Tetrahydropyridothienopyrimidine compounds and methods of use thereof

1. A compound of formula (I)

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R 1 represents H, (C 1 -C 4 )alkyl, or halo;

either

(a)

R 2 is selected from the group consisting of H, —CN, halo, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl ; and

R 3 is selected from the group consisting of H, halo, —CN, (C 1 -C 4 )alkyl, ethynyl, propargyl, and *—O(CH 2 ) p Ar, wherein p is 0, 1, or 2, and Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo; or

(b)

R 2 and R 3 are joined, and taken together with the carbon atoms to which they are attached, form a fused five- or six-membered saturated or unsaturated carbocycle, or form a fused heterocycle in which the combined R 2 and R 3 groups are represented by the formula

wherein Ar′ and Ar″ each represents phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl and wherein Ar′ and Ar″ each optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo;

R 4 is selected from the group consisting of H, —CN, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, halo, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl;

R 5 represents H or halo;

when n is 0, R 7 is H;

when n is 1, 2 or 3, R 7 represents:

H;

hydroxyl;

—NR 12 R 13 wherein

R 12 represents H or (C 1 -C 6 )alkyl which optionally bears 1 or 2 hydroxyl or mono- or di- ((C 1 -C 4 )alkyl)amino groups; and

R 13 represents H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, said alkyl and cycloalkyl groups optionally bearing 1 or 2 hydroxyl or mono- or di- ((C 1 -C 4 )alkyl)amino groups;

in which R 14 is hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or mono-or di- ((C 1 -C 4 )alkyl)amino, each alkyl substituent in turn optionally bearing a hydroxyl substituent;

which optionally bears 1 or 2 hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or mono- or di- ((C 1 -C 4 )alkyl)amino substituents, each alkyl substituent in turn optionally bearing a hydroxyl substituent; and

wherein r is 0, 1, or 2;

which optionally bears 1 or 2 (C 1 -C 4 )alkyl substituents, each alkyl substituent in turn optionally bearing a hydroxyl substituent; and wherein

X represents O, S(O) s , or NR 15 , in which s is 0, 1 or 2; and

R 15 represents (C 1 -C 4 )alkyl;

or

when n =2, R 7 and R 9 are optionally joined, and taken together with the carbon atoms to which they are attached and the intervening carbon atoms, form a ring of

structure

wherein R 16 represents (C 1 -C 4 )alkyl;

R 8 represents halo, hydroxyl, or (C 1 -C 4 )alkyl; and

either

(a)

R 9 represents H or —CH 2 —Y, wherein Y is mono- or di- ((C 1 -C 4 )alkyl)amino, or

and

R 10 represents H;

or

(b)

R 9 and R 10 are taken together to form a bond, resulting in an acetylenic linkage;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein m is 0, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein n is 1, or a pharmaceutically acceptable salt thereof

4. The compound of claim 3 , wherein q is 0, or a pharmaceutically acceptable salt thereof

5. The compound of claim 1 , wherein

R 1 is hydrogen or fluoro;

R 2 is selected from the group consisting of H, —CN, halo, (C 1 -C 4 )alkyl, and (C 2 -C 4 )alkynyl;

R 3 is selected from the group consisting of H, halo, and *—O(CH 2 ) p Ar, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar can optionally be substituted with 1 or 2 halogens, and wherein p is 0 or 1;

R 4 is selected from the group consisting of H, —CN, and halo;

R 5 is hydrogen;

R 7 is —NR 12 R 13 wherein

R 12 represents H or (C 1 -C 6 )alkyl; and

R 13 represents H or (C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein

R 1 is H;

R 2 is selected from the group consisting of H, halo, and ethynyl;

R 3 is selected from the group consisting of H, halo, —CN, methyl, and *—O(CH 2 ) p Ar, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar can alternatively be substituted with 0, 1 or 2 halogens, and wherein p is 0 or 1;

R 4 is selected from the group consisting of H, halo, and (C 1 -C 4 )alkyl;

R 5 is hydrogen; and

R 7 is a mono- or di- ((C 1 -C 4 )alkyl)amino group;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein

R 2 is ethynyl;

R 3 is selected from the group consisting of H, halo, and *—O(CH 2 ) p Ar, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar can alternatively be substituted with 0, 1 or 2 halogens, and wherein p is 0 or 1; and

R 4 is hydrogen;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein

R 2 is halo; and

R 3 is selected from the group consisting of H, halo, and *—O(CH 2 ) p Ar, wherein Ar is phenyl, pyridyl, or pyrazinyl, and wherein Ar can alternatively be substituted with 0, 1 or 2 halogens, and wherein p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein R 3 is halo;

or a pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[(2E)-4-(diethylamino)but-2-enoyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[(2E)-4-(dimethylamino)but-2-enoyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-(3-chloro-4-fluorophenyl)-7-[(2E)-4-(dimethylamino)but-2-enoyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-(3-chloro-4-fluorophenyl)-7-[(2E)-4-(diethylamino)but-2-enoyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

7-[(2E)-4-(diethylamino)but-2-enoyl]-N-(3-ethynylphenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

7-[(2E)-4-(dimethylamino)but-2-enoyl]-N-(3-ethynylphenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-(3-chloro-4-fluorophenyl)-7- {(2E)-4-[isopropyl(methyl)amino]but-2-enoyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-(3-chloro-4-fluorophenyl)-7- {(2E)-4-[ethyl(isopropyl)amino]but-2-enoyl}-5,6,7,8 -tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine;

N-(3,4-dichlorophenyl)-7-[(2E)-4-(dimethylamino)but-2-enoyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine; and

N-(3 ,4-dichlorophenyl)-7- {(2E)-4-[isopropyl(methyl)amino]but-2-enoyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine.

