阅读说明：本技术 选择性地抑制β-葡糖醛酸糖苷酶和减轻与药物治疗引起的腹泻有关的副作用的化合物、组合物和方法 (Compounds, compositions and methods for selectively inhibiting beta-glucuronidase and reducing side effects associated with drug therapy-induced diarrhea ) 是由 F·X·塔瓦勒斯 B·D·瓦尔拉斯 W·佩特尔森 于 2020-03-06 设计创作，主要内容包括：本公开内容描述了抑制β-葡糖醛酸糖苷酶活性的化合物和组合物,以及通过施用选择性β-葡糖醛酸糖苷酶抑制剂来减轻一种或多种药物的副作用并改善药物效力的方法。(The present disclosure describes compounds and compositions that inhibit beta-glucuronidase activity, as well as methods of alleviating side effects of one or more drugs and improving drug efficacy by administering selective beta-glucuronidase inhibitors.)

1. A compound of formula (I):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R_bis hydrogen, C (O) NHR_cOr C (O) R_d；

R_cIs an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a glucuronide thereof,

or a pharmaceutically acceptable salt thereof.

2. A compound of formula (IG):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, which optionally has one or more heteroatoms selected from N, O or S, andoptionally having one or more unsaturations;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R_bis hydrogen, C (O) NHR_c、C(O)R_dOr

Wherein each R^xIndependently is hydrogen or C (O) R^z,

R^yIs H or R^zAnd is and

each R^zIndependently is C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_9-20Alkyl radical, C_9-20Alkenyl or C_9-20An alkynyl group;

R_cis an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1 or 2, wherein R_1AIs hydrogen.

4. The compound of any one of claims 1-3, wherein R_1BIs substituted or unsubstituted C_1-6An alkyl group.

5. The compound of any one of claims 1-4, wherein R_1CIs substituted or unsubstituted C_1-6An alkyl group.

6. According to any one of claims 1 to 5The compound of (1), wherein R₂Is hydrogen or C_1-6An alkyl group.

7. The compound of any one of claims 1-6, wherein R₃Is hydrogen.

8. The compound of any one of claims 1-7, wherein R₄Is a substituted or unsubstituted phenyl group.

9. The compound of any one of claims 1-8, wherein R₄Is a substituted phenyl group.

10. The compound of claim 9, wherein R₄Is phenyl substituted by one or more of the following groups: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, by Si (CH)₃)₃Substituted C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, halogen, aryl, C_3-6Cycloalkyl or SO₂R_eWherein R is_eIs hydrogen or C_1-6An alkyl group.

11. The compound of claim 10, wherein R₄Is phenyl and is monosubstituted.

12. The compound of claim 10, wherein R₄Is phenyl and is disubstituted.

13. The compound of any one of claims 1-12, wherein R₅Is (L)₁)_nR_aWherein L is₁Is C₂Alkylene, n is 1, and R_aIs OR_bWherein R is_bIs hydrogen.

14. The compound of any one of claims 1-13, wherein R_bIs that

Wherein each R^xIs hydrogen, and R^yIs hydrogen.

15. The compound of claim 14, wherein each R^xIs C (O) R^zAnd R is^yIs R^z。

16. The compound of claim 15, wherein each R^zIs C_1-6An alkyl group.

17. A compound selected from:

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2-phenyl-acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) propionamide;

2- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methylsulfonylphenyl) acetamide;

2- (2-chlorophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-chloro-4-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide; 2- (2-bromo-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

1- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) methanesulfonamide;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethoxy) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

3- (4-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2, 6-dimethylphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-isopropylphenyl) urea;

3- (2-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

6, 8-dibromo-3- (hydroxymethyl) quinolin-2 (1H) -one;

6, 8-dibromo-2-oxo-1, 2-dihydroquinoline-3-carbaldehyde;

3- (2-cyclopropylphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (pyridin-3-yl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-iodophenyl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (2-chloro-6, 8-dimethylquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (m-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (3-ethynyl-4-fluorophenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2- ((trimethylsilyl) ethynyl) phenyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

2-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide; n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-phenylacetamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) propionamide;

1- (3-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) methanesulfonamide;

2- (2-bromo-5-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3- (2-bromo-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3- (methylsulfonyl) phenyl) acetamide;

2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

3- (2-chloro-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethoxy) phenyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-4-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2-isopropylphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetamido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetylamino) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

18. A compound selected from:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

19. A compound selected from:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

20. A composition comprising: one or more compounds according to any one of claims 1-19 and one or more pharmaceutically acceptable carriers.

21. A method of reducing side effects of one or more drugs, the method comprising: administering to a subject in need thereof an effective amount of one or more compounds according to any one of claims 1-19.

22. The method of claim 21, wherein the one or more compounds selectively inhibit β -glucuronidase.

23. The method of claim 21 or 22, wherein the one or more compounds may be co-administered with one or more therapeutic compounds or products.

24. A compound according to any one of claims 1-19 for use in medicine.

25. The compound of claim 24, wherein the compound selectively inhibits β -glucuronidase.

26. A compound according to any one of claims 1-19 for use in the manufacture of a medicament for use in alleviating a side effect of one or more drugs.

27. The compound of claim 26, wherein the compound selectively inhibits β -glucuronidase.

28. Use of a compound according to any one of claims 1-19 to reduce side effects of one or more drugs.

29. The use of claim 28, wherein the compound selectively inhibits β -glucuronidase.

Technical Field

The present disclosure describes compounds and compositions that inhibit beta-glucuronidase (beta-glucuronidase) activity, and methods of alleviating side effects of one or more drugs and improving drug efficacy by administering selective beta-glucuronidase inhibitors.

Background

Diarrhea is a common adverse effect associated with drug therapy. There are hundreds of drugs involved in causing diarrhea or gastrointestinal discomfort, including antibiotics, laxatives, magnesium-containing antacids, lactose or sorbitol-containing products, non-steroidal anti-inflammatory drugs, prostanoids, colchicine, anti-neoplastic drugs, anti-arrhythmic drugs and cholinergic drugs. All of these drugs are administered in a delicate balance between effective treatment and patient discomfort and/or severe gastrointestinal discomfort. Drug-induced diarrhea may occur without warning and escalate to severe diarrhea within hours. Even mild to moderate diarrhea can be life threatening when combined with vomiting, dehydration or neutropenia. Chemotherapy regimens containing irinotecan (IRI) and 5-fluorouracil/folinic acid (5-FU/LV) have revolutionized the treatment of advanced colorectal cancer patients early in the 2000's, but their therapeutic benefit is compromised by diarrhea occurring in up to 88% of patients. Clinical trials of IRI plus high doses of 5-FU/LV have shown an early mortality rate of 2.2% to 4.8%, mainly due to gastrointestinal toxicity.

Drug Induced Diarrhea (DID) is a burden in several respects and may have psychosocial effects on patients who may be embarrassed, isolated and troubled. Patients avoid social contact and may not seek medical assistance until the problem is escalated. Several studies have shown that DID is not adequately reported in clinical trials and in practical settings. In a recent survey of breast cancer patients, diarrhea is second only to nausea/vomiting and is a feared chemotherapeutic toxicity. When offered a choice to stop chemotherapy-induced specific deaths or to continue chemotherapy-induced chronic diarrhea, 42% of respondents selected deaths. For patients who cannot tolerate the aforementioned diarrhea, the last resort often by oncologists is to reduce or stop chemotherapy before it kills the patient. In addition, DID often becomes a dose limiting side effect of drug therapy, which can impair the therapeutic effect.

One of the potential mechanisms of DID is caused by enterobacteria expressing a β -glucuronidase (bGUS) enzyme classified as a hydrolase. "glucuronidation" is a common metabolic process involved in drug metabolism in which glucuronide (glucuronide) functions as a conjugate molecule and is bound to a substrate by catalysis of glucuronidase (UGT) enzyme. Glucuronidation is used by the human body to make various substances more water soluble, which allows for easy clearance from the body by urine and/or feces. Beta-glucuronidase involves cleavage of glucuronide conjugates. However, drugs or metabolites thereof, which are substrates of glucuronidase, can change their respective properties by hydrolysis by glucuronidase. For example, if a drug, agent, compound, or metabolite thereof has been metabolized to a glucuronide, hydrolysis of the glucuronide can reactivate the drug, agent, compound, or metabolite thereof. In many cases, this reactivation can cause adverse reactions, including but not limited to gastrointestinal discomfort, which leads to diarrhea.

For example, IRI (also known as CPT-11) is an intravenously injected prodrug that is metabolized systemically by carboxylesterase to the active moiety SN-38, a potent topoisomerase-1 inhibitor. SN-38 is cytotoxic to rapidly dividing cancer cells as well as intestinal epithelial cells and neutrophils. It is metabolized by liver UGT enzymes into the inactive glucuronide metabolite SN-38G, which is then excreted into the small intestine along with bile secretions. As SN-38G is transported along the lower GI tract, enteric bacteria expressing the β -glucuronidase (bGUS) enzyme excise SN-38G back to SN-38, which accumulates to toxic levels in the intestinal lumen. Local reactivation of SN-38 in the intestinal lumen by intestinal bacteria is considered to be an upstream triggering event that leads to a delay in diarrhea.

Although broad spectrum antibiotics have been used to eliminate intestinal bacteria from the gastrointestinal tract prior to chemotherapy treatment to reduce reactivation, this approach has some drawbacks. First, enterobacteria (i.e., the normal flora) play a crucial role in carbohydrate metabolism, vitamin production, and processing of bile acids, sterols, and xenobiotics. Thus, partial or complete removal of enteric bacteria is not ideal for subjects who have been challenged with cancer and chemotherapy. Secondly, the elimination of symbiotic intestinal bacteria even from healthy subjects greatly increases the risk of infection by pathogenic bacteria, including enterohemorrhagic Escherichia coli (Escherichia coli) and Clostridium difficile (Clostridium difficile). Third, bacterial resistance to antibiotics is a crisis to human health, and unnecessary use of antibiotics is a significant factor contributing to this crisis.

