US2023373932A1PendingUtilityA1
Dihydropyrimidin-2-one compounds and medical use thereof
Est. expiryDec 12, 2034(~8.4 yrs left)· nominal 20-yr term from priority
Inventors:Masahiro YokotaTaku IkenogamiEiichi WatanabeNoriyoshi SekiTakayuki SakaiShingo FujiokaMakoto ShiozakiKatsunori SuwaYosuke OgoshiMasato NoguchiKatsuya Maeda
C07D 239/22A61P 37/00C07D 413/04A61P 43/00A61K 31/505A61P 17/00C07D 401/04A61K 31/695A61P 27/00A61K 31/506C07C 265/02C07C 275/06C07F 7/0812A61P 25/00C07F 7/12A61P 3/00C07D 403/04C07D 405/04C07D 405/10A61P 29/00C07D 239/36C07D 403/06A61P 1/04A61P 3/10A61P 17/06A61P 19/02A61P 19/04A61P 19/08A61P 37/06
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Claims
Abstract
A compound of Formula [I] or a pharmaceutically acceptable salt thereof:wherein each symbol is defined as in the specification.
Claims
exact text as granted — not AI-modified1 - 37 . (canceled)
38 . A method of inhibiting RORγ, comprising administering to a mammal a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
39 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
40 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
41 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
42 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
43 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
44 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 38 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
46 . A method of treating a disease selected from the group consisting of allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
47 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
48 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
49 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
50 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
51 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
52 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
53 . The method of claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
54 . The method according to any one of claims 46 to 53 , wherein the disease is allergic disease.
55 . The method according to any one of claims 46 to 53 , wherein the disease is dry eye.
56 . The method according to any one of claims 46 to 53 , wherein the disease is fibrosis.
57 . The method according to any one of claims 46 to 53 , wherein the disease is metabolic disease.
58 . A method of preparing a compound of Formula [Q-109]:
the method comprising reacting a compound of Formula [Q-107]:
with a compound of Formula [Q-108]:
H 2 N—R 5q [Q108]
in a solvent and optionally in the presence of a base, wherein
R 1 is
(1) C 4-8 alkyl,
(2) C 3-8 alkyl substituted with one hydroxy,
(3) C 4-8 alkyl substituted with one halogen,
(4) C 4-8 alkenyl,
(5) C 4-8 alkynyl,
(6) C 3-7 alkyl substituted with one trifluoromethyl,
(7) C 1-5 alkyl substituted with one substituent selected from Group X a1 ,
(8) C 3-6 alkoxy,
(9) C 2-7 alkoxy substituted with one trifluoromethyl,
(10) C 1-3 alkoxy substituted with one substituent selected from Group X a2 ,
(11) C 4-6 cycloalkyl,
(12) C 3-6 cycloalkyl substituted with the same or different one to two C 1-5 alkyl,
(13) C 5-6 cycloalkenyl optionally substituted with the same or different one to two C 1-4 alkyl,
(14) spiro C 6-11 cycloalkyl,
(15) C 1-3 alkoxycarbonyl,
(16) C 3-6 alkylsulfanyl,
(17) C 3-6 alkylsulfinyl,
(18) C 3-6 alkylsulfonyl,
(19) C 3-6 cycloalkylsulfanyl,
(20) C 3-6 cycloalkylsulfinyl,
(21) C 3-6 cycloalkylsulfonyl,
(22) cyclobutylidenemethyl,
(23) cyclopentylidenemethyl,
(24) cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3 alkyl,
(25) tetrahydropyran-4-ylidenemethyl,
(26) C 3-6 cycloalkyl substituted with one to the same two halogen, or
(27) C 5-6 cycloalkenyl substituted with one to the same two halogen;
Group X a1 is
(a) C 3-6 cycloalkyl optionally substituted with the same or different one to three C 1-5 alkyl,
