Plant growth regulator compounds

Abstract

The present invention relates to relates to novel strigolactone derivatives of formula (I), to processes for preparing these derivatives including intermediate compounds, to seeds comprising these derivatives, to plant growth regulator or seed germination promoting compositions comprising these derivatives and to methods of using these derivatives in controlling the growth of plants and/or promoting the germination of seeds. ##STR00001##

Claims

1. A compound of formula (I) ##STR00126## wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy; X is O(R.sup.3); R.sup.3 is selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl; Y is O; Z is selected from the group consisting of a bond, CH.sub.2, CH.sub.2-CH.sub.2, CH.sub.2 (wherein the oxygen atom is bonded to the carbon positioned alpha to the A.sub.1 substituent) and oxygen; A.sub.1 to A.sub.4 are each independently selected from the group consisting of a bond, CR.sup.8, N, S and O, wherein A.sub.1 to A.sub.4 together with the atoms to which they are joined form a 5 to 6 membered aryl or heteroaryl; and each R.sup.8 is selected from the uroup consisting of hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl; or two R.sup.8 groups are joined via —OCH.sub.2O—to form a dioxolane ring; or salts thereof.

2. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, methyl, ethyl and methoxy.

3. A compound according to claim 1, wherein R.sup.1 is methyl and R.sup.2 is hydrogen or methyl.

4. A compound according to claim 3, wherein R.sup.2 is methyl.

5. A compound according to claim 1, wherein R.sup.3 is selected from the group consisting of hydrogen, methyl and ethyl.

6. A compound according to claim 1, wherein A.sub.1 to A.sub.4 are each independently selected from the group consisting of a bond, CR.sup.8, N, S and O, and A.sub.1 to A.sub.4 together with the atoms to which they are joined form a 5 to 6 membered aryl or heteroaryl.

7. A compound according to claim 1, wherein A.sub.1 to A.sub.4 are each CR.sup.8.

8. A composition comprising a compound according to claim 1, and an agriculturally acceptable formulation adjuvant.

9. A mixture comprising a compound as defined in claim 1, and a further active ingredient.

10. A crop yield enhancing composition, comprising a compound according to claim 1.

11. A method for improving the tolerance of a plant to abiotic stress, promoting seed germination of a plant, or regulating or improving the growth of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material, or plant growing locus a compound according to claim 1.

12. A compound according to claim 1, wherein Z is CH.sub.2 .

13. A compound according to claim 1, selected from: ethyl (E)-2-indan-1 -yl-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]-2-indan-l-yl-prop-2-enoate; methyl (E)-2-indan-l-yl-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; methyl (E)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]-2-indan-l-yl-prop-2-enoate; ethyl (E)-2-(5,6-dimethoxyindan-l-yl)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-2-(5,6-dimethoxyindan-1 -yl)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-2-(6,7-dihydro-5H-cyclopenta[f[[1,3]benzodioxol-7-yl)-3-[(4-methyl-5-oxo-2H-furan-2-y 1)oxy]prop-2-enoate; ethyl (E)-2-(4-methylindan-l-yl)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]-2-[4-(trifluoromethyl)indan-l-yl]prop-2-enoate; ethyl (E)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]-2-(6-hydroxyindan-l-yl)prop-2-enoate; ethyl (E)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]-2-tetralin-l-yl-prop-2-enoate; ethyl (E)-2-(7-bicyclo[4.2.0]octa-l(6),2,4-trienyl)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-2-chroman-4-yl-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; ethyl (E)-2-chroman-4-yl-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate; and ethyl (E)-2-(2,3-dihydrobenzofuran-3-yl)-3-[(3,4-dimethyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate.

Description

COMPOUND SYNTHESIS AND CHARACTERIZATION

(1) The following abbreviations are used throughout this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; bd=broad doublet; t=triplet; td=triplet doublet; bt=broad triplet; tt=triple triplet; q=quartet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; DME=1,2-dimethoxyethane; THF=tetrahydrofuran; M.p.=melting point; RT=retention time, MH.sup.+=molecular cation (i.e. measured molecular weight).

(2) The following HPLC-MS methods were used for the analysis of the compounds:

(3) Method A:

(4) Spectra were recorded on a ZQ Mass Spectrometer from Waters (Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone: 30.00 V, Extractor: 2.00 V, Source Temperature: 100° C., Desolvation Temperature: 250° C., Cone Gas Flow: 50 L/Hr, Desolvation Gas Flow: 400 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters (Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., flow rate 0.85 mL/min; DAD Wavelength range (nm): 210 to 500) Solvent Gradient: A=H.sub.2O+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH) gradient: 0 min 10% B; 0-1.2 min 100% B; 1.2-1.50 min 100% B.

(5) Method B:

(6) Spectra were recorded on a ZQ Mass Spectrometer from Waters (Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone: 30.00 V, Extractor: 2.00 V, Source Temperature: 100° C., Desolvation Temperature: 250° C., Cone Gas Flow: 50 L/Hr, Desolvation Gas Flow: 400 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters (Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., flow rate 0.85 mL/min; DAD Wavelength range (nm): 210 to 500) Solvent Gradient: A=H.sub.2O+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH) gradient: 0 min 10% B; 0-2.7 min 100% B; 2.7-3.0 min 100% B.

Example 1: Preparation of Compound of Formula (VI-1-1/2)

(7) ##STR00018##

(8) Under argon, ethyl 2-diethoxyphosphorylacetate (12 g, 54 mmol) was added to a suspension of sodium hydride (60 mass %, 2.3 g, 57 mmol) in 80 mL of dry tetrahydrofuran. The reaction mixture was then stirred for 15 min and a solution of compound of formula (VII-1) in 40 mL of tetrahydrofuran was added dropwise. The reaction mixture was then slowly warmed to room temperature and stirred at reflux. After 16 hours, the solution was poured into an aqueous HCl solution (300 ml, 1M) follow by extraction with ethyl acetate. The combined organic fractions were then washed with brine, dried over sodium sulfate and concentrated under reduce pressure. The crude reaction residue was purified by flash chromatography on silica gel affording compound of formula (VI-1) as a yellow oil and as a mixture of isomers in 59% yield (5.4 g, 27 mmol). LCMS: RT 1.09 min; ES+ 203 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-1-1(E): δ ppm 6.47 (bs, 1H), 3.33 (m, 2H), 3.10 (m, 1H).

(9) A Similar Procedure was Used to Prepare the Following Compounds:

(10) ##STR00019##

(11) LCMS (Method A): RT 1.06 min, ES+ 189 (M+H.sup.+); RT 1.17 min, ES+ 510 (M+H+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-76 (E): δ ppm 7.19-7.39 (m, 4H), 6.02 (m, 1H), 4.22 (q, 2H), 4.01 (s, 2H), 1.31 (t, 3H).

