QUINOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND USES THEREOF FOR THE TREATMENT OF CANCER

Abstract

The present invention relates to compounds of the general formula (I): (I), wherein V, W, M, R, R and Y have the designations cited below, or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof, and to processes for the preparation of compounds of the general formula (I) or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof. The invention also relates to compounds of the general formula (I) or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof for use as a medicament. Further, the invention relates to compounds of the general formula (I) or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof for use in the treatment of cancer. Moreover, the invention relates to compounds of the general formula (I) or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof for treating cancer in simultaneous, alternating or subsequent combination with another cancer therapy.

##STR00001##

Claims

1. A compound of the general formula (I) ##STR00391## wherein R is —H, or —C.sub.1-C.sub.4-alkyl, preferably —H, -methyl or -ethyl; in particular methyl; R.sub.1 is —H, or -methyl, preferably —H; M is CH or N; preferably CH; V is —H, —OH, —Cl, —F, or —C.sub.1-C.sub.4-alkyl, preferably —H, —Cl, —F, or -methyl; W is ##STR00392## R.sub.2 and R.sub.3 are identical or different and are —H, —C.sub.1-C.sub.4-alkyl, halogen-C.sub.1-C.sub.4-alkyl, —C.sub.1-C.sub.4-alkoxy, —C.sub.1-C.sub.4-dialkylamino, —C.sub.2-C.sub.6-alkenyl, —C.sub.2-C.sub.6-alkynyl, -halogen, —CN or —CO—NH.sub.2; preferably —H, —C.sub.1-C.sub.4-alkyl, —CF.sub.3, —OCH.sub.3, —NHCH.sub.3, —N(CH.sub.3).sub.2, —F, or —Cl; X is -halogen, or —CN, preferably —F, with n=1 or 2 or with m=1; n=0, 1, or 2, preferably 0 or 1; m=0 or 1, preferably 0; Y is —NR.sub.4R.sub.5 with R.sub.4 is —H, or —C.sub.1-C.sub.4-alkyl, preferably —H or -methyl, and R.sub.5 is —H, —C.sub.1-C.sub.4-alkyl, an unsubstituted or substituted —C.sub.3-C.sub.6-cycloalkyl, preferably -methyl, -ethyl, -isopropyl, or -cyclopropyl; or an unsubstituted or substituted pyridine residue; or an unsubstituted or substituted phenyl residue, preferably substituted at the para position; or Y is —NR.sub.4R.sub.5 with N, R.sub.4 and R.sub.5 forming an unsubstituted or substituted 4-, 5- or 6-membered saturated heterocycle, preferably an unsubstituted or substituted azetidine residue, an unsubstituted or substituted piperidine residue, an unsubstituted or substituted pyrrolidine residue, an unsubstituted or substituted piperazine residue, an unsubstituted or substituted morpholine residue, or an unsubstituted or substituted tetrahydropyridine residue; or Y is —OR.sub.6, with R.sub.6 is —H or —C.sub.1-C.sub.4-alkyl, preferably —H, -methyl, -ethyl, -isopropyl, or -tert-butyl; or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

2. The compound of claim 1, wherein W is ##STR00393## R.sub.3 is —H, —C.sub.1-C.sub.4-alkyl, —CF.sub.3, —OCH.sub.3, —N(CH.sub.3).sub.2, acetylenyl, —F, —Cl, —Br, —CN, or —CO—NH.sub.2; R.sub.2 is —H, -methyl, -ethyl, isopropyl, —CF.sub.3, —F, or —Cl; and X is —F with n=1; preferably, wherein X is at the para-position of the phenyl ring; or n=0.

3. The compound of claim 1, wherein W is ##STR00394## R.sub.2 is —H, -methyl, -ethyl, isopropyl, —Cl, preferably -methyl or —Cl; R.sub.3 is —H, -methyl or —Cl; preferably R.sub.2 is -methyl and R.sub.3 is -methyl, or R.sub.2 is —Cl and R.sub.3 is —Cl; and n=0.

4. The compound of claim 1, wherein Y is —NR.sub.4R.sub.5 with R.sub.4 is —H, or —C.sub.1-C.sub.4-alkyl, preferably —H or -methyl, and R.sub.5 is —H, —C.sub.1-C.sub.4-alkyl, unsubstituted —C.sub.3-C.sub.4-cycloalkyl, —C.sub.4-cycloalkyl substituted with —COO—CH.sub.3, preferably -methyl, -ethyl, -isopropyl, or -cyclopropyl.

5. The compound of claim 1, wherein Y is —NR.sub.4R.sub.5 with R.sub.4 is —H, or —C.sub.1-C.sub.4-alkyl, preferably —H or -methyl, and R.sub.5 is an unsubstituted pyridine residue; or an unsubstituted or substituted phenyl residue, preferably unsubstituted or substituted with one substituent at the para position; wherein the substituents are selected from the group consisting of: C.sub.1-C.sub.4-alkyl, —C.sub.1-C.sub.4-alkoxy, —(CH.sub.2).sub.2—OH, —COOH, or —CO—O—(C.sub.1-C.sub.4-alkyl).

6. The compound of claim 1, wherein Y is —NR.sub.4R.sub.5 with N, R.sub.4 and R.sub.5 forming an unsubstituted or substituted azetidine residue, an unsubstituted or substituted piperidine residue, an unsubstituted or substituted piperazine residue, an unsubstituted or substituted pyrrolidine residue, an unsubstituted or substituted morpholine residue, or an unsubstituted or substituted tetrahydropyridine residue, preferably an unsubstituted or substituted piperidine residue, each optionally and independently substituted with one or more, preferably with one of the following residues: —C.sub.1-C.sub.4-alkyl; —C(OH)-cyclopropyl); —C(COOH)-cyclopropyl; unsubstituted or substituted —C.sub.3-C.sub.6-cycloalkyl; preferably hydroxycyclopropyl, or carboxycyclopropyl; —(CH.sub.2).sub.o—COOR.sub.7 with R.sub.7 is —H, —C.sub.1-C.sub.8-alkyl, preferably —H, -methyl, -ethyl, -isopropyl, or -tert-butyl, and o=0, 1 or 2; preferably 0 or 1; ##STR00395## and o is as defined above; —(CH.sub.2).sub.pCONR.sub.8R.sub.9 with R.sub.8 and R.sub.9 independently are —H, —OH, —CN or —C.sub.1-C.sub.4-alkyl, preferably —H or -methyl, and p=0, 1 or 2; preferably 0 or 1; —C(CH.sub.3).sub.2—COOH; ═O or —OH; —CO-cyclopropyl; —CO—(C.sub.1-C.sub.4-alkyl), preferably —CO—CH.sub.2—CH.sub.3; —CO—(CH.sub.2).sub.q—NR.sub.12R.sub.13 with R.sub.12 and R.sub.13 independently are —H, —C.sub.1-C.sub.4-alkyl or —CN, preferably —CO—(CH.sub.2).sub.q—NH.sub.2, more preferably —CO—CH.sub.2—NH.sub.2, and q=0, 1 or 2, preferably 0 or 1; —NH.sub.2, —NH—CO-cyclopropyl, —NH—CO—CH.sub.2—Cl, —NH—CO—CH.sub.2—CH.sub.3, —NH—CO—NH—C(CH.sub.3).sub.3, —NH—SO.sub.2CH.sub.3, —NH—CO-phenyl, —NOH—CO—CH.sub.3; —F; —CN; R.sub.14 and R.sub.15 forming a pyrrolidinone ring, a cyclopropanecarboxlic acid ring, an oxetane ring, or a —CH.sub.2— group; or —(CH.sub.2).sub.rSO.sub.2NR.sub.10R.sub.11 with R.sub.10 and R.sub.11 independently are —H, or —C.sub.1-C.sub.4-alkyl, preferably —H or -methyl, preferably —CH.sub.2SO.sub.2NH.sub.2 and r=0, 1 or 2, preferably 0 or 1.

7. The compound of claim 1, wherein Y is —NR.sub.4R.sub.5 with N, R.sub.4 and R.sub.5 forming an unsubstituted or substituted piperidine reside, an unsubstituted or substituted piperazine residue, an unsubstituted or substituted pyrrolidine residue, or an unsubstituted or substituted morpholine residue, each optionally and independently substituted with one or more, preferably with one of the following residues: —C.sub.1-C.sub.4-alkyl; —C(OH)cyclopropyl; hydroxycyclopropyl or carboxycyclopropyl; —(CH.sub.2).sub.o—COOR.sub.7 with R.sub.7 is —H, —C.sub.1-C.sub.8-alkyl, preferably —H, -methyl, -ethyl, -isopropyl, or -tert-butyl, and o=0, 1 or 2; ##STR00396## —(CH.sub.2).sub.pCONR.sub.8R.sub.9 with R.sub.8 and R.sub.9 independently are —H, —OH, —CN, -methyl, or -tert-butyl and p=0; —C(CH.sub.3).sub.2—COOH; ═O or —OH; —CO-cyclopropyl; —CO—CH.sub.2—CH.sub.3; —CO-tert-butyl; —NH.sub.2, —CO—CH.sub.2—NH.sub.2; —NH—CO—CH.sub.2—CH.sub.3, —NH—CO—NH—C(CH.sub.3).sub.3, —NH—SO.sub.2CH.sub.3, —NH—CO-phenyl, —NOH—CO—CH.sub.3; —CN; R.sub.14 and R.sub.15 forming a pyrrolidinone ring, a cyclopropanecarboxlic acid ring, an oxetane ring; or a —CH.sub.2— group; —SO.sub.2NR.sub.10R.sub.11 with R.sub.10 and R.sub.11 independently are —H or -methyl; or —CH.sub.2SO.sub.2NH.sub.2.

8. The compound of claim 1, wherein Y is —NR.sub.4R.sub.5 with N, R.sub.4 and R.sub.5 forming an unsubstituted or substituted piperidine residue, optionally and independently substituted with one or more, preferably with one of the following residues: —COOH, —COOCH3, —COOC2H5, —CH.sub.2COOH, —C(CH.sub.3).sub.2—COOH, —CH2COOCH3, —CH2COOCH2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —SO.sub.2NH.sub.2 or —CH.sub.2SO.sub.2NH.sub.2.

9. The compound of claim 1, wherein Y is —OR.sub.6, with R.sub.6 is —H, -methyl, -ethyl, -isopropyl, or -tert-butyl, preferably -ethyl.

10. The compound of claim 1, wherein V is —H, —Cl, —F, or -methyl, preferably —H.

11. The compound of claim 1, wherein R is -methyl, preferably —(R)-methyl; and R.sub.1 is —H.

12. The compound of claim 1, selected from (3S)-1-[(2R)-2-[[4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, ethyl (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, 2-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, ethyl 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, (3R)-1-[(2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, ethyl 2-[(3R)-1-[(2R)-2-[[4-(o-tolyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[(3S)-3-(2H-tetrazol-5-yl)-1-piperidyl]propan-1-one, (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-2-fluoro-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(o-tolyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, ethyl (3S)-1-[(2R)-2-[[4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, ethyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, 2-[(3R)-1-[(2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidine-3-carboxylic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(1-piperidyl)propan-1-one, 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, rac-(3S)-1-[2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-4-carboxylic acid, (3S)-1-[rac-(2R)-2-[[2-chloro-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 3-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]amino]benzoic acid ethyl (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(4-propanoylpiperazin-1-yl)propan-1-one, tert-butyl (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoate, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carbonitrile, (3S)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-isopropyl-N-methyl-propanamide, 1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (3S)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2-methyl-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, isopropyl (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoate, methyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]acetate, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-N-methylpiperidine-3-carboxamide, 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]acetic acid, ethyl (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-2-fluoro-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-pyrrolidin-1-yl-propan-1-one, (2R)-2-[[2-chloro-4-(o-tolyl)-7-quinolyl]oxy]propanoic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N,N-dimethyl-propanamide, rac-(3S)-1-[2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]acetyl]piperidine-3-carboxylic acid, (2R)—N-tert-butyl-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanamide, (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-N-isopropyl-propanamide, ethyl 2-[(3R)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, ethyl (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoate, ethyl 4-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]amino]benzoate, (3S)-1-[(2R)-2-[[2-chloro-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxamide, (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-1-(1-piperidyl)propan-1-one, methyl 3-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]amino]cyclobutanecarboxylate, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-piperazin-1-yl-propan-1-one, 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2-methyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, ethyl 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-4-carboxylate, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 4-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]amino]benzoic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-isopropyl-propanamide, (3S)-1-[2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine-3-carboxylic acid, 4-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperazin-2-one, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-3-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (3S)-1-[(2R)-2-[(4-phenyl-7-quinolyl)oxy]propanoyl]piperidine-3-carboxylic acid, methyl 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]acetate, 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]-N-methyl-acetamide, 2-[(3R)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]-1-[4-(cyclopropanecarbonyl)piperazin-1-yl]propan-1-one, methyl (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]-1-(4-propanoylpiperazin-1-yl)propan-1-one, tert-butyl (2R)-2-[[2-chloro-4-(o-tolyl)-7-quinolyl]oxy]propanoate, ethyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, ethyl (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidine-3-carboxylate, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxamide, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-cyclopropyl-propanamide, (3S)-1-[(2S)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-methyl-3-thienyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[rac-(3R)-1-[2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3 piperidyl]acetic acid, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxamide, isopropyl 2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]acetate, (3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (2R)-1-[4-(2-aminoacetyl)piperazin-1-yl]-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propan-1-one, 2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-N,N-dimethyl-propanamide, ethyl (3S)-1-[2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]acetyl]piperidine-3-carboxylate, (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-N,N-dimethyl-propanamide, ethyl 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, (2R)-2-[[4-(2-chlorophenyl)-2-fluoro-7-quinolyl]oxy]propanoic acid, (2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoic acid, ethyl 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, ethyl 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate, ethyl (3S)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2-methyl-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-(4-pyridyl)propanamide, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-N-methylpiperidine-3-carboxamide, methyl 3-[[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]amino]cyclobutanecarboxylate, 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]-N-methyl-acetamide, (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]-1-(1-piperidyl)propan-1-one, (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-N,N-dimethylpiperidine-3-carboxamide, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (3R)-1-[(2S)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoic acid, (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7-quinolyl]oxy]-1-piperazin-1-yl-propan-1-one, (3S)—N-methyl-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxamide, 2-[[4-(o-tolyl)-7-quinolyl]oxy]acetamide, (2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(1-piperidyl)propan-1-one, ethyl 3-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]amino]benzoate, 2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]-N-isopropyl-propanamide, 2-[(3R)-1-[(2R)-2-[[4-(2-fluorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, tert-butyl (3S)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylate, 2-[1-[(2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-4-piperidyl]acetic acid, (3S)-1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-2-methyl-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3R)-1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-2-methyl-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3R)-1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-2-methyl-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, 3-[1-[(2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]propanoyl]-4-piperidyl]propanoic acid, 1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, 2-[(3R)-1-[(2R)-2-[[4-(2,6-dichlorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-ethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-isopropylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, [1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]methanesulfonamide, 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-2-methyl-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-[4-(2-hydroxyethyl)phenyl]propanamide, (3S)-1-[(2R)-2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine-3-carboxylic acid, (3S)-1-[(2S)-2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine-3-carboxylic acid, (3S)-1-[(2S)-2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[5-(2-chloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3-piperidyl]acetic acid, (3S)-1-[(2R)-2-[[4-(2,6-dichlorophenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-(2-pyridyl)propanamide, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-N-ethyl-propanamide, (3S)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(4-methyl-3-thienyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(3-methyl-2-thienyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-methoxyphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-[2-(trifluoromethyl)phenyl]-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-[2-(trifluoromethoxy)phenyl]-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, 2-[(3R)-1-[2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-2-methyl-propanoyl]-3-piperidyl]acetic acid, 2-[rac-(3R)-1-[2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]butanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-6-methyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-bromophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-cyanophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-ethynylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-[2-(dimethylamino)phenyl]-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-carbamoylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2,6-difluorophenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2,4-dimethyl-3-thienyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-[2-chloro-6-(trifluoromethyl)phenyl]-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-bromo-6-chloro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-[2,6-bis(trifluoromethyl)phenyl]-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-6-methoxy-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 2-[(3R)-1-[(2R)-2-[[4-(2,6-diisopropylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (2R)-1-[(3R)-3-amino-1-piperidyl]-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propan-1-one, (2R)-1-[(3S)-3-amino-1-piperidyl]-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propan-1-one, N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]propanamide, N-tert-butyl-4-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperazine-1-carboxamide, (2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1-piperidyl]propan-1-one, 8-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-2,8-diazaspiro[4.5]decan-1-one, (2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]-1-(3,5-dimethylpiperazin-1-yl)propan-1-one, N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]-N-hydroxy-acetamide, 1-[4-[(2R)-2-[[4-(2,6-di methyl phenyl)-7-quinolyl]oxy]propanoyl]piperazin-1-yl]-2,2-dimethyl-propan-1-one, N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]methanesulfonamide, N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]benzamide, (3S)—N-cyano-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxamide, (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carbohydroxamic acid, 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]ethanehydroxamic acid, (2R)-1-(3-aminoazetidin-1-yl)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propan-1-one, (2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]-1-[3-(1H-tetrazol-5-yl)azetidin-1-yl]propan-1-one, 3-hydroxy-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid, 5-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane-2-carboxylic acid, (3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]piperidine-3-sulfonamide, (3S)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-methylpiperidine-3-carboxylic acid, 5-[rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane-2-carboxylic acid, (3R)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-methyl-piperidine-3-carboxylic acid, (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]-1-[(2S)-2-methyl-1-piperidyl]propan-1-one, 5-[rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane-2-carboxylic acid, (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]-1-morpholino-propan-1-one, (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one, rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1-piperidyl]propan-1-one, 8-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-2,8-diazaspiro[4.5]decan-1-one, 1-[1-[rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]cyclopropanecarboxylic acid, 2-[(3R)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, (3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-methylpiperidine-3-carboxylic acid, N-[(3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]-N-hydroxy-acetamide, 2-methyl-2-[1-[rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]propanoic acid, (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]-1-[(2R)-2-methyl-1-piperidyl]propan-1-one, (3R)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-methylpiperidine-3-carboxylic acid, (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-methylpiperidine-3-carboxylic acid, [1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]methanesulfonamide, rac-(2R)-1-(2,6-di methyl-1-piperidyl)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7-quinolyl]oxy]propan-1-one, 2-[(3R)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid, 5-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane-2-carboxylic acid, 1-[1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]cyclopropanecarboxylic acid, 2-methyl-2-[1-[rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]propanoic acid, 1-[1-[rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]cyclopropanecarboxylic acid, 2-methyl-2-[1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]propanoic acid, (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-methylpiperidine-3-carboxylic acid, (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[(2S)-2-methyl-1-piperidyl]propan-1-one, rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-methyl-1-piperidyl)propan-1-one, (2R)-2-[[4-(2,6-di chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-morpholino-propan-1-one, 8-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-2,8-diazaspiro[4.5]decan-1-one, rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1-piperidyl]propan-1-one, (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[(2R)-2-methyl-1-piperidyl]propan-1-one, 8-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-2,8-diazaspiro[4.5]decan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-morpholino-propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1-piperidyl]propan-1-one, (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one, N-hydroxy-N-[rac-(3S)-1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetamide, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2,6-dimethyl-1-piperidyl)propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-oxa-8-azaspiro[3.5]nonan-8-yl)propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.4]octan-7-yl)propan-1-one, 1-tert-butyl-3-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]urea, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(3,3,5,5-tetramethylpiperazin-1-yl)propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(3,5-dimethylpiperazin-1-yl)propan-1-one, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-[(1R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]propan-lone, (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-1-one, 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid, 2-[(3R)-1-[(2R)-2-[[5-(2,6-dichloro-4-fluoro-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3-piperidyl]acetic acid, and 2-[(3R)-1-[(2R)-2-[[5-(4-fluoro-2,6-dimethyl-phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3-piperidyl]acetic acid, or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

13. A process for manufacturing a compound of formula (I) according to claim 1, wherein V is —H, —OH, —Cl, or —C.sub.1-C.sub.4-alkyl, comprising the steps of: (a) alkylating a compound of formulae (D.sub.1 to D.sub.5) ##STR00397## wherein in D.sub.1 V is —H, M is CH, and W is as defined in any one of claims 1 to 3, in D.sub.2 V is —OH, M is CH, and W is as defined in any one of claims 1 to 3, in D.sub.3 V is —Cl, M is CH, and W is as defined in any one of claims 1 to 3, in D.sub.4 V is —H, M is N, and W is as defined in any one of claims 1 to 3, and in D.sub.5 V is —C.sub.1-C.sub.4-alkyl, M is CH, and W is as defined in any one of claims 1 to 3, with an alkylating agent, preferably with an alkylating agent of the formula Z—OH or Z—Br, wherein Z is the group ##STR00398## wherein R, R.sub.1 and Y are as defined in any one of claim 1, or 4 to 11, to obtain a compound of formulae (E.sub.1 to E.sub.5) ##STR00399## wherein in E.sub.1 Vis-H, M is CH, and W and Z are as defined above, in E.sub.2 V is —OH, M is CH, and W and Z are as defined above, in E.sub.3 V is —Cl, M is CH, and W and Z are as defined above, in E.sub.4 V is —H, M is N, and W and Z are as defined above, and in E.sub.5 V is —C.sub.1-C.sub.4-alkyl, M is CH, and W and Z are as defined above.

14. A pharmaceutical composition comprising a compound of claim 1 and pharmaceutically or veterinary acceptable carriers and/or excipients.

15. A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1.

16. A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 in simultaneous, alternating or subsequent combination with an additional cancer therapy.

17. The method of claim 15, wherein the cancer is selected from the group consisting of melanoma, metastatic melanoma, pancreatic cancer, hepatocellular carcinoma, lymphoma, acute myeloid leukemia, breast cancer, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer.

18. The method of claim 16, wherein the additional cancer therapy is selected from the group consisting of chemotherapy, immunotherapy, hormone therapy, stem cell transplantation therapy, radiation therapy and surgery.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0927] FIG. 1 shows an Example of numbering of a compound of formula F.

[0928] FIG. 2 corresponds to Scheme 1. Scheme 1 shows an exemplary preparation of a compound of formula (D), specifically D.sub.1-D.sub.4. All residues of the formulae shown in Scheme 1 are as defined herein.

[0929] FIG. 3 corresponds to Scheme 2. Scheme 2 shows an exemplary preparation of a compound of formula (E), specifically E.sub.1-E.sub.6. All residues of the formulae shown in Scheme 2 are as defined herein.

[0930] FIG. 4 corresponds to Scheme 3. Scheme 3 shows an exemplary preparation of a compound of formula (J), specifically J.sub.1-J.sub.6. All residues of the formulae shown in Scheme 3 are as defined herein.

[0931] FIG. 5 corresponds to Scheme 4. Scheme 4 shows an exemplary preparation of a compound of formulae (K), (L), (M), (P), (Q), (R) and (S). All residues of the formulae shown in Scheme 3 are as defined herein.

EXAMPLES

Abbreviations and Acronyms

[0932] Abbreviations and Acronyms used in the description of the chemistry and in the Examples that follow are: [0933] Abs Absolute configuration (at least one stereocenter) [0934] aq. aqueous [0935] BB building block [0936] BBr.sub.3 boron tribromide [0937] BPO benzoyl peroxide [0938] br. broad [0939] Bu.sub.3SnN.sub.3 tributyltin azide [0940] CDCl.sub.3 deuterated chloroform [0941] CD.sub.3OD deuterated methanol [0942] CHCl.sub.3 chloroform [0943] cHex cyclohexane [0944] Cs.sub.2CO.sub.3 caesium carbonate [0945] d doublet [0946] DCM dichloromethane [0947] DIAD diisopropylazodicarboxylate [0948] DIPEA Diisopropylethylamine [0949] DMF dimethylformamide [0950] DMSO dimethylsulfoxide [0951] DMSO-d.sub.6 deuterated dimethylsulfoxide [0952] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [0953] ES electrospray [0954] Et.sub.3N triethylamine [0955] Et.sub.2O diethylether [0956] EtOAc ethyl acetate [0957] EtOH ethanol [0958] FA formic acid [0959] h hour [0960] HATU O-(7-Azabenzotriazol-1-yl)-N,N, W, W-tetramethyluronium-hexafluorphosphate [0961] HCl hydrochloric acid [0962] H.sub.2O water [0963] HOBt 1H-benzo[d][1,2,3]triazol-1-ol [0964] H.sub.3PO.sub.4 polyphosphoric acid [0965] K.sub.2CO.sub.3 potassium carbonate [0966] m multiplet [0967] MeCN acetonitrile [0968] MeOH methanol [0969] min minutes [0970] MS mass spectrometry [0971] N.sub.2 nitrogen [0972] NaHCO.sub.3 sodium hydrogencarbonate [0973] NaCl sodium chloride [0974] NaH sodium hydride [0975] NH.sub.4Cl ammonium chloride [0976] NMR nuclear magnetic resonance [0977] PCl.sub.5 phosphorus (V) chloride [0978] Pd(amphos)Cl.sub.2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) [0979] Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) [0980] PPh.sub.3 triphenylphosphine [0981] q quartet [0982] quint quintet [0983] rt room temperature [0984] s singlet [0985] sat. saturated [0986] SOCl.sub.2 thionyl chloride [0987] t triplet [0988] TFA trifluoroacetic acid [0989] THF tetrahydrofuran

[0990] 1. Methods of Making the Compounds of Formula (I) of the Present Invention

[0991] In general, the compounds of formula (I) used of the invention might be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to conventional chemical methods. The particular processes to be utilised in the preparation of the compounds of formula (I) of this invention depends upon the specific compound desired. Such factors as the type of substitution at various locations of the molecule and the commercial availability of the starting materials play a role in the path to be followed and in the chosen reaction conditions for the preparation of the specific compounds of formula (I) of this invention. Those factors are readily recognised by one of ordinary skill in the art.

[0992] The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.

[0993] 2. Experimental Procedures

LC-MS Method

[0994] HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with a SQ 3100 Mass detector spectrometer. [0995] Column: Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm [0996] Flow: 0.500 mL/min [0997] Eluents: A: H.sub.2O with 0.05% formic acid and B: MeCN with 0.05% formic acid. [0998] Gradient: elution from 5% to 100% B over 3.5 min with an initial hold of 0.5 min and a final hold at 100% B of 0.5 min. Total run time: 5 min. [0999] The gradient described could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

Preparative HPLC Method

[1000] Preparative HPLC was performed using a Waters System consisting of a Waters 2767 Sample Manager, a Waters 2545 Binary Gradient Module, a Waters SFO (System Fluidics Organizer), a Waters 3100 Mass Detector, and a Waters 2498 UV/Visible Detector. [1001] Column: XBridge® Prep C18 5 μm OBD™, 19×150 mm [1002] Flow: 20 mL/min [1003] Eluents: A: H.sub.2O with 0.1% TFA and B: MeCN with 0.1% TFA.

[1004] Alternatively, preparative HPLC was performed using an Agilent System consisting of a Agilent Infinity 1260 Autosampler, an Agilent Infinity 1260 Binary Gradient Module, an Agilent 6120 Quadrupole Mass Detector and an Agilent Infinity 1260 DAD VL UV/Visible Detector. [1005] Column: XBridge® BEH Prep C18 5 μm, 19 mm×150 mm [1006] Flow: 32 mL/min [1007] Eluents: A: H.sub.2O with 0.1% TFA and B: MeCN with 0.1% TFA. [1008] General Gradient: elution from X % to Y % B over 20 min with an initial hold of 2 min and a final increase to 100% B over 2 min and hold at 100% B of 2 min followed by a 1 min gradient back to the initial composition. Total run time: 26 min. X=Y−30% where Y=concentration of elution on the above described LC-MS method.

[1009] The gradient described could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

Chiral LC-MS Method

[1010] Chiral HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with a SQ 3100 Mass detector spectrometer. [1011] Column: Lux 5 u Cellulose-2; 150×4.6 mm [1012] Flow: 0.500 mL/min-1.000 mL/min [1013] Eluents: A: H.sub.2O with 0.05% formic acid and B: MeCN with 0.05% formic acid. [1014] Gradient elution from X % to Y % B over 15 min with an initial hold of 0.5 min and a return to 100% B and final hold at of 2.5 min. Total run time: 18 min. [1015] The gradient could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

[1016] Alternatively, Chiral HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using an Agilent 1100 Series with DAD detector spectrometer. [1017] Column: Lux 5 μm Cellulose-2; 150×4.6 mm [1018] Flow: 1.500 mL/min

[1019] Eluents for reverse phase analysis (1) and normal phase analysis (2) are described below: [1020] Eluents (1): A: H.sub.2O with 20 mM NH.sub.4HCO.sub.3, 0.1% DEA and B: MeCN with 0.1% DEA. [1021] Gradient: elution from 25-50% B over 20 min. [1022] Eluents (2): A: n-Hexane with 0.1% DEA and B: Isopropanol with 0.1% DEA. [1023] Gradient: elution from 60-90% B over 20 min. [1024] The gradient could be altered in function of the physico-chemical properties of the compound analysed and is in no way restrictive.

Chiral Preparative HPLC Method

[1025] Preparative HPLC was performed using a Waters System consisting of a Waters 2767 Sample Manager, a Waters 2545 Binary Gradient Module, a Waters SFO (System Fluidics Organizer), a Waters 3100 Mass Detector, and a Waters 2498 UV/Visible Detector. [1026] Column: Lux 5 u Cellulose-2, 150×21.2 mm (Phenomenex) [1027] Flow: 20 mL/min-30 mL/min [1028] Eluents: A: H.sub.2O with 0.1% TFA and B: MeCN with 0.1% TFA. [1029] The gradient could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

GC-MS Method

[1030] Gas Chromatography—Mass spectra were obtained using Agilent 7820A GC with 5977E MSD [1031] Column: HP-5MS 30 m, 0.25 mm ID, 0.25 μm [1032] Flow: 2 mL/min. He [1033] Injection: 100 μl/s, 250° C.; Split Flow: 20 mL/min. Split Ratio: 10 [1034] Detection: Agilent 5977E [1035] Gradient: 0 min 50° C.; 0.5 min 50° C.; 7.6 min 300° C.; 9.6 min 300° C. [1036] The gradient described could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

NMR Methods

[1037] Proton (.sup.1H) nuclear magnetic resonance (NMR) spectra were measured with an Oxford Varian 400/54 (400 MHz) spectrometer or a Bruker Avance II (300 MHz) spectrometer with residual protonated solvent (CHCl.sub.3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. The NMR data of the synthesized examples are in agreement with their corresponding structural assignments.

