IP Library › Granted Patent US 8,133,998

Granted Patent B2

US 8,133,998 · App. 12/118,492 · Granted Mar 13, 2012

Bicyclic pyrimidine derivatives as calcium channel blockers

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Quick Facts

Patent No.: US 8,133,998
App. No.: 12/118,492
Granted: Mar 13, 2012
Kind: B2

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Abstract

Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted T-type calcium channel activity are disclosed. Specifically, a series of compounds containing thienopyrimidine or oxoquinazoline derivatives are disclosed of the general formula (1) or formula (2) where X is a linker and Y is an aromatic moiety or N(R5)(R6).

Claims (381)

1. A pharmaceutical composition comprising a compound of the formula:

or a pharmaceutically acceptable salt or conjugate thereof in admixture with a pharmaceutically acceptable excipient, wherein

each R 1 and R 2 is, independently, H, or an optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, C 2-6 heteroalkynyl, C 6-10 aryl, C 5-12 heteroaryl, or C 6-12 aryl-C 1-6 alkyl; or R 1 and R 2 together form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;

each R 3 and R 4 is, independently, H, halo or an optionally substituted C 1-3 alkyl or C 1-3 heteroalkyl;

X is an optionally substituted C 1-3 alkylene or C 1-3 heteroalkylene;

Y is Ar or N(R 5 )(R 6 ), wherein Ar is an optionally substituted C 6-10 aryl or C 5-12 heteroaryl and R 5 and R 6 are independently, H, or an optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, C 2-6 heteroalkynyl, C 6-10 aryl, C 5-12 heteroaryl, or C 6-12 aryl-C 1-6 alkyl; or R 5 and R 6 together form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;

wherein the optional substituents on each X, Ar, R 1 , R 2 , R 3 , R 4 and R 5 is, independently, selected from the group consisting of halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, and NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, and C 2-6 heteroalkynyl; or the optional substituents may be one or more optionally substituted groups selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, and C 2-6 heteroalkynyl; and wherein the optional substituent on X, R 1 , R 2 , R 5 and R 6 may further be selected from ═O or ═NOR′;

and wherein optional substituents on a heterocyclic ring formed with R 1 and R 2 or R 5 and R 6 may independently be selected from the group consisting of ═O, ═NOR′, halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, and NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, and C 2-6 heteroalkynyl; or the optional substituents may be one or more optionally substituted groups selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 heteroalkenyl, and C 2-6 heteroalkynyl, C 6-10 aryl, C 5-12 heteroaryl, and C 6-12 aryl-C 1-6 alkyl;

with the following two provisos that for compounds of formula (I): when Y is N(R 5 )(R 6 ), a carbon atom in X or Y that is adjacent to the N in Y is substituted by ═O;

and when Y is Ar, then neither R 1 nor R 2 are arylalkyl.

2. The pharmaceutical composition of claim 1 , wherein X is an optionally substituted ethylene or an optionally substituted methylene.

3. The pharmaceutical composition of claim 2 , wherein X is CH 2 C═O, CH 2 CH 2 , CH(CH 3 )C═O or CH 2 .

4. The pharmaceutical composition of claim 1 , wherein Y is an optionally substituted phenyl.

5. The pharmaceutical composition of claim 4 , wherein Y is phenyl, 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl.

6. The pharmaceutical composition of claim 1 , wherein Y is N(R 5 )(R 6 ).

7. The pharmaceutical composition of claim 6 , wherein R 5 and R 6 are independently H, or an optionally substituted C 1-6 alkyl, C 1-6 heteroalkyl or C 6-10 aryl.

8. The pharmaceutical composition of claim 7 , wherein R 5 and R 6 are independently H, or an optionally substituted methyl, ethyl, butyl, cyclohexyl, cyclopentyl, cyclopropyl or phenyl.

9. The pharmaceutical composition of claim 6 , wherein R 5 and R 6 together with N to which they are attached form an optionally substituted 3-8 membered heterocyclic or 5-12 membered heteroaromatic ring.

