Heterocyclic compounds as antibacterials

Abstract

The present invention relates to the following compounds ##STR00001##
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.

Claims

1. A compound of formula (I) ##STR00025## or a pharmaceutically acceptable salt thereof wherein R.sup.1 represents C.sub.1-6 alkyl or hydrogen; L.sup.1 represents a linker group —C(R.sup.a)(R.sup.b)—; X.sup.1 represents an optional carbocyclic aromatic linker group, which linker group may itself be optionally substituted by one or more substituents selected from fluoro, —OH, —OC.sub.1-6 alkyl and C.sub.1-6 alkyl, wherein the latter two alkyl moieties are themselves optionally substituted by one or more fluoro atoms; n1 and n2 independently represent 0 or 1; R.sup.a and R.sup.b independently represent hydrogen or C.sub.1-6 alkyl optionally substituted by one or more fluoro atoms; X.sup.a represents or —C(R.sup.a1)(R.sup.b1).sub.m— or —N(R.sup.c1)—; m represents 1; each R.sup.a1 and R.sup.b1 independently represents fluoro, hydrogen or C.sub.1-6 alkyl; R.sup.c1 represents hydrogen or C.sub.1-6 alkyl; Q.sup.5 represents one or more independent substituents selected from: halo; C.sub.1-6 alkyl optionally substituted by one or more halo; —OC.sub.1-6 alkyl optionally substituted by one or more halo; aryl; and heteroaryl, which latter two aromatic groups may themselves be optionally substituted by one or more substituents selected from halo, C.sub.1-6 alkyl and —OC.sub.1-6 alkyl, which latter two alkyl moieties may themselves be substituted with one or more fluoro atoms; ring A is a 5-membered aromatic ring containing at least one heteroatom; ring B is a 5- or 6-membered ring, which may be aromatic or non-aromatic, optionally containing one to four heteroatoms; either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, C.sub.1-6 alkyl optionally substituted by one or more halo atoms or —OC.sub.1-6alkyl optionally substituted by one or more fluoro atoms.

2. The compound as claimed in claim 1, wherein: R.sup.1 represents hydrogen; R.sup.a and R.sup.b independently represent hydrogen; and/or L.sup.1 represents —CH.sub.2—.

3. The compound as claimed in claim 1, wherein X.sup.1 represents a carbocyclic aromatic linker group that is: -phenylene-: or ##STR00026## -naphthylene; ##STR00027##

4. The compound as claimed in claim 1, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

5. The compound as claimed in claim 1 wherein: ring A is represented as follows: ##STR00028## and/or ring B is represented as follows: ##STR00029## wherein “SUB” and “Sub” represent one or more possible substituents on the relevant atom.

6. The compound as claimed in claim 1, wherein the combined ring systems Ring A and Ring B may be represented as follows: ##STR00030## ##STR00031## where “SUB” represents one or more possible substituents on the bicycle and “Sub” represents a possible optional substituent on the N atom of the bicycle.

7. The compound of formula (I) as defined in claim 1 wherein: L.sup.1 represents —CH.sub.2—; X.sup.a represents —CH.sub.2— and which is substituted by one or two Q.sup.5 substituent(s).

8. The compound as claimed in claim 7, wherein: Q.sup.5 represents halo or C.sub.1-3 alkyl optionally substituted by one or more fluoro atoms; one or two Q.sup.5 substituents are only present on V.

9. The compound as claimed in claim 7, wherein: ring A and ring B together represent a 8 or 9-membered bicyclic ring containing at least one nitrogen atom wherein at least one nitrogen atom is common to both rings; optional substituents on ring A and ring B are halo, C.sub.1-3 alkyl and —OC.sub.1-3 alkyl.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in claim 7.

11. A method for treating a patient suffering from tuberculosis, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) as defined in claim 1.

12. A method of treatment of a bacterial infection, which method comprises administration of a therapeutically effective amount of a compound according to claim 1.

