Quinolyl-substituted carboxylic acid compound or pharmaceutically acceptable salt thereof, pharmaceutical composition of the same, and use of the same

Abstract

The present application provides a quinolyl-substituted carboxylic acid compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, as well as a method for preparing the compound, a use of the compound, and a formulation containing the quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof. This type of compounds are inhibitors for AXL and/or VEGFR2 protein kinase, and can be used to treat diseases caused by abnormality of the two protein kinases, such as, tumor, etc. ##STR00001##

Claims

1. A quinolyl-substituted carboxylic acid compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, ##STR00046## wherein V.sup.1 and V.sup.2 are each independently selected from hydrogen, deuterium, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R is hydrogen, C.sub.1-12 alkyl, or C.sub.1-12 alkoxy, and hydrogen of R is selectively substituted by G.sup.1; L is C.sub.1-12 alkylene, and hydrogen of L is selectively substituted by G.sup.2; M is selected from: (a) hydrogen, deuterium, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, and C.sub.3-12 heteroalicyclic group, wherein hydrogen of M is selectively substituted by G.sup.3; or (b) monovalent, divalent, trivalent, and tetravalent metal ions, preferably monovalent and divalent metal ions, and more preferably lithium ion, sodium ion, potassium ion, rubidium ion, cesium ion, magnesium ion, calcium ion, strontium ion, and barium ion; or (c) ammonium ion and an organic amine being protonated, the organic amine including, but not limited to, aliphatic amines substituted with C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, or C.sub.3-12 heteroalicyclic group, the aliphatic amines being selectively substituted with one or more halogens or hydroxyls; wherein G.sup.1, G.sup.2 and G.sup.3 are each independently selected from hydrogen, deuterium, CN, CF.sub.3, CO.sub.2H, halogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 heteroalicyclic group, R.sup.1O, R.sup.1R.sup.2N, R.sup.1S(O).sub.m, R.sup.1R.sup.2NS(O).sub.m, R.sup.3C(O), R.sup.1R.sup.2NC(O), R.sup.1OC(O), R.sup.3C(O)O, R.sup.1R.sup.2NC(O)O, R.sup.3C(O)NR.sup.1, R.sup.1R.sup.2NC(O)NR.sup.4, R.sup.1OC(O)NR.sup.4, R.sup.1S(O).sub.mNR.sup.4, R.sup.1R.sup.2NS(O).sub.mNR.sup.4, R.sup.1R.sup.2NC(NR.sup.5)NR.sup.4, R.sup.1R.sup.2NC(CHNO.sub.2)NR.sup.4, R.sup.1R.sup.2NC(NCN)NR.sup.4, R.sup.1R.sup.2NC(NR.sup.5), R.sup.1S(O)(NR.sup.5)NR.sup.4, and R.sup.1R.sup.2NS(O)(NR.sup.5); R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, and C.sub.3-12 heteroalicyclic group; R.sup.1 and R.sup.2, when being bonded to a same nitrogen atom, form a C.sub.3-12 heteroalicyclic ring together with the nitrogen atom, wherein the C.sub.3-12 heteroalicyclic ring selectively contains a hetero atom of O, N, S(O).sub.m; hydrogen of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is selectively substituted by halogen, CN, C.sub.1-12 alkyl or C.sub.3-12 cycloalkyl; and m is from 0 to 2.

2. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein V.sup.1 and V.sup.2 are each independently selected from hydrogen, deuterium, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R is hydrogen, C.sub.1-12 alkyl, or C.sub.1-12 alkoxy; L is C.sub.1-12 alkylene; M is selected from: (a) hydrogen, and deuterium; or (b) lithium ion, sodium ion, potassium ion, rubidium ion, cesium ion, magnesium ion, calcium ion, strontium ion, and barium ion; or (c) ammonium ion and an organic amine being protonated, wherein the organic amine includes aliphatic amines substituted with C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, or C.sub.3-12 heteroalicyclic group, the aliphatic amines being selectively substituted with one or more halogens or hydroxyls.

3. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein V.sup.1 and V.sup.2 are each independently selected from hydrogen, deuterium, and halogen; preferably, V.sup.1 and V.sup.2 are identical and are hydrogen, deuterium, or halogen, and V.sup.1 and V.sup.2 are located in the 2-position and the 4-position of the six-membered rings substituted with them, respectively.

4. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein V.sup.1 and V.sup.2 are each independently selected from hydrogen, deuterium, and halogen, R is C.sub.1-12 alkoxy, and L is C.sub.1-12 alkylene.

5. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein V.sup.1 and V.sup.2 are each independently selected from hydrogen and halogen; R is methoxy, ethoxy, n-propoxy, or isopropoxy; and L is C.sub.1-6 alkylene.

6. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein M is selected from hydrogen, and deuterium; or M is selected from lithium ion, sodium ion, potassium ion, magnesium ion, and calcium ion; or M is selected from ammonium ion, protonated methylamine, protonated ethylamine, protonated n-propylamine, protonated isopropylamine, protonated n-butylamine, protonated isobutylamine, protonated sec-butylamine, protonated tert-butylamine, protonated dimethylamine, protonated diethylamine, protonated di-n-propylamine, protonated diisopropylamine, protonated di-n-butylamine, protonated diisobutylamine, protonated di-sec-butylamine, protonated di-tert-butylamine, protonated trimethylamine, protonated triethylamine, protonated tri-n-propylamine, protonated triisopropylamine, protonated tri-n-butylamine, protonated triisobutylamine, protonated tri-sec-butylamine, protonated tri-tert-butylamine, protonated diisopropylethylamine, and protonated 2-amino-2-(hydroxymethyl)propane-1,3-diol.

7. The quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid; lithium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; sodium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; potassium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; magnesium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; calcium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; ammonium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; triethylammonium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 2-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionic acid; lithium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; sodium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; potassium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; magnesium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; calcium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; ammonium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; triethylammonium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 3-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid; lithium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; sodium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; potassium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; magnesium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; calcium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; ammonium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; triethylammonium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid; lithium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; sodium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; potassium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; magnesium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; calcium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; ammonium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; triethylammonium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 5-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid; lithium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; sodium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; potassium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; magnesium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; calcium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; ammonium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; triethylammonium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoic acid; lithium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; sodium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; potassium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; magnesium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; calcium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; ammonium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; triethylammonium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid; lithium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; sodium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; potassium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; magnesium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; calcium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; ammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; triethylammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionic acid; lithium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; sodium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; potassium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; magnesium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; calcium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; ammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; triethylammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid; lithium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; sodium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; potassium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; magnesium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; calcium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; triethylammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid; lithium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; sodium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; potassium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; magnesium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; calcium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; ammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; triethylammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid; lithium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; sodium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; potassium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; magnesium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; calcium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; triethylammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoic acid; lithium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; sodium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; potassium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; magnesium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; calcium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; ammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; triethylammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid; lithium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; sodium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; potassium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; magnesium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; calcium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; ammonium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; triethylammonium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 2-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate; 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionic acid; lithium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; sodium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; potassium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; magnesium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; calcium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; ammonium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; triethylammonium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 3-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]propionate; 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid; lithium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; sodium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; potassium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; magnesium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; calcium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; ammonium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; triethylammonium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate; 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid; lithium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; sodium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; potassium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; magnesium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; calcium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; ammonium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; triethylammonium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 5-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate; 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid; lithium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; sodium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; potassium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; magnesium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; calcium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; ammonium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; triethylammonium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate; 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoic acid; lithium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; sodium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; potassium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; magnesium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; calcium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; ammonium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; triethylammonium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 7-[[4-[2-chloro-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate; 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetic acid; lithium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; sodium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; potassium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; magnesium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; calcium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; ammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; triethylammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate; 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionic acid; lithium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; sodium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; potassium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; magnesium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; calcium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; ammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; triethylammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 3-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]propionate; 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyric acid; lithium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; sodium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; potassium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; magnesium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; calcium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; triethylammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]butyrate; 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valeric acid; lithium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; sodium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; potassium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; magnesium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; calcium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; ammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; triethylammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]valerate; 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproic acid; lithium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; sodium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; potassium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; magnesium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; calcium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; triethylammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]caproate; 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoic acid; lithium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; sodium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; potassium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; magnesium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; calcium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; ammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; triethylammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane carbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate; and 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]heptanoate.

8. A preparation method of the quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, comprising, but not limited to, the following steps: ##STR00047## wherein V.sup.1, V.sup.2, R, L and M are as defined in claim 1; LG is F, Cl, Br, I, CH.sub.3SO.sub.3, CH.sub.3CH.sub.2SO.sub.3, CH.sub.3(CH.sub.2).sub.2SO.sub.3, (CH.sub.3).sub.2CHSO.sub.3, tert-BuSO.sub.3, PhSO.sub.3, o-CH.sub.3PhSO.sub.3, m-CH.sub.3PhSO.sub.3, p-CH.sub.3PhSO.sub.3, o-O.sub.2NPhSO.sub.3, m-O.sub.2NPhSO.sub.3, p-O.sub.2NPhSO.sub.3, or CF.sub.3SO.sub.3; and RR is hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl or C.sub.3-12 heteroalicyclic group, and hydrogen of RR is selectively substituted by G.sup.4; wherein G.sup.4 is selected from hydrogen, deuterium, CN, CF.sub.3, CO.sub.2H, halogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 heteroalicyclic group R.sup.1O, R.sup.1R.sup.2N, R.sup.1S(O).sub.m, R.sup.1R.sup.2NS(O).sub.m, R.sup.3C(O), R.sup.1R.sup.2NC(O), R.sup.1OC(O), R.sup.3C(O)O, R.sup.1R.sup.2NC(O)O, R.sup.3C(O)NR.sup.1, R.sup.1R.sup.2NC(O)NR.sup.4, R.sup.1OC(O)NR.sup.4, R.sup.1S(O).sub.mNR.sup.4, R.sup.1R.sup.2NS(O).sub.mNR.sup.4, R.sup.1R.sup.2NC(NR.sup.5)NR.sup.4, R.sup.1R.sup.2NC(CHNO.sub.2)NR.sup.4, R.sup.1R.sup.2NC(NCN)NR.sup.4, R.sup.1R.sup.2NC(NR.sup.5), R.sup.1S(O)(NR.sup.5)NR.sup.4, and R.sup.1R.sup.2NS(O)(NR.sup.5); R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, and C.sub.3-12 heteroalicyclic group; R.sup.1 and R.sup.2, when being bonded to a same nitrogen atom, form a C.sub.3-12 heteroalicyclic ring together with the nitrogen atom, wherein the C.sub.3-12 heteroalicyclic ring selectively contains a hetero atom of O, N, and S(O).sub.m; and hydrogen of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is selectively substituted by halogen, CN, C.sub.1-12 alkyl or C.sub.3-12 cycloalkyl; and m is 0 to 2.