Thus, there remains a need to mitigate the side effects of drugs such as DID, and also to improve the efficacy of DID-causing drugs by administering selective β -glucuronidase inhibitors.

International application PCT/US2018/48891 (incorporated herein by reference in its entirety) describes novel compounds useful for alleviating side effects of one or more drugs by selectively inhibiting β -glucuronidase.

Disclosure of Invention

One embodiment of the present disclosure includes compounds of formula (I):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylamino alkyl radicalC substituted or unsubstituted_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or substitutedA substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R_bis hydrogen, C (O) NHR_cOr C (O) R_d；

R_cIs an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a glucuronide thereof,

or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a compound of formula (IG):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R_bis hydrogen, C (O) NHR_c、C(O)R_dOr

Wherein each R^xIndependently is hydrogen or C (O) R^z，

R^yIs H or R^zAnd is and

each R^zIndependently is C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_9-20Alkyl radical, C_9-20Alkenyl or C_9-20An alkynyl group;

R_cis an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a pharmaceutically acceptable salt thereof.

One aspect of the present disclosure includes wherein R_1AIs hydrogen. One aspect of the present disclosure includes wherein R_1BIs substituted or unsubstituted C_1-6An alkyl group. One aspect of the present disclosure includes wherein R_1CIs substituted or unsubstituted C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₂Is hydrogen or C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₃Is hydrogen. One aspect of the present disclosure includes wherein R₄Is a substituted or unsubstituted phenyl group. One aspect of the present disclosure includes wherein R₄Is a substituted phenyl group. One aspect of the present disclosure includes wherein R₄Is formed by one or more C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, halogen or SO₂R_eSubstituted phenyl, wherein R_eIs hydrogen or C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₄Is phenyl and is monosubstituted. One aspect of the present disclosure includes wherein R₄Is phenyl and is disubstituted. One aspect of the present disclosure includes wherein R₅Is (L)₁)_nR_aWherein L is₁Is C₂Alkylene, n is 1, and R_aIs OR_bWherein R is_bIs hydrogen. One aspect of the present disclosure includes wherein R_b

Wherein each R^xIs hydrogen, and R^yIs hydrogen. One aspect of the present disclosure includes wherein each R^xIs C (O) R^zAnd R is^yIs R^z. One aspect of the present disclosure includes wherein each R^zIs C_1-6An alkyl group.

One embodiment of the present disclosure includes a compound selected from the group consisting of:

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2-phenyl-acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) propionamide;

2- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methylsulfonylphenyl) acetamide;

2- (2-chlorophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-chloro-4-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide; 2- (2-bromo-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

1- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) methanesulfonamide;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethoxy) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

3- (4-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2, 6-dimethylphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-isopropylphenyl) urea;

3- (2-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

6, 8-dibromo-3- (hydroxymethyl) quinolin-2 (1H) -one;

6, 8-dibromo-2-oxo-1, 2-dihydroquinoline-3-carbaldehyde;

3- (2-cyclopropylphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (pyridin-3-yl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-iodophenyl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (2-chloro-6, 8-dimethylquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (m-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (3-ethynyl-4-fluorophenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2- ((trimethylsilyl) ethynyl) phenyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

2-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide; n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-phenylacetamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) propionamide;

1- (3-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) methanesulfonamide;

2- (2-bromo-5-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3- (2-bromo-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3- (methylsulfonyl) phenyl) acetamide;

2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

3- (2-chloro-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethoxy) phenyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-4-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2-isopropylphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetamido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetylamino) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a compound selected from the group consisting of:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a compound selected from the group consisting of:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a composition comprising one or more compounds of the present disclosure and one or more pharmaceutically acceptable carriers.

One embodiment of the present disclosure includes a method of reducing side effects of one or more drugs by administering to a subject in need thereof an effective amount of one or more compounds of the present disclosure. In one aspect of one embodiment, the one or more compounds selectively inhibit β -glucuronidase. In one aspect of one embodiment, one or more compounds may be co-administered with one or more therapeutic compounds or products (products).

One embodiment of the present disclosure includes a compound of the present disclosure for use in medicine (medicine). In one aspect of one embodiment, the one or more compounds selectively inhibit β -glucuronidase. In one aspect of one embodiment, one or more compounds may be co-administered with one or more therapeutic compounds or products.

One embodiment of the present disclosure includes a compound of the present disclosure for use in the preparation of a medicament for reducing a side effect of one or more drugs. In one aspect of one embodiment, the one or more compounds selectively inhibit β -glucuronidase. In one aspect of one embodiment, one or more compounds may be co-administered with one or more therapeutic compounds or products.

One embodiment of the disclosure includes the use of a compound of the disclosure for reducing side effects of one or more drugs. In one aspect of one embodiment, the one or more compounds selectively inhibit β -glucuronidase. In one aspect of one embodiment, one or more compounds may be co-administered with one or more therapeutic compounds or products.

Although not specifically described, one or more aspects and embodiments may be combined in different embodiments. That is, all aspects and embodiments may be combined in any manner or combination.

Detailed Description

Definition of

When referring to the compounds disclosed herein, the following terms have the following meanings, unless otherwise indicated. The following definitions are intended to clarify, but not limit, the defined terms. A particular term used herein should not be considered ambiguous if it is not specifically defined. Rather, the terms are used within their acceptable meaning.

As used herein, the term "alkoxy" refers to the group-OR, wherein R is alkyl. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy.

As used herein, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably 1-6 carbon atoms. The hydrocarbon chain may be straight or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Similarly, an "alkenyl" group refers to an alkyl group having one or more double bonds in the chain. "alkynyl" refers to an alkyl group having one or more triple bonds in the chain.

As used herein, "alkylamino" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably 1-6 carbon atoms, in which at least one hydrogen atom is substituted with an amine. Similarly, "alkylaminoalkyl" refers to a dialkyl "alkylamino" or an alkylamino group having more than one alkyl chain.

As used herein, "aryl" refers to an aromatic ring system containing 5 to 10 ring atoms. Exemplary aryl groups include phenyl and naphthyl.

As used herein, "beta-glucuronidase" refers to a bacterial or mammalian enzyme capable of hydrolyzing beta-glucuronide. As used herein, "glucuronide" refers to a substance produced by linking glucuronic acid to another substance. Illustrative examples of glucuronides are those derived from neoplastic agents, such as the glucuronide of 7-ethyl-10-hydroxycamptothecin, which is derived from camptothecin antineoplastic agents.

As used herein, "co-administration" refers to prior to, concurrent with, or subsequent to the administration of the glucuronidase substrate reagent or compound as defined below.

As used herein, "cycloalkyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 6 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and partially saturated forms thereof, such as cyclohexenyl and cyclohexadienyl.

As used herein, "dose limiting" refers to side effects caused by administration of a drug or a glucuronidase substrate agent or compound that prevent a subject in need of the drug or the glucuronidase substrate agent or compound from receiving a therapeutically effective amount.

As used herein, "effective amount" refers to an amount sufficient to achieve a therapeutic effect when administered to a patient in need of treatment.

As used herein, "halogen" or "halo" refers to halogen. In some embodiments, the halogen is preferably Br, Cl or F.

As used herein, "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably 1-6 carbon atoms, wherein at least one hydrogen atom is substituted with a halogen, including but not limited to perhalo groups wherein all hydrogen atoms are substituted with halogen atoms. The haloalkyl chain may be straight or branched. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, "haloalkenyl" refers to haloalkyl groups having one or more double bonds in the chain. "haloalkynyl" refers to a haloalkyl group having one or more triple bonds in the chain.

As used herein, "haloalkylthio" refers to a monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, wherein at least one hydrogen atom is substituted with a halogen, including but not limited to perhalogenated groups, wherein all hydrogen atoms are substituted with halogen atoms and the second hydrogen atom is substituted with sulfur. The haloalkylthio chain may be linear or branched.

As used herein, "one or more glucuronidase substrate reagents or compounds" refers to any drug, reagent, compound, or metabolite thereof that can act as a glucuronidase substrate. In certain instances, the term as used herein per se includes drugs, compounds or agents that are not substrates per se but are metabolized into substrates. Any drug, compound, agent, or metabolite thereof that is acidified (glucuronidated) with a glucuronide, also known as a glucuronide, can be a substrate for glucuronidase, and is also referred to herein as a glucuronidase substrate reagent or compound. Many drugs, agents or compounds undergo glucuronidation at some point during their metabolism. Alternatively, the drug, agent or compound may be a glucuronide prodrug. These glucuronides can have properties that differ from the parent drug, agent or compound.

As used herein, "optionally having one or more heteroatoms" refers to the substitution of a ring carbon atom with a nitrogen, oxygen, or sulfur atom. Similarly, "optionally having one or more unsaturations" means that the number of bonds between the ring atoms changes due to any substitution in the ring atoms, resulting in a change in the number of valence electrons available for bonding.

As used herein, "pharmaceutically acceptable salt" refers to any salt of a compound disclosed herein that retains its biological properties and is non-toxic or not undesirable for pesticidal, veterinary, or pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include: (1) with organic or inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and the like.

By way of example only, salts also include salts of non-toxic organic or inorganic acids, such as halides, e.g., chlorides and bromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, caproates, cyclopentylpropionates, glycolates, glutamates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3- (4-hydroxybenzoyl) benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (methanesulfonates), ethanesulfonates, 1, 2-ethane-disulfonates, 2-hydroxyethanesulfonates, phenylsulfonates (benzenesulfonates), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo [2.2.2] -oct-2-ene-1-formate, glucoheptonate, 3-phenylpropionate, pivalate, t-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinic acid salt, muconate (muconate), and the like.

As used herein, the term "selectively inhibit" or the like means that the β -glucuronidase inhibitor reduces the β -glucuronidase activity of a bacterium or a mammal.

As used herein, the terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "patient" refer to primates, e.g., monkeys, e.g., cynomolgus monkeys, chimpanzees, and humans or non-primates. In one embodiment, the subject is a human. In another embodiment, the subject is a companion animal, such as a dog or cat. In another embodiment, the subject is an animal of agricultural importance, such as sheep, cattle, horses, goats, fish, pigs or poultry (e.g., chickens, turkeys, ducks or geese).

