Carboxy substituted (hetero) aromatic ring derivatives and preparation method and uses thereof

Patent metadata

Field	Value
Publication number	US-2018230102-A1
Application number	US-201615750205-A
Country	US
Kind code	A1
Filing date	Aug 31, 2016
Priority date	Sep 2, 2015
Publication date	Aug 16, 2018
Grant date	—

Abstract

Carboxy-substituted (hetero)aryl derivatives, pharmaceutical compositions comprising these compounds, and methods of preparing such compounds and compositions are provided. The compounds or compositions are useful in inhibiting xanthine oxidase and urate anion transporter 1, and also can be used in the treatment or prevention of diseases associated with high blood uric acid level in mammals, especially humans.

First claim

1 . A compound of Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof

wherein:
U is phenyl or 5- to 6-membered heteroaryl;
each R 1 and R 2 is independently H, D, halogen, OH, NH 2 , NO 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl is independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from OH, oxo (═O), NH 2 , NO 2 or CN;
T is H, D, F, Cl, Br, NO 2 , CN or CF 3 ;
X is CR 4 or N;
R 4 is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 1-6 haloalkoxy;
each of Y and Z is independently C, CH or N;
“ ” refers to a single bond or a double bond;
Q is phene, C 4-7 carbocycle, 4- to 7-membered heterocycle or 5- to 6-membered heteroaromatic ring;
each R 3 is independently H, D, halogen, oxo (═O), OH, NH 2 , NO 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, naphthyl or G, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl is independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from OH, oxo (═O), NH 2 , NO 2 , CN or G;
G is substituted C 1-6 aliphatic hydrocarbon, wherein each of the methylene groups of the C 1-6 aliphatic hydrocarbon is optionally and independently substituted with J;
J is —NH—, —S—, —O—, —C(═O)—, —C(═O)NH—, —SO—, —SO 2 —, —NHC(═O)—, —C(═O)O—, —SO 2 NH— or —NHC(═O)NH—;
m is 0, 1, 2 or 3; and
n is 0, 1, 2, 3 or 4;
with the proviso that:
(1) when T is F, Cl, Br or CF 3 , R 1 is OH;

(2) when T is H, and Q is not phene;
(3) when T is NO 2 , R 1 is not H.

2 . The compound of claim 1 having Formula (II) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt and a prodrug thereof,

3 . The compound of claim 1 , wherein U is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, furanyl, thiazolyl, thienyl, oxazolyl or isoxazolyl.

4 . The compound of claim 1 , wherein U is phenyl,

wherein * refers to the position of the U ring attached to

5 . The compound of claim 1 having Formula (III) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt and a prodrug thereof,

6 . The compound of claim 1 , wherein each R 1 and R 2 is independently H, D, halogen, OH, NH 2 , NO 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 haloalkylamino, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 haloalkylamino, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl is independently and optionally substituted with 1, 2 or 3 substituents selected from OH, oxo (═O), NH 2 , NO 2 or CN.

7 . The compound of claim 1 , wherein each R 1 and R 2 is independently H, D, halogen, OH, NH 2 , NO 2 , CN, methyl, ethyl, i-propyl, butyl, hydroxymethyl, hydroxyethyl, aminomethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, i-propoxy, t-butoxy, n-butoxy, methylamino, ethylamino, difluoromethoxy, trifluoromethoxy, acetyl, acetoxy, acetylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolidinyl or tetrahydrofuranyl.

8 . The compound of claim 1 , wherein each R 3 is independently H, D, halogen, oxo (═O), OH, NH 2 , NO 2 , CN, methyl, ethyl, i-propyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, i-propoxy, difluoromethoxy, trifluoromethoxy, formyl, carboxy, formamido, acetyl, carbamoyl, propylsulfonamido, cyclopropyl, cyclobutyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, quinolyl, indolyl, phenyl or naphthyl.

9 . The compound of claim 1 , wherein R 4 is H, D, halogen, methyl, ethyl, i-propyl, t-butyl, n-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, t-butoxy, methylamino, difluoromethoxy or trifluoromethoxy; and

10 . The compound of claim 1 , wherein

wherein *1 refers to the position attached to the U ring.

11 . The compound of claim 1 having one of the following formulas:

12 . A pharmaceutical composition comprising the compound of claim 1 .

13 . The pharmaceutical composition of claim 12 further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

14 . The pharmaceutical composition of claim 13 further comprising a drug for preventing or treating hyperuricemia, tophi, gouty arthritis, kidney disorders associated with hyperuricemia or urolithiasis, wherein the drug comprises colchicine, a non

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Yang Xinye
• Huang Changwei
• Ma Facheng
• Zhang Ji
• Wang Xiaojun
• Zhang Yingjun

Classifications

• C07D263/56

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2 · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• C07D249/18

  Benzotriazoles · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07D307/79

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title