(12) ##STR00020##

(13) LCMS (Method A): RT 1.11 and 1.18 min, ES+ 217 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-68-1(E): δ ppm 7.00-7.47 (m, 3H), 6.29 (m, 1H), 4.23 (q, 2H), 3.31 (m, 2H), 2.97 (m, 2H), 2.29 (s, 3H), 1.33 (t, 3H).

(14) ##STR00021##

(15) LCMS (Method A): RT 1.21 min, ES+ 271 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-70-1(E): δ ppm 7.34-7.80 (m, 3H), 6.36 (m, 1H), 4.22 (q, 2H), 3.35 (m, 2H), 3.26 (m, 2H), 1.34 (t, 3H).

(16) ##STR00022##

(17) LCMS (Method A): RT 1.06 min, ES.sup.+ 247 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-66-1(E): δ ppm 6.97 (s, 1H), 6.76 (s, 1H), 6.07 (t, 1H), 6.00 (s, 2H), 4.21 (q, 2H), 3.27-3.33 (m, 2H), 2.97 (m, 2H), 1.32 (t, 3H).

(18) ##STR00023##

(19) LCMS (Method A): RT 1.07 min, ES.sup.+ 209 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-82-1(E): δ ppm 7.49 (d, 1H), 6.97 (d, 1H), 5.94 (m, 1H), 4.17 (q, 2H).

(20) ##STR00024##

(21) LCMS (Method A): RT 1.25 min, ES.sup.+ 209 (M+H.sup.+)

(22) ##STR00025##

(23) LCMS (Method A): RT 1.11 and 1.17 min, ES.sup.+ 217 (M+H.sup.+)

(24) ##STR00026##

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.63 (m, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 4.20 (q, 2H), 3.70 (m, 2H), 1.27 (t, 3H).

(26) ##STR00027##

(27) LCMS (Method A): RT 1.00 and 1.07 min, ES.sup.+ 218 (M+H.sup.+)

(28) ##STR00028##

(29) LCMS (Method A): RT 1.15 and 1.22 min, ES.sup.+ 231 (M+H.sup.+)

(30) ##STR00029##

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.31-7.36 (m, 1H), 7.16-7.26 (m, 3H), 5.93 (bt, 1H), 4.14 (q, 2H), 3.48 (bd, 2H), 2.27 (m, 2H), 1.57 (bs, 3H), 1.45 (bs, 3H), 1.21 (t, 3H).

Example 2: Preparation of Compound of Formula (VI-64)

(32) ##STR00030##

(33) In a sealed vial, known compound of formula (VII-64) (WO2008073452) (1.5 g, 7.8 mmol) was dissolved in tetrahydrofuran (15 mL) and ethyl 2-bromoacetate (2.6 g, 16 mmol) follow by Zinc (1.5 g, 23 mmol) was added. The resulting brown suspension was then heated to 70° C., stirred for 1 hour and quenched with a saturated aqueous NH.sub.4Cl solution. 5 mL of an aqueous HCl (4N) solution was added and the reaction mixture was stirred for 5 minutes at room temperature. The phases were then separated follow by extraction with ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated under vacuum. The resulting crude residue was purify by flash chromatography on silica gel and compound of formula (VI-64) was isolated in 64% yield (1.3 g, 5.0 mmol). LCMS: RT 1.01 min; ES+ 263 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.00 (s, 1H), 6.85 (s, 1H), 6.12 (m, 1H), 4.22 (q, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 3.30 (m, 2H), 3.02 (m, 2H), 1.33 (t, 3H).

(34) A Similar Procedure was Used to Prepare the Following Compounds:

(35) ##STR00031##

(36) Compound of formula (VI-72-1) and (VI-72-2) were obtained as a mixture of isomers as in example 1; LCMS (Method A): RT 1.14 and 1.19 min, ES− 279 (M−H.sup.+) and ES+ 271 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) meaningful signals for compound VI-72-1(E): δ ppm 7.44-7.85 (m, 3H), 6.38 (m, 1H), 4.23 (q, 2H), 3.36 (m, 2H), 3.13 (m, 2H), 1.33 (t, 3H).

Example 3: Preparation of Compound of Formula (IVa-1)

(37) ##STR00032##

(38) Under argon atmosphere, compounds of formula (VI-1-1/2) (3.16 g, 15.6 mmol) was dissolved in ethanol and Pd/C (1.56 mmol) was added. Argon was then replaced by hydrogen by two vacuum/H2 cycles and the resulting reaction mixture was stirred at room temperature under hydrogen atmosphere (1 bar). After 16 hours, the reaction was filtered on Celite® and the filter cake washed with ethanol. The solution was then concentrated under vacuum yielding to compound of formula (IV-1) as a yellow oil in 91% yield (2.9 g, 14 mmol). LCMS: RT 1.09 min; ES+ 205 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.03-7.20 (m, 4H), 4.11 (q, 2H), 3.52 (m, 1H), 2.65-2.93 (m, 3H), 2.26-2.40 (m, 2H), 1.68 (m, 1H), 1.21 (t, 3H).

(39) A Similar Procedure was Used to Prepare the Following Compounds:

(40) ##STR00033##

(41) LCMS: RT 1.05 min; ES+ 191 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 6.99-7.30 (m, 4H), 4.19 (q, 2H), 3.84 (m, 1H), 3.44 (dd, 1H), 2.85 (bd, 1H), 2.72 (m, 2H), 1.28 (t, 3H).

(42) ##STR00034##

(43) LCMS: RT 1.16 min; ES+ 219 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.09 (m, 1H), 7.00 (m, 2H), 4.18 (q, 2H), 3.59 (m, 1H), 2.82-2.92 (m, 1H), 2.71-2.82 (m, 2H), 2.34-2.46 (m, 2H), 2.26 (s, 3H), 1.75 (m, 1H), 1.28 (t, 3H).

(44) ##STR00035##

(45) LCMS: RT 1.19 min; ES+ 273 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.44 (m, 1H), 7.35 (m, 1H), 7.26 (m, 1H), 4.19 (q, 2H), 3.61 (m, 1H), 3.08-3.20 (m, 1H), 2.95-3-07 (m, 1H), 2.75 (dd, 1H), 2.38-2.52 (m, 2H), 1.82 (m, 1H), 1.28 (t, 3H).

(46) ##STR00036##

(47) LCMS: RT 1.05 min; ES+ 249 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 6.68 (bs, 1H), 6.65 (bs, 1H), 5.91 (m, 2H), 4.18 (q, 2H), 3.49 (m, 1H), 2.71-2.88 (m, 2H), 2.67 (dd, 1H), 2.33-2.43 (m, 2H), 1.76 (m, 1H), 1.28 (t, 3H).

