IP Library › Granted Patent US 8,329,690

Granted Patent B2

US 8,329,690 · App. 12/420,085 · Granted Dec 11, 2012

Cyclothiocarbamate derivatives as progesterone receptor modulators

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Quick Facts

Patent No.: US 8,329,690
App. No.: 12/420,085
Granted: Dec 11, 2012
Kind: B2

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Abstract

Methods of using compounds which are progesterone receptor agonists for contraception and the treatment of progesterone-related maladies alone or in combination with an estrogen receptor agonist or progesterone receptor antagonist are provided. These compounds have the structure: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and Q 1 are defined herein.

Claims (229)

1. A method for providing hormone replacement therapy comprising delivering to a female a composition comprising a compound of formula I and an estrogen receptor agonist to said female, wherein formula I is:

wherein:

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 ;

R A 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, amino, C 1 to C 3 aminoalkyl, and 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 1 to C 6 alkenyl, alkynyl, substituted alkynyl, or COR C ;

R C 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 4 is selected from the group consisting of H, halogen, CN, NO 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 a substituted benzene ring having the substituents X, Y and Z:

X is selected from the group consisting of H, 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, 5 or 6 membered heterocyclic ring containing 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; and

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, substituted heterocyclic, 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, substituted heterocyclic, NO 2 , CN, and CO 2 R 10 ;

R 10 is C 1 to C 3 alkyl;

or CR 8 R 9 comprise a six membered ring of the structure:

R 11 and R 12 are independently selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, and sulfonyl;

or a tautomer or a pharmaceutically acceptable salt thereof.

2. A method for providing hormone replacement therapy comprising delivering to a female a composition comprising a compound of formula I and an estrogen receptor agonist to said female, wherein formula I is:

wherein:

R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of (i), (ii), and (iii), said spirocyclic ring being optionally substituted by from 1 to 3 substituents selected from the group consisting of H and C 1 to C 3 alkyl:

(i) a carbon-based saturated 3 to 8 membered spirocyclic ring;

(ii) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds in said ring; or

(iii) a 3 to 8 membered spirocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;

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 1 to C 6 alkenyl, alkynyl, substituted alkynyl, or COR C ;

R 5 is selected from the group consisting of a) and b):

a) a substituted benzene ring having the substituents X, Y and Z:

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; and

b) a five or six membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, S(O), S(O 2 ), and NR 6 and containing 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, C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, C 1 to C 3 thioalkoxy, 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 6 is H or C 1 to C 3 alkyl;

Q 1 is S, NR 7 , or CR 8 R 9 ;

R 10 is C 1 to C 3 alkyl;

or CR 8 R 9 comprise a six membered ring of the structure:

3. The method according to claim 2 , wherein:

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 5 is the five or six membered ring b) containing one or two 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;

Q 1 is S.

4. The method according to claim 2 , wherein:

R 1 and R 2 are C 1 to C 3 alkyl or R 1 and R 2 are fused to form a 3 to 6 membered saturated spirocyclic ring;

R 3 is H;

R 4 is H, halogen, NO 2 , C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 5 is the substituted benzene ring a), wherein said ring has the structure:

Z is H;

X is selected from the group consisting 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 containing in its backbone 1 to 3 heteroatoms, and C 1 to C 3 thioalkoxy;

Y 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; and

Q 1 is S.

5. The method according to claim 2 , wherein:

R 1 and R 2 are C 1 to C 3 alkyl or R 1 and R 2 are fused to form a 3 to 6 membered saturated spirocyclic ring;

R 3 is H;

R 4 is H, halogen, NO 2 , C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 5 is the five-membered ring b) of the structure:

X′ is selected from the group consisting 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 containing in its backbone 1 to 3 heteroatoms, and C 1 to C 3 thioalkoxy;

Y′ 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;

U is O, S, or NR 6 ; and

Q 1 is S.

6. The method according to claim 2 , wherein:

R 1 and R 2 are C 1 to C 3 alkyl or R 1 and R 2 are fused to form a 3 to 6 membered saturated spirocyclic ring;

R 3 is H;

R 4 is H, halogen, NO 2 , C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 5 is the six-membered ring b) of the structure:

X 1 is CX 2 ;

X 2 is halogen, CN, or NO 2 ; and

Q 1 is S.