Numbering

[1038] The specific and unequivocal numbering of the intermediates comprising a subscript, defining the substituents of the quinoline scaffold, and a prefix, defining the substituents of the phenyl group, is explained in Table 1 and Table 2. In particular, in Table 2, Examples of intermediates at different stages are given for a specific aryl substituent. The numbering of intermediates F and G is self-explanatory and highlighted in Table 4 of the synthetic methods: an indication of the stereochemistry ((R), (S) or (rac)) and a suffix defining the type of ester (_Et or _tBu) are given. (gem) describes the gem-dimethyl-compound and (rac)-Et refers to the ethyl substituted linker. FIG. 1 shows a general example of numbering structures F. Numbering of the most advanced intermediates and final compounds is unique and assigned in the procedures for preparing the compounds of the invention or in Table 6.

TABLE-US-00001 TABLE 1 Numbering of the scaffolds of intermediates of formulas C-E: Subscripts Structure Subscript Examples [00063] embedded image W/Hal C.sub.1-6-E.sub.1-6/C.sub.1x-6x-E.sub.1x-6x V = H M = CH 1/1x [00064] V = OH M = CH 2/2x C.sub.2-E.sub.2 V = Cl M = CH 3/3x C.sub.3-E.sub.3 V = H M = N 4/4x C.sub.4-E.sub.4 V = Me M = CH 5/5x C.sub.5-E.sub.5 V = F M = CH 6/6x C.sub.6-E.sub.6

TABLE-US-00002 TABLE 2 Numbering of intermediates of formulas A-E: Prefix Structure Prefix Examples [00065] embedded image W 1-7A-E [00066] 1 [00067] [00068] 2 [00069] [00070] 3 [00071] [00072] 4 [00073] [00074] 5 5A-E [00075] 6 [00076] [00077] 7 7A-E [00078] 8 8A-E [00079] 9 9A-E

Synthetic Methods

[1039] The general synthesis of a compound of this invention is described below in Schemes 1-4. The starting materials are either commercially available or are prepared in similar manners as described in literature procedures or in the specific examples. The desired quinolines D, were either commercially available (such as 4-chloro-2-methylquinolin-7-ol, CAS 148018-30-8) or were synthesized from the possibly substituted 4-chloro-7-methoxyquinolines through a Suzuki Coupling to obtain compounds C, followed by demethylation with BBr.sub.3. Alternatively, the intermediate quinolines C where substituent V is OH or Cl were prepared from the corresponding β-ketoesters and 3-methoxy-aniline followed by cyclisation and potential further halogenation as described by Chen et al. (2015) and Upton et al. (1986) and highlighted in Scheme 1 (see FIG. 2).

[1040] When the β-ketoesters could not be purchased, they were synthesized from the required acetophenones and ethyl potassium malonate under basic conditions in a similar manner as indicated in Scheme 1. Alternative syntheses, for example starting from benzoylchlorides and diethylcarbonate, are dearly also possible.

[1041] In the case of 1,8-naphthyridines, where M is N, the specific synthesis, analogue to what suggested by Nicoleti et al. (2012) was employed, which is also outlined in Scheme 1 and is described for intermediates C.sub.4x and C.sub.4.

##STR00080##

[1042] It should be apparent to those skilled in the art that the sequence of the synthetic steps is dependent on starting materials availability and functional group compatibility and could vary from compound to compound.

[1043] The quinoline can be further alkylated with a commercial alkylbromide (Z—Br) or subjected to a Mitsunobu (Z—OH) reaction with a commercial alcohol to produce compounds of formula E as outlined in Scheme 2 (see FIG. 3).

##STR00081##

[1044] In particular, and for the purpose of rapid diversification, the Mitsunobu/alkylation reaction step (D to E and D.sub.1 to E.sub.1) and the Suzuki Coupling step (C.sub.x to C and E.sub.x to E), described in Schemes 1 and 2, could be reversed. This was applied, for example, to the synthesis of different mono- and bis-ortho-substituted phenyl intermediates ((R)-2F.sub.1_Et, (R)-3F.sub.1_tBu, (R)-4F.sub.1_tBu, (R)-6F.sub.1_tBu, (R)-3F.sub.5_tBu, (R)-4F.sub.5_tBu, (R)-6F.sub.5_tBu), (R)-4F.sub.4_Et, (R)-8F.sub.4_Et, and (R)-9F.sub.4_Et. Building block D.sub.5x (Table 3) is commercially available, and was used in the Mitsunobu reaction directly to obtain intermediate (R)—F.sub.5x_Bu. Conditions for the Suzuki Coupling of intermediates E.sub.x are described in method M3a and M3b.

[1045] Scheme 2 also illustrates how intermediate E.sub.1 (V═H) could be transformed into intermediate E.sub.6 (V═F) through reaction with AgF.sub.2 as described by Fier and Hartwig (2013) or other fluorination agents known in the art. The specific procedures are listed below.

[1046] For the Examples of this invention, Z was generally a potentially substituted alkyl acetate group (compound F); which was usually further modified by hydrolysis to the corresponding carboxylic acid G, followed by coupling with a commercially available, optionally substituted amine, according to standard procedures known in the art, and as described in Scheme 3 (see FIG. 4), to produce structure J. Alternatively, the Mitsunobu reaction could be carried out with a suitable, synthesized or commercially available 2-hydroxyacetamide H to obtain a compound of structure J directly. Again, for the purpose of parallel synthesis and rapid di versification of group W, intermediate F.sub.1x-6x could be modified using a similar reaction sequence to obtain compounds of formula J through intermediates G.sub.1x-6x and J.sub.1x-6x, carrying a halogen substituent, which is subjected to a Suzuki coupling in the final stages of the syn thesis. Alternatively, intermediates F.sub.1x-6x can be transformed into intermediate F.sub.1-6 via Suzuki coupling.

##STR00082##

[1047] When R.sub.4 and R.sub.5 form an optionally substituted cyclic amide, this amide can carry an ester moiety or a carbamate moiety, as highlighted in formulas K.sub.x, K or N of Scheme 4, which can be further hydrolyzed or deprotected to obtain compounds of substructure L or P. As it will be obvious to a person skilled in the art, compounds K could be obtained by linear synthesis through a coupling reaction as for compounds of formula J as described in Scheme 3, or in a parallel manner using compounds K. Examples are outlined in Scheme 4 (see FIG. 5). The amide could also carry a nitrile moiety (compound 11), which could be transformed into a tetrazole to produce a carboxylic acid bioisostere, as in exemplified with M12 for compound 30. When the commercially available ester building blocks were racemic, or intermediate F was prepared according to method M7, the coupling reaction was sometimes followed by chiral preparative HPLC to allow separation of the diastereomers.

[1048] In case of non-commercially available amide building blocks, the synthesis of compounds M required further derivatization of compound L, in a way that is described in method M11a. Amines P could also be further modified using methods known in the art, to obtain amides of formula Q. An example of such modification is described in method M11d for compound 28. Further hydrolysis of Q, when Q carries a Boc-protected amine, is also possible, as in the case of compound 85. When P was a primary amine, this could also be further modified using methods known in the art, to obtain, over three subsequent reactions and without isolation of the intermediates, N-hydroxyacetamides of formula R; or it could be reacted with an isocyanate to obtain ureas of formula S. Examples of such modifications are described herein exemplarily for compounds 209 and 214. Additionally, the tetrazole derivative 11 de scribed in Table 6 was synthesized from the corresponding nitrile, compound 30, according to method 12.

[1049] The compounds of formulae E, F, G, J, K, L, M, P, Q, R, and S are compounds of the general formula I of the invention.

##STR00083## ##STR00084##

3. Experimental Examples of the Invention

[1050] The following specific examples are presented to illustrate the invention, but they should not be construed as limiting the scope of the invention in any way. In the tables listing the intermediates, the compounds might have characterization such as (M+H).sup.+ mass spectrometry data, HPLC purity and/or NMR. Those that have no characterization are commercially avail able, and a CAS number is given.

3.1 Preparation of Intermediates for the Preparation of Compounds of Formula (I)

[1051] At least one intermediate example per method is described below:

3.1.1 Synthesis of Substituted β-Ketoesters of Formula (A)

Intermediate 4A—Synthesis According to Method 1 (M1)

Ethyl 3-(2-chloro-4-fluorophenyl)-3-oxopropanoate

[1052] ##STR00085##

[1053] 60% NaH in mineral oil (34.2 g, 852 mmol) was washed with pentane and dried under a flow of N.sub.2. Dry toluene (2.4 L) was added and the suspension was cooled to 0° C. Diethyl carbonate (192 g, 1.62 mol) was added dropwise over a period of 35 min, the mixture was stirred 30 min, upon which 2-Chloro-4-fluoroacetophenone (70 g, 406 mmol) was added over a period of 35 min. The cooling bath was removed, and the reaction heated to 50° C. and stirred for 20 h. The reaction mixture was allowed to cool to rt and was poured onto ice-water (2.5 L). The aqueous layer was extracted with Et.sub.2O, then acidified to pH 2 with 10% aq. HCl and extracted with Et.sub.2O. The combined organic phases were washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo to yield the desired product 4A (37.9 g, 38%) as a mixture of tautomers, which was used in the following step without further purification.

[1054] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.63 (dd, J=8.7, 6.0 Hz, 1H), 7.14-6.93 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.96 (s, 2H), 1.18 (t, J=7.1 Hz, 3H)-tautomer 1, ethyl 3-(2-chloro-4-fluorophenyl)-3-oxopropanoate

[1055] .sup.1H NMR (300 MHz, Chloroform-d) δ 12.43 (s, 1H), 7.52 (dd, J=8.7, 6.1 Hz, 1H), 7.14-6.93 (m, 2H), 5.48 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H)-tautomer 2, (Z)-ethyl 3-(2-chloro-4-fluorophenyl)-3-hydroxyacrylate

[1056] MS (ES) C.sub.11H.sub.10ClFO.sub.3 requires: 244/246, found: 245/247 (M+H).sup.+, ˜93%

3.1.2 Preparation of Intermediate Compounds of Formula (B)

Intermediate 4B—Synthesis According to Method 2 (M2)

3-(2-chloro-4-fluorophenyl)-N-(3-methoxyphenyl)-3-oxopropanamide

[1057] ##STR00086##

[1058] A mixture of compound 4A (20.8 g, 85 mmol) and 3-methoxyaniline (10.47 g, 9.5 mL, 85 mmol) was heated to 140° C. and stirred for 3.5 h. The mixture was allowed to cool to rt and diluted with 1,4-dioxane (90 mL) before addition of 10% aq. HCl solution (45 mL). The reaction was stirred for 2 h, upon which the mixture was diluted with H.sub.2O and extracted with EtOAc. The combined organic layers were washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product 4B (12.2 g, 45%) as a mixture of tautomers, which was used in the following step without further purification.

[1059] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.63 (dd, J=8.7, 5.9 Hz, 1H), 7.28-6.86 (m, 5H), 6.66-6.56 (m, 1H), 4.02 (s, 2H), 3.74 (s, 3H).-tautomer 1,3-(2-chloro-4-fluorophenyl)-N-(3-methoxyphenyl)-3-oxopropanamide

[1060] .sup.1H NMR (300 MHz, Chloroform-d) δ 13.96 (s, 1H), 7.55 (dd, J=8.8, 6.2 Hz, 1H), 7.28-6.86 (m, 6H), 6.66-6.56 (m, 1H), 5.48 (s, 1H), 3.72 (s, 3H).-tautomer 2, (Z)-3-(2-chloro-4-fluorophenyl)-3-hydroxy-N-(3-methoxyphenyl)acrylamide

[1061] MS (ES) C.sub.16H.sub.13ClFO.sub.3 requires: 321/323, found: 322/324 (M+H).sup.+, ˜94%

3.1.3 Preparation of Intermediate Compounds of Formula (C)

Intermediate 2C.SUB.1.— Synthesis According to Method 3a (M3a)

4-(2-chlorophenyl)-7-methoxyquinoline (2C.SUB.1.)

[1062] ##STR00087##

[1063] A mixture of 4-chloro-7-methoxyquinoline C.sub.1x (1.5 g, 7.75 mmol), Pd(amphos)Cl.sub.2 (274 mg, 0.387 mmol), 2-chlorophenylboronic acid (1.82 g, 11.6 mmol) and K.sub.2CO.sub.3 (3.2 g, 22.8 mmol) was purged with N.sub.2 before addition of toluene (35 mL) and H.sub.2O (5 mL). The reaction was then stirred at 85° C. for 3.5 h, upon which the mixture was diluted with DCM and washed with H.sub.2O. The aqueous phase was extracted with DCM, and the combined organic layers were washed with a sat. NaHCO.sub.3 solution and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product 2C.sub.1 (1.0 g, 48%) as a yellow solid.

[1064] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.82 (d, J=4.5 Hz, 1H), 7.55-7.39 (m, 2H), 7.42-7.25 (m, 3H), 7.30-7.19 (m, 1H), 7.20-7.01 (m, 2H), 3.90 (s, 3H).

[1065] MS (ES) C.sub.16H.sub.12ClNO requires: 269/271, found: 270/272 (M+H).sup.+, 91%

Intermediate 4C.SUB.2.— Synthesis According to Method 4 (M4)

4-(2-chloro-4-fluorophenyl)-7-methoxyquinolin-2(1H)-one (4C.SUB.2.)

[1066] ##STR00088##

[1067] A mixture of compound 4B (12.2 g, 37.9 mmol) and H.sub.3PO.sub.4 (100 g) was heated to 150° C. for 1 h, upon which the reaction was carefully quenched by slow addition of a 2N NaOH aq. solution (400 mL). The precipitate was filtered, washed with H.sub.2O and dried in vacuo to yield the desired product 4C.sub.2 (9.75 g, 85%) as a yellow solid.

[1068] .sup.1H NMR (300 MHz, Chloroform-d) δ 12.21 (s, 1H), 7.28-7.17 (m, 2H), 7.06 (td, J=8.2, 2.6 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.68 (dd, J=8.9, 2.4 Hz, 1H), 6.41 (s, 1H), 3.84 (s, 3H).

[1069] MS (ES) C.sub.16H.sub.11ClFO.sub.2 requires: 303/305, found: 304/306 (M+H).sup.+, 89%

Intermediate 4C, —Synthesis According to Method 5 (M5)

2-chloro-4-(2-chloro-4-fluorophenyl)-7-methoxyquinoline (4C.SUB.3.)

[1070] ##STR00089##

[1071] To compound 4C.sub.2 (9.75 g, 32.1 mmol) was added dry DMF (2.5 mL) and SOCl.sub.2 (110 mL). The resulting mixture was heated at 50° C. for 22 h, upon which the mixture was allowed to cool to rt and slowly poured over water-ice (˜800 mL). The mixture was then extracted with Et.sub.2O and the combined organic layers were washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product 4C.sub.3 (5.18 g, 50%) as an off-white solid.

[1072] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.35 (d, J=2.6 Hz, 1H), 7.30-7.10 (m, 3H), 7.15-6.97 (m, 3H), 3.87 (s, 3H).

[1073] MS (ES) C.sub.16H.sub.10Cl.sub.2FO requires: 321/323, found: 322/324 (M+H).sup.+, 92%

[1074] All 7-methoxyquinoline intermediates C were synthesized in a similar manner as for intermediates 2C.sub.1, 4C.sub.2 or 4C.sub.3.

Intermediate C.SUB.4a.—Synthesis According to Nicoleti et al. (2012)

5-(((6-methoxypyridin-2 yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (C.SUB.4a.)

[1075] ##STR00090##

[1076] A mixture of Meldrum acid (26 g, 179 mmol) and 110 mL of trimethyl orthoformate was refluxed for 2 h. The solution was allowed to cool to rt, 2-amino-6-methoxypyridine (10 g, 80.6 mmol) was added and the solution refluxed for 30 min. The mixture was cooled to rt, and the resulting precipitate was filtered, washed with EtOH (60 mL) and dried in vacuo to yield the desired product C.sub.4a (20.89 g, 93%) as an orange solid.

[1077] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.34 (d, J=13.8 Hz, 1H), 9.19 (d, J=13.9 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 3.91 (s, 3H), 1.69 (s, 6H).

[1078] MS (ES) C.sub.13H.sub.14N.sub.2O.sub.5 requires: 278, found: 279 (M+H).sup.+, 100%

7-methoxy-1,8-naphthyridin-4(1H)-one (C.SUB.4b.)

[1079] ##STR00091##

[1080] Diphenyl ether (860 mL) was heated to 150° C. and intermediate C.sub.4a (20.8 g, 74.82 mmol) was added slowly. The resulting mixture was heated to 225° C. for 90 min, upon which it was allowed to cool to rt. The mixture was diluted with Et.sub.2O. The resulting precipitate was filtered, washed with Et.sub.2O and dried in vacuo, to yield the desired product C.sub.4b (11.06 g, 84%) as an as an orange solid.

[1081] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.98 (s, 1H), 8.29 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.03 (d, J=7.6 Hz, 1H), 3.96 (s, 3H).

[1082] MS (ES) C.sub.9H.sub.8N.sub.2O.sub.2 requires: 176, found: 177 (M+H).sup.+, 99%

5-chloro-2-methoxy-1,8-naphthyridine (C.SUB.4x.)

[1083] ##STR00092##

[1084] A solution of compound C.sub.4b (11 g, 62.4 mmol) in PCl.sub.5 (225 mL) was heated to 95° C. for 2 h, after which the mixture was allowed to cool to rt and ice was added slowly under vigorous stirring. The pH of the mixture was adjusted to ˜8 by careful addition of 25% aq. NH.sub.3OH solution. The resulting solid was filtered, washed with H.sub.2O and dried in vacuo, to yield the desired product C.sub.4x (11.36 g, 86%) as a yellow solid.

[1085] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.75 (d, J=4.9 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.34 (d, J=4.9 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 4.10 (s, 3H).

[1086] MS (ES) C.sub.9H.sub.7ClN.sub.2O requires: 194/196, found: 195/197 (M+H).sup.+, 95%

5-(2-chloro-4-fluorophenyl)-2-methoxy-1,8-naphthyridine (4C.SUB.4.)—Synthesis According to Method 3b (M3b)

[1087] ##STR00093##

[1088] To a mixture of compound C.sub.4x (10.45 g, 53.7 mmol), 2-chloro-4-fluorophenylboronic acid (11.2 g, 64.4 mmol) and Pd(PPh.sub.3).sub.4 (3.1 g, 2.68 mmol) was added toluene (135 mL), EtOH (18 mL) and 2M aq. Na.sub.2CO.sub.3 solution (48 mL, 96 mmol). The mixture was stirred under N.sub.2 atmosphere at 80° C. for 15 h. The reaction was then diluted with H.sub.2O and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of MeOH in DCM to yield compound 4C.sub.4 (12.86 g, 83%) as a yellow solid.

[1089] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.93 (d, J=4.6 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.33-7.11 (m, 3H), 7.08 (ddd, J=8.6, 7.9, 2.6 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 4.11 (s, 3H).

[1090] MS (ES) C.sub.15H.sub.10ClFN.sub.2O requires: 288/290, found: 289/291 (M+H).sup.+, 86%.

[1091] All 2-methoxy-1,8-naphthyridine intermediates C were synthesized in a similar manner as intermediates 4C.sub.4.

3.1.4 Preparation of Intermediate Compounds of Formula (D)

5-(2-chloro-4-fluorophenyl)-1,8-naphthyridin-2-ol (4D.SUB.4.)—Synthesis According to Method 6 (M6)

[1092] ##STR00094##

[1093] Compound 4C.sub.4 (12.85 g, 44.5 mmol) was dissolved in DCM (95 mL) and BBr.sub.3 (25 g, 99.8 mmol) in DCM (40 mL) was added at −50° C. The mixture was allowed to warm up to rt and was stirred for 18 h, upon which it was cooled to 0° C. Additional BBr.sub.3 (25 g, 99.8 mmol) in DCM (40 mL) was added. The reaction mixture was then stirred at rt for 6 days before being carefully poured over a mixture of ice-water (˜500 mL) and aq. 25% NH.sub.4OH solution (150 mL) under vigorous stirring. The resulting precipitate was twice filtered, washed with H.sub.2O and dried in vacuo to yield the desired product 4D.sub.4 (9.88 g, 81%) as a yellow solid.

[1094] .sup.1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.71 (dd, J=8.9, 2.6 Hz, 1H), 7.53 (dd, J=8.6, 6.2 Hz, 1H), 7.49-7.31 (m, 2H), 7.17 (d, J=4.9 Hz, 1H), 6.55 (dd, J=9.8, 1.9 Hz, 1H).

[1095] MS (ES) C.sub.14H.sub.8ClFN.sub.2O requires: 274/276, found: 275/277 (M+H).sup.+, 89%.

[1096] The following quinoline and naphthyridine intermediates D in Table 3, unless commercially available, were synthesized from intermediates C according to M6 in a similar manner as for intermediate 4D.sub.4.

TABLE-US-00003 TABLE 3 7-Hydroxy-Quinolines of formula (D and D.sub.x) Inter- me- diate Structure (M + H).sup.+, purity D.sub.1x [00095] embedded image CAS: 181950-57-2 1D.sub.1 [00096] MS (ES) C.sub.15H.sub.11NO requires: 221, found 222 (M + H).sup.+, >95% 2D.sub.1 [00097] MS (ES) C.sub.15H.sub.11ClNO requires: 255/257, found: 256/258 (M + H).sup.+, 92% 3D.sub.1 [00098] MS (ES) C.sub.16H.sub.13NO requires: 235, found: 236 (M + H).sup.+, 90% 4D.sub.1 [00099] embedded image MS (ES) C.sub.15H.sub.9ClFNO requires: 273/275, found: 274/276 (M + H).sup.+, 91% 6D.sub.1 [00100] MS (ES) C.sub.17H.sub.15NO requires: 249, found: 250 (M + H).sup.+, 91% 7D.sub.1 [00101] MS (ES) C.sub.15H.sub.9Cl.sub.2NO requires: 289/291, found: 290/292 (M + H).sup.+, 92% 8D.sub.1 [00102] embedded image MS (ES) C.sub.17H.sub.14FNO requires: 267/268, found: 268/269 (M + H).sup.+, 89% 9D.sub.1 [00103] MS (ES) C.sub.15H.sub.8Cl.sub.2FNO requires: 307/309, found: 308/310 (M + H).sup.+, 99% 1D.sub.2 [00104] MS (ES) C.sub.15H.sub.11NO.sub.2 requires: 237, found: 238 (M + H).sup.+, 85% 3D.sub.2 [00105] embedded image MS (ES) C.sub.16H.sub.13NO.sub.2 requires: 251, found: 252 (M + H).sup.+, 93% 2D.sub.3 [00106] MS (ES) C.sub.15H.sub.9Cl.sub.2NO requires: 289/291, found: 290/292 (M + H).sup.+, >95% 3D.sub.3 [00107] MS (ES) C.sub.16H.sub.12ClNO requires: 269/271, found: 270/272 (M + H).sup.+, >95% 4D.sub.3 [00108] embedded image MS (ES) C.sub.15H.sub.8Cl.sub.2FNO requires: 307/309, found: 308/310 (M + H).sup.+, 92% 5D.sub.3 [00109] MS (ES) C.sub.16H.sub.11CIFNO requires: 287/289, found: 288/290 (M + H).sup.+, 93% 6D.sub.3 [00110] MS (ES) C.sub.17H.sub.14ClNO requires: 283/285, found: 284/286 (M + H).sup.+, 31%- used without purification 4D.sub.4 [00111] embedded image MS (ES) C.sub.14H.sub.8ClFN.sub.2O requires: 274/276, found: 275/277 (M + H).sup.+, 89% 8D.sub.4 [00112] MS (ES) C.sub.16H.sub.13FN.sub.2O requires: 268/269, found: 269/270 (M + H).sup.+, 78% 9D.sub.4 [00113] MS (ES) C.sub.14H.sub.7Cl.sub.2FN.sub.2O requires: 308/310, found: 309/311 (M + H).sup.+, 58% D.sub.5x [00114] embedded image CAS: 148018-30-8

3.1.5 Preparation of Compounds of Formula (E and F)

Compound of Formula E (106)—Synthesis According to Method 7 (M7)

2-((4-(o-tolyl)quinolin-7-yl)oxy)acetamide (106)

[1097] ##STR00115##

[1098] Intermediate 3D.sub.1 (80 mg, 0.34 mmol) was suspended in dry DMF (1.5 mL) and Cs.sub.2CO.sub.3 (286 mg, 0.879 mmol) was added, followed by 2-bromoacetamide (47 mg, 0.34 mmol) in dry DMF (1 mL). The reaction was stirred at rt for 24 h. The mixture was diluted with EtOAc (50 mL) and the organic phase was washed with H.sub.2O and brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by preparative TLC on silica gel using an eluent mixture of DCM: MeOH 19:1 containing 0.05% of 25% NH.sub.4OH solution to yield the desired product (106) (12 mg, 12%) as a white solid.

[1099] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.84 (d, J=4.5 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.34-7.21 (m, 3H), 7.16-7.05 (m, 3H), 6.52 (s, 1H), 5.69 (s, 1H), 4.61 (s, 2H), 1.96 (s, 3H).

[1100] MS (ES) C.sub.18H.sub.16N.sub.2O.sub.2 requires: 292, found: 293 (M+H).sup.+, 96%

(rac)-4F.SUB.4_.Et—Synthesis According to Method 7 (M7)

ethyl 2-((5-(2-chloro-4-fluorophenyl)-1,8-naphthyridin-2 yl)oxy)propanoate (rac)-4F.SUB.4_.Et)

[1101] ##STR00116##

[1102] Intermediate 4D.sub.4 (1 g, 3.64 mmol) was reacted with ethyl-2-bromopropionate (0.71 mL, 5.46 mmol) according to M7 to yield the desired product (rac)-4F.sub.4_Et (1.03 g, 75%).

[1103] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.93 (d, J=4.6 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.34-7.14 (m, 3H), 7.18-6.96 (m, 2H), 5.84 (qd, J=7.0, 4.5 Hz, 1H), 4.29-4.06 (m, 2H), 1.62 (d, J=7.0 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H).

[1104] MS (ES) C.sub.19H.sub.16ClFN.sub.2O.sub.3 requires: 374/376, found: 375/377 (M+H).sup.+, 97%

(R)-4F.SUB.1_.Et—Synthesis According to Method 8 (M8)

(R)-ethyl 2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoate ((R)-4F.SUB.1_.Et)

[1105] ##STR00117##

[1106] Intermediate 4D.sub.1 (100 mg, 0.365 mmol) and PPh.sub.3 (105 mg, 0.402 mmol) were dissolved in THE (5.5 mL), and (−)-Ethyl (S)-2-hydroxypropionate (50 μl, 0.438 mmol) was added. The reaction was cooled to 0° C. and DIAD (79 μl, 0.402 mmol) was added dropwise. The reaction was then stirred at rt for 1 h, upon which further reagents were added in the same amounts, and the reaction stirred for a further 6 h. The mixture was diluted with EtOAc and washed with a sat. NaHCO.sub.3 solution, a sat. NH.sub.4Cl solution, and H.sub.2O. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product (R)-4F.sub.1_Et (163 mg, ˜20% excess weight), which was carried through to the following step without further purification.

[1107] MS (ES) C.sub.20H.sub.17ClFNO.sub.3 requires: 373/375, found: 374/376 (M+H).sup.+, 94%

3.1.6 Preparation of Intermediate Compounds of Formula (F.SUB.x.) Through Intermediates

(D.SUB.1.)

Intermediate (R)—F.SUB.1x_.tBu—Synthesis According to Method 8 (M8)

(R)-tert butyl 2-((4-chloroquinolin-7-yl)oxy)propanoate (R)—F.SUB.1x_.tBu

[1108] ##STR00118##

[1109] 4-chloroquinolin-7-ol (D.sub.1x) (200 mg, 1.11 mmol) was reacted with tert-butyl (2S)-2-hydroxypropanoate (244 mg, 1.67 mmol) according to M8 to yield the desired product (R)-F.sub.1xtBu (222 mg, 65%) as a colorless glue.

[1110] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.76 (d, J=4.7 Hz, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.60 (dd, J=4.8, 0.5 Hz, 1H), 7.47-7.40 (m, 1H), 7.31 (d, J=2.6 Hz, 1H), 5.06 (q, J=6.7 Hz, 1H), 1.57 (dd, J=6.8, 0.6 Hz, 3H), 1.39 (d, J=0.5 Hz, 9H).

[1111] MS (ES) C.sub.16H.sub.18ClNO.sub.3 requires: 307/309, found: 308/310 (M+H).sup.+, 100%

(R)-4F.SUB.1_.tBu—Synthesis According to Method 3b (M3b)

(R)-tert butyl 2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoate ((R)-4F.SUB.1_.tBu)

[1112] ##STR00119##

[1113] Intermediate (R)-F.sub.1x_tBu (110 mg, 0.356 mmol) was reacted with (2-chloro-4-fluorophenyl)boronic acid (75 mg, 0.427 mmol) according to M3b to yield the desired product (R)-4F.sub.1_tBu (95 mg, 66%) as a white solid.

[1114] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.87 (d, J=4.4 Hz, 1H), 7.67 (dt, J=8.9, 2.7 Hz, 1H), 7.51 (ddd, J=8.5, 7.3, 6.2 Hz, 1H), 7.45-7.36 (m, 1H), 7.35-7.18 (m, 4H), 5.05-4.93 (m, 1H), 1.55 (d, J=6.7 Hz, 3H), 1.40 (s, 9H).