(48) ##STR00037##

(49) LCMS: RT 1.00 min; ES+ 265 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 6.76 (s, 1H), 6.73 (s, 1H), 4.18 (q, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.76-2.94 (m, 2H), 2.71 (dd, 1H), 2.33-2.46 (m, 2H), 1.77 (m, 1H), 1.28 (t, 3H).

(50) ##STR00038##

(51) LCMS: RT 1.18 min; ES+ 273 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.39-7.46 (m, 2H), 7.29-7.34 (m, 1H), 4.19 (m, 1H), 3.63 (m, 1H), 2.85-3.04 (m, 2H), 2.77 (dd, 1H), 2.38-2.54 (m, 2H), 1.82 (m, 1H), 1.27 (t, 3H).

(52) ##STR00039##

(53) LCMS: RT 1.07 min; ES+ 211 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.20 (d, 1H), 6.81 (d, 1H), 4.22 (q, 2H), 3.69 (m, 1H), 2.85-2.69 (m, 3H), 2.67-2.54 (m, 2H), 2.19-2.10 (m, 1H).

(54) ##STR00040##

(55) .sup.1H NMR (400 MHz, CDCl.sub.3): (data given for both diastereoisomers) δ ppm 4.12 (q, 4H), 1.38-2.28 (m, 27H), 1.25 (t, 6H), 1.22-1.28 (m, 2H), 1.12 (s, 3H), 1.01 (s, 3H).

(56) ##STR00041##

(57) LCMS: RT 1.14 min; ES+ 219 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.03-7.19 (m, 4H), 4.17 (q, 2H), 3.35 (m, 1H), 2.73-2.83 (m, 2H), 2.70 (dd, 1H), 2.52 (dd, 1H), 1.65-1.97 (m, 4H), 1.27 (t, 3H).

(58) ##STR00042##

(59) LCMS: RT 0.97 min; ES+ 207 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.10-7.20 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.75 (t, 1H), 4.26 (dd, 1H), 4.18 (q, 2H), 3.83-3.92 (m, 1H), 2.79 (dd, 1H), 2.58 (dd, 1H), 1.28 (t, 3H).

(60) ##STR00043##

(61) LCMS: RT 1.01 min; ES+ 221 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.07-7.14 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.13-4.24 (m, 4H), 3.36 (m, 1H), 2.79 (dd, 1H), 2.52 (dd, 1H), 2.16 (m, 1H), 1.79-1.90 (m, 1H), 1.28 (t, 3H).

(62) ##STR00044##

(63) LCMS: RT 1.19 min; ES+ 233 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm) 7.05-7.17 (m, 4H), 4.13 (q, 2H), 3.48 (m, 1H), 2.76-2.97 (m, 3H), 2.69 (dd, 1H), 1.66-1.94 (m, 4H), 1.47-1.64 (m, 2H), 1.22 (t, 3H).

(64) ##STR00045##

(65) LCMS: RT 1.21 min; ES+ 247 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm) 7.35 (m, 1H), 7.10-7.22 (m, 3H), 4.20 (q, 2H), 3.36 (dq, 1H), 2.69 (dd, 1H), 2.57 (dd, 1H), 2.00 (m, 1H), 1.79 (m, 1H), 1.67-1.75 (m, 1H), 1.51-1.64 (m, 1H), 1.24-1.36 (m, 9H).

Example 4: Preparation of Compound of Formula (IVb-28)

(66) ##STR00046##

(67) Compound of formula (IVa-1) (9.3 g, 46 mmol) was dissolved in tetrahydrofuran (90 mL) and methanol (46 mL) and a solution of lithium hydroxide (2.2 g, 91 mmol) in water (46 mL) was added dropwise. The resulting solution was stirred at room temperature for 1 hour and the volatiles were removed under reduce pressure. The aqueous residue was then acidified using an aqueous HCl solution (2M) and diluted with ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. Compound of formula (IVb-28) was obtained as a white solid in quantitative yield (46 mmol). LCMS: RT 0.85 min; ES+ 177 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.13-7.29 (m, 4H), 3.60 (m, 1H), 2.80-3.02 (m, 3H), 2.37-2.56 (m, 2H), 1.73-1.85 (m, 1H).

Example 4: Preparation of Compound of Formula (IVa-10)

(68) ##STR00047##

(69) Compound of formula (IVb-28) (0.80 g, 4.5 mmol) was dissolved in methanol (14 mL), sulfuric acid was added dropwise (0.026 mL, 0.45 mmol) and the resulting reaction mixture was stirred for 16 hours at 70° C. Water was then added and the pH adjusted to 7/8 using a saturated aqueous NaHCO.sub.3 solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude reaction residue was purified by flash chromatography on silica gel and compound of formula (IVa-10) was obtained as a light yellow oil in 98% yield (0.85 g, 4.47 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.12-7.34 (m, 4H), 3.75 (s, 3H), 3.62 (m, 1H), 2.85-3.02 (m, 2H), 2.81 (dd, 1H), 2.36-2.52 (m, 2H), 1.77 (m, 1H).

(70) A Similar Procedure was Used to Prepare the Following Compound:

(71) ##STR00048##

(72) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.16-7.28 (m, 4H), 3.59 (m, 1H), 2.84-3.02 (m, 2H), 2.73 (1H, dd), 2.34-2.46 (m, 2H), 1.79 (m, 1H), 1.51 (s, 9H).

Example 5: Preparation of Compound of Formula (IVc-37)

(73) ##STR00049##

(74) Under argon atmosphere, compound of formula (IVb-28) (2.0, 11 mmol) and one drop of dimethylformamide (DMF) was solved in dichloromethane (33 mL) and oxalyl chloride (1.26 mL, 13.2 mmol) was then added dropwise. The resulting reaction mixture was stirred for 3 hours at room temperature, purged with nitrogen and the volatiles were removed under vacuum. The resulting crude residue was then dissolved in tetrahydrofuran (THF, 22 mL), the solution cooled to 0° C., and methylamine (2M in THF, 16 mL, 33.0 mmol) was carefully added (dropwise) over 10 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The suspension was then diluted with dichloromethane and washed with an aqueous HCl solution (0.5M). The phases were separated and the organic phase was dried over sodium sulfate and concentrated under vacuum. The crude reaction residue was purified by flash chromatography on silica gel yielding to compound of formula (IVc-37) as a beige solid in 96% yield (2.0 g, 11 mmol). LCMS: RT 0.75 min; ES+ 190 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.14-7.27 (m, 4H), 5.42 (bs, 1H), 3.67 (m, 1H), 2.80-3.01 (m, 5H), 2.63 (dd, 1H), 2.40 (m, 1H), 2.31 (dd, 1H), 1.76 (m, 1H).

