.sub.4, filtered off, concentrated and purified by preparative LC (irregular SiOH, 15-40 μm, 40 g Grace, loading (DCM), mobile phase gradient: from Heptane/EtOAc: 50/50 to 0/100 in 7 CV then EtOAc 100% in 7 CV). The fractions containing product were combined and evaporated to give 116 mg as a white solid. It was purified by preparative LC (spherical C18 25 μm, 40 g YMC-ODS-25, (MeOH/MeCN), mobile phase gradient 0.2% aq. NH.sub.4.sup.+HCO.sub.3.sup.−/MeCN from 70:30 to 0:100). The fraction containing product were combined and evaporated to give 86 mg of compound 132 as white solid (39%).

[0772] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1H), 8.35 (t, J=5.9 Hz, 1H), 7.64 (s, 1H), 7.45 (t, J=8.6 Hz, 1H), 7.11-7.27 (m, 2H), 4.48 (d, J=5.9 Hz, 2H), 4.11 (br t, J=5.2 Hz, 2H), 3.83 (s, 3H), 3.57 (br t, J=4.9 Hz, 2H), 2.99 (q, J=7.5 Hz, 2H), 2.40 (s, 3H), 1.26 (t, J=7.5 Hz, 3H)

[0773] Syntheses of Compound 141

##STR00091##

[0774] Preparation of Intermediate AC-1

[0775] To a solution of 5-Chloro-4-fluoro-2-pyridinamine (CAS [1393574-54-3], 250 mg, 1.71 mmol) in Me-THF (8 mL) at 5° C. were added iodobenzene diacetate (550 mg, 1.71 mmol) and ethyl-ethyl 3-oxovalerate (0.4 mL, 2.80 mmol). Then Boron trifluoride etherate (25 μL, 95.5 μmol) was added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was warmed to room temperature and stirred for 18. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO.sub.4),evaporated and purified by preparative LC (irregular SiOH, 15-40 μm, 40 g, grace, loading (DCM) mobile phase gradient: from heptane/EtOAc 90:10 to 10:90 over 10 CV) to afford 119 mg of intermediate AC-1 as a pale brown solid (P1; 26%)

[0776] Preparation of Intermediate AC-2

[0777] A mixture of intermediate AC-1 (200 mg, 0.739 mmol), Lithium hydroxide (177 mg, 7.39 mmol), water (3.2 mL) and THF (4.4 mL) was stirred at 50° C. for 18h. EtOAc and aq. KHSO.sub.4 10% was added. The organic layer was dried (MgSO.sub.4) and evaporated to give 179 mg of intermediate AC-2 as yellow solid (Quant.).

[0778] Preparation of Compound 141

[0779] Accordingly, compound 141 was prepared in the same way as compound 132 starting from intermediate AC-2 (0.78 mmol) and intermediate R7 affording 0.127 g (27%) as a white powder.

[0780] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (d, J=7.3 Hz, 1H), 8.45 (br t, J=5.8 Hz, 1H), 7.79 (d, t, J=9.9 Hz, 1H), 7.45 (t, t, J=8.7 Hz, 1H), 7.12-7.27 (m, 2H), 4.49 (d, t, J=5.9 Hz, 2H), 4.11 (t, t, J=4.9 Hz, 2H), 3.83 (s, 3H), 3.57 (t, t, J=4.9 Hz, 2H), 2.99 (q, t, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H)

[0781] Synthesis of Compound 158

##STR00092##

[0782] Preparation of Intermediate AD-1

[0783] Accordingly, compound AD-1 was prepared in the same way as compound AC-1 starting from 6,7-dihydro-5h-cyclopenta[d]pyrimidin-2-amine (CAS [108990-72-3], 7.4 mmol) affording 0.726 g (38%).

[0784] Preparation of Intermediate AD-2

[0785] Accordingly, compound AD-2 was prepared in the same way as compound AB-2 starting from AD-1 (0.77 mmol) affording 0.446 g (44%).

[0786] Preparation of Compound 158

[0787] Accordingly, compound 158 was prepared in the same way as compound 132 starting from intermediate AD-2 (0.77 mmol) and intermediate R7 affording 0.145 g (32%) as a white powder.

[0788] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1H), 8.39 (t, J=6.0 Hz, 1H), 7.44 (t, J=8.5 Hz, 1H), 7.12-7.26 (m, 2H), 4.47 (d, J=5.9 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.83 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 2.89-3.03 (m, 6H), 2.05-2.16 (m, 2H), 1.26 (t, J=7.6 Hz, 3H)

[0789] Preparation of Compound 193

##STR00093##

[0790] Accordingly, compound 193 was prepared in the same way as compound 158 starting from intermediate AI-3 (0.44 mmol) and intermediate R-7 (0.37 mmol) affording a white solid, 0.108 g (52%).

[0791] .sup.1H NMR (400 MHz, DMSO) δ 9.19-9.10 (m, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.44 (t, J=5.9 Hz, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.26-7.14 (m, 2H), 4.49 (d, J=5.9 Hz, 2H), 4.14-4.03 (m, 2H), 3.83 (s, 3H), 3.59-3.53 (m, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.34 (d, J=0.6 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H).

[0792] Preparation of Compound 194

##STR00094##

[0793] Accordingly, compound 194 was prepared in the same way as compound 158 starting from 6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS [874830-60-1] (0.7 mmol) and intermediate R-7 (0.47 mmol) affording a white solid, 0.110 g (39%).

[0794] .sup.1H NMR (400 MHz, DMSO) δ 9.23 (t, J=5.8 Hz, 1H), 8.35 (s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.52-7.37 (m, 2H), 7.19 (m, 2H), 4.51 (d, J=5.8 Hz, 2H), 4.17-4.07 (m, 2H), 3.84 (s, 3H), 3.63-3.55 (m, 2H), 2.34 (s, 3H).

[0795] Preparation of Compound 204

##STR00095##

[0796] Accordingly, compound 204 was prepared in the same way as compound 158 starting from 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1368682-64-7], 0.84 mmol) and intermediate R-7 (0.7 mmol) affording a white solid, 0.132 g (34%).

[0797] .sup.1H NMR (400 MHz, DMSO) δ 9.09-9.01 (m, 1H), 8.40 (t, J=5.9 Hz, 1H), 7.73-7.64 (m, 1H), 7.53-7.41 (m, 2H), 7.25-7.14 (m, 2H), 4.49 (d, J=5.9 Hz, 2H), 4.15-4.05 (m, 2H), 3.83 (s, 3H), 3.61-3.51 (m, 2H), 3.00 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).

[0798] Preparation of Compound 206

##STR00096##

[0799] Accordingly, compound 206 was prepared in the same way as compound 158 starting from intermediate AM-2 (0.61 mmol) and intermediate R-7 (0.47 mmol) affording a beige powder, 0.07 g (24%).

[0800] .sup.1H NMR (400 MHz, DMSO) δ 9.02 (t, J=5.7 Hz, 1H), 8.92 (d, J=1.7 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.61 (dd, J=9.6, 2.0 Hz, 1H), 7.52-7.16 (m, 4H), 4.51 (d, J=5.7 Hz, 2H), 4.13-4.07 (m, 2H), 3.83 (s, 3H), 3.60-3.55 (m, 2H).

[0801] Preparation of Compound 209

##STR00097##

[0802] Accordingly, compound 209 was prepared in the same way as compound 158 starting from intermediate AQ-2 (0.56 mmol) and intermediate R-7 (0.4 mmol) affording a white powder, 0.142 g (59%).

[0803] .sup.1H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.41 (t, J=5.9 Hz, 1H), 7.80 (s, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.26-7.14 (m, 2H), 4.48 (d, J=5.9 Hz, 2H), 4.15-4.06 (m, 2H), 3.83 (s, 3H), 3.60-3.52 (m, 2H), 2.97 (q, J=7.5 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J=7.5 Hz, 3H).

[0804] Preparation of Compound 210

##STR00098##

[0805] Accordingly, compound 210 was prepared in the same way as compound 158 starting from intermediate AL-2 (0.55 mmol) and intermediate R-7 (0.4 mmol) affording a white solid, 0.161 g (68%).

[0806] .sup.1H NMR (400 MHz, DMSO) δ 8.92 (d, J=1.4 Hz, 1H), 8.60 (t, J=5.9 Hz, 1H), 7.62 (dd, J=10.6, 1.6 Hz, 1H), 7.45 (t, J=8.6 Hz, 1H), 7.26-7.15 (m, 2H), 4.50 (d, J=5.8 Hz, 2H), 4.15-4.06 (m, 2H), 3.83 (s, 3H), 3.61-3.52 (m, 2H), 3.01 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).

[0807] Preparation of Intermediate AA-3

##STR00099##

[0808] Preparation of Intermediate AA-1

[0809] A solution of intermediate R4 (19.6 g, 48.4 mmol) and Trimethylorthoformate (15.9 mL, 145 mmol) in HFIP (490 mL) was stirred at 60° C. for 45 min. The reaction mixture was evaporated. The residue was diluted in DCM and a 10% aq. solution of K.sub.2CO.sub.3 was added. The aqueous layer was extracted twice with DCM/MeOH (95/5). The combined organic layers were dried on MgSO.sub.4, filtered off and evaporated. The crude (m=25.6 g) was purified by preparative LC (regular SiOH 30 μm, 330 g, dry loading (Celite®), mobile phase gradient: from Heptane 75%, EtOAc/MeOH (9:1) 25% to Heptane 25%, EtOAc/MeOH (9:1). Fractions containing product were combined and evaporated to give 14.61 g of intermediate AA-1 as a colorless oil which crystallized on standing (85%).

[0810] Preparation of Intermediate AA-2

[0811] To a solution of intermediate AA-1 (14.6 g, 42.7 mmol) and DIPE (22.1 mL, 128 mmol) in dry DCM (340 mL) at −5° C. (ice/NaCl solid) was added dropwise Tf.sub.2O 1M in DCM (47 mL, 47 mmol) over 15 min using a dropping funnel and stirring was continued for 5 min. The reaction mixture was quenched with a saturated aqueous solution of NaHCO.sub.3. The layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layer was dried over MgSO.sub.4, filtered off and concentrated. The crude (m=36.4 g) was purified by preparative LC (regular SiOH, 30 μm, 120 g, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc 90/10 to 70/30). The fractions containing product were combined and evaporated under vacuum to give 10.18 g of intermediate AA-2 as a white solid (50%).

[0812] Preparation of Intermediate AA-3

[0813] In a steal bomb, a mixture of intermediate AA-2 (10.2 g, 21.5 mmol), Palladium hydroxide 20% on carbon nominally 50% water (3.01 g, 2.15 mmol) and aqueous HCl 3M (7.15 mL, 7.15 mmol) in MeOH (150 mL) and EtOAc (150 mL) was hydrogenated under 5 bar of H.sub.2 at room temperature for 1 h. The mixture was filtered on a pad of Celite® and washed with MeOH. The filtrate was evaporated then co-evaporated with MeOH (twice) to give 7.86 g of intermediate AA-3.

[0814] Synthesis of Compound 163

##STR00100##

[0815] HATU (0.083 g, 0.22 mmol) was added to a solution of 6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS [1131613-58-5], 0.04 g, 0.19 mmol) and DIPEA (0.082 mL, 0.48 mmol) in dry Me-THF (1.28 mL) and DCM (0.43 mL) under N.sub.2. The solution was stirred at room temperature for 15 min. Then intermediate AA-3 (0.083 g, 0.22 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated then the residue was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO.sub.3, water then brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to give a colorless oil. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording a white foam, 0.096 g. It was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. affording compound 163 as white powder, 0.088 g, 86%.

[0816] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.14 (br t, J=5.8 Hz, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 7.32 (t, J=8.5 Hz, 1H), 7.20 (br d, J=13.1 Hz, 1H), 7.16 (br d, J=8.2 Hz, 1H), 4.44 (br d, J=6.0 Hz, 2H), 4.10 (br s, 2H), 3.59-3.68 (m, 2H), 2.88 (q, J=7.5 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J=7.5 Hz, 3H)

##STR00101##

[0817] Accordingly, compound 147 was prepared in the same way as compound 163 starting from 2-(Difluoromethyl)-5H,6H,7H,8H-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [2060043-79-8], 0.19 mmol) and intermediate AA-3 affording a white powder, 0.08 g (77%).

[0818] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.79 (br t, J=5.6 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J=8.6 Hz, 1H), 7.07-7.23 (m, 2H), 6.95 (t, J=54.2 Hz, 1H), 4.41 (br d, J=5.9 Hz, 2H), 4.10 (br s, 2H), 4.02 (br t, J=5.5 Hz, 2H), 3.65 (br t, J=4.6 Hz, 2H), 2.68-2.91 (m, 2H), 1.89 (br d, J=4.3 Hz, 2H), 1.83 (br d, J=5.3 Hz, 2H)

[0819] Synthesis of Compound 159

##STR00102##

[0820] Accordingly, compound 159 was prepared in the same way as compound 163 starting from 2-(Difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [2059954-47-9], 0.19 mmol) and intermediate AA-3 affording a white powder, 0.084 g (82%).

[0821] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.00 (br s, 1H), 8.81 (br d, J=7.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.08-7.59 (m, 7H), 4.52 (br s, 2H), 4.10 (br s, 2H), 3.66 (br t, J=4.5 Hz, 2H)

##STR00103##

[0822] Accordingly, compound 135 was prepared in the same way as compound 163 starting from 2-Chloro-6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS [2089471-58-7], 0.21 mmol) and intermediate AA-3 affording a white powder, 0.056 g (49%).

[0823] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.31 (m, 1H), 8.28 (br t, J=5.8 Hz, 1H), 7.38 (m, 1H), 7.33 (br t, J=8.5 Hz, 1H), 7.21 (br d, J=13.4 Hz, 1H), 7.16 (br d, J=8.2 Hz, 1H), 4.45 (br d, J=5.8 Hz, 2H), 4.10 (br s, 2H), 3.64 (br t, J=4.4 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 1.22 (br t, J=7.5 Hz, 3H)

[0824] Synthesis of Compound 152

##STR00104##

[0825] Accordingly, compound 152 was prepared in the same way as compound 163 starting from 2-(Trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [73221-19-9], 0.92 mmol) and intermediate AA-3 affording a white powder, 0.418 g (82%).