13. A combination of (a) a compound according to claim 1, and (b) one or more other anti-tuberculosis agent.

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

15. The compound as claimed in claim 2, wherein X′ represents a carbocyclic aromatic linker group that is: -phenylene-: or ##STR00032## -naphthylene: ##STR00033##

16. The compound as claimed in claim 1, wherein X.sup.1 is absent.

17. The compound as claimed in claim 2, wherein X.sup.1 is absent.

18. The compound as claimed in claim 2, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

19. The compound as claimed in claim 3, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

20. The compound as claimed in claim 15, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

21. The compound as claimed in claim 16, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

22. The compound as claimed in claim 17, wherein: X.sup.a represents —CH.sub.2— which is substituted by one or more Q.sup.5 substituents; and/or Q.sup.5 represents halo.

Description

EXAMPLES

Synthesis of Compound 1

(1) ##STR00017##

Preparation of Intermediate M

(2) A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [12161242-18-5], 1 g, 4.45 mmol), 4-iodobenzenemethanamine (CAS [39959-59-6], 1.09 g, 4.67 mmol), EDCI.HCl (1.28 g, 6.68 mmol), HOBT (0.601 g, 4.45 mmol) and triethylamine (1.24 mL, 9 mmol) in dichloromethane (8 mL) was stirred and heated at 45° C. for 24 hours. The solution was cooled down to 15° C. The solid was collected by filtration, washed with water and acetonitrile and the solid was dried (vacuum, 45° C., 1 hour) to give intermediate M, 1.2 g, 55%.

(3) Preparation of Compound 1

(4) A solution of 5-fluorooctahydrocyclopenta[c]pyrrole (CAS [1554431-13-8], 0.1 g, 0.604 mmol), intermediate M (0.319 g, 0.725 mmol), Pd(dba).sub.2 (0.035 g, 0.06 mmol), Xphos (0.052 g, 0.12 mmol) and sodium tert-butoxide (0.29 g, 3.02 mmol) in 1,4-dioxane (5 mL) was irradiated under microwave at 110° C. for 1 h under N2. Dichloromethane (50 mL) was added and the mixture was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/0 to 0/1). The desired fractions were collected and concentrated. The residue was washed with methanol (10 mL), dried (vacuum, 45° C., 1 hour) to give Compound 1, 0.105 g, 38%.

(5) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ=9.52 (d, J=1.7 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.58-7.48 (m, 1H), 7.34-7.27 (m, 1H), 7.24 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H), 6.67-6.56 (m, 2H), 6.14 (br. s., 1H), 5.99 (br. s., 1H), 5.35-5.12 (m, 1H), 4.64 (d, J=5.9 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H), 3.39-3.28 (m, 2H), 3.20 (dd, J=2.2, 9.5 Hz, 2H), 2.99-2.98 (m, 1H), 3.08-2.98 (m, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.43-2.23 (m, 2H), 1.82-1.72 (m, 1H), 1.66-1.62 (m, 1H), 1.43-1.32 (m, 3H)

Synthesis of Compound 2, Compound 3 and Compound 4

(6) ##STR00018##

(7) Preparation of Intermediate A′

(8) A mixture of 4-fluorobenzonitrile (CAS [1194-02-1], 0.366 g, 3.02 mmol), 5-fluorooctahydrocyclopenta[c]pyrrole (CAS [1554431-13-8], 0.5 g, 3.02 mmol) and potassium carbonate (1.25 g, 9.06 mmol) in DMSO (50 mL) was stirred at 120° C. for 4 hours. The mixture was diluted with ethyl acetate (10 mL) and the mixture was washed with water (50 mL) and brine (50 mL). The separated organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 10/1) to give intermediate A′, 0.43 g, 590/%.