Description

DETAILED DESCRIPTION

(1) The present application is described in detail below in combination with the specific examples, in order to facilitate the understanding of the compounds, the method for preparing the compounds, and the beneficial effects of the present application. However, the contents claimed in the present application are not limited to the specific examples.

(2) The English abbreviations used in the examples and the corresponding meanings are listed below. If an abbreviation unlisted herein appears in the examples, it represents a generally accepted meaning.

(3) HPLC: high performance liquid chromatography

(4) g: gram

(5) mg: milligram

(6) mol: mole

(7) mmol: millimole

(8) nM: nanomole (concentration unit)

(9) M: micromole (concentration unit)

(10) M: mole (concentration unit)

(11) N: equivalent concentration

(12) L: liter

(13) L: microliter

(14) [M+H].sup.+: molecular ion peak in mass spectrometry

(15) m/z: mass-to-charge ratio

(16) : chemical shift

(17) MeOH: methanol

(18) EtOH: ethanol

(19) DMSO-d.sub.6: dimethyl sulfoxide-d.sub.6

(20) CDCl.sub.3: deuterated chloroform

(21) CD.sub.3OD: deuterated methanol

(22) TMS: tetramethylsilane

(23) HCl: hydrogen chloride or hydrochloric acid

(24) LiOH.H.sub.2O: lithium hydroxide hydrate

(25) Ca(OH).sub.2: calcium hydroxide

(26) KOH: potassium hydroxide

(27) NaOH: sodium hydroxide

(28) DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

(29) DABCO: 1,4-diazabicyclo[2.2.2]octane

(30) General Experimental Conditions:

(31) Nuclear magnetic resonance hydrogen and carbon spectra were obtained on a Varian 300 or 400 MHz instrument or a Bruker 300 or 400 MHz instrument (using deuterated DMSO, deuterated chloroform, deuterated methanol, etc. as solvent, TMS as internal standard). Mass spectrum was obtained by liquid chromatography-mass spectrometry (using ESI or APCI ion source ZQ4000, Waters, USA). Ultraviolet spectrum was measured by a UV-3010 ultraviolet spectrophotometer (Hitachi, Japan). Infrared spectrum was obtained by using a NICOLET6700 infrared spectrometric analyzer (KBr pellet). High performance liquid chromatography was performed by using a Waters 2695 ZORBAX high performance liquid chromatograph (Bx-C8 5, 1504.6 mm chromatographic column), unless otherwise specified. Melting point was measured by using an Electrothermal digital melting point meter IA9100 and was uncalibrated.

(32) Starting materials, reagents and solvents were purchased from the following suppliers: Beta-Pharma; Shanghai PI Chemicals; AndaChem; Taiyuan; Shanghai FWD Chemicals; Sigma-Aldrich, Milwaukee, Wis., USA; Acros, Morris Plains, N.J., USA; Frontier Scientific, Logan, Utah, USA; Alfa Aesar, Ward Hill, Mass., USA, etc., or synthesized by methods reported in the literatures. Unless otherwise indicated, the solvent from the supplier's is generally used directly without drying or dried through molecular sieves.

Example 1

(33) 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid (I-2) is prepared according to the following reaction equation:

(34) ##STR00027##

(35) LiOH.H.sub.2O (44 mg, 1.04 mmol) was added into a solution of methyl 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)aminocarbonyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate (I-1, 60 mg, 0.104 mmol, prepared according to the method described in WO2013/040801A1) dissolved in methanol (1.0 mL) and water (0.3 mL). The obtained mixture was stirred at room temperature for 1 h, and the reaction solution was diluted with water and adjusted to pH 4 with HCl (1N). After filtration, the obtained solid product was collected and washed with acetonitrile, so as to obtain 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid (I-2) (26 mg, yield: 44%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =13.29 (s, br, 1H), 10.44 (s, 1H), 10.00 (s, 1H), 8.63 (s, 1H), 7.94 (d, J=12.8 Hz, 1H), 7.66-7.46 (m, 5H), 7.37 (s, 1H), 7.18-7.14 (m, 2H), 6.66-6.62 (m, 1H), 4.97 (s, 2H), 4.02 (s, 3H), 1.49 (d, J=6.8 Hz, 4H). Mass spectrum (ESI) m/z: 564.1 [M+H].sup.+.