As used herein, "substituted" refers to the substitution of a hydrogen atom that would otherwise be present on a substituent. When discussing a ring system, optional substituents are typically 1,2 or 3 substituents replacing the hydrogen normally present. However, when referring to straight and branched chain moieties, the number of substitutions may be greater, occurring wherever hydrogen is normally present. The substitutions may be the same or different. Exemplary substitutions include nitro, -NR ' R ", cyano, -NR ' COR '", alkyl, alkenyl, alkynyl, alkylsilylalkynyl (i.e., -C.ident.C-Si-alkyl), C (O), SO₂R”’，NR’SO₂R”’，SO₂NR’R”，CONR’R”，CONHC₆H₅Hydroxy, alkoxy, alkylsulfonyl, haloalkyl, haloalkenyl, haloalkoxy, mercapto (i.e., -SH), thioalkyl, halogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R' and R ", which may be the same or different, each represent hydrogen or alkyl; or when R 'and R "are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing 4 to 6 ring atoms, and wherein R'" is alkyl or haloalkyl.

In some cases, the substituents shown may contribute to optical and/or stereoisomerism. Compounds having the same molecular formula but differing in the bonding properties or bonding order of the atoms or arrangement of the atoms in space are referred to as "isomers". Isomers in which the arrangement of atoms in space is different are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are not superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and assigned either (R) or (S) according to the rules of Cahn and Prelog (Cahn et al, 1966, Angew. chem.78:413-447, Angew. chem. int. Ed. Engl.5:385-414(errata: Angew. chem. int. Ed. Engl.5: 511); Prelog and Helmchen,1982, Angew. chem.94:614-631, Angew. chem. Internat. Ed. Eng.21: 567-583; Mata and Lobo,1993, Tetrahedron: Asymmetry 4:657-668), or by: wherein the molecule rotates the plane of polarized light and is referred to as dextrorotatory or levorotatory (referred to as (+) -or (-) -isomer, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

In certain embodiments, the compounds disclosed herein may have one or more asymmetric centers; and thus these compounds can be produced as the individual (R) -or (S) -enantiomers or mixtures thereof. Unless otherwise indicated, such as by specifying stereochemistry at any position of the formula, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures thereof, racemates or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art. In particular embodiments, stereoisomers of the compounds provided herein are depicted after treatment with base.

In certain embodiments, the compounds disclosed herein are "stereochemically pure". A stereochemically pure compound has a certain level of stereochemical purity which is considered "pure" by those skilled in the art. Of course, the purity level may be less than 100%. In certain embodiments, "stereochemically pure" refers to a compound that is substantially free of other isomers, i.e., at least about 85% or more free of other isomers. In particular embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% free of other isomers.

The present disclosure includes all pharmaceutically acceptable isotopically-labeled compounds of the present invention wherein one or more atoms are substituted with one or more substituents selected from the group consisting ofAtoms in which the atomic mass or mass number is different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, for example²H and³isotopes of H, carbon, e.g.¹¹C，¹³C and¹⁴isotopes of C, chlorine, e.g.³⁶Isotopes of Cl, fluorine, e.g.¹⁸Isotopes of F, iodine, e.g.¹²³I，¹²⁵I, isotopes of nitrogen, e.g.¹³N and¹⁵isotopes of N, oxygen, e.g.¹⁵O，¹⁷O and¹⁸isotopes of O, phosphorus, e.g.³²P, and isotopes of sulfur, e.g.³⁵And S. Certain isotopically-labeled compounds of the present invention, for example those into which a radioactive isotope has been incorporated, are useful in drug or substrate tissue distribution studies. With radioactive isotopes of tritium³H and carbon 14 i¹⁴C is particularly useful for this purpose because of the ease of their incorporation and the ready means of detection. Using heavier isotopes such as deuterium, i.e.²Replacement of H may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., longer in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. Using positron-emitting isotopes (e.g. of the type¹¹C，¹⁸F，¹⁵O and¹³n) can be used in Positron Emission Tomography (PET) studies to examine the occupancy of substrate receptors. Isotopically-labelled compounds of the present invention can generally be prepared by: the appropriate isotopically labeled reagents are used in place of the non-labeling reagents previously employed by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations.

Compounds that inhibit beta-glucuronidase activity

The present disclosure provides compounds and methods for inhibiting beta-glucuronidase activity. Also described herein are methods of alleviating side effects of one or more drugs comprising administering a compound described herein.

Drugs, agents, compounds or their metabolites as substrates of β -glucuronidase (glucuronidase substrate agents) can change their respective properties by glucuronidase hydrolysis. For example, if a drug, agent, compound, or metabolite thereof has been metabolized to a glucuronide, hydrolysis of the glucuronide can reactivate the drug, agent, compound, or metabolite thereof. In many cases, this reactivation can cause adverse reactions, including but not limited to gastrointestinal discomfort, resulting in diarrhea.

For example, camptothecin-derived antineoplastic agents are useful in the treatment of solid malignancies of the brain, colon and lung, as well as refractory leukemias and lymphomas. Irinotecan is a prodrug that must be converted to its active form, SN-38 (7-ethyl-10-hydroxycamptothecin), in order to have antitumor activity. During its excretion, SN-38 is glucuronidated to SN-38 glucuronide (SN-380) by the drug metabolism UDP-glucuronidase. As more and more drugs are administered to a subject, increased metabolites may therefore serve as substrates for β -glucuronidase. The resulting reactivated metabolites not only cause severe side effects (especially gastrointestinal discomfort) that adversely affect the health of the subject, but also impair the therapeutic efficacy by limiting the amount of glucuronidase substrate that can be administered to the subject.

Another example of a commonly used glucuronidase substrate reagent is non-steroidal anti-inflammatory drugs (NSAIDs). Gastrointestinal Injury (GI) is one of the major NSAID adverse effects. This iatrogenic disease is manifested by ulceration and bleeding, inflammation and even perforation of the mucosa (Allison et al, New Engl. J. Med., 327: 749-. A portion of the carboxylic acid-containing NSAID is conjugated to glucuronic acid in vivo and forms an acylglucuronide. While not wishing to be bound by this, it is believed that inhibition of carboxylic acid NSAID/glucuronic acid deconjugation (deconjugation) by inhibiting β -glucuronidase activity results in reduced exposure of the intestinal mucosa to the NSAID, thereby reducing the toxicity of the NSAID.

Thus, without intending to be bound by any particular theory, it is believed that the compounds provided herein inhibit the interaction between β -glucuronidase and its substrate. Compounds contemplated by the present disclosure include, but are not limited to, the exemplary compounds provided herein and salts thereof.

Compound (I)

One embodiment of the present disclosure includes compounds of formula (I):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstitutedC of (A)_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation；

R_bIs hydrogen, C (O) NHR_cOr C (O) R_d；

R_cIs an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a glucuronide thereof,

or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a compound of formula (IG):

wherein

R_1A、R_1B、R_1CEach of which is independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenated alkyl sulfurRadical, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₂is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₃is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstitutedSubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

x is CO or SO₂；

Y is CH or N;

R₄is selected from a substituted or unsubstituted 3-10 membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R₅is (L)₁)_nR_aWherein L is₁Is C_1-6An alkylene chain, n is 0 or 1, and R_aIs OR_b、C_1-6Alkylamino or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation;

R_bis hydrogen, C (O) NHR_c、C(O)R_dOr

Wherein each R^xIndependently is hydrogen or C (O) R^z,

R^yIs H or R^zAnd is and

each R^zIndependently is C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_9-20Alkyl radical, C_9-20Alkenyl or C_9-20An alkynyl group;

R_cis an aryl group; and is

R_dIs substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_1-6Haloalkyl, substituted or unsubstituted C_1-6Alkoxy, substituted or unsubstituted C_1-6Alkylthio, substituted or unsubstituted C_1-6Haloalkoxy, substituted or unsubstitutedSubstituted C_1-6Halogenoalkylthio, substituted or unsubstituted C_1-6Alkylamino, substituted or unsubstituted C_1-6Alkylaminoalkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Haloalkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_2-6Haloalkynyl, halogen, cyano, nitro or a substituted or unsubstituted 3-to 10-membered ring, said ring optionally having one or more heteroatoms selected from N, O or S, and optionally having one or more degrees of unsaturation,

or a pharmaceutically acceptable salt thereof.

One aspect of the present disclosure includes wherein R_1AIs hydrogen. One aspect of the present disclosure includes wherein R_1BIs substituted or unsubstituted C_1-6An alkyl group. One aspect of the present disclosure includes wherein R_1CIs substituted or unsubstituted C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₂Is hydrogen or C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₃Is hydrogen. One aspect of the present disclosure includes wherein R₄Is a substituted or unsubstituted phenyl group. One aspect of the present disclosure includes wherein R₄Is a substituted phenyl group. One aspect of the present disclosure includes wherein R₄Is formed by one or more C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, halogen or SO₂R_eSubstituted phenyl, wherein R_eIs hydrogen or C_1-6An alkyl group. One aspect of the present disclosure includes wherein R₄Is phenyl and is monosubstituted. One aspect of the present disclosure includes wherein R₄Is phenyl and is disubstituted. One aspect of the present disclosure includes wherein R₅Is (L)₁)_nR_aWherein L is₁Is C₂Alkylene, n is 1, and R_aIs OR_bWherein R is_bIs hydrogen. One aspect of the present disclosure includes wherein R_b

Wherein each R^xIs hydrogen, and R^yIs hydrogen. One aspect of the present disclosure includes wherein each R^xIs C (O) R^zAnd R is^yIs R^z. One aspect of the present disclosure includes wherein each R^zIs C_1-6An alkyl group.

