US2012220558A1PendingUtilityA1
Methods of Treating Hormone-Related Conditions Using Thio-Oxindole Derivatives
Est. expiryJun 25, 2022(expired)· nominal 20-yr term from priority
A61P 35/00A61P 5/24A61P 7/04A61K 31/404A61P 15/12A61P 15/18A61P 15/00A61P 13/08A61P 11/00A61P 1/00A61K 45/06
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Claims
Abstract
The present invention provides methods of inducing contraception which includes delivering to a female a composition containing a compound of formula I, or tautomers thereof, in a regimen which involves delivering one or more of a selective estrogen receptor modulator, wherein formula I is: and wherein R 1 -R 5 and Q 1 are defined as described herein. Methods of providing hormone replacement therapy and for treating carcinomas, dysfunctional bleeding, uterine leiomyomata, endometriosis, and polycystic ovary syndrome is provided which includes delivering a compound of formula I and a selective estrogen receptor modulator are also described.
Claims
exact text as granted — not AI-modified1 . A method of treating carcinomas, said method comprising delivering to a mammal in need thereof a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to a mammal, wherein formula I is:
wherein:
R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
or R 1 and R 2 are joined to form a ring selected from the group consisting of —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 2 —, —O(CH 2 ) m CH 2 —, —O(CH 2 ) p O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 N(H)CH 2 CH 2 —, and —CH 2 CH 2 N(alkyl)CH 2 CH 2 —;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
p is an integer from 1 to 4;
or R 1 and R 2 form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);
R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;
R A is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, and substituted C 1 to C 6 aminoalkyl;
R 5 is selected from the group consisting of a), b) and c):
a) a substituted benzene ring having the structure:
X is selected from the group consisting of halogen, OH, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, substituted C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR C COR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 thioalkyl, and substituted C 1 to C 3 thioalkyl;
b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO 2 , C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, COR D , CSR D , and NR E COR D ;
R D is H, NH 2 , C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
or
c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;
Q 1 is S, NR 7 , or CR 8 R 9 ;
R 7 is selected from the group consisting of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11 , and NR 11 R 12 ;
R 8 and R 9 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 16 ;
R 10 is C 1 to C 3 alkyl or substituted C 1 to C 3 alkyl;
or CR 8 R 9 comprise a six membered ring having the structure:
R 11 and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
2 . The method according to claim 1 , wherein said carcinomas are selected from the group consisting of ovary, breast, colon, endometrial, uterine, and prostate carcinomas.
3 . The method according to claim 1 , wherein R 1 and R 2 are alkyl or substituted alkyl and R 3 is H.
4 . The method according to claim 1 , wherein:
R 1 and R 2 are joined to form a ring selected from the group consisting of —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 2 —, —O(CH 2 ) m CH 2 —, —O(CH 2 ) p O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 N(H)CH 2 CH 2 —, and —CH 2 CH 2 N(alkyl)CH 2 CH 2 —; and R 3 is H.
5 . The method according to claim 1 , wherein:
R 3 is H; and Q 1 is S or NR 7 .