Example 2

(36) Calcium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate (1:1) (I-3) is prepared according to the following reaction equation:

(37) ##STR00028##

(38) An aqueous solution of Ca(OH).sub.2 (0.031 N, 1 mL, 0.031 mmol) was added into a solution of 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetic acid (I-2, 35 mg, 0.062 mmol) dissolved in methanol (0.5 mL). The mixture was stirred at room temperature for 16 h, diluted with water, and then freeze-dried to obtain calcium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]acetate (1:1) (I-3) (29 mg, yield: 80%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =10.49 (s, 1H), 10.11 (s, 1H), 8.42 (d, J=4.5 Hz, 1H), 7.91-7.86 (m, 1H), 7.67-7.62 (m, 2H), 7.49-7.34 (m, 4H), 7.19-7.12 (m, 3H), 6.35 (d, J=5.1 Hz, 1H), 4.40 (s, 2H), 3.94 (s, 3H), 1.46 (s, 4H). Mass spectrum (ESI) m/z: 564.1 [M+H].sup.+.

Example 3

(39) 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid (II-2) is prepared according to the following reaction equation:

(40) ##STR00029##

(41) LiOH.H.sub.2O (194 mg, 4.628 mmol) was added into a solution of methyl 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate (II-1, 280 mg, 0.463 mmol, prepared according to the method described in WO2013/040801A1) dissolved in methanol (3.0 mL) and water (1.0 mL). The obtained mixture was stirred at room temperature for 1 h, and the reaction solution was diluted with water and adjusted to pH 4 with HCl (1N). After filtration, the obtained solid product was collected and washed with acetonitrile, so as to obtain 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid (II-2) (191.3 mg, yield: 70%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =12.22 (s, 1H), 10.49 (s, 1H), 10.00 (s, 1H), 8.75 (d, J=6.0 Hz, 1H), 7.97 (d, J=12.8 Hz, 1H), 7.71 (s, 1H), 7.67-7.50 (m, 5H), 7.18-7.14 (m, 2H), 6.83 (d, J=6.4 Hz, 1H), 4.25 (t, J=6.4 Hz, 2H), 4.03 (s, 3H), 2.51-2.45 (m, 2H), 2.12-2.05 (m, 2H), 1.49 (d, J=9.6 Hz, 4H). Mass spectrum (ESI) m/z: 592.1 [M+H].sup.+.

Example 4

(42) Sodium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate (II-3) is prepared according to the following reaction equation:

(43) ##STR00030##

(44) An aqueous solution of NaOH (0.041 N, 1 mL, 0.041 mmol) was added into a solution of 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid (II-2, 24 mg, 0.041 mmol) dissolved in methanol (0.5 mL). The mixture was stirred at room temperature for 16 h, diluted with water, and then freeze-dried to obtain sodium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate (II-3) (23 mg, yield: 92%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =10.45 (s, 1H), 10.10 (s, 1H), 8.47 (d, J=5.4 Hz, 1H), 7.92 (d, J=11.1 Hz, 1H), 7.69-7.40 (m, 6H), 7.20-7.12 (m, 2H), 6.42-6.40 (m, 1H), 4.18 (t, J=6.6 Hz, 2H), 3.96 (s, 3H), 2.37 (d, J=6.9 Hz, 2H), 2.07-1.98 (m, 2H), 1.48 (s, 4H). Mass spectrum (ESI) m/z: 592.1 [M+H].sup.+.

Example 5

(45) 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate (II-4) is prepared according to the following reaction equation:

(46) ##STR00031##

(47) A methanol solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (0.041 N, 1 mL, 0.041 mmol) was added into a solution of 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyric acid (II-2, 24 mg, 0.041 mmol) dissolved in methanol (0.5 mL). The obtained mixture was stirred at room temperature for 16 h, diluted with water, and then freeze-dried to obtain 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 4-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]butyrate (II-4) (27 mg, yield: 93%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.94-7.87 (m, 1H), 7.68-7.39 (m, 6H), 7.19-7.12 (m, 2H), 6.43-6.41 (m, 1H), 5.12 (br, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.44 (s, 6H), 2.50-2.42 (m, 2H), 2.09-2.00 (m, 2H), 1.48 (s, 4H). Mass spectrum (ESI) m/z: 592.1 [M+H].sup.+.

