US2002111355A1PendingUtilityA1
Cyclic urea and cyclic amide derivatives
Est. expiryMay 4, 2019(expired)· nominal 20-yr term from priority
Inventors:Puwen ZhangArthur A. SantilliAndrew FensomeEugene A. TerefenkoAndrew Q. VietJay E. WrobelJames P. EdwardsTodd K. JonesChristopher M. TegleyLin Zhi
A61P 5/36A61P 5/24A61P 35/00A61P 5/00A61P 5/34A61P 15/00A61P 1/00C07D 498/04A61P 15/08A61P 15/18A61P 13/08A61P 15/16
47
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Claims
Abstract
This invention provides compounds of the formula: wherein: A, B and D are N or CH, with the proviso that A, B and D cannot all be CH; R 1 and R 2 are independent substituents selected from H, COR A , NR B COR A , or as defined herein; or R 1 and R 2 are fused to form an optionally substituted 3 to 8 membered spirocyclic or heterocyclic ring; R 3 is H, OH, NH 2 , or optionally substituted alkyl, or alkenyl, or COR C ; R 4 is a substituted benzene ring or a five or six membered ring with 1, 2, or 3 heteroatoms from the group defined herein or Q is O, S, NR 6 , or CR 7 R 8 ; R 6 , R 7 and R 8 are as defined herein; or CR 7 R 8 form a six membered ring; W is O or a chemical bond; as well as their use and pharmaceutical compositions as agonists and antagonists of the progesterone receptor.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that two or three of A, B and D are N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is (i) or (i):
(i) a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, 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 in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;
R D is 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, 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;
Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or
(ii) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NW and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ;
R F is 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, or substituted C 1 to C 3 aminoalkyl;
R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 5 is H or C 1 to C 3 alkyl;
Q is O or S;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , wherein:
R 1 and R 2 are H, C 1 to C 6 alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ; R 3 is 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, or COR C ; R 4 is (iii) or (iv):
(iii) the substituted benzene ring, wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, a 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ; or
(iv) the five or six membered ring having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy.
3 . The compound according to claim 1 , wherein:
R 1 =R 2 and are C 1 to C 3 alkyl or R 1 and R 2 are fused to form the 3 to 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR C ; R C is H, C 1 to C 3 alkyl, or C 1 to C 3 alkoxy; R 4 is selected from the group consisting of (v), (vi), and (vii):
(v) the substituted benzene ring of the formula:
wherein:
X is selected from the group consisting of of halogen, CN, 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 in its backbone 1 to 3 heteroatoms, and C 1 to C 3 thioalkoxy;
Y is on the 4′ or 5′ position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy;
(vi) the five membered ring of the structure:
wherein:
U is O, S, or NR 5 ;
X′ is selected from the group consisting of halogen, CN, NO 2 , C 1 to C 3 alkyl, and C 1 to C 3 alkoxy;
Y′ is selected from the group consisting of H and C 1 to C 3 alkyl; and
(vii) the six membered ring of the structure:
wherein:
X 1 is N or CX 2 ;
X 2 is halogen, CN or NO 2 .
4 . The compound according to claim 1 , wherein:
R 1 =R 2 and are CH 3 or R 1 and R 2 are fused to form a 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 , CH 3 , substituted CH 3 , or COR C ; R C is H, C 1 to C 3 alkyl, or C 1 to C 3 alkoxy; R 4 is the substituted benzene ring having the substituents X and Y as shown below: wherein: X is halogen, CN, C 1 alkoxy, NO 2 , or 5-membered heterocyclic ring; wherein said heterocyclic ring is 2-thiazole; Y is on the 4′ or 5′ position and is H or halogen; wherein said halogen is F.
5 . The compound according to claim 4 wherein R 4 is the moiety:
6 . The compound according to claim 1 , wherein:
R 1 =R 2 and are CH 3 or R 1 and R 2 are fused to form a 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 , CH 3 , substituted CH 3 , or COR C ; R C is H, C 1 to C 3 alkyl, or C 1 to C 3 alkoxy; R 4 is the five membered ring of the structure: U is O, S, or NH; X′ is halogen, CN, or NO 2 ; Y′ is H or C 1 to C 3 alkyl.
7 . The compound according to claim 6 wherein R 4 is the moiety:
wherein:
Y′ is H or C 1 to C 3 alkyl.