(9) Preparation of Intermediate B′

(10) A solution of intermediate A′ (0.38 g, 1.65 mmol) in ammonia 7M in MeOH (7 M, 20 mL) was hydrogenated (15 psi) at 15° C. with Raney Nickel (0.038 g) as a catalyst for 16 hours. The catalyst was filtered off and the filtrate was concentrated under vacuum to give intermediate B′, 0.38 g, 98%.

(11) Preparation of Compound 2

(12) A mixture of 6-Ethyl-2-imidazo[2,1b]thiazole-5-carboxylic acid (CAS [1131613-58-5], 0.09 g, 0.427 mmol), intermediate B′ (0.1 g, 0.427 mmol), HATU (0.211 g, 0.555 mmol) and DIPEA (0.166 g, 1.28 mmol) in dichloromethane (2 mL) was stirred at 25° C. for 2 hours. The mixture was purified by high performance liquid chromatography over Gemini 150×25×5μ (eluent: 0.05% ammonium water/acetonitrile 21/79). The desired fractions were collected and lyophilized to give crude product. The crude product was further purified by high performance liquid chromatography over Boston Green ODS 150×30×5μ (eluent: 0.05% hydrochloride water/acetonitrile 40/60 to 30/70). The desired fractions were collected and lyophilized to give pure Compound 2 as HCl salt, 0.05 g, 24% .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (t, J=5.8 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.29 (br. s., 2H), 5.37-5.14 (m, 1H), 4.45 (d, J=5.8 Hz, 2H), 3.53 (br. s., 2H), 3.37 (d, J=9.8 Hz, 2H), 3.03 (q, J=7.4 Hz, 4H), 2.50 (s, 3H), 2.25-2.08 (m, 2H), 2.06-1.78 (m, 2H), 1.27 (t, J=7.5 Hz, 3H)

(13) Preparation of Compound 3

(14) ##STR00019##

(15) Accordingly, Compound 3 was prepared in the same way as Compound 2, starting from 2-ethyl-5H,6H,7H, 8H-imidazo[1,2-a]pyridine-3-carboxylic acid CAS [1529528-99-1] and intermediate B′, yielding 0.045 g, 28%.

(16) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.4 Hz, 2H), 5.84 (br. s., 1H), 5.36-5.10 (m, 1H), 4.48 (d, J=5.3 Hz, 2H), 4.22 (t, J=5.7 Hz, 2H), 3.40-3.26 (m, 2H), 3.25-3.12 (m, 2H), 3.09-2.96 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.67 (q, J=7.5 Hz, 2H), 2.42-2.21 (m, 2H), 1.98-1.83 (m, 4H), 1.81-1.57 (m, 2H), 1.23 (t, J=7.5 Hz, 3H)

(17) Preparation of Compound 4

(18) ##STR00020##

(19) Preparation of Intermediate J

(20) NBS (45.1 g, 254 mmol) and NH.sub.4OAc (5.33 g, 69.2 mmol) were added to a solution of methyl-3-oxovalerate (CAS[30414-53-0], 30 g, 231 mmol) in methyl t-butylether (600 mL). The mixture was stirred at room temperature for 48 h. The mixture was filtered and washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 20/1) to give intermediate J (20.0 g, yield: 35%).

(21) Preparation of Intermediate K

(22) A solution of 5-Chloro-2-pyridinamine (CAS [5428-89-7], 12.0 g, 93.0 mmol) and intermediate J (25.0 g, 112 mmol) in ethanol (60 mL) was refluxed overnight. The mixture was concentrated under vacuum. The residue was dissolved into ethyl acetate (100 mL). The solution was washed with water (2×100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 3/1) to give intermediate K (700 mg, yield: 3%).

(23) Preparation of Intermediate L

(24) A mixture of intermediate K (700 mg, 2.10 mmol) and sodium hydroxide (252 mg, 6.30 mmol) in ethanol (2 ml) and H.sub.2O (2 mL) was stirred overnight at room temperature. Water (20 mL) was added and the solution was acidified with 2 M aqueous hydrochloride to pH ˜3. The solution was lyophilized to give crude intermediate L (2 g).