10. The pharmaceutical composition of claim 9 , wherein R 5 and R 6 together with N to which they are attached form a 5-6 membered heterocyclic ring.

11. The pharmaceutical composition of claim 1 , wherein R 1 and R 2 together with N to which they are attached form an optionally substituted 3-8 membered heterocyclic or 5-12 membered heteroaromatic ring.

12. The pharmaceutical composition of claim 11 , wherein R 1 and R 2 together with N to which they are attached form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridinyl or pyrrolyl.

13. The pharmaceutical composition of claim 1 , wherein R 1 and R 2 are independently H or an optionally substituted C 1-6 alkyl, C 1-6 heteroalkyl, C 5-12 heteroaryl or C 6-12 aryl-C 1-6 alkyl.

14. The pharmaceutical composition of claim 13 , wherein R 1 and R 2 are independently H, methyl, butyl, phenyl or benzyl.

15. The pharmaceutical composition of claim 1 , wherein R 4 is H.

16. The pharmaceutical composition of claim 1 , wherein R 3 is H or methyl.

17. The pharmaceutical composition of claim 16 , wherein the compound is of formula 1 and R 3 is methyl.

18. The pharmaceutical composition of claim 16 , wherein the compound is of formula 2 and R 3 is H.

19. The pharmaceutical composition of claim 1 , wherein the compound is:

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide;

N,N-diethyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N,N-diethyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(2-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide;

2-(6-(4-(4-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide;

2-(6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide;

N,N-diethyl-2-(6-(4-(3-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N,N-diethylacetamide;

N,N-diethyl-2-(5-methyl-4-oxo-6-(4-(2-(trifluoromethyl)phenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N,N-diethyl-2-(5-methyl-4-oxo-6-(4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(6-(4-(4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(5-methyl-4-oxo-6-(4-(3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(6-(4-(4-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(3,5-bis(trifluoromethyl)phenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-tert-butylacetamide;

N-cyclohexyl-2-(5-methyl-4-oxo-6-(4-tertbutylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(4-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclohexylacetamide;

N-cyclohexyl-2-(6-(4-(3-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(6-(4-(4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclohexylacetamide;

N-cyclohexyl-2-(6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(5-methyl-4-oxo-6-(piperidine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(6-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(5-methyl-6-(4-(4-methoxy phenyl)piperazine-1-carbonyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(5-methyl-6-(4-(3-nitrophenyl)piperazine-1-carbonyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(4,4-difluorocyclohexyl)-2-(5-methyl-4-oxo-6-(4-(phenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(4,4-difluorocyclohexyl)-2-(5-methyl-4-oxo-6-(4-(2-fluorophenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(4,4-difluorocyclohexyl)-2-(5-methyl-4-oxo-6-(4-(3-chlorophenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclohexyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclohexyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclohexyl-2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclopentyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclopentylacetamide;

2-(6-(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclopentylacetamide;

N-cyclopentyl-2-(5-methyl-6-(4-methylpiperazine-1-carbonyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopentyl-2-(5-methyl-6-(4-tertbutylpiperazine-1-carbonyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopentyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(4-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclopentylacetamide;

N-cyclopentyl-2-(6-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopentyl-2-(6-(4-(4-methoxyphenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopentyl-2-(6-(4-(3-nitrophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopentyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclopentyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclopentyl-2-(6-(4-(4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanamide;

N-cyclopropyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-cyclopropyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-phenylacetamide;

2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)-N-phenylacetamide;

2-(6-(4-(3,5-bis(trifluoromethyl)phenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-phenylacetamide;

2-(5-methyl-6-(4-methylpiperazine-1-carbonyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-phenylacetamide;

2-(6-(4-phenylpiperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(3,5-difluorophenyl)acetamide;

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(3,5-difluorophenyl)acetamide;

(S)-N-(3,5-difluorophenyl)-2-(6-(3-fluoropyrrolidin-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