[0826] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.29 (t, J=5.8 Hz, 1H), 8.57 (d, J=6.9 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.56 (ddd, J=9.1, 6.9, 1.1 Hz, 1H), 7.39 (s, 1H), 7.36 (t, J=8.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.18-7.22 (m, 2H), 4.53 (d, J=5.8 Hz, 2H), 4.11 (br t, J=4.3 Hz, 2H), 3.67 (t, J=4.7 Hz, 2H)

##STR00105##

[0827] To a solution of 6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS [874830-60-1], 100 mg, 0.378 mmol) and DIPEA (0.306 mL, 1.80 mmol) in DMF (1.7 mL) was added HATU (164 mg, 0.432 mmol). After 10 min of stirring, intermediate AA-3 (137 mg, 0.360 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The brown paste was purified by preparative LC (regular SiOH 30 μm, 25 g, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc 90/10 to 30/70). The fractions containing product were combined and evaporated to give 216 mg as a yellow solid. It was triturated in Et.sub.2O. The mixture was filtered off. The solid was rinsed with Et.sub.2O, collected and dried under vacuum to give 172 mg as a white solid. It was dissolved in EtOAc and evaporated (3 times) to give 158 mg as a white solid. It was coevaporated with MeCN (3 times) and dried under vacuum to give 143 mg of compound 124 as a white solid (50%).

[0828] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (br s, 1H), 8.75 (m, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.65 (dd, J=9.4, 1.8 Hz, 1H), 7.31-7.41 (m, 2H), 7.15-7.30 (m, 2H), 4.54 (br d, J=4.1 Hz, 2H), 4.10 (br t, J=4.0 Hz, 2H), 3.67 (br t, J=4.6 Hz, 2H)

[0829] Synthesis of Compound 129

##STR00106##

[0830] Accordingly, compound 129 was prepared in the same way as compound 124 starting from 8-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1517795-25-3], 0.6 mmol) and intermediate AA-3 affording 0.136 g (41%) as white powder.

[0831] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (br d, J=6.9 Hz, 1H), 8.59 (br t, J=5.6 Hz, 1H), 7.59 (br d, J=7.5 Hz, 1H), 7.30-7.46 (m, 2H), 7.15-7.29 (m, 2H), 7.01 (br t, J=7.1 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H), 4.10 (br t, J=4.4 Hz, 2H), 3.65 (br t, J=4.9 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 1.27 (br t, J=7.6 Hz, 3H)

[0832] Synthesis of Compound 133

##STR00107##

[0833] Accordingly, compound 133 was prepared in the same way as compound 124 starting from 2-chloro-6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (CAS [2089471-57-6], 0.52 mmol) and intermediate AA-3 affording 0.142 g (51%) as white solid.

[0834] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 8.25 (br t, J=5.9 Hz, 1H), 7.38 (br s, 1H), 7.33 (t, J=8.5 Hz, 1H), 7.14-7.25 (m, 2H), 4.45 (br d, J=5.9 Hz, 2H), 4.10 (br t, J=4.5 Hz, 2H), 3.64 (br t, J=4.8 Hz, 2H), 2.52 (s, 1H)

[0835] Synthesis of Compound 136

##STR00108##

[0836] Accordingly, compound 136 was prepared in the same way as compound 124 starting from 2-Methyl-6-(trifluoromethyl)imidazo[2,1-b]thiazole-5-carboxylic acid (CAS [1369332-25-1], 0.58 mmol) and intermediate AA-3 affording 0.173 g (56%) as white powder.

[0837] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.99 (br t, J=4.3 Hz, 1H), 7.86 (br s, 1H), 7.39, (m, 1H), 7.35 (br t, J=8.5 Hz, 1H), 7.14-7.24 (m, 2H), 4.47 (br d, J=5.5 Hz, 2H), 4.11 (m, 2H), 3.67 (br t, J=4.3 Hz, 2H), 2.48 (br s, 3H)

[0838] Synthesis of Compound 164

##STR00109##

[0839] Accordingly, compound 164 was prepared in the same way as compound 124 starting from 2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1216036-36-0], 0.64 mmol) and intermediate AA-3 affording 0.11 g (33%) as a white solid.

[0840] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.75-8.84 (br s, 1H), 8.37 (t, J=6.0 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.32-7.41 (m, 2H), 7.17-7.28 (m, 3H), 4.50 (br d, J=5.9 Hz, 2H), 4.11 (br t, J=4.2 Hz, 2H), 3.66 (t, J=4.7 Hz, 2H), 2.98 (q, J=7.5 Hz, 2H), 2.31 (s, 3H), 1.37 (t, J=7.5 Hz, 3H)

[0841] Synthesis of Compound 157

##STR00110##

[0842] Accordingly, compound 157 was prepared in the same way as compound 124 starting from intermediate AC-2 (0.78 mmol) and intermediate AA-3 affording 0.106 g (24%) as white powder.

[0843] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (d, J=7.3 Hz, 1H), 8.42-8.53 (m, 1H), 7.80 (d, J=9.7 Hz, 1H), 7.29-7.40 (m, 2H), 7.17-7.28 (m, 2H), 4.50 (d, J=5.9 Hz, 2H), 4.07-4.13 (m, 2H), 3.65 (br t, J=4.6 Hz, 2H), 2.99 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H)

##STR00111##

[0844] Accordingly, compound 154 was prepared in the same way as compound 124 starting from intermediate AD-2 (0.78 mmol) and intermediate AA-3 affording 0.092 g (21%) as white solid.

[0845] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (d, J=7.3 Hz, 1H), 8.42-8.54 (br t, J=5.9 Hz, 1H), 7.80 (d, J=9.8 Hz, 1H), 7.30-7.41 (m, 2H), 7.16-7.28 (m, 2H), 4.50 (br d, J=5.9 Hz, 2H), 4.10 (br t, J=4.9 Hz, 2H), 3.65 (br t, J=4.7 Hz, 2H), 2.99 (br q, J=7.4 Hz, 2H), 1.27 (br t, J=7.5 Hz, 3H)

[0846] Synthesis of Compound 156

##STR00112##

[0847] Accordingly, compound 156 was prepared in the same way as compound 124 starting from 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1368682-64-7], 0.27 mmol) and intermediate AA-3 affording a white solid, 0.096 g (68%).

[0848] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.99-9.12 (m, 1H), 8.41 (br t, J=7.5 Hz, 1H), 7.65-7.77 (m, 1H), 7.44-7.57 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.28 (m, 2H), 4.51 (br t, J=5.9 Hz, 2H), 4.11 (br t, J=4.5 Hz, 2H), 3.66 (t, J=4.6 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 1.28 (br t, J=7.5 Hz, 3H)

##STR00113##

[0849] Accordingly, compound 153 was prepared in the same way as compound 124 starting from 2,6-dimethylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS [1007875-19-5], 0.67 mmol) and intermediate AA-3 affording a white solid, 0.138 g (42%).

[0850] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.11 (t, J=6.0 Hz, 1H), 7.84-7.95 (m, 1H), 7.38 (br s, 1H), 7.32 (br t, J=8.7 Hz, 1H), 7.14-7.23 (m, 2H), 4.45 (d, J=6.0 Hz, 2H), 4.10 (br t, J=4.4 Hz, 2H), 3.64 (br t, J=4.9 Hz, 2H), 2.51 (s, 3H), 2.41 (d, J=1.2 Hz, 3H)

[0851] Synthesis of Compound 146

##STR00114##

[0852] Accordingly, compound 146 was prepared in the same way as compound 124 starting from 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (CAS [2059140-68-8], 0.26 mmol) and intermediate AA-3 affording a white solid, 0.154 g (74%).

[0853] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (d, J=2.7 Hz, 1H), 8.69 (d, J=2.7 Hz, 1H), 8.58 (m, 1H), 7.31-7.40 (m, 2H), 7.18-7.28 (m, 2H), 4.51 (m, 2H), 4.10 (br t, J=4.5 Hz, 2H), 3.65 (br t, J=4.8 Hz, 2H), 3.04 (br q, J=7.5 Hz, 2H), 1.29 (br t, J=7.5 Hz, 3H)

##STR00115##

[0854] Accordingly, compound 175 was prepared in the same way as compound 124 starting from 6-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS [874830-67-8], 0.53 mmol) and intermediate AA-3 affording 0.117 g (53%) as white powder.

[0855] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.32 (dd, J=9.2, 1.6 Hz, 1H), 7.19 (s, 1H), 7.17-7.08 (m, 2H), 6.63 (br s, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.13-4.04 (m, 2H), 3.74-3.65 (m, 2H), 2.41 (s, 3H).

[0856] Synthesis of Compound 125

##STR00116##

[0857] Preparation of Intermediate AE-1

[0858] Accordingly, intermediate AE-1 was prepared in the same way as intermediate AC-1 starting from 2-amino-4-chloropyrimidine (CAS [3993-78-0], 15.4 mmol) affording 0.94 g (26%).

[0859] Preparation of Intermediate AE-2

[0860] Accordingly, intermediate AE-2 was prepared in the same way as intermediate AC-2 starting from intermediate AE-1 (1.25 mmol) affording 0.26 g (92%).

[0861] Preparation of Intermediate AE-3

[0862] A mixture of intermediate AE-2 (175 mg, 0.776 mmol) in thionyl chloride (4.4 mL) was stirred at 60° C. for 20 h. The reaction mixture was evaporated to give 0.288 g as a brown paste. (The purity was calculated to give a quantitative yield).

[0863] Preparation of Compound 125

[0864] A mixture of intermediate AE-3 (288 mg, 0.779 mmol) and intermediate AA-3 (295 mg, 0.779 mmol) and DIPEA (0.331 mL, 1.95 mmol) in dry DCM (4.8 mL) was stirred at room temperature for 10 min. Water was added. The aqueous layer was extracted with DCM (once). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered off and evaporated to give 0.4 g as a brown foam. It was purified by preparative LC (regular SiOH 30 μm, 25 g, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc 90/10 to 50/50). The fraction containing products were combined and evaporated to give 0.229 g of a yellow foam. The yellow foam was sonicated in Et.sub.2O. The precipitate was filtered off to give 146 mg of compound 125 as a white solid (33%).

[0865] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.29 (d, J=7.2 Hz, 1H), 8.53-8.61 (m, 1H), 7.38 (br s, 1H), 7.34 (br t, J=8.7 Hz, 1H), 7.17-7.28 (m, 3H), 4.49 (br d, J=5.9 Hz, 2H), 4.08-4.12 (m, 2H), 3.65 (br t, J=4.9 Hz, 2H), 3.01 (br q, J=7.4 Hz, 2H), 1.27 (br t, J=7.4 Hz, 3H)

##STR00117##

[0866] Preparation of Intermediate AF-1

[0867] Accordingly, intermediate AF-1 was prepared in the same way as intermediate AC-1 starting from 2-amino-5-fluoropyrimidine (CAS [1683-85-8], 17.68 mmol) affording 1.18 g (27%).

[0868] Preparation of Intermediate AF-2

[0869] To a solution of intermediate AF-1 (1.1 g, 4.64 mmol) in EtOH (24 mL) and water (24 mL) was added potassium carbonate (3.2 g, 23.2 mmol) and the mixture was heated at 65° C. and stirred for 3 h. (Alternative conditions re depicted in the scheme above.) The mixture was acidified to pH=1 with HCl 3M (no precipitation occurred) then evaporated in vacuo. The residue was taken up with EtOH/water (1:1), sonicated then filtered off (precipitate only contained K.sub.2CO.sub.3) and the filtrate was concentrated and then coevaporated twice with DCM to give 0.92 g of intermediate AF-2 as a brown solid (95%). The crude was used as such.

[0870] Preparation of Compound 130

[0871] Accordingly, compound 130 was prepared in the same way as compound 124 starting from intermediate AF-2 (0.96 mmol) and intermediate AA-3 affording a white solid, 0.194 g (39%).

[0872] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.39-9.48 (m, 1H), 8.77-8.89 (m, 1H), 8.50-8.59 (m, 1H), 7.17-7.42 (m, 4H), 4.52 (br d, J=4.4 Hz, 2H), 4.07-4.13 (m, 2H), 3.62-3.68 (m, 2H), 3.05 (br q, J=7.2 Hz, 2H), 1.29 (br t, J=7.5 Hz, 3H)

[0873] Synthesis of Compound 131

##STR00118##

[0874] Preparation of Intermediate AG-1

[0875] To a solution of 2H,3H-furo[2,3-c]pyridin-5-amine (CAS [1785357-12-1], 500 mg, 3.67 mmol) in ACN (8.4 mL) were added ethyloxovalerate (1.05 mL, 7.35 mmol) and boron tetrabromide (2.44 g, 7.35 mmol) and the reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO.sub.4, filtered off, concentrated and purified by preparative LC (irregular SiOH, 15-40 μm, 40 g, liquid loading (DCM), mobile phase gradient: from Heptane/EtOAc: 100/0 to 0/100 in 10 CV then EtOAc 100% for 5 CV). The fractions containing product were combined and evaporated to give 0.21 g of intermediate AG-1 (22%).

[0876] Preparation of Intermediate AG-2

[0877] A mixture of intermediate AG-1 (186 mg, 0.715 mmol), aqueous NaOH 3M (1.19 mL, 3.57 mmol) and MeOH (2 mL) was stirred 60° C. for 2 days. The mixture was evaporated to give 0.33 g of intermediate AG-2 (purity was estimated to give a quantitative yield).

[0878] Preparation of Compound 131

[0879] Accordingly, compound 131 was prepared in the same way as compound 124 starting from intermediate AG-2 (0.71 mmol) and intermediate AA-3 affording a white solid, 0.09 g (23%).