(25) Preparation of Compound 4

(26) Accordingly, Compound 4 was prepared in the same way as Compound 2, starting from intermediate L and intermediate B′, yielding 0.031 g, 16%.

(27) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.52 (s, 1H), 8.5 (s, 1H), 7.2 (d, J=8.4 Hz, 2H), 6.54 (d, J=9.3 Hz, 2H), 6.02 (br. s., 1H), 5.99 (br. s., 1H), 4.58 (s, 2H), 3.32 (m, 2H), 3.28 (m, 2H), 2.94 (m, 4H), 2.3-2.4 (m, 2H), 1.6-1.7 (m, 2H), 1.38 (t, J=7.3 Hz, 3H)

(28) Synthesis of Compound 5

(29) ##STR00021##

(30) Preparation of Intermediate C′

(31) To a solution of 5,5-difluorooctahydrocyclopenta[c]pyrrole (CAS [1260788-72-4], 0.3 g, 2.04 mmol) in DMF (20 mL) was added 4-fluorobenzonitrile (CAS [1194-02-1], 0.245 g, 2.04 mmol) and potassium carbonate (0.563 g, 4.08 mmol). The mixture was stirred at 100° C. for 10 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were dried over sodium sulfate and concentrated in vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/1). The product fractions were collected and the solvent was evaporated to give intermediate C′, 0.16 g, 32%.

(32) Preparation of Intermediate D′

(33) To a solution of intermediate C′ (120 mg, 0.48 mmol) in ammonia 4M in MeOH (15 mL) was added Raney Ni (50 mg) under N2. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 psi) at 25° C. for 10 hours. The suspension was filtered through a pad of Celite® and the pad was washed with methanol (20 mL). The combined filtrates were concentrated in vacuum to give intermediate D′, 0.12 g, 98%.

(34) Preparation of Compound 5

(35) To a solution of 2-ethyl-5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxylic acid CAS [1529528-99-1], 0.226 g, 0.53 mmol, purity=45%) in DMF (10 mL) was added intermediate D′ (0.12 g, 0.476 mmol), HATU (217.01 mg, 0.57 mmol) and diisopropylethylamine (0.184 g, 1.43 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mL×3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by high performance liquid chromatography (Waters Xbridge Prep OBD C18 150×30 5μ, 25 ml/min, mobile phase: water (containing 0.05% NH.sub.3.H.sub.2O)/Acetonitrile, 50/50). The desired fraction was collected and evaporated to remove off acetonitrile in vacuum. The residue was lyophilized to give Compound 5, 0.055 g, 27%.

(36) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ=7.22 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 5.83 (br. s., 1H), 4.50 (d, J=5.3 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 3.43 (t, J=7.7 Hz, 2H), 3.25 (dd, J=2.6, 9.7 Hz, 2H), 2.97 (br. s., 2H), 2.86 (t, J=6.4 Hz, 2H), 2.68 (q, J=7.5 Hz, 2H), 2.52-2.35 (m, 2H), 2.15-2.02 (m, 2H), 1.98-1.85 (m, 4H), 1.24 (t, J=7.5 Hz, 3H).

(37) Compound 6

(38) Synthesis of Compound 6

(39) ##STR00022##

(40) Preparation of Intermediate E′

(41) A solution of 6-Methylimidazo[2,1-B][1,3]thiazole-5-carboxylic acid (CAS [77628-51-4], 1.96 g, 10.75 mmol), 4-Bromobenzylamine (CAS [3959-07-7], 2.4 g, 12.9 mmol), EDCI.HCl (1.67 g, 10.75 mmol), HOBT (1.45 g, 10.75 mmol) and diisopropylethylamine (1.85 mL, 10.75 mmol) in DCM (40 mL) and THF (40 mL) was stirred at room temperature overnight. Water and DCM were added. The organic layer was separated with an hydrophobic frit and evaporated. EtOH (20 mL) was added and the residue was stirred for 30 min at room temperature. The precipitate was filtered off and dried under vacuum to give intermediate E′ as a pale beige powder, 1.78 g, 47%.

