US 2014/0275019 A1 · TETRAHYDROPYRIDINE DERIVATIVES AS FABI INHIBITORS

Abstract

The present invention relates to tetrahydropyridine derivatives of formula (1) which may be therapeutically useful as anti-bacterial agents, more particularly FabI inhibitors. in which X, Y, Z and “n” have the same meanings given in the specification, and pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting Enoyl-ACP reductase enzyme (FabI) activity. The present invention also provides methods for synthesizing and administering the FabI inhibitory compounds. The present invention also provides pharmaceutical formulations comprising at least one of the FabI inhibitory compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Claims22

Dependent claims

A compound of formula (1)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof,
wherein,
X represents N or CH;
Y represents NR1 or CHR1;
Z represents CR2R3;
R1 represents hydrogen or alkyl;
R2 and R3 are independently selected from hydrogen and alkyl;
alternatively, R2 and R3 may be taken together with the carbon atoms to which they are attached to form an optionally substituted 3-7 membered ring containing 0-3 hetero atoms or groups;
wherein the optional substituent is R4 and the heteroatoms are independently selected from N, O, NH and CO in any stable combination;
alternatively, R1 and R2 may be taken together with the carbon or nitrogen atom to which they are attached to form 5-membered fused ring;
R4 at each occurrence is selected from alkyl, —COOR5, —COR5, —CONR5R5, —SO2R5;
—COCH2OR5, —CO(CH2)2COOR5, —COCH2NR5R5 and cycloalkyl;
R5 at each occurrence is selected from hydrogen, alkyl, cycloalkyl and heterocyclyl;
and
‘n’ is selected from an integer 0 or 1.

12 more elements

A compound selected from the group consisting of

(E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-Spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (Compound 1);
(E)-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclopropane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 2);
(E)-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclobutane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 3);
(E)-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclohexane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 4);
(E)-6′-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclohexane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 5);
(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-2′,3′,5′,6′-tetrahydro-1H-spiro[[1,8]naphthyridine-3,4′-pyran]-2(4H)-one (Compound 6);
(E)-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-2′,3′,5′,6′-tetrahydro-1H-spiro[[1,8]naphthyridine-3,4′-pyran]-2(4H)-one (Compound-7);
(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1′-pivaloyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 8);
(E)-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1′-pivaloyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 9);
(E)-1′-(cyclopropanecarbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 10);
(E)-1′-(cyclopropanecarbonyl)-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 11);
(E)-N-(tert-butyl)-2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxamide (Compound 12);
(E)-N-(tert-butyl)-2-oxo-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxamide (Compound 13);
(E)-1′-(azetidine-1-carbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1 (2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 14);
(E)-1′-(azetidine-1-carbonyl)-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 15);
(E)-1′-(morpholine-4-carbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 16);
(E)-1′-(methylsulfonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 17);
(E)-tert-butyl 4-oxo-4-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydro pyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-1′-yl)butanoate (Compound 18);
(E)-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[azepane-4,3′-[1,8]naphthyridine]-2′,7(4′H)-dione (Compound 19);
(E)-6′-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[azepane-4,3′-[1,8]naphthyridine]-2′,7(4′H)-dione (Compound 20);
(E)-3-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound 21);
(E)-3-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (Compound 22);
(E)-7′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-e][1,4]diazepin]-2′(1′H)-one (Compound 23);
(E)-7′-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-4′,5′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-e][1,4]diazepin]-2′(1′H)-one (Compound 24);
(E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Compound 25);
(E)-3,3-dimethyl-6-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Compound 26);
(E)-3,3-diethyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Compound 27);
(E)-6′-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclopropane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 28);
(E)-6′-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[cyclobutane-1,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 29);
(E)-1-methyl-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[azepane-4,3′-[1,8]naphthyridine]-2′,7(4′H)-dione (Compound 30);
(E)-1′-(cyclopentanecarbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 31);
(S,E)-3-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-one (Compound 32);
(S,E)-3-(3-oxo-3-(4-(thiophen-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-one (Compound 33);
(E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound 34);
(E)-1′-methyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 35);
(E)-1′-cyclopropyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 36);
(E)-1′-(2-hydroxyacetyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 37);
(E)-1′-(furan-2-carbonyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 38);
(E)-2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxamide (Compound 39);
(E)-4-oxo-4-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-1′-yl)butanoic acid (Compound 40);
(E)-1′-(2-aminoacetyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one hydrochloride (Compound 41);
(E)-1′-(2-(tert-butylamino)acetyl)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound 42);
and
(E)-1-(2-hydroxyacetyl)-6′-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1′H-spiro[azetidine-3,3′-[1,8]naphthyridin]-2′(4′H)-one (Compound 43),
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.

42 more elements

Dependencies are inferred from the claim text.

Tetrahydropyridine derivatives as fabi inhibitors

Life of this patent

Tetrahydropyridine derivatives as fabi inhibitors

Life of this patent

Abstract

Claims22