[0880] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 8.19-8.32 (m, 1H), 7.47 (s, 1H), 7.38 (br s, 1H), 7.29-7.36 (m, 1H), 7.14-7.25 (m, 2H), 4.61 (t, J=8.2 Hz, 2H), 4.47 (br d, J=5.7 Hz, 2H), 4.09 (br t, J=4.3 Hz, 2H), 3.65 (t, J=4.7 Hz, 2H), 3.25-3.32 (m, 2H), 2.94 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H)

[0881] Synthesis of Compound 134

##STR00119##

[0882] Preparation of Intermediate AH-1

[0883] A solution of 6-bromo-1,3-Dioxolo[4,5-c]-pyridine (CAS [2230730-23-9], 3.87 g, 19.2 mmol) in dry toluene (100 mL) was c with N.sub.2 (3 times). Pd.sub.2(dba).sub.3 (1.75 g, 1.92 mmol) and CyJohnPhos (2.80 g, 7.66 mmol) were added and the reaction mixture was degassed with N.sub.2 (3 times). LiHMDS (1.0M in THF) (23 mL, 23 mmol) was then added dropwise at room temperature and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted in EtOAc, water and acidified with an aqueous solution of HCl (1N). The aqueous layer was extracted with EtOAc (twice). The aqueous layer was then basified with a solution of NaOH (3M) and extracted with EtOAc (3 times). The combined organic layers were dried over MgSO.sub.4, filtered off and evaporated to give 1.84 g of intermediate AH-1 as a brown solid (70%).

[0884] Preparation of Intermediate AH-2

[0885] Accordingly, intermediate AH-2 was prepared in the same way as intermediate AB-1 starting from intermediate AH-1 (3.62 mmol) affording 0.165 g (17%).

[0886] Preparation of Intermediate AH-3

[0887] Accordingly, intermediate AH-3 was prepared in the same way as intermediate AB-2 starting from intermediate AH-2 (0.95 mmol) affording 0.421 g (purity was estimated to give a quantitative yield).

[0888] Preparation of Compound 134

[0889] Accordingly, compound 134 was prepared in the same way as compound 124 starting from intermediate AH-3 (0.45 mmol) and intermediate AA-3 affording a white solid, 0.194 g (84%).

[0890] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (br s, 1H), 8.24 (t, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J=8.6 Hz, 1H), 7.14-7.24 (m, 2H), 7.08 (s, 1H), 6.16 (br s, 2H), 4.47 (br d, J=5.8 Hz, 2H), 4.07-4.12 (m, 2H), 3.65 (br t, J=4.6 Hz, 2H), 2.91 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H)

##STR00120##

[0891] Preparation of Intermediate AI-1 2-amino-5-bromopyrimidine (10.0 g; 57.5 mmol) was suspended in dry 2-MeTHF (250 mL). ethyl 3-oxovalerate (8.2 mL, 57.5 mmol, 1 eq.) and iodobenzene diacetate (18.5 g, 57.5 mmol, 1 eq.) were added. boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) was then added dropwise and the reaction mixture was stirred at 60° C. for 1.5 hours. An extra amount of ethyl ethyl 3-oxovalerate (4.10 mL, 28.7 mmol, 0.5 eq.), iodobenzene diacetate (9.25 g, 28.7 mmol, 0.5 eq.) and boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) were added at room temperature and the mixture was stirred at 60° C. for 1h. The mixture was cooled down to room temperature then EtOAc and water were added. The organic layer was separated and washed with a saturated solution of NaHCO.sub.3 (twice), then with brine (twice). The organic layer was dried over MgSO.sub.4, filtered off and concentrated to give 19.7 g as a brown oil. The crude was purified by preparative LC (irregular SiOH, 15-40 μm, 330 g, dry loading (SiOH), mobile phase gradient: from DCM 100% to DCM 85%, EtOAc 15%) to give intermediate AI-1, 9.03 g as yellow crystals (53%).

[0892] Preparation of Intermediate AI-2

[0893] In a sealed tube under N.sub.2, to a solution of intermediate AI-1 (500 mg, 1.68 mmol) and Pd(PPh.sub.3).sub.4 (96.9 mg, 0.084 mmol) in THE (12 mL) degassed under N2 was added trimethylaluminum 2m in Hexanes (2 eq., 1.68 mL, 3.35 mmol). The mixture was purged again with N2 and was heated at 65° C. for 1 h. An extra amount of trimethylaluminum 2m in Hexanes (1 eq., 0.839 mL, 1.68 mmol) was added and the mixture was stirred at 65° C. for 1 h. The mixture was diluted with DCM, cooled down to 0° C. and 1 mL of water was added carefully. The mixture was stirred at room temperature overnight then MgSO.sub.4 was added. After 30 min under stirring, the mixture was filtered over a plug of Celite® and evaporated to give 412 mg of as an orange gum. The crude was purified by preparative LC (regular SiOH, 30 μm, 40 g, dry loading (Celite®), mobile phase eluent: Heptane 95%, EtOAc 5% to Heptane 50%, EtOAc 50%). Fractions containing product were combined and concentrated to obtain intermediate AI-2, 354 mg of as a yellow gum (90%).

[0894] Preparation of Intermediate AI-3

[0895] To a solution of intermediate AI-2 (120 mg, 0.514 mmol) in water (1 mL) and EtOH (4 mL) was added NaOH (62 mg, 1.55 mmol) and the mixture was stirred at room temperature overnight. The mixture was evaporated then co-evaporated with EtOH to give intermediate AI-3, 190 mg as a yellow solid. The crude was used as such in next step.

[0896] Preparation of Compound 161

[0897] A mixture of intermediate AI-3 (190 mg, 0.518 mmol), HATU (280 mg, 0.736 mmol), DIPEA (0.163 mL, 0.958 mmol) and DMF (2.5 mL) was stirred at room temperature for 15 min then intermediate AA-3 (180 mg, 0.473 mmol) was added and stirring was continued over 3 days. DMF was evaporated. The residue was taken-up in DCM and water then washed with a saturated aqueous solution of NaHCO.sub.3 (twice), brine (twice), dried over MgSO.sub.4, filtered off and concentrated. The crude (m=378 mg) was purified by preparative LC (regular SiOH, 30 μm, 24 g, mobile phase gradient: from Heptane 85%, EtOAc/MeOH (9:1) 15% to Heptane 25%, EtOAc/MeOH (9:1) 75). Fractions containing product were combined and concentrated to afford 277 mg as a white solid. The solid was recrystallized from EtOAc, filtered off and dried under high vacuum to afford 162 mg of compound 161 as a white solid (54%).

[0898] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (d, J=1.2 Hz, 1H), 8.52 (br d, J=2.3 Hz, 1H), 8.44-8.49 (m, 1H), 7.38 (br s, 1H), 7.34 (m, J=8.6 Hz, 1H), 7.17-7.27 (m, 2 H), 4.50 (br d, J=5.9 Hz, 2H), 4.07-4.13 (m, 2H), 3.65 (br t, J=4.6 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.34 (br s, 3H), 1.28 (t, J=7.5 Hz, 3H)

[0899] Synthesis of Compounds 162, 148 & 151

##STR00121##

[0900] Preparation of Intermediate AJ-1

[0901] The reaction was performed in anhydrous conditions under nitrogen atmosphere.

[0902] To a solution of 3-Fluoro-5-methylpyridin-2-amine (2.00 g, 15.9 mmol) in 2-MeTHF (60 mL) at 5° C. under N.sub.2 were added Ethyl propionylacetate (3.60 mL, 24.8 mmol), Iodobenze diacetate (7.80 g, 24.2 mmol) and Boron trifluoride diethyl etherate (200 μL, 1.62 mmol). The reaction was stirred 1 h at 5° C. then at room temperature for 48 h. EtOAc (200 mL) and water (200 mL) were added. The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO.sub.3 (200 mL), brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford 4.92 g as a brown paste. The crude was purified via preparative LC (SiOH, 120 g, 50 ptm, Eluent: Cyclohexane/EtOAc, from 95:05 to 50:5), fractions containing product were collected, evaporated and triturated with pentane (2×20 mL) to afford 1.68 g of intermediate AJ-1 as a white solid (42%).

[0903] Preparation of Intermediate AJ-2

[0904] To a solution of intermediate AJ-1 (500 mg, 2.00 mmol) in water (12.5 mL) and EtOH (12.5 mL) was added NaOH (275 mg, 6.880 mmol). The reaction mixture was stirred for 16 h at 40° C. The crude was washed with DCM (30 mL) and with EtOAc (30 mL), the aqueous phase was acidified with an aqueous solution of HCl (3N) until pH=2. The formed precipitate was recuperated using a sintered glass under vacuum, washed with water (2×2 mL) and dried in a vacuum chamber at 50° C. overnight to afford 415 mg of intermediate AJ-2 as an off-white solid (93%).

[0905] Preparation of Compound 162

[0906] Accordingly, compound 162 was prepared in the same way as compound 161 starting from intermediate AJ-2 (0.36 mmol) and intermediate AA-3 affording 0.113 g (48%) as white solid.

[0907] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (br s, 1H), 8.53 (br t, J=5.9 Hz, 1H), 7.31-7.40 (m, 2H), 7.17-7.27 (m, 3H), 4.50 (d, J=5.9 Hz, 2H), 4.10 (br t, J=4.5 Hz, 2H), 3.65 (br t, J=4.5 Hz, 2H), 2.98 (q, J=7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J=7.5 Hz, 3H)

[0908] Preparation of Intermediate AK-1

[0909] Accordingly, intermediate AK-1 was prepared in the same way as intermediate AJ-1 starting from 2-Amino-3,5-difluoropyridine (CAS [732306-31-9], 15.37 mmol) affording 0.89 g (23%) as white solid.

[0910] Preparation of Intermediate AK-2

[0911] Accordingly, intermediate AK-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AK-1 (1.97 mmol) giving 0.345 g (78%).

[0912] Preparation of Compound 148

[0913] Accordingly, compound 148 was prepared in the same way as compound 161 starting from intermediate AK-2 (0.35 mmol) and intermediate AA-3 affording 0.189 g (82%) as white solid.

[0914] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.92 (dd, J=4.7, 1.8 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H), 7.64-7.74 (m, 1H), 7.38 (br s, 1H), 7.35 (t, J=8.5 Hz, 1H), 7.18-7.27 (m, 2H), 4.50 (d, J=5.9 Hz, 2H), 4.10 (br t, J=4.7 Hz, 2H), 3.65 (t, J=4.9 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H)

[0915] Preparation of Intermediate AL-1

[0916] Accordingly, intermediate AL-1 was prepared in the same way as intermediate AJ-1 starting from 2-Amino-5-chloro-3-fluoropyridine (CAS [20712-16-7], 17.06 mmol) affording 0.52 g (11%) as white solid.

[0917] Preparation of Intermediate AL-2

[0918] Accordingly, intermediate AL-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AL-1 (1.77 mmol) giving 0.26 g (60%).

[0919] Preparation of Compound 151

[0920] Accordingly, compound 151 was prepared in the same way as compound 161 starting from intermediate AL-2 (0.43 mmol) and intermediate AA-3 affording 0.104 g (38%) as white solid.

[0921] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (d, J=1.0 Hz, 1H), 8.58-8.67 (m, 1H), 7.63 (dd, J=10.6, 1.4 Hz, 1H), 7.31-7.40 (m, 2H), 7.17-7.28 (m, 2H), 4.51 (br d, J=5.6 Hz, 2H), 4.07-4.13 (m, 2H), 3.65 (t, J=4.6 Hz, 2H), 3.01 (q, J=7.4 Hz, 2H), 1.27 (t, J=7.4 Hz, 3H)

[0922] Synthesis of Compounds 145 & 144

##STR00122##

[0923] Preparation of Intermediate AM-1

[0924] Accordingly, intermediate AM-1 was prepared in the same way as AJ-1 starting from 2-amino-5-chloropyridine (CAS [1072-98-6], 3.89 mmol) and Ethyl 4,4-difluoro-3-oxobutyrate (CAS [352-24-9]) giving 0.248 g (23%) as white solid.

[0925] Preparation of Intermediate AM-2

[0926] Accordingly, intermediate AM-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AM-1 (0.73 mmol) giving 0.175 g (96%).

[0927] Preparation of Compound 145

[0928] Accordingly, compound 145 was prepared in the same way as compound 161 starting from intermediate AM-2 (0.39 mmol) and intermediate AA-3 affording 0.164 g (64%) as white solid.

[0929] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 8.88-8.96 (m, 1H), 7.83 (dd, J=9.6, 1 Hz, 1H), 7.61 (dd, J=9.6, 2.1 Hz, 1H), 7.46-7.47 (m, 1H), 7.33-7.40 (m, 2H), 7.19-7.30 (m, 2H), 4.51-4.54 (m, 2H), 4.08-4.12 (m, 2H), 3.66 (br t, J=4.9 Hz, 2H)

[0930] Preparation of Intermediate AN-1

[0931] Accordingly, intermediate AN-1 was prepared in the same way as AJ-1 starting from 5-Chloro-4-fluoropyridin-2-amine (CAS [1393574-54-3], 6.82 mmol) and Ethyl 4,4-difluoro-3-oxobutyrate (CAS [352-24-9]) giving 0.57 g (28%) as white solid.

[0932] Preparation of Intermediate AN-2

[0933] Accordingly, intermediate AN-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AN-1 (0.85 mmol) giving 0.145 g (64%).

[0934] Preparation of Compound 144

[0935] Accordingly, compound 144 was prepared in the same way as compound 161 starting from intermediate AM-2 (0.41 mmol) and intermediate AA-3 affording 0.204 g (72%) as white solid.

[0936] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J=7.2 Hz, 1H), 9.03-9.07 (m, 1H), 7.98 (d, J=9.6 Hz 1H), 7.20-7.40 (m, 4H), 4.52 (br d, J=4.6 Hz, 2H), 4.09-4.13 (m, 2H), 3.65-3.68 (m, 2H), 2.53 (br s, 1H)

[0937] Synthesis of Compound 138, 139 & 140 and Compound 143

##STR00123## ##STR00124##

[0938] Preparation of Intermediate AO-1

[0939] Accordingly, intermediate AO-1 was prepared in the same way as AJ-1 starting from 4-bromo-5-methylpyridin-2-amine (CAS [1033203-32-5], 5.35 mmol) and ethyl 3-oxovalerate (CAS [4949-44-4]) giving 0.88 g (50%) as white solid.

[0940] Preparation of Intermediate AO-2

[0941] Accordingly, intermediate AO-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AO-1 (0.48 mmol) giving 0.205 g (78%).

[0942] Preparation of intermediate AO-3

[0943] Accordingly, intermediate AO-3 was prepared in the same way as compound 161 starting from intermediate AO-2 (0.49 mmol) and intermediate AA-3 affording 0.27 g (71%) as white solid.