One embodiment of the present disclosure includes a compound selected from the group consisting of:

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2-phenyl-acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) propionamide;

2- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methylsulfonylphenyl) acetamide;

2- (2-chlorophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

n- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

2- (2-chloro-4-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide; 2- (2-bromo-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide;

1- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) methanesulfonamide;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethoxy) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

3- (4-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2- (trifluoromethyl) phenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2, 6-dimethylphenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-methoxyphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-isopropylphenyl) urea;

3- (2-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

6, 8-dibromo-3- (hydroxymethyl) quinolin-2 (1H) -one;

6, 8-dibromo-2-oxo-1, 2-dihydroquinoline-3-carbaldehyde;

3- (2-cyclopropylphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (pyridin-3-yl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-iodophenyl) urea; 1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (2-chloro-6, 8-dimethylquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-methoxyphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (m-tolyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-isopropylphenyl) urea;

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (3-ethynyl-4-fluorophenyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2- ((trimethylsilyl) ethynyl) phenyl) -1- (2-hydroxyethyl) urea;

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide;

2-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide; n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-phenylacetamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide;

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) propionamide;

1- (3-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) methanesulfonamide;

2- (2-bromo-5-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

3- (2-bromo-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3- (methylsulfonyl) phenyl) acetamide;

2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

3- (2-chloro-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea;

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethoxy) phenyl) urea;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

n- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide;

2- (2-chloro-4-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2-isopropylphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetamido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

6- (2- (2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetylamino) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure is a compound selected from the group consisting of:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present disclosure is a compound selected from the group consisting of:

or a glucuronide thereof, or a pharmaceutically acceptable salt thereof.

Composition for inhibiting beta-glucuronidase activity

One embodiment described in the present disclosure provides a composition that inhibits beta-glucuronidase activity. Generally, compositions that inhibit β -glucuronidase activity in humans and animals will comprise a pharmaceutically acceptable excipient or diluent, as well as a compound having the formula provided above for formula (I).

In one embodiment described herein is a composition comprising one or more compounds described herein and one or more pharmaceutically acceptable carriers.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions for administering the compounds of the present disclosure may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Generally, a pharmaceutical composition is prepared by: the active ingredient is combined with liquid carriers or finely divided solid carriers or both uniformly and intimately, and the product is then shaped into the desired formulation, if necessary. In the pharmaceutical composition, the active subject compound is included in an amount sufficient to produce the desired effect on the process or condition of the disease.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches (troche), lozenges (lozenge), aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying agents, as described in U.S. Pat. No. 6,451,339, hard or soft capsules, or syrups or elixirs. Compositions for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as cellulose, silicon dioxide, alumina, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be enterically coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be identified by U.S. Pat. nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral administration may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Alternatively, emulsions can be prepared with water-immiscible ingredients such as oils and the emulsions stabilized with surfactants such as mono-diglycerides, PEG esters, and the like.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents (suspending agents), for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia. Dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and a surfactant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile axel oil (axed oil) is commonly used as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. In addition, the compounds may be administered by ocular delivery via a solution or ointment. Still further, transdermal delivery of the subject compounds may be accomplished with the aid of iontophoretic patches and the like.

For topical use, creams, ointments, gels, solutions or suspensions containing the compounds of the present disclosure are used. As used herein, topical application is also intended to include the use of mouthwash and gargle (gargle). Formulations suitable for topical administration in the oral cavity include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in inert ingredients, such as gelatin and glycerin, or sucrose and acacia; mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dose formulations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of an active ingredient as described herein above.

The present subject matter further provides a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier therefore. Veterinary carriers are materials that can be used for the purpose of administering the composition, and can be solid, liquid or gaseous materials that are veterinary inert or acceptable and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

In certain embodiments, preferred pharmaceutical compositions comprise one or more of the presently disclosed compounds and one or more chemotherapeutic agents.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a timed release formulation for oral administration to a human may contain from about 1 to 1000mg of the active material, admixed with an appropriate and convenient amount of carrier material which may comprise from about 5% to about 95% (weight: weight) of the total composition. The pharmaceutical compositions can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution for intravenous infusion may contain about 3 to 500 μ g of active ingredient per mL of solution so that a suitable volume can be infused at a rate of about 30 mL/hr.

Method for inhibiting beta-glucuronidase activity and reducing side effect of medicine

In another aspect, the present disclosure provides a method of reducing side effects of one or more drugs comprising administering to a subject an effective amount of one or more compounds of formula (I) described herein. Compounds useful in the present methods include those according to formula (I), those provided above as embodiments, those specifically exemplified in the examples below and those provided with specific structures herein.

In one embodiment described herein is a method of reducing a side effect of one or more drugs comprising administering to a subject an effective amount of one or more compounds any described herein. In one aspect of the embodiments, the compounds described herein selectively inhibit β -glucuronidase. In one aspect described herein, the compound may be co-administered with one or more drugs.

The pharmaceutical compositions and methods of the present disclosure may further comprise other therapeutically active compounds described herein, including but not limited to the following treatments: 1) allergic diseases such as systemic anaphylaxis or hypersensitivity, drug allergy, insect bite allergy and food allergy, (2) inflammatory bowel diseases such as crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and allergic diseases of the respiratory tract such as allergic asthma, allergic rhinitis, hypersensitivity pneumopathy, etc.; (9) autoimmune diseases, such as fibromyalgia, scleroderma, ankylosing spondylitis, juvenile reactive arthritis (juvenile RA), Still's disease, polyarticular juvenile reactive arthritis, oligoarticular juvenile reactive arthritis, rheumatic polymyalgia, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, type II diabetes, glomerulonephritis, and the like; (10) graft rejection (including allograft rejection), (11) graft v host disease (including both acute and chronic) (12) other diseases in which undesirable inflammatory responses are to be suppressed, such as atherosclerosis, myositis, neurodegenerative diseases (e.g. alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome, and gout; (13) immune-mediated food allergies, such as abdominal (Celiac) disease (Coeliac disease); (14) pulmonary fibrosis and other fibrotic diseases; and (15) irritable bowel syndrome.

In another set of embodiments, diseases or conditions that may cause a side effect of treatment with a β -glucuronidase inhibitor compound include, but are not limited to, cancer, including, but not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies (lymphoid malignanes). More specific examples of such cancers include melanoma, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer, including melanoma of the lung, multiple myeloma, small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung (squamous carcinoma), peritoneal cancer, hepatocellular cancer, gastric or gastric cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma multiforme, KRAS mutant solid tumors, indolent non-hodgkin's lymphoma, Chronic Lymphocytic Leukemia (CLL), diffuse large B-cell lymphoma, thyroid cancer, non-hodgkin's lymphoma, basal cell carcinoma, hematological tumors, B-cell non-hodgkin's lymphoma, Acute Myeloid Leukemia (AML), cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, including triple negative breast cancer (triple negative cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer. Also included are "hematologic malignancies" or "hematologic cancers," which are types of cancer that affect the blood, bone marrow, and lymph nodes. Hematological malignancies may arise from two major blood cell lineages: myeloid and lymphoid cell lines. Myeloid (myeloid) cell lines typically produce granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; lymphoid cell lines give rise to B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias and myelomas are derived from lymphoid lineages, while acute and chronic myelogenous leukemias, myelodysplastic syndromes and myeloproliferative diseases originate from the bone marrow (myeloid). Leukemias include Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMOL) and Small Lymphocytic Lymphoma (SLL). Lymphomas include hodgkin's lymphoma (all four subtypes) and non-hodgkin's lymphoma (NHL, all subtypes), cardiovascular diseases, diseases in which angiogenesis or neovascularization plays a role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases (viral infections, e.g., HIV infections and bacterial infections) and immunosuppressive diseases (e.g., organ transplant conditions and skin transplant conditions), chronic inflammation, autoimmune diseases, e.g., rheumatoid arthritis, and immune-mediated food allergy (e.g., coeliaic (coeliaic) disease).

Another embodiment described herein includes a method for improving the treatment of a variety of diseases, including tumors of bone, brain, milk, cervix, colon, intestine, kidney, liver, lung, pancreas, prostate, rectum, stomach, larynx, uterus, and the like.