Example 6: Preparation of Compound of Formula (IVd-37)

(75) ##STR00050##

(76) Compound of formula (IVc-37) (0.58 g, 2.85 mmol) was dissolved in dichloromethane, Boc.sub.2O (1.3 g, 5.87 mmol), Et.sub.3N (0.50 mL, 3.52 mmol) and DMAP (0.04 g, 0.29 mmol) was added and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture was then diluted with dichloromethane and washed with an aqueous HCl (0.5M) solution, a saturated aqueous NaHCO.sub.3 solution and brine. The phases were separated and the organic phase was dried over sodium sulfate and concentrated under vacuum. The crude yellow oil was then purify by flash chromatography on silica gel affording compound of formula (IVd-37) as a yellow oil in 97% yield (0.87 g, 2.86 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.11-7.28 (m, 4H), 3.67 (m, 1H), 3.38 (dd, 1H), 3.18 (s, 3H), 2.80-3.03 (m, 3H), 2.41 (m, 1H), 1.70 (m, 1H), 1.51 (bs, 9H).

Example 7: Preparation of Compound of Formula (IIIa-1)

(77) ##STR00051##

(78) Compound of formula (Iva-1) (1.0 g, 4.89 mmol) was dissolved in dichloromethane (14.7 mL) and ethyl formate was added. The resulting reaction mixture was cooled to 0° C. and TiCl4 (1.07 mL, 9.79 mmol) was added dropwise followed by slow addition of Et.sub.3N (1.63 mL, 11.7 mmol). The resulting solution was then stirred for 1.5 hours at 0° C., diluted with dichloromethane and quenched with ice-water. The organic phase was washed three times with water, dried over sodium sulfate and concentrated under vacuum. The crude reaction residue was purified by flash chromatography on silica gel affording compound of formula (IIa-I) as a yellow oil (mixture of isomer, Z/E-enol and aldehyde) in 96% yield (1.15 g, 4.70 mmol). LCMS: RT 1.17 min; ES-231 (M−H.sup.+).

(79) A Similar Procedure was Used to Prepare the Following Compounds:

(80) TABLE-US-00002 LCMS Compounds (method A) (IIa-76) 1.16 min; 217 (M − H.sup.+) (IIa-70) 1.26 min; 299 (M − H.sup.+) (IIa-68) 1.25 min; 245 (M − H.sup.+) (IIa-66) 1.14 min; 275 (M − H.sup.+) (IIa-64) 1.09 min; 291 (M − H.sup.+) (IIa-72) 1.23 min; 301 (M + H.sup.+) (IIa-10) 1.10 min; 217 (M − H.sup.+) (IIa-82) 1.16 min; 237 (M − H.sup.+) 0 (IIa-86) 1.32 min; 237 (M − H.sup.+) (IIa-74) 0.91 min; 233 (M + H.sup.+) (IIa-94) 1.03 min; 233 (M − H.sup.+) (IIa-90) 1.09 min; 248 (M − H.sup.+) (IIa-102) 1.24 min; 259 (M − H.sup.+) (IIa-98) 1.30 min; 273 (M − H.sup.+)

Example 8: Preparation of Compound of Formula (IIa-19)

(81) ##STR00066##

(82) Compound of formula (Iva-19) (0.2 g, 0.86 mmol) was dissolved in tetrahydrofurane (2.6 mL), the solution cooled to −78° C. and a solution of lithiumdiisopropylamide (0.16 mL, 1.3 mmol) was slowly added dropwise. After 30 min at −78° C., ethyl formate (0.19 g, 2.58 mmol) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature and further stirred for 3 hours. The reaction was then diluted with ethyl acetate and quenched with an aqueous HCl solution (0.50 M) until pH reached 6. The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic fractions were dried over sodium sulfate, concentrated under vacuum affording compound of formula (IIa-19) as an orange oil in 93% yield (0.22 g, 0.80 mmol). LCMS: RT 1.30 min; ES− 259 (M−H.sup.+).

Example 9: Preparation of Compound of Formula (IId-37)

(83) ##STR00067##

(84) Compound of formula (IVd-37) (0.37 g, 1.28 mmol) was treated with Bredereck's reagent (1.24 g, 1.47 mL, 4.39 mmol) and the reaction mixture was heated to 100° C. and stirred for 9 hours. The reaction mixture was then diluted with ethyl acetate (90 ML) and washed with water (35 mL) and brine (35 mL). The phases were separated and the organic phase was dried over sodium sulfate and concentrated under vacuum affording compound of formula (Vd-37) as a a crude brown oil in 87% yield (0.48 g, 1.11 mmol) which was progressed in the next step without further purification.

(85) Compound of formula (Vd-37) (0.48 g, 1.11 mmol) was dissolved in dioxane (4.5 mL), aqueous HCl (1M, 1.11 mL) was added and the resulting solution was stirred for 4 hours at room temperature. Saturated aqueous NaHCO.sub.3 solution was added followed by ethyl acetate (30 mL). After vigorous stirring for 5 minutes, the phases were separated and the organic fraction was washed with brine, dried over sodium sulfate and concentrated under vacuum affording compound of formula (IId-37) (0.3 g, 0.97 mmol) which was progressed in the next step without further purification.

Example 10: Preparation of Compound of Formula (I-1)

(86) ##STR00068##

(87) Compound of formula (IIa-1) (0.15 g, 0.61 mmol) was dissolved in anhydrous 1,2-dimethoxyethane (4 mL), the resulting solution cooled to 0° C. and tBuOK (0.08 g, 0.73 mmol) was then added. After 10 minutes at 0° C., known compound of formula (IIIa-1) (0.1 g, 0.74 mmol) was added as a solution in 1 mL of DME. The reaction mixture was then slowly warmed to room temperature. After 16 hours, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude reaction residue was purified by flash chromatography on silica gel affording compound of formula (I-1) as a colorless oil and as a mixture of diastereoisomers in 60% yield (0.12 g, 0.36 mmol). LCMS: RT 1.09 min; ES+ (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for one diastereoisomers: δ ppm 7.56 (bs, 1H), 6.86-7.13 (m, 4H), 6.74 (m, 1H), 6.01 (bs, 1H), 4.38 (m, 1H), 4.03 (q, 2H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 1.89 (m, 3H), 1.09 (t, 3H).

(88) A Similar Procedure was Used to Prepare the Following Compounds:

(89) ##STR00069##

(90) Using compound known compound 2-chloro-3,4-dimethyl-2H-furan-5-one (IIIa-2) (WO 2012/056113).