[0944] Preparation of Compound 138

[0945] A mixture of intermediate AO-3 (210 mg, 0.347 mmol), benzophenone imine (116 μL, 0.694 mmol), cesium carbonate (226 mg, 0.694 mmol) and 1,4-dioxane (1.75 mL) was purged with N.sub.2, Pd(OAc).sub.2 (3.9 mg, 0.017 mmol) and BINAP (21.6 mg, 0.0347 mmol) were added. The mixture was purged with N.sub.2 and stirred at 100° C. for 18 h. The mixture was filtered over a pad of Celite® and the cake was washed with EtOAc. The organic layer was concentrated then the residue was stirred in 1,4-dioxane (2.5 ml) and aqueous HCl 1M (2.5 mL) at room temperature for 16 h. The mixture was diluted with EtOAc and slowly quenched with a saturated aqueous solution of NaHCO.sub.3. The layers were separated, and the aqueous layer was extracted with EtOAc (twice). The organic layers were combined, dried over MgSO.sub.4, filtered off and evaporated. The residue was purified by preparative LC (regular SiOH, 30 μm, 24 g, mobile phase eluent: from Heptane 90%, EtOAc/MeOH/aq. NH.sub.3 (90:9.5:0.5) 10% to Heptane 20%, EtOAc/MeOH/aq. NH.sub.3 (90:9.5:0.5) 80%). Fractions containing product were combined and concentrated to obtain 0.125 g as a white solid. This solid was recrystallized from EtOAc, filtered off and dried under high vacuum to obtain 97 mg of compound 138 as a white solid (52%).

[0946] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.70 (m, 1H), 7.89 (t, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J=8.5 Hz, 1H), 7.14-7.22 (m, 2H), 6.46-6.47 (m, 1H), 5.69-5.72 (m, 2H), 4.44 (br d, J=5.8 Hz, 2H), 4.10 (br t, J=4.3 Hz, 2H), 3.64 (t, J=4.6 Hz, 2H), 2.87 (q, J=7.5 Hz, 2H), 2.08 (s, 3H), 1.21 (t, J=7.5 Hz, 3H)

[0947] Preparation of Intermediate AP-1

[0948] Accordingly, intermediate AP-1 was prepared in the same way as AJ-1 starting from 4,5-dimethylpyridin-2-amine (CAS [57963-11-8], 4.09 mmol) and ethyl 3-oxovalerate (CAS [4949-44-4]) giving 0.73 g (72%) as white solid.

[0949] Preparation of Intermediate AP-2

[0950] Accordingly, intermediate AP-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AP-1 (0.81 mmol) giving 0.3 g (quantitative).

[0951] Preparation of Compound 139

[0952] Accordingly, compound 139 was prepared in the same way as compound 161 starting from intermediate AP-2 (0.49 mmol) and intermediate AA-3 affording 0.142 g (58%) as white solid.

[0953] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.78 (br s, 1H), 8.24 (t, J=5.9 Hz, 1H), 7.38 (s, 2H), 7.34 (t, J=8.5 Hz, 1H), 7.16-7.25 (m, 2H), 4.48 (d, J=5.9 Hz, 2H), 4.10 (br t, J=4.7 Hz, 2H), 3.65 (t, J=4.5 Hz, 2H), 2.95 (q, J=7.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 1.25 (t, J=7.5 Hz, 3H)

[0954] Preparation of Intermediate AQ-1

[0955] Accordingly, intermediate AQ-1 was prepared in the same way as AJ-1 starting from 4-chloro-5-methylpyridin-2-amine (CAS [1033203-31-4], 7.01 mmol) and ethyl 3-oxovalerate (CAS [4949-44-4]) giving 0.39 g (20%) as white solid.

[0956] Preparation of Intermediate AQ-2

[0957] Accordingly, intermediate AQ-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AQ-1 (0.45 mmol) giving 0.15 g (quantitative).

[0958] Preparation of Compound 140

[0959] Accordingly, compound 140 was prepared in the same way as compound 161 starting from intermediate AQ-2 (0.45 mmol) and intermediate AA-3 affording 0.23 g (68%) as white powder.

[0960] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.45 (br t, J=5.9 Hz, 1H), 7.81 (br s, 1H), 7.38 (br s, 1H), 7.34 (t, J=8.5 Hz, 1H), 7.17-7.26 (m, 2H), 4.50 (d, J=5.9 Hz, 2H), 4.10 (br t, J=4.4 Hz, 2H), 3.65 (t, J=4.7 Hz, 2H), 2.97 (q, J=7.3 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J=7.4 Hz, 3H)

[0961] Preparation of Intermediate AR-1

[0962] Accordingly, intermediate AR-1 was prepared in the same way as AJ-1 starting from 4-bromo-5-chloropyridin-2-amine (CAS [1187449-01-9], 9.64 mmol) and ethyl 3-oxovalerate (CAS [4949-44-4]) giving 0.655 g (21%).

[0963] Preparation of Intermediate AR-2

[0964] Accordingly, intermediate AR-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AR-1 (2.05 mmol) giving 0.94 g (quantitative).

[0965] Preparation of Intermediate AR-3

[0966] Accordingly, intermediate AR-3 was prepared in the same way as compound 161 starting from intermediate AR-2 (2.06 mmol) and intermediate AA-3 affording 0.42 g (33%) as an off-white solid.

[0967] Preparation of Compound 143

[0968] Accordingly, compound 143 was prepared in the same way as compound 138 starting from intermediate AR-3 (0.4 mmol) giving 0.08 g (33%) as white solid.

[0969] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.01 (t, J=5.7 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J=8.6 Hz, 1H), 7.15-7.24 (m, 2H), 6.63 (br s, 1H), 6.12 (br s, 2H), 4.45 (d, J=5.9 Hz, 2H), 4.07-4.12 (m, 2H), 3.64 (t, J=4.5 Hz, 2H), 2.90 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H)

##STR00125##

[0970] Preparation of Intermediate AS-1

[0971] To a solution of 4,5-dichloropyrimidin-2-amine (CAS [403854-21-7], 12.5 g, 76.2 mmol) in Me-THF (315 mL) at 0° C. were added iodobenzene diacetate (73.7 g, 229 mmol) and ethyl 3-oxovalerate (16.5 mL, 116 mmol). Then boron trifluoride etherate (1.92 mL, 15.2 mmol) was added dropwise. The mixture was stirred at 5° C. for 1 h and then at room temperature for 16 h. Extra boron trifluoride etherate (1.92 mL, 15.2 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 28 h. EtOAc and water were added. The organic layer was washed with brine, dried over MgSO.sub.4 and evaporated to give a brown oil. The oil was purified by preparative LC (irregular SiOH, 15-40 μm, 330 g, gradient: Heptane 100% to heptane/EtOAc 75/25). The fractions containing product were combined and evaporated to give a yellow mixture which was triturated in pentane. The supernatant was removed by pipette and the residue was dried under vacuum to give 1.16 g of intermediate AS-1 as a white solid (5%). The supernatant was evaporated to give a yellow mixture. The supernatant was removed by pipette to give 5.02 g of intermediate AS-1 as a yellow paste (32%).

[0972] Preparation of Intermediate AS-2

[0973] A mixture of intermediate AS-1 (5.02 g, 5.58 mmol, purity 32%), 4-methoxybenzylamine (CAS [2393-23-9], 2.19 mL, 16.7 mmol) and 1,4-dioxane (16 mL) was stirred at 100° C. for 1 h. The mixture was evaporated and purified by preparative LC (irregular SiOH, 15-40 μm, 120 g, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc: 70/30 to 30/70). The fractions containing product were combined and evaporated to give 1.6 g of intermediate AS-2 (74%).

[0974] Preparation of Intermediate AS-3

[0975] A mixture of intermediate AS-2 (0.900 g, 2.31 mmol), NaOH (278 mg, 6.94 mmol) and MeOH (9.2 mL) was stirred at 60° C. for 40 h. The mixture was evaporated to give 1.05 g of intermediate AS-3 (quantitative).

[0976] Preparation of Intermediate AS-4

[0977] A mixture of intermediate AS-3 (1.05 g, 2.30 mmol, purity 84%), EDCI.HCl (0.8783 g, 4.61 mmol), HOBT.H.sub.2O (0.706 mg, 4.61 mmol), DIPEA (1.19 ml, 6.91 mmol) and DMF (35 mL) was stirred at 50° C. for 30 min. Intermediate AA-3 (865 mg, 2.42 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO.sub.4, filtered off, concentrated and purified by preparative LC (irregular SiOH, 15-40 μm, 120 g, mobile phase gradient: from heptane/EtOAc 50/50 to 0/100). The fractions containing product were combined and evaporated to give 560 mg of intermediate AS-4 (36%).

[0978] Preparation of Compound 126

[0979] A mixture of intermediate AS-4 (560 mg, 0.820 mmol), TFA (4.5 mL) and DCE (4.5 mL) was stirred at 80° C. for 20 h. The mixture was evaporated and purified by preparative LC (spherical C18 25 μm, 120 g YMC-ODS-25, liquid loading (DMSO), mobile phase gradient 0.2% aq. NH.sub.4.sup.−HCO.sub.3.sup.−/MeCN from 75:25 to 20:80). The fractions containing product were evaporated to give 204 mg as white solid. and 350 mg of impure desired product. This second fraction was purified by preparative LC (spherical C18 25 μm, 120 g YMC-ODS-25, liquid loading (DMSO), mobile phase gradient 0.2% aq. NH.sub.4.sup.+HCO.sub.3.sup.−/MeCN from 75:25 to 20:80). The fractions containing product were evaporated to give 65 mg as white solid. Fractions of pure compounds were solubilized with EtOAc at reflux. The mixture was slowly cooled to room temperature with a slow stirring. The precipitate was filtered to give 0.355 g of compound 126 as a white solid (93%).

[0980] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.06 (s, 1H), 8.12 (t, J=6.0 Hz, 1H), 6.99-7.64 (m, 6H), 4.45 (d, J=6.0 Hz, 2H), 4.09 (br d, J=5.2 Hz, 2H), 3.64 (t, J=4.7 Hz, 2H), 2.87 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H)

[0981] Synthesis of Compound 155

##STR00126##

[0982] Preparation of Intermediate AT-1

[0983] Accordingly, intermediate AT-1 was prepared in the same way as AJ-1 starting from 5-chloro-4-methylpyrimidin-2-amine (CAS [40439-76-7], 6.96 mmol) and ethyl 3-oxovalerate (CAS [4949-44-4]) giving 0.37 g (20%) as white solid.

[0984] Preparation of Intermediate AT-2

[0985] Accordingly, intermediate AT-2 was prepared in the same way as intermediate AJ-2 starting from intermediate AT-1 (0.37 mmol) giving 0.165 g (quantitative).

[0986] Preparation of Compound 155

[0987] Accordingly, compound 155 was prepared in the same way as compound 161 starting from intermediate AT-2 (0.38 mmol) and intermediate AA-3 affording 0.055 g (26%) as white powder.

[0988] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.35 (br s, 1H), 8.48 (t, J=6.1 Hz, 1H), 7.30-7.40 (m, 2H), 7.16-7.28 (m, 2H), 4.50 (br d, J=5.6 Hz, 2H), 4.06-4.13 (m, 2H), 3.65 (br t, J=4.5 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.62 (s, 3H), 1.27 (t, J=7.5 Hz, 3H)

[0989] Synthesis of Compound 150

##STR00127##

[0990] HATU (0.097 g, 0.26 mmol) was added to a solution of 2-(Trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [73221-19-9], 0.051 g, 0.22 mmol) and DIPEA (0.096 mL, 0.56 mmol) in dry Me-THF (1.5 mL) and DCM (0.5 mL) under N.sub.2. The solution was stirred at room temperature for 15 min. Then intermediate N3 (0.095 g, 0.24 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated then the residue was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO.sub.3, water then brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to give a yellow oil, 0.314 g. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording 0.119 g as white foam. It was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. affording compound 150 as white powder, 0.103 g (82%).

[0991] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.21 (br t, J=5.3 Hz, 1H), 8.53 (br d, J=6.7 Hz, 1H), 7.79 (br d, J=9.0 Hz, 1H), 7.55 (br t, J=7.8 Hz, 1H), 7.29 (br d, J=8.4 Hz, 2H), 7.13-7.22 (m, 3H), 4.47 (br d, J=5.5 Hz, 2H), 4.07-4.15 (m, 2H), 3.86 (s, 3H), 3.76 (br t, J=4.6 Hz, 2H)

##STR00128##

[0992] Accordingly, compound 88 was prepared in the same way as compound 150 starting from 2-(Difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [2059954-47-9], 0.23 mmol) and intermediate N3 affording a white powder, 0.104 g (86%).

[0993] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.94 (br t, J=5.1 Hz, 1H), 8.79 (d, J=7.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.19-7.43 (m, 3H), 7.14-7.19 (m, 3H), 4.47 (br d, J=5.2 Hz, 2H), 4.07-4.14 (m, 2H), 3.85 (s, 3H), 3.71-3.79 (m, 2H)

[0994] Preparation of Compound 200

##STR00129##

[0995] Accordingly, compound 200 was prepared in the same way as compound 150 starting from intermediate AI-3 (0.64 mmol) and intermediate N3 (0.51 mmol) affording a white powder, 0.085 g (31%).

[0996] .sup.1H NMR (400 MHz, DMSO) δ 9.15-9.11 (m, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.41 (t, J=5.9 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 4.45 (d, J=5.8 Hz, 2H), 4.15-4.06 (m, 2H), 3.85 (s, 3H), 3.76-3.70 (m, 2H), 2.98 (q, J=7.5 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J=7.5 Hz, 3H).

[0997] Synthesis of Compound 169 & Compound 180

##STR00130##

[0998] Preparation of Intermediate AU-1

[0999] In a screw top vial, a mixture of Ethyl propionylacetate (0.105 g, 0.73 mmol), 5H,6H,8H-pyrano[3,4-d]pyrimidin-2-amine (CAS [1781072-41-0], 0.11 g, 0.73 mmol), Potassium hydrogen carbonate (0.08 g, 0.8 mmol) and Bromotrichloromethane (0.143 mL, 1.45 mmol) in Acetonitrile (12 mL) at room temperature was stirred at 80° C. for 16 hours. Additional Ethyl propionylacetate (0.105 g, 0.73 mmol), Potassium hydrogen carbonate (0.08 g, 0.8 mmol) and Bromotrichloromethane (0.143 mL, 1.45 mmol) were added to the mixture and it was stirred at 80° C. for 24 hours. Then, the mixture was diluted with EtOAc and washed with sat. NaHCO.sub.3 aq. solution (3 x). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (12 g, EtOAc/Heptane from 0/100 to 100/0). The desired fractions were collected, and the solvent evaporated in vacuo to give intermediate AU-1 as a yellow sticky solid (0.084 g, 42%).