(42) Preparation of Compound 6

(43) A mixture of intermediate E′ (0.2 g, 0.57 mmol), 6-(trifluoromethyl)-3-azabicyclo-[3.1.0]hexane hydrochloride (CAS [1311314-49-4], 0.13 g, 0.69 mmol), sodium tert-butoxide (0.16 g, 1.71 mmol) and Xphos (0.033 g, 0.057 mmol) in F (4.2 mL) was purged with N2 flow for 5 min under stirring. Then Pd(dba).sub.2 (0.026 g, 0.029 mmol) was added and the solution was heated at 100° C. overnight. The mixture was poured out into water, extracted with EtOAc, the mixture was filtered through a short pad of Celite®, the organic layer was separated, washed with water and brine, dried (MgSO.sub.4) and evaporated till dryness, 0.245 g.

(44) DIPE (25 mL) was added and the residue was triturated and stirred at room temperature for 30 min. The precipitate was filtered off and dried under vacuum at 60° C. to give a pale beige powder, 0.190 g.

(45) A purification was performed via Reverse phase (Stationary phase: X-Bridge-C18 5 μm 30×150 mm, Mobile phase: Gradient from 65% NH.sub.4HCO.sub.3 0.5%, 35% ACN to 25% NH.sub.4HCO.sub.3 0.5%, 75% ACN). Pure fractions were collected and evaporated to give, 0.095 g, 39%.

(46) The residue was crystallized from DIPE, filtered off and dried under vacuum at 60° C. affording Compound 6 as a white powder, 0.084 g, 35%.

(47) 1H NMR (500 MHz, DMSO-d6) δ ppm 8.05 (d, J=4.4 Hz, 1H) 8.02 (t, J=6.0 Hz, 1H) 7.31 (d, J=4.4 Hz, 1H) 7.16 (d, J=8.5 Hz, 2H) 6.55 (d, J=8.5 Hz, 2H) 4.35 (d, J=5.7 Hz, 2H) 3.62 (d, J=9.5 Hz, 2H) 3.15 (br d, J=9.1 Hz, 2H) 2.47 (s, 3H) 2.17 (br s, 2H) 1.73-1.83 (m, 1H)

(48) Compound 7

(49) Synthesis of Compound 7

(50) ##STR00023##

(51) Preparation of Intermediate F′

(52) A solution of 6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane hydrochloride (CAS [1311314-49-4], 0.5 g, 2.67 mmol), 4-Fluorobenzonitrile (CAS [1194-02-1], 0.27 g, 2.22 mmol) and potassium carbonate (0.46 g, 3.33 mmol) in DMF (4.3 mL) was heated at 110° C. for 18 hours. The solution was cooled down to room temperature. Water and EtOAc were added. The organic layer was extracted, dried over MgSO.sub.4, filtered and evaporated. Purification was carried out by flash chromatography over silica gel (Irregular SiOH, 15-35 μm, 40 g, Heptane/EtOAc 70/30). Pure fractions were collected and evaporated to give intermediate F′ as a white powder, 0.214 g, 38%.

(53) Preparation of Intermediate G′

(54) Lithium Aluminium hydride 1M in THF (3.39 mL, 3.39 mmol) was slowly added dropwise to a solution of intermediate F′ (0.21 g, 0.85 mmol) in THF (7.9 mL) cooled in a ice bath at 5° C. The solution was stirred 1 hour at 5° C. after the addition and then the mixture was stirred at room temperature for 2 hours. The solution was cooled down to 0° C. and then a solution of THF/H.sub.2O (90/10) was slowly added dropwise. The mixture was filtered off throught a pad of Celite® and washed with EtOAc. The organic layer was separated, dried (MgSO.sub.4), filtered and evaporated affording intermediate G′ as a white powder, 0.215 g, 94%.