[1115] MS (ES) C.sub.22H.sub.21ClFNO.sub.3 requires: 401/403, found: 402/404 (M+H).sup.+, 92%

(R)-2F.SUB.6_.tBu—Synthesis According to Fier and Hartwig (2013)

(R)-tert butyl 2-((4-(2-chlorophenyl)-2-fluoroquinolin-7-yl)oxy)propanoate ((R)-2F.SUB.6._tBu)

[1116] ##STR00120##

[1117] Compound (R)-2F.sub.1_tBu (34.5 mg, 0.090 mmol) was dissolved in dry ACN (1 mL) and AgF.sub.2 (39.4 mg, 0.270 mmol) was added at rt. The resulting suspension was stirred under N.sub.2 atmosphere for 2 h. A second aliquot of AgF.sub.2 (39.4 mg, 0.270 mmol) was added and stirring was continued for 90 min. The mixture was diluted with EtOAc and washed with sat. NaHCO.sub.3 solution and brine. The organic layer was dried over MgSO.sub.4, filtered through a plug of celite and evaporated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product (R)-2F.sub.6_tBu (14.3 mg, 40%) as a colorless oil.

[1118] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.59-7.53 (m, 1H), 7.48-7.35 (m, 3H), 7.34-7.29 (m, 1H), 7.22 (dd, J=5.5, 2.6 Hz, 1H), 7.18-7.12 (m, 1H), 6.87 (dd, J=2.2, 1.0 Hz, 1H), 4.81 (qd, J=6.8, 4.4 Hz, 1H), 1.66 (d, J=6.8 Hz, 3H), 1.48 (s, 9H).

[1119] MS (ES) C.sub.22H.sub.21ClFNO.sub.3 requires: 401/403, found: 402/404 (M+H).sup.+, 100%

3.1.7 Preparation of Compounds of Formula (G)

(R)-4G.SUB.1.—Synthesis According to Method 9 (M9)

(R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7 yl)oxy)propanoic acid ((R)-4G.SUB.1.)-44

[1120] ##STR00121##

[1121] Compound (R)-4F.sub.1_Et (156 g, ˜0.365 mmol) was dissolved in THE (6.3 mL) and 2M NaOH aq. solution (1.3 mL) was added. MeOH was added dropwise until the mixture became homogeneous. The reaction was stirred at rt for 30 min. The mixture was acidified with 2M HCl to pH5 and extracted with EtOAc. The combined organic layers were washed with H.sub.2O, dried over MgSO.sub.4, filtered, and evaporated in vacuo. The crude was purified by column chromatography using a gradient of MeOH in DCM to yield the desired product (R)-4G.sub.1 (44) (66 mg, 52% over 2 steps) as a white solid.

[1122] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.85 (dd, J=4.4, 0.6 Hz, 1H), 7.67 (dt, J=8.9, 2.3 Hz, 1H), 7.49 (ddd, J=8.1, 6.2, 1.8 Hz, 1H), 7.39 (tt, J=8.5, 2.4 Hz, 1H), 7.32-7.27 (m, 2H), 7.26 (dd, J=4.4, 0.6 Hz, 1H), 7.22 (dd, J=9.2, 2.6 Hz, 1H), 5.00 (q, J=6.5 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H).

[1123] MS (ES) C.sub.18H.sub.13ClFNO.sub.3 requires: 345/347, found: 346/348 (M+H).sup.+, 96%

(R)-4G.SUB.1.—Synthesis According to Method 10a (M10a)

(R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoic acid trifluoroacetic acid salt ((R)-4G.SUB.1.)-44

[1124] ##STR00122##

[1125] Compound (R)-4F.sub.1_tBu (93 mg, 0.232 mmol) was dissolved in a 4:1 DCM:TFA solution (2.3 ml) and the reaction was stirred at rt for 1.5 h, upon which the solvents were removed in vacuo and a fresh 4:1 DCM:TFA solution (2.3 ml) was added and the mixture stirred for further 4 h. The solvents were evaporated in vacuo to yield the desired product (R)-4G.sub.1 (44) (132 mg, ˜23% excess weight) as a brown glue (TFA salt), which was used in the following step without further purification.

[1126] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.99 (d, J=4.7 Hz, 1H), 7.70 (ddd, J=8.9, 2.5, 1.8 Hz, 1H), 7.53 (ddd, J=8.9, 6.2, 3.0 Hz, 1H), 7.49-7.39 (m, 3H), 7.39-7.30 (m, 2H), 5.09 (q, J=6.8 Hz, 1H), 1.59 (d, J=6.8 Hz, 3H).

[1127] MS (ES) C.sub.18H.sub.13ClFNO.sub.3 requires: 345/347, found: 346/348 (M+H).sup.+, 92%

[1128] The ethyl esters and carboxylic acids shown in Table 4 were synthesized in a similar manner as described for intermediates (rac)-4F.sub.4_Et, (R)-4F.sub.1_Et, (R)—F.sub.1x, (R)-4F.sub.1_tBu, (R)-2F.sub.6_tBu and (R)-4G.sub.1.

TABLE-US-00004 TABLE 4 Esters and carboxylic acids compounds (F) and (G) Compounds Structure (M + H).sup.+, purity (R)-F.sub.1x_Et (R)-F.sub.1x_tBu (R)-G.sub.1x [00123] embedded image Et: MS (ES) C.sub.14H.sub.14ClNO.sub.3 requires: 279/281, found: 280/282 (M + H).sup.+, >95% tBu: MS (ES) C.sub.16H.sub.18ClNO.sub.3 re- quires: 307/309, found: 308/310 (M + H).sup.+, 100% H: MS (ES) C.sub.12H.sub.10ClNO.sub.3 requires: 251/253, found: 252/253 (M + H).sup.+, >95% (R)-1F.sub.1_Et (R)-1F.sub.1_tBu (R)-1G.sub.1 [00124] embedded image Et: MS (ES) C.sub.20H.sub.17ClFNO.sub.3 re- quires: 373/375, found: 374/376 (M + H).sup.+, 94% tBu: MS (ES) C.sub.22H.sub.21ClFNO.sub.3 re- quires: 401/403, found: 402/404 (M + H).sup.+, 92% H: MS (ES) C.sub.18H.sub.13ClFNO.sub.3 re- quires: 345/347, found: 346/348 (M + H).sup.+, 92% 2F.sub.1_Et 2G.sub.1 [00125] embedded image Et: MS (ES) C.sub.19H.sub.16ClNO.sub.3 requires: 341/343, found: 342/344 (M + H).sup.+, 92% H: MS (ES) C.sub.17H.sub.12ClNO.sub.3 requires: 313/315, found: 314/316 (M + H).sup.+, 93% (R)-2F.sub.1_Et (R)-2F.sub.1_tBu (R)-2G.sub.1 [00126] Et: MS (ES) C.sub.20H.sub.18ClNO.sub.3 requires: 355/357, found: 356/358 (M + H).sup.+, >95% tBu: MS (ES) C.sub.22H.sub.22ClNO.sub.3 re- quires: 383/385, found: 384/386 (M + H).sup.+, 92% H: MS (ES) C.sub.18H.sub.14ClNO.sub.3 requires: 327/329, found: 328/330 (M + H).sup.+, >95% (R)-3F.sub.1_tBu (R)-3G.sub.1 [00127] embedded image tBu: MS (ES) C.sub.23H.sub.25NO.sub.3 requires: 363, found: 364 (M + H).sup.+, 96% H: MS (ES) C.sub.19H.sub.17NO.sub.3 requires: 307, found: 308 (M + H).sup.+, 96% (R)-4F.sub.1_Et (R)-4F.sub.1_tBu (R)-4G.sub.1 [00128] Et: MS (ES) C.sub.20H.sub.17ClFNO.sub.3 re- quires: 373/375, found: 374/376 (M + H).sup.+, 94% tBu: MS (ES) C.sub.22H.sub.21ClFNO.sub.3 re- quires: 401/403, found: 402/404 (M + H).sup.+, 92% H: MS (ES) C.sub.18H.sub.13ClFNO.sub.3 re- quires: 345/347, found: 346/348 (M + H).sup.+, 92% (R)-6F.sub.1_Et (R)-6G.sub.1 [00129] embedded image Et: MS (ES) C.sub.22H.sub.23NO.sub.3 requires: 349, found: 350 (M + H).sup.+, >95% H: MS (ES) C.sub.20H.sub.19NO.sub.3 requires: 321, found: 322 (M + H).sup.+, >95% (gem)-2F.sub.1_Et (gem)-2G.sub.1 [00130] Et: MS (ES) C.sub.21H.sub.20ClNO.sub.3 requires: 369/371, found: 370/372 (M + H).sup.+, 98% H: MS (ES) C.sub.19H.sub.16ClNO.sub.3 requires: 341/343, found: 342/344 (M + H).sup.+, 92% (rac)-Et-2F.sub.1_Et (rac)-Et-2G.sub.1 [00131] embedded image Et: MS (ES) C.sub.21H.sub.20ClNO.sub.3 requires: 369/371, found: 370/372 (M + H).sup.+, 98% H: MS (ES) C.sub.19H.sub.16ClNO.sub.3 requires: 341/343, found: 342/344 (M + H).sup.+, 97% (R)-7F.sub.1_Et (R)-7G.sub.1 [00132] Et: MS (ES) C.sub.20H.sub.17Cl.sub.2NO.sub.3 re- quires: 389/391, found: 390/392 (M + H).sup.+, >95% H: MS (ES) C.sub.18H.sub.13Cl.sub.2NO.sub.3 re- quires: 361/363, found: 362/364 (M + H).sup.+, >95% (R)-8F.sub.1_Et (R)-8G.sub.1 [00133] embedded image Et: MS (ES) C.sub.22H.sub.22FNO.sub.3 requires: 367/368, found: 368/369 (M + H).sup.+, 95% H: MS (ES) C.sub.20H.sub.18FNO.sub.3 requires: 339/340, found: 340/341 (M + H).sup.+, >99% (R)-9F.sub.1_Et (R)-9G.sub.1 [00134] Et: MS (ES) C.sub.20H.sub.16Cl.sub.2FNO.sub.3 re- quires: 408/409, found: 408/410 (M + H).sup.+, 95% H: MS (ES) C.sub.18H.sub.12Cl.sub.2FNO.sub.3 re- quires: 380/382, found: 381/383 (M + H).sup.+, used as crude (R)-1F.sub.3_tBu (R)-1G.sub.3 [00135] embedded image tBu: MS (ES) C.sub.23H.sub.24ClNO.sub.3 re- quires: 397/399, found: 398/400 (M + H).sup.+, >95% H: MS (ES) C.sub.19H.sub.16ClNO.sub.3 requires: 341/343, found: 342/344 (M + H).sup.+, >95% (R)-2F.sub.3_Et (R)-2G.sub.3 [00136] Et: MS (ES) C.sub.20H.sub.17Cl.sub.2NO.sub.3 re- quires: 389/391, found: 390/392 (M + H).sup.+, >95% H: MS (ES) C.sub.18H.sub.13Cl.sub.2NO.sub.3 re- quires: 361/363, found: 362/364 (M + H).sup.+, >95% (R)-4F.sub.3_Et (R)-4G.sub.3 [00137] embedded image Et: MS (ES) C.sub.20H.sub.16Cl.sub.2FNO.sub.3 re- quires: 407/409, found: 408/410 (M + H).sup.+, >95% H: MS (ES) C.sub.18H.sub.12Cl.sub.2FNO.sub.3 re- quires: 379/381, found: 380/382 (M + H).sup.+, >95% (R)-6F.sub.3_Et (R)-6G.sub.3 [00138] Et: MS (ES) C.sub.21H.sub.19ClFNO.sub.3 re- quires: 387/389, found: 388/390 (M + H).sup.+, >95% H: MS (ES) C.sub.19H.sub.15ClFNO.sub.3 re- quires: 359/361, found: 360/362 (M + H).sup.+, >95% (rac)-4F.sub.4_Et (rac)-4G.sub.4 [00139] embedded image Et: MS (ES) C.sub.19H.sub.16ClFN.sub.2O.sub.3 re- quires: 374/376, found: 375/377 (M + H).sup.+, 97% H: MS (ES) C.sub.19H.sub.16ClFN.sub.2O.sub.3 re- quires: 374/376, found: 375/377 (M + H).sup.+, 97% (R)-8F.sub.4_Et (R)-8G.sub.4 [00140] Et: MS (ES) C.sub.21H.sub.21FN.sub.2O.sub.3 requires: 368/369, found: 369/370 (M + H).sup.+, 86% H: MS (ES) C.sub.19H.sub.17FN.sub.2O.sub.3 requires: 340/341, found: 341/342 (M + H).sup.+, 94% (R)-9F.sub.4_Et (R)-9G.sub.4 [00141] embedded image Et: MS (ES) C.sub.19H.sub.15Cl.sub.2FN.sub.2O.sub.3 re- quires: 408/410, found: 409/411 (M + H).sup.+, 89% H: MS (ES) C.sub.17H.sub.11Cl.sub.2FN.sub.2O.sub.3 requires: 380/382, found: 381/383 (M + H).sup.+, used as crude (R)-F.sub.5x_tBu [00142] tBu: MS (ES) C.sub.17H.sub.20ClNO.sub.3 re- quires: 321/323, found: 322/324 (M + H).sup.+, 100% (R)-3F.sub.5_tBu (R)-3G.sub.5 [00143] embedded image tBu: MS (ES) C.sub.24H.sub.27NO.sub.3 requires: 377, found: 378 (M + H).sup.+, 96% H: MS (ES) C.sub.20H.sub.19NO.sub.3 requires: 321, found: 322 (M + H).sup.+, 96% (R)-4F.sub.5_tBu (R)-4G.sub.5 [00144] tBu: MS (ES) C.sub.23H.sub.23ClFNO.sub.3 re- quires: 415/417, found: 416/418 (M + H).sup.+, 100% H: MS (ES) C.sub.19H.sub.15ClFNO.sub.3 re- quires: 359/361, found: 360/362 (M + H).sup.+, 98% (R)-6F.sub.5_tBu (R)-6G.sub.5 [00145] embedded image tBu: MS (ES) C.sub.25H.sub.29NO.sub.3 requires: 391, found: 392 (M + H).sup.+, 97% H: MS (ES) C.sub.21H.sub.21NO.sub.3 requires: 335, found: 336 (M + H).sup.+, 97% (R)-2F.sub.6_tBu (R)-2G.sub.6 [00146] tBu: MS (ES) C.sub.22H.sub.21ClFNO.sub.3 re- quires: 401/403, found: 402/404 (M + H).sup.+, 100% H: MS (ES) C.sub.18H.sub.13ClFNO.sub.3 re- quires: 345/347, found: 346/348 (M + H).sup.+, 96%

3.1.8 Preparation of Compounds of Formula (J)

Compound 63—Synthesis According to Method 11a (M11a)

(R)-4-(2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoyl)piperazin-2-one (63)

[1129] ##STR00147##

[1130] Compound (R)-4G, (35.0 mg, 0.101 mmol) and 2-oxopiperazine (16.2 mg, 0.162 mmol) were dissolved in dry DMF (0.8 mL). DIPEA (51.6 μL, 39.3 mg, 0.304 mmol) and HATU (57.7 mg, 0.152 mmol) were added, and the mixture was stirred at rt overnight. The reaction was diluted with EtOAc and washed with H.sub.2O, sat. NaHCO.sub.3 solution and brine. The organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of MeOH in DCM to yield the de sired product 63 (31.5 mg, 73%) as a white solid.

[1131] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J=4.4 Hz, 1H), 8.14 (d, J=10.8 Hz, 1H), 7.69 (ddd, J=8.9, 2.6, 1.3 Hz, 1H), 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.45-7.21 (m, 5H), 5.57 (q, J=6.6 Hz, 1H), 4.40-4.07 (m, 1H), 4.06-3.52 (m, 3H), 3.30-3.13 (m, 2H), 1.51 (ddd, J=13.4, 6.5, 2.5 Hz, 3H).

[1132] MS (ES) C.sub.22H.sub.19ClFN.sub.3O.sub.3 requires: 427/429, found: 428/430 (M+H).sup.+, 97%

3.1.9 Preparation of Intermediate Compounds of Formula (K)

[1133] Compound 15—Synthesis According to Method 11b (M11 b)

ethyl 2-((R)-1-((R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetate (15)

[1134] ##STR00148##

[1135] Compound (R)-4G.sub.1 (129 mg, 0.282 mmol), EDC.HCl (135 mg, 0.704 mmol), and HOBt.xH.sub.2O (108 mg, 0.704 mmol) were dissolved in DMF (4 mL) and (S)-piperidine-3-carboxylic acid ethyl ester hydrochloride (146 mg, 0.704 mmol) was added slowly. Et.sub.3N (98 μL, 0.704 mmol) was added, and the mixture was stirred at rt overnight. The reaction was diluted with EtOAc and washed with H.sub.2O, a sat. NaHCO.sub.3 solution, and again with H.sub.2O. The organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the de sired product 15 (50 mg, 36%) as a colorless glue.

[1136] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.88 (dd, J=7.3, 4.4 Hz, 1H), 7.73-7.63 (m, 1H), 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.42 (dddd, J=8.7, 7.8, 3.0, 2.2 Hz, 1H), 7.34-7.20 (m, 4H), 5.65-5.35 (m, 1H), 4.20 (d, J=13.1 Hz, 2H), 4.11-3.92 (m, 3H), 3.19-2.60 (m, 1H), 2.36-2.12 (m, 2H), 1.91-1.45 (m, 8H), 1.19-1.09 (m, 3H).

[1137] MS (ES) C.sub.27H.sub.28ClFN.sub.2O.sub.4 requires: 498/500, found: 499/501 (M+H).sup.+, 97%.

Intermediate (R,R)-2K.SUB.1x_Cl.—Synthesis According to Method 11c (M11c)

ethyl 2-((R)-1-((R)-2-((4-chloroquinolin-7-yl)oxy)propanoyl)piperidin-3 yl)acetate ((R,R)-2K.SUB.1x.)

[1138] ##STR00149##

[1139] A mixture of intermediate (R)-G.sub.1x (1.2 g, 4.77 mmol) and 1,1′-carbonyldiimidazole (775 mg, 4.77 mmol) in dry THF (24 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was poured over a solution of ethyl-(R)-2-(3-piperidyl)acetate hydrochloride (990 mg, 4.47 mmol) and triethylamine (506 mg, 5.00 mmol) in dry THF (24 mL). After stirring for 12 hours, the mixture was diluted with EtOAc and washed with H.sub.2O. The aqueous phase was further extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude was purified by flash chromatography using a gradient of EtOAc in cHex to yield the desired product (R,R)-2K.sub.1x (1.36 g, 70%) as white solid.

[1140] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.61 (t, J=5.3 Hz, 1H), 8.07 (dd, J=9.1, 4.1 Hz, 1H), 7.36-7.16 (m, 3H), 5.24-5.08 (m, 1H), 4.50-4.14 (m, 1H), 4.13-3.74 (m, 4H), 3.16-2.72 (m, 1H), 2.57 (ddd, J=13.2, 7.8, 3.2 Hz, 1H), 2.29-1.98 (m, 2H), 1.92-1.70 (m, 1H), 1.68-1.26 (m, 4H), 1.28-1.06 (m, 5H).

[1141] MS (ES) C.sub.21H.sub.25ClN.sub.2O.sub.4 requires: 404/406, found: 405/407 (M+H).sup.+, 100%.

Intermediate (R,S)-1K.SUB.1_l.—Synthesis According to Bissember and Banwell (2009)

(S)-ethyl 1-((R)-2-((4-iodoquinolin-7-yl)oxy)propanoyl)piperidine-3-carboxylate ((R,S)-1K.SUB.1_l.)

[1142] ##STR00150##

[1143] Intermediate (R,S)-1K.sub.1_Cl (379 mg, 0.97 mmol) was dissolved in MeCN (1.5 mL) and NaI (1.45 g, 9.7 mmol) and AcCl were added (112 mg, 1.43 mmol). The suspension was heated to 80° C. for 5 min in a microwave. The mixture was diluted with DCM and washed with H.sub.2O, a sat. Na.sub.2S.sub.2O.sub.3 solution, H.sub.2O, and brine. The organic layer was dried over MgSO.sub.4, filtered and evaporated in vacuo to yield the desired product (R,S)-1K.sub.1_l (481 mg, ˜100%) as yellow solid.

[1144] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.28 (d, J=3.9 Hz, 1H), 7.92-7.75 (m, 2H), 7.32-7.21 (m, 2H), 5.27-5.12 (m, 1H), 4.51-4.09 (m, 3H), 4.08-3.75 (m, 2H), 3.44-2.76 (m, 2H), 2.57-2.36 (m, 1H), 2.31-1.85 (m, 1H), 1.80-1.54 (m, 3H), 1.26-1.09 (m, 5H).

[1145] MS (ES) C.sub.20H.sub.231N.sub.2O.sub.4 requires: 482, found: 483 (M+H).sup.+, 86%.

[1146] The library building blocks shown in Table 5 were synthesized in a similar manner.

TABLE-US-00005 TABLE 5 Building Blocks (J) and (K) Intermediates Structure (M +H).sup.+, purity (R,S)-1K.sub.1_Cl [00151] embedded image MS (ES) C.sub.20H.sub.23ClN.sub.2O.sub.4 quires: 390/392, found: 391/393 (M + H).sup.+, 89% (R,S)-1K.sub.1_I [00152] MS (ES) C.sub.20H.sub.23IN.sub.2O.sub.4 requires: 482, found: 483 (M + H).sup.+, 89% (R,R)-2K.sub.1x [00153] MS (ES) C.sub.21H.sub.25ClN.sub.2O.sub.4 quires: 404/406, found: 405/407 (M + H).sup.+, 100%

3.1.10 Preparation of Intermediate Compound (S,S)-1H for the Direct Synthesis of Intermediates of formula (K)

Intermediate (S,S)-1H—Synthesis According to Method 11a (M11a)

(S)-ethyl 1-((S)-2-hydroxypropanoyl)piperidine 3-carboxylate ((S,S)-1H)

[1147] ##STR00154##

[1148] L-(+)-Lactic acid (10 g, 111 mmol) and (S)-(+)-Nipecotic acid ethyl ester (17.5 g, 111 mmol) were reacted according to M11a to yield the desired product (S,S)-1H (12.7 g, 50%) as an off-white solid.

[1149] .sup.1H-NMR (300 MHz, CDCl.sub.3) δ 4.59-4.40 (m, 2H), 4.20-4.09 (m, 2H), 3.84-3.62 (m, 2H), 3.15-2.70 (m, 2H), 2.50-2.40 (m, 1H), 2.21-2.08 (m, 1H), 1.80-1.51 (m, 3H), 1.32-1.25 (m, 6H).

[1150] GC-MS C.sub.11H.sub.19NO.sub.4 requires: 229, found: 229 (M′), 93%.

3.1.11 Preparation of Intermediate Compounds of Formula (N)

Compound 4N.SUB.1_.piperazine—Synthesis According to Method 11a (M11a)

(R)-tert butyl 4-(2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoyl)piperazine-1-carboxylate (4N.SUB.1_.piperazine)

[1151] ##STR00155##

[1152] Compound (R)-4G.sub.1 (100.0 mg, 0.289 mmol) and tert-butyl piperazine-1-carboxylate (80.8 mg, 0.434 mmol) were reacted according to M11a to yield the desired product 4N.sub.1 piperazine after lyophilization (114 mg, 77%) as a white solid.

[1153] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J=4.4 Hz, 1H), 7.69 (ddd, J=8.9, 2.6, 0.9 Hz, 1H), 7.54-7.49 (m, 1H), 7.45-7.39 (m, 1H), 7.37-7.28 (m, 3H), 7.23 (ddd, J=9.3, 2.7, 1.0 Hz, 1H), 5.59-5.49 (m, 1H), 3.78-3.66 (m, 1H), 3.62-3.50 (m, 2H), 3.45-3.20 (m, 5H), 1.51 (dd, J=6.5, 2.1 Hz, 3H), 1.46-1.39 (m, 9H).

[1154] MS (ES) C.sub.2H.sub.29ClFN.sub.3O.sub.4 requires: 513/515, found: 514/516 (M+H).sup.+, 96%.

Intermediate (4N.SUB.1_.piperidine-NH.SUB.2.)—Synthesis According to Method (M11a)

Tert butyl N-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]carbamate (4N.SUB.1_.piperidine-NH.SUB.2.)

[1155] ##STR00156##

[1156] Intermediate (R)-4G.sub.1 (200.0 mg, 0.578 mmol) and (S)-3-Boc-aminopiperidine (174.0 mg, 0.868 mmol) were reacted according to M11a to yield the desired product 4N.sub.1_piperidine-NH.sub.2 (277 mg, 91%), which was used in the following step without further purification.

[1157] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.89 (dd, J=8.5, 4.5 Hz, 1H), 7.70 (dd, J=8.9, 2.8 Hz, 1H), 7.55-7.39 (m, 2H), 7.33-7.21 (m, 4H), 5.57-5.42 (m, 1H), 3.99-3.90 (m, 1H), 3.21-2.82 (m, 3H), 1.92-1.67 (m, 3H), 1.52 (d, J=6.4 Hz, 3H), 1.43-1.32 (m, 12H).

[1158] MS (ES) C.sub.28H.sub.31ClFN.sub.3O.sub.4 requires: 527/529, found: 528/530 (M+H).sup.+, 95%.

Compound (4N.SUB.1_.pirrolidine-NH.SUB.2.)—Synthesis According to Method (M11a)

Tert-butyl N-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]carbamate (4N.SUB.1_.pirrolidine-NH.SUB.2.)

[1159] ##STR00157##

[1160] Intermediate (R)-4G.sub.1 (100.0 mg, 0.289 mmol) and (R)-3-(Boc-amino)pyrrolidine hydrochloride (97.0 mg, 0.434 mmol) were reacted according to M11a to yield the desired product 4N.sub.1 pyrrolidine-NH.sub.2 (139 mg, 94%) as an off-white solid.

[1161] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.89 (d, J=4.4 Hz, 1H), 7.70 (dd, J=8.9, 2.4 Hz, 1H), 7.54-7.39 (m, 2H), 7.33-7.20 (m, 4H), 5.28-5.23 (m, 1H), 4.12-3.84 (m, 2H), 3.55-3.16 (m, 2H), 2.69 (s, 1H), 2.27-1.70 (m, 3H), 1.51-1.47 (m, 3H), 1.38 (s, 9H).

3.1.12 Preparation of Compounds of Formula (P)

[1162] Compound 4P.sub.1_piperazine—Synthesis According to Method 10a (M10a)

(R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7 yl)oxy)-1-(piperazin-1 yl)propan-1-one 2×TFA salt (4P.SUB.1_.piperazine)_55

[1163] ##STR00158##

[1164] Intermediate 4N.sub.1_piperazine (111 mg, 0.215 mmol) was reacted according to M10a to yield the desired product 4P.sub.1_piperazine (55) (135 mg, 97%) as a white solid after coevaporation with toluene.

[1165] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.94 (d, J=4.6 Hz, 1H), 7.70 (dd, J=8.9, 2.6 Hz, 1H), 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.51-7.39 (m, 1H), 7.43-7.33 (m, 3H), 7.27 (dt, J=9.2, 2.0 Hz, 1H), 5.58 (p, J=6.7 Hz, 1H), 3.94-3.59 (m, 4H), 3.25-3.02 (m, 4H), 1.51 (dd, J=6.5, 2.3 Hz, 3H).

[1166] MS (ES) C.sub.22H.sub.21ClFN.sub.3O.sub.2 requires: 413/415, found: 414/416 (M+H).sup.+, 97%.

Compound 4P.SUB.1_.piperidine-NH.SUB.2.—Synthesis According to Method 10b (M10b)

(2R)-1-[(3S)-3-amino-1-piperidyl]-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propan-1-one hydrochloride (4P.SUB.1_.piperidine-NH.SUB.2.)

[1167] ##STR00159##

[1168] Intermediate 4N.sub.1_piperidine-NH.sub.2 (270 mg, 0.511 mmol) was dissolved in 0.5 mL of 1,4-dioxane with 1.3 mL of 4N HCl in 1,4-dioxane and stirred at rt over 2.5 days. The solvents were evaporated in vacuo to yield the desired product 4P.sub.1_piperidine-NH.sub.2 (240 mg, 99%) as a white solid (HCl salt) after freeze drying.

[1169] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.22 (m, 1H), 8.58 (bs, 1H), 8.30 (bs, 2H), 7.81-7.46 (m, 7H), 5.64 (m, 1H), 4.46-4.41 (m, 1H), 4.14-3.67 (m, 2H), 3.28-3.08 (m, 2H), 2.87-2.79 (m, 1H), 2.08-1.83 (m, 2H), 1.63-1.53 (m, 4H).

[1170] MS (ES) C.sub.23H.sub.23ClFN.sub.3O.sub.2 requires: 427/429, found: 428/430 (M+H).sup.+, 95%.

Compound 4P.SUB.1 .piperidine-NH.SUB.2.—Synthesis According to Method 10b (M10b)

(2R)-1-[(3R)-3-aminopyrrolidin-1-yl]-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propan-1-one hydrochloride (4P.SUB.1_.piperidine-NH.SUB.2.)

[1171] ##STR00160##

[1172] Intermediate 4N.sub.1_pyrrolidine-NH.sub.2 (137 mg, 0.267 mmol) was reacted with HCl in dioxane according to Method 10b to yield the desired product 4P.sub.1_pyrrolidine-NH.sub.2 (106 mg, 91%) as a white solid (HCl salt) after freeze drying.

[1173] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.28-9.19 (m, 1H), 8.54-8.44 (m, 3H), 7.84-7.49 (m, 7H), 5.33-5.23 (m, 1H), 4.37-3.51 (m, 5H), 2.50-2.26 (m, 2H), 1.58 (d, J=1.6 Hz, 3H).

[1174] MS (ES) C.sub.22H.sub.21ClFN.sub.3O.sub.2 requires: 413/415, found: 414/416 (M+H).sup.+, 95%.

3.2. Preparation of Compounds of Formula (I) of the Invention

Compound 18—Synthesis According to Method 9 (M9)

2-((R)-1-((R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetic acid (18)

[1175] ##STR00161##

[1176] Compound 4K (48 mg, 0.096 mmol) was reacted with 2 M NaOH aq. solution according to M9 to yield the desired product 18 (33 mg, 73%) as a white solid.