Example 6

(48) 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid (III-2) is prepared according to the following reaction equation:

(49) ##STR00032##

(50) LiOH.H.sub.2O (149 mg, 3.54 mmol) was added into a solution of methyl 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate (III-1, 220 mg, 0.354 mmol, prepared according to the method described in WO2013/040801A1) dissolved in methanol (3.0 mL) and water (1.0 mL). The obtained mixture was stirred at room temperature for 1 h, and the reaction solution was diluted with water and adjusted to pH 4 with HCl (1N). After filtration, the obtained solid product was collected and washed with acetonitrile, so as to obtain 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid (III-2) (184 mg, yield: 85%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =12.12 (s, 1H), 10.51 (s, 1H), 10.01 (s, 1H), 8.76 (d, J=6.0 Hz, 1H), 8.00-7.96 (m, 1H), 7.71 (s, 1H), 7.67-7.51 (m, 5H), 7.19-7.15 (m, 2H), 6.83 (d, J=6.4 Hz, 1H), 4.24 (t, J=6.4 Hz, 2H), 4.03 (s, 3H), 2.37-2.33 (m, 2H), 1.90-1.86 (m, 2H), 1.76-1.70 (m, 2H), 1.53-1.47 (m, 4H). Mass spectrum (ESI) m/z: 606.1 [M+H].sup.+.

Example 7

(51) Potassium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate (III-3) is prepared according to the following reaction equation:

(52) ##STR00033##

(53) An aqueous solution of KOH (0.040 N, 1 mL, 0.040 mmol) was added into a solution of 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid (III-2, 24 mg, 0.040 mmol) dissolved in methanol (0.5 mL). The obtained mixture was stirred at room temperature for 16 h, diluted with water, and then freeze-dried to obtain potassium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate (III-3) (24 mg, yield: 94%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =10.35 (s, br, 2H), 8.47 (d, J=5.4 Hz, 1H), 7.94-7.89 (m, 1H), 7.68-7.38 (m, 6H), 7.19-7.13 (m, 2H), 6.42-6.40 (m, 1H), 4.15 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 2.28-2.21 (m, 2H), 1.87-1.66 (m, 4H), 1.47 (m, 4H). Mass spectrum (ESI) m/z: 606.1 [M+H].sup.+.

Example 8

(54) Triethylammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate (III-4) is prepared according to the following reaction equation:

(55) ##STR00034##

(56) An acetonitrile solution of triethylamine (0.040 N, 1 mL, 0.040 mmol) was added into a solution of 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valeric acid (III-2, 24 mg, 0.040 mmol) dissolved in methanol (0.3 mL) and water (0.5 mL). The obtained mixture was stirred at room temperature for 16 h, diluted with water, and then freeze-dried to obtain triethylammonium 5-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]valerate (III-4) (24 mg, yield: 86%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =12.07 (s, 1H), 10.40 (s, 1H), 10.02 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.67-7.40 (m, 6H), 7.19-7.13 (m, 2H), 6.44 (d, J=4.5 Hz, 1H), 4.17 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.12-3.06 (m, 2.5 H), 2.34 (d, J=6.9 Hz, 1H), 2.28-2.21 (m, 2H), 1.87-1.68 (m, 4H), 1.48 (m, 4H), 1.19 (t, J=7.2 Hz, 2.5 H). Mass spectrum (ESI) m/z: 606.1 [M+H].sup.+.

Example 9

(57) 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2) is prepared according to the following reaction equation:

(58) ##STR00035##

(59) Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise into a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013/040801A1) dissolved in ethanol (350 mL). After the dropwise addition was completed, water (50 mL) was added. The obtained mixture was stirred at 20-25 C. for 18 h. The reaction mixture was diluted with water (100 mL), stirred for 20 min, and adjusted to pH 3-4 with HCl (1N). The reaction mixture was concentrated under reduced pressure to distillate ethanol (about 300 mL), and then filtrated to collect the solid product. The obtained crude product (28.4 g) was purified by silica gel column chromatography (eluent: ethyl acetate:methanol=1:1, v/v) to obtain 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2) (9.6 g, yield: 28.1%). Analysis data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =8.17 (d, J=8.0 Hz, 1H), 7.81 (dd, J=2.8, 13.4 Hz, 1H) 7.62 (m, 2H), 7.51 (m, 4H), 7.39 (t, J=2.4 Hz, 2H), 6.44 (d, J=20.0 Hz, 1H), 4.13 (t, J=8.5 Hz, 2H), 3.85 (s, 3H), 2.27 (t, J=4.0 Hz, 2H), 1.83 (m, 2H), 1.68-1.46 (m, 8H). Mass spectrum (ESI) m/z: 620.2 [M+H].sup.+.

Example 10

(60) Sodium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-3) is prepared according to the following reaction equation:

(61) ##STR00036##

(62) A solution of NaOH (34.29 mg, 0.857 mmol) dissolved in water (5 mL) was added into a solution of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2, 500 mg, 0.807 mmol) dissolved in ethanol (20 mL). The obtained mixture was stirred at room temperature for 30 min, and distillated under reduced pressure (the temperature is controlled at 40 C.), so as to obtain sodium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-3) (617.2 mg, yield: 96%). Mass spectrum (ESI) m/z: 620.2 [M+H].sup.+.

Example 11

(63) Potassium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-4) is prepared according to the following reaction equation:

(64) ##STR00037##

(65) A solution of KOH (55.44 mg, 0.988 mmol) dissolved in water (5 mL) was added into a solution of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2, 500 mg, 0.807 mmol) dissolved in ethanol (20 mL). The obtained mixture was stirred at room temperature for 30 min, and distillated under reduced pressure (the temperature is controlled at 40 C.), so as to obtain potassium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-4) (555.46 mg, yield: 100%). Mass spectrum (ESI) m/z: 620.2 [M+H].sup.+.