[1000] Preparation of Intermediate AU-2

[1001] In a screw top vial, Potassium carbonate 15% aqueous solution (0.8 mmol, 0.87 mmol) was added over a solution of intermediate AU-1 in EtOH (4 mL) at room temperature. The reaction mixture was heated at 75° C. and stirred for 36h. Then, HCl 2M aq. solution was added until pH 3, and the solvent was evaporated in vacuo to yield intermediate AU-2 as an orange solid, that was used in the next step without further purification (0.18 g, quantitative)/

[1002] Preparation of Compound 169

[1003] Accordingly, compound 169 was prepared in the same way as compound 161 starting from intermediate AU-2 (0.41 mmol) and intermediate AA-3 affording 0.051 g (28%) as white powder.

[1004] 1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 7.44 (t, J=8.5 Hz, 1H), 7.19 (s, 1H), 7.16-7.05 (m, 2H), 6.18 (br t, J=5.6 Hz, 1H), 4.84 (s, 2H), 4.64 (d, J=5.8 Hz, 2H), 4.13-4.05 (m, 2H), 4.02 (t, J=5.7 Hz, 2H), 3.71-3.63 (m, 2H), 3.05-2.89 (m, 4H), 1.45 (t, J=7.5 Hz, 3H).

[1005] Preparation of Compound 180

[1006] Accordingly, compound 180 was prepared in the same way as compound 161 starting from intermediate AU-2 (0.081 mmol) and intermediate R-7 affording 0.012 g (30%) as white powder.

[1007] .sup.1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 7.46 (t, J=8.6 Hz, 1H), 7.10 (m, 2H), 6.17 (br t, J=5.5 Hz, 1H), 4.84 (s, 2H), 4.63 (d, J=5.8 Hz, 2H), 4.15-4.05 (m, 2H), 4.02 (t, J=5.7 Hz, 2H), 3.89 (s, 3H), 3.65-3.55 (m, 2H), 3.07-2.92 (m, 4H), 1.45 (t, J=7.5 Hz, 3H).

[1008] Synthesis of Compound 177

##STR00131## ##STR00132##

[1009] Preparation of Intermediate AV-1

[1010] The reaction was divided in two batches of 1.5 g each one.

[1011] 2,4-Dimethoxybenzylamine (CAS [20781-20-8], 2.97 mL, 19.76 mmol) was added dropwise to a solution of 2,4-Dichloro-5-fluoropyrimidine (CAS [2927-71-1], 3 g, 17.97 mmol) and triethylamine (3 mL, 21.5 mmol) in THF dry in a round bottom flask under nitrogen at 0° C. The reaction mixture was allowed to warm to room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc. The organic layer was separated, dried with MgSO.sub.4, filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography over silica gel (80 g, ethyl acetate in heptane from 100/0 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate AV-1 as a beige solid, 4.8 g (85%).

[1012] Preparation of Intermediate AV-2

[1013] The reaction was divided in two batches of 2.4 g each one.

[1014] Tris(dibenzylideneacetone)dipalladium (0) (0.7 g, 0.77 mmol) and XPhos (0.73 g, 1.53 mmol) were added to a solution of AV-1 (4.32 g, 15.32 mmol) in dry dioxane (31 mL) while nitrogen was bubbling in a glass pressure bottle. Then lithium bis(trimethylsilyl)amide solution, 1M in THE (33.7 mL, 33.7 mmol) was added dropwise and the resulting solution was heated at 80° C. for 3 h.

[1015] Tris(dibenzylideneacetone)dipalladium(O) (0.7 g, 0.77 mmol), XPhos (0.73 g, 1.53 mmol) and lithium bis(trimethylsilyl)amide solution, 1M in THE (33.7 mL, 33.7 mmol) were added while nitrogen was bubbling and the reaction mixture was heated at 80° C. for 16 h. The reaction was acidified with HCl 1N solution and stirred for 30 min. Then the result was extracted with EtOAc. The aqueous layer was neutralized with 1N NaOH solution and extracted with DCM. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvents were evaporated in vacuo to yield intermediate AV-2 as a brown solid, 3.4 g (76%).

[1016] Preparation of Intermediate AV-3

[1017] The reaction was set up in 2 batches with the same quantity of reactive AV-2.

[1018] Potassium bicarbonate (0.6 g, 6.04 mmol) and Ethyl propionylacetate (0.89 mL, 6.04 mmol) were added to a solution of AV-2 (1.12 g, 4.02 mmol) in ACN (8.1 mL) in a screw top vial at rt. Then, Bromotricloromethane (1.19 mL, 12.07 mmol) was added at room temperature and the mixture was stirred at 80° C. for 16h. The batches were mixed to be worked out together. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude was purified by flash chromatography column over silica gel (25 g; EtOAc in Heptane 0/100 to 35/65). The desired fractions were collected and concentrated in vacuo to yield intermediate AV-3 as a yellow foam solid, 0.42 g (22%).

[1019] Preparation of Intermediate AV-4

[1020] TFA (9.64 mL, 128.43 mmol) was added to AV-3 (1.06 g, 2.37 mmol) in a round bottom flask at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was neutralized with sat. aqueous NaHCO.sub.3 solution and extracted with DCM. The organic layer was washed with water and concentrated in vacuo. The result was triturated with DIPE and the solid was filtered to yield intermediate AV-4 as a beige solid, 0.6 g (95%).

[1021] Preparation of Intermediate AV-5

[1022] Isoamylnitrite (CAS [110-46-3], 0.46 mL, 3.38 mmol) and copper (II) chloride (0.318 g, 2.36 mmol) were added to a suspension of AV-4 (0.6 g, 2.25 mmol) in dry ACN (36 mL) in a round bottom flask at room temperature. The mixture was stirred at reflux for 3 h. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvents were evaporated in vacuo. The crude was purified by flash chromatography column over silica gel (12 g; EtOAc in Heptane 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield intermediate AV-5 as a white solid, 0.315 g (51%).

[1023] Preparation of Intermediate AV-6

[1024] Iron (III) acetylacetonate (0.051 g, 0.14 mmol) was added to a solution of AV-5 (0.39 g, 1.41 mmol) in dry THE (8 mL) and NMP (0.7 mL) in a round bottom flask under nitrogen at 0° C. Then methylmagnesium bromide solution 3.0 M in diethyl ether (0.71 mL, 2.12 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for 30 min. TLC showed complete conversion. The reaction was quenched with saturated aqueous NH.sub.4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO.sub.4, filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography over silica gel (12 g; EtOAc in heptane 0/100 to 15/75). The desired fractions were collected and concentrated in vacuo to yield a white solid, intermediate AV-6, 0.325 g (91%).

[1025] Preparation of Intermediate AV-7

[1026] 15% aqueous potassium carbonate (0.88 mL, 0.96 mmol) was added to a solution of AV-6 (0.152 g, 0.6 mmol) in EtOH (2 mL) in a screw top vial at room temperature. The mixture was stirred at 90° C. for 18 h. 15% aqueous potassium carbonate (0.88 mL, 0.96 mmol) was added to a reaction mixture. The mixture was stirred at 90° C. for 2 h. Then, 1M aqueous HCl solution was added until pH 7. The mixture was concentrated in vacuo to yield intermediate AV-7 as a white solid (0.188 g, quantitative).

[1027] Preparation of Compound 177

[1028] Intermediate AA-3 (0.158 g, 0.4 mmol) was added to a solution of AV-7 (0.187 g, 0.6 mmol), HATU (0.198 g, 0.52 mmol), and DIPEA (0.42 mL, 2.4 mmol) in dry DMF (5 mL) in a round bottom flask at room temperature. The mixture was stirred at room temperature for 1 h. Saturated aqueous NaHCO.sub.3 solution was added and the mixture was extracted with EtOAc (×3). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography over silica gel (12 g; (DCM/MeOH 9:1) in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo. The result was triturated with DIPE and the solid was filtered to yield compound 177 as a beige solid, 0.092 g (41%).

[1029] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (d, J=5.5 Hz, 1H), 8.44 (br t, J=5.9 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J=8.6 Hz, 1H), 7.25 (br d, J=13.2 Hz, 1H), 7.20 (br d, J=8.3 Hz, 1H), 4.50 (d, J=5.8 Hz, 2H), 4.17-4.02 (m, 2H), 3.72-3.58 (m, 2H), 3.02 (q, J=7.5 Hz, 2H), 2.56 (d, J=2.7 Hz, 3H), 1.28 (t, J=7.5 Hz, 3H).

[1030] Synthesis of Compound 142 and Compound 181

##STR00133## ##STR00134##

[1031] Preparation of Intermediate AW-1

[1032] A solution of 6-chloro-5-fluoronicotinonitrile (CAS [1020253-14-8], 13.57 g, 86.68 mmol), n-boc-1,2-diaminoethane (CAS [57260-73-8], 17.8 mL, 113 mmol) and Et.sub.3N (48.2 mL, 347 mmol) in dry DMSO (155 mL) was stirred at 120° C. for 16 h. EtOAc and water were added to the reaction mixture. The layers were separated, and the organic layer was washed with brine (5 times), dried over MgSO.sub.4, filtered off and evaporated to give an orange solid. The solid was purified by preparative LC (regular SiOH 30 μm, 330 g, liquid loading (DCM), mobile phase gradient: Heptane/EtOAc 95/5 to Heptane/EtOAc 40/60). The fractions containing product were combined and evaporated to give 22.55 g of intermediate AW-1 as a yellow solid (93% yield).

[1033] Preparation of Intermediate AW-2

[1034] To a solution of AW-1 (3.2 g, 11.42 mmol) in NH.sub.3 (7M in MeOH) (179 mL), purged with nitrogen, was added Raney Nickel (5.3 g, 91.3 mmol) then the reaction mixture was hydrogenated under atmospheric pressure at room temperature for 16 hours. The mixture was filtered through a pad of Celite® and the Celite® was rinsed with MeOH and the filtrate was concentrated in vacuo. The residue was diluted in DCM, MgSO.sub.4 was added. The mixture was filtered through a pad of Celite®, the Celite® was washed with DCM and the filtrate was evaporated in vacuo to give of mmotte_8598_1, 3.18 g, as colourless oil (96%).

[1035] Preparation of Intermediate AW-3

[1036] A round-bottom flask was charged with a solution of AW-2 (3.18 g, 10.96 mmol), DIPEA (2.17 mL, 12.6 mmol) and DMAP (0.04 g, 0.33 mmol) in dry DCM (68.2 mL). The reaction mixture was connected to a nitrogen flow then cooled down to 0° C. Benzylchloroformate (1.72 mL, 12.06 mmol) was added dropwise. The reaction mixture was then stirred at 0° C. for 1h. The reaction mixture was quenched by addition of water and stirred for 10 minutes at room temperature. The aqueous layer was extracted with DCM (twice). The combined organic layer was dried over MgSO.sub.4, filtered off and evaporated to give 5.38 g as crude. Purification was carried out by flash chromatography over silica gel (120 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording intermediate AW-3 as pale beige solid, 3.54 g (77%).

[1037] Preparation of Intermediate AW-4

[1038] AW-3 (3.54 g, 8.46 mmol) was solubilized at 40° C. in Me-THF (65 mL) and AcOH (4.84 mL, 84.59 mmol). Then isoamylnitrite (5.68 mL, 42.3 mmol) was added dropwise and the mixture was stirred at 40° C. for 2 hours. The solution was diluted in EtOAc (60 mL) and water (30 mL), washed with a saturated solution of NaHCO.sub.3 (twice), brine, dried on MgSO.sub.4 and evaporated to give 4.67 g as pale-yellow oil. Purification was carried out by flash chromatography over silica gel (80 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording intermediate AW-4 as a yellow oil, 3.99 g (97% with 92% purity, used as such for next step).

[1039] Preparation of Intermediate AW-5

[1040] Zinc, dust (4.29 g, 65.63 mmol) was added to a solution of AW-4 (3.99 g, 8.2 mmol) and AcOH (7 mL, 123.05 mmol) in EtOH (170.9 mL) and water (42.7 mL) at room temperature. The mixture was stirred at room temperature for 1.5 hour. Water was added, the aqueous layer was extracted 3 times with DCM, the combined organic layers were dried over MgSO.sub.4 and concentrated under reduced pressure giving a colourless oil, 4.12 g. Purification was carried out by flash chromatography over silica gel (80 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording intermediate AW-5, 1.88 g as colourless oil (50%).

[1041] Preparation of Intermediate AW-6

[1042] To a solution of AW-5 (1.88 g, 4.08 mmol) in MeOH (40.2 mL) was added dropwise TMSCl (4.14 mL, 32.61 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give intermediate AW-6, 1.45 g (80%), used as such for next step.

[1043] Preparation of Intermediate AW-7

[1044] A solution of AW-6 (1.45 g, 3.21 mmol) and B (1.41 mL, 12.85 mmol) in C (32.4 mL) was stirred at 70° C. overnight. The reaction mixture was evaporated. The residue was diluted in DCM and a 10% aq. solution of K.sub.2CO.sub.3. The aqueous layer was extracted twice with DCM/MeOH (95/5). The combined organic layers were dried on MgSO.sub.4, filtered off and evaporated to give a yellow solid. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 90/10). Pure fractions were collected and evaporated affording intermediate AW-7 as colorless oil, 0.58 g, used as such for next step.

[1045] Preparation of Intermediate AW-8

[1046] To a solution of AW-7 (0.58 g, 1.69 mmol) and DIPEA (0.87 mL, 5.07 mmol) in dry DCM (14.6 mL), cooled at 5° C. in an ice bath, was added dropwise Tf.sub.2O 1M in DCM (1.69 mL, 1.69 mmol). The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was immediately quenched with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with DCM (twice). The combined organic layer was washed with brine (once), dried over MgSO.sub.4, filtered off and evaporated. Purification was carried out by flash chromatography over silica gel (24 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording intermediate AW-8, as pale-yellow oil which crystalized on standing, 0.59 g (73%).