(b) C 3-6 cycloalkyl substituted with the same or different one to two halogen,
(c) phenyl,
(d) C 2-4 alkoxy,
(e) trimethylsilyl,
(f) carboxy, or
(g) tetrahydropyran-4-yl;
Group X a2 is
(a) C 3-6 cycloalkyl,
(b) phenyl, or
(c) C 1-4 alkoxy;
R 2 is
(1) halogen,
(2) C 1-6 alkyl,
(3) C 1-3 alkoxy optionally substituted with phenyl, or
(4) trifluoromethyl;
n is an integer of 0, 1 or 2, provided that when n is 2, each R 2 may be different from each other; or
R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl;
R 3q i is —Y b —CH 2 OP 2 , C 1-6 alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6 cycloalkyl optionally substituted with the same or different one to three substituents from Group X b , 4-tetrahydropyranyl, or I-methanesulfonyl-3-azetidinyl;
Y b is C 1-6 alkylene or C 3-6 cycloalkylene;
P 2 is a protective group selected from the group consisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl;
Group X b is halogen or C 1-6 alkyl;
R 4 is
(1) hydrogen or
(2) methyl;
R 5q is —Y c —COO—R 50 , hydrogen, C 1-4 alkyl optionally substituted with one C 1-3 alkoxy, or C 3-6 cycloalkyl optionally substituted with hydroxy-C 1-4 alkyl protected with one P 2 ;
R q50 is C 1-4 alkyl;
Y c is C 1-6 alkylene optionally substituted with hydroxy protected with one P 2 , CH 2 —CH 2 —O—CH 2 , or (CH 2 ) m —Y c1 —(CH 2 ) w ;
m is an integer of 0, 1, or 2;
w is an integer of 0, 1, or 2; and
Y c1 is C 3-6 cycloalkylene optionally substituted with one C 1-3 alkyl, phenylene, crosslinked C 5-8 cycloalkylene, or
and
R 6 is
(1) hydrogen or
(2) methyl.
59 . The method of claim 58 , wherein
the base is triethylamine; and the solvent is benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or any mixture of the foregoing; and the reacting is carried out at a temperature of from 0° C. to 80° C.
60 . The method of claim 58 , wherein the compound of Formula [Q-107] is obtained by reacting a compound of Formula [Q-106]:
with an azidation agent followed by a Curtius rearrangement in the presence of a base and a solvent.
61 . The method of claim 60 , wherein
the azidation agent is diphenylphosphoryl azide (DPPA); the base is triethylamine or diisopropylethylamine; the solvent is benzene, toluene, or xylene; and the reacting is carried out at a temperature of from 0° C. to 140° C.
62 . The method of claim 60 , wherein the compound of Formula [Q-106] is obtained by an Ireland Claisen rearrangement reaction of Formula [Q-105]:
by in a solvent, in the presence of a base and a chlorosilane compound, and optionally in the presence of an additive.
63 . The method of claim 62 , wherein
the base is lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LFMDS), or lithium 2,2,6,6-tetramethylpiperidide (LiTMP); the chlorosilane compound is trimethylsilyl chloride or tert-butyldimethylsilyl chloride; the additive is hexamethylphosphoric triamide (HMPA) or N,N′-dimethylpropyleneurea (DMPU); the solvent is diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran; and the Ireland Claisen rearrangement reaction is carried out at a temperature of from −78° C. to 80° C.
64 . The method of claim 62 , wherein the compound of Formula [Q-105] is obtained by reacting a compound of formula [Q-103]:
with a compound of Formula [Q-104]:
in the presence of a condensation agent, a solvent, and optionally an additive.
65 . The method of claim 64 , wherein
the condensation agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), or carbonyldiimidazole; the additive is 1-hydroxy-1H-benzotriazole monohydrate (HOBt·H 2 O) or 4-dimethylaminopyridine (DMAP); and the solvent is toluene, dichloromethane, chloroform, tetrahydrofuran, dixoane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or any mixture of the foregoing; and the reacting is carried out at a temperature of from 0° C. to 100° C.