Another embodiment described herein includes methods for enhancing the efficacy of other drugs including, but not limited to: chemotherapeutic agents, including but not limited to camptothecin, indozino, irinotecan, diflucan, irinotecan, gemecan, irinotecan, clarithromycin (karenietin), lurtotecan, rubitecan, slatikon (silatecan), topotecan, NSAID, sorafenib, alkylating agents, such as thiotepa and cyclophosphamideAlkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa (benzodopa), carboquone (carboquone), metodopa (meteredopa) and myreodopa (uredopa); ethyleneimines and methylmelamines (melamines), including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; polyacetylens (acetogenins) (in particular bullatacin and bullatacin); delta-9-tetrahydrocannabinol (dronabinol,) (ii) a Beta-lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analog topotecan)CPT-11 (irinotecan,) Acetyl camptothecin, scopolectin (scopolectin) and 9-aminocamptothecin); bryodin; pemetrexed; callystatin; CC-1065 (including its adolesin, kazelesin and bizelesin synthetic analogs); podophyllotoxin; podophyllinic acid; (ii) teniposide; nostoc species (especially nostoc 1 and nostoc 8); dolastatin; doxokamicin (including synthetic analogs, KW-2189 and CB1-TM 1); eleutherobin (eleutherobin); (ii) coprinus atramentarius alkali; TLK-286; CDP323, an oral α -4 integrin inhibitor; latex epireticulin (sarcodictyin); spongistatin (spongistatin); nitrogen mustards, such as chlorambucil, chlorophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine (mechlorethamine), dichloromethyldiethylamine oxide hydrochloride (mechlorethamine oxide hydrochloride), melphalan, neomustard, cholesterol p-phenylacetic acid mustard, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorouramicin, fotemustine, lomustine, nimustine, and ranimustine; anti-hormonal agents, such as anti-estrogens and Selective Estrogen Receptor Modulators (SERMs), including for example tamoxifen (includingTamoxifen citrate), raloxifene, droloxifene, 4-hydroxyttamoxifen, trooxifene, keoxifene (keoxifene), LY117018, onapristone and(toremifene citrate); aromatase inhibitors which inhibit the enzyme aromatase, which regulates the production of adrenal estrogens, such as 4(5) -imidazole, aminoglutethimide,(megestrol acetate),(exemestane; pyroxene), formestane (formestanie), fadrozole,(vorozole) which is a compound of formula (i),(letrozole; noval) and(anastrozole; Asricon); antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; and troxacitabine (1, 3-dioxolane nucleoside cytosine analogues); (iv) protein kinase inhibitors; a lipid kinase inhibitor; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways associated with abnormal cell proliferation, such as PKC- α, Ralf, and H-Ras; (vii) ribozymes, e.g., VEGF expression inhibitors (e.g.) And inhibitors of HER2 expression; (viii) vaccines, e.g. gene therapy vaccines, e.g.And rIL-2; topoisomerase 1 inhibitors, e.g. rmRH; (ix) anti-angiogenic agents, e.g. bevacizumab (C)Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing; NSAIDs, including but not limited to salicylates, p-aminophenol derivatives, propionic acid derivatives, carboxylic acid derivatives, enolic acid derivatives, fenamic acid derivatives, sulfonanilides and selective COX-2 inhibitors. "NSAID salicylates" include, but are not limited to, aspirin (acetylsalicylic acid), diflunisal, and salsalate. "NSAID p-aminophenol derivatives" include, but are not limited to, acetaminophen and phenacetin. "NSAID propionic acid derivatives" include, but are not limited to ibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen. "NSAID carboxylic acid derivatives" include, but are not limited to, indomethacin, sulindac, etodolac, ketorolac, diclofenac. NSAID carboxylic acid derivatives include NSAID acetic acid derivatives. NSAID carboxylic acid derivatives are also referred to herein as "carboxylic acid NSAIDs". "NSAID enolic acid derivatives" include, but are not limited to, piroxicam, meloxicam, tenoxicam, chryseneOxicams, lornoxicam (lomoxicam) and isoxicam. "NSAID fenamic acid derivatives" include, but are not limited to, mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid. "NSAID sulfonanilides" includes, but is not limited to, nimesulide. "NSAID selective COX-2 inhibitors" include, but are not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, and nonoxib; antibiotics, including but not limited to cephalosporins such as cefixime and cefpodoxime, clindamycin, penicillins, fluoroquinolones such as ciprofloxacin and levofloxacin, enediynes antibiotics (e.g., calicheamicins, especially calicheamicin gamma 1I and calicheamicin omega 1 (see, e.g., Nicolaou et al, Angew. chem Intl. ed. Engl.,33: 183-) (1994)), diramimycins including diramicin A, epsipromycin, and the novel oncostatin chromophoresAnd related chromophoric chromenes, enediynes antibiotics, aclacinomysins, actinomycins, anthranomycin, azaserine, bleomycin, actinomycin c, karabicin, carminomycin, carvacomycin, pheochromomycin, chromomycin, dactinomycin, ditorelbumin, 6-diazo-5-oxo-L-norleucine, doxorubicin (includingMorpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino (pyrrolino) -doxorubicin, doxorubicin HCl liposome injectionAnd doxorubicine), epirubicin, esorubicin, idarubicin, sisomicin, mitomycins, such as mitomycin C, mycophenolic acid, noradriamycin, olivomycin, pellomycin, pofiromycin (potfiromycin), roxithromycin, trirubicin, roxobicin, streptonigrin, streptozotocin, tubercidin, ubenimex, netstatin, zorubicin; antimetabolite substances, e.g. methotrexate, gemcitabineTegafurCapecitabineEpothilones and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine and floxuridine; anti-adrenergic agents (anti-adrenergic), such as aminoglutethimide, mitotane, trostane;folic acid supplements, such as folic acid (frilic acid); acetic acid glucurolactone; an aldehydic phosphoramide glycoside; aminolevulinic acid; eniluracil; amsacrine; amoxicillin (bestrabucil); a bisantrene group; edatrexae; desphosphamide (defofamine); colchicine; diazaquinone; isoflurine (elfornithine); ammonium etiolate; etoglut; gallium nitrate; a hydroxyurea; lentinan; lonidamine (lonidainine); maytansinoids (maytansinoids), such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidazine; nifurtan; pentostatin; methionine mustard (phenamett); pirarubicin; losoxanthraquinone; 2-ethyl hydrazide; procarbazine;polysaccharide complex (JHS Natural Products, Eugene, OR); lezoxan; rhizomycin; a texaphyrin; a germanium spiroamine; (ii) zonecanoic acid; a tri-imine quinone; 2, 2' -trichlorotriethylamine; trichothecenes (especially T-2 toxin, Verluculin A, bacillocin A and snakesin); uratan; vindesineDacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; a polycytidysine; arabinoside ("Ara-C"); thiotepa; taxanes (taxoids), e.g. paclitaxelAlbumin engineered nanoparticle formulation (ABRAXANE) of paclitaxel^TM) And docetaxelChlorambucil (chlorenbucil); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastinePlatinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristineOxaliplatin; leucovorin (leucovovin); vinorelbineThe Noxiaolin area; edatrexae; erythromycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids (e.g., retinoic acid); a pharmaceutically acceptable salt, acid or derivative of any of the foregoing; and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone) and FOLFOX (oxaliplatin in combination with 5-FU and leucovorin (Leucovin)^TM) Abbreviations for treatment regimens of (a); vaccines, e.g.Vaccines and gene therapy vaccines, e.g.A vaccine is provided which comprises a vaccine,a vaccine anda vaccine; topoisomerase 1 inhibitors (e.g. topoisomerase 1 inhibitors)) (ii) a Antiestrogens, such as fulvestrant; EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors, such as bevacizumab; irinotecan (arinotecan); rmRH (e.g. rmRH)) (ii) a 17AAG (a geldanamycin derivative that is a heat shock protein (Hsp)90 poison), and a pharmaceutically acceptable salt, acid, or derivative of any of the foregoing; anti-hormonal agents which regulate, reduceBlocking or inhibiting the action of hormones that can promote the growth of cancer, and generally takes the form of systemic or systemic treatment. They may be hormones themselves. Examples include antiestrogens and Selective Estrogen Receptor Modulators (SERMs), including, for example, tamoxifen (includingTamoxifen), raloxifeneDroloxifene, 4-hydroxyttamoxifen, trooxifene, keoxifene (keoxifene), LY117018, onapristone and toremifeneAnti-progestin; estrogen Receptor Downregulators (ERDs); estrogen receptor antagonists, such as fulvestrantAgents having ovarian-suppressing or ovarian-closing function, e.g. luteinizing hormone-releasing hormone (LHRH) agonists, e.g. leuprolide acetate (L: (L))And) Goserelin acetate, buserelin acetate and tripterygium wilfordii; antiandrogens, such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors which inhibit the enzyme aromatase, which regulates the production of adrenal estrogens, such as 4(5) -imidazole, aminoglutethimide, megestrol acetateExemestaneFormestane, fadrozole, vorozoleLetrozoleAnd anastrozoleIn addition, the definition of such chemotherapeutic agents includes bisphosphonates, such as clodronates (e.g., clodronate)Or) Etidronate or esterNE-58095, zoledronic acid/zoledronic acid salts or estersAlendronate or esterPamidronate or esterTiludronate or esterOr risedronateAnd troxacitabine (1, 3-dioxolane nucleoside cytosine analogues); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways associated with abnormal cell proliferation, such as PKC- α, Raf, H-Ras and epidermal growth factor receptor (EGF-R); immunosuppressants and antirejection agents, including but not limited to tacrolimus and cyclosporinePlain, mycophenolate mofetil, mycophenolate sodium, azathioprine, sirolimus and prednisone; other beta-glucuronidase substrate drugs, including but not limited to morphine, acetaminophen, oxazepam, androsterone, carbamazepine, codeine, lamotrigine, lorazepam, temazepam, testosterone, and zidovudine.

Preparation of beta-glucuronidase inhibitors

The following examples are provided to illustrate but not to limit the claimed disclosure.

In addition, one skilled in the art will recognize that the molecules claimed in this patent can be synthesized using a variety of standard organic chemical transformations. The compounds described herein can be synthesized using corresponding deuterated and optionally other isotopically-containing reagents and/or intermediates, or such methods can be performed by calling standard synthetic protocols known in the art for introducing isotopic atoms into chemical structures.

Some general reaction types widely used for synthesizing the target compounds in the present disclosure are summarized in the examples. In particular, a general procedure for the formation of sulfonamides, pyridine N-oxides and 2-aminophenyl-aryl ketones via Friedel-Crafts type processes is given, but many other standard chemical procedures are described and routinely used herein.

Although not intended to be exhaustive, the following includes representative synthetic organic transformations that may be used to prepare the compounds of the present disclosure.

These representative transformations include: standard functional group manipulations; such as the reduction of nitro groups to amino groups; oxidation of functional groups including alcohols and pyridines; aryl substitution via IPSO or other mechanisms that introduce a variety of groups including nitrile groups, methyl groups, and halogens; introduction and removal of protection groups; formation of grignard reagents and reaction with electrophiles; metal-mediated cross-coupling, including but not limited to Buckwald, Suzuki and Sonigashira reactions; halogenation and other electrophilic aromatic substitution reactions; the formation of diazonium salts and the reaction of these species; etherification; cyclocondensation (cyclic condensation), dehydration, oxidation and reduction, which results in heteroaryl groups; aryl metallation and transition metalation and subsequent reaction of aryl metal species with electrophiles (e.g., acid chlorides or Weinreb amides); amidation; esterification; nucleophilic substitution reaction; alkylation; acylation; formation of a sulfonamide; chlorosulfonyl acylation; esters and related hydrolysis, and the like.

Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variations of these compounds are within the scope of the disclosure.

In the synthetic description that follows, some precursors are available from commercial sources. Such commercial sources include Aldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated, Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS Chemicals.

The compounds of the present disclosure can be prepared by the methods and routes described in the experimental section below, as well as by using standard organic chemical transformations well known to those skilled in the art.

Examples

The present disclosure expressly encompasses those compounds presented herein. Compositions comprising therapeutically acceptable amounts of any of these compounds are also within the scope of the invention. The compounds may be synthesized using the techniques described and illustrated herein.