[1047] Preparation of Intermediate AW-9

[1048] In a steal bomb, a mixture of AW-8 (0.59 g, 1.24 mmol), palladium hydroxide 20% on carbon nominally 50% water (0.17 g, 0.12 mmol) and aqueous HCl 3M (0.41 mL, 1.24 mmol) in MeOH (8.7 mL) and EtOAc (8.7 mL) was hydrogenated under 3 bar of H.sub.2 at room temperature for 3 hours. The mixture was filtered on a pad of Celite® and washed with MeOH. The filtrate was evaporated then co-evaporated with MeOH (twice) to give intermediate AW-9, 0.484 g (90%) as pale beige powder.

[1049] Preparation of Compound 142

##STR00135##

[1050] HATU (0.15 g, 0.4 mmol) was added to a solution of 6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.078 g, 0.35 mmol) and DIPEA (0.21 mL, 1.21 mmol) in dry Me-THF (2.8 mL) and dry DCM (2 mL) under N.sub.2 flow. The solution was stirred at room temperature for 15 min. Then AW-9 (0.118 g, 0.35 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated then the residue was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHCO.sub.3, water then brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to give a brown residue. Purification was carried out by flash chromatography over silica gel (40 g, irregular SiOH 25-40 μM, solid deposit on Celite®, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording a pale-yellow powder, 0.512 g. A purification was performed via achiral SFC (Stationary phase: Whelk-O1 (S,S) 5 μm 250*30 mm, Mobile phase: 60% CO.sub.2, 40% mixture of MeOH/DCM 80/20 v/v+0.3% iPrNH.sub.2). Pure fractions were collected and evaporated affording a white solid, 0.31 g. This was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. giving compound 142 as white powder, 0.29 g (47%).

[1051] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J=1.4 Hz, 1H), 8.46 (t, J=5.8 Hz, 1H), 8.13 (br s, 1H), 7.63-7.75 (m, 2H), 7.47 (dd, J=9.4, 2.1 Hz, 1H), 7.37 (s, 1H), 4.51 (br d, J=5.8 Hz 2H), 4.13 (br t, J=4.5 Hz, 2H), 3.92 (t, J=4.8 Hz, 2H), 2.99 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H)

[1052] Preparation of Compound 181

##STR00136##

[1053] AW-9 (0.09 g, 0.24 mmol) was added to a solution of AJ-2 (0.099 g, 0.38 mmol), HATU (0.12 g, 0.31 mmol) and DIPE (0.25 mL, 1.43 mmol) in dry DMF (5 mL) in a round bottom flask at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with an aqueous saturated NaHCO.sub.3 solution and extracted with DCM. The organic layer was separated, dried (MgSO.sub.4), filtered and the solvents concentrated in vacuo to yield a brown oil. The crude product was triturated with DCM and the solid was filtered and dried in vacuo to yield a white solid, compound 181, 0.059 g (45%).

[1054] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.51 (br t, J=5.8 Hz, 1H), 8.13 (s, 1H), 7.69 (dd, J=12.7, 1.7 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J=11.7, 0.9 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.17-4.10 (m, 2H), 3.96-3.89 (m, 2H), 2.97 (q, J=7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J=7.5 Hz, 3H).

[1055] Preparation of Compound 201

##STR00137##

[1056] Accordingly compound 201 was prepared in the same way as compound 142 starting from intermediate AI-3 (0.64 mmol) and intermediate AW-9 (0.4 mmol) affording a white solid, 0.063 g (30%).

[1057] .sup.1H NMR (400 MHz, DMSO) δ 9.19-9.12 (m, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.13 (s, 1H), 7.69 (dd, J=12.7, 1.7 Hz, 1H), 7.36 (s, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.13 (t, J=4.6 Hz, 2H), 3.96-3.87 (m, 2H), 3.00 (q, J=7.5 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J=7.5 Hz, 3H).

[1058] Synthesis of Compound 213

##STR00138##

[1059] Preparation of Intermediate AX-1

[1060] N,N Dimethylacetamide dimethyl acetal (0.2 mL; 1.26 mmol) was added to a solution of intermediate D6 (0.3 g; 0.63 mmol) in HFIP (10.8 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and treated with an aqueous saturated solution of NaHCO.sub.3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give a colorless oil. Purification was carried out by flash chromatography over silica gel (24 g, irregular SiOH 25-40 μM, DCM/MeOH from 95/5 to 90/10). Pure fractions were collected and evaporated affording intermediate AX-1 as colorless oil, 0.176 g (65%).

[1061] Preparation of Compound 213

[1062] To a solution of intermediate AX-1 (0.139 g, 0.32 mmol) and DIPEA (0.17 mL, 0.97 mmol) in dry DCM (2.8 mL), cooled at 5° C. in an ice bath, was added dropwise Tf.sub.2O 1M in DCM (0.32 mL, 0.32 mmol). The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was immediately quenched with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with DCM (twice). The combined organic layer was washed with brine (once), dried over MgSO.sub.4 and filtered off to give a crude. Dry DCM (2.8 mL) was added to the crude, the solution was cooled down to 5° C. then DIPEA (0.056 mL, 0.32 mmol) was added, followed by Tf.sub.2O 1M in DCM (0.13 mL, 0.13 mmol). The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was immediately quenched with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with DCM (twice). The combined organic layer were washed with brine (once), dried over MgSO.sub.4 and filtered off to give 0.217 g as an oil. Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording compound 213, as beige powder, 0.093 g (51%). Purification was carried out by flash chromatography over silica gel (12 g, irregular SiOH 25-40 μM, DCM/MeOH from 100/0 to 97/3). Pure fractions were collected and evaporated affording compound 213, as beige powder, 0.075 g (41%). This one was crystallized from DIPE/Heptane, triturated, filtered off and dried under vacuum at 60° C. affording compound 213 as white powder, 0.063 g (35%).

[1063] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.04-9.11 (m, 1H), 8.47 (t, J=5.9 Hz, 1H), 7.64-7.72 (m, 1H), 7.46 (dd, J=9.5, 2.1 Hz, 1H), 7.29-7.38 (m, 1H), 7.13-7.27 (m, 2H), 5.12-5.18 (m, 1H), 4.49 (d, J=6.0 Hz, 2H), 3.95-4.06 (m, 2H), 3.67-3.77 (m, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.25 (s, 3H), 1.22-1.31 (t, J=7.5 Hz, 3H).

[1064] Synthesis of Intermediate AY-3

##STR00139##

[1065] Preparation of Intermediate AY-1

[1066] N,N Dimethylacetamide dimethyl acetal (1.68 mL; 10.33 mmol) was added to a solution of intermediate E6 (2 g; 5.16 mmol) in HFIP (88 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and treated with an aqueous saturated solution of NaHCO.sub.3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 40 μm, 40 g, from DCM/MeOH 95/5 to 90/10) to give 442 mg of intermediate AY-1 as a colorless residue which crystallized on standing (25%).

[1067] Preparation of Intermediate AY-2

[1068] Accordingly, intermediate AY-2 was prepared in the same way as compound 213 starting from AY-1 (1.31 mmol), yielding a beige powder, 0.388 g (63%).

[1069] Preparation of Intermediate AY-3

[1070] In a steal bomb, a mixture of AY-2 (0.39 g, 0.82 mmol), palladium hydroxide 20% on carbon nominally 50% water (0.12 g, 0.082 mmol) and aqueous HCl 1M (0.82 mL, 0.82 mmol) in MeOH (5.8 mL) and EtOAc (5.8 mL) was hydrogenated under 5 bar of H.sub.2 at room temperature for 1.5 hour. The mixture was filtered on a pad of celite and washed with MeOH. The filtrate was evaporated to give intermediate AY-3, 0.32 g (96%, purity 92%), used as such for next step.

[1071] Preparation of Compound 214

##STR00140##

[1072] Accordingly, compound 214 was prepared in the same way as compound 181 starting from 2-(Trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS [73221-19-9], 0.34 mmol) and intermediate AY-3 (0.39 mmol) yielding a white powder, 0.098 g (52%).

[1073] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.17-9.29 (m, 1H), 8.48-8.58 (m, 1H), 7.73-7.83 (m, 1H), 7.49-7.60 (m, 1H), 7.30 (br d, J=8.2 Hz, 2H), 7.13-7.24 (m, 3H), 4.42-4.52 (m, 2H), 4.01 (br s, 2H), 3.84 (br d, J=4.3 Hz, 2H), 2.27 (s, 3H)

[1074] Preparation of Compound 215

##STR00141##

[1075] Accordingly, compound 215 was prepared in the same way as compound 181 starting from 2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1216036-36-0], 0.34 mmol) and intermediate AY-3 (0.39 mmol) affording a white powder, 0.129 g (72%).

[1076] .sup.1H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (s, 1H), 8.29-8.36 (m, 1H), 7.47-7.54 (m, 1H), 7.27-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.14-7.19 (m, 2H), 4.41-4.49 (m, 2H), 4.06-4.09 (m, 1H), 3.96-4.05 (m, 2H), 3.79-3.84 (m, 2H), 2.90-3.02 (m, 2H), 2.31 (s, 3H) 2.26 (s, 3H), 1.20-1.30 (m, 3H)

[1077] Preparation of Compound 217

##STR00142##

[1078] Accordingly, compound 217 was prepared in the same way as compound 181 starting from intermediate AU-2 (0.31 mmol) and intermediate AY-3 yielding a white foam, 0.018 g (10%).

[1079] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.17 (s, 1H), 8.40 (t, J=6.0 Hz, 1H), 7.27-7.35 (m, 2H), 7.12-7.21 (m, 2H), 4.69-4.77 (m, 2H), 4.41-4.49 (m, 2H), 3.98-4.04 (m, 2H), 3.91-3.97 (m, 2H), 3.79-3.84 (m, 2H), 2.95-3.01 (m, 2H), 2.89-2.94 (m, 2H), 2.25 (s, 3H), 1.22-1.29 (m, 4H)

[1080] Preparation of Compound 218

##STR00143##

[1081] Accordingly compound 218 was prepared in the same way as compound 181 starting from 6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS [1131613-58-5], 0.29 mmol) and intermediate AY-3 yielding a white foam, 0.059 g (38%).

[1082] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.09 (t, J=6.0 Hz, 1H), 7.80-7.91 (m, 1H), 7.21-7.32 (m, 2H), 7.08-7.19 (m, 2H), 4.40 (d, J=6.0 Hz, 2H), 4.00 (t, J=4.9 Hz, 2H), 3.81 (t, J=4.9 Hz, 2H), 2.85 (q, J=7.5 Hz, 2H), 2.40-2.46 (m, 3H), 2.22-2.28 (m, 3H), 1.20 (t, J=7.5 Hz, 3H)

##STR00144##

[1083] Preparation of Intermediate AZ-1

[1084] Trimethyl Orthoisobutyrate (0.2 mL; 1.26 mmol) was added to a solution of intermediate D (0.3 g; 0.63 mmol) in HFIP (10.8 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and treated with an aqueous saturated solution of NaHCO.sub.3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure to give an oil. Purification was carried out by flash chromatography over silica gel (4 g, irregular SiOH, DCM/MeOH from 95/5 to 85/15). Pure fractions were collected and evaporated affording intermediate AZ-1 as colourless oil, 0.105 g (37%).

[1085] Preparation of Compound 216

[1086] To a solution of AZ-1 (0.11 g, 0.23 mmol) and DIPEA (0.12 mL, 0.69 mmol) in dry DCM (2 mL), cooled at 5° C. in a ice bath, was added dropwise Tf.sub.2O 1M in DCM (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was immediately quenched with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with DCM (twice). The combined organic layer were washed with brine (once), dried over MgSO.sub.4 and filtered off and evaporated. DCM (2 mL) was added to the residue, the solution was cooled down to 5° C. then DIPEA (0.04 mL, 0.23 mmol) was added, followed by Tf.sub.2O 1M in DCM (0.092 mL, 0.092 mmol). The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was immediately quenched with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with DCM (twice). The combined organic layer were washed with brine (once), dried over MgSO.sub.4 and filtered off to give 0.725 g. A purification was carried out by flash chromatography over silica gel (4 g, irregular SiOH 25-40 μM, Heptane/EtOAc from 90/10 to 70/30). Pure fractions were collected and evaporated affording a beige powder, 0.06 g. This one was triturated with DIPE and a few Heptane, the precipitate was filtered off and dried under vacuum at 60° C. affording compound 216 as white powder, 0.040 g.

[1087] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.03-9.18 (m, 1H), 8.47 (br t, J=5.5 Hz, 1H), 7.63-7.73 (m, 1H), 7.43-7.50 (m, 1H), 7.30-7.38 (m, 1H), 7.16-7.27 (m, 2H), 4.50 (br d, J=5.6 Hz, 2H), 3.87-3.94 (m, 2H), 3.80 (br s, 2H), 2.93-3.05 (m, 3H), 1.24-1.32 (m, 3H), 1.14-1.21 (m, 6H)

[1088] Synthesis of Intermediate BA-3

##STR00145##

[1089] Preparation of Intermediate BA-1

[1090] According, intermediate BA-1 was prepared in the same way as AZ-1 starting from intermediate E6 (6.45 mol) yielding a colorless oil, 1.82 g (77%).

[1091] Preparation of Intermediate BA-2

[1092] Accordingly, intermediate BA-2 was prepared in the same way as compound 216 starting from BA-1 (4.97 mmol), yielding a beige powder, 1.58 g (58%).

[1093] Preparation of Intermediate BA-3

[1094] According, intermediate BA-3 was prepared in the same way as AY-3 starting from intermediate BA-2 (3.17 mol) yielding a beige solid, 1.39 g (91%, purity around 90%, used as such for next step).