[1177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.86 (dd, J=9.3, 4.4 Hz, 1H), 7.67 (dd, J=8.9, 2.5 Hz, 1H), 7.49 (t, J=7.4 Hz, 1H), 7.40 (ddt, J=10.7, 8.6, 2.2 Hz, 1H), 7.32-7.18 (m, 4H), 5.47 (dt, J=33.1, 7.4 Hz, 1H), 4.34-3.88 (m, 2H), 3.13-2.87 (m, 1H), 2.64-2.04 (m, 3H), 2.01-1.44 (m, 6H), 1.35-1.16 (m, 2H).

[1178] MS (ES) C.sub.25H.sub.24ClFN.sub.2O.sub.4 requires: 470/472, found: 471/473 (M+H).sup.+, 98%

Compound 8K—Synthesis According to Method 3a (M3a)

ethyl 2-((R)-1-((R)-2-((4-(2-ethylphenyl)quinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetate (8K)

[1179] ##STR00162##

[1180] Intermediate (R,R)-2K.sub.1x (50 mg, 0.123 mmol) was reacted with (2-ethylphenyl)boronic acid according to M3a. The reaction was evaporated in vacuo to yield the crude desired product 8K which was used in the following step without further purification.

[1181] MS (ES) C.sub.29H.sub.34N.sub.2O.sub.4 requires: 474, found: 475 (M+H).sup.+, 70%.

Compound 121—Synthesis According to Method 9 (M9)

2-((R)-1-((R)-2-((4-(2-ethylphenyl)quinolin-7-yl)oxy)propanoyl)piperidin-3-yl)acetic acid (121)

[1182] ##STR00163##

[1183] Crude 8K (160 mg) was reacted with 2 M NaOH aq. solution according to M9 to yield the desired product 121 (31 mg, 56% over 2 steps) as a white solid.

[1184] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.85 (dd, J=7.8, 4.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.40-7.30 (m, 1H), 7.30-7.13 (m, 5H), 5.49 (dd, J=27.5, 6.2 Hz, 1H), 4.24 (d, J=12.9 Hz, 1H), 4.17-3.94 (m, 1H), 3.22-2.54 (m, 1H), 2.44-2.07 (m, 3H), 1.92-1.58 (m, 4H), 1.51 (dd, J=16.4, 6.4 Hz, 3H), 1.33-1.19 (m, 3H), 0.99-0.82 (m, 3H).

[1185] MS (ES) C.sub.27H.sub.90N.sub.2O.sub.4 requires: 466, found: 467 (M+H).sup.+, 99%.

[1186] The tetrazole derivative 11 described in Table 6 was synthesized from the corresponding nitrile according to Method 12:

Compound 11—Synthesis According to Method 12 (M12)

(R)-1-((S)-3-(2H-tetrazol-5-yl)piperidin-1 yl)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propan-1-one (30)

[1187] ##STR00164##

[1188] Compound 30 (16 mg, 0.036 mmol) was dissolved in o-dichlorobenzene (360 μl) and Bu.sub.3SnN.sub.3 (61 mg, 0.182 mmol) was added in a sealed tube. The reaction was stirred at 125° C. for 1 h, then at rt overnight. The crude product was absorbed onto Hydromatrix and purified by flash chromatography on silica gel using a gradient of MeOH in DCM to yield the desired product 11 (12.6 mg, 73%) as an off-white solid.

[1189] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.90 (t, J=4.2 Hz, 1H), 7.70 (ddd, J=8.9, 2.5, 1.2 Hz, 1H), 7.53 (dd, J=8.6, 6.2 Hz, 1H), 7.47-7.28 (m, 4H), 7.24 (dd, J=9.2, 2.6 Hz, 1H), 5.60 (dt, J=37.7, 6.8 Hz, 1H), 4.49 (dd, J=102.7, 12.9 Hz, 1H), 4.22 (dd, J=52.2, 13.2 Hz, 1H), 3.56-2.75 (m, 2H), 2.30-2.11 (m, 1H), 1.84 (dd, J=35.4, 18.1 Hz, 2H), 1.53 (ddd, J=18.3, 6.6, 2.3 Hz, 4H), 1.39-1.08 (m, 1H).

[1190] MS (ES) C.sub.24H.sub.22ClFN.sub.6O.sub.2 requires: 480/482, found: 481/483 (M+H).sup.+, 99%.

[1191] The isopropylic ester 36 was synthesized from precursor (R)-2G.sub.1 as described below:

Compound 36—Synthesis According to Method 13 (M13)

(R)-isopropyl 2-((4-(2-chlorophenyl)quinolin-7 yl)oxy)propanoate FA salt (36)

[1192] ##STR00165##

[1193] Compound (R)-2G.sub.1 (20 mg, 0.061 mmol) was dissolved in isopropanol (1 mL) and 1 drop conc. H.sub.2SO.sub.4 was added. The mixture was stirred at rt overnight, then heated to 60° C. for 4 h, and stirred at it overnight. The reaction mixture was evaporated in vacuo and the crude product was purified by flash chromatography on reverse phase silica gel using a gradient of MeCN in H.sub.2O (both solvents containing 0.05% FA) to yield the desired product 36 as a FA salt (16 mg, 73%) as a beige glue.

[1194] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.87 (d, J=4.4 Hz, 1H), 7.66 (dt, J=7.7, 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.43 (ddd, J=7.2, 5.0, 2.0 Hz, 1H), 7.33-7.26 (m, 3H), 7.24 (dd, J=9.2, 2.5 Hz, 1H), 5.21-5.08 (m, 1H), 4.96 (pd, J=6.2, 1.1 Hz, 1H), 1.56 (d, J=6.7 Hz, 3H), 1.23 (dd, J=6.2, 3.2 Hz, 3H), 1.14 (dd, J=6.3, 1.4 Hz, 3H).

[1195] MS (ES) C.sub.21H.sub.20ClNO.sub.3 requires: 369/371, found: 370/372 (M+H).sup.+, 98%.

Compound 98—Method 11a (M11a)

2-((R)-1-((R)-2-((2-chlor-4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)propanoyl)piperidin-3-yl)-N-methylacetamide (98)

[1196] ##STR00166##

[1197] Compound 56 (27 mg, 0.053 mmol) and 2M methylamine in THE (0.13 mL, 0.26 mmol) were reacted according to M11a to yield the desired product 98 after lyophilization (5.6 mg, 20%) as a white solid.

[1198] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.82 (t, J=4.1 Hz, 1H), 7.55-6.98 (m, 7H), 5.97 (m, 1H), 5.39-5.06 (m, 1H), 4.43-3.56 (m, 2H), 3.48-3.29 (m, 2H), 3.06-2.45 (m, 3H), 2.27 (s, 1H), 2.10-1.68 (m, 3H), 1.71-1.54 (m, 3H), 1.33-0.72 (m, 1H).

[1199] MS (ES) C.sub.25H.sub.25ClFN.sub.3O.sub.3 requires: 469/471, found: 470/472 (M+H).sup.+, 99%.

Compound 28—Method 11d (M11d)

(R)-2-((4-(2-chloro-4-fluorophenyl)quinolin-7-yl)oxy)-1-(4-propionylpiperazin-1-yl)propan-1-one (28)

[1200] ##STR00167##

[1201] To an ice-cold solution of compound 4N.sub.1_piperazine (20.3 mg, 0.043 mmol) and DIPEA (29 μL, 0.172 mmol) in dry DCM (1 mL), propionyl chloride (4.5 μL, 0.052 mmol) in dry DCM (0.5 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min followed by 3 h at rt. The reaction was then diluted with DCM and washed with H.sub.2O, a sat. NaHCO.sub.3 solution and brine. The organic phase was dried over MgSO.sub.4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of MeOH in DCM to yield the desired product 28 (25.5 mg, 68%) as a white solid.

[1202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.89 (dd, J=4.4, 0.8 Hz, 1H), 7.69 (ddd, J=8.9, 2.5, 1.1 Hz, 1H), 7.55-7.48 (m, 1H), 7.45-7.21 (m, 5H), 5.57 (s, 1H), 3.81-3.34 (m, 8H), 2.34 (d, J=8.0 Hz, 2H), 1.52 (dd, J=6.5, 2.5 Hz, 3H), 0.99 (tdd, J=7.4, 2.1, 0.8 Hz, 3H).

[1203] MS (ES) C.sub.25H.sub.25ClFN.sub.3O.sub.3 requires: 469/471, found: 470/472 (M+H).sup.+, 96%.

Compound 209

N-hydroxy-N-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]acetamide (209)

[1204] ##STR00168##

[1205] The desired compound was synthesized in three steps starting from intermediate 4P.sub.1_piperidine-NH.sub.2:

[1206] A solution of BPO (355 mg, 1.10 mmol) in DCM (5.5 mL) was added quickly to a mixture of intermediate 4P.sub.t_piperidine-NH.sub.2 (240 mg, 0.517 mmol) in buffer solution at pH 10 (NaOH/NaHCO.sub.3, 5.5 mL) at rt. The reaction mixture was stirred for 2 h at rt, and the pH adjusted to ˜10 by the addition of 10 M NaOH. Further BPO (355 mg, 1.10 mmol) was added, and the mixture stirred at rt for 18 h, upon which the reaction was deemed complete. Acetyl chloride (328 mg, 4.14 mmol) was added, and the reaction was further stirred at rt for 18 h. The mixture was extracted DCM, and the combined organic phases were washed with Na.sub.2CO.sub.3 and brine, dried over MgSO.sub.4, and the solvents removed in vacuo, to yield (39 mg, 13%) of the desired intermediate N-(benzoyloxy)-acetamide, which was taken to the next step without further analysis or purification.

[1207] MS (ES) C32H29ClFN305 requires: 589/591, found: 590/592 (M+H).sup.+, 91%

[1208] The crude N-(benzoyloxy)-N-(piperidin-3-yl)acetamide was treated with 3.5N NH.sub.3 in MeOH (0.4 mL) at rt for 1 h. The solvents were removed in vacuo and the residue purified by preparative HPLC using NH.sub.4HCO.sub.3 as an additive to yield the desired product 209 (18 mg, 56% over 3 steps) as a white solid.

[1209] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.83-9.58 (m, 1H), 8.88 (dd, J=8.9, 4.4 Hz, 1H), 7.68 (dd, J=8.8, 2.1 Hz, 1H), 7.57-7.38 (m, 2H), 7.36-7.19 (m, 4H), 5.61-5.46 (m, 1H), 4.36-3.96 (m, 3H), 3.02-2.63 (m, 1H), 2.02-1.97 (m, 3H), 1.87-1.77 (m, 4H), 1.58-1.22 (m, 4H).

[1210] MS (ES) C.sub.23H.sub.26ClFN.sub.3O.sub.4 requires: 485/487, found: 486/488 (M+H).sup.+, 98%.

Compound 214—Synthesis According to Method 14 (M14)

1-tertbutyl-3-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3-yl]urea_214

[1211] ##STR00169##

[1212] 4P.sub.1_pyrrolidine-NH.sub.2.HCl (109 mg, 0.242 mmol) was dissolved in DCM (1.0 mL) at 0° C. under the atmosphere of nitrogen. DIPEA (66 mg, 0.508 mmol) was added to the suspension, followed by tert-butyl isocyanate (29 mg, 0.290 mmol), and the reaction was stirred and allowed to slowly warm up to rt over 4 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC using NH.sub.4HCO.sub.3 as an additive to yield the desired product 214 (65 mg, 52%) as a white solid.

[1213] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.90-8.80 (m, 1H), 7.69 (dd, J=8.7, 1.9 Hz, 1H), 7.54-7.39 (m, 2H), 7.35-7.20 (m, 4H), 5.97-5.94 (m, 1H), 5.59-5.54 (m, 1H), 5.32-5.21 (m, 1H), 4.21-3.98 (m, 1H), 3.93-3.75 (m, 1H), 3.60-3.39 (m, 2H), 3.29-3.06 (m, 1H), 2.16-1.93 (m, 1H), 1.84-1.59 (m, 1H), 1.50-1.48 (m, 3H), 1.21-1.20 (m, 9H).

[1214] MS (ES) C.sub.27H.sub.30ClFN.sub.4O.sub.3 requires: 512/514, found: 513/515 (M+H).sup.+, 95%.

[1215] The compounds exemplifying the invention are described in Table 6.

[1216] When not otherwise specified, it should be assumed that M7, M11a, M11 b, M11c, M12 or M13, optionally followed by M9, M10a, M10b, M11d, or M14 were used to yield the target compound. Tetrazoles can be obtained from the corresponding nitriles as exemplified in M8. Piperazines carbamates N could also be further modified according to M10a to obtain amines P followed by M11a, M11b, M11c or M11d to yield amides of formula Q. Primary amines such as compounds of formula P_piperidine-NH.sub.2 could be further modified to obtain N-hydroxyacetamides of formula R, using the multi-step method described for compound 209. Primary amines such as compounds of formula P_pyrrolidine could be further modified to obtain ureas of formula S, by reacting with tert-butyl-isocyanate as described for compound 214. It should be apparent to a person skilled in the art that reaction conditions such as temperature, dilution, reaction time or work-up procedures, including pH adjustment, are dependent on reaction partners and functional group compatibility and could vary from compound to compound.

[1217] Generally, enantiomeric excess (ee) of the compounds (esters F and K, carboxylic acids G) was not measured, and was assumed equal to the value determined by chiral HPLC for the final compounds (usually carboxylic acids L). Chiral separation of the diastereomeric mixture was occasionally required to improve ee, particularly when any of the hydroxy-quinolines of formula D were alkylated via M7. Use of HATU as a coupling reagent (M11a) usually resulted in lower ee as compared to the coupling mixture EDC.HCl/HOBt.xH.sub.2O (M11b).