Example 12

(66) Calcium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (1:1) (IV-5) is prepared according to the following reaction equation:

(67) ##STR00038##

(68) A solution of Ca(OH).sub.2 (30.245 mg, 0.408 mmol) dissolved in water (5 mL) was added into a solution of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2, 500 mg, 0.807 mmol) dissolved in ethanol (20 mL). The obtained mixture was stirred at room temperature for 30 min, and distillated under reduced pressure (the temperature is controlled at 40 C.), so as to obtain calcium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (1:1) (IV-5) (309.19 mg, yield: 58%). Mass spectrum (ESI) m/z: 620.2 [M+H].sup.+.

Example 13

(69) 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-6) is prepared according to the following reaction equation:

(70) ##STR00039##

(71) A solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (102.75 mg, 0.848 mmol) dissolved in water (5 mL) was added into a solution of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproic acid (IV-2, 500 mg, 0.807 mmol) dissolved in ethanol (20 mL). The obtained mixture was stirred at room temperature for 1 h, and distillated under reduced pressure (the temperature is controlled at 40 C.), so as to obtain a light yellow oil product, which is dried to obtain 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]caproate (IV-6) (394.11 mg, yield: 66%). Mass spectrum (ESI) m/z: 620.2 [M+H].sup.+.

Example 14

(72) 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoic acid is prepared according to the following reaction equation:

(73) ##STR00040##

(74) A solution of potassium hydroxide (86.4 mg) dissolved in water (2 mL) was added into a solution of methyl 7-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate (VI-1, 1.0 g, 1.53 mmol) dissolved in ethanol (10 mL). The obtained mixture was stirred at room temperature for 5 h. Then, the reaction solution was adjusted to about pH 3 and extracted with ethyl acetate. The obtained extract was evaporated to dry under reduced pressure so as to obtain the target product (VI-2) (715 mg, yield: 74%). Mass spectrum (ESI) m/z: 635.4 [M+H].sup.+.

Example 15

(75) 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoic acid is prepared according to the following reaction equation:

(76) ##STR00041##

(77) A solution of potassium hydroxide (84.3 mg) dissolved in water (2 mL) was added into a solution of methyl 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate (VII-1, 1.0 g, 1.51 mmol) dissolved in ethanol (10 mL). The obtained mixture was stirred at room temperature for 4.5 h. Then, the reaction solution was adjusted to about pH 3 and extracted with ethyl acetate. The obtained extract was evaporated to be dry under reduced pressure so as to obtain the target product (VII-2) (700 mg, yield: 71%). Mass spectrum (ESI) m/z: 651.1 [M+H].sup.+.

Example 16

(78) Calcium 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]heptanoate is prepared according to the following reaction equation:

(79) ##STR00042##

(80) A solution of calcium hydroxide (43.1 mg) dissolved in water (5 mL) was added into a solution of 7-[[4-[2-fluoro-4-[[1-[(3-chlorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]pentanoic acid (VIII-1, 1.0 g, 1.54 mmol) dissolved in ethanol (10 mL). The obtained mixture was stirred at about 50 C. for 4 h. Then, the reaction solution was evaporated to be dry to obtain the target product (VIII-2) (909 mg, yield: 90%).

Example 17

(81) 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-isopropoxy-7-quinolyl]oxy]acetic acid is prepared according to the following reaction equation:

(82) ##STR00043##

(83) A solution of potassium hydroxide (147.8 mg) dissolved in water (5 mL) was added into a solution of methyl 2[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-isopropoxy-7-quinolyl]oxy]acetate (IX-1, 800 mg, 1.32 mmol) dissolved in ethanol (12 mL). The obtained mixture was stirred at room temperature for 4 h. Then, the reaction solution was adjusted to about pH 3 and extracted with ethyl acetate. The obtained extract was evaporated to be dry under reduced pressure so as to obtain the target product (IX-2) (633 mg, yield: 81%). Mass spectrum (ESI) m/z: 593.3 [M+H].sup.+.

Example 18

(84) Potassium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate is prepared according to the following reaction equation:

(85) ##STR00044##

(86) A solution of potassium hydroxide (57.0 mg) dissolved in water (5 mL) was added into a solution of 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetatic acid (X-1, 500 mg, 0.865 mmol) dissolved in ethanol (10 mL). The obtained mixture was stirred at room temperature for 4 h. Then, the reaction solution was evaporated to be dry under reduced pressure so as to obtain the target product (X-2) (513 mg, yield: 96%).

Example 19

(87) Ammonium 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetate is prepared according to the following reaction equation:

(88) ##STR00045##

(89) A solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (105 mg, 0.865 mmol) dissolved in water (5 mL) was added into a solution of 2-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-ethoxy-7-quinolyl]oxy]acetic acid (XI-1, 500 mg, 0.865 mmol) dissolved in ethanol (15 mL). The obtained mixture was stirred at room temperature for 3 h. Then, the reaction solution was evaporated to be dry under reduced pressure so as to obtain the target product (XI-2) (450 mg, yield: 74%).