(S)-N-(3,5-difluorophenyl)-2-(6-(3,3-difluoropyrrolidin-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-difluorophenyl)-2-(6-(4-fluoropiperidin-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-difluorophenyl)-2-(6-(4,4-difluoropiperidin-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-difluorophenyl)-2-(6-(3,3-difluoropiperidin-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;

2-(5-methyl-(4-oxo-6-(4-(trifluoromethyl)piperidin-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;

N-(3,5-bis(trifluoromethyl)phenyl)-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-bis(trifluoromethyl)phenyl)-2-(5-methyl-4-oxo-6-(piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-N,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide;

3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide;

3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-N-tert-butyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide;

N-(3,5-bis(trifluoromethyl)phenyl)-2-(5-methyl-4-oxo-6-(piperidine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-bis(trifluoromethyl)phenyl)-2-(5-methyl-4-oxo-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

(S)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(5-methyl-4-oxo-6-(3-fluoropyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-(3,5-bis(trifluoromethyl)phenyl)-2-(5-methyl-4-oxo-6-(4-fluoropiperidine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

(R)-6-(4-(3-chlorophenyl)-piperazine-1-carbonyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

(S)-6-(4-(3-chlorophenyl)-piperazine-1-carbonyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

(S)-6-(4-(2-fluorophenyl)-piperazine-1-carbonyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlorophenyl)-piperazine-1-carbonyl)-3-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlororophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(2-trifluoromethyl)pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(piperidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

4-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)-6-(4-(3-chloro phenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-3-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-((4-trifluoromethyl)piperidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-6-(4-(4-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

(S)-6-(4-(4-fluorophenyl)-piperazine-1-carbonyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

5-methyl-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3,5-bis(trifluoromethyl)phenyl)piperazine-1-carbonyl)-5-methyl-3-(2-(2-oxopyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(4-chlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-(2-oxopyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-(2-oxopyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

3-benzyl-N,N,5-trimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide;

3-(2-fluorobenzyl)-N,N,5-trimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide;

6-(3,5-dimethylpiperazine-1-carbonyl)-3-(2-fluorobenzyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-fluorobenzyl)-5-methyl-6-(piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-3-(2-fluorobenzyl)-5-methyl thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)-3-(2-fluorobenzyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-fluorobenzyl)-5-methyl-6-(4-(3,4,5-trimethoxybenzoyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(4-(3-chlorophenyl)piperazine-1-yl)-2-oxoethyl)-5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

(S)-3-(2-(4-(3-chlorophenyl)piperazine-1-yl)-2-oxoethyl)-5-methyl-6-(3-fluoro pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(4-(3-chlorophenyl)piperazine-1-yl)-2-oxoethyl)-6-(3,3-difluoro pyrrolidine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

3-(2-(4-(3-chlorophenyl)piperazine-1-yl)-2-oxoethyl)-6-(3,3-difluoro piperidine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4,4-difluoropiperidine-1-carbonyl)-3-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

N-ethyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

N-ethyl-2-(6-(4-(phenyl piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

N-ethyl-2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide;

N-ethyl-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

N-ethyl-2-(5-methyl-4-oxo-6-(4-phenylpiperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

N-ethyl-2-(5-methyl-4-oxo-6-(4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)thieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide;

N-tert-butyl-2-(6-(4-(3-chloro-4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

N-tert-butyl-2-(6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(3-chloro-4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-cyclohexylacetamide;

6-(4-(3-chloro-4-fluorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3,4-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

(S)-6-(4-(3-chloro-4-fluorophenyl)piperazine-1-carbonyl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one;

6-(4-(3,5-dichlorophenyl)piperazine-1-carbonyl)-5-methyl-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidin-4(3H)-one;

N-(2,4-difluorophenyl)-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide;

2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(2,4-difluorophenyl)acetamide;

(S)-N-(3,5-difluorophenyl)-2-(6-(3-fluoropyrrolidine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide; or

2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide;

or a pharmaceutically acceptable salt of one of these.

20. The pharmaceutical composition of claim 1 , wherein the compound is: