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

1. A compound of Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a metabolite, an ester, or a pharmaceutically acceptable salt 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 metabolite, an ester, or a pharmaceutically acceptable salt 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 metabolite, an ester, or a pharmaceutically acceptable salt 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 nonsteroidal anti-inflammatory drug, a glucocorticoid, an anti-uric acid drug, a uricosuric drug, a urinary alkalizing agent or a combination thereof.

15. A method for treating hyperuricemia, tophi, gouty arthritis, kidney disorders associated with hyperuricemia or urolithiasis in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .

16. A method for lowering the level of uric acid in blood of a subject comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .

17. A method for inhibiting xanthine oxidase and urate anion transporter 1 in a subject comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .

18. A method for treating hyperuricemia, tophi, gouty arthritis, kidney disorders associated with hyperuricemia or urolithiasis in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according claim 12 .

19. A method for lowering the level of uric acid in blood of a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 12 .

20. A method for inhibiting xanthine oxidase and urate anion transporter 1 in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 12 .