Example 20

(90) Biochemical inhibitory activity against AXL and VEGFR2 kinases: the biochemical IC.sub.50 values of the compound according to the present application for inhibiting AXL and VEGFR2 kinases were measured by ProQinase GmbH Company (Breisacher Str. 117, D-79106 Freiburg, Germany, www.proqinase.com). The specific steps are described as follows:

(91) Firstly, the compound according to the present application was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution of 110.sup.3 M. 10 different concentrations (from 110.sup.5 M to 310.sup.10 M) were prepared by the serial semi-logarithmic dilution.

(92) The biochemical activities of AXL and VEGFR2 were determined by the radioactive protein kinase assay (33PanQinase Activity Assay). The assay was performed using a FlashPlates 96-well plate manufactured by Perkin Elmer (Boston, Mass., USA) with a reaction volume of 50 L. The reaction mixture was added by a dropper in the following four steps:

(93) (1) 20 L of buffer solution (standard buffer);

(94) (2) 5 L of an aqueous solution of ATP;

(95) (3) 5 L of the compound (10% DMSO solution);

(96) (4) 10 L of a substrate/10 L of a solution of the kinase.

(97) The solution to be measured contains HEPES-NaOH (70 mM, pH=7.5), MgCl.sub.2 (3 mM), MnCl.sub.2 (3 mM), Na-orthovanadate (3 M), DTT (1.2 mM), PEG.sub.20000 (50 g/mL), ATP (in a concentration that is same as K.sub.m of the kinase and varies depending on different kinases), [-.sup.33P]-ATP (about 410.sup.5 cpm/well), kinase and substrate.

(98) The used amounts of kinase and substrate per well are summarized in Table 1:

(99) TABLE-US-00005 TABLE 1 Measurement Parameters Kinase Kinase ATP Concentration Concentration Concentration Substrate Substrate No. Kinase (ng/50 L) (nM) (M) Name (g/50 L) 1 AXL 25 6.5 0.3 Poly(Glu, Tyr) 0.250 4:1 2 VEGFR2 20 4.6 1.0 Poly(Glu, Tyr) 0.125 4:1

(100) The reaction was carried out at 30 C. for 60 minutes, and 50 L of 2% (v/v) phosphoric acid was added to terminate the reaction. The reaction mixture in each well was aspirated and washed twice with 200 L of 0.9% (w/v) NaCl solution. The amount of the incorporation of .sup.33P was determined by using a microplate scintillation counter.

(101) The results are summarized in Table 2.

(102) TABLE-US-00006 TABLE 2 Biochemical activity of the compounds against two kinases AXL and VEGFR2. Biochemical IC.sub.50 (nM) Example AXL VEGFR2 1 55.3 24.5 3 9.86 6.56 4 9.05 8.03 6 7.49 6.60 8 6.08 8.66 9 10.2 16.0 10 11.9 13.9 11 14.9 13.6 12 10.7 10.4 13 8.63 12.6 14 13.7 13.6 16 19.8 18.9 18 10.7 9.86

(103) As described previously, the compounds of the present application have strong inhibitory activity against both of the two kinases AXL and VEGFR2, and the IC.sub.50 values for AXL are in a range of 6.08-55.3 nM, and the IC50 values for VEGFR2 are in a range of 6.56-24.5 nM. Therefore, the compounds in this application can be used to treat diseases caused by abnormal activities of these kinases, for example, tumors, etc.

Example 21: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(104) compound prepared in Example 1:100;

(105) lactose, Ph EUR: 182.75;

(106) sodium carboxymethyl cellulose: 12.0;

(107) corn starch slurry (5 w/v %): 2.25; and

(108) magnesium stearate: 3.0;

(109) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 22: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(110) compound prepared in Example 5: 100;

(111) other components and contents thereof are same as in Example 21;

(112) suitable human subjects: those with a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 23: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(113) compound prepared in Example 9: 50;

(114) lactose, PhEUR: 223.75;

(115) sodium carboxymethyl cellulose: 6.0;

(116) corn starch: 15.0;

(117) polyvinylpyrrolidone (5 w/v %): 2.25; and

(118) magnesium stearate: 3.0;

(119) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 24: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(120) compound prepared in Example 9: 50;

(121) other components and contents thereof are same as in Example 23;

(122) suitable human subjects: those with a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 25: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(123) compound prepared in Example 13: 1.0;

(124) lactose, PhEUR: 93.25;

(125) sodium carboxymethyl cellulose: 4.0;

(126) corn starch slurry (5 w/v %): 0.75; and

(127) magnesium stearate: 76;

(128) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 26: Composition and Preparation of Medicine: Tablets (mg/Tablet)

(129) compound prepared in Example 13: 1.0;

(130) other components and contents thereof are same as in Example 25;

(131) suitable human subjects: those with a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 27: Composition and Preparation of Medicine: Capsules (mg/Capsule)

(132) compound prepared in Example 7: 10.0;