8 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically effective carrier or excipient.
9 . A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10 . A method of treatment or prevention of benign or malignant neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
11 . The method according to claim 10 , wherein the benign or malignant neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas or adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors.
12 . A method of treatment or prevention in a mammal of carcinomas or adenocarcinomas of the endometrium, ovary, breast, colon, or prostate, the method comprising administering to a mammal in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that two or more of A, B and D is N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is (i) or (ii):
(i) a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 amino alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;
R D is 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, 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;
Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or
(ii) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 5 and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ;
R F is 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, or substituted C 1 to C 3 aminoalkyl;
R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 5 is H or C 1 to C 3 alkyl;
Q is O, S, NR 6 , or CR 7 R;
R 6 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, substituted heterocyclic, and SO 2 CF 3 ;
R 7 and R 8 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, substituted heterocyclic, NO 2 , CN, and CO 2 R 9 ;
R 9 is C 1 to C 3 alkyl;
or CR 7 R 8 form a six membered ring having the structure below:
W is a chemical bond;
or a pharmaceutically acceptable salt thereof.
14 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that two or more of A, B and D is N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR E COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is (i) or (ii):
(i) a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, 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 in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR B COR D ;
R D is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 amino alkyl, 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;
Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or
(ii) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 5 and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ;
R F is 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, or substituted C 1 to C 3 aminoalkyl;
R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 5 is H or C 1 to C 3 alkyl;
Q is NR 6 or CR 7 R 8 ;
R 6 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, substituted heterocyclic, and SO 2 CF 3 ;
R 7 and R 8 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 Cg cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN, and CO 2 R 9 ;
R 9 is C 1 to C 3 alkyl;
or CR 7 R 8 form a six membered ring having the structure below:
W is O;
or a pharmaceutically acceptable salt thereof.
15 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that two or three of A, B and D are N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, 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 in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;
R D is 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, or substituted C 1 to C 3 amino alkyl;
R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y and Z are independent substituents selected from the group consisting of halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy;
Q is O, S, NW, or CR 7 R 8 ;
R 6 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, substituted heterocyclic, and SO 2 CF 3 ;
R 7 and R 8 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, substituted heterocyclic, NO 2 , CN, and CO 2 R 9 ;
R 9 is C 1 to C 3 alkyl;
or CR 7 R 8 form a six membered ring having the structure below:
W is O;
or a pharmaceutically acceptable salt thereof.
16 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that one of A, B and D is N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is (i), (ii), (iii), or (iv):
(i) a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, 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 in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;
R D is 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, 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;
Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy;
(ii) a five membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 5 and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ;
(iii) a six membered ring having in its backbone 1 NR 5 heteroatom and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ; or
(iv) a six membered ring having in its backbone 2 or 3 heteroatoms selected from the group consisting of O, S, SO, and SO 2 and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR G COR F ;
R F is 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, or substituted C 1 to C 3 aminoalkyl;
R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 5 is H or C 1 to C 3 alkyl;
Q is O;
W is a chemical bond;
or a pharmaceutically acceptable salt thereof.
17 . A compound of the formula:
wherein:
A, B and D are N or CH, with the proviso that one of A, B and D is N;
R 1 and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;
or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of a), b) and c):
a) a 3 to 8 membered saturated spirocyclic ring;
b) a 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds; and
c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;
R A is 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, or substituted C 1 to C 3 aminoalkyl;
R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 3 is 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, or COR C ;
R C is 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, or substituted C 1 to C 3 aminoalkyl;
R 4 is (i) or (ii):
(i) a substituted benzene ring having the substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, 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 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, 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 in its backbone 1 to 3 heteroatoms, COR D , OCOR D , and NR E COR D ;
R D is 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, 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;
Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or
(ii) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 5 and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , and NR E COR F ;
R F is 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, or substituted C 1 to C 3 aminoalkyl;
R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 5 is H or C 1 to C 3 alkyl;
Q is S, NR 6 , or CR 7 R 8 ;
R 6 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, substituted heterocyclic, and SO 2 CF 3 ;
R 7 and R 8 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, substituted heterocyclic, NO 2 , CN, and CO 2 R 9 ;
R 9 is C 1 to C 3 alkyl;
or CR 7 R 8 form a six membered ring having the structure below:
W is a chemical bond;
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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