66 . A compound selected from the group consisting of:
wherein
R 1 is
(1) C 4-8 alkyl,
(2) C 3-8 alkyl substituted with one hydroxy,
(3) C 4-8 alkyl substituted with one halogen,
(4) C 4-8 alkenyl,
(5) C 4-8 alkynyl,
(6) C 3-7 alkyl substituted with one trifluoromethyl,
(7) C 1-5 alkyl substituted with one substituent selected from Group X a1 ,
(8) C 3-6 alkoxy,
(9) C 2-7 alkoxy substituted with one trifluoromethyl,
(10) C 1-3 alkoxy substituted with one substituent selected from Group X a2 ,
(11) C 4-6 cycloalkyl,
(12) C 3-6 cycloalkyl substituted with the same or different one to two C 1-5 alkyl,
(13) C 5-6 cycloalkenyl optionally substituted with the same or different one to two C 1 _4 alkyl,
(14) spiro C 6-11 cycloalkyl,
(15) C 1-3 alkoxycarbonyl,
(16) C 3-6 alkylsulfanyl,
(17) C 3-6 alkylsulfinyl,
(18) C 3-6 alkylsulfonyl,
(19) C 3-6 cycloalkylsulfanyl,
(20) C 3-6 cycloalkylsulfinyl,
(21) C 3-6 cycloalkylsulfonyl,
(22) cyclobutylidenemethyl,
(23) cyclopentylidenemethyl,
(24) cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3 alkyl,
(25) tetrahydropyran-4-ylidenemethyl,
(26) C 3-6 cycloalkyl substituted with one to the same two halogen, or
(27) C 5-6 cycloalkenyl substituted with one to the same two halogen;
Group X a1 is
(a) C 3-6 cycloalkyl optionally substituted with the same or different one to three C 1-5 alkyl,
(b) C 3-6 cycloalkyl substituted with the same or different one to two halogen,
(c) phenyl,
(d) C 2-4 alkoxy,
(e) trimethylsilyl,
(f) carboxy, or
(g) tetrahydropyran-4-yl;
Group X a2 is
(a) C 3-6 cycloalkyl,
(b) phenyl, or
(c) C 1-4 alkoxy;
R 2 is
(1) halogen,
(2) C 1-6 alkyl,
(3) C 1-3 alkoxy optionally substituted with phenyl, or
(4) trifluoromethyl;
n is an integer of 0, 1 or 2, provided that when n is 2, each R 2 may be different with each other; or
R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl;
R 3q1 is —Y b —CH 2 OP 2 , C 1-6 alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6 cycloalkyl optionally substituted with the same or different one to three substituents from Group X b , 4-tetrahydropyranyl, or 1-methanesulfonyl-3-azetidinyl;
Y b is C 1-6 alkylene or C 3-6 cycloalkylene;
P 2 is a protective group selected from the group consisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl;
Group X b is halogen or C 1-6 alkyl;
R 4 is
(1) hydrogen or
(2) methyl;
R 5q is —Y c —COO—R q50 , hydrogen, C 1-4 alkyl optionally substituted with one C 1-3 alkoxy or C 3-6 cycloalkyl optionally substituted with hydroxy-C 1-4 alkyl protected with one P 2 ;
R q50 is C 1-4 alkyl;
Y c is C 1-6 alkylene optionally substituted with hydroxy protected with one P 2 , CH 2 —CH 2 —O—CH 2 or (CH 2 ) m —Y c1 —(CH 2 ) w ;
m is an integer of 0, 1, or 2;
w is an integer of 0, 1, or 2; and
Y c1 is C 3-6 cycloalkylene optionally substituted with one C 1-3 alkyl, phenylene, crosslinked C 5-8 cycloalkylene, or
and
R 6 is
(1) hydrogen or
(2) methyl.
67 . The compound of claim 66 , wherein the compound is
68 . The compound of claim 66 , wherein the compound isCited by (0)
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