(91) LCMS: RT 1.13 min; ES+ 343 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.58 (bs, 1H), 7.53 (bs, 1H), 6.87-7.13 (m, 8H), 5.79 (bs, 1H), 5.65 (bs, 1H), 4.38 (bt, 2H), 4.09 (q, 2H), 4.02 (m, 2H), 2.75-3.01 (m, 4H), 2.19-2.30 (m, 2H), 1.99-2.12 (m, 2H), 1.76 (bs, 3H), 1.74 (bs, 3H), 1.50 (bs, 3H), 1.48 (bs, 3H), 1.15 (t, 3H), 1.07 (t, 3H).

(92) ##STR00070##

(93) Using compound (IIIa-1). LCMS: RT 1.03 min; ES+ 315 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.65 (bs, 1H), 7.63 (bs, 1H), 6.96-7.24 (m, 8H), 6.81 (m, 1H), 6.65 (m, 1H), 6.08 (m, 1H), 6.00 (m, 1H), 4.47 (td, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.01-3.11 (m, 2H), 2.86-2.97 (m, 2H), 2.28-2.38 (m, 2H), 2.13-2.23 (m, 2H), 1.98 (m, 6H),

(94) ##STR00071##

(95) Using compound (IIIa-2). LCMS: RT 1.07 min; ES+ 329 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.67 (bs, 1H), 7.62 (bs, 1H), 6.97-7.23 (m, 8H), 5.87 (s, 1H), 5.74 (s, 1H), 4.48 (m, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 2.86-3.12 (m, 4H), 2.30-2.40 (m, 2H), 2.09-2.24 (m, 2H), 1.88 (bs, 3H), 1.85 (bs, 3H), 1.83 (bs 3H), 1.56 (m, 3H).

(96) ##STR00072##

(97) Using compound (IIIa-1). LCMS: RT 1.15 min; ES+ 343 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.61 (bs, 1H), 7.60 (bs, 1H), 6.97-7.04 (m, 2H), 6.89-6.96 (m, 2H), 6.77-6.85 (m, 3H), 6.66 (m, 1H), 6.09 (bs, 1H), 6.00 (bs, 1H), 4.46 (m, 2H), 4.02-4.14 (m, 4H), 2.92-3.04 (m, 2H), 2.73-2.84 (m, 2H), 2.24 (bs, 6H), 2.07-2.38 (m, 4H), 1.97 (m, 6H), 1.15 (q, 3H), 1.14 (q, 3H).

(98) ##STR00073##

(99) Using compound (IIIa-2). LCMS: RT 1.19 min; ES+ 357 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.63 (bs, 1H), 7.60 (bs, 1H), 6.96-7.05 (m, 2H), 6.88-6.95 (m, 2H), 6.77-6.87 (m, 2H), 5.87 (bs, 1H), 5.73 (bs, 1H), 4.46 (m, 2H), 4.03-4.19 (m, 4H), 2.87-3.05 (m, 2H), 2.71-2.85 (m, 2H), 2.24 (s, 3H), 2.23 (s, 3H), 1.94-2.40 (m, 4H), 1.84 (s, 3H), 1.82 (s, 3H), 1.57 (s, 3H), 1.54 (s, 3H), 1.22 (t, 3H), 1.14 (t, 3H).

(100) ##STR00074##

(101) Using compound (IIIa-1). LCMS: RT 1.16 min; ES+ 397 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.66 (bs, 1H), 7.65 (bs, 1H), 7.38 (bs, 1H), 7.37 (bs, 1H), 7.28 (bs, 1H), 7.26 (bs, 1H), 7.23 (bs, 1H), 7.19 (bs, 1H), 6.84 (m, 1H), 6.61 (m, 1H), 6.11 (m, 1H), 6.00 (m, 1H), 4.46 (t, 2H), 4.01-418 (m, 4H), 3.00.3.15 (m, 2H), 2.87-2.99 (m, 2H), 2.32-2.44 (m, 2H), 2.09-2.27 (m, 4H), 1.98 (m, 3H), 1.95 (m, 3H), 1.18 (m, 3H), 1.12 (m, 3H).

(102) ##STR00075##

(103) Using compound (IIIa-2). LCMS: RT 1.19 min; 419 ES− (M−H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.68 (s, 1H), 7.64 (s, 1H), 7.38 (bs, 1H), 7.36 (bs, 1H), 7.24-7.31 (m, 3H), 7.19 (bs, 1H), 5.89 (bs, 1H), 5.72 (bs, 1H), 4.47 (t, 2H), 4.19 (q, 2H), 4.03-4.15 (m, 2H), 2.86-3.15 (m, 4H), 2.34-2.45 (m, 2H), 2.05-2.29 (m, 2H), 1.87 (bs, 3H), 1.85 (bs, 3H), 1.80 (bs, 3H), 1.46 (bs, 3H), 1.25 (t, 3H), 1.14 (t, 3H).

(104) ##STR00076##

(105) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.60 (bs, 1H), 7.58 (bs, 1H), 6.83 (m, 1H), 6.75 (m, 1H), 6.72 (bs, 2H), 6.53 (bs, 1H), 6.49 (bs, 1H), 6.10 (m, 1H), 6.03 (m, 1H), 4.41 (td, 2H), 4.05-4.14 (m, 4H), 3.85 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 2.94-3.03 (m, 2H), 2.79-2.90 (m, 2H), 2.32 (m, 2H), 2.11-2.21 (m, 2H), 1.98 (m, 6H), 1.17 (t, 3H), 1.15 (t, 3H).

(106) ##STR00077##

(107) Using compound (IIIa-2). LCMS: RT 1.04 min; 402 ES+(M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.63 (bs, 1H), 7.57 (bs, 1H), 6.72 (bs, 2H), 6.55 (bs, 1H), 6.50 (bs, 1H), 5.87 (bs, 1H), 5.76 (bs, 1H), 4.42 (t, 2H), 4.06-4-19 (m, 4H), 3.84 (s, 6H), 3.81 (s, 3H), 3.78 (s, 3H), 2.78-3.02 (m, 4H), 2.28-2.40 (m, 2H), 2.08-2.20 (m, 2H), 1.88 (bs, 3H), 1.84 (bs, 3H), 1.83 (bs, 3H), 1.68 (bs, 3H), 1.22 (t, 3H), 1.17 (t, 2H).