(55) Preparation of Compound 7

(56) A solution of 6-Ethyl-2-imidazo[2,1b]thiazole-5-carboxylic acid (CAS [1131613-58-5], 0.11 g, 0.52 mmol), intermediate G′ (0.17 g, 0.63 mmol), EDCI.HCl (0.1 g, 0.52 mmol), HOBT (0.08 g, 0.52 mmol) and diisopropylethylamine (0.18 mL, 1.05 mmol) in DCM (3.8 mL) and 2-MeTHF (10 mL) was stirred at room temperature overnight. Water and DCM were added. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. Purification was carried out by flash chromatography over silica gel (Irregular SiOH 15-35 μm, 40 g, CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH from 100/0/0 to 97/3/0.1). Pure fractions were evaporated to give 0.184 g. The residue was crystallized from DIPE, filtered off and dried under vacuum at 60° C. affording Compound 7, 0.169 g, 72%.

(57) 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (t, J=6.0 Hz, 1H) 7.87 (d, J=1.6 Hz, 1H) 7.15 (d, J=8.5 Hz, 2H) 6.55 (d, J=8.8 Hz, 2H) 4.34 (d, J=6.0 Hz, 2H) 3.62 (d, J=9.5 Hz, 2H) 3.14 (br d, J=9.1 Hz, 2H) 2.83 (q, J=7.6 Hz, 2H) 2.41 (d, J=1.3 Hz, 3H) 2.17 (br s, 2H) 1.75-1.84 (m, 1H) 1.19 (t, J=7.6 Hz, 3H)

(58) The following compounds were also prepared in accordance with the procedures described herein:

(59) ##STR00024##

(60) TABLE-US-00001 Characterising Data Table LCMS Compound Meting Point UV MW BPM1/ LCMS No (Kofler or DSC) Rt Area % exact BPM2 Method Cpd 1 3.14 96.8 440.2 441.1 Method C Cpd 6 222° C. (Kofler) 2.99 98.8 420.1 421/419 Method A Cpd 7 230° C. (Kofler) 3.26 100.0 448.2 449/417 Method A Cpd 4 3.54 99.7 441.2 442.1 Method C Cpd 2 4.49 95.3 426.2 427.2 Method B Cpd 3 2.86 98.7 410.2 411.2 Method C Cpd 5 3.06 99.7 428.2 429.2 Method C Cpd 8 173.10/−76.63 Jg{circumflex over ( )}−1, 2.91 98.8 392.2   393/451.2 Method A 25° C. to [M + CH.sub.3COO].sup.− 300° C./10° C. min/40 μl Al Cpd 9 207.51° C./−87.87 3.12 97.7 459.2   460/458.2 Method A Jg{circumflex over ( )}−1, 25° C. to 350° C./10° C. min/40 μl Al (DSC: 25° C. to 350° C./10° C. min/40 μl Al)

(61) Analytical Methods

(62) LCMS

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

(64) General Procedure

(65) 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).

(66) 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.

(67) 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+NH.sub.4].sup.+, [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.

(68) Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.

(69) TABLE-US-00002 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 Method Waters: Waters: A: 95% 84.2% A for 0.343 6.2 A Acquity BEH C18 CH.sub.3COONH.sub.4 0.49 min, to 10.5% A 40 UPLC ® - (1.7 μm, 7 mM/5% in 2.18 min, held for 40 DAD and 2.1 × 100 mm) CH.sub.3CN, B: 1.94 min, back to Quattro CH.sub.3CN 84.2% A in 0.73 min, Micro ™ held for 0.73 min.

(70) Hereinafter, “MSD” Mass Selective Detector, “DAD” Diode Array Detector.