6 . The method according to claim 1 , wherein said compound is selected from the group consisting of:
5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-thione, 3-(1′,2′-dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile, 4-(1′,2′-dihydro-2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile, 3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile, 4-methyl-5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]-indol]-5-yl)-2-thiophenethioamide, 5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-H-pyrrole-2-carbonitrile, 5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile, 5-(1,2-dihydro-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile, 5-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 3-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile, 5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione, 3-benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione, 4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile, 5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione, 3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-pyridinecarbonitrile, 5-(3,4-difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(5-chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-3-furancarbonitrile, 5-(3-chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(3,5-difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile, 5-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile, 5″-(3-chlorophenyl)spiro[cyclobutane-1,3″-[3H]indol]-2″(1″H)-thione, 5″-(2-chlorophenyl)spiro[cyclohexane-1,3″-[3H]indol]-2″(1″H)-thione, 5″-(4-chlorophenyl)spiro[cyclohexane-1,3″-[3H]indol]-2″(1″H)-thione, 5-(1″,2″-dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-4-methyl-2-thiophenecarbonitrile, 5-(1″,2″-dihydro-2″-thioxospiro[cyclohexane-1,3″-[3H]indol]-5″-yl)-2-thiophenecarbonitrile, 5″-(3-fluorophenyl)spiro[cyclohexane-1,3″-[3H]indol]-2″(1″H)-thione, 5-(3-hydroxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione, 5-(4-fluoro-3-(trifluoromethyl)phenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile, 5-(3-fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-(3-chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3H]indol]-2-amine, N-(acetyloxy)-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2″-amine, 5′-(3-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(2-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(3,4-difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(3-methoxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(3-nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 5′-(3-cyanophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one oxime, 3-(1′,2′-dihydro-2′-(hydroxyimino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile, 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarbonitrile, 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarbonitrile, 4-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarbonitrile, 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile, 5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-1H-pyrrole-2-carbonitrile, 4-(spiro[cyclohexane-1,3′-[3H]indol]-2′(acetoxyimino)-5′-yl)-2-thiophenecarbonitrile, 3-fluoro-N′-hydroxy-5-(2′-(hydroxyamino)spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzenecarboximidamide, N′-hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-4-methyl-2-thiophenecarboximidamide, N′-hydroxy-4-(spiro[cyclohexane-1,3′-[3H]indol]-2′-hydroxyimino)-5′-yl-2-thiophenecarboximidamide, N′-hydroxy-5-(spiro[cyclohexane-1,3′-[3H]indol]-2′-(hydroxyimino)-5′-yl)-2-thiophenecarboxidamide, 5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, 5′-(3-cyano-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, 5′-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2-ylidenecyanamide, 5′-(5-cyano-thiophen-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, 5′-(5-cyano-3-methyl-thiophen-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, 5′-(5-cyano-thiophen-3-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, 3-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile, 5-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-2-carbonitrile, 5-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-2-carbonitrile, 5-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-4-methyl-thiophene-2-carbonitrile, and 4-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-2-carbonitrile, or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
7 . The method according to claim 1 , wherein said compound is 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide, or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
8 . The method according to claim 1 , wherein said compound is:
wherein:
R 11 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNHOH, CNH 2 NOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
9 . The method according to claim 1 , wherein said compound is:
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
10 . The method according to claim 1 , wherein said compound is:
wherein:
R 8 is selected from the group consisting of H, CO 2 R 10 , acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;
R 10 is C 1 to C 3 alkyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
11 . The method according to claim 1 , wherein said compound is:
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
12 . The method according to claim 1 , wherein said selective estrogen receptor modulator is selected from the group consisting of tamoxifene, 4-hydroxy-tamoxifene, raloxifene, droloxifene, toremifene, iodotamoxifen, idoxifene, ICI182780, EM-800, EM-652, arzoxifene, lasofoxifene, clomiphene, pipendoxifene, tibolone, levormeloxifene, centchroman, bazedoxifene, ZK186619, cycladiene, nafoxidine, nitromifene citrate, 13-ethyl-17α-ethynyl-17β-hydroxygona-4-9-11-trien-3-one, diphenol hydrochryscne, erythro-MEA, allenolic acid, cyclofenyl, chlorotrianisene, ethamoxytriphetol, triparanol, CI-626, CI-680, U-11,555A, U-11,100A, ICI-46,669, ICI-46,474, and CN-55,945 or a salt thereof.