7. The method according to claim 2 , wherein the compound is selected from the group consisting of:

6-(3-Chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-thione;

4-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile;

3-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile;

3-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl-1-methyl-1H-pyrrole-2-carbonitrile;

6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitrile;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;

tert-Butyl-2-cyano-5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate;

[6-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile;

5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile;

4-(1,2-Dihydro-2-thioxospiro[4H-3,1-benzoxazin-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile;

6-(5-Bromopyridin-3-yl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Chloro-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-thione;

6-(3-Bromo-5-methylphenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

3-(1,2-Dihydro-2-thioxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-5-fluorobenzonitrile;

3-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-methylbenzonitrile;

6-(3,5-Dichlorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

5-(4,4-Dimethyl-1,2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) isophthalonitrile;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-furonitrile;

4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Chlorophenyl)-4-methyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

4-Allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

3-Chloro-5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-yl)benzonitrile;

6-(3,5-Difluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Fluoro-5-methoxyphenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

3-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-methoxybenzonitrile;

6-(3-Fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-[3-Fluoro-5-(trifluoromethyl)phenyl]-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(2-Fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3,4-Difluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(4-Fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

3-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-fluorobenzonitrile;

6-(2,3-Difluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

3-(8-Bromo-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile;

4,4-Dimethyl-6-(3-nitrophenyl)-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Methoxyphenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(2-Chlorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

4-Benzyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile;

3-Fluoro-5-(8-fluoro-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzonitrile;

3-(1,2-Dihydro-2-thioxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)benzonitrile;

5-(1,2-Dihydro-2-thioxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-4-methyl-2-thiophenecarbonitrile;

5-(1,2-Dihydro-2-thioxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile;

6-(3-Chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-propylthiophene-2-carbonitrile;

4-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-furonitrile;

6-(3-Bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

2-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)thiophene-3-carbonitrile; and

a pharmaceutically acceptable salt thereof.

8. The method according to claim 2 , wherein R 1 and R 2 are C 1 to C 6 alkyl.

9. The method according to claim 2 , wherein:

R 5 is the five or six membered ring b) containing one or two 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; and

Q 1 is S.

10. The method according to claim 2 , wherein R 1 and R 2 are CH 3 .

11. The method according to claim 2 , wherein:

R 1 is 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, COR A , or NR B COR A ;

R 2 is 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 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ;

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 5 is the five or six membered ring b) containing one or two 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;

12. A method of preparing a compound of formula I:

wherein:

or R 1 and R 2 are fused to form a spirocyclic ring selected from the group consisting of (i), (ii), and (iii), said spirocyclic ring being optionally substituted by from 1 to 3 substituents selected from the group consisting of H and C 1 to C 3 alkyl:

(i) a carbon-based saturated 3 to 8 membered spirocyclic ring;

(ii) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds in said ring; or

(iii) a 3 to 8 membered spirocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;

R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 3 is H;

R 4 is H;

Ar is an aryl group;

Q 1 is S;

or a tautomer or a pharmaceutically acceptable salt thereof;

said method comprising:

(i) reacting R 2 MgBr with

wherein X′ is Br, I, Cl, or alkoxy, to form the following compound:

(ii) reacting the product of (i) with a condensing agent to form the following compound:

(iii) coupling the product of (ii) with an aryl boronic acid, aryl stannane, or aryl zinc compound to form the following compound:

(iv) thionating the product of (iii).

13. A method of preparing a compound of formula I:

wherein:

(i) a carbon-based saturated 3 to 8 membered spirocyclic ring;

(ii) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds in said ring; or

(iii) a 3 to 8 membered spirocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;

R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 3 is H;

R 4 is H;

R 5 is selected from the group consisting of a) and b):

a) a substituted benzene ring having the substituents X, Y and Z:

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; and

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 6 is H or C 1 to C 3 alkyl;

Q 1 is NR 7 ;

R 7 is C 1 to C 6 alkyl;

or a tautomer or a pharmaceutically acceptable salt thereof;

said method comprising:

(i) reacting R 2 MgBr with

wherein X is Br, I, Cl, or alkoxy, to form the following compound:

(ii) coupling the product of (i) with a coupling reagent comprising a R 5 group to form the following compound:

(iii) reacting the product of (ii) with

14. A method for preparing a compound of formula I:

wherein:

(i) a carbon-based saturated 3 to 8 membered spirocyclic ring;

(ii) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds in said ring; or

(iii) a 3 to 8 membered spirocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;

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 1 to C 6 alkenyl, alkynyl, substituted alkynyl, or COR C ;

R 5 is selected from the group consisting of a) and b):

a) a substituted benzene ring having the substituents X, Y and Z:

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; and

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 6 is H or C 1 to C 3 alkyl;

Q 1 is CR 8 R 9 ;

R 8 and R 9 are independent substituents selected from the group consisting of C 1 to C 6 alkyl and CO 2 R 10 ;

R 10 is C 1 to C 3 alkyl;

or CR 8 R 9 comprise a six membered ring of the structure:

or a tautomer or a pharmaceutically acceptable salt thereof;

said method comprising:

(i) reacting R 2 MgBr with

wherein X is Br, I, Cl, or alkoxy, to form the following compound:

(ii) coupling the product of (i) with a coupling reagent comprising a R 5 group to form the following compound:

(iii) reacting the product of (ii) with