[1095] The following compounds are/were also prepared in accordance with the methods described herein:

##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##

4. Characterizing Data Table

[1096]

TABLE-US-00002 Melting LCMS Compound point Retention UV M number (° C.) time (%) exact [M + H].sup.+ [M − H].sup.− Method 1 183.46 3.2 98.9 528.1 529.1 527.2 A 31 3.26 97.1 528.1 529.3 527.4 A 32 3.25 96.86 528.1 529.3 527.4 A 29 195.09 3.25 96.17 528.1 529.3 527.4 A 28 199.08 3.26 98.84 528.1 529.3 527.4 A 30 213.87 3.26 96.73 528.1 529.3 527.4 A 21 157.49 3.36 100 542.1 543.2 541.3 A 19 196.34 2.73 96.2 518.2 519.2 517.3 A 2 178.31 3.52 99.8 556.1 557.2 555.3 A 56 236.36 2.32 99.8 396.1 397.1 395.1 A 20 209.36 2.65 98 474.1 475.1 473.2 A 3 189.22 2.82 100 498.2 499.3 557.4 A [M + CH.sub.3CO.sub.2].sup.− 57 211.47 1.85 95.7 366.2 367.2 425.4 A [M + CH.sub.3CO.sub.2].sup.− 13 215.87 3.06 97.1 529.1 530.3 528.3 A 58 2.32 97.7 488.2 489.4 547.5 A [M + CH.sub.3CO.sub.2].sup.− 14 192.27 2.93 99.9 510.1 511.2 569.4 A [M + CH.sub.3CO2].sup.− 59 202.94 2.52 99.7 424.2 425.2 423.3 A 15 206.66 2.53 99 410.2 411.2 409.2 A 6 3.28 99.4 558.1 559.3 557.4 A 16 158.10 3.21 100 546.1 547.5 545.5 B 4 2.23 99.1 410.2 411.6 409.5 B 18 245.36 2.56 99.7 439.2 439.3 437.3 A 5 3.29 100 542.1 543.3 541.4 A 17 196.82 3.08 97.6 516.2 517.4 515.5 A 22 175.12 3.29 92.2 558.1 559.4 557.4 A 23 207.21 2.94 97.82 517.2 518.4 516.5 A 10 171.42 2.97 99.59 513.1 514.3 512.4 A 24 258.01 2.38 97.6 439.2 440.3 438.4 A 26 2.93 98.42 525.1 526.4 524.5 A 11 179.76 3.17 98.6 514.1 515.3 513.4 A 12 109.51, 2.81 99.8 495.1 496.3 494.4 A 164.64, 179.98 9 153.26, 3.3 99.6 546.1 547.3 545.4 A 177.06 8 167.12 3.15 98.8 544.1 545.5 543.5 B 25 125.56 3.24 97.97 558.1 559.3 557.5 A 7 208.41 3.19 98.34 541.1 542.3 540.5 A 27 174.88 3.16 100 559.1 560.3 558.4 A 60 2.78 98.9 566.2 567.3 625.5 A [M + AcO].sup.− 61 193.44 2.74 97.6 552.2 553.3 611.4 A [M + AcO].sup.− 62 2.94 97.2 537.1 538.2 596.5 A [M + CH.sub.3CO.sub.2].sup.− 33 225.92 2.85 98.52 539.2 540.3 538.3 A 38 255.93 2.52 98.91 424.1 425.1 423.2 A 39 211.19 3.08 98.89 558.1 559.2 557.3 A 40 2.98 100 572.1 573.3 571.4 A 63 159.95 3.12 100 566.2 567.4 565.4 A 41 2.82 98.72 573.1 574.3 572.7 A 34 86.24, 3.04 100 540.1 541.2 599. 4 A 147.08 [M + AcO].sup.− 35 152.93 3.25 99.56 564.1 565.3 563.4 A 64 193.79 3.26 98.82 558.1 559.3 557.3 A 65 228.15 3.3 98.84 563.2 564.4 562.5 A 42 147.57 3.06 98.5 524.1 525.3 523.4 A 43 169.05 3.02 100 538.2 539.3 537.4 A 66 211.30 3.08 98.23 492.1 493.2 491.2 A 67 206.99 3.22 99.6 558.1 559.3 557.3 A 36 142.03 3.11 98.33 554.2 555.3 553.3 A 37 193.36 3.37 99.74 576.1 577.2 575.3 A 44 173.29 3.1 99.83 558.1 559.3 617.5 A [M + AcO].sup.− 45 155.29 3.29 99.85 588.1 589.3 587.3 A 68 3.29 99.62 588.1 589.3 587.5 A 46 176.82 3.34 100 606.1 607.3 605.4 A 47 149.44 3.09 100 565.1 566.3 564.4 A 69 163.46 2.99 98.43 561.1 562.3 560.2 A 70 138.71 3.01 99.79 558.1 559.3 617.6 A [M + CH3COO]− 48 74.60 3.19 99.7 572.1 573.3 571.4 A 49 3.37 99.7 606.1 607.3 605.3 A 50 101.66/ 3.06 100 573.1 574.3 572.3 A 150.99 51 185.08 3.04 97.89 524.1 525.3 523.3 A 52 164.28 3.11 99.62 554.2 555.5 553.3 A 71 3.14 98.26 549.1 550.3 548.4 A 72 216.25 3.07 98.33 519.1 520.2 518.2 A 53 3.11 100 602.2 603.4 601.4 A 54 233.23 3.25 99.45 509.1 510.3 508.5 A 55 193.51 3.38 99.24 586.1 587.4 585.4 A 73 212.08 3.18 100 567.1 568.3 566.5 A 74 3.42 99.2 585.2 586.4 584.5 A 75 135.16 3.16 97.19 572.1 573.3 571.4 A 76 232.40 2.95 99.82 479.1 480.3 478.4 A 77 3.14 100 567.1 568.3 566.3 A

[1097] Further Characterising Data:

TABLE-US-00003 Melting point (° C.) LCMS Compound (DSC Retention UV M number or MT) time (%) exact [M + H].sup.+ [M − H].sup.− Method 132 179.05 3.52 99.47 590.1 591.5 589.4 A 107 207.55 3.35 98.4 542.1 543.4 541.3 A 93 187.84 3.24 99.46 576.1 577.5 575.5 A 116 175.40 3.39 99.8 560.1 561.4 559.4 A 108 3.41 100 572.1 573.5 571.4 A 146 173.85 3.12 99.58 547.1 548.4 546.3 A 120 183.66 3.36 98.02 508.1 509.4 507.3 A 92 3.22 99.71 549.1 550.4 548.3 A 94 192.26 3.26 99.24 593 594.3 592.3 A 141 198.76 3.46 98.37 594.1 594.4 593.4 A 110 175.59 2.75 98.27 444.1 445.3 443.3 A 96 133.99 2.7 98.5 426.2 427.3 425.3 A 156 151.06 3.13 99.16 530.1 531.4 529.4 A 164 3.12 100 526.1 527.4 525.4 A 91 2.74 100 513.1 514.2 512.2 C 99 2.79 100 552 555 553.1 C 123 157.82 3.06 100 556.1 557.4 555.4 A 147 147.39 2.82 97 538.1 539.3 537.3 B 157 183.19 3.35 99.4 564.1 565.3 563.3 A 152 169.75 3.15 100 552.1 553.3 551.3 A 159 134.19 2.91 100 534.1 535.3 533.4 B 103 169.72 3.15 100 530.1 531.3 529.2 A 103 197.38 3.58 100 624 625.2 623.2 A 154 172.60 3.01 99.51 553.2 554.4 552.5 A 118 188.26 3.54 98.6 580 581.4 579.3 A 119 173.10 3.13 99.41 567.2 568.5 566.5 A 142 190.96 3.15 100 547.1 548.3 546.3 A 163 158.33 3.21 100 532.1 533.3 531.3 A 125 141.53 3.11 99.53 547.1 548.3 546.4 A 86 152.96 3.01 100 577.1 578.1 576.2 A 115 137.25 3.04 100 543.1 544.5 542.5 A 111 176.27 2.65 100 527.1 528.1 526.3 C 98 168.32 2.83 99.44 568.1 569.2 567.3 C 150 120.10 2.92 100 564.1 565.1 563.2 C 109 137.30 2.76 98.5 550.1 551.2 549.3 C 149 145.84 2.85 100 546.1 547.1 545.2 C 153 177.80 2.82 100 518.1 519 517.2 C 130 2.75 100 51/1 532.1 530.2 C 133 165.25 3.27 99.55 538 539.3 537.3 A 126 239.37 2.88 100 562.1 563.4 561.3 A 129 135.91 3.19 99.77 546.1 547.4 545.4 A 101 171.00 3.26 100 552.2 553.5 551.5 A 161 167.34 2.93 100 527.1 528.4 526.4 A 88 194.58 3.02 100 538.1 539.3 537.4 A 127 179.93 3.12 99.4 534.1 535.3 533.3 A 104 154.40 2.93 100 520.1 521.4 519.4 A 128 170.22 3.04 100 516.1 517.3 515.3 A 158 163.01 3.09 100 583.2 584.5 582.5 A 87 171.19 3.51 99.75 580 581.3 579.4 A 155 181.61 3.2 100 561.1 562.4 560.4 A 151 183.62 3.39 100 564.1 565.3 563.4 A 112 146.66 3.12 100 586.1 587.4 585.4 A 137 136.03 3.04 100 568.1 569.4 567.3 A 160 127.38 3.14 99.38 564.1 565.4 563.4 A 113 194.44 3.27 99.1 552.2 553.5 551.5 A 85 158.44 3.48 100 560.1 561.4 559.3 A 145 149.39 3.29 100 568.1 569.3 567.3 A 95 154.17 3.29 100 540.2 541.4 539.4 A & 147.66 124 161.38 3.35 100 586 587.3 585 A 144 146.89 3.35 100 586 587.3 585.3 A 114 169.31 3.4 97.63 604 605.3 603.3 A 117 164.15 3.42 100 616.1 617.3 615.3 A 102 174.33 3.32 100 560.1 561.4 559.4 A 148 157.00 3.24 99.21 548.1 549.3 547.3 A 89 153.88 3.29 98.1 544.1 545.4 543.4 A 162 160.65 3.22 99.3 544.1 545.4 543.4 A 105 172.82 3.21 98.93 556.2 557.4 555.4 A 143 226.52 301 100 561 562.3 560.3 A 136 147.95 3.37 100 572.1 573.3 571.3 A 135 167.06 3.14 99.4 552 553.1 551.1 C 131 199.18 3.04 98.71 554.1 555.4 553.4 A 134 185.60 3.02 100 556.1 557.3 555.3 A 106 198.37 3.2 99.02 556.2 557.4 555.3 A 100 174.31 3.02 100 570.1 571.3 569.3 A 139 176.81 3.21 100 540.2 541.4 539.4 A 140 183.14 3.41 99.01 560.1 561.3 559.3 A 90 233.3 3.2 97 569.1 570.1 D (MT) 97 3.45 1°° 604.1 605.4 603.3 A 83 3.02 99.46 576.1 577.3 575.3 A 121 149.7 3.712 98 561.1 562.1 D (MT) 80 3.13 97.74 575.1 576.4 574.3 A 138 2.87 100 541.2 542.4 540.4 A 84 141.30 3.3 100 600.2 601.5 659.4 A [M + CH3CO2]− 81 173.01 3.46 100 626.2 627.5 685.5 A [M + CH3COO]− 82 187.66 3.45 100 616.1 617.4 615.4 A 165 189.8 3.553 99 553 554 D (MT) 166 3.12 100 604.1 605.1 603.2 C 167 153.0 3.89 98 587 588 D (MT) 168 148.1 3.525 97 548.1 549.1 D (MT) 169 3.296 98 569.1 570.3 D 170 3.333 97 546.1 547.3 D 171 203.43 3.22 99.48 529.1 530.3 538.2 A 173 183.2 3.82 99 516.1 516 D (MT) 174 148.1 3.52 97 548 549 D (MT) 175 146.4 4.048 98 566.1 567.1 D (MT) 176 163.1 3.814 99 567.1 568.1 D (MT) 177 166.4 3.693 95 545.1 546.1 D (MT) 178 193.2 3.563 99 517.1 518.1 D (MT) 179 169.8 3.721 99 561.1 562.1 D (MT) 180 3.457 99 599.1 600.1 D 181 198.3 3.641 99 545.1 546.1 D (MT) 182 184.7 3.762 97 571.1 572.1 D 183 198.1 2.966 97 541.1 542.1 D 184 193.2 3.931 98 585.1 586.1 D (MT) 185 181.5 2.875 98 541.1 542.1 D (MT) 186 158.1 3.987 99 570.1 571.2 D (MT) 187 216.6 1.668 98 413.1 414.1 D (MT) 188 3.138 98 547.1 548.1 D 189 169.8 4.286 99 637.1 638.2 D (MT) 190 4.015 98 567.1 566.1 D 191 178.1 2.96 99 583.1 584.1 D (MT) 192 189.9 1.816 98 420.1 421.1 D (MT) 193 153.1 3.535 99 557.1 558.1 D (MT) 194 137.9 4.136 98 596.1 597.1 D (MT) 195 226.7 3.05 99 591.1 592.1 D (MT) 196 1.454 97 395.2 396.2 D 198 173.1 1.807 99 412.2 413.2 D (MT) 199 120.4 1.863 98 429.1 430.1 D (MT) 200 166.4 3.431 99 539.1 540.1 D (MT) 201 159.8 3.103 99 528.1 529.1 D (MT) 202 214.9 2.03 97 432.1 433.1 D (MT) 203 208.2 1.48 99 421.2 422.2 D (MT) 204 186.4 3.655 99 560.1 561.1 D (MT) 205 201.5 2.906 97 584.1 585.1 D (MT) 206 4.025 99 598.1 599.1 D 207 157.42 2.88 100 553.1 554.4 552.4 A 208 178.11 3.29 100 543.1 544.3 542.3 A 209 159.7 3.881 99 590.1 591.1 D (MT) 210 178.5 4.33 99 594.1 595.1 D (MT) 211 153.35 3.07 100 571.2 572.4 570.5 A 212 3.04 98 541.2 542.4 540.4 A 213 159.38 3.46 100 560.1 561.4 559.3 A 214 106.9 3.28 97 548.1 549.4 547.4 A 215 152.81 3.26 97 522.2 523.3 521.4 A 216 3.74 96.2 558.14 589.4 587.6 A 217 3.03 100 565.2 566.4 564.4 A 218 3.33 100 528.1 529.3 527.5 A 219 3.36 99 550.2 551.2 549.3 C 220 3.36 98 576.1 577.1 575.2 C 221 3.18 96 551.2 552.2 550.3 C 222 3.25 98 577.2 578.2 576.4 C 223 3.44 99 556.1 557.2 555.2 C 224 3.7 99 576.1 577.2 575.2 C 225 3.35 96 554.2 555.2 553.3 C 226 3.65 96 584.2 585.2 583.3 C 79 113.95 3.22 99.6 582.1 583.4 581.4 A

5. Biological Assays/Pharmacological Examples

[1098] MIC Determination for Testing Compounds Against M. tuberculosis.