TABLE-US-00006 TABLE 6 Compounds of formula (I) of the invention LC purity Ex Structure BB .sup.1H-NMR % ee 1 [00170] embedded image 3D.sub.1 + (S,S)-1H + M9 (300 MHz, DMSO-d.sub.6) δ 12.50 (s, 1H), 8.90 (t, J = 4.2 Hz, 1H), 7.54-7.19 (m, 8H), 5.56-5.54 (m, 1H), 4.49-3.87 (m, 2H), 3.59- 3.10 (m, 2H), 3.08-2.74 (m, 1H), 2.48-2.25 (m, 1H), 2.14-1.77 (m, 4H), 1.76-1.60 (m, 2H), 1.54 (dd, J = 10.2, 6.4 Hz, 3H). 99% 2 [00171] embedded image 4 (300 MHz, DMSO-d.sub.6) δ 12.41 (s, 1H), 8.88 (t, J = 4.5 Hz, 1H), 7.35-7.08 (m, 7H), 5.60-5.47 (m, 1H), 4.44-3.84 (m, 2H), 3.65- 2.74 (m, 2H), 2.46-2.21 (m, 1H), 2.19-1.74 (m, 1H), 1.88-1.77 (m, 6H), 1.71-1.55 (m, 2H), 1.50 (dd, J = 10.5, 6.3 Hz, 3H), 1.40-1.09 (m, 1H). 95% 3 [00172] embedded image 6 (300 MHz, Chloroform-d) δ 8.88-8.74 (m, 1H), 7.45 (s, 1H), 7.31-7.20 (m, 3H), 7.17-7.07 (m, 3H), 5.43- 5.07 (m, 1H), 4.12-3.67 (m, 3H), 3.38-2.93 (m, 2H), 2.58-2.25 (m, 2H), 2.23-2.05 (m, 1H), 1.81 (d, J = 5.6 Hz, 6H), 1.90- 1.29 (m, 6H). 98% 4 [00173] 6D.sub.1 + (S,S)-1H (300 MHz, Chloroform-d) δ 8.82 (t, J = 4.1 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.27-7.15 (m, 2H), 7.15- 6.98 (m, 4H), 5.19 (dq, J = 16.1, 6.6 Hz, 1H), 4.54- 4.21 (m, 1H), 4.08 (dq, J = 23.5, 7.0, 6.5 Hz, 2H), 3.93- 3.24 (m, 1H), 3.03 (ddd, J = 38.7, 13.6, 10.2 Hz, 1H), 2.87-2.56 (m, 2H), 2.37 (dtd, J = 82.7, 10.4, 4.5 Hz, 1H), 2.10 (s, 1H), 1.82 (d, 95% J = 3.0 Hz, 6H), 1.80-1.55 (m, 4H), 1.44-1.08 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H). 5 [00174] embedded image (R)-6G.sub.1 + M11a + M9 (300 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.83 (dd, J = 28.5, 4.8 Hz, 1H), 7.38- 7.04 (m, 7H), 5.41-5.05 (m, 1H), 4.39 (d, J = 13.7 Hz, 1H), 4.34-3.79 (m, 1H), 3.26-3.12 (m, 1H), 2.90-2.64 (m, 1H), 2.55 (dd, J = 16.1, 4.0 Hz, 1H), 2.33 (dd, J = 16.3, 10.2 Hz, 1H), 2.22-2.02 (m, 1H), 2.03-1.85 (m, 1H), 1.83- 1.74 (m, 7H), 1.72-1.41 94% (m, 4H), 1.34 (d, J = 12.3 Hz, 1H). 6 [00175] embedded image (R)-6G.sub.1 (300 MHz, Chloroform-d) δ 8.82 (dd, J = 9.8, 4.5 Hz, 1H), 7.40-7.02 (m, 7H), 5.30-5.11 (m, 1H), 4.56- 3.45 (m, 5H), 3.12-2.52 (m, 2H), 2.32-1.98 (m, 2H), 1.93-1.74 (m, 7H), 1.71-1.54 (m, 4H), 1.50- 1.06 (m, 5H). 91% 7 [00176] 71 (400 MHz, DMSO-d.sub.6) δ 8.89 (t, J = 4.6 Hz, 1H), 7.73- 7.65 (m, 1H), 7.60-7.50 (m, 2H), 7.44 (dd, J = 7.3, 1.9 Hz, 1H), 7.37-7.26 (m, 3H), 7.22 (dd, J = 9.2, 2.6 Hz, 1H), 5.67-5.40 (m, 1H), 4.47-3.94 (m, 2H), 3.20 (s, 2H), 2.82 (t, J = 12.0 Hz, 1H), 2.63-2.16 (m, 1H), 2.08-1.90 (m, 1H), 1.82-1.56 (m, 2H), 1.54-1.30 (m, 3H). 98% ee86% 8 [00177] embedded image (R)-3G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.85 (dd, J = 7.1, 4.4 Hz, 1H), 7.47-7.16 (m, 8H), 5.61- 5.35 (m, 1H), 4.19 (d, J = 11.6 Hz, 1H), 4.11-3.91 (m, 2H), 3.19-2.90 (m, 1H), 2.71-2.10 (m, 3H), 2.01-1.95 (m, 3H), 1.87- 1.46 (m, 6H), 1.32-1.20 (m, 3H), 1.14 (qd, J = 7.0, 2.0 Hz, 3H). 100% 9 [00178] embedded image 2D.sub.1 + (S,S)-1H + M9 (400 MHz, DMSO-d.sub.6) δ 8.88 (t, J = 4.9 Hz, 1H), 7.68 (dt, J = 7.6, 1.3 Hz, 1H), 7.61- 7.50 (m, 2H), 7.44 (dd, J = 7.2, 2.0 Hz, 1H), 7.38- 7.25 (m, 3H), 7.22 (dd, J = 9.1, 2.4 Hz, 1H), 5.56 (q, J = 6.5 Hz, 1H), 4.45-3.83 (m, 2H), 3.53-3.08 (m, 2H), 3.01-2.73 (m, 1H), 2.43-2.23 (m, 1H), 2.10- 1.86 (m, 1H), 1.86-1.29 (m, 2H), 1.55-1.45 (m, 97% ee85% 3H). 10 [00179] embedded image 27 (400 MHz, DMSO-d.sub.6) δ 8.88 (t, J = 4.9 Hz, 1H), 7.69 (ddd, J = 9.0, 2.7, 1.4 Hz, 1H), 7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.42 (tt, J = 6.7, 5.9, 2.4 Hz, 1H), 7.37- 7.26 (m, 3H), 7.22 (dd, J = 9.3, 2.5 Hz, 1H), 5.61- 5.50 (m, 1H), 4.47-3.83 (m, 2H), 3.22-2.73 (m, 2H), 2.44-2.21 (m, 2H), 2.10-1.88 (m, 1H), 1.84- 1.27 (m, 2H), 1.50 (dd, J = 13.5, 6.6 Hz, 3H). 98% 11 [00180] embedded image 30 (400 MHz, DMSO-d.sub.6) δ 8.90 (t, J = 4.2 Hz, 1H), 7.70 (ddd, J = 8.9, 2.5, 1.2 Hz, 1H), 7.53 (dd, J = 8.6, 6.2 Hz, 1H), 7.47-7.28 (m, 4H), 7.24 (dd, J = 9.2, 2.6 Hz, 1H), 5.60 (dt, J = 37.7, 6.8 Hz, 1H), 4.49 (dd, J = 102.7, 12.9 Hz, 1H), 4.22 (dd, J = 52.2, 13.2 Hz, 1H), 3.56-2.75 (m, 2H), 2.30- 2.11 (m, 1H), 1.84 (dd, J = 35.4, 18.1 Hz, 2H), 1.53 (ddd, J = 18.3, 6.6, 2.3 Hz, 4H), 1.39-1.08 (m, 1H). 99% 12 [00181] embedded image (R)-2G.sub.6 + M11a + M10a (400 MHz, DMSO-d.sub.6) δ 12.47 (br. s, 1H), 7.70 (dt, J = 7.9, 1.3 Hz, 1H), 7.63- 7.47 (m, 3H), 7.31-7.15 (m, 4H), 5.57 (q, J = 6.3 Hz, 1H), 4.44-3.75 (m, 2H), 3.22-2.62 (m, 2H), 2.46- 2.22 (m, J = 1.9 Hz, 1H), 2.35-2.23 (m, 1H), 2.07- 1.89 (m, 1H), 1.82-1.28 (m, 5H). 94% 13 [00182] embedded image 8 (400 MHz, DMSO-d.sub.6) δ 12.15 (br. s, 1H), 8.83 (s, 1H), 7.52-7.09 (m, 8H), 5.58-5.34 (m, J = 33.9 Hz, 1H), 4.32-3.91 (m, 2H), 3.14-2.61 (m, 1H), 2.65 (s, 2H), 2.28-2.03 (m, 2H), 1.95 (s, 3H), 1.90-1.40 (m, 5H), 1.23 (s, 2H). 99% 14 [00183] (R)-3G.sub.1 (300 MHz, Chloroform-d) δ 8.79 (d, J = 4.4 Hz, 1H), 7.40-7.03 (m, 8H), 5.20 (dq, J = 13.0, 6.8 Hz, 1H), 4.37 (dd, J = 55.5, 13.3 Hz, 1H), 4.20-3.96 (m, 2H), 3.92-3.20 (m, 1H), 3.17- 2.13 (m, 3H), 2.08-1.89 (m, 4H), 1.81-1.27 (m, 8H), 1.16 (td, J = 7.1, 1.2 Hz, 3H). 97% 15 [00184] embedded image (R)-4G.sub.1 400 MHz, DMSO-d.sub.6) δ 8.88 (dd, J = 7.3, 4.4 Hz, 1H), 7.73-7.63 (m, 1H), 7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.46-7.38 (m, 1H), 7.34- 7.20 (m, 4H), 5.65-5.35 (m, 1H), 4.20 (d, J = 13.1 Hz, 2H), 4.11-3.92 (m, 3H), 3.19-2.60 (m, 1H), 2.36-2.12 (m, 2H), 1.91- 1.45 (m, 8H), 1.19-1.09 (m, 3H). 95% 16 [00185] embedded image (R)-2G.sub.1 + M11b + M9 (400 MHz, DMSO-d.sub.6) δ 8.86 (dd, J = 8.8, 4.4 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.58-7.48 (m, 2H), 7.42 (d, J = 7.3 Hz, 1H), 7.33- 7.16 (m, 4H), 5.61-5.36 (m, 1H), 4.35-3.88 (m, 2H), 3.00 (d, J = 58.4 Hz, 2H), 2.14 (d, J = 36.0 Hz, 2H), 1.93-1.42 (m, 6H), 1.23 (s, 2H). 97% 17 [00186] embedded image 71 (300 MHz, DMSO-d.sub.6) δ 12.57 (s, 1H), 8.95 (t, J = 4.1 Hz, 1H), 7.76 (dd, J = 9.0, 2.5 Hz, 1H), 7.65- 7.24 (m, 6H), 5.73-5.50 (m, 1H), 4.50-3.99 (m, 2H), 3.34-3.14 (m, 2H), 2.99-2.76 (m, 1H), 2.69- 2.21 (m, 2H), 2.16-1.61 (m, 1H), 1.57 (dd, J = 6.5, 2.8 Hz, 3H), 1.49-1.27 (m, 1H). 100% 18 [00187] embedded image 15 (400 MHz, DMSO-d.sub.6) δ 8.86 (dd, J = 9.3, 4.4 Hz, 1H), 7.67 (dd, J = 8.9, 2.5 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.40 (ddt, J = 10.7, 8.6, 2.2 Hz, 1H), 7.32-7.18 (m, 4H), 5.47 (dt, J = 33.1, 7.4 Hz, 1H), 4.34-3.88 (m, 2H), 3.13-2.87 (m, 1H), 2.64-2.04 (m, 3H), 2.01- 1.44 (m, 6H), 1.35-1.16 (m, 2H). 99% 19 [00188] embedded image 75 (300 MHz, Chloroform-d) δ 8.88 (d, J = 4.5 Hz, 1H), 7.69 (dd, J = 8.9, 2.5 Hz, 1H), 7.52 (dd. J = 8.7, 6.2 Hz, 1H), 7.41 (td, J = 8.5, 2.5 Hz, 1H), 7.34-7.19 (m, 4H), 5.33-5.23 (m, 1H), 3.92-3.21 (m, 5H), 3.17- 2.99 (m, 1H), 2.23-1.88 (m, 1H), 1.55-1.44 (m, 3H). 98% 20 [00189] embedded image 4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (dd, J = 4.4, 0.7 Hz, 1H), 7.81-7.63 (m, 1H), 7.52 (ddt, J = 8.2, 6.2, 0.9 Hz, 1H), 7.46-7.38 (m, 1H), 7.34-7.26 (m, 3H), 7.22 (dd, J = 9.1, 2.6 Hz, 1H), 5.51 (p, J = 6.6 Hz, 1H), 3.72-3.39 (m, 4H), 1.72- 1.37 (m, 9H). 100% 21 [00190] 3G.sub.3 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 7.53-7.16 (m, 8H), 5.64-5.44 (m, 1H), 4.37-3.84 (m, 2H), 3.18-2.89 (m, 1H), 2.64 (s, 1H), 2.23 (t, J = 4.7 Hz, 1H), 2.14 (dd, J = 6.9, 4.1 Hz, 1H), 2.01 (s, 3H), 1.80 (s, 2H), 1.67 (s, 1H), 1.53 (dd, J = 16.3, 6.4 Hz, 3H), 1.26 (s, 1H). 99% 22 [00191] embedded image 89 (300 MHz, DMSO-d.sub.6) δ 12.25 (s, 1H), 8.95 (dd, J = 5.9, 4.4 Hz, 1H), 7.76 (dd, J = 8.9, 2.5 Hz, 1H), 7.63- 7.44 (m, 2H), 7.41-7.33 (m, 3H), 7.29 (dd, J = 9.1, 2.6 Hz, 1H), 5.54 (dt, J = 10.7, 7.0 Hz, 1H), 4.20 (ddd, J = 52.0, 31.3, 13.1 Hz, 2H), 3.30-2.81 (m, 1H), 2.68-2.56 (m, 1H), 2.39-1.66 (m, 5H), 1.63- 1.51 (m, 3H), 1.48-1.20 (m, 2H). 90% 23 [00192] embedded image 2D.sub.1 + (S,S)-1H + M9 (300 MHz, Methanol-d4) δ 8.77-8.66 (m, 1H), 7.57- 7.47 (m, 1H), 7.52-7.11 (m, 7H), 5.55-5.26 (m, 1H), 4.53-3.67 (m, 2H), 3.58-2.58 (m, 1H), 2.54- 2.21 (m, 1H), 2.15-1.29 (m, 7H) 91%- racemi- sation occurred 24 [00193] 58 (300 MHz, DMSO-d.sub.6) δ 12.32 (s, 1H), 8.86-8.76 (m, 1H), 7.63 (dd, J = 8.9, 2.6 Hz, 1H), 7.51-7.29 (m, 2H), 7.30-7.11 (m, 4H), 5.56-4.75 (m, 1H), 4.24- 3.88 (m, 1H), 3.24-2.35 (m, 3H), 2.50 (s, 1H), 1.97- 0.74 (m, 7H). 100% 25 [00194] embedded image 3D.sub.3 + (S,S)-1H + M9 (300 MHz, DMSO-d.sub.6) δ 12.50 (s, 1H), 7.47-7.17 (m, 8H), 5.56 (dd, J = 6.6, 4.0 Hz, 1H), 4.36-3.84 (m, 2H), 3.32 (s, 1H), 3.00- 2.78 (m, 1H), 2.43-2.20 (m, 1H), 1.98 (d, J = 1.8 Hz, 4H), 1.80-1.42 (m, 5H), 1.27 (d, J = 25.9 Hz, 1H). 98% 26 [00195] (R)-4G.sub.1 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 13.06 (s, 1H), 10.59 (d, J = 4.0 Hz, 1H), 8.91 (dd, J = 4.4, 1.7 Hz, 1H), 8.32 (q, J = 2.2 Hz, 1H), 7.98-7.86 (m, 1H), 7.79-7.64 (m, 2H), 7.60-7.41 (m, 4H), 7.39 (d, J = 2.1 Hz, 2H), 7.33 (dd, J = 4.4, 1.0 Hz, 1H), 5.19 (q, J = 6.5 Hz, 1H), 1.74-1.65 (m, 3H). 100% 27 [00196] embedded image 4D.sub.1 + (S,S)-1H or (R)- 4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (t, J = 5.2 Hz, 1H), 7.74- 7.64 (m, 1H), 7.51 (ddd, J = 9.4, 6.1, 3.5 Hz, 1H), 7.42 (tt, J = 8.5, 2.5 Hz, 1H), 7.36-7.26 (m, 3H), 7.22 (dt, J = 9.3, 2.0 Hz, 1H), 5.69-5.42 (m, 1H), 4.32- 3.42 (m, 5H), 3.27-2.92 (m, 2H), 2.65-2.28 (m, 1H), 2.09-1.85 (m, 1H), 1.82-1.55 (m, 2H), 1.51 (dd, J = 14.1, 6.4 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 95% 28 [00197] embedded image 1P (400 MHz, DMSO-d.sub.6) δ 8.89 (dd, J = 4.4, 0.8 Hz, 1H), 7.69 (ddd, J = 8.9, 2.5, 1.1 Hz, 1H), 7.55-7.48 (m, 1H), 7.45-7.21 (m, 5H), 5.57 (s, 1H), 3.81-3.34 (m, 8H), 2.34 (d, J = 8.0 Hz, 2H), 1.52 (dd, J = 6.5, 2.5 Hz, 3H), 0.99 (tdd, J = 7.4, 2.1, 0.8 Hz, 3H). 96% 29 [00198] embedded image (R)-F.sub.1x (400 MHz, Chloroform-d) δ 8.88 (d, J = 4.5 Hz, 1H), 7.58-7.53 (m, 1H), 7.47- 7.37 (m, 4H), 7.35-7.29 (m, 1H), 7.24-7.15 (m, 2H), 4.86 (qd, J = 6.8, 4.3 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H). 95% 30 [00199] (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (d, J = 4.5 Hz, 1H), 7.38 (td, J = 11.5, 9.3, 5.5 Hz, 2H), 7.30-7.00 (m, 5H), 5.26-5.10 (m, 1H), 4.26-3.82 (m, 1H), 3.77- 3.68 (m, 1H), 3.42 (tdd, J = 29.1, 13.9, 7.8 Hz, 2H), 2.98-2.48 (m, 1H), 1.99 (s, 1H), 1.80 (d, J = 12.7 Hz, 2H), 1.67-1.25 (m, 4H). 98% 31 [00200] embedded image (R)-3G.sub.5 + M11a + M10a (400 MHz, DMSO-d.sub.6) δ 7.63-7.19 (m, 8H), 5.56 (q, J = 6.7 Hz, 1H), 4.32-3.79 (m, 2H), 3.51-3.12 (m, 1H), 2.83 (s, 4H), 2.44-2.26 (m, 2H), 2.02 (s, 4H), 1.79- 1.47 (m, 5H). 97% 32 [00201] (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.89-8.75 (m, 1H), 7.43- 7.00 (m, 7H), 5.26-5.06 (m, 1H), 4.90-4.16 (m, 1H), 2.84 (dd, J = 48.2, 1.4 Hz, 3H), 1.60 (ddd, J = 6.6, 5.4, 1.1 Hz, 3H), 1.26- 0.98 (m, 6H). 99% 33 [00202] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.80 (d, J = 4.8 Hz, 1H), 7.48-7.21 (m, 4H), 7.17- 7.01 (m, 3H), 5.80-5.05 (m, 2H), 4.67-4.21 (m, 2H), 3.98-3.23 (m, 2H), 3.17-2.69 (m, 1H), 2.61- 1.71 (m, 2H), 1.69-1.12 (m, 4H). 100% 34 [00203] 2G.sub.3 + M11a + M9 (400 MHz, DMSO-d.sub.6) δ 12.45 (s, 1H), 7.73-7.67 (m, 1H), 7.63-7.47 (m, 3H), 7.39 (d, J = 2.6 Hz, 1H), 7.36-7.23 (m, 3H), 5.57 (q, J = 6.6 Hz, 1H), 4.16 (dd, J = 113.6, 13.5 Hz, 1H), 3.93 (s, 1H), 3.52- 3.05 (m, 1H), 3.04-2.79 (m, 1H), 2.47-2.22 (m, 1H), 2.06-1.87 (m, 1H), 1.82-1.55 (m, 2H), 1.54- 1.44 (m, 3H), 1.28 (d, J = 99% 35.1 Hz, 1H). 35 [00204] embedded image 6G.sub.3 + M11a + M9 (300 MHz, Chloroform-d) δ 7.44-7.21 (m, 1H), 7.18- 6.87 (m, 6H), 5.47-5.00 (m, 1H), 4.35-3.60 (m, 3H), 3.38-3.08 (m, 1H), 2.66-2.46 (m, 1H), 2.18- 2.00 (m, 1H), 1.99-1.91 (m, 4H), 1.91-1.76 (m, 2H), 1.73-1.42 (m, 3H). 99% 36 [00205] (R)-2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.87 (d, J = 4.4 Hz, 1H), 7.66 (dt, J = 7.7, 2.0 Hz, 1H), 7.58- 7.48 (m, 2H), 7.43 (ddd, J = 7.2, 5.0, 2.0 Hz, 1H), 7.33- 7.26 (m, 3H), 7.24 (dd, J = 9.2, 2.5 Hz, 1H), 5.21- 5.08 (m, 1H), 4.96 (pd, J = 6.2, 1.1 Hz, 1H), 1.56 (d, J = 6.7 Hz, 3H), 1.23 (66, J = 6.2, 3.2 Hz, 3H), 1.14 (dd, J = 6.3, 1.4 Hz, 3H). 98% 37 [00206] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (d, J = 4.6 Hz, 1H), 7.37-7.20 (m, 4H), 7.19- 7.03 (m, 3H), 4.99 (p, J = 6.5 Hz, 1H), 3.87-3.49 (m, 5H), 3.43-3.30 (m, 1H), 3.10-1.95 (m, 5H), 1.72- 1.46 (m, 4H). 97% 38 [00207] 66 (300 MHz, Chloroform-d) δ 8.82 (t, J = 4.1 Hz, 1H), 7.55-6.98 (m, 7H), 5.97 (m, 1H), 5.39-5.06 (m, 1H), 4.43-3.56 (m, 2H), 3.48-3.29 (m, 2H), 3.06- 2.45 (m, 3H), 2.27 (s, 1H), 2.10-1.68 (m, 3H), 1.71- 1.54 (m, 3H), 1.33-0.72 (m, 1H). 99% 39 [00208] embedded image 67 (300 MHz, DMSO-d.sub.6) δ 12.10 (s, 1H), 8.75 (d, J = 4.3 Hz, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (dd, J = 8.6, 6.2 Hz, 1H), 7.29 (tdd, J = 8.5, 2.6, 1.4 Hz, 1H), 7.21-7.06 (m, 4H), 5.20-5.06 (m, 1H), 3.92- 3.68 (m, 1H), 3.52-3.08 (m, 2H), 3.08-2.76 (m, 1H), 2.51-2.32 (m, 1H), 2.23 (dd, J = 7.4, 3.6 Hz, 2H), 2.06-1.81 (m, 1H), 1.63-1.28 (m, 4H). 100% 40 [00209] embedded image 37 (300 MHz, DMSO-d.sub.6) δ 12.25 (s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 7.70 (dd, J = 8.9, 2.5 Hz, 1H), 7.58- 7.39 (m, 2H), 7.35-7.19 (m, 4H), 5.24 (p, J = 6.3 Hz, 1H), 3.82-3.56 (m, 2H), 3.33 (s, 3H), 2.47-2.30 (m, 2H), 2.21-1.92 (m, 1H), 1.73-1.46 (m, 4H). 100% 41 [00210] (R)-2G.sub.6 (400 MHz, Chloroform-d) δ 7.56 (dd, J = 7.7, 1.4 Hz, 1H), 7.49-7.34 (m, 3H), 7.33-7.22 (m, 2H), 7.15 (q, J = 8.0, 7.4 Hz, 1H), 6.87 (d, J = 5.7 Hz, 1H), 5.34-5.12 (m, 1H), 4.57- 3.74 (m, 4H), 3.55-2.89 (m, 2H), 2.43 (dt, J = 86.3, 9.7 Hz, 1H), 2.15-1.96 (m, 1H), 1.85-1.60 (m, 5H), 1.25 (p, J = 7.1 Hz, 4H). 98% 42 [00211] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.80 (d, J = 4.6 Hz, 1H), 7.38-7.00 (m, 7H), 5.01 (q, J = 6.6 Hz, 1H), 3.70 (ddd, J = 9.7, 7.8, 4.1 Hz, 1H), 3.56-3.33 (m, 3H), 2.09-1.65 (m, 4H), 1.60 (d, J = 6.5 Hz, 3H). 99% 43 [00212] 73 (300 MHz, Chloroform-d) δ 7.62 (t, J = 2.8 Hz, 1H), 7.47-7.07 (m, 7H), 5.15- 5.01 (m, 1H), 2.08-1.97 (m, 3H), 1.87 (d, J = 6.9 Hz, 3H). 93% 44 [00213] embedded image (R)- 4F.sub.1_Et (400 MHz, DMSO-d.sub.6) δ 8.85 (dd, J = 4.4, 0.6 Hz, 1H), 7.67 (dt, J = 8.9, 2.3 Hz, 1H), 7.49 (ddd, J = 8.1, 6.2, 1.8 Hz, 1H), 7.39 (tt, J = 8.5, 2.4 Hz, 1H), 7.32- 7.27 (m, 2H), 7.26 (dd, J = 4.4, 0.6 Hz, 1H), 7.22 (dd, J = 9.2, 2.6 Hz, 1H), 5.00 (q, J = 6.5 Hz, 1H), 1.55 (d, J = 6.8 Hz, 3H). 96% 45 [00214] embedded image 4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.4 Hz, 1H), 7.69 (ddd, J = 8.9, 2.6, 1.4 Hz, 1H), 7.51 (ddd, J = 7.9, 6.2, 1.5 Hz, 1H), 7.42 (tt, J = 8.5, 2.3 Hz, 1H), 7.35- 7.19 (m, 4H), 5.58-5.41 (m, 1H), 3.16 (d, J = 7.5 Hz, 3H), 2.87 (d, J = 3.0 Hz, 3H), 1.50 (dd, J = 6.5, 1.5 Hz, 3H). 97% 46 [00215] embedded image 2G + M11b + M9 (400 MHz, DMSO-d.sub.6) δ 12.47 (br. s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.55 (dtd, J = 15.9, 7.4, 1.6 Hz, 2H), 7.45 (dt, J = 4.7, 2.0 Hz, 2H), 7.33-7.22 (m, 3H), 5.17-4.96 (m, 2H), 4.42- 3.67 (m, 2H), 3.51-3.02 (m, 2H), 2.92-2.53 (m, 1H), 2.45-1.34 (m, 4H). 100% 47 [00216] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.89-8.77 (m, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.45- 7.18 (m, 3H), 7.20-7.00 (m, 3H), 6.21 (d, J = 11.0 Hz, 1H), 4.71 (qd, J = 6.7, 3.3 Hz, 1H), 1.56 (dd, J = 6.7, 0.9 Hz, 3H), 1.28 (d, J = 2.8 Hz, 9H). 97% 48 [00217] (R)-2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (dd, J = 4.5, 0.8 Hz, 1H), 8.13 (t, J = 7.7 Hz, 1H), 7.68 (dq, J = 7.6, 1.3 Hz, 1H), 7.61-7.49 (m, 2H), 7.44 (ddd, J = 7.0, 3.4, 1.5 Hz, 1H), 7.35-7.20 (m, 3H), 4.86 (q, J = 6.6 Hz, 1H), 4.07-3.69 (m, 1H), 1.49 (dt, J = 6.5, 1.2 Hz, 3H), 1.10 (ddd, J = 6.4, 5.3, 0.9 Hz, 3H), 1.04 (ddd, J = 6.2, 5.0, 0.9 Hz, 3H). 100% 49 [00218] embedded image (R)-3G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.49- 7.05 (m, 8H), 5.53-5.34 (m, 1H), 4.32-3.82 (m, 4H), 3.04 (dq, J = 69.0, 11.4, 10.4 Hz, 1H), 2.66 (s, 4H), 2.37-2.08 (m, 2H), 1.98 (d, J = 3.6 Hz, 3H), 1.79 (s, 2H), 1.70-1.45 (m, 4H), 1.32-1.20 (m, 2H), 1.15 (qd, J = 7.0, 2.3 Hz, 3H). 100% 50 [00219] embedded image 2D.sub.1 (300 MHz, Chloroform-d) δ 8.82 (d, J = 4.4 Hz, 1H), 7.52-7.45 (m, 1H), 7.43- 7.26 (m, 4H), 7.27-7.21 (m, 1H), 7.17-7.09 (m, 2H), 4.90 (qd, J = 6.8, 2.4 Hz, 1H), 4.27-4.10 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). 94% 51 [00220] (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.84 (d, J = 4.4 Hz, 1H), 8.48-8.34 (m, 1H), 7.99- 7.87 (m, 2H), 7.59 (dq, J = 8.6, 2.3 Hz, 3H), 7.41 (dd, J = 9.1, 1.0 Hz, 1H), 7.31- 7.02 (m, 5H), 5.01 (qd, J = 6.8, 1.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.70 (d, J = 6.7 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 100% 52 [00221] embedded image 25 (300 MHz, Chloroform-d) δ 7.38-7.02 (m, 7H), 6.93- 6.76 (m, 1H), 6.31 (d, J = 90.5 Hz, 1H), 5.87-5.36 (m, 1H), 5.28-5.06 (m, 1H), 4.06-2.96 (m, 3H), 2.49-2.11 (m, 1H), 2.13- 1.90 (m, 5H), 1.89-1.62 (m, 2H), 1.58 (d, J = 6.5 Hz, 3H), 1.61-1.25 (m, 1H). 100% 53 [00222] (R)-2G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (d, J = 4.5 Hz, 1H), 7.54-7.42 (m, 1H), 7.43- 7.27 (m, 4H), 7.26-7.21 (m, 1H), 7.20-7.03 (m, 2H), 5.17 (td, J = 7.0, 5.8 Hz, 1H), 3.63-3.39 (m, 4H), 1.69-1.31 (m, 10H). 92% 54 [00223] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 8.66- 8.56 (m, 1H), 7.69 (ddd, J = 8.9, 2.6, 17 Hz, 1H), 7.52 (ddd, J = 8.8, 6.2, 2.8 Hz, 1H), 7.45-7.24 (m, 5H), 4.88 (dtd, J = 8.6, 4.3, 2.5 Hz, 1H), 4.45-4.08 (m, 1H), 3.60 (dd, J = 9.3, 1.1 Hz, 3H), 3.10-2.76 (m, 1H), 2.46-2.04 (m, 4H), 1.50 (ddd, J = 6.9, 5.8, 1.5 Hz, 3H). 96% 55 [00224] embedded image 4N.sub.1_piper- azine (400 MHz, DMSO-d.sub.6) δ 8.94 (d, J = 4.6 Hz, 1H), 7.70 (dd, J = 8.9, 2.6 Hz, 1H), 7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.51-7.39 (m, 1H), 7.43-7.33 (m, 3H), 7.27 (dt, J = 9.2, 2.0 Hz, 1H), 5.58 (p, J = 6.7 Hz, 1H), 3.94-3.59 (m, 4H), 3.25- 3.02 (m, 4H), 1.51 (dd, J = 6.5, 2.3 Hz, 3H). 97% 56 [00225] embedded image 93 (300 MHz, Chloroform-d) δ 7.33-7.21 (m, 4H), 7.17- 7.00 (m, 3H), 5.26-5.09 (m, 1H), 4.43-4.30 (m, 1H), 4.16-4.00 (m, 1H), 3.84-3.06 (m, 1H), 2.96- 2.62 (m, 2H), 2.38-1.75 (m, 4H), 1.71-1.52 (m, 4H), 1.46-1.11 (m, 2H). 98% 57 [00226] (R)-6G.sub.3 + M11a + M9 (300 MHz, Chloroform-d) δ 7.33-7.21 (m, 2H), 7.14- 6.86 (m, 5H), 6.69 (s, 1H), 5.27-5.07 (m, 1H), 4.64- 2.45 (m, 4H), 2.38-2.09 (m, 2H), 2.15-1.73 (m, 5H), 1.70-1.12 (m, 6H). 100% 58 [00227] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (t, J = 5.5 Hz, 1H), 7.48-7.31 (m, 2H), 7.28- 7.20 (m, 2H), 7.18-7.01 (m, 3H), 5.23-5.12 (m, 1H), 4.34 (d, J = 14.6 Hz, 1H), 4.16-3.90 (m, 3H), 3.44-3.01 (m, 1H), 2.95- 2.78 (m, 1H), 2.58-2.39 (m, 1H), 2.02-1.46 (m, 7H), 1.18 (q, J = 7.1 Hz, 3H). 96% 59 [00228] embedded image (R)-4G.sub.5 + M11a + M9 (400 MHz, DMSO-d.sub.6) δ 7.73 (dd, J = 8.9, 2.5 Hz, 1H), 7.58-7.19 (m, 6H), 5.67- 5.44 (m, 1H), 4.31-3.79 (m, 2H), 3.50-3.08 (m, 1H), 2.98-2.72 (m, 4H), 2.43-2.25 (m, 1H), 1.96 (d, J = 15.8 Hz, 1H), 1.77- 1.44 (m, 6H). 98% 60 [00229] 51 (300 MHz, DMSO-d.sub.6) δ 10.66 (d, J = 4.3 Hz, 1H), 8.87 (dd, J = 4.4, 1.5 Hz, 1H), 7.91 (dd, J = 8.6, 1.7 Hz, 2H), 7.82-7.66 (m, 3H), 7.61-7.26 (m, 6H), 5.18 (q, J = 6.5 Hz, 1H), 1.67 (d, J = 6.5 Hz, 3H). 94% 61 [00230] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 12.78 (s, 1H), 8.85 (d, J = 4.5 Hz, 1H), 7.48 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.25 (ddd, J = 8.7, 6.5, 2.4 Hz, 2H), 7.24-7.02 (m, 3H), 6.28-6.15 (m, 1H), 4.81 (qd, J = 6.7, 2.7 Hz, 1H), 4.17-3.94 (m, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.13 (dd, J = 6.6, 2.3 Hz, 3H), 1.03 (dd, J = 6.5, 3.8 Hz, 3H). 97% 62 [00231] embedded image (rac)-4G.sub.4 + M11a + M9 (300 MHz, Chloroform-d) δ 8.92-8.76 (m, 1H), 7.77- 7.59 (m, 1H), 7.35-7.00 (m, 5H), 6.23-5.63 (m, 1H), 4.88-4.43 (m, 2H), 3.49-2.67 (m, 2H), 2.55 (tt, J = 12.6, 3.7 Hz, 1H), 2.31-2.16 (m, 1H), 2.08- 1.80 (m, 1H), 1.56 (dd, J = 13.1, 6.8 Hz, 3H), 1.77- 1.12 (m, 2H). 99% 63 [00232] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 10.8 Hz, 1H), 7.69 (ddd, J = 8.9, 2.6, 1.3 Hz, 1H), 7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.45-7.21 (m, 5H), 5.57 (q, J = 6.6 Hz, 1H), 4.40-4.07 (m, 1H), 4.06- 3.52 (m, 3H), 3.30-3.13 (m, 2H), 1.51 (ddd, J = 13.4, 6.5, 2.5 Hz, 3H). 97% 64 [00233] embedded image (R)-4G.sub.3 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 12.41 (s, 1H), 7.59 (ddd, J = 8.9, 2.6, 1.0 Hz, 1H), 7.44 (ddd, J = 7.9, 6.2, 1.7 Hz, 1H), 7.38-7.25 (m, 2H), 7.24-7.07 (m, 3H), 5.51- 5.40 (m, 1H), 4.25-3.68 (m, 2H), 3.39-2.94 (m, 1H), 2.87-2.65 (m, 1H), 2.45-1.73 (m, 2H), 1.66- 1.42 (m, 3H), 1.36 (dd, J = 10.2, 6.4 Hz, 3H). 99% 65 [00234] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.32 (s, 1H), 8.98 (dd, J = 7.4, 4.4 Hz, 1H), 7.66 (qd, J = 8.6, 6.1 Hz, 2H), 7.53- 7.19 (m, 5H), 5.70-5.49 (m, 1H), 4.38-4.03 (m, 2H), 3.25-2.96 (m, 1H), 2.84-2.46 (m, 1H), 2.36- 2.13 (m, 2H), 2.00-1.66 (m, 3H), 1.59 (dd, J = 16.0, 6.4 Hz, 3H), 1.33 (s, 2H). 90% 66 [00235] embedded image 1D.sub.1 + (S,S)-1H + M9 (300 MHz, DMSO-d.sub.6) δ 12.49 (s, 1H), 8.85 (t, J = 4.1 Hz, 1H), 7.76 (dd, J = 9.3, 2.4 Hz, 1H), 7.65- 7.48 (m, 5H), 7.40-7.20 (m, 3H), 5.57 (q, J = 6.5 Hz, 1H), 4.42-3.88 (m, 2H), 3.50-3.08 (m, 2H), 3.01- 2.68 (m, 1H), 2.43-1.72 (m, 2H), 1.73-1.45 (m, 4H), 1.26 (d, J = 15.3 Hz, 1H). 97% 67 [00236] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (d, J = 4.5 Hz, 1H), 7.39-7.01 (m, 7H), 5.01 (dq, J = 6.8, 5.5 Hz, 1H), 4.04-3.60 (m, 5H), 3.59- 3.29 (m, 1H), 3.15-3.00 (m, 1H), 2.76-2.24 (m, 3H), 2.20-1.98 (m, 1H), 1.85-1.36 (m, 4H). 100% 68 [00237] 83 (300 MHz, Chloroform-d) δ 7.49 (dt, J = 7.6, 2.1 Hz, 1H), 7.43-7.17 (m, 5H), 7.16-7.07 (m, 2H), 6.62- 6.37 (m, 1H), 5.23-5.00 (m, 1H), 3.92-3.78 (m, 1H), 3.71-3.06 (m, 2H), 2.82-2.67 (m, 3H), 2.49- 2.26 (m, 1H), 2.24-1.84 (m, 1H), 1.72 (td, J = 8.8, 4.2 Hz, 1H), 1.61 (dd, J = 17.1, 6.6 Hz, 4H), 1.52- 0.65 (m, 4H). 100% 69 [00238] embedded image 49 (400 MHz, DMSO-d.sub.6) δ 7.65- 7.18 (m, 8H), 5.50 (dt, J = 24.4, 6.9 Hz, 1H), 4.41- 3.68 (m, 2H), 2.84 (s, 4H), 2.70-2.54 (m, 1H), 2.37- 2.07 (m, 2H), 2.03 (s, 3H), 1.80 (s, 3H), 1.70-1.50 (m, 4H), 1.25 (s, 1H) 100% 70 [00239] 104 (400 MHz, DMSO-d.sub.6) δ 7.71- 7.67 (m, 1H), 7.62-7.52 (m, 2H), 7.49 (dt, J = 7.3, 2.1 Hz, 1H), 7.40 (s, 1H), 7.37-7.24 (m, 3H), 5.59 (s, 1H), 3.68 (s, 8H), 1.99 (s, 1H), 1.52 (dd, J = 6.5, 2.6 Hz, 3H), 0.82-0.62 (m, 4H). 100% 71 [00240] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.82 (t, J = 4.0 Hz, 1H), 7.46-7.01 (m, 7H), 5.21 (dt, J = 32.8, 6.5 Hz, 1H), 4.66-3.81 (m, 3H), 3.73- 3.10 (m, 4H), 3.06-2.44 (m, 2H), 2.42-1.86 (m, 2H), 1.82-1.13 (m, 4H). 100% 72 [00241] 104 (400 MHz, DMSO-d.sub.6) δ 7.71- 7.67 (m, 1H), 7.63-7.46 (m, 3H), 7.40 (s, 1H), 7.36- 7.24 (m, 3H), 5.58 (d, J = 6.3 Hz, 1H), 3.77-3.37 (m, 8H), 2.34 (d, J = 7.6 Hz, 2H), 1.51 (dd, J = 6.5, 2.6 Hz, 3H), 1.05-0.94 (m, 3H). 100% 73 [00242] embedded image 3D.sub.3 (300 MHz, Chloroform-d) δ 7.37-7.20 (m, 5H), 7.15- 7.04 (m, 3H), 4.75 (qd, J = 6.8, 2.5 Hz, 1H), 1.97 (d, J = 1.6 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 2.9 Hz, 9H). 95% 74 [00243] (R)-4G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.67 (dd, J = 8.9, 2.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.41 (tt, J = 8.6, 2.3 Hz, 1H), 7.33-7.10 (m, 4H), 5.61-5.30 (m, 1H), 4.28- 3.85 (m, 4H), 3.04 (dq, J = 63.3, 11.6 Hz, 1H), 2.73- 2.51 (m, 4H), 2.37-2.11 (m, 3H), 1.89-1.45 (m, 7H), 1.15 (dt, J = 7.1, 4.9 Hz, 3H). 99% 75 [00244] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.5 Hz, 1H), 7.70 (dd, J = 8.9, 2.6 Hz, 1H), 7.61-7.39 (m, 2H), 7.44- 7.17 (m, 4H), 5.28 (tt, J = 6.5, 4.5 Hz, 1H), 4.16 (qd, J = 7.1, 2.4 Hz, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.97-3.36 (m, 4H), 3.31-3.07 (m, 1H), 2.28-1.97 (m, 2H), 1.57-1.46 (m, 3H), 1.26- 1.08 (m, 3H). 100% 76 [00245] embedded image 34 (300 MHz, Chloroform-d) δ 7.48 (dd, J = 7.6, 1.7 Hz, 1H), 7.42-7.28 (m, 4H), 7.26-7.06 (m, 4H), 6.51- 5.96 (m, 1H), 5.77-5.40 (m, 1H), 5.28-5.06 (m, 1H), 4.14-3.96 (m, 1H), 3.96-3.72 (m, 1H), 3.71- 2.88 (m, 2H), 2.51-2.36 (m, 1H), 2.17-125 (m, 7H). 100% 77 [00246] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.73 (d, J = 4.5 Hz, 1H), 8.24- 8.12 (m, 1H), 7.54 (dt, J = 8.8, 2.0 Hz, 1H), 7.36 (ddd, J = 8.4, 6.2, 2.1 Hz, 1H), 7.26 (tt, J = 8.5, 2.2 Hz, 1H), 7.20-7.06 (m, 4H), 4.68 (q, J = 6.5 Hz, 1H), 2.55-2.43 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H), 0.51- 0.41 (m, 2H), 0.32-0.22 (m, 2H). 100% 78 [00247] embedded image (400 MHz, DMSO-d.sub.6) δ 8.89 (t, J = 4.6 Hz, 1H), 7.68 (dt, J = 7.7, 1.2 Hz, 1H), 7.61- 7.49 (m, 2H), 7.47-7.42 (m, 1H), 7.38-7.26 (m, 3H), 7.22 (dd, J = 9.2, 2.6 Hz, 1H), 5.83-5.40 (m, 1H), 4.44-3.95 (m, 2H), 3.27-3.10 (m, 1H), 2.82 (t, J = 12.0 Hz, 1H), 2.63- 1.89 (m, 2H), 1.83-1.28 (m, 6H). 98%, ee90% 79 [00248] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.83 (dd, J = 7.9, 4.4 Hz, 1H), 7.61-7.48 (m, 2H), 7.32- 7.18 (m, 3H), 7.09 (d, J = 5.2 Hz, 1H), 5.61-5.40 (m, 1H), 4.30-3.94 (m, 2H), 3.15-2.87 (m, 1H), 2.50 (p, J = 1.9 Hz, 2H), 2.27 (s, 3H), 2.24-1.95 (m, 2H), 1.92-1.59 (m, 1H), 1.52 (dd, J = 17.0, 6.4 Hz, 3H), 1.30-1.06 (m, 3H). 99% 80 [00249] embedded image (rac)-4G.sub.4 + M11a + M9 (300 MHz, Chloroform-d) δ 9.02-8.74 (m, 1H), 7.75- 7.60 (m, 1H), 7.32-7.00 (m, 5H), 6.46-5.63 (m, 1H), 4.52-4.22 (m, 1H), 4.09-3.68 (m, 1H), 3.60- 3.30 (m, 1H), 3.29-2.03 (m, 3H), 1.88-1.67 (m, 1H), 1.65-1.49 (m, 3H), 1.50-1.13 (m, 2H). 98% 81 [00250] embedded image 64 (300 MHz, Chloroform-d) δ 7.36-7.20 (m, 4H), 7.18- 7.03 (m, 3H), 6.43-5.73 (m, 1H), 5.56-5.03 (m, 2H), 4.11-3.00 (m, 4H), 2.47 (d, J = 10.8 Hz, 1H), 2.08 (dd, J = 15.4, 8.9 Hz, 1H), 1.91-1.13 (m, 6H). 100% 82 [00251] 2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.90 (dd, J = 4.4, 0.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.61- 7.51 (m, 2H), 7.48-7.43 (m, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.35-7.25 (m, 3H), 5.03 (pd, J = 6.3, 0.8 Hz, 1H), 4.95 (d, J = 0.7 Hz, 2H), 1.24 (d, J = 6.2 Hz, 6H). 97% 83 [00252] embedded image 92 (300 MHz, Chloroform-d) δ 7.49 (dd, J = 7.6, 1.6 Hz, 1H), 7.42-7.03 (m, 7H), 5.30-5.07 (m, 1H), 4.33- 3.61 (m, 2H), 3.28-2.71 (m, 2H), 2.54-1.72 (m, 5H), 1.72-1.36 (m, 4H), 1.32- 1.15 (m, 1H). 90% 84 [00253] (R,S)- 1K.sub.1_Cl (300 MHz, DMSO-d.sub.6) δ 12.60 (s, 1H), 8.95 (t, J = 4.6 Hz, 1H), 7.43-7.12 (m, 6H), 5.60 (q, J = 6.5 Hz, 1H), 4.52-3.88 (m, 2H), 3.59-3.14 (m, 1H), 3.12- 2.92 (m, 1H), 2.96-2.72 (m, 1H), 2.40 (d, J = 35.6 Hz, 1H), 2.18-1.51 (m, 10H), 1.24-1.16 (m, 2H). 91% 85 [00254] embedded image 104 + M10a (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 3H), 7.70 (dd, J = 8.0, 1.3 Hz, 1H), 7.63-7.46 (m, 3H), 7.41 (s, 1H), 7.37- 7.25 (m, 3H), 5.61 (dt, J = 14.6, 7.1 Hz, 1H), 3.91 (s, 2H), 3.80-3.36 (m, 8H), 1.53 (d, J = 5.7 Hz, 3H). - TFA Salt 99% 86 [00255] 2D.sub.1 (300 MHz, Chloroform-d) δ 8.81 (dd, J = 4.5, 0.9 Hz, 1H), 7.53-7.42 (m, 1H), 7.42-7.02 (m, 6H), 5.16 (qd, J = 6.6, 2.5 Hz, 1H), 3.09 (d, J = 1.0 Hz, 3H), 2.94 (d, J = 2.2 Hz, 3H), 1.60 (d, J = 6.6 Hz, 3H). 93% 87 [00256] embedded image 2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 (dtd, J = 15.9, 7.4, 1.7 Hz, 2H), 7.49-7.43 (m, 2H), 7.34-7.23 (m, 3H), 5.21-4.97 (m, 2H), 4.34- 3.41 (m, 4H), 3.21-2.92 (m, 2H), 2.48-2.37 (m, 1H), 2.05-1.38 (m, 4H), 1.28-1.12 (m, 3H). 93% 88 [00257] embedded image 2D.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.48-7.40 (m, 1H), 7.36-7.18 (m, 4H), 5.57-5.45 (m, 1H), 3.16 (d, J = 7.3 Hz, 3H), 2.87 (d, J = 3.0 Hz, 3H), 1.50 (dd, J = 6.5, 1.5 Hz, 3H). 100% 89 [00258] (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.81 (t, J = 4.0 Hz, 1H), 7.45-7.28 (m, 2H), 7.28- 7.20 (m, 2H), 7.18-7.00 (m, 3H), 5.28-5.10 (m, 1H), 4.37 (t, J = 13.1 Hz, 1H), 4.17-3.82 (m, 3H), 3.27-2.65 (m, 1H), 2.65- 2.41 (m, 1H), 2.28-1.28 (m, 9H), 1.28-1.09 (m, 4H). 98% 90 [00259] embedded image (R)- 2F.sub.6_tBu (400 MHz, Chloroform-d) δ 7.59-7.50 (m, 2H), 7.49- 7.35 (m, 3H), 7.34-7.13 (m, 2H), 6.87 (t, J = 1.4 Hz, 1H), 5.06 (p, J = 6.7 Hz, 1H), 1.84 (dd, J = 6.8, 1.2 Hz, 3H). 96% 91 [00260] (R)- 4F.sub.3_Et (300 MHz, DMSO-d.sub.6) δ 7.72 (dt, J = 8.9, 2.3 Hz, 1H), 7.58 (ddd, J = 8.2, 6.2, 1.8 Hz, 1H), 7.51-7.37 (m, 2H), 7.37-7.22 (m, 3H), 5.03 (d, J = 7.0 Hz, 1H), 1.56 (d, J = 6.7 Hz, 3H). 99% 92 [00261] embedded image (R)-2G.sub.3 (300 MHz, Chloroform-d) δ 7.48 (dd, J = 7.6, 1.7 Hz, 1H), 7.44-7.21 (m, 4H), 7.27-7.13 (m, 1H), 7.19- 7.06 (m, 2H), 5.16 (p, J = 6.1, 5.5 Hz, 1H), 4.51- 4.13 (m, 1H), 4.06 (qd, J = 7.2, 3.1 Hz, 3H), 3.13- 2.74 (m, 1H), 2.57 (dd, J = 17.3, 9.5 Hz, 1H), 2.31- 2.15 (m, 1H), 2.12-1.74 (m, 2H), 1.68-1.55 (m, 6H), 1.25-1.10 (m, 4H). 95% 93 [00262] embedded image (R)-4G.sub.3 (300 MHz, DMSO-d.sub.6) δ 7.73 (dd, J = 8.9, 2.5 Hz, 1H), 7.63-7.51 (m, 1H), 7.51- 7.38 (m, 2H), 7.38-7.19 (m, 3H), 5.61-5.44 (m, 1H), 4.18 (dd, J = 21.8, 12.7 Hz, 1H), 4.10-3.83 (m, 3H), 3.01 (dd, J = 38.7, 24.1 Hz, 1H), 2.69-2.53 (m, 1H), 2.36-2.10 (m, 2H), 1.89-1.59 (m, 3H), 1.51 (dd, J = 12.2, 6.4 Hz, 3H), 1.26 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H). 98% 94 [00263] embedded image (R)-6G.sub.3 (300 MHz, Chloroform-d) δ 7.34-6.88 (m, 7H), 5.14 (dq, J = 12.8, 6.6 Hz, 1H), 4.52-4.14 (m, 1H), 4.12- 2.41 (m, 4H), 2.32-2.13 (m, 1H), 2.11-1.72 (m, 5H), 1.71-1.48 (m, 5H), 1.45-1.08 (m, 4H). 100% 95 [00264] (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 11.68 (s, 1H), 8.93 (dd, J = 4.6, 1.4 Hz, 1H), 8.78- 8.69 (m, 2H), 8.18-8.10 (m, 2H), 7.71 (dd, J = 8.9, 2.5 Hz, 1H), 7.56-7.33 (m, 6H), 5.31 (qd, J = 6.6, 2.8 Hz, 1H), 1.70 (dd, J = 6.6, 1.5 Hz, 3H). 100% 96 [00265] embedded image 34 (300 MHz, Chloroform-d) δ 8.06-7.64 (m, 1H), 7.49 (dt, J = 7.6, 1.4 Hz, 1H), 7.45-7.27 (m, 3H), 7.23 (dt, J = 6.5, 2.9 Hz, 2H), 7.17-7.06 (m, 2H), 6.37- 5.32 (m, 1H), 5.13 (q, J = 6.3 Hz, 1H), 4.43-3.22 (m, 3H), 2.89 (s, 1H), 2.82 (s, 1H), 2.80-2.73 (m, 1H), 2.70 (d, J = 4.4 Hz, 2H), 2.42-2.31 (m, 1H), 2.18- 1.98 (m, 1H), 1.87-1.75 (m, 1H), 1.69-1.53 (m, 3H). 96% 97 [00266] embedded image 2G.sub.3 (400 MHz, DMSO-d.sub.6) δ 8.60 (td, J = 8.4, 7.9, 4.0 Hz, 1H), 7.69 (dt, J = 8.0, 1.5 Hz, 1H), 7.63-7.51 (m, 2H), 7.49 (dt, J = 7.5, 2.3 Hz, 1H), 7.41-7.39 (m, 1H), 7.35-7.28 (m, 3H), 4.98-4.82 (m, 1H), 4.41- 4.11 (m, 1H), 3.66-3.55 (m, 3H), 3.08-2.77 (m, 1H), 2.47-2.04 (m, 4H), 1.53-1.45 (m, 3H). 100% 98 [00267] embedded image 56 (300 MHz, Chloroform-d) δ 7.34-7.03 (m, 7H), 6.54- 6.35 (m, 1H), 5.21-5.01 (m, 1H), 3.91-3.76 (m, 1H), 3.69-3.07 (m, 3H), 2.82-2.67 (m, 3H), 2.47- 2.12 (m, 2H), 2.01-1.30 (m, 6H), 1.20 (d, J = 8.2 Hz, 2H). 