(108) ##STR00078##

(109) Using compound (IIIa-1). LCMS: RT 1.06 min; 373 ES+ (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.61 (bs, 1H), 7.59 (bs, 1H), 6.86 (m, 1H), 6.77 (m, 1H), 6.64 (bs, 1H), 6.63 (bs, 1H), 6.46 (bs, 1H), 6.43 (bs, 1H), 6.09 (m, 1H), 6.03 (m, 1H), 5.86-5.90 (m, 4H), 4.35 (t, 2H), 4.05-4.16 (m, 4H), 2.88.2-97 (m, 2H), 2.13-2.23 (m, 2H), 1.99 (m, 6H), 1.19 (t, 3H), 1.18 (t, 3H).

(110) ##STR00079##

(111) Using compound (IIIa-1). LCMS: RT 1.19 min; ES+ 397 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.64 (bs, 1H), 7.60 (bs, 1H), 7.33-7.42 (m, 1H), 7.13-7.22 (m, 2H), 6.77 (bs, 1H), 6.86 (bs, 1H), 6.04 (bs, 1H), 6.00 (bs, 1H), 4.48 (m, 2H), 4.10 (q, 4H), 3.17-3.30 (m, 2H), 2.96-3.09 (m, 2H), 2.39 (m, 2H), 2.15 (m, 2H), 1.97 (s, 3H), 1.93 (s, 3H), 1.15 (t, 6H).

(112) ##STR00080##

(113) Using compound (IIIa-1). LCMS: RT 1.07 min; ES+ 315 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.55 (bs, 1H), 7.54 (bs, 1H), 7.09-7.20 (m, 2H), 6.97-7.04 (m, 2H), 6.80 (m, 1H), 6.70 (m, 1H), 6.03 (m, 1H), 6.00 (m, 1H), 4.58 (m, 1H), 4.07-4.17 (m, 4H), 3.44-3.53 (m, 2H), 3.26 (td, 2H), 1.96-2.00 (m, 6H), 1.17 (t, 3H), 1.16 (t, 3H).

(114) ##STR00081##

(115) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.55 (s, 2H), 7.16-7.22 (m, 2H), 7.08-7.14 (m, 4H), 6.96-7.04 (m, 2H), 6.85 (m, 1H), 6.72 (m, 1H), 6.11 (m, 1H), 6.03 (m, 1H), 4.44 (m, 2H), 2.87-3.07 (m, 4H), 2.26-2.36 (m, 2H), 2.12-2.24 (m, 2H), 1.99 (m, 6H), 1.31 (s, 9H), 1.27 (s, 9H).

(116) ##STR00082##

(117) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.56 (bs, 1H), 7.55 (bs, 1H), 6.97-7.21 (m, 81H), 5.89 (bs, 1H), 5.77 (bs, 1H), 4.45 (bt, 2H), 2.95 (m, 2H), 2.28-2.38 (m, 2H), 2.03-2.24 (m, 4H), 1.93 (bs, 3H), 1.86 (bs, 3H), 1.84 (bs, 3H), 1.64 (bs, 3H), 1.38 (s, 9H), 1.29 (s, 9H).

(118) ##STR00083##

(119) Using compound (IIIa-1). LCMS: RT 1.06 min; ES+ 335 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.53 (bs, 1H), 7.51 (bs, 1H), 7.13 (m, 2H), 6.87 (m, 1H), 6.73 (m, 2H), 6.69 (m, 1H), 6.08 (m, 1H), 5.98 (m, 1H), 4.53-4.46 (m, 2H), 4.19-4.07 (m, 4H), 2.93-2.80 (m, 2H), 2.79-2.66 (m, 4H), 2.53-2.42 (m, 2H), 1.99 (m, 3H), 1.98 (m, 3H), 1.22 (t, 3H), 1.18 (t, 3H).

(120) ##STR00084##

(121) Using compound (IIIa-2). LCMS: RT 1.11 min; ES+ 349 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.57 (s, 1H), 7.51 (s, 1H), 7.12 (m, 1H), 6.72 (m, 1H), 5.87 (bs, 1H), 5.75 (bs, 1H), 4.48-4.55 (m, 2H), 4.08-4.22 (m, 4H), 2.66-2.83 (m, 6H), 2.39-2.55 (m, 2H), 1.93 (m, 3H), 1.86 (m, 3H), 1.84 (m, 3H), 1.68 (m, 3H), 1.26 (t, 3H), 1.20 (t, 3H).

(122) ##STR00085##

(123) Using compound (IIIa-1). (I-86) obtained and isolated as a mixture of diastereoisomers. LCMS: RT 1.21 min; ES+ 335 (M+H.sup.+).

(124) ##STR00086##

(125) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.12 min; ES+ 343 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.62 (s, 1H), 7.61 (s, 1H), 6.91-7.06 (m, 8H), 6.80 (m, 1H), 6.62 (m, 1H), 6.08 (m, 1H), 5.96 (m, 1H), 4.11-4.18 (m, 2H), 4.00-4.10 (m, 4H), 2.69-2.88 (m, 4H), 1.89-1.99 (m, 12H), 1.14 (t, 3H), 1.10 (t, 3H).

(126) ##STR00087##

(127) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.16 min; ES+ 357 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.62 (s, 1H), 7.60 (s, 1H), 6.92-7.05 (m, 8H), 5.86 (bs, 1H), 5.71 (bs, 1H), 4.00-4.20 (m, 6H), 2.70-2.87 (m, 4H), 1.87-2.00 (m, 9H), 1.80-1.85 (m, 6H), 1.64-1.76 (m, 2H), 1.54 (m, 3H), 1.20 (t, 3H), 1.12 (t, 3H).

(128) ##STR00088##

(129) Using compound (IIIb, WO2015/128321). LCMS: RT 1.31 min; ES− 538 (M−H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 8.16 (bs, 4H), 7.69 (bs, 1H), 7.66 (bs, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.12-7.17 (m, 2H), 7.06 (m, 2H), 6.97-7.03 (m, 1H), 6.94 (m, 1H), 6.80 (m, 1H), 6.74 (m, 1H), 6.66 (m, 1H), 6.59 (m, 1H), 6.18 (m, 1H), 6.11 (m, 1H), 4.41 (m, 2H), 3.95-4.09 (m, 4H), 2.79-3.04 (m, 4H), 2.19-2.29 (m, 1H), 1.95-2.12 (m, 9H), 1.09 (t, 3H), 1.03 (t, 3H).

(130) ##STR00089##

(131) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 0.98 min; ES+ 331 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.66 (bs, 1H), 7.63 (bs, 1H), 7.06-7.14 (m, 2H), 6.98-7.05 (m, 2H), 6.73-6.85 (m, 5H), 6.68 (m, 1H), 6.10 (m, 1H), 6.00 (m, 1H), 4.77-4.85 (m, 2H), 4.67-4.75 (m, 2H), 4.45-4.52 (m, 2H), 4.08-4.22 (m, 4H), 2.00 (m, 3H), 1.98 (m, 3H), 1.20 (t, 3H), 1.17 (t, 3H).

