Granted Patent B2

US 12,258,317 · App. 17/608,842 · Granted Mar 25, 2025

Inventors: Zheng Gu (Dongguan, CN); Jianhao Li (Dongguan, CN); Weihua Wang (Dongguan, CN); Haoxiong Qin (Dongguan, CN); Xinshan Deng (Dongguan, CN)

Assignee: SUNSHINE LAKE PHARMA CO., LTD.

C07D217/24A61P1/16C07D401/06C07F9/3817C07F9/4006

Abstract

Claims (43)

1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a pharmaceutically acceptable salt thereof,

wherein,

R 1 is F, Cl, Br or I;

R 2 is H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl or

each of R 3a , R 3b and R 3c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxy C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;

W is -L-R 4 or —(CR a R b ) t —P(═O)(R 5 )(R 6 );

L is —(CR a R b ) p —C(═O)—NR c , —(CR a R b ) q —S—, —(CR a R b ) q —S(═O)—, —(CR a R b ) s —S(═O) 2 —, —(CR a R b ) q —S(═O) 2 —NR c — or —(CR a R b ) q —S(═O)—NR c —;

each of q, p, s and t is independently 0, 1, 2, 3, 4 or 5;

each of R a , R b and R c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxyl C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;

R 4 is H, deuterium, C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein each of the C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

or R c and R 4 together with the nitrogen atom to which they are attached, form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 3-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

each of R 5 and R 6 is independently OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy or 5-6 membered heteroarylamino, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and 5-6 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

or R 5 and R 6 together with the phosphorus atom to which they are attached, form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 3-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

each R y is independently deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —SH, —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkoxy, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, carboxy C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

2. The compound according to claim 1 , wherein the R 4 is H, deuterium, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein each of the C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

or R c and R 4 together with the nitrogen atom to which they are attached, form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

3. The compound according to claim 1 , wherein the R 4 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, propenyl, ethynyl, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, propenyl, ethynyl, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl is independently unsubstituted or substituted by 1, 2, 3 or 4 R y ;

or R c and R 4 together with the nitrogen atom to which they are attached, form pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, pyrazinyl, thiazolyl or pyrimidinyl, wherein each of the pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, pyrazinyl, thiazolyl and pyrimidinyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

4. The compound according to claim 1 , wherein each of the R 5 and R 6 is independently OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy or 5-6 membered heteroarylamino, wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and 5-6 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

or R 5 and R 6 together with the phosphorus atom to which they are attached, form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

5. The compound according to claim 1 , wherein each of the R 5 and R 6 is independently OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-n-propylamino, N-isopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclo hexyloxy, N-cyclopropylamino, N,N-dicyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, phenyl, phenyloxy, N-phenylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy or 5-6 membered heteroarylamino, wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-n-propylamino, N-isopropylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclo hexyloxy, N-cyclopropylamino, N,N-dicyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclylamino, phenyl, phenyloxy, N-phenylamino, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy and 5-6 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R y ;

or R 5 and R 6 together with the phosphorus atom to which they are attached, form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R y .

6. The compound according to claim 1 , wherein each R y is independently deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —SH, —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, —S(═O) 2 —C 1-4 alkyl, —S(═O) 2 —C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, carboxy C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

7. The compound according to claim 1 , wherein each R y is independently deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —SH, —C(═O)-methyl, —C(═O)-ethyl, —C(═O)-methoxy, —C(═O)-ethoxy, —S(═O) 2 -methyl, —S(═O) 2 -ethyl, —S(═O) 2 -n-propyl, —S(═O) 2 -isopropyl, —S(═O) 2 -n-butyl, —S(═O) 2 -tert-butyl, —S(═O) 2 -methylamino, —S(═O) 2 -ethylamino, —S(═O) 2 -n-propylamino, —S(═O) 2 -isopropylamino, —S(═O) 2 -tert-butylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , trifluoromethoxy, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, carboxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

8. The compound according to claim 1 , wherein each of R a , R b and R c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, carboxyl C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

9. The compound according to claim 1 , wherein each of R a , R b and R c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , trifluoromethoxy, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, cyanomethyl, carboxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

10. The compound according to claim 1 , wherein the R 2 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl or

each of R 3a , R 3b and R 3c is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , —COOH, OH, NH 2 , —C(═O)-methyl, —C(═O)-ethyl, —C(═O)-methoxy, —C(═O)-ethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, —CHF 2 , —CF 3 , —CH 2 CHF 2 , —CH 2 CF 3 , trifluoromethoxy, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, cyanomethyl, carboxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

11. The compound according to claim 1 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, phosphate, oxalate, maleate, tartrate, citrate, malate or methanesulfonate.

14. A pharmaceutical composition comprising the compound of claim 1 , optionally, further comprising any one of pharmaceutically acceptable carriers, excipients, adjuvants, vehicles or combinations thereof.

15. A method of inhibiting SSAO/VAP-1, or treating or ameliorating a disease related to SSAO/VAP-1 protein or regulated by SSAO/VAP-1 in a subject comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 ;

wherein the disease related to SSAO/VAP-1 protein or regulated by SSAO/VAP-1 is inflammation and/or a disease related to inflammation.

16. The method of claim 15 , wherein the inflammation and/or a disease related to inflammation is arthritis, synovitis, a Crohn's disease, ulcerative colitis, an inflammatory bowel disease, hepatopathy, or an eye disease.

17. The method of claim 16 , wherein the arthritis is osteoarthritis, rheumarthritis, rheumatoid arthritis or juvenile rheumatoid arthritis; the inflammatory bowel disease is irritable bowel syndrome; the hepatopathy is a liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, an alcoholic liver disease or a non-alcoholic fatty liver disease; the eye disease is uveitis, iritis, retinitis, autoimmune ophthalmia, inflammation driven by angiogenesis and/or lymphogenesis, macular degeneration;

wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.

18. A method of inhibiting SSAO/VAP-1, or treating or lessening a disease related to SSAO/VAP-1 protein or regulated by SSAO/VAP-1 in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 14 .

19. The method of claim 18 , wherein the inflammation and/or a disease related to inflammation is arthritis, synovitis, a Crohn's disease, ulcerative colitis, an inflammatory bowel disease, hepatopathy, or an eye disease.

20. The method of claim 19 , wherein the arthritis is osteoarthritis, rheumarthritis, rheumatoid arthritis or juvenile rheumatoid arthritis; the inflammatory bowel disease is irritable bowel syndrome; the hepatopathy is a liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, an alcoholic liver disease or a non-alcoholic fatty liver disease; the eye disease is uveitis, iritis, retinitis, autoimmune ophthalmia, inflammation driven by angiogenesis and/or lymphogenesis, macular degeneration;

wherein the non-alcoholic fatty liver disease is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.

Assignments (2)

Priority Claims (1)

Continuity (1)

References Cited (20)