100% 99 [00268] 2D.sub.3 (300 MHz, Chloroform-d) δ 7.53-7.41 (m, 1H), 7.44- 7.06 (m, 7H), 5.12 (qd, J = 6.6, 1.7 Hz, 1H), 3.70- 3.54 (m, 1H), 3.52-3.32 (m, 3H), 1.59 (dd, J = 6.6, 1.3 Hz, 9H). 100% 100 [00269] embedded image 34 (300 MHz, Chloroform-d) δ 7.49 (dd. J = 7.7, 1.7 Hz, 1H), 7.45-7.18 (m, 5H), 7.17-7.01 (m, 2H), 5.21- 4.99 (m, 1H), 4.55 (d, J = 9.9 Hz, 1H), 4.29-3.83 (m, 1H), 3.35-2.92 (m, 3H), 2.85 (d, J = 7.6 Hz, 3H), 2.79-2.66 (m, 2H), 2.60- 2.16 (m, 1H), 1.97-1.17 (m, 7H). 100% 101 [00270] embedded image 74 (400 MHz, DMSO-d.sub.6) δ 7.75 (dd, J = 8.9, 2.5 Hz, 1H), 7.63-7.43 (m, 4H), 7.40- 7.26 (m, 2H), 5.66-5.35 (m, 1H), 4.35-3.80 (m, 2H), 2.84 (s, 4H), 2.60 (d, J = 10.1 Hz, 1H), 2.28-2.19 (m, 1H), 2.12 (dt, J = 15.2, 7.8 Hz, 1H), 1.89-1.48 (m, 6H), 1.26 (s, 2H). 98% 102 [00271] embedded image (400 MHz, DMSO-d.sub.6) δ 8.89 (t, J = 4.9Hz, 1H), 7.68 (dt, J = 7.7, 1.3 Hz, 1H), 7.60- 7.49 (m, 2H), 7.45 (dd, J = 7.3, 1.9 Hz, 1H), 7.38- 7.26 (m, 3H), 7.22 (dd, J = 9.2, 2.5 Hz, 1H), 5.80- 5.46 (m, 1H), 4.42-3.85 (m, 2H), 3.58-3.09 (m, 1H), 3.04-2.76 (m, 1H), 2.47-2.21 (m, 1H). 2.10- 1.89 (m, 1H), 1.85-1.56 (m, 2H), 1.55-1.45 (m, 3H), 1.33 (s, 1H). 94% ee 85% 103 [00272] embedded image (R)- 2F.sub.1_Et (400 MHz, DMSO-d.sub.6) δ 13.19 (s, 1H), 8.88 (d, J = 4.4 Hz, 1H), 7.72-7.65 (m, 1H), 7.61-7.49 (m, 2H), 7.48-7.41 (m, 1H), 7.35- 7.21 (m, 4H), 5.05 (q, J = 6.7 Hz, 1H), 1.58 (dd, J = 6.7, 0.9 Hz, 3H). 94% 104 [00273] 2G.sub.3 + M11a + M101 (400 MHz, DMSO-d.sub.6) δ 8.88 (s, 2H), 7.70 (dd, J = 7.9, 1.4 Hz, 1H), 7.58 (dtd, J = 20.0, 7.4, 1.6 Hz, 2H), 7.49 (ddd, J = 7.5, 5.6, 1.9 Hz, 1H), 7.42 (d, J = 1.1 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.33-7.25 (m, 2H), 5.59 (p, J = 6.6 Hz, 1H), 3.95-3.60 (m, 4H), 3.27- 3.05 (m, 4H), 1.52 (dd, J = 6.5, 2.6 Hz, 3H). - TFA Salt 100% 105 [00274] embedded image 64 (300 MHz, Chloroform-d) δ 7.34-7.24 (m, 1H), 7.31- 7.10 (m, 4H), 7.16-7.01 (m, 3H), 6.42-5.31 (m, 1H), 5.23-5.06 (m, 1H), 4.35-3.25 (m, 3H), 2.83- 2.73 (m, 1H), 2.72-2.63 (m, 2H), 2.42-2.27 (m, 1H), 2.16-1.99 (m, 1H), 1.87- 1.73 (m, 1H), 1.73-1.49 (m, 5H). 100% 106 [00275] 3D.sub.1 (300 MHz, Chloroform-d) δ 8.84 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.34-7.21 (m, 3H), 7.16- 7.05 (m, 3H), 6.52 (s, 1H), 5.69 (s, 1H), 4.61 (s, 2H), 1.96 (s, 3H). 96% 107 [00276] embedded image 4G.sub.3 (300 MHz, DMSO-d.sub.6) δ 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 7.65 (dd, J = 8.6, 6.1 Hz, 1H), 7.59-7.46 (m, 1H), 7.49 (s, 1H), 7.44-7.28 (m, 3H), 5.61 (p, J = 6.3 Hz, 1H), 3.79-3.59 (m, 2H), 3.57-3.49 (d, J = 5.3 Hz, 2H), 1.74-1.62 (m, 4H), 1.61-1.44 (m, 5H). 99% 108 [00277] 4G.sub.1 (300 MHz, Chloroform-d) δ 8.84 (d, J = 4.5 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.01-7.89 (m, 2H), 7.73 (dq, J = 7.7, 1.5 Hz, 1H), 7.59 (t, J = 2.5 Hz, 1H), 7.47-7.02 (m, 7H), 5.08- 4.95 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.70 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 100% 109 [00278] embedded image (rac)-4G.sub.4 (300 MHz, Chloroform-d) δ 8.95 (dd, J = 4.6, 1.7 Hz, 1H), 7.76-7.66 (m, 1H), 7.33-7.19 (m, 3H), 7.10 (td, J = 8.2, 2.5 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.36 (s, 1H), 5.88 (p, J = 6.8 Hz, 1H), 4.14-3.99 (m, 1H), 1.60 (dd, J = 6.7, 2.0 Hz, 3H), 1.22-1.06 (m, 6H). 100% 110 [00279] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.28 (s, 1H), 8.95 (dd, J = 7.2, 4.5 Hz, 1H), 7.68 (tdd, J = 7.4, 5.3, 2.0 Hz, 1H), 7.63-7.35 (m, 5H), 7.41- 7.27 (m, 2H), 5.69-5.49 (m, 1H), 4.35-4.02 (m, 2H), 3.09 (dt, J = 40.8, 12.0 Hz, 1H), 2.81-2.46 (m, 1H), 2.36-2.09 (m, 2H), 2.00-1.65 (m, 3H), 1.58 (dd, J = 15.9, 6.4 Hz, 3H), 1.31 (s, 2H). 100% 111 [00280] embedded image (R)-3G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.45- 7.30 (m, 4H), 7.28-7.16 (m, 2H), 7.10 (d, J = 10.9 Hz, 2H), 5.48 (d, J = 8.3 Hz, 1H), 4.23-3.20 (m, 3H), 3.18-2.88 (m, 1H), 2.64 (s, 4H), 2.40-2.25 (m, 2H), 1.98 (d, J = 3.3 Hz, 4H), 1.76-1.43 (m, 4H), 1.37 (d, J = 2.8 Hz, 9H). 97% 112 [00281] embedded image (R)-2G.sub.1 + M11a + M9 (300 MHz, Chloroform-d) δ 9.05-8.71 (m, 1H), 8.15 (br. s, 1H), 7.49 (dd, J = 7.6, 1.7 Hz, 1H), 7.48- 7.28 (m, 3H), 7.34-7.12 (m,4H), 5.29-5.09 (m, 1H), 4.59 (t, J = 15.8 Hz, 1H), 3.99 (t, J = 16.0 Hz, 1H), 3.65-3.07 (m, 1H), 2.83-2.60 (m, 1H), 2.38 (dd, J = 41.1, 6.6 Hz, 2H), 2.23-1.75 (m, 3H), 1.62 (dd, J = 6.7, 3.8 Hz, 3H), 96% 1.49 (m, 1H), 1.31-1.11 (m, 1H). 113 [00282] embedded image (R)-6G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.54- 7.42 (m, 1H), 7.39-7.23 (m, 6H), 6.98 (d, J = 32.2 Hz, 2H), 5.63-5.42 (m, 1H), 4.81-3.95 (m, 2H), 3.39-2.99 (m, 1H), 2.95- 2.57 (m, 5H), 2.30-2.09 (m, 1H), 1.93-1.63 (m, 9H), 1.62-1.46 (m, 3H). 95% 114 [00283] (R)-6G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.61- 7.48 (s, 1H), 7.46-7.22 (m, 6H), 7.01-6.89 (m, 2H), 5.58-5.37 (m, 1H), 4.86-4.04 (m, 2H), 3.26- 3.04 (m, 1H), 2.95-2.78 (m,4H), 2.74-2.58 (m, 1H), 2.18 (d, J = 12.7 Hz, 1H), 1.96-1.77 (m,7H), 1.75-1.37 (m, 5H). 100% 115 [00284] embedded image (R)-4G.sub.5 (400 MHz, DMSO-d.sub.6) δ 7.82- 7.68 (m, 1H), 7.61-7.21 (m, 6H), 7.07-6.89 (m, 2H), 5.61-5.36 (m, 1H), 4.84-4.07 (m, 2H), 3.30- 3.07 (m, 1H), 2.91-2.58 (m, 5H), 2.23-2.08 (m, 1H), 1.93-1.76 (m, 1H), 1.76-1.62 (m, 1H), 1.62- 1.49 (m, 3H), 1.50-1.33 (m, 1H). 100% 116 [00285] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.99 (d, J = 4.5 Hz, 1H), 7.72 (dd, J = 8.9, 2.6 Hz, 1H), 7.54 (ddd, J = 8.4, 6.1, 3.8 Hz, 1H), 7.48-7.37 (m, 3H), 7.35-7.26 (m, 2H), 7.04-6.86 (m, 2H), 5.69- 5.38 (m, 1H), 4.83-3.97 (m, 2H), 3.38-2.57 (m, 3H), 2.29-2.06 (m, 1H), 1.96-1.45 (m, 6H). 100% 117 [00286] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 9.01 (d, J = 4.8 Hz, 1H), 7.73 (ddd, J = 8.9, 2.6, 1.3 Hz, 1H), 7.60-7.27 (m, 6H), 7.07-6.87 (m, 2H), 5.64- 5.36 (m, 1H), 4.89-4.04 (m, 2H), 3.32-3.07 (m, 1H), 2.92-2.55 (m, 2H), 2.31-2.07 (m, 1H), 1.97- 1.32 (m, 6H). 100% 118 [00287] (R)-2G.sub.1 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 8.89 (dd, J = 4.5, 2.6 Hz, 1H), 7.69 (dd, J = 7.5, 1.8 Hz, 1H), 7.64- 7.47 (m, 2H), 7.45 (dd, J = 7.1, 2.3 Hz, 1H), 7.38- 7.18 (m, 4H), 5.60-5.46 (m, 1H), 4.34 (d, J = 12.7 Hz, 1H), 4.12 (s, 1H), 3.13 (dd, J = 30.7, 16.5 Hz, 1H), 2.61 (t, J = 13.0 Hz, 1H), 2.34-2.15 (m, 2H), 1.80- 1.61 (m, 2H), 1.57-0.74 (m, 6H). 98% 119 [00288] embedded image (R)-6G.sub.1 (300 MHz, DMSO-d.sub.6) δ 9.03 (t, J = 4.8Hz, 1H), 7.51- 7.23 (m, 7H), 7.21-7.06 (m, 2H), 5.76-5.39 (m, 1H), 4.75 (dd, J = 118.6, 12.4 Hz, 1H), 4.48-4.19 (m, 1H), 3.42-3.14 (m, 1H), 3.03-2.89 (m, 1H), 2.81 (t, J = 11.8 Hz, 1H), 2.41-2.18 (m, 1H), 2.09- 1.77 (m, 9H), 1.73-1.52 (m, 3H). 95% 120 [00289] embedded image (R)-7G.sub.1 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 8.93 (dd, J = 8.4, 4.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.66-7.54 (m, 1H), 7.36- 7.13 (m, 4H), 5.62-5.43 (m, 1H), 4.31-4.18 (m, 1H), 4.17-3.94 (m, 1H), 3.14-2.90 (m, 1H), 2.74- 2.40 (m, 1H), 2.29-2.07 (m, 2H), 1.92-1.44 (m, 6H), 1.33-1.20 (m, 2H). 97% 121 [00290] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.85 (dd, J = 7.8, 4.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.40- 7.30 (m, 1H), 7.30-7.13 (m, 5H), 5.49 (dd, J = 27.5, 6.2 Hz, 1H), 4.24 (d, J = 12.9 Hz, 1H), 4.17-3.94 (m, 1H), 3.22-2.54 (m, 1H), 2.44-2.07 (m, 3H), 1.92-1.58 (m, 4H), 1.58- 1.43 (m, 3H), 1.33-1.19 (m, 3H), 0.99-0.82 (m, 3H). 99% 122 [00291] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.21 (br. s, 1H), 8.81 (dd, J = 7.8, 4.4 Hz, 1H), 7.56- 7.40 (m, 2H), 7.35-7.06 (m, 6H), 5.56-5.37 (m, 1H), 4.20 (d, J = 12.9 Hz, 1H), 4.14-3.91 (m, 1H), 3.16-2.51 (m, 1H), 2.47- 2.36 (m, 1H), 2.24-2.02 (m, 2H), 1.89-1.56 (m, 4H), 1.53-1.40 (m, 3H), 1.28-1.17 (m, 2H), 1.06- 0.94 (m, 6H). 99% 123 [00292] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.99 (dd, J = 9.0, 4.5 Hz, 1H), 7.74 (dd, J = 8.9, 2.5 Hz, 1H), 7.63-7.23 (m, 6H), 7.11-6.98 (m, 1H), 6.94- 6.75 (m, 1H), 5.68-5.38 (m, 1H), 4.42-3.87 (m, 2H), 3.37-2.58 (m, 4H), 2.32-1.87 (m, 2H), 1.87- 1.29 (m, 6H). 99% 124 [00293] (R)-6G.sub.5 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 7.35-7.01 (m, 7H), 5.54-5.35 (m, 1H), 4.37-3.80 (m, 2H), 3.19-2.87 (m, 1H), 2.78- 2.41 (m, 4H), 2.31-2.07 (m, 2H), 1.90-1.73 (m, 8H), 1.69-1.62 (m, 1H), 1.58-1.43 (m, 4H), 1.33- 1.20 (m, 2H). 92% 125 [00294] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 10.27 (d, J = 5.3 Hz, 1H), 8.96 (d, J = 4.7 Hz, 1H), 7.72 (dd, J = 9.0, 2.5 Hz, 1H), 7.57-7.36 (m, 8H), 7.15 (dd. J = 8.5, 2.3 Hz, 2H), 5.12 (q, J = 6.4 Hz, 1H), 3.55 (td, J = 7.1, 1.1 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 1.64 (dd, J = 6.6, 1.5 Hz, 3H). 100% 126 [00295] embedded image 62 + chiral HPLC separation (300 MHz, DMSO-d.sub.6) δ 12.37 (s, 1H), 9.20-8.85 (m, 1H), 7.81-7.67 (m, 2H), 7.61-7.49 (m, 1H), 7.50-7.35 (m, 2H), 7.16 (d, J = 9.0 Hz, 1H), 6.08- 5.82 (m, 1H), 4.45-3.94 (m, 2H), 3.49-3.06 (m, 1H), 2.82-2.63 (m, 1H), 2.40 (s, 1H), 2.21-1.94 (m, 1H), 1.67 (d, J = 17.1 Hz, 2H), 1.55-1.19 (m, 4H). 95% 127 [00296] embedded image 62 + chiral HPLC separation (400 MHz, DMSO-d.sub.6) δ 12.38 (br. s, 1H), 8.97 (d, J = 4.5 Hz, 1H), 7.77-7.66 (m, 2H), 7.52 (dt, J = 8.9, 5.8 Hz, 1H), 7.46-7.34 (m, 2H), 7.13 (d, J = 9.1 Hz, 1H), 6.07-5.88 (m, 1H), 4.52-3.90 (m, 2H), 3.24- 2.54 (m, 1H), 2.35-1.63 (m, 4H), 1.48 (d, J = 6.6 Hz, 5H). 93% 128 [00297] embedded image 80 + chiral HPLC separation (400 MHz, DMSO-d.sub.6) δ 8.98 (t, J = 5.1 Hz, 1H), 7.79- 7.68 (m, 2H), 7.60-7.51 (m, 1H), 7.48-7.36 (m, 2H), 7.16 (dd, J = 9.0, 3.4 Hz, 1H), 6.07-5.83 (m, 1H), 4.28-3.93 (m, 2H), 3.18-3.05 (m, 1H), 2.86- 2.31 (m, 2H), 2.23-2.04 (m, 2H), 1.99-1.59 (m, 2H), 1.57-1.43 (m, 3H), 1.39-1.20 (m, 2H). 98% 129 [00298] embedded image (R)-7G.sub.1 + M11a + M9 (300 MHz, DMSO-d.sub.6) δ 12.55 (br. s, 1H), 8.94 (t, J = 4.9 Hz, 1H), 7.76-7.66 (m, 2H), 7.66-7.54 (m, 1H), 7.39-7.13 (m, 4H), 5.63-5.53 (m, 1H), 4.46- 3.81 (m, 2H), 3.54-3.12 (m, 1H), 3.08-2.70 (m, 1H), 2.61-1.73 (m, 3H), 1.73-1.17 (m, 5H). 98% 130 [00299] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 10.98 (d, J = 10.2 Hz, 1H), 8.96 (d, J = 4.7 Hz, 1H), 8.38 (dd, J = 4.8, 2.2 Hz, 1H), 8.03 (dd, J = 8.4, 3.9 Hz, 1H), 7.85-7.66 (m, 2H), 7.59-7.33 (m, 6H), 7.16 (ddt, J = 7.3, 4.9, 1.2 Hz, 1H), 5.32 (q, J = 6.6 Hz, 1H), 1.65 (d, J = 6.5 Hz, 3H). 100% 131 [00300] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.99 (dd, J = 4.7, 0.9 Hz, 1H), 8.28 (q, J = 5.8 Hz, 1H), 7.72 (ddd, J = 8.9, 2.6, 1.1 Hz, 1H), 7.54 (ddd, J = 9.0, 6.2, 3.0 Hz, 1H), 7.44 (ddt, J = 13.6, 9.2, 3.3 Hz, 4H), 7.35 (ddd, J = 9.2, 2.5, 1.4 Hz, 1H), 4.91 (q, J = 6.6 Hz, 1H), 3.18-3.05 (m, 2H), 1.52 (dd, J = 6.6, 1.4 Hz, 3H), 1.01 (td, J = 7.2, 4.4 Hz, 3H). 100% 132 [00301] embedded image (R,S)- 1L.sub.1_l (300 MHz, DMSO-d.sub.6) δ 8.94 (t, J = 5.1 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.39-7.14 (m, 4H), 5.65-5.53 (m, 1H), 4.44-3.80 (m, 2H), 3.56-3.08 (m, 1H), 3.06- 2.70 (m, 1H), 2.32 (dd, J = 34.5, 7.6 Hz, 1H), 1.98 (d, J = 42.0 Hz, 1H), 1.83-1.12 (m, 6H). 92% 133 [00302] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.30 (s, 1H), 8.89 (dd, J = 7.4, 4.4 Hz, 1H), 7.66 (d, J = 3.2 Hz, 1H), 7.63-7.45 (m, 2H), 7.38-7.25 (m, 3H), 5.56 (dq, J = 28.9, 6.5 Hz, 1H), 4.30 (d, J = 12.6 Hz, 1H), 4.14 (dd, J = 36.9, 13.3 Hz, 1H), 3.09 (dt, J = 42.5, 12.1 Hz, 1H), 2.82- 2.45 (m, 1H), 2.36-2.09 (m, 2H), 2.04 (s, 3H), 1.97- 1.64 (m, 3H), 1.58 (dd, J = 16.0, 6.4 Hz, 3H), 1.41- 1.21 (m, 2H). 100% 134 [00303] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.32 (s, 1H), 8.90 (dd, J = 7.5, 4.5 Hz, 1H), 7.77 (d, J = 5.1 Hz, 1H), 7.74-7.67 (m, 1H), 7.43-7.26 (m, 3H), 7.20 (d, J = 5.1 Hz, 1H), 5.57 (dq, J = 28.1, 6.6 Hz, 1H), 4.30 (d, J = 12.6 Hz, 1H), 4.13 (dd, J = 36.0, 13.4 Hz, 1H), 3.23-2.92 (m, 1H), 2.76-2.47 (m, 1H), 2.36-2.11 (m, 2H), 2.10 (d, J = 1.4 Hz, 3H), 1.86 (q, J = 17.3, 15.2 Hz, 3H), 1.58 (dd, J = 16.1, 6.4 Hz, 3H), 1.33 (d, J = 13.0 Hz, 2H). 100% 135 [00304] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.32 (s, 1H), 8.88 (dd, J = 7.2, 4.5 Hz, 1H), 7.58 (td, J = 7.9, 1.8 Hz, 1H), 7.44 (dt, J = 10.7, 2.9 Hz, 1H), 7.37- 7.12 (m, 6H), 5.64-5.45 (m, 1H), 4.36-3.99 (m, 2H), 3.73 (s, 3H), 3.22- 2.93 (m, 1H), 2.77-2.44 (m, 1H), 2.24 (dt, J = 25.8, 6.7 Hz, 2H), 1.76 (d, J = 42.9 Hz, 3H), 1.57 (dd, J = 15.8, 6.4 Hz, 3H), 1.31 (s, 2H). 100% 136 [00305] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.29 (s, 1H), 8.91 (dd, J = 7.6, 4.4 Hz, 1H), 8.07- 7.97 (m, 1H), 7.94-7.76 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.38-7.16 (m, 4H), 5.65-5.46 (m, 1H), 4.29 (d, J = 12.9 Hz, 1H), 4.12 (dd, J = 35.2, 13.4 Hz, 1H), 3.09 (dt, J = 39.3, 11.4 Hz, 1H), 2.80-2.45 (m, 1H), 2.35-2.09 (m, 2H), 1.96- 1.64 (m, 2H), 1.57 (dd, J = 15.9, 6.4 Hz, 3H), 1.38- 1.24 (m, 2H). 99% 137 [00306] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 12.29 (s, 1H), 8.95 (dd, J = 7.5, 4.4 Hz, 1H), 7.83- 7.55 (m, 4H), 7.48-7.25 (m, 4H), 5.69-5.48 (m, 1H), 4.37-3.98 (m, 2H), 3.24-2.95 (m, 1H), 2.80- 2.46 (m, 1H), 2.34-2.09 (m, 2H), 1.96-1.65 (m, 3H), 1.58 (dd, J = 16.2, 6.4 Hz, 3H), 1.38-1.24 (m, 2H). 100% 138 [00307] embedded image (R)-6G.sub.1 (400 MHz, DMSO-d.sub.6) δ 9.05 (d, J = 4.9 Hz, 1H), 7.44 (s, 1H), 7.39-7.21 (m, 6H), 7.08-6.87 (m, 2H), 5.65- 5.42 (m, 1H), 4.87-3.97 (m, 2H), 3.59-2.60 (m, 3H), 2.29-2.08 (m, 1H), 2.02-1.65 (m, 9H), 1.61- 1.47 (m, 3H). 100% 139 [00308] (gem)-2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 12.08 (s, 1H), 8.87 (d, J = 4.4 Hz, 1H), 7.67 (dt, J = 7.8, 1.5 Hz, 1H), 7.60- 7.43 (m, 3H), 7.35-7.25 (m, 3H), 7.21-7.11 (m, 1H), 4.66-4.44 (m, 1H), 4.41-4.19 (m, 1H), 3.12- 2.33 (m, 2H), 2.18-1.94 (m, 2H), 1.74-1.54 (m, 8H), 1.25-1.21 (m, 1H), 1.17 (d, J = 4.7 Hz, 2H). 93% 140 [00309] embedded image (R)-Et- 2G.sub.1 (400 MHz, DMSO-d.sub.6) δ 9.02 (dd, J = 6.9, 4.8 Hz, 1H), 7.78-7.27 (m, 8H), 5.42- 5.20 (m, 1H), 4.34-3.94 (m, 2H), 3.33-2.71 (m, 1H), 2.65-2.37 (m, 1H), 2.36-1.60 (m, 7H), 1.43- 1.17 (m, 2H), 1.12-0.98 (m, 3H). 100% 141 [00310] (R,R)- 2K.sub.1x (400 MHz, DMSO-d.sub.6) δ 8.94 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.90 (dd, J = 7.7, 7.5 Hz, 1H), 7.75 (dd, J = 7.7, 7.6 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.44- 7.23 (m, 4H), 5.63-5.43 (m, 1H), 4.29-3.95 (m, 2H), 3.14-2.86 (m, 1H), 2.70-2.37 (m, 1H), 2.22- 2.01 (m, 2H), 1.91-1.44 (m, 6H), 1.32-1.14 (m, 2H). 91% 142 [00311] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.88 (dd, J = 7.7, 4.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.63-7.38 (m, 3H), 7.35-7.18 (m, 4H), 5.62- 5.41 (m, 1H), 4.24 (d, J = 12.7 Hz, 1H), 4.18-3.94 (m, 1H), 3.16-2.87 (m, 1H), 2.75-2.40 (m, 1H), 2.33-2.04 (m, 1H), 1.92- 1.60 (m, 4H), 1.52 (dd, J = 16.2, 6.4 Hz, 3H), 1.35- 1.17 (m, 2H). 96% 143 [00312] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.98- 8.88 (m, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.90 (dd, J = 7.7, 7.5 Hz, 1H), 7.75 (dd, J = 7.7, 7.6 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.44-7.23 (m, 4H), 5.63-5.43 (m, 1H), 4.30-3.95 (m, 2H), 3.13-2.88 (m, 1H), 2.71- 2.37 (m, 1H), 2.22-2.00 (m, 2H), 1.93-1.43 (m, 6H), 1.32-1.14 (m, 2H). 91% 144 [00313] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.86 (dd, J = 7.6, 4.5 Hz, 1H), 7.75-7.66 (m, 1H), 7.65- 7.49 (m, 2H), 7.46-7.32 (m, 2H), 7.31-7.16 (m, 3H), 5.60-5.38 (m, 1H), 4.32-3.95 (m, 2H), 3.92 (d, J = 3.3 Hz, 1H), 3.16- 2.89 (m, 1H), 2.70-2.41 (m, 1H), 2.27-2.06 (m, 1H), 1.70 (d, J = 42.7 Hz, 4H), 1.52 (dd, J = 15.5, 6.3 Hz, 3H), 1.25 (s, 2H). 93% 145 [00314] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.66 (dd, J =8.2, 4.5 Hz, 1H), 7.35-7.20 (m, 2H), 7.19- 6.86 (m, 6H), 5.37-5.21 (m, 1H), 3.98 (dd, J = 51.5, 22.6 Hz, 2H), 3.00-2.39 (m, 2H), 2.31-2.17 (m, 6H), 2.07-1.89 (m, 1H), 1.52 (d, J = 44.9 Hz, 4H), 1.35 (dd, J = 17.7, 6.4 Hz, 3H), 1.08 (s, 2H). 97% 146 [00315] embedded image 147 [00316] 148 [00317] 149 [00318] 150 [00319] 151 [00320] (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.92- 8.85 (m, 1H), 8.28 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.77-7.72 (m, 1H), 7.35- 7.14 (m, 4H), 5.61-5.40 (m, 1H), 4.30-3.94 (m, 2H), 3.15-2.89 (m, 1H), 2.70-2.38 (m, 1H), 2.28- 2.00 (m, 2H), 1.94-1.42 (m, 7H), 1.34-1.11 (m, 2H). 97% 152 [00321] embedded image (R,R)- 2K.sub.1x (300 MHz, DMSO-d.sub.6) δ 8.89- 8.82 (m, 1H), 7.53 (t, J = 8.3 Hz, 1H), 7.28-7.14 (m, 6H), 5.59-5.40 (m, 1H), 4.30-3.95 (m, 2H), 3.63 (s, 3H), 3.15-2.54 (m, 2H), 2.33-2.05 (m, 2H), 1.94- 1.43 (m, 6H), 1.36-1.15 (m, 2H). 95% 153 [00322] 154 [00323] 155 [00324] 156 [00325] embedded image 157 [00326] 158 [00327] 159 [00328] 160 [00329] 161 [00330] 162 [00331] 163 [00332] 164 [00333] 165 [00334] 166 [00335] 167 [00336] 168 [00337] 169 [00338] 170 [00339] 171 [00340] 172 [00341] (R)-6G.sub.1 (400 MHz, DMSO-d.sub.6) δ 9.04 (d, J = 4.9 Hz, 1H), 7.44 (d, J = 4.9 Hz, 1H), 7.38-7.15 (m, 6H), 7.05-6.85 (m, 2H), 5.60-5.33 (dd, J = 48.4, 6.8 Hz, 1H), 4.88- 4.00 (m, 2H), 3.33-3.05 (m, 1H), 2.91-2.77 (m, 1H), 2.72-2.56 (m, 1H), 2.25- 2.09 (m, 1H), 1.93-1.60 (m, 8H), 1.58-1.32 (m, 4H). 97% 173 [00342] embedded image (R)-9G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.96- 8.88 (m, 1H), 7.82-7.20 (m, 6H), 5.81-5.47 (m, 1H), 4.18-3.94 (m, 1H), 3.80-3.06 (m, 3H), 2.95- 2.59 (m, 1H), 2.19-1.23 (m, 7H), 1.17-0.91 (m, 2H). 92% ee98% 174 [00343] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.40-7.06 (m, 6H), 5.59-5.40 (m, 1H), 3.78-3.40 (m, 3H), 1.90-1.66 (m, 9H), 1.63- 1.40 (m, 5H), 1.26-0.71 (m, 3H). 98% ee 96% (methyl- group) 175 [00344] embedded image (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 3.6 Hz, 1H), 7.29 (d, J = 10.1 Hz, 1H), 7.20- 7.14 (m, 3H), 7.10 (d, J = 9.8 Hz, 2H), 5.66-5.42 (m, 1H), 4.01-3.58 (m, 2H), 3.50-3.13 (m, 2H), 2.08- 1.77 (m, 7H), 1.69-1.37 (m, 6H), 1.22-0.93 (m, 3H). 99% ee100% 176 [00345] (R)-8G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.90- 8.86 (m, 1H), 7.30-7.06 (m, 6H), 5.49 (q, J = 6.4 Hz, 1H), 4.75-4.33 (m, 1H), 4.31-3.88 (m, 1H), 3.21- 2.68 (m, 1H), 1.87-1.80 (m, 6H), 1.76-1.37 (m, 10H), 1.27-1.02 (m, 2H). 99% 177 [00346] embedded image (R)- 9F.sub.1_Et (400 MHz, DMSO-d.sub.6) δ 8.97- 8.91 (m, 1H), 7.83-7.73 (m, 2H), 7.44-7.19 (m, 4H), 5.63-5.45 (m, 1H), 3.80-3.40 (m, 4H), 1.87- 1.40 (m, 8H), 1.27-0.71 (m, 2H). 96% 178 [00347] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.21-7.14 (m, 3H), 7.10 (d, J = 10.0 Hz, 2H), 5.52 (q, J = 6.5 Hz, 1H), 3.80-3.37 (m, 8H), 1.85 (s, 3H), 1.83 (s, 3H), 1.51 (d, J = 6.5 Hz, 3H). 98% ee 92% 179 [00348] embedded image (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.87 (d, J = 4.4 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.20-7.07 (m, 5H), 5.51 (q, J = 6.5 Hz, 1H), 4.41-4.28 (m, 4H), 3.68-3.34 (m, 4H), 1.94- 1.68 (m, 4H), 1.84 (s, 3H), 1.82 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H). 98% ee92% 180 [00349] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.41-7.06 (m, 6H), 5.56-5.40 (m, 1H), 5.18-5.06 (m, 1H), 4.54-4.34 (m, 1H), 4.22- 3.89 (m, 1H), 3.17-2.88 (m, 1H), 1.91-1.64 (m, 8H), 1.60-1.39 (m, 4H), 1.36-0.87 (m, 2H), 0.57- 0.19 (m, 4H). 95% ee92% (methyl group) 181 [00350] embedded image (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.92- 8.85 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.34-7.06 (m, 6H), 5.58-5.47 (m, 1H), 4.21-4.00 (m, 2H), 3.44- 3.14 (m, 3H), 3.03-2.87 (m, 1H), 2.08-1.94 (m, 2H), 1.85 (s, 3H), 1.83 (s, 3H), 1.67-1.33 (m, 7H). 98% 182 [00351] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.40-7.07 (m, 6H), 5.54-5.45 (m, 1H), 4.39 (d, J = 12.4 Hz, 1H), 4.17-3.98 (m, 1H), 3.25-2.88 (m, 1H), 2.68- 2.41 (m, 1H), 1.89-1.81 (m, 6H), 1.79-1.18 (m, 9H), 1.09-0.59 (m, 3H). 99% 183 [00352] embedded image (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.90- 8.81 (m, 1H), 7.29-7.06 (m, 6H), 5.55-5.40 (m, 1H), 4.29-3.96 (m, 3H), 3.15-2.91 (m, 1H), 2.70- 2.43 (m, 1H), 2.24-2.03 (m, 2H), 1.91-1.40 (m, 12H), 1.33-1.17 (m, 1H). 95% ee 97% 184 [00353] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.84 (m, 1H), 7.63-7.06 (m, 6H), 5.74-5.43 (m, 1H), 4.17-3.93 (m, 1H), 3.80-3.10 (m, 2H), 2.98- 2.65 (m, 1H), 2.18-1.70 (m, 8H), 1.67-1.23 (m, 6H), 1.18-0.90 (m, 2H). 99% ee96% (methyl group) 185 [00354] embedded image (R)-8G.sub.1 (300 MHz, Chloroform-d) δ 8.91-8.71 (m, 1H), 7.62- 7.45 (m, 1H), 7.35-7.08 (m, 3H), 6.90 (d, J = 9.4 Hz, 2H), 5.25 (q, J = 6.6 Hz, 1H), 4.59-4.19 (m, 2H), 3.57-3.42 (m, 1H), 3.09- 2.90 (m, 1H), 2.56-2.40 (m, 1H), 2.19-1.51 (m, 16H). 97% 186 [00355] (R)-8G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.40-7.07 (m, 6H), 5.55-5.34 (m, 1H), 4.49-4.35 (m, 1H), 4.15-3.92 (m, 1H), 2.98- 2.65 (m, 1H), 3.13-2.81 (m, 1H), 2.48-2.28 (m, 1H), 1.90-1.44 (m, 12H), 1.38-0.91 (m, 7H). 97% 187 [00356] embedded image (R)-8G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.90- 8.86 (m, 1H), 7.30-7.06 (m, 6H), 5.49 (q, J = 6.4 Hz, 1H), 4.75-4.32 (m, 1H), 4.31-3.88 (m, 1H), 3.20- 2.68 (m, 1H), 1.88-1.79 (m, 6H), 1.76-1.36 (m, 10H), 1.27-1.02 (m, 2H). 99% 188 [00357] (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.96- 8.86 (m, 1H), 7.83-7.73 (m, 2H), 7.41-7.19 (m, 4H), 5.73-5.45 (m, 1H), 4.46-4.02 (m, 4H), 2.07- 1.80 (m, 1H), 1.68-1.35 (m, 6H), 1.27-0.91 (m, 3H). 96% ee96% 189 [00358] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.90- 8.83 (m, 1H), 7.72-7.18 (m, 7H), 5.78-5.42 (m, 1H), 4.24-3.90 (m, 2H), 3.80-3.06 (m, 1H), 2.97- 2.58 (m, 1H), 2.19-0.85 (m, 10H). 95% ee100% 190 [00359] (R)-6G.sub.1 (300 MHz, DMSO-d.sub.6) δ 9.03 (dd, J = 6.9, 4.1 Hz, 1H), 7.49-7.17 (m, 8H), 7.04 (d, J = 6.5 Hz, 1H), 6.85 (d, J = 3.5 Hz, 1H), 5.64-5.35 (m, 1H), 4.36- 3.88 (m, 2H), 3.38-2.18 (m, 5H), 2.01 (s, 2H), 1.84 (d, J = 7.6 Hz, 7H), 1.65 (d, J = 19.8 Hz, 1H), 1.58- 1.34 (m, 5H). 91% 191 [00360] embedded image (R)-8G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.91- 8.86 (m, 1H), 7.34-7.07 (m, 6H), 5.56-5.30 (m, 1H), 4.69-4.07 (m, 2H), 2.04-1.76 (m, 7H), 1.69- 1.41 (m, 9H), 1.32-1.11 (m, 5H). 96% 192 [00361] (R)-9G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.95- 8.90 (m, 1H), 7.81-7.73 (m, 2H), 7.40-7.22 (m, 4H), 5.59-5.43 (m, 1H), 4.29-3.94 (m, 2H), 3.13- 2.90 (m, 1H), 2.69-2.40 (m, 1H), 2.23-2.00 (m, 2H), 1.92-1.46 (m, 6H), 1.33-1.17 (m, 2H). 98% ee100% 193 [00362] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.87 (m, 1H), 7.71-7.19 (m, 7H), 5.60-5.44 (m, 1H), 3.77-3.32 (m, 4H), 1.86-1.40 (m, 8H), 1.30- 0.73 (m, 2H). 99% ee 99% (methyl group) 194 [00363] (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.91- 8.87 (m, 1H), 7.72-7.20 (m, 7H), 5.57-5.46 (m, 1H), 4.44-4.00 (m, 2H), 3.19-2.56 (m, 2H), 1.84- 1.20 (m, 8H), 1.09-0.67 (m, 4H). 98% 195 [00364] embedded image (R)-9G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.96- 8.90 (m, 1H), 7.82-7.73 (m, 2H), 7.41-7.20 (m, 4H), 5.59-5.30 (m, 1H), 4.48-3.95 (m, 2H), 3.13- 2.81 (m, 1H), 2.53-2.27 (m, 1H), 1.89-1.20 (m, 8H), 1.16-0.80 (m, 6H). 96% ee100% (methyl group) 196 [00365] (R)-9G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.95- 8.90 (m, 1H), 7.82-7.73 (m, 2H), 7.43-7.21 (m, 4H), 5.58-5.48 (m, 1H), 4.42-4.03 (m, 2H), 3.26- 2.88 (m, 1H), 2.69-2.40 (m, 1H), 1.86-1.20 (m, 8H), 1.08-0.67 (m, 4H). 98% ee100% (methyl group) 197 [00366] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.92- 8.84 (m, 1H), 7.73-7.66 (m, 1H), 7.56-7.18 (m, 6H), 5.60-5.29 (m, 1H), 4.49-4.32 (m, 1H), 4.17- 3.93 (m, 1H), 3.14-2.77 (m, 1H), 2.45-2.24 (m, 1H), 1.89-1.19 (m, 8H), 1.15-0.78 (m, 6H). 98% ee100% 198 [00367] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.3 Hz, 1H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 7.56-7.37 (m, 2H), 7.35- 7.18 (m, 4H), 5.77-5.42 (m, 1H), 4.03-3.62 (m, 2H), 3.42-3.03 (m, 2H), 2.05-1.32 (m, 7H), 1.19- 0.89 (m, 3H). 95% ee100% 199 [00368] embedded image (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.93 (d, J = 4.3 Hz, 1H), 7.83- 7.73 (m, 2H), 7.41-7.19 (m, 4H), 5.58-5.47 (m, 1H), 4.73-4.32 (m, 1H), 4.30-3.87 (m, 1H), 3.21- 2.68 (m, 1H), 1.77-1.33 (m, 10H), 1.27-1.00 (m, 2H). 99% 200 [00369] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.92- 8.85 (m, 1H), 7.69 (dd, J = 9.0, 1.4 Hz, 1H), 7.55- 7.38 (m, 2H), 7.35-7.15 (m, 4H), 5.59-5.33 (m, 1H), 4.75-3.91 (m, 2H), 3.21-2.63 (m, 1H), 1.84- 1.01 (m, 12H). 95% 201 [00370] embedded image (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.94 (d, J = 4.4 Hz, 1H), 7.82- 7.75 (m, 2H), 7.41-7.35 (m, 3H), 7.25 (dd, J = 9.1, 2.6 Hz, 1H), 5.60-5.52 (m, 1H), 3.80-3.35 (m, 8H), 1.51 (d, J = 6.5 Hz, 3H). 99% ee92% 202 [00371] (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.97- 8.91 (m, 1H), 7.83-7.60 (m, 3H), 7.41-7.29 (m, 3H), 7.24 (dd, J = 9.1, 2.5 Hz, 1H), 5.62-5.51 (m, 1H), 4.22-3.97 (m, 2H), 3.44-2.84 (m, 4H), 2.08- 1.93 (m, 2H), 1.83-1.22 (m, 7H). 98% ee100% 203 [00372] embedded image (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.96- 8.89 (m, 1H), 7.84-7.73 (m, 2H), 7.41-7.19 (m, 4H), 5.61-5.43 (m, 1H), 5.18-5.05 (m, 1H), 4.53- 3.96 (m, 2H), 3.18-2.88 (m, 1H), 2.55-2.37 (m, 1H), 1.85-1.64 (m, 2H), 1.59-0.85 (m, 6H), 0.58- 0.12 (m, 4H). 99% ee100% (methyl group) 204 [00373] embedded image (R)-9G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.98- 8.80 (m, 1H), 7.85-7.73 (m, 2H), 7.43-7.14 (m, 4H), 5.62-5.37(m, 1H), 4.75-4.45 (m, 1H), 4.31- 3.96 (m, 1H), 3.31-2.64 (m, 1H), 1.87-1.42 (m, 8H), 1.35-1.02 (m, 4H). 99% 205 [00374] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.92- 8.85 (m, 1H), 7.72-7.20 (m, 8H), 5.61-5.48 (m, 1H), 4.21-3.97 (m, 2H), 3.46-3.14 (m, 3H), 3.04- 2.83 (m, 1H), 2.08-1.94 (m, 2H), 1.82-1.21 (m, 7H) 95% ee100% 206 [00375] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 7.70 (dd, J = 8.9, 1.9 Hz, 1H), 7.56-7.38 (m, 2H), 7.36- 7.30 (m, 2H), 7.29 (d, J = 4.4 Hz, 1H), 7.23 (dd, J = 9.2, 2.5 Hz, 1H), 5.60- 5.50 (m, 1H), 3.82-3.35 (m, 8H), 1.51 (d, J = 6.5 Hz, 3H). 95% 207 [00376] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.69 (dd, J = 8.9, 1.1 Hz, 1H), 7.56- 7.38 (m, 2H), 7.37-7.17 (m, 4H), 5.60-5.41 (m, 1H), 5.16-5.04 (m, 1H), 4.54-3.97 (m, 2H), 3.15- 2.86 (m, 1H), 2.54-2.37 (m, 1H), 1.86-0.86 (m, 8H), 0.59-0.11 (m, 4H). 95% 208 [00377] embedded image (R)-9G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.92 (d, J = 4.4 Hz, 1H), 7.82- 7.73 (m, 2H), 7.40-7.30 (m, 3H), 7.23 (dd, J = 9.1, 2.2 Hz, 1H), 5.58-5.51 (m, 1H), 4.40-4.29 (m, 4H), 3.66-3.32 (m, 4H), 1.93- 1.66 (m, 4H), 1.49 (d, J = 6.4 Hz, 3H). 97% ee92% 209 [00378] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 9.83- 9.58 (m, 1H), 8.88 (dd, J = 8.9, 4.4 Hz, 1H), 7.68 (dd, J = 8.8, 2.1 Hz, 1H), 7.57- 7.38 (m, 2H), 7.36-7.19 (m, 4H), 5.61-5.46 (m, 1H), 4.36-3.96 (m, 3H), 3.02- 2.63 (m, 1H), 2.02-1.97 (m, 3H), 1.87-1.77 (m, 4H), 1.58-1.22 (m, 4H). 98% 210 [00379] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.87 (d, J = 4.4 Hz, 1H), 7.70 (dd, J = 8.3, 2.2 Hz, 1H), 7.55-7.37 (m, 2H), 7.34- 7.19 (m, 4H), 5.59-5.48 (m, 1H), 4.40-4.28 (m, 4H), 3.69-3.33 (m, 4H), 1.94-1.64 (m, 4H), 1.48 (d, J = 6.4 Hz, 3H). 95% 211 [00380] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.91- 8.85 (m, 1H), 7.72-7.66 (m, 1H), 7.56-7.19 (m, 6H), 5.57-5.34 (m, 1H), 4.69-4.56 (m, 1H), 4.54- 4.15 (m, 1H), 2.01-1.40 (m, 10H), 1.33-1.04 (m, 5H). 94% 212 [00381] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.3 Hz, 1H), 7.72- 7.65 (m, 1H), 7.57-7.18 (m, 6H), 5.75-5.44 (m, 1H), 4.56-3.83 (m, 6H), 3.72-3.47 (m, 2H), 2.01- 1.70 (m, 2H), 1.67-1.34 (m, 5H). 95% 213 [00382] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.90- 8.86 (m, 1H), 7.69 (66, J = 8.9, 2.0 Hz, 1H), 7.55- 7.38 (m, 2H), 7.35-7.19 (m, 4H), 5.36-5.22 (m, 1H), 4.63-4.40 (m, 4H), 4.04-3.33 (m, 3H), 3.17 (d, J = 5.2 Hz, 1H), 2.30- 2.00 (m, 2H), 1.55-1.43 (m, 3H). 95% 214 [00383] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.90- 8.80 (m, 1H), 7.69 (dd, J = 8.7, 1.9 Hz, 1H), 7.54- 7.39 (m, 2H), 7.35-7.20 (m, 4H), 5.97-5.94 (m, 1H), 5.59-5.54 (m, 1H), 5.32-5.21 (m, 1H), 4.21- 3.98 (m, 1H), 3.93-3.75 (m, 1H), 3.60-3.39 (m, 2H), 3.29-3.06 (m, 1H), 2.16-1.93 (m, 1H), 1.84- 1.59 (m, 1H), 1.50-1.48 (m, 3H), 1.21-1.20 (m, 9H). 95% 215 [00384] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.4 Hz, 1H), 7.72- 7.66 (m, 1H), 7.55-7.47 (m, 1H), 7.46-7.19 (m, 5H), 5.50 (q, J = 6.3 Hz, 1H), 3.57-3.43 (m, 2H), 3.25-3.15 (m, 1H), 2.91 (d, J = 12.4, 4.4 Hz, 1H), 1.65 (bs, 1H), 1.52 (d, J = 6.3 Hz, 3H), 1.30-1.20 (m, 3H), 1.10-0.95 (m, 9H). 95% 216 [00385] embedded image (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 10.10-9.29 (m, 3H), 9.23- 9.12 (m, 1H), 7.84-7.41 (m, 4H), 5.83-5.54 (m, 1H), 4.50-4.00 (m, 3H), 3.66-2.68 (m, 4H), 1.61- 1.12 (m, 10H). 95% 217 [00386] (R)-4G.sub.1 (300 MHz, DMSO-d.sub.6) δ 8.89 (d, J = 4.4 Hz, 1H), 7.69 (dd, J = 8.9, 2.3 Hz, 1H), 7.52 (dd, J = 8.4, 6.4 Hz, 1H), 7.42 (dt, J = 8.5, 2.4 Hz, 1H), 7.35-7.17 (m, 4H), 5.41-5.03 (m, 1H), 4.93-4.50 (m, 1H), 3.71- 3.36 (m, 2H), 3.09-2.35 (m, 4H), 1.78-0.89 (m, 5H). 90% 218 [00387] embedded image (R)-4G.sub.1 (300 MHz, Chloroform-d) δ 8.88 (d, J = 4.6 Hz, 1H), 7.57 (bs, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.36-7.27 (m, 2H), 7.25-7.11 (m, 3H), 4.93 (q, J = 6.7 Hz, 1H), 4.87 (d, J = 7.0 Hz, 1H), 4.82 (d, J = 7.0 Hz, 1H), 4.77-4.69 (m, 1H), 4.73 (d, J = 7.0 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 11.0 Hz, 1H), 4.16 (d, J = 11.0 Hz, 1H), 1.65 (d, J = 6.7 Hz, 3H). 95% 219 [00388] embedded image (R)-4G.sub.1 (400 MHz, DMSO-d.sub.6) δ 8.88 (d, J = 4.2 Hz, 1H), 7.69 (ddd, J = 8.9, 2.6, 1.4 Hz, 1H), 7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.42 (tdd, J = 8.5, 2.6, 1.8 Hz, 1H), 7.37- 7.17 (m, 4H), 7.00-6.92 (m, 1H), 5.68-5.48 (m, 1H), 4.45-3.98 (m, 2H), 3.84-3.48 (m, 3H), 2.47- 2.18 (m, 2H), 1.59-1.45 (m, 3H). 100% ee94% 220 [00389] embedded image (R)-9G.sub.4 (400 MHz, DMSO-d.sub.6) δ 9.05- 9.02 (m, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.45-7.42 (m, 1H), 7.16 (d, J = 8.9 Hz, 1H), 5.99-5.86 (m, 1H), 4.24-3.98 (m, 2H), 3.16- 2.70 (m, 2H), 2.32-1.63 (m, 6H), 1.55-1.24 (m, 5H). 95% ee90% 221 [00390] (R)-8G.sub.4 (400 MHz, DMSO-d.sub.6) δ 9.00- 8.96 (m, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.31-7.28 (m, 1H), 7.13-7.08 (m, 3H), 5.99-5.86 (m, 1H), 4.24- 3.91 (m, 2H), 3.17-2.64 (m, 2H), 2.46-2.07 (m, 3H), 1.93-1.82 (m, 8H), 1.71- 1.46 (m, 6H). 97% ee96%
The IUPAC chemical names for the compounds shown in Table 6 are provided in Table 7 below.