(133) lactose, Ph EUR: 488.5; and

(134) magnesium: 1.5;

(135) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 28: Composition and Preparation of Medicine: Capsules (mg/Capsule)

(136) compound prepared in Example 2: 10.0;

(137) other components and contents thereof are same as in Example 27;

(138) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 29: Composition and Preparation of Medicine: Injection (50 mg/mL)

(139) compound prepared in Example 6: 5%;

(140) 1 M sodium hydroxide solution: 15%;

(141) 0.1 M hydrochloric acid solution (adjusting pH=7.6);

(142) polyethylene glycol 400: 5%; and

(143) the remaining of 100%: water for injection;

(144) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 30: Composition and Preparation of Medicine: Injection (50 mg/mL)

(145) compound prepared in Example 12: 5%;

(146) other components and contents thereof are same as in Example 29; and

(147) the remaining of 100%: water for injection;

(148) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 31: Composition and Preparation of Medicine: Injection (10 mg/mL)

(149) compound prepared in Example 11: 1%;

(150) disodium hydrogen phosphate BP: 3.6%;

(151) 0.1 M sodium hydroxide solution: 15%; and

(152) the remaining of 100%: water for injection;

(153) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 32: Composition and Preparation of Medicine: Injection (10 mg/mL)

(154) compound prepared in Example 9: 1%;

(155) other components and contents thereof are same as in Example 31; and

(156) the remaining of 100%: water for injection;

(157) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 33: Composition and Preparation of Medicine: Injection (1 mg/mL)

(158) compound prepared in Example 6: 0.1%;

(159) disodium hydrogen phosphate BP: 2.26%;

(160) citric acid: 0.38%;

(161) polyethylene glycol 400: 3.5%; and

(162) the remaining of 100%: water for injection;

(163) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 34: Composition and Preparation of Medicine: Injection (1 mg/mL) (pH was Adjusted to 6)

(164) compound prepared in Example 10: 0.1%;

(165) other components and contents thereof are same as in Example 33;

(166) the remaining of 100%: water for injection;

(167) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 35: Composition and Preparation of Medicine: Aerosol (mg/mL)

(168) compound prepared in Example 1: 10;

(169) sorbitan monooleate: 13.5;

(170) trichlorofluoromethane: 910.0; and

(171) dichlorodifluoromethane: 490.0;

(172) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 36: Composition and Preparation of Medicine: Aerosol (mg/mL)

(173) compound prepared in Example 3: 10;

(174) other components and contents thereof are same as in Example 35;

(175) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 37: Composition and Preparation of Medicine: Aerosol (mg/mL)

(176) compound prepared in Example 4: 0.2;

(177) sorbitan monooleate: 0.27;

(178) trichlorofluoromethane: 70.0;

(179) dichlorodifluoromethane: 280.0; and

(180) dichlorotetrafluoroethane: 1094.0;

(181) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 38: Composition and Preparation of Medicine: Aerosol (mg/mL)

(182) compound prepared in Example 7: 0.2;

(183) other components and contents thereof are same as in Example 37;

(184) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 39: Composition and Preparation of Medicine: Aerosol (mg/mL)

(185) compound prepared in Example 8: 2.5;

(186) sorbitan monooleate: 3.38;

(187) trichlorofluoromethane: 67.5;

(188) dichlorodifluoromethane: 1086.0; and

(189) dichlorotetrafluoroethane: 191.60;

(190) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 40: Composition and Preparation of Medicine: Aerosol (mg/mL)

(191) compound prepared in Example 11: 2.5;

(192) other components and contents thereof are same as in Example 39;

(193) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 41: Composition and Preparation of Medicine: Aerosol (mg/mL)

(194) compound prepared in Example 4: 2.5;

(195) soybean lecithin: 2.7;

(196) trichlorofluoromethane: 67.5;

(197) dichlorodifluoromethane: 1086.0; and

(198) dichlorotetrafluoroethane: 191.60;

(199) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 42: Composition and Preparation of Medicine: Aerosol (mg/mL)

(200) compound prepared in Example 13: 2.5;

(201) other components and contents thereof are same as in Example 41;

(202) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 43: Composition and Preparation of Medicine: Ointment (/mL)

(203) compound prepared in Example 1: 40 mg;

(204) ethanol: 300 l;

(205) water: 300 l;

(206) 1-dodecylazacycloheptanone: 50 l; and

(207) the remaining of 1 mL: propylene glycol;

(208) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

Example 44: Composition and Preparation of Medicine: Ointment (/mL)

(209) compound prepared in Example 7: 40 mg;

(210) other components and contents thereof are same as in Example 43;

(211) suitable human subjects: those having a disease caused by abnormality of AXL protein kinase and/or VEGFR2 protein kinase.

(212) The technical solutions of the above-mentioned embodiments can be further combined or substituted. The embodiments described above are merely the preferred embodiment of the present application, but not intended to limit the concept or scope of the present application. Any change and improvement to the technical solutions of the present application, which are made by those skilled in the art without departing from the invention concept of the present application, shall fall within the protection scope of the present application.