(132) ##STR00090##

(133) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.02 min; ES+ 345 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.70 (bs, 1H), 7.63 (bs, 1H), 6.98-7.14 (m, 4H), 6.71-6.86 (m, 4H), 5.87 (bs, 1H), 5.76 (bs, 1H), 4.78-4.88 (m, 2H), 4.67-4.77 (m, 2H), 4.41-4.52 (m, 2H), 4.10-4.20 (m, 4H), 1.91 (m, 3H), 1.86 (m, 3H), 1.85 (m, 3H), 1.64 (m, 3H), 1.28 (t, 3H), 1.20 (t, 3H).

(134) ##STR00091##

(135) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.01 min; ES+ 345 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.66 (bs, 1H), 7.63 (bs, 1H), 6.99-7.09 (m, 2H), 6.88-6.96 (m, 2H), 6.71-6.81 (m, 5H), 6.50 (m, 1H), 6.04 (m, 1H), 5.90 (m, 1H), 4.04-4.34 (m, 10H), 2.22-2.36 (m, 2H), 1.92-2.02 (m, 8H), 1.18 (t, 3H), 1.15 (t, 3H).

(136) ##STR00092##

(137) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.04 min; ES+ 359 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.66 (bs, 1H), 7.62 (bs, 1H), 6.95-7.06 (m, 3H), 6.91 (m, 1H), 6.70-6.81 (m, 3H), 5.82 (bs, 1H), 5.66 (bs, 1H), 4.05-4.32 (m, 10H), 2.17-2.32 (m, 2H), 1.93-2.05 (m, 2H), 1.87 (m, 3H), 1.80 (m, 6H), 1.47 (m, 3H), 1.25 (t, 3H), 1.17 (t, 3H).

(138) ##STR00093##

(139) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.13 min; ES+ 357 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.74 (bs, 1H), 7.72 (bs, 1H), 7.04-7.14 (m, 6H), 6.94-7.00 (m, 2H), 6.84 (m, 2H), 6.11 (m, 1H), 6.08 (m, 1H), 4.23-4.29 (m, 2H), 4.18 (m, 4H), 2.73-3.00 (m, 5H), 1.83-2.04 (m, 15H), 1.29-1.42 (m, 2H), 1.27 (t, 3H), 1.26 (t, 3H).

(140) ##STR00094##

(141) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.17 min; ES+ 371 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.76 (bs, 1H), 7.73 (bs, 1H), 7.03-7.13 (m, 6H), 6.96-7.01 (m, 2H), 5.90 (bs, 1H), 5.88 (bs, 1H), 4.25-4.30 (m, 2H), 4.18 (q, 4H), 2.89-3.01 (m, 2H), 2.74-2.86 (m, 2H), 1.81-2.03 (m, 22H), 1.30-1.40 (m, 2H), 1.27 (t, 6H).

(142) ##STR00095##

(143) Using compound (IIIa-1). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.20 min; ES+ 371 (M+H.sup.+)

(144) ##STR00096##

(145) Using compound (IIIa-2). .sup.1H NMR (400 MHz, CDCl.sub.3) LCMS: RT 1.23 min; ES+ 385 (M+H.sup.+)

Example 10: Preparation of Compound of Formula (I-37)

(146) ##STR00097##

(147) Compound of formula (IId-37) (0.27 g, 0.74 mmol) was dissolved in anhydrous 1,2-dimethoxyethane (6 mL), the resulting solution cooled to 0° C. and tBuOK (0.10 g, 0.89 mmol) was then added. After 10 minutes at 0° C., known compound of formula (IIIa-1) (0.11 g, 0.89 mmol) was added as a solution in 1.4 mL of DME. The reaction mixture was then slowly warmed to room temperature. After 3 hours, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude reaction residue was purified and the isomers separated by flash chromatography on silica gel affording compound of formula (I-37-1) (0.033 g, 0.10 mmol) and compound of formula (I-37-2) (0.087 g, 0.28 mmol) in 14 and 37% yield respectively.

(148) Compound of formula (I-37-1) LCMS: RT 0.88 min; ES+ 314 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.52 (s, 2H), 7.07-7.23 (m, 8H), 6.87 (m, 1H), 6.84 (m, 1H), 6.14 (m, 1H), 6.11 (m, 1H), 4.99 (m, 2H), 4.56 (m, 2H), 2.86-3.06 (m, 4H), 2.61-2.65 (m, 6H), 2.27-2.40 (m, 2H), 1.94-2.06 (m, 8H).

(149) Compound of formula (I-37-2) LCMS: RT 0.87 min; ES+ 314 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.09-7.26 (m, 8H), 6.87 (m, 2H), 6.64 (bs, 1H), 6.55 (bs, 1H), 6.20 (s, 1H), 6.19 (s, 1H), 5.93 (m, 1H), 5.90 (m, 1H), 4.37 (m, 2H), 2.79-3.00 (m, 10H), 2.48 (m, 2H), 1.98 (bs, 6H), 1.84-1.94 (m, 2H).

(150) An identical procedure was used to prepare compounds of formula (I-55-1/2) using intermediate (IIIb, WO2015/128321):

(151) ##STR00098##

(152) LCMS (I-55-1): RT 1.12 min; ES− 523 (M−H.sup.+); LCMS (I-55-2): RT 1.16 min; ES− 523 (M−H.sup.+);

(153) A Similar Synthetic Route was Used to Prepare the Following Compounds:

(154) For compound numbers with a suffix, the suffix refers to different isomeric forms, for example I-49-1 and I-49-2 refer to the E and Z isomers respectively of compound I-49.

(155) Compound of Formula (I-49-1)

(156) ##STR00099##

(157) LCMS: RT 0.91 min; ES+ 328 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.08-7.23 (m, 8H), 6.79 (m, 2H), 6.48 (bs, 2H), 6.01 (m, 2H), 4.34 (t, 2H), 2.80-3.03 (m, 4H), 2.94 (bs, 12H), 2.30-2.40 (m, 2H), 2.06-2.16 (m, 2H), 1.95 (m, 6H).

(158) Compound of Formula (I-49-2)

(159) ##STR00100##

(160) LCMS: RT 0.88 min; ES+ 328 (M+H.sup.+); .sup.1H NMR (400 MHz, CDCl.sub.3) Data given for the two diastereoisomers: δ ppm 7.13-7.32 (8H), 6.84 (m, 2H), 6.00 (m, 1H), 5.95 (m, 1H), 5.90 (m, 1H), 5.88 (m, 1H), 4.08 (m, 1H), 3.98 (m, 1H), 2.76-3.04 (m, 4H), 2.97 (bs, 3H), 2.95 (bs, 3H), 2.91 (bs, 3H), 2.89 (bs, 3H), 2.26-2.38 (m, 2H), 2.01-2.16 (m, 2H), 1.95 (m, 6H).