[1099] Test 1

[1100] Test compounds and reference compounds were dissolved in DMSO and 1 μl of solution was spotted per well in 96 well plates at 200× the final concentration. Column 1 and column 12 were left compound-free, and from column 2 to 11 compound concentration was diluted 3-fold. Frozen stocks of Mycobacterium tuberculosis strain EH4.0 expressing green-fluorescent protein (GFP) were previously prepared and titrated. To prepare the inoculum, 1 vial of frozen bacterial stock was thawed to room temperature and diluted to 5×10 exp5 colony forming units per ml in 7H9 broth. 200 μl of inoculum, which corresponds to 1×10 exp5 colony forming units, were transferred per well to the whole plate, except column 12. 200 μl 7H9 broth were transferred to wells of column 12. Plates were incubated at 37° C. in plastic bags to prevent evaporation. After 7 days, fluorescence was measured on a Gemini EM Microplate Reader with 485 excitation and 538 nm emission wavelengths and IC.sub.50 and/or pIC.sub.50 values (or the like, e.g. IC.sub.50, IC.sub.90, pIC.sub.90, etc) were (or may be) calculated.

[1101] Test 2

[1102] Appropriate solutions of experimental/test and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv were taken from cultures in logarithmic growth phase. These were first diluted to obtain an optical density of 0.3 at 600 nm wavelength and then diluted 1/100, resulting in an inoculum of approximately 5×10 exp5 colony forming units per ml. 100p of inoculum, which corresponds to 5×10 exp4 colony forming units, were transferred per well to the whole plate, except column 12. Plates were incubated at 37° C. in plastic bags to prevent evaporation. After 7 days, resazurin was added to all wells. Two days later, fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 nm emission wavelengths and MIC.sub.50 and/or pIC.sub.50 values (or the like, e.g. IC.sub.50, IC.sub.90, pIC.sub.90, etc) were (or may be) calculated.

[1103] Test 3: Time Kill Assays

[1104] Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill kinetic assay using the broth dilution method. In this assay, the starting inoculum of M. tuberculosis (strain H37Rv and H37Ra) is 10.sup.6 CFU/ml in Middlebrook (1×) 7H9 broth. The test compounds are tested alone or in combination with another compound (e.g. a compound with a different mode of action, such as with a cytochrome bd inhibitor) at a concentration ranging from 10-30 μM to 0.9-0.3 μM respectively. Tubes receiving no antibacterial agent constitute the culture growth control. The tubes containing the microorganism and the test compounds are incubated at 37° C. After 0, 1, 4, 7, 14 and 21 days of incubation samples are removed for determination of viable counts by serial dilution (10.sup.0 to 10.sup.−6) in Middlebrook 7H9 medium and plating (100 μl) on Middlebrook 7H111 agar. The plates are incubated at 37° C. for 21 days and the number of colonies are determined. Killing curves can be constructed by plotting the log.sub.10 CFU per ml versus time. A bactericidal effect of a test compound (either alone or in combination) is commonly defined as 2-log.sub.10 decrease (decrease in CFU per ml) compared to Day 0. The potential carryover effect of the drugs is limited by using 0.400 charcoal in the agar plates, and by serial dilutions and counting the colonies at highest dilution possible used for plating.

[1105] Results

[1106] Compounds of the invention/examples, for example when tested in Test 1 described above, may typically have a pIC.sub.50 from 3 to 10 (e.g. from 4.0 to 9.0, such as from 5.0 to 8.0)

6. Biological Results

[1107] Compounds of the examples were tested in Test 1 described above (in section “Pharmacological Examples”) and the following results were obtained:

[1108] Biological Data Table

TABLE-US-00004 Compound Compound Compound number pIC.sub.50 number pIC.sub.50 number pIC.sub.50 1 8.15 132 8.08 97 7.47 31 8.04 107 7.62 83 6.43 32 7.94 93 7.31 121 7.89 29 8 116 7.82 80 6.30 28 8.6 108 7.69 138 8.21 30 7.9 146 8.42 84 6.70 21 8.6 120 7.89 81 6.30 19 7.4 92 7.27 82 6.30 2 7.8 94 7.41 165 56 3.8 141 8.31 166 6.61 20 7.5 110 7.73 167 7.06 3 7.5 96 7.44 168 7.41 57 6.3 156 8.86 169 8.00 13 8.4 164 9.61 170 6.50 58 6.6 91 7.19 171 7.60 14 8.2 99 7.49 173 7.30 59 6.7 123 7.99 174 6.30 15 7.6 147 8.42 175 8.80 6 8.2 157 8.86 176 7.80 16 8.2 152 8.70 177 8.10 4 7.4 159 8.92 178 6.70 18 7.8 122 7.98 179 6.90 5 8.1 103 7.55 180 8.40 17 7.7 154 8.77 181 8.20 22 6.4 118 7.86 182 7.50 23 7.9 119 7.87 183 6.70 10 7.2 142 8.33 184 7.50 24 7.8 163 9.50 185 7.33 26 8.6 125 8.01 186 8.44 11 7.1 86 7.05 187 6.30 12 8.5 115 7.80 188 6.30 9 9.2 111 7.74 189 6.30 8 6.6 98 7.48 190 6.76 25 8 150 8.53 191 7.42 7 7.2 109 7.70 192 <6.301 27 8.7 149 8.45 193 9.05 60 6.7 153 8.75 194 8.62 61 6.3 130 8.06 195 7.98 62 6.3 133 8.12 196 6.46 33 7.6 126 8.01 198 7.03 38 7.2 129 8.05 199 <6.301 39 7.1 101 7.53 200 8.26 40 7.2 161 9.11 201 7.92 63 6.3 88 7.08 202 6.41 41 7.3 127 8.02 203 <6.301 34 8 104 7.55 204 8.35 35 8.3 128 8.04 205 7.18 64 6.5 158 8.86 206 8.61 65 6.3 87 7.05 207 6.73 42 8.2 155 8.79 208 7.16 43 8 151 8.58 209 7.95 66 6.6 112 7.76 210 8.52 67 6.7 137 8.21 211 8.64 36 8.4 160 8.92 212 7.59 37 8.4 113 7.79 213 8.46 44 8.6 85 7.02 214 7.87 45 7.4 145 8.39 215 9.04 68 6.3 95 7.42 216 8.67 46 7 124 8.00 217 7.85 47 8.5 144 8.38 218 8.24 69 6.9 114 7.79 79 8.43 70 6.3 117 7.83 48 8.8 102 7.53 49 7.63 148 8.42 50 8.97 89 7.08 51 7.34 162 9.41 52 7.38 105 7.56 71 6.78 143 8.35 72 6.8 136 8.20 53 7.09 135 8.14 54 7.96 131 8.06 55 7.59 134 8.12 73 7.29 106 7.59 74 8.17 100 7.50 75 8.2 139 8.24 76 7.87 140 8.26 77 8.1 90 7.13

7. Further Data on Representative Compounds of the Invention/Examples

[1109] The compounds of the invention/examples may have advantages associated with in vitro potency, kill kinetics (i.e. bactericidal effect) in vitro, PK properties, food effect, safety/toxicity (including liver toxicity, coagulation, 5-LO oxygenase), metabolic stability, Ames II negativity, MNT negativity, aqueous based solubility (and ability to formulate) and/or cardiovascular effect e.g. on animals (e.g. anesthetized guinea pig). The data below that was generated/calculated may be obtained using standard methods/assays, for instance that are available in the literature or which may be performed by a supplier (e.g. Microsomal Stability Assay—Cyprotex, Mitochondrial toxicity (Glu/Gal) assay —Cyprotex, as well as literature CYP cocktail inhibition assays). In some instances, GSH was measured (reactive metabolites, glucuronidation) to observe if a dihydrodiol is observed by LCMS (fragmentation ions), which would correspond to a dihydroxylation on the core heterocycle.

[1110] This following data was generated on Compound 1:

[1111] cLogP=4.3/TPSA=107.7

[1112] CVS (Na Ch, Ca Ch, hERGdof), IC.sub.50=>10, >10, >10

[1113] Cocktail Cyp-450, IC.sub.50=>20 (except CYP3A4, which was not conclusive)

[1114] CLint (μl/min/mg prot)=(H) 29.6/(M) 21.5

[1115] The following data was generated on Compound 13:

[1116] cLogP=3.3/TPSA=120.7

[1117] CVS (Na Ch, Ca Ch, hERGdof), IC.sub.50=>10, >10, 7.4

[1118] Cocktail Cyp-450, IC.sub.50=>20 (except CYP3A4 and CY2D6, which were not conclusive)

[1119] CLint (μl/min/mg prot)=(H) 16.3/(M) 13.3

[1120] The following data was generated on Compound 20:

[1121] cLogP=3.75/TPSA=107.7

[1122] CVS (Na Ch, Ca Ch, hERGdof), IC.sub.50=>10, >10, >10

[1123] Cocktail Cyp-450, IC.sub.50=>20 (except CYP3A4, IC.sub.50=13.2 μM)

[1124] CLint (μl/min/mg prot)=(H) 56.6/(M) 15.9

[1125] The following data was generated on Compound 73:

[1126] It was tested and showed no measure of GSH

[1127] c Log P=3.2/TPSA 140.8

[1128] CVS (Ca, Na, Herg), IC.sub.50=>10

[1129] Cocktail Cyp-450, IC.sub.50=>20 (for all)

[1130] CLint (μl/min/mg prot)=(H) 18/(M) 93

[1131] The following data was generated on Compound 9

[1132] c Log P=4.4/TPSA 107.8

[1133] CVS (Ca, Na, Herg), IC.sub.50=>10

[1134] Cocktail Cyp-450, IC.sub.50=>20 (for all)

[1135] CLint (μl/min/mg prot)=(H) 19/(M) 41

[1136] The following data was generated on Compound 26

[1137] c Log P=3.1/TPSA 129.9

[1138] CVS (Ca, Na, Herg), IC.sub.50=>10

[1139] Cocktail Cyp-450, IC.sub.50=>20 (for all)

[1140] CLint (μl/min/mg prot)=(H) 37/(M) 35

[1141] The following data was generated on Compound 16

[1142] c Log P=4.4/TPSA 107.8

[1143] CVS (Ca, Na, Herg), IC.sub.50=>10

[1144] Cocktail Cyp-450, IC.sub.50=>20 (for all)

[1145] CLint (μl/min/mg prot)=(H) 24/(M) 18

[1146] The following data was generated on Compound 6

[1147] It was tested and showed no measure of GSH

[1148] c Log P=4.3/TPSA 117

[1149] CVS (Ca, Na, Herg), IC.sub.50=>10

[1150] Cocktail Cyp-450, IC.sub.50=>20 (for all)

[1151] CLint (μl/min/mg prot)=(H) 37.6/(M) 49

[1152] The following further data/results were generated

[1153] Compound 1: [1154] Was found to have low mitotoxicity (<3 in the Glu/Gal assay)—hence no mitotoxicity alerts [1155] Had good bioavailaibility (as shown in rodents)

[1156] Compound 6: [1157] Was found to have low mitotoxicity (<3 in the Glu/Gal assay)—hence no mitotoxicity alerts [1158] Did not produce unwanted reactive metabolites (it showed no measure of GSH)

[1159] Compound 152: [1160] Found to have low mitotoxicity (<3 in the Glu/Gal assay)—hence no mitotoxicity alerts [1161] Had good bioavailaibility (as shown in rodents) [1162] The formation of reactive metabolites was blocked

[1163] Compound 161: [1164] Found to have low mitotoxicity (<3 in the Glu/Gal assay)—hence no mitotoxicity alerts [1165] Had good bioavailaibility (as shown in rodents) [1166] The formation of reactive metabolites was blocked

[1167] Specific Data on Compound 161:

[1168] TPSA=120.6

[1169] HTEq Sol (μg/mL)—pH 2: 33, pH 7: <0.02, FaSSIF: 5, FeSSIF: 16

[1170] Cocktail Cyp-450, IC.sub.50 (μM)=>20

[1171] Cyp 3A4 induction (% control)—at 1 μM=3.0

[1172] CLint Hep (ml/min/10.sup.6 cells)=(M) 0.012/(R) 0.019/(D) 0.0047/(H) 0.0067

[1173] PPB (% unbound) (H) 1.5/(M) 2.45

[1174] AMES II—negative (Score 1)

[1175] Glu/Gal—negative (ratio <3)

[1176] GSH/CN—no reactive metabolites

[1177] Kinase panel—negative

[1178] CTCM (μM)—clean up to 5 μM

[1179] CVS (Na Ch, Ca Ch, hERGdof), IC.sub.50=>10, >10, 15.85

[1180] Oral Bioavailability of Compound 161 in Rat

[1181] Compound 161 was administer PO in rat (5 mg/kg, PEG4000 (sol.), 0.5 w/v Methocel (susp.) and the following results were obtained for the solution and suspension.

TABLE-US-00005 Solution Suspension (Compound 161) (Compound 161) C.sub.max (ng/mL) 1228 ± 406 787 ± 226 T.sub.max (h) 4.0 2.0 (1.0-2.0) AUC.sub.0-inf (ng .Math. h/mL) 10880 ± 1715 5610 ± 2747 t.sub.1/2 (h)  3.55 ± 0.45 3.49 ± 0.91 F (%) 106 ± 17 55 ± 27

CONCLUSIONS

[1182] Compounds of the invention/examples (e.g. as exemplified by Compound 161), may therefore have the advantage that: [1183] No in vitro cardiotoxicity is observed (for example either due to the CVS results or due to the Glu/Gal assay results); [1184] No reactive metabolite formation is observed (e.g. GSH); and/or [1185] There is a relatively higher unbound fraction, for instance as compared to other compounds, for instance prior art compounds.

[1186] Certain compounds of the invention/examples may also have the additional advantage that they do not form degradants (e.g. that are undesired or may elicit unwanted side-effects).

[1187] Compounds of the invention/examples (for instance, as represented by Compound 161), may have the advantage that a faster oral absorption and improved bioavailability are displayed (as may be shown by the oral bioavailability data in rat).