4. Homogeneous TR-FRET Assay for HTS and Activity Determination

[1218] The TR-FRET assay was basically conducted as described in WO2016/193231A1, especially as described in example 1 (hereby incorporated by reference). With respect to the back ground of the mitochondrial transcription it is referred to Falkenberg et al. (2002) and Posse et al. (Posse et al., 2015). The method monitors the activity of mitochondrial RNA-polymerase via detection of the formation of its product, a 407 bp long RNA sequence. Detection of the product is facilitated by hybridization of two DNA-oligonucleotide probes to specific and adjacent sequences within the RNA product sequence. Upon annealing of the probes, two fluorophores that are coupled directly to an acceptor nucleotide probe (ATT0647, 5′) or introduced via a coupled streptavidin interacting with a biotinylated donor nucleotide probe on the other side (Europium cryptate, 3′) are brought into sufficient proximity to serve as a fluorescence-donor-acceptor pair as generally described in Walters and Namchuk (2003). Thus, a FRET signal at 665 nm is generated upon excitation at 340 nm.

[1219] Briefly, the protocol described here was applied for screening and activity determination in a low-volume 384-well microtiter plate with non-binding surface. For high-throughput application in the 1536-well microtiter plate format, volumes of the reagent mixes were adjusted, maintaining the volumetric ratio. Proteins POLRMT (NM_172551.3), TFAM (NM_009360.4) and TFB2M (NM_008249.4) were diluted from their stocks to working concentrations of 150 nM, 1.8 μM and 330 nM respectively, in a dilution buffer containing 100 mM Tris-HCl pH 8.0, 200 mM NaCl, 10% (v/v) glycerole, 2 mM glutathione (GSH), 0.5 mM EDTA and 0.1 mg/mL BSA. Protein dilutions and template DNA, comprising a pUC18 plasmid encoding the mitochondrial light strand promoter, restriction linearized proximal to the promoter 3′-end (pUC-LSP), were mixed at the twofold final assay-concentration in a reaction buffer, containing 10 mM Tris-HCl pH 7.5, 10 mM MgCl.sub.2, 40 mM NaCl, 2 mM GSH, 0.01% (w/v) Tween-20 and 0.1 mg/mL BSA.

[1220] 5 μL of this mix were dispensed, depending on the chosen microtiter plate format, using multi-channel pipettes or a Multidrop® dispenser (Thermo Fisher Scientific, Waltham Mass.) into the wells of a microtiter plate and incubated at room temperature (rt) for 10 min. Chemical compounds under scrutiny in the assay were applied using contact-free acoustic droplet-dispensing (Echo520® Labcyte Inc., Sunnyvale Calif.) from 10 mM compound stocks in 100% DMSO, to a final concentration of 10 μM or in serial dilution series of the required concentration range. Equal amounts of DMSO without any compound were added to positive control samples, followed by an incubation step at rt for 10 min.