Example B1—Corn Seed Germination

(161) The effect of compounds of formula (I) on the germination of NK Falkone 2015 corn seeds under cold stress was evaluated as follows. NK Falkone corn seeds were sorted by size using 2 sieves, one excluding very big seeds and the other with round holes of 8 to 9 mm diameter. The seeds retained by the latter sieve were used for the germination test. The corn seeds were placed in 24 well plates (each plate was considered as one experimental unit or replicate). Germination was initiated by the addition of 250 μl of distilled water containing 0.5% DMSO per well as a means for compound solubilization. 8 replicates (ie, 8 plates) were used for each treatment characterization. Plates were sealed using seal foil (Polyolefin Art. Nr. 900320) from HJ-BIOANALYTIK. All plates were placed horizontally on trolleys in a climatic chamber at 15° C. The experiment was laid out in a completely randomized design in climatic chamber with 75% Relative Humidity. Foils were pierced, one hole per well using a syringe after 72 hours for experiments performed at 15° C.

(162) Germination was followed over time by taking photographs at different time points. Image analysis was performed automatically with a macro which was developed using the Image J software. A dynamic analysis of germination was carried out by fitting a logistic curve. Three parameters were calculated from the logistic curve: the T50; the slope and the plateau. All three parameters have a high agronomical relevance and are key requirements to ensure a good early crop-establishment. The T50 and slope for compounds tested are shown in Table 2 below. All the values are expressed as percentages compared to an untreated control. All the three parameters are calculated considering 8 replicates and the kinetic parameters are separately determined for each germination curve. Data in bold indicate germination enhancing statistically significant differences between treated seeds and untreated control (p<0.05). The T50 corresponds to the time needed for half of the seed population to germinate. Higher negative %-values indicate faster germination. The slope indicates how synchronous the germination of the seed population is. Positive values indicate steeper curve; the steeper the curve, the better and more uniform the germination is.

(163) TABLE-US-00003 TABLE 2 Effect of strigolactone analogues on germination of Falkone 2015 corn seeds under cold stress condition (15° C.) at various concentrations. Slope (% vs T50 (% vs Compound Reference Rate (μM).sup.a control).sup.b control).sup.b 01   Prior art 1: GR24 J. Chem. Soc., Perkin Trans. 1: Organic and Bio-Organic Chemistry, 1981, 6, 1734-1743  2 10 50 250   −0.7   −11.3     6.2     36.3   −1.5   −0.1   −1.85  −3.40 02   Prior art 2 Plant Physiology, 2012, 159, 1524-1544  2 10 50 250   −1.3     1.4     9.6     15.8   −1.5     1.7   −1.6   −2.1  03   Prior art 3 J. Chem. Soc., Perkin Trans. 1: Organic and Bio-Organic Chemistry, 1981, 6, 1734-1743  2 10 50 250   −0.7     2.2     4.0     14.1     1.6     0     −0.8   −0.5  04   Prior art 4 J. Agrlc. Food Chem. 40, 1992, 1222-1229  2 10 50 250   −7.7     14.9   −11.4     4.1     1.2   −3.4     2.4     0.1  05   Prior art 5 J. Agrlc. Food Chem. 40, 1992, 1222-1229 (R═Me)  2 10 50 250     0.9     7.4     21.8     23.9     3.1     1.8   −0.7   −2.7  06   Compound I-1 n/a  2 10 50 250     8.1     10.0     27.9    142.0   −0.5     1.6   −2.8   −7.2  07   Compound I-2 n/a  2 10 50 250   −11.8     18.1     47.0    121.2     2.3   −3.0   −6.2  −10.1  08   Compound I-10 n/a  2 10 50 250     8.2     10.7     30.3     82.5   −0.9   −0.8   −3.3   −7.4  09   Compound I-11 n/a  2 10 50 250     11.4     7.4     20.1     89.6   −1.0     0.2   −5.1   −6.9  0   Compound I-64 n/a  2 10 50 250     1.1   −1.6     27.9     83.8   −1.4   −3.2   −4.6  −10.7    Compound I-65 n/a  2 10 50 250     1.0     18.8     23.0    122.9   −0.9   −3.1   −2.6  −12.6    Compound I-76 n/a   0.4  2 10 50  −5.6   −5.0     50.6    121.6   −0.5   −0.7   −6.4   −8.8    Compound I-73 n/a  2 10 50 250   −1.1     14.2     57.8     54.1   −3.5   −6.3   −7.8   −9.2    Compound I-70 n/a  2 10 50 250     9.0     18.4     87.9    114.6   −2.5   −0.2   −6.8   −8.6    Compound I-68 n/a  2 10 50 250     23.4     3.8     44.7    112.7   −1.2   −0.6   −5.7   −6.8    Compound I-66 n/a  2 10 50 250     22.6     2.9     34.5     31.6   −5.2   −2.9   −5.1   −5.8    Compound I-83 n/a  2 10 50 250     6.5     34.1     32.6    157.2   −3.0   −2.2   −4.8   −8.6    Compound I-75 n/a  2 10 50 250     4.9     5.6     58.4     44.2   −3.5   −2.6   −6.5   −5.0    Compound I-55-1 n/a  2 10 50 250   −8.1     3.8     61.1     89.8     1.7   −1.4   −6.8  −10.6  0   Compound I-7 n/a  2 10 50 250     63.9     69.8     78.8     11.3   −3.4   −3.5   −6.6   −1.8    Compound I-37-1 n/a  2 10 50 250     10.8   −15.7     5.2     51.7   −1.3   −2.5   −2.6   −4.6    Compound I-86 n/a  2 10 50 250     17.1     20.2    138.3    149.9     0.2   −2.7   −9.7  −11.2    Compound I-95 n/a  2 10 50 250   −2.0   −13.9     2.7     81.5     1.6     1.6     0.6   −6.7    Compound I-90 n/a  2 10 50 250   −10     −0.32    4.6     83.6     3.2     2.8     0.45  −6.7    Compound I-91 n/a  2 10 50 250   −15.3   −5.4    18.8     67.4     2.5     2.7   −1.5   −6.1  .sup.aConcentration of compound in 250μl distilled water containing 0.5% DMSO .sup.bControl = 250μl distilled water containing 0.5% DMSO; T50 = 110 hours

(164) The results show that corn seeds treated with compounds of the present invention exhibited faster (more negative T50) and more synchronous (more positive slope) germination than prior art compounds.