The substituents and variables used in the schemes of the present disclosure are not intended to be the same as the substituents and variables used to define the compounds of formula (I) and (IG) of the present disclosure. Although not identical, the respective definitions are clear.

Protocols from PCT/US2018/048891 (incorporated herein by reference in their entirety for any synthetic teaching) can be used for reference:

synthesis scheme 1：

Treatment of 2, 6-dimethylbenzoic acid with nitric/sulfuric acid affords the nitro compound, which is subsequently subjected to borane reduction to yield the alcohol. The nitro group is then reduced and subsequently acetylated to give the N-acetyl derivative. The N-acetylated compound was then subjected to DMF/POCl3 conditions to afford 7- (chloromethyl) -6, 8-dimethyl-2-oxo-1H-quinoline-3-carbaldehyde (I) directly. Intermediate (I) is then treated with ethanolamine to provide intermediate (II), or with various amines to provide intermediate (III). The intermediate (III) is reductively aminated with various amines to give Intermediate (IV). Intermediate (IV) is then reacted with various isocyanates or isothiocyanates to provide the final compound (V).

Synthesis scheme 2：

Scheme for the synthesis of Inh-1 glucuronide:

inh-1 in dichloromethane was cooled to-10 degrees and treated with 2,3, 4-tri-O-acetyl-1-O-trichloroacetimidoyl) -alpha-D-glucopyranosuronic acid (glucopyranosic acid) methyl ester followed by boron trifluoride etherate (etherate) solution. After stirring for 30 min, the reaction was warmed to room temperature, stirred for 3h, and then saturated NaHCO was used₃And (4) quenching. After separating the organic layer and drying, the crude reaction was taken to the next step. Hydrolysis of the acetate and methyl esters with 1N NaOH gave the desired Inh-1 glucuronide. LCMS (ESI)602(M + H).

Alternative glucuronide synthesis:

for the production of inhibitor-glucuronide by non-chemical synthesis, use is made ofSupersomes^TMUGT biosynthesis technology. UGT superfluids (supersomes) are baculovirus-produced UGTs and are more pure than the normal microsomal fraction. Briefly, the activation of the suprabody requires a propeptide (alamethicin) (pore-forming molecule), UGT suprabody, BSA, microsomal buffer (100mM Tris ph 7.5,100mM NaCl) and MgCl₂. The mixture was incubated on ice for 30 minClock to allow for pore formation, then add the receptor parent drug substrate and incubate for an additional 5 minutes at 37 ℃. The reaction was initiated by addition of UGT cofactor UDP-glucuronic acid (UDP-GA), incubated at 37 ℃ and incubated overnight.

Since it is not clear which particular UGT forms a conjugate with the inhibitor, a master mix (14 total from UGT1 and UGT 2) of all available UGTs was created for the UGT reaction.

UDP-Glo Using Promega^TMThe assay kit quantitates the amount of inhibitor glucuronide produced. The luciferase reaction can detect the formation of UDP molecules produced during the UGT reaction that converts UDP-GA to UDP in a one-to-one molar ratio, which serves as an inhibitor-glucuronide production.

Examples of Synthesis of Compounds

Scheme 3

General procedure for compounds having structure a: compound 5(0.1g,0.4mmol) was dissolved in DMF (2ml) and DIEA (0.1ml,0.6mmol), compound 46(1 eq) and HATU (0.18g,0.48mmol) were added. The mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture and the organic layer was separated over MgSO₄Dried and the solvent removed. The crude was purified by column chromatography (12g, silica gel) using a gradient of 0-4% MeOH in DCM to give compound a.

The following compounds were synthesized according to the general procedure.

Example 1

Example 1

N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide LCMS ESI (M + H)379

Example 2

N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.25-2.32(m,3H)2.35-2.41(m,3H)3.39-3.68(m,4H)3.80-4.03(m,1H)4.38-4.56(m,1H)6.92-7.02(m,1H)7.11-7.18(m,1H)7.22-7.36(m,2H)7.55-7.61(m,1H)7.66-7.71(m,1H)7.74-7.89(m,1H)10.91-11.05(m,1H)；LCMS ESI(M+H)491

example 3

Example 3

N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2-phenyl-acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.25-2.31(m,3H)2.35-2.39(m,3H)3.34-3.59(m,4H)3.70-3.89(m,2H)4.34-4.51(m,2H)7.07(s,1H)7.11-7.20(m,2H)7.22-7.36(m,5H)10.81-11.14(m,1H)；LCMS ESI(M+H)365。

example 4

Example 4

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.28-2.30(m,3H)2.37-2.40(m,3H)3.38-3.70(m,4H)3.81-4.08(m,2H)4.31-4.58(m,2H)7.09-7.23(m,3H)7.25-7.39(m,3H)7.48-7.69(m,2H)10.94(br.s.,1H)；LCMS ESI(M+H)443。

example 5

Example 5

2- (2-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) propionamide:

LCMS ESI(M+H)457,459。

example 6

Example 6

2- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.28(s,3H)2.36-2.40(m,3H)3.38-3.64(m,4H)3.75-3.93(m,2H)4.35-4.54(m,2H)7.10-7.21(m,2H)7.26-7.39(m,3H)7.42-7.54(m,2H)10.87-11.07(m,1H)；LCMS ESI(M+H)443,445。

example 7

Example 7

N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methylsulfonylphenyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.25-2.29(m,3H)2.34-2.38(m,3H)3.13-3.16(m,3H)3.17-3.19(m,1H)3.35-3.63(m,4H)3.88-4.07(m,2H)4.30-4.58(m,2H)7.10-7.41(m,2H)7.45-7.63(m,3H)7.68-7.85(m,2H)10.90(br.s.,1H)；LCMS ESI(M+H)443。

example 8

Example 8

2- (2-chlorophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide:

LCMS ESI(M+H)399。

example 9

Example 9

N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide:

LCMS ESI(M+H)395。

example 10

Example 10

2- (2-chloro-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.29-2.36(m,3H)2.41-2.46(m,3H)3.40-3.71(m,4H)3.76(s,3H)3.84-4.05(m,2H)4.42-4.63(m,2H)6.81-6.99(m,2H)7.17-7.40(m,3H)7.51-7.70(m,1H)10.89-11.19(m,1H)；LCMS ESI(M+H)429,431。

example 11

Example 11

2- (2-chloro-4-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide:

1H NMR(500MHz,DMSO-d₆)δppm 2.25-2.32(m,3H)2.35-2.41(m,3H)3.35-3.63(m,4H)3.66-3.95(m,5H)4.30-4.57(m,2H)6.80-7.05(m,2H)7.04-7.60(m,4H)10.88-11.07(m,1H)；LCMS ESI(M+H)429。

scheme 4

Compound 58, scheme 4

3- [ [2- [ tert-butyl (dimethyl) silyl ] group]Oxyethylamino group]Methyl radical]To a solution of compound 5(0.6g,2.4mmol) in DMF (6mL) was added imidazole (0.4g,0.06mol) and TBDMS-Cl (0.44g,2.9mmol) and the mixture was stirred at room temperature overnight. More imidazole (0.4g) and TBDMS-Cl (0.44g) were then added and the mixture was stirred at room temperature overnight. Water (100mL) and ethyl acetate (200mL) were added to the reaction mixture. The organic layer was separated and washed with water and MgSO₄Dried, filtered and the solvent evaporated under reduced pressure. The crude was purified by silica gel plug using a gradient of 0-10% MeOH in DCM to give 660mg of compound 58 (75%) as a yellow solid. LCMS ESI (M + H)

Compound 59, scheme 4

2- (2-bromo-5-methoxy-phenyl) -N- [2- [ tert-butyl (dimethyl) silyl]Oxyethyl radical]-N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl]Acetamide compound 5(0.075g,0.2mmol) was dissolved in DMF (2ml) and DIEA (0.05ml,0.3mmol), 2- (2-bromo-5-methoxy-phenyl) acetic acid (0.051,0.2mmol) and HATU (0.091g,0.24mmol) were added. The mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture and the organic layer was separated over MgSO₄The solvent was dried and removed to give crude 59 as a yellow oil. LCMS ESI (M + H)587

Example 12

2- (2-bromo-5-methoxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl]To a solution of crude 59 in THF (3mL) was added 0.19g of TBAF.3H₂O (3 equivalents, assuming 100% yield of 59), and the mixture was stirred at room temperature for 1 hour. Then water and ethyl acetate were added, the organic layer was separated over MgSO₄Dried and the solvent evaporated under reduced pressure. Purify the crude by column chromatography (silica gel, 12g) using a 0-12% MeOH/DCM gradient to give 100mg of compound 60 (about 100%) from compound 58 as a white solid.

1H NMR(500MHz,DMSO-d₆)δppm 2.24-2.28(m,3H)2.32-2.38(m,3H)3.46-3.62(m,4H)3.67(s,3H)3.74-4.00(m,2H)4.26-4.52(m,2H)6.61-6.91(m,2H)7.08-7.68(m,4H)10.82-11.05(m,1H)；LCMS ESI(M+H)473。

Scheme 5

Compound 61, scheme 5

1- (3-bromophenyl) -N- [2- [ tert-butyl (dimethyl) silyl]Oxyethyl radical]-N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl]To a solution of compound 58(0.1g,0.28mmol) in DCM (2mL) was added pyridine (0.135mL,0.0017mol) and (3-bromophenyl) methanesulfonyl chloride (0.11g,0.42mmol), and the reaction mixture was stirred at room temperature overnight. Water was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined and MgSO₄Dried and concentrated under reduced pressure to give crude 61(170mg) as a white solid. LCMS ESI (M + H) 593.

Example 13

1- (3-bromophenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl]N- (2-hydroxyethyl) methanesulfonamide to a solution of crude 61 in THF (3mL) was added 0.18g of TBAF.3H₂O (3 equivalents, assuming 100% yield of 61), and the mixture was stirred at room temperature overnight. Then water and ethyl acetate were added, the organic layer was separated over MgSO₄Dried and the solvent evaporated under reduced pressure. Purify the crude by column chromatography (silica gel, 12g) using a gradient of 0-5% MeOH/DCM to obtain 8mg of compound 62 (6%) from compound 58 as a white solid. LCMS ESI (M + H) 479.