13 . A method of treating dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, or combinations thereof, said method comprising delivering to a female in need thereof a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula I is:
wherein:
R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
or R 1 and R 2 are joined to form a ring selected from the group consisting of —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 2 —, —O(CH 2 ) m CH 2 —, —O(CH 2 ) p O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 N(H)CH 2 CH 2 —, and —CH 2 CH 2 N(alkyl)CH 2 CH 2 —;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
p is an integer from 1 to 4;
or R 1 and R 2 form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);
R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;
R A is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, and substituted C 1 to C 6 aminoalkyl;
R 5 is selected from the group consisting of a), b) and c):
a) a substituted benzene ring having the structure:
X is selected from the group consisting of halogen, OH, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NRCCOR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 thioalkyl, and substituted C 1 to C 3 thioalkyl;
b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO 2 , C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, COR D , CSR D , and NR E COR D ;
R D is H, NH 2 , C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
or
c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;
Q 1 is S, NR 7 , or CR 8 R 9 ;
R 7 is selected from the group consisting of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11 , and NR 11 R 12 ;
R 8 and R 9 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 16 ;
R 10 isl C 1 to C 3 alkyl or substituted C 1 to C 3 alkyl;
or CR 8 R 9 comprise a six membered ring having the structure:
R 11 and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
14 . The method according to claim 13 , wherein said compound is:
wherein:
R 11 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNHOH, CNH 2 NOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
15 . The method according to claim 13 , wherein said compound is:
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
16 . The method according to claim 13 , wherein said compound is:
wherein:
R 8 is selected from the group consisting of H, CO 2 R 10 , acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;
R 10 is C 1 to C 3 alkyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ;
or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
17 . The method according to claim 13 , wherein said compound is:
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .
18 . The method according to claim 13 , wherein said selective estrogen receptor modulator is selected from the group consisting of tamoxifene, 4-hydroxy-tamoxifene, raloxifene, droloxifene, toremifene, iodotamoxifen, idoxifene, ICI182780, EM-800, EM-652, arzoxifene, lasofoxifene, clomiphene, pipendoxifene, tibolone, levormeloxifene, centchroman, bazedoxifene, ZK186619, cycladiene, nafoxidine, nitromifene citrate, 13-ethyl-17α-ethynyl-17β-hydroxygona-4-9-11-trien-3-one, diphenol hydrochryscne, erythro-MEA, allenolic acid, cyclofenyl, chlorotrianisene, ethamoxytriphetol, triparanol, CI-626, CI-680, U-11,555A, U-11,100A, ICI-46,669, ICI-46,474, and CN-55,945 or a salt thereof.
19 . A method of contraception, said method comprising delivering to a female of child-bearing age a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula I is:
wherein:
R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
or R 1 and R 2 are joined to form a ring selected from the group consisting of —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 2 —, —O(CH 2 ) m CH 2 —, —O(CH 2 ) p O—, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 N(H)CH 2 CH 2 —, and —CH 2 CH 2 N(alkyl)CH 2 CH 2 —;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
p is an integer from 1 to 4;
or R 1 and R 2 form a double bond to C(CH 3 ) 2 , C(cycloalkyl), O, or C(cycloether);
R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;
R A is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, and substituted C 1 to C 6 aminoalkyl;
R 5 is selected from the group consisting of a), b) and c):
a) a substituted benzene ring having the structure:
X is selected from the group consisting of halogen, OH, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, substituted C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH 2 , CSNH 2 , CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR C COR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 thioalkyl, and substituted C 1 to C 3 thioalkyl;
b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO 2 , C 1 to C 4 alkyl, substituted C 1 to C 4 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, COR D , CSR D , and NR E COR D ;
R D is H, NH 2 , C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;
R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl; or
c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO 2 , alkoxy, substituted alkoxy, and CF 3 ;
Q 1 is S, NR 7 , or CR 8 R 9 ;
R 7 is selected from the group consisting of CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 11 , and NR 11 R 12 ;
R 8 and R 9 are independent substituents selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aroyl, substituted aroyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 16 ;
R 10 is C 1 to C 3 alkyl or substituted C 1 to C 3 alkyl;
or CR 8 R 9 comprise a six membered ring having the structure:
R 11 and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
20 . The method according to claim 19 , wherein said compound is selected from the group consisting of (a), (b), (c), and (d):
wherein:
R 11 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNHOH, CNH 2 NOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ;
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl; or
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 7 , CSN(alkyl), or NO 2 ;
wherein:
R 8 is selected from the group consisting of H, CO 2 R 10 , acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;
R 10 is C 1 to C 3 alkyl;
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C1 to C3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ; and
wherein:
R 5 is (i), (ii), or (iii):
(i) a substituted benzene ring having the structure:
wherein:
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , CNHNOH, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C 1 to C 3 thioalkyl;
Y is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;
(ii) a five membered ring having the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl;
X′ is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H, F, and C 1 to C 4 alkyl;
(iii) a six membered ring having the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 .Cited by (0)
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