[1221] The enzymatic reaction was started by the addition of 5 μL of a mix of dNTPs in reaction buffer to a final concentration of 500 μM each. No nucleotide mix was added to negative control samples. The content of the wells was mixed using a VarioTeleshaker™ (Thermo Fisher Scientific, Waltham Mass.) at 1500 rpm for 45 sec after which the microtiter plate was centrifuged at 500×g for 1 min. The samples were incubated for 2 h at rt with humidity control to avoid evaporation. The detection reagents were prepared in a buffer that was composed, such that the enzymatic reaction was terminated due to chelating of Mg-ions and increased ionic strength, containing 50 mM Tris-HCl pH 7.5, 700 mM NaCl, 20 mM EDTA, and 0.01% (w/v) Tween-20. Importantly Eu-cryptate-coupled streptavidin had to be preincubated with a 100-fold molar excess of a random sequence oligonucleotide for 10 min at rt in the dark to block unspecific binding of single stranded RNA to the protein. Subsequently, the blocked streptavidin(-Eu) was mixed with the DNA-probes on ice and kept away from light until use.

[1222] At the end of the enzymatic reaction time 10 μL detection reagent mix was added, such that the final concentration of fluorescent-donor probe (bio-5′-AACACATCTCT(-bio)GCCAAACCCCA-bio-3′), fluorescent-acceptor probe (ATTO647N-5′-ACAAAGAACCCTAACACCAG-3′) and streptavidin(-Eu) in each assay well was 1 nM, 3 nM, and 1 nM respectively. Assay plates were again mixed and centrifuged as above and stored at rt, protected from light for at least 2 h or until binding of the DNA probes to RNA product and binding of streptavidin(-Eu) to the biotinylated DNA probe led to the development of the maximal FRET signal. The generated signal was measured with an EnVision plate reader, including TRF light unit (Perkin Elmer, Waltham Mass.), using excitation at 320 nm, an integration time of 200 μs and a delay time of 100 μs, prior to detection at 620 nm and 665 nm. The ratio of donor- and acceptor-fluorescence was used to assess the specific FRET signal, as a measure of the generated product content (i.e. enzymatic activity).

5. Quantitative Real Time-PCR to Assess Cellular Activity

[1223] Quantitative real-time PCR (qRT-PCR), based on the TaqMan™ (Thermo Fisher Scientific, Waltham Mass.) technology, was carried out essentially as described in Held et al. (1996). HeLa cells were plated one day before compound treatment in RPMI medium supplemented with 10% Fetal Calf Serum and 2 mM L-glutamine. Cells were incubated with dilution series of compounds or vehicle (DMSO) for 4 h, prior to harvest and extraction of the RNA using the RNeasy Mini Kit (Qiagen, Hilden D), according to the manufacturer's instructions. RNA concentrations were measured spectroscopically, using a NanoDrop-2000 (Thermo Fisher Scientific, Waltham Mass.) and normalized prior to cDNA synthesis, using a ‘High-Capacity cDNA Reverse Transcription Kit’ (Thermo Fisher Scientific, Waltham Mass.). qRT-PCR was carried out using the ‘TaqMan Fast Advance Master Mix’ (Thermo Fisher Scientific, Waltham Mass.) on a 7500 Fast Real-Time PCR machine (Applied Biosystems, Foster City Calif.)

[1224] For these measurements, three genes were used to compare the effect of the scrutinized compounds in relation to their concentration. The POLRMT-gene was used to detect potential influences on nuclear transcription. Mitochondrial transcription in vivo was monitored by measurements 7S RNA. The TBP (TATA-box binding protein) gene was employed as the control (housekeeping gene) during qRT-PCR. The short-lived mitochondrial 7S RNA, which is not post-transcriptionally stabilized, allowed us to monitor rapid changes in mitochondrial transcription activity following compound addition. Biological triplicates were analyzed using the comparative CT Method (ΔΔCt) method (Bubner and Baldwin, 2004) and reported as Rq % values (Rq=Relative quantification=2−ΔΔCt).

6. Biological Activities of Compounds

[1225] Activities of compounds are listed in Table 7 together with compound number and IUPAC names as determined by the homogeneous TR-FRET assay for mitochondrial transcription activity according to Example 4 and the quantitative real time-PCR assay of inhibition of mitochondrial transcription according to Example 5 were grouped according to the following scheme:

TABLE-US-00007 mitochondrial transcription <20 nM 20 nM ≤ x < 100 nM 100 nM ≤ x < 1 μM 1μM ≤ x < 10 μM activity (IC-50) +++ ++ + (+) cellular qPCR assay <10 nM 10 nM ≤ x < 50 nM 50 nM ≤ x < 500 nM 500 nM ≤ x < 5 μM IMT (IC-50) +++ ++ + (+)

Table 7—IUPAC Chemical Names and Biological Activities

[1226]

TABLE-US-00008 mitochon- drial transcrip- cellular tion qPCR Ex IUPAC Name activity assay 1 (3S)-1-[(2R)-2-[[4-(o-tolyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 2 (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 3 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ +++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 4 ethyl (3S)-1-[(2R)-2[[4-(2,6-dimethylphenyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3-carboxylate 5 2-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ +++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 6 ethyl 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)- +++ 7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate (3R)-1-[(2R)-2-[[4-(2-chlorophenyl)-7- 7 quinolyl]oxy]propanoyl]piperidine-3-carboxylic +++ +++ acid (formic acid salt) 8 ethyl 2-[(3R)-1-[(2R)-2-[[4-(o-tolyl)-7- +++ + quinolyl]oxy]propanoyl]-3-piperidyl]acetate 9 (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid (formic acid salt) 10 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- +++ ++ quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid (formic acid salt) 11 (2R)-2[[4-(2-chloro-4-fluoro-phenyl)-7- +++ + quinolyl]oxy]-1-[(3S)-3-(2H-tetrazol-5-yl)-1- piperidyl]propan-1-one 12 (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-2-fluoro-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid (trifluoroacetic acid salt) 13 2-[(3R)-1-[(2R)-2-[[4-(o-tolyl)-7- ++ ++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid (formic acid salt) 14 ethyl (3S)-1-[(2R)-2-[[4-(o-tolyl)-7- ++ + quinolyl]oxy]propanoyl]piperidine-3-carboxylate 15 ethyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- ++ + phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetate 16 2-[(3R)-1-[(2R)-2-[[4-(2-chlorophenyl)-7- ++ + quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid (formic acid salt) 17 (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ + quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 18 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- ++ + 7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid (formic acid salt) 19 (3S)-1-[(2R)-2[[4-(2-chloro-4-fluoro-phenyl)- ++ + 7-quinolyl]oxy]propanoyl]pyrrolidine-3- carboxylic acid 20 (2R)-2[[4-(2-chloro-4-fluoro-phenyl)-7- ++ ++ quinolyl]oxy]-1-(1-piperidyl)propan-1-one (formic acid salt) 21 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(o-tolyl)-7- ++ (+) quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 22 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- ++ + 7-quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 23 rac-(3S)-1-[2-[[4-(2-chlorophenyl)-7- ++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 24 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ + quinolyl]oxy]propanoyl]piperidine-4- carboxylic acid 25 (3S)-1-[(2R)-2-[[2-chloro-4-(o-tolyl)-7- ++ ++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 26 3-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ + quinolyl]oxy]propanoyl]amino]benzoic acid 27 ethyl (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- ++ (+) phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylate 28 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-(4-propanoylpiperazin-1- yl)propan-1-one 29 tert-butyl (2R)-2-[[4-(2-chlorophenyl)-7- + +++ quinolyl]oxy]propanoate 30 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]propanoyl]piperidine-3-carbonitrile 31 (3S)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7- + +++ quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid (trifluoroacetic acid salt) 32 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-N-isopropyl-N-methyl- propanamide 33 1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + +++ quinolyl]oxy]propanoyl]piperidine-3-sulfonamide 34 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- + ++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 35 (3S)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2-methyl- + +++ phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 36 isopropyl (2R)-2-[[4-(2-chlorophenyl)-7- + + quinolyl]oxy]propanoate (formic acid salt) 37 methyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4- + fluoro-phenyl)-7- quinolyl]oxy]propanoyl]pyrrolidin-3-yl]acetate 38 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- + ++ 7-quinolyl]oxy]propanoyl]-N-methyl- piperidine-3-carboxamide 39 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + + phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin- 3-yl]acetic acid 40 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + + phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin- 3-yl]acetic acid 41 ethyl (3S)-1-[(2R)-2-[[4-(2-chlorophenyl)-2- + (+) fluoro-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylate 42 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-1-pyrrolidin-1-yl-propan-1-one 43 (2R)-2-[[2-chloro-4-(o-tolyl)-7- + quinolyl]oxy]propanoic acid 44 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + quinolyl]oxy]propanoic acid 45 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-N,N-dimethyl-propanamide (formic acid salt) 46 (3S)-1-[2-[[4-(2-chlorophenyl)-7- + + quinolyl]oxy]acetyl]piperidine-3-carboxylic acid (formic acid salt) 47 (2R)-N-tert-butyl-2-[[4-(2-chloro-4-fluoro- + ++ phenyl)-7-quinolyl]oxy]propanamide 48 (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]-N- + + isopropyl-propanamide (formic acid salt) 49 ethyl 2-[(3R)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)- + ++ 7-quinolyl]oxy]propanoyl]-3-piperidyl]acetate 50 ethyl (2R)-2-[[4-(2-chlorophenyl)-7- + ++ quinolyl]oxy]propanoate 51 ethyl 4-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- + 7-quinolyl]oxy]propanoyl]amino]benzoate 52 (3S)-1-[(2R)-2-[[2-chloro-4-(o-tolyl)-7- + ++ quinolyl]oxy]propanoyl]piperidine-3- carboxamide 53 (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]- + ++ 1-(1-piperidyl)propan-1-one 54 methyl 3-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- + 7-quinolyl]oxy]propanoyl]amino]cyclobutane- carboxylate 55 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-1-piperazin-1-yl-propan-1-one (trifluoroacetic acid salt) 56 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4- + + fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 57 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2- + + methyl-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 58 ethyl 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + quinolyl]oxy]propanoyl]piperidine-4-carboxylate 59 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-2- + ++ methyl-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 60 4-[[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]propanoyl]amino]benzoic acid (trifluoroacetic acid salt) 61 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-N-isopropyl-propanamide 62 (3S)-1-[2-[[5-(2-chloro-4-fluoro-phenyl)-1,8- + ++ naphthyridin-2-yl]oxy]propanoyl]piperidine-3- carboxylic acid 63 4-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]propanoyl]piperazin-2-one 64 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro- + + phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 65 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-3-fluoro- ++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 66 (3S)-1-[(2R)-2-[(4-phenyl-7- + ++ quinolyl)oxy]propanoyl]piperidine-3- carboxylic acid 67 methyl 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidin-3- yl]acetate 68 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)- + + 7-quinolyl]oxy]propanoyl]-3-piperidyl]-N- methyl-acetamide 69 2-[(3R)-1-[(2R)-2-[[2-methyl-4-(o-tolyl)-7- + ++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid (trifluoroacetic acid salt) 70 (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- + (+) quinolyl]oxy]-1-[4- (cyclopropanecarbonyl)piperazin- 1-yl]propan-1-one 71 methyl (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + phenyl)-7-quinolyl]oxy]propanoyl]piperidine- 3-carboxylate 72 (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- + quinolyl]oxy]-1-(4-propanoylpiperazin-1- yl)propan-1-one 73 tert-butyl (2R)-2-[[2-chloro-4-(o-tolyl)-7- + + quinolyl]oxy]propanoate 74 ethyl 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + + phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetate 75 ethyl (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- + phenyl)-7-quinolyl]oxy]propanoyl]pyrrolidine- 3-carboxylate 76 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)- + ++ 7-quinolyl]oxy]propanoyl]piperidine- 3-carboxamide 77 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-N-cyclopropyl-propanamide 78 (3S)-1-[(2S)-2-[[4-(2-chlorophenyl)-7- + (+) quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid (formic acid salt) 79 2-[(3R)-1-[(2R)-2-[[4-(2-methyl-3-thienyl)-7- + + quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 80 2-[rac-(3R)-1-[2-[[5-(2-chloro-4-fluoro-phenyl)- (+) + 1,8-naphthyridin-2-yl]oxy]propanoyl]-3- piperidyl]acetic acid 81 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4-fluoro- (+) + phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxamide 82 isopropyl 2-[[4-(2-chlorophenyl)-7- (+) quinolyl]oxy]acetate (formic acid salt) 83 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2- (+) (+) chlorophenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 84 (3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 85 (2R)-1-[4-(2-aminoacetyl)piperazin-1-yl]- (+) 2-[[2-chloro-4-(2-chlorophenyl)-7- quinolyl]oxy]propan- 1-one (trifluoroacetic acid salt) 86 2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]- (+) + N,N-dimethyl-propanamide 87 ethyl (3S)-1-[2-[[4-(2-chlorophenyl)-7- (+) quinolyl]oxy]acetyl]piperidine-3-carboxylate 88 (2R)-2-[[4-(2-chlorophenyl)-7-quinolyl]oxy]- (+) + N,N-dimethyl-propanamide (formic acid salt) 89 ethyl 2-[(3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- (+) phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetate 90 (2R)-2-[[4-(2-chlorophenyl)-2-fluoro-7- (+) quinolyl]oxy]propanoic acid (trifluoroacetic acid salt) 91 (2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)-7- (+) quinolyl]oxy]propanoic acid 92 ethyl 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2- (+) chlorophenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetate 93 ethyl 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4- (+) fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetate 94 ethyl (3S)-1-[(2R)-2-[[2-chloro-4-(4-fluoro-2- (+) methyl-phenyl)-7- quinolyl]oxy]propanoyl]piperidine-3-carboxylate 95 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-N-(4-pyridyl)propanamide (trifluoroacetic acid salt) 96 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- (+) quinolyl]oxy]propanoyl]-N-methyl-piperidine-3- carboxamide 97 methyl 3-[[(2R)-2-[[2-chloro-4-(2-chlorophenyl)- (+) 7-quinolyl]oxy]propanoyl]amino]cyclobutane- carboxylate 98 2-[(3R)-1-[(2R)-2-[[2-chloro-4-(2-chloro-4- (+) fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]-N-methyl-acetamide 99 (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- (+) (+) quinolyl]oxy]-1-(1-piperidyl)propan-1-one 100 (3S)-1-[(2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- (+) quinolyl]oxy]propanoyl]-N,N-dimethyl- piperidine-3-carboxamide 101 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro- (+) (+) phenyl)-2-methyl-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid (trifluoroacetic acid salt) 102 (3R)-1-[(2S)-2-[[4-(2-chlorophenyl)-7- (+) quinolyl]oxy]propanoyl]piperidine-3-carboxylic acid (formic acid salt) 103 (2R)-2-[[4-(2-chlorophenyl)-7- (+) quinolyl]oxy]propanoic acid 104 (2R)-2-[[2-chloro-4-(2-chlorophenyl)-7- (+) + quinolyl]oxy]-1-piperazin-1-yl-propan-1-one (trifluoroacetic acid salt) 105 (3S)-N-methyl-1-[(2R)-2-[[2-chloro-4- (+) (2-chloro-4-fluoro-phenyl)-7- quinolyl]oxy]propanoyl]piperidine-3- carboxamide 106 2-[[4-(o-tolyl)-7-quinolyl]oxy]acetamide (+) 107 (2R)-2-[[2-chloro-4-(2-chloro-4-fluoro-phenyl)- (+) 7-quinolyl]oxy]-1-(1-piperidyl)propan-1-one 108 ethyl 3-[[(2 R)-2-[[4-(2-chloro-4-fluoro-phenyl)- (+) 7-quinolyl]oxy]propanoyl]amino]benzoate 109 2-[[5-(2-chloro-4-fluoro-phenyl)-1,8- (+) naphthyridin-2-yl]oxy]-N-isopropyl-propanamide 110 2-[(3R)-1-[(2R)-2-[[4-(2-fluorophenyl)-7- (+) quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 111 tert-butyl (3S)-1-[(2R)-2-[2-methyl-4-(o-tolyl)-7- (+) quinolyl]oxy]propanoyl]piperidine-3-carboxylate 112 2-[1-[(2R)-2-[[4-(2-chlorophenyl)-7- ++ ++ quinolyl]oxy]propanoyl]-4-piperidyl]acetic acid 113 (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-2- + + methyl-7-quinolyl]oxy]propanoyl]piperidine-3- sulfonamide (trifluoroacetic acid salt) 114 (3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-2- + ++ methyl-7-quinolyl]oxy]propanoyl]piperidine-3- sulfonamide (trifluoroacetic acid salt) 115 (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- (+) + 2-methyl-7-quinolyl]oxy]propanoyl]piperidine- 3-sulfonamide (trifluoroacetic acid salt) 116 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + +++ quinolyl]oxy]propanoyl]piperidine-3-sulfonamide (trifluoroacetic acid salt) 117 (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]propanoyl]piperidine-3-sulfonamide (trifluoroacetic acid salt) 118 3-[1-[(2R)-2-[[4-(2-chlorophenyl)-7- +++ ++ quinolyl]oxy]propanoyl]-4- piperidyl]propanoic acid 119 1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3-sulfonamide 120 2-[(3R)-1-[(2R)-2-[[4-(2,6-dichlorophenyl)-7- +++ ++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 121 2-[(3R)-1-[(2R)-2-[[4-(2-ethylphenyl)-7- ++ ++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 122 2-[(3R)-1-[(2R)-2-[[4-(2-isopropylphenyl)-7- (+) quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 123 [1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]propanoyl]-3-piperidyl] methanesulfonamide (trifluoroacetic acid salt) 124 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-2- + + methyl-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 125 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- (+) quinolyl]oxy]-N-[4-(2-hydroxyethyl)phenyl]pro- panamide(trifluoroacetic acid salt) 126 (3S)-1-[(2R)-2-[[5-(2-chloro-4-fluoro-phenyl)- + ++ 1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine- 3-carboxylic acid (formic acid salt) 127 (3S)-1-[(2S)-2-[[5-(2-chloro-4-fluoro-phenyl)- (+) 1,8-naphthyridin-2-yl]oxy]propanoyl]piperidine- 3-carboxylic acid 128 2-[(3R)-1-[(2R)-2-[[5-(2-chloro-4-fluoro- + + phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]-3- piperidyl]acetic acid (formic acid salt) 129 (3S)-1-[(2R)-2-[[4-(2,6-dichlorophenyl)-7- +++ +++ quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 130 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + (+) quinolyl]oxy]-N-(2-pyridyl)propanamide (trifluoroacetic acid salt) 131 (2R)-24+4-(2-chloro-4-fluoro-phenyl)-7- (+) + quinolyl]oxy]-N-ethyl-propanamide (trifluoroacetic acid salt) 132 (3S)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 133 2-[(3R)-1-[(2R)-2-[[4-(4-methyl-3-thienyl)-7- + + quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 134 2-[(3R)-1-[(2R)-2-[[4-(3-methyl-2-thienyl)-7- (+) quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 135 2-[(3R)-1-[(2R)-2-[[4-(2-methoxyphenyl)-7- (+) quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 136 2-[(3R)-1-[(2R)-2-[[4-[2- + (trifluoromethyl)phenyl]-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 137 2-[(3R)-1-[(2R)-2-[[4-[2- (+) (trifluoromethoxy)phenyl]-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 138 (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ quinolyl]oxy]propanoyl]piperidine-3-sulfonamide 139 2-[(3R)-1-[2-[[4-(2-chlorophenyl)-7- (+) quinolyl]oxy]-2-methyl-propanoyl]-3- piperidyl]acetic acid 140 2-[rac-(3R)-1-[2-[[4-(2-chlorophenyl)-7- ++ quinolyl]oxy]butanoyl]-3-piperidyl]acetic acid 141 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-6-methyl- +++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 142 2-[(3R)-1-[(2R)-2-[[4-(2-bromophenyl)-7- +++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 143 2-[(3R)-1-[(2R)-2-[[4-(2-cyanophenyl)-7- + quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 144 2-[(3R)-1-[(2R)-2-[[4-(2-ethynylphenyl)-7- ++ quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 145 2-[(3R)-1-[(2R)-2-[[4-[2- + (dimethylamino)phenyl]-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 146 2-[(3R)-1-[(2R)-2-[[4-(2-carbamoylphenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 147 2-[(3R)-1-[(2R)-2-[[4-(2,6-difluorophenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 148 2-[(3R)-1-[(2R)-2-[[4-(2,4-dimethyl-3-thienyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 149 2-[(3R)-1-[(2R)-2-[[4-[2-chloro-6- (trifluoromethyl)phenyl]-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 150 2-[(3R)-1-[(2R)-2-[[4-(2-bromo-6-chloro- phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 151 2-[(3R)-1-[(2R)-2-[[4-[2,6-bis(trifluoromethyl) (+) phenyl]-7-quinolyl]oxy]propanoyl]- 3-piperidyl]acetic acid 152 2-[(3R)-1-[(2R)-2-[[4-(2-chloro-6-methoxy- (+) phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 153 2-[(3R)-1-[(2R)-2-[[4-(2,6-diisopropylphenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetic acid 154 (2R)-1-[(3R)-3-amino-1-piperidyl]-2-[[4-(2,6- dimethylphenyl)-7-quinolyl]oxy]propan-1-one 155 (2R)-1-[(3S)-3-amino-1-piperidyl]-2-[[4-(2,6- dimethylphenyl)-7-quinolyl]oxy]propan-1-one 156 N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-3- piperidyl]propanamide 157 N-tert-butyl-4-[(2R)-2-[[4-(2,6-dimethylphenyl)- 7-quinolyl]oxy]propanoyl]piperazine-1- carboxamide 158 (2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1- piperidyl]propan-1-one 169 8-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-2,8- diazaspiro[4.5]decan-1-one 160 (2R)-2-[[4-(2,6-dimethylphenyl)-7-quinolyl]oxy]- 1-(3,5-dimethylpiperazin-1-yl)propan-1-one 161 N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]-N-hydroxy- acetamide 162 1-[4-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]piperazin-1-yl]-2,2- dimethyl-propan-1-one 163 N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-3- piperidyl]methanesulfonamide 164 N-[(3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]benzamide 165 (3S)-N-cyano-1-[(2R)-2-[[4- (2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]piperidine- 3-carboxamide 166 (3S)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]piperidine-3- carbohydroxamic acid 167 2-[(3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-3- piperidyl]ethanehydroxamic acid 168 (2R)-1-(3-aminoazetidin-1-yl)-2-[[4-(2,6- dimethylphenyl)-7-quinolyl]oxy]propan-1-one 169 (2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]-1-[3-(1H-tetrazol-5-yl)azetidin- 1-yl]propan-1-one 170 3-hydroxy-1-[(2R)-2-[[4-(2,6-dimethylphenyl)- 7-quinolyl]oxy]propanoyl]piperidine-3- carboxylic acid 171 5-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane- 2-carboxylic acid 172 (3R)-1-[(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ quinolyl]oxy]propanoyl]piperidine-3- sulfonamide 173 (3S)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3-methyl- piperidine-3-carboxylic acid 174 5-[rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-5- azaspiro[2.5]octane-2-carboxylic acid 175 (3R)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3-methyl- piperidine-3-carboxylic acid 176 (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7- +++ ++ quinolyl]oxy]-1-[(2S)-2-methyl-1- piperidyl]propan-1-one 177 5-[rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-5- azaspiro[2.5]octane-2-carboxylic acid 178 (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7- +++ ++ quinolyl]oxy]-1-morpholino-propan-1-one 179 (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7- +++ +++ quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7- yl)propan-1-one 180 rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)- +++ +++ 7-quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)- 1-piperidyl]propan-1-one 181 8-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7- +++ +++ quinolyl]oxy]propanoyl]-2,8- diazaspiro[4.5]decan-1-one 182 1-[1-[rac-(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]cyclopropanecarboxylic acid 183 2-[(3R)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 184 (3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3-methyl- piperidine-3-carboxylic acid 185 N-[(3S)-1-[(2R)-2-[[4-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3-piperidyl]- N-hydroxy-acetamide 186 2-methyl-2-[1-[rac-(2R)-2-[[4-(4-fluoro-2,6- +++ +++ dimethyl-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]propanoic acid 187 (2R)-2-[[4-(4-fluoro-2,6-dimethyl-phenyl)-7- +++ +++ quinolyl]oxy]-1-[(2R)-2-methyl-1- piperidyl]propan-1-one 188 (3R)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro- +++ ++ phenyl)-7-quinolyl]oxy]propanoyl]-3-methyl- piperidine-3-carboxylic acid 189 (3S)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- +++ +++ quinolyl]oxy]propanoyl]-3-methyl-piperidine-3- carboxylic acid 190 [1-[rac-(2R)-2-[[4-(2,6-dimethylphenyl)-7- +++ quinolyl]oxy]propanoyl]-3- piperidyl]methanesulfonamide 191 rac-(2R)-1-(2,6-dimethyl-1-piperidyl)-2- +++ +++ [[4-(4-fluoro-2,6-dimethyl-phenyl)-7- quinolyl]oxy]propan-1-one 192 2-[(3R)-1-[(2R)-2-[[4-(2,6-dichloro-4-fluoro- ++ +++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]acetic acid 193 5-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ ++ quinolyl]oxy]propanoyl]-5-azaspiro[2.5]octane- 2-carboxylic acid 194 1-[1-[rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- ++ ++ 7-quinolyl]oxy]propanoyl]-3- piperidyl]cyclopropanecarboxylic acid 195 2-methyl-2-[1-[rac-(2R)-2-[[4-(2,6-dichloro-4- ++ ++ fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]propanoic acid 196 1-[1-[rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro- ++ ++ phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]cyclopropanecarboxylic acid 197 2-methyl-2-[1-[rac-(2R)-2-[[4-(2-chloro-4- ++ ++ fluoro-phenyl)-7-quinolyl]oxy]propanoyl]-3- piperidyl]propanoic acid 198 (3R)-1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)- ++ +++ 7-quinolyl]oxy]propanoyl]-3-methyl-piperidine- 3-carboxylic acid 199 (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- ++ +++ quinolyl]oxy]-1-[(2S)-2-methyl-1- piperidyl]propan-1-one 200 rac-(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ +++ quinolyl]oxy]-1-(2-methyl-1- piperidyl)propan-1-one 201 (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-morpholino-propan-1-one 202 8-[(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]propanoyl]-2,8- diazaspiro[4.5]decan-1-one 203 rac-(2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-143-(1-hydroxycyclopropyl)-1- piperidyl]propan-1-one 204 (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-[(2R)-2-methyl-1- piperidyl]propan-1-one 205 8-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]propanoyl]-2,8- diazaspiro[4.5]decan-1-one 206 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-morpholino-propan-1-one 207 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + +++ quinolyl]oxy]-1-[3-(1-hydroxycyclopropyl)-1- piperidyl]propan-1-one 208 (2R)-2-[[4-(2,6-dichloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7- yl)propan-1-one 209 N-hydroxy-N-[rac-(3S)-1-[rac-(2R)-2- + ++ [[4-(2-chloro-4-fluoro-phenyl)-7- quinolyl]oxy]propanoyl]-3-piperidyl]acetamide 210 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.5]nonan-7- yl)propan-1-one 211 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + ++ quinolyl]oxy]-1-(2,6-dimethyl-1- piperidyl)propan-1-one 212 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + +++ quinolyl]oxy]-1-(2-oxa-8-azaspiro[3.5]nonan-8- yl)propan-1-one 213 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-1-(2-oxa-7-azaspiro[3.4]octan-7- yl)propan-1-one 214 1-tert-butyl-3-[(3R)-1-[(2R)-2-[[4-(2-chloro- + + 4-fluoro-phenyl)-7- quinolyl]oxy]propanoyl]pyrrolidin-3-yl]urea 215 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-1-(3,3,5,5-tetramethylpiperazin- 1-yl)propan-1-one 216 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- + + quinolyl]oxy]-1-(3,5-dimethylpiperazin-1- yl)propan-1-one 217 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- (+) quinolyl]oxy]-1-[(1R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]propan-1-one 218 (2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- (+) quinolyl]oxy]-1-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propan-1-one 219 1-[(2R)-2-[[4-(2-chloro-4-fluoro-phenyl)-7- ++ + quinolyl]oxy]propanoyl]-3,6-dihydro-2H- pyridine-5-carboxylic acid 220 2-[(3R)-1-[(2R)-2-[[5-(2,6-dichloro-4-fluoro- ++ +++ phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]- 3-piperidyl]acetic acid 221 2-[(3R)-1-[(2R)-2-[[5-(4-fluoro-2,6-dimethyl- +++ +++ phenyl)-1,8-naphthyridin-2-yl]oxy]propanoyl]- 3-piperidyl]acetic acid

7. Inhibition of Various Cancer Cell Lines In Vitro

[1227] The CellTiter-Glo Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture. It is based on quantification of ATP, indicating the presence of metabolically active cells. The assay can be used to determine the inhibitory activity of the compounds of the invention on the growth of cancer cells in vitro.

[1228] Cells are seeded on day 1 at cell numbers that assure assay linearity and optimal signal intensity. After incubation for 3 h in humidified chambers at 37° C./5% CO.sub.2 compounds/DMSO are added at different concentrations. Cells are further incubated for 72 h at 37° C. and 5% CO.sub.2. Cells treated with the compound vehicle DMSO are used as positive controls and cells treated with 10 μM Staurosporine served as negative controls. At day 4 the CellTiter Glo Reagent is prepared according to the instructions of the kit (Promega Inc.): Reagent is mixed 1:1 with cell culture medium. Thereon, mixture and assay plates are equilibrated at room temperature for 20 min. Equal volumes of the reagent-medium-mixture are added to the volume of culture medium present in each well.

[1229] The plates are mixed at ˜200 rpm for 2 minutes on an orbital shaker. The microplates are then incubated at room temperature for 10 minutes for stabilization of the luminescent signal. Following incubation the luminescence is recorded on a Victor microplate reader (Perkin Elmer) using 200 ms integration time. The data are then analyzed with Excel using the XLFIT Plugin (dose response Fit 205) for IC.sub.50-determination. As quality control, the Z′-factor is calculated from 16 positive and negative control values. Only assay results showing a Z′-factor ≥0.5 are used for further analysis.

[1230] A suitable cell line panel for the CellTiter GLO viability assay is CA-46 (lymphoma), HEC-59 (endometrial), HRT-18 (colon), NCI-H1299 (lung), NCI-H23 (lung), NCI-H596 (lung), SW403 (colon), SW48 (colon), SW948 (colon)

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