(71) TABLE-US-00003 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 Method Agilent: Agilent: TC- A: CF.sub.3COOH 100% A for 1 min, 0.8 10.5 B 1100/1200 - C18 (5 μm, 0.1% in water, to 40% A in 50 DAD and 2.1 × 50 mm) B: CF.sub.3COOH 4 min, to 15% A in MSD 0.05% in 2.5 min, back to CH.sub.3CN 100% A in 2 min. Method Agilent: Agilent: TC- A: CF.sub.3COOH 90% A for 0.8 10.5 C 1100/1200 - C18 (5 μm, 0.1% in water, 0.8 min, to 20% A 50 DAD and 2.1 × 50 mm) B: CF.sub.3COOH in 3.7 min, held 50 MSD 0.05% in for 3 min, back to 50 CH.sub.3CN 90% A in 2 min.

Pharmacological Examples

(72) MIC Determination for Testing Compounds Against M. tuberculosis.

(73) Test 1

(74) Appropriate solutions of experimental 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 well. 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.

(75) Test 2

(76) Round-bottom, sterile 96-well plastic microtiter plates are filled with 100 μl of Middlebrook (1×) 7H9 broth medium. Subsequently, an extra 100 μl medium is added to column 2. Stock solutions (200× final test concentration) of compounds are added in 2 μl volumes to a series of duplicate wells in column 2 so as to allow evaluation of their effects on bacterial growth. Serial 2-fold dilutions are made directly in the microtiter plates from column 2 to 11 using a multipipette. Pipette tips are changed after every 3 dilutions to minimize pipetting errors with high hydrophobic compounds. Untreated control samples with (column 1) and without (column 12) inoculum are included in each microtiter plate. Approximately 10000 CFU per well of Mycobacterium tuberculosis (strain H37RV), in a volume of 100 μl in Middlebrook (1×) 7H9 broth medium, is added to the rows A to H, except column 12. The same volume of broth medium without inoculum is added to column 12 in row A to H. The cultures are incubated at 37° C. for 7 days in a humidified atmosphere (incubator with open air valve and continuous ventilation). On day 7 the bacterial growth is checked visually.

(77) The 90% minimal inhibitory concentration (MIC.sub.90) is determined as the concentration with no visual bacterial growth.

(78) Test 3: Time Kill Assays

(79) Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill assay using the broth dilution method. In a time kill assay on Mycobacterium tuberculosis (strain H37RV), the starting inoculum of M. tuberculosis is 10.sup.6 CFU/ml in Middlebrook (1×) 7H9 broth. The antibacterial compounds are used at the concentration of 0.1 to 10 times the MIC.sub.90. 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′- to 10′) in Middlebrook 7H9 medium and plating (100 μl) on Middlebrook 7H11 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 is commonly defined as 3-log.sub.10 decrease in number of CFU per ml as compared to untreated inoculum. The potential carryover effect of the drugs is removed by serial dilutions and counting the colonies at highest dilution used for plating.

(80) Test 4 (See Also Test 1 Above; in this Test a Different Strain of Mycobacterium tuberculosis Strain is Employed)

(81) Appropriate solutions of experimental and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain EH 4.0 (361.269) were taken from cultures in stationary 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 well. 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 nm excitation and 590 nm emission wavelengths and MIC50 and/or pIC50 values (or the like, e.g. IC50, IC90, pIC90, etc) were (or may be) calculated. pIC.sub.50 values may be recorded below in μg/mL.

(82) Results

(83) Compounds of the invention/examples, for example when tested in Test 1 or Test 2 decribed above, may typically have an IC.sub.90 value from 0.01 to 10 μg/ml. Compounds of the invention/examples, for example when tested in Test 1 or Test 2 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)

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

(85) Biological Data Table

(86) Compounds of the examples were tested in Test 4 described above (in section “Pharmacological Examples”) and the following results were obtained:

(87) TABLE-US-00004 Compound No pIC.sub.50 Cpd 1 7.4 Cpd 6 7 Cpd 7 7.5 Cpd 4 6.95 Cpd 2 7.3 Cpd 3 7 Cpd 5 7.1 Cpd 8 5.95 Cpd 9 7.8