11. A process for preparing a compound as described in claim 1 , comprising

(i) reacting a compound of formula (7)

with a compound of formula (10)

wherein X is hydroxy, chloro or bromo, or

(ii) reacting a compound of formula (9)

wherein LG is a leaving group, with a compound of formula R 7 —H; or

(iii) reacting a compound of the formula (14):

wherein LG is a leaving group,

with a compound of the formula (15):

wherein LG is a leaving group,

under conditions such that a compound as described in claim 1 is prepared.

12. A pharmaceutical composition comprising a compound as defined in claim 1 , together with a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , in a form suitable for intravenous administration.

14. A process for preparing a pharmaceutical composition, comprising combining at least one compound as defined in claim 1 with at least one pharmaceutically acceptable carrier, and bringing the resulting combination into a suitable administration form.

15. A compound of formula (7)

wherein

m is 0, 1, or 2;

q is 0 or 1;

R 1 represents H, (C 1 -C 4 )alkyl, or halo;

either

(a)

R 2 is selected from the group consisting of H, —CN, halo, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl;

R 3 is selected from the group consisting of H, halo, —CN, (C 1 -C 4 )alkyl, ethynyl, propargyl, and *—O(CH 2 ) p Ar, wherein p is 0, 1, or 2, and Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo; or

(b)

R 2 and R 3 are joined, and taken together with the carbon atoms to which they are attached, form a fused five- or six-membered saturated or unsaturated carbocycle, or form a fused heterocycle in which the combined R 2 and R 3 groups are represented by the formula

wherein Ar′ and Ar″ each represents phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl and wherein Ar′and Ar″each optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo;

R 4 is selected from the group consisting of H, —CN, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, halo, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl;

R 5 represents H or halo; and

R 8 represents halo, hydroxyl, or (C 1 -C 4 )alkyl.

16. A compound of formula (9)

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

q is 0 or 1;

R 1 represents H, (C 1 -C 4 )alkyl, or halo;

either

(a)

R 2 is selected from the group consisting of H, —CN, halo, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl ; and

R 3 is selected from the group consisting of H, halo, —CN, (C 1 -C 4 )alkyl, ethynyl, propargyl, and *—O(CH 2 ) p Ar, wherein p is 0, 1, or 2, and Ar represents phenyl, pyridyl, thiazolyl, thiophenyl, or pyrazinyl, and wherein Ar optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo; or

(b)

R 2 and R 3 are joined, and taken together with the carbon atoms to which they are attached, form a fused five- or six-membered saturated or unsaturated carbocycle, or form a fused heterocycle in which the combined R 2 and R 3 groups are represented by the formula

wherein Ar′and Ar″each represents phenyl, pyridyl, thiazolyl, thienyl, or pyrazinyl and wherein Ar′ and Ar″ each optionally bears 1 or 2 substituents selected from the group consisting of (C 1 -C 4 )alkyl and halo;

R 4 is selected from the group consisting of H, —CN, (C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, halo, (C 2 -C 4 )alkenyl, and (C 2 -C 4 )alkynyl;

R 5 represents H or halo;

R 8 represents halo, hydroxyl, or (C 1 -C 4 )alkyl;

either

(a)

R 9 represents H or —CH 2 —Y, wherein Y is mono- or di- ((C 1 -C 4 )alkyl)amino, or

and

R 10 represents H;

or

(b)

R 9 and R 10 are taken together to form a bond, resulting in an acetylenic linkage;

and

LG is a leaving group.

17. A compound of formula (14):

wherein

m is 0, 1, or 2;

n is 0, 1, 2, or 3; q is 0 or 1;

when n is 0, R 7 is H;

when n is 1, 2 or 3, R 7 represents:

H;

hydroxyl;

—NR 12 R 13 wherein

R 12 represents H or (C 1 -C 6 )alkyl which optionally bears 1 or 2 hydroxyl or mono- or di- ((C 1 -C 4 )alkyl)amino groups; and

R 13 represents H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, said alkyl and cycloalkyl groups optionally bearing 1 or 2 hydroxyl or mono- or di- ((C 1 -C 4 )alkyl)amino groups;

in which R 14 is hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or mono- or di- ((C 1 -C 4 )alkyl)amino, each alkyl substituent in turn optionally bearing a hydroxyl substituent;

which optionally bears 1 or 2 hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or mono- or di- ((C 1 -C 4 )alkyl)amino substituents, each alkyl substituent in turn optionally bearing a hydroxyl substituent; and

wherein r is 0, 1, or 2;

which optionally bears 1 or 2 (C 1 -C 4 )alkyl substituents, each alkyl substituent in turn optionally bearing a hydroxyl substituent; and wherein

X represents O, S(O)s, or NR 15 , in which s is 0, 1 or 2; and

R 15 represents (C 1 -C 4 )alkyl;

or

when n=2, R 7 and R 9 are optionally joined, and taken together with the carbon atoms to which they are attached and the intervening carbon atoms, form a ring of structure

wherein R 16 represents (C 1 -C 4 )alkyl;

R 8 represents halo, hydroxyl, or (C 1 -C 4 )alkyl;

either

(a)

R 9 represents H or —CH 2 —Y, wherein Y is mono- or di- ((C 1 -C 4 )alkyl)amino, or

and

R 10 represents H;

or

(b)

R 9 and R 10 are taken together to form a bond, resulting in an acetylenic linkage; and

LG is a leaving group.

18. A method of treating a cancer selected from non-small cell lung cancer, gastric cancer, and epidermoid cancer in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound as defined in claim 1 .

19. The method of claim 18 , wherein the cancer is non-small cell lung cancer.

20. The method of claim 18 , wherein the cancer is gastric cancer.

21. The method of claim 18 , wherein the cancer is epidermoid cancer.