With reference to the general synthetic description provided in PCT/US2018/48891 (incorporated herein by reference for such teaching), the following additional compounds were prepared:

example 14

Example 15

Scheme 6:

general glucuronidation protocol: dried in an oven(2-hydroxyethyl) intermediate 3X (1.1mmol) and methyl 2,3, 4-tri-O-acetyl-1-O- (trichloroacetimidoyl) - α -D-glucuronate (1.26mmol) were dissolved in anhydrous DCM (20mL/1mmol of 3X) in the presence of molecular sieves. The reaction was stirred at room temperature for 30 minutes and then cooled at-50 ℃ for 15 minutes. Dropwise addition of BF by syringe₃A solution of the etherate (1.1mmol) in anhydrous DCM (2 mL). The reaction was stirred while warming to room temperature over 2h while the chalk-like solution became clear, then saturated NaHCO₃Quenched and extracted with DCM, washed with brine, over MgSO₄Drying and evaporating. Purification by flash chromatography (silica gel, 0-100% EA/hexanes) gave the desired product as a white solid; the yield is 45-80%.

CG-1CY198 (2S,3S,4S,5R,6R) -methyl 3,4, 5-triacetoxy-6- [2- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl- [ (4-ethoxyphenyl) carbamoyl ] amino ] ethoxy ] tetrahydropyran-2-carboxylate methyl 1H NMR (500MHz, DMSO-d6) δ ppm 1.28(t, J ═ 7.09Hz,3H)1.94(S,3H)1.97(S,3H)1.98(S,3H)2.30(S,3H)2.41(S,3H)3.38-3.52(m,2H)3.61(S,3H)3.68-3.75(m,1H)3.83-3.90(m,1H)3.94(q, J ═ 7.01H) 4.01(q, 4H), j ═ 7.34Hz,1H)4.32-4.39(m,1H)4.40-4.48(m,2H)4.78-4.84(m,1H) 4.904.97 (m,2H)5.33(t, J ═ 9.54Hz,1H)6.80(d, J ═ 8.80Hz,2H)7.20(s,1H)7.31(d, J ═ 8.80Hz,2H)7.35(s,1H)7.78(s,1H)11.29(br.s, 1H); LCMS ESI (M + H) 726.4.

CG-1CY179 (2S,3S,4S,5R,6R) -3,4, 5-triacetoxy-6- [2- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl- [ (2-isopropylphenyl) carbamoyl ] amino ] ethoxy ] tetrahydropyran-2-carboxylic acid methyl ester 1H NMR (500MHz, DMSO-d6) δ ppm 1.09(d, J ═ 6.85Hz,6H)1.95(S,3H)1.97(S,3H)2.00(S,3H)2.31(S,3H)2.41(S,3H)3.13-3.21(m,1H)3.42-3.52(m,2H)3.60(S,3H)3.72(ddd, J ═ 11.00,5.87,5.62, 2H)3.89(ddd, 10.89.01, 15.89 Hz, 89Hz,1H)4.01(q, J ═ 6.85Hz,1H)4.35-4.41(m,1H)4.43-4.51(m,2H)4.79-4.85(m,1H)4.91-4.98(m,2H)5.35(t, J ═ 9.54Hz,1H)7.06-7.11(m,2H)7.19(s,1H)7.20-7.25(m,2H)7.32(s,1H)7.74(br.s.,1H)11.17(br.s., 1H); LCMS ESI (M + H) 724.8.

CG-1CY187 (2S,3S,4S,5R,6R) -3,4, 5-triacetoxy-6- [2- [ (2-tert-butylphenyl) carbamoyl- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] tetrahydropyran-2-carboxylic acid methyl ester 1H NMR (500MHz, DMSO-d6) delta ppm 1.31(S,9H)1.95(S,3H)1.97(S,3H)2.01(S,3H)2.31(S,3H)2.39(S,3H)3.41-3.48(m,1H)3.50-3.58(m,1H)3.60(S,3H)3.67-3.74(m,1H)3.89(ddd, J ═ 10.15,5.01,4.89, 1H)4.39 (J ═ 17 Hz), 1H)4.45(d, J ═ 10.27Hz,1H)4.50(d, J ═ 17.12Hz,1H)4.79-4.83(m,1H)4.90-4.97(m,2H)5.33(t, J ═ 9.54Hz,1H)7.01-7.06(m,1H)7.12-7.16(m,2H)7.19(s,1H) 7.307.35 (m,2H)7.73(br.s.,1H)11.13(br.s., 1H); LCMS ESI (M + H) 738.3.

CG-1CY191 methyl (2S,3S,4S,5R,6R) -3,4, 5-triacetoxy-6- [2- [ [2- (2-chlorophenyl) acetyl ] - [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] tetrahydropyran-2-carboxylate 1H NMR (500MHz, DMSO-d6) δ ppm 1.88-2.03(m,9H)2.30(d, J ═ 2.93Hz,3H)2.38(d, J ═ 9.29Hz,3H)3.59(d, J ═ 15.65Hz,3H)3.72-4.01(m,6H)4.32-4.56(m,4H)4.86-5.01(m,2H)7.11-7.44(m,8H)7.45-7.69(m, 11.93-11H) 11.11(m, 11H), 2H) (ii) a LCMS ESI (M + H) 715.4.

CG-1CY226 (2S,3S,4S,5R,6R) -3,4, 5-triacetoxy-6- [2- [ [2- (2-bromophenyl) acetyl ] - [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] tetrahydropyran-2-carboxylic acid methyl ester 1H NMR (500MHz, DMSO-d6) delta ppm 2.29(br.s.,4H)2.30(br.s.,3H)2.37(S,3H)2.39(S,3H)3.58(S,3H)3.61(S,3H)3.88(d, J ═ 15.65Hz,2H)4.31-4.39(m,2H)4.41-4.49(m,2H)4.87-5.00(m,4H) 5.295.38 (m,2H) 7.7-16.21H) (m,3H), 3H)7.30(dd, J ═ 11.49,3.67Hz,2H)7.51-7.59(m,2H)7.65-7.70(m,1H)10.93-11.06(m, 1H); LCMS ESI (M + H) 759.5.

1CY225 coupling of 2- (2-chloro-4-hydroxy-phenyl) -N- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] -N- (2-hydroxyethyl) acetamide in the presence of EDCI, HOBt and Hunig's base of 3- [ (2-hydroxyethylamino) methyl ] -6, 8-dimethyl-1H-quinolin-2-one (60mg,0.2mmol) with 2- (2-chloro-4-hydroxy-phenyl) acetic acid (37mg,0.2mmol) is currently carried out very slowly.

Representative procedure for hydrolysis of methyl and acetyl groups of glucuronic acid units: the glucuronidated product A (0.4mmol) in a THF/MeOH mixture (6: 1; 21mL) at 0 deg.C was treated slowly with 1N NaOH (6 mL). The reaction was stirred in an ice-water bath for 2h, and the organic solvent was removed in vacuo (no heating). The aqueous residue (white suspension) was neutralized to pH 7 with 1N HCl, then cooled at-78 ℃ and lyophilized to give the sodium salt of the desired product as a white solid.

CG-1CY199 (2S,3S,4S,5R,6R) -6- [2- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl- [ (4-ethoxyphenyl) carbamoyl ] amino ] ethoxy ] -3,4, 5-trihydroxy-tetrahydropyran-2-carboxylic acid.

1H NMR(500MHz,DMSO-d6)δppm 1.28(t,J＝6.85Hz,3H)2.29(s,3H)2.40(s,3H)2.97(t,J＝8.31Hz,1H)3.07-3.12(m,1H)3.16(t,J＝8.56Hz,1H)3.25(d,J＝9.78Hz,2H)3.44-3.50(m,2H)3.58(d,J＝3.91Hz,2H)3.78(ddd,J＝10.88,5.62,5.50Hz,1H)3.85(ddd,J＝10.52,5.62,5.38Hz,1H)3.94(q,J＝7.17Hz,2H)4.21(d,J＝7.83Hz,1H)4.46(s,2H)4.98-5.25(m,2H)6.78(d,J＝9.29Hz,2H)7.18(s,1H)7.33(d,J＝8.80Hz,2H)7.41(s,1H)7.96(br.s.,1H)9.42(br.s.,1H)11.24(br.s.,1H)；LCMS ESI(M+H)586.1。

CG-1CY185 (2S,3S,4S,5R,6R) -6- [2- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl- [ (2-isopropylphenyl) carbamoyl ] amino ] ethoxy ] -3,4, 5-trihydroxy-tetrahydropyran-2-carboxylic acid.

1H NMR(500MHz,DMSO-d6)δppm 1.10(d,6H)2.30(s,3H)2.40(s,3H)2.99(t,J＝8.07Hz,1H)3.05 3.10(m,1H)3.14(d,J＝8.80Hz,1H)3.16-3.21(m,1H)3.22(d,J＝9.78Hz,1H)3.51(br.s.,2H)3.70 3.77(m,1H)3.84-3.90(m,1H)4.19(d,J＝7.83Hz,1H)4.44-4.56(m,3H)5.07(br.s.,1H)5.17(br.s.,1H)7.05-7.09(m,2H)7.17(br.s.,1H)7.20-7.24(m,2H)7.36(br.s.,1H)7.91(br.s.,1H)8.79(br.s.,1H)11.15(br.s.,1H)；LCMS ESI(M+H)584.4。

1CY188 (2S,3S,4S,5R,6R) -6- [2- [ (2-tert-butylphenyl) carbamoyl- [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] -3,4, 5-trihydroxy-tetrahydropyran-2-carboxylic acid 1H NMR (500MHz, DMSO-d6) δ ppm 1.33(S,9H)2.31(S,3H)2.39(S,3H)2.95(t, J ═ 8.31Hz,1H) 3.023.08 (m,1H)3.10-3.15(m,1H)3.17-3.23(m,1H)3.55(d, J ═ 7.34Hz,2H)3.68-3.75(m,1H) 3.833.90 (m,1H)4.17(d, J ═ 7.83, 4H) 46.59 Hz (m,1H), 2H)5.00(br.s.,1H)5.08(br.s, 1H)7.02-7.06(m,1H)7.10-7.15(m,2H)7.17(br.s, 1H)7.27-7.41(m,2H)7.92(br.s, 1H)8.58(s,1H)11.14(s, 1H); LCMS ESI (M + H) 598.7.

1CY192 (2S,3S,4S,5R,6R) -6- [2- [ [2- (2-chlorophenyl) acetyl ] - [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] -3,4, 5-trihydroxy-tetrahydropyran-2-carboxylic acid 1H NMR (500MHz, DMSO-d6) δ ppm 2.29(br.s.,3H)2.39(d, J ═ 7.83Hz,3H)2.89-2.95(m,1H) 2.993.06 (m,2H)3.06-3.11(m,1H)3.14(dd, J ═ 9.54,5.14Hz,2H)3.49-3.56(m,1H)3.62(d, J ═ 5.38, 1H)3.66-3.76(m,1H)3.84(d, J ═ 5.87, 3H) 3.93H (d, 93H), 3.87 (d, 3H) 3.87 Hz, 3.93H, 3.3., 1H)4.08(br.s.,1H)4.09-4.21(m,1H) 4.304.47 (m,1H)4.59(d, J ═ 7.83Hz,1H)5.00-5.45(m,2H)7.13(br.s.,1H)7.20-7.29(m,2H)7.30-7.42(m,2H)7.51-7.79(m,1H)10.99(br.s., 1H); LCMS ESI (M + H) 575.4.

1CY228 (2S,3S,4S,5R,6R) -6- [2- [ [2- (2-bromophenyl) acetyl ] - [ (6, 8-dimethyl-2-oxo-1H-quinolin-3-yl) methyl ] amino ] ethoxy ] -3,4, 5-trihydroxy-tetrahydropyran-2-carboxylic acid 1H NMR (500MHz, DMSO-d6) delta ppm … …; LCMS ESI (M + H) 519.3.

Example 16

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) -1- (2-hydroxyethyl) urea

Example 17

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethyl) phenyl) urea

Example 18

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4- (trifluoromethoxy) phenyl) urea

Example 19

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea

Example 20

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethyl) phenyl) urea

Example 21

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea

Example 22

3- (4-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 23

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2- (trifluoromethyl) phenyl) urea

Example 24

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2, 6-dimethylphenyl) -1- (2-hydroxyethyl) urea

Example 25

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-methoxyphenyl) urea

Example 26

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea

Example 27

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (4-isopropylphenyl) urea

Example 28

3- (2-bromophenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 29

6, 8-dibromo-3- (hydroxymethyl) quinolin-2 (1H) -one

Example 30

6, 8-dibromo-2-oxo-1, 2-dihydroquinoline-3-carbaldehyde

Example 31

3- (2-Cyclopropylphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 32

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 33

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (pyridin-3-yl) urea

Example 34

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (2-iodophenyl) urea

Example 35

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea

Example 36

1- (1- (2-chloro-6, 8-dimethylquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea

Example 37

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (2-isopropylphenyl) urea

Example 38

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (4-fluoro-2-iodophenyl) -1- (2-hydroxyethyl) urea

Example 39

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (o-tolyl) urea

Example 40

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (4-methoxyphenyl) urea

EXAMPLE 41

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-methoxyphenyl) urea

Example 42

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (m-tolyl) urea

Example 43

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -1- (2-hydroxyethyl) -3- (3-isopropylphenyl) urea

Example 44

1- (1- (6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) ethyl) -3- (3-ethynyl-4-fluorophenyl) -1- (2-hydroxyethyl) urea

Example 45

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-fluoro-2- ((trimethylsilyl) ethynyl) phenyl) -1- (2-hydroxyethyl) urea

Example 46

3- ([1,1' -biphenyl ] -2-yl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 47

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (o-tolyl) acetamide

Example 48

2-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide

Example 49

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (2-iodophenyl) acetamide

Example 50

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-phenylacetamide

Example 51

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide

Example 52

3-bromo-N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) benzamide

Example 53

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide

Example 54

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide

Example 55

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -3-iodobenzamide

Example 56

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2-iodobenzamide

Example 57

2- (2-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) propionamide

Example 58

1- (3-bromophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) methanesulfonamide

Example 59

2- (2-bromo-5-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide

Example 60

3- (2-bromo-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 61

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3- (methylsulfonyl) phenyl) acetamide

Example 62

2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide

Example 63

2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide

Example 64

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide

Example 65

3- (2-chloro-5-methoxyphenyl) -1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) urea

Example 66

1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -1- (2-hydroxyethyl) -3- (3- (trifluoromethoxy) phenyl) urea

Example 67

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide

Example 68

N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) -2- (3-methoxyphenyl) acetamide

Example 69

2- (2-chloro-4-methoxyphenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -N- (2-hydroxyethyl) acetamide

Example 70

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (4-ethoxyphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

Example 71

6- (2- (1- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) -3- (2-isopropylphenyl) ureido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

Example 72

6- (2- (2- (2- (tert-butyl) phenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetamido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

Example 73

6- (2- (2- (2-chlorophenyl) -N- ((6, 8-dimethyl-2-oxo-1, 2-dihydroquinolin-3-yl) methyl) acetamido) ethoxy) -3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

Biological examples

The compounds of the present disclosure can be tested for biological activity using the following test methods.

Successful drug candidate compounds can be subjected to a number of biochemical and cellular assays. Purified bacterial beta-glucuronidase can be challenged with compounds to determine inhibitory properties in a standard robust activity assay using p-nitrophenylglucuronide (PNPG) as the enzyme substrate. The reaction (n-3/inhibitor concentration) can be performed in a 96-well assay consisting of PNPG substrate (12 concentrations between 25 μ M and 5 mM), inhibitor solution (8 concentrations between 0.1nM and 100 μ M) and 5nM enzyme. Preferred compounds exhibit<1 μ M effective IC₅₀The value is obtained.

In addition, preferred compounds show negligible effect (if any) on purified mammalian β -glucuronidase, in particular, preferred compounds have > 500-fold selectivity and effectiveness for purified bacterial enzymes. Purified bovine liver and human β -glucuronidase can be dissolved in a reaction mixture containing 1 μ M enzyme and 1mM PNPG as substrates.

Live, cultured bacterial cells (e.coli, Bacteroides vulgatus, Clostridium ramosum) as well as Lactobacillus reuteri and Bifidobacterium infantis (Bifidobacterium infantis) mixed with compounds (8 concentrations, between 0.1nM and 100 μ M) may have reduced beta-glucuronidase activity when challenged with 1mM PNPG as a substrate. Effective inhibitory properties are observed for preferred compounds of the invention, i.e. exhibiting an EC of < 500nM₅₀The value is obtained.

In addition, live cells can be incubated with drug candidates (semilogarithmic units from 1. mu.M to 10mM) for extended time points and plated on LB-agar plates for standard colony formation assays. After extended incubation of the NCE and cultured bacteria, an observable or quantifiable effect on cell growth and viability can be determined. As such, preferred compounds of the present disclosure do not exhibit antimicrobial characteristics. In addition, cultured mammalian cells (HCT116 cells) incubated with drug candidates (6-24 hour incubation time points) can continue to grow and be viable as evidenced by the conversion of resazurin to resorufin (resorufin), which is indicative of the viability of the mammalian cells. Importantly, these compounds may not be cytotoxic to mammalian cells.

The in vivo efficacy of the compounds can be determined in a therapeutic mouse model developed by symbrix, inc. Efficacy can be determined by a reduction in bloody diarrhea (observed and scored) and decreased SN-38 levels in the stool (determined by bioanalysis). The compounds can be administered orally to multiple cohorts of mice (cohort) including untreated, vehicle, inhibitor only, and treated groups, twice daily at a dose intensity of 0.1mg/kg to 1 mg/kg. Unless otherwise stated, the therapeutic dose is 50 mg/kg. The compounds of the invention show a reduction in bacterial beta-glucuronidase activity due to inhibition, as evidenced by a reduction in the incidents of bloody diarrhea in mice and a reduction in the levels of SN-38 in the feces.

Table 1 describes data demonstrating the increased potency of inhibitor-glucuronide in the cell assay described with 2 hours incubation time.

The glucoside ester prodrug can be activated by esterases to produce the inhibitor glucuronide, which has been demonstrated to have increased potency in a cell-based e. These prodrugs remain inactive in the cell in the absence of ester cleavage. This was demonstrated in a cell-based assay using example CG-1CY179(SY 65-G-acetate) with and without pretreatment with rabbit or pig liver esterase. For esterase activation, the former drug was treated with 5mg/mL esterase at 37 ℃ for 30 minutes to cleave the ester bond, thereby producing a glucuronide moiety. After treatment, inhibitor titers at concentrations ranging from 10uM to 10pM were mixed and preincubated with live E.coli at 37 ℃ for 5 minutes or 4 hours in microplate containing assay buffer (HEPES pH 7, NaCl). Chemically synthesized SY65-G was included as a positive control. After pre-incubation, 4-methylumbelliferyl glucuronide (4MUG) was added to the cell and inhibitor mixture at a final concentration of 100 uM. The conversion of 4MUG to 4MU was detected by fluorescence (excitation/emission: 360/460). As shown in table 3, the esterase treated glucuronide prodrug was as effective as the glucuronide positive control. The untreated prodrug had no activity.

All publications, patents, and patent applications cited in this specification are herein incorporated by reference for the purpose of using the teachings of such citations.

The test compounds used in the experiments described herein can be used in free form or in salt form.

The specific response observed may vary according to and depending upon the particular active compound selected or whether a carrier is present, as well as the type of formulation and mode of administration used, and such expected variations or differences in the results are contemplated in accordance with the practice of the present disclosure.

Although specific embodiments of the present disclosure have been illustrated and described in detail herein, the invention is not so limited. The above detailed description is provided as an example of the present disclosure and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.