Fused pyrimidines as inhibitors of P97 complex
Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fused pyrimidine compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
A is CH 2 , NR 1 , O or S;
m is an integer of 1-3;
n is 0 or an integer of 1-2;
the ring containing A is a five or six member ring and the sum of m and n is no greater than 2;
Y is selected from the group consisting of halogen, OR c , CN, CO 2 H, CON(R c ) 2 , C(NR c )N(R c ) 2 , CH 2 N(R c ) 2 , SO 2 N(R c ) 2 , tetrazolyl, SO 2 R c and SO 3 H wherein each R c is independently selected from the group consisting of hydrogen and alkyl of 1 to 4 carbons;
Z is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxymethoxy, methoxyethoxy, morpholinyl, piperidinyl, piperazinyl, pyrrolidonyl, pyrrolidinyl, trifluoromethyl, pentafluoroethyl;
R 1 is selected from a group consisting of hydrogen and unsubstituted alkyl of 1 to 6 carbons, and,
Ar is phenyl or fluorophenyl.
2. A pharmaceutical composition according to according to claim 1 wherein R c of Y is hydrogen or methyl.
3. A pharmaceutical composition according to claim 1 wherein Y is selected from the group consisting of carboxyl, sulfo, methylsulfonyl, carboxamido, sulfonamido, N-alkyl carboxamido, N,N-dialkylearboxamido, N-alkylsulfonamido, N,N-dialkylsulfonamido, and wherein each alkyl group is independently selected from 1 to 4 carbons.
4. A pharmaceutical composition according to claim 1 wherein Ar is an unsubstituted phenyl.
5. A pharmaceutical composition according to claim 1 , wherein A is CH 2 .
6. A pharmaceutical composition according to claim 1 , wherein A is NR 1 .
7. A pharmaceutical composition according to claim 1 , wherein A is O.
8. A pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and a fused pyrimidine compound of Formula I selected from any one of the following names or a salt or hydrate thereof:
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methoxy-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-sulfonamide;
N-benzyl-2-(4-methanesulfonyl-2-methyl-1H-indol-1-yl)-5,6,7,8-tetrahydroquinazolin-4-amine;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-ethyl-1H-indole-4-carboxamide;
N-benzyl-2-[2-methyl-4-(1H-1,2,3,4-tetrazol-5-yl)-1H-indol-1-yl]-5,6,7,8-tetrahydroquinazolin-4-amine;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-(2-methoxyethoxy)-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-(propan-2-yl)-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-cyclopropyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N,2-dimethyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N,N,2-trimethyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N-ethyl-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N-(2-methoxyethyl)-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-ethoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-(2-methoxyethoxy)-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-N,2-dimethyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-N, N,2-trimethyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-N-(propan-2-yl)-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-N-(butan-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-sulfonamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-ethyl-1H-indole-4-carboxamide;
N-benzyl-2-(4-methanesulfonyl-2-methyl-1H-indol-1-yl)-5H,7H,8H-pyrano[4,3-d]pyrimidin-4-amine;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboximidamide;
N-benzyl-2-[2-methyl-4-(1H-1,2,3,4-tetrazol-5-yl)-1H-indol-1-yl]-5H,7H,8H-pyrano[4,3-d]pyrimidin-4-amine;
1-(4-{[(4-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-(4-{[(2-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
2-[4-(aminomethyl)-2-methyl-1H-indol-1-yl]-N-benzyl-5H,7H,8H-pyrano[4,3-d]pyrimidin-4-amine,
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-(propan-2-yl)-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-cyclopropyl-1H-indole-4-carboxamide;
1-(4-{[(3-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
N-benzyl-2-(4-fluoro-2-methyl-1H-indol-1-yl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-amine;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-6-carbonitrile;
N-benzyl-2-(4-methoxy-2-methyl-1H-indol-1-yl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-amine;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carbonitrile;
1-[4-(benzylamino)-6-methyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1Hindole-4-carbonitrile;
1-[4-(benzylamino)-6-ethyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1Hindole-4-carbonitrile;
N-{1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indol-4-yl}acetamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-N,2-dimethyl-1Hindole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-N,N,2-trimethyl-1Hindole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-N-(propan-2-yl)-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-N-(butan-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-sulfonamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
N-benzyl-2-(4-methanesulfonyl-2-methyl-1H-indol-1-yl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-amine;
And,
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-(2-methoxyethoxy)-1H-indole-4-carboxamide.
9. A pharmaceutical composition according to claim 8 wherein the fused pyrimidine compound is selected from any one of the following names:
a) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carbonitrile;
b) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carboxamide;
c) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
d) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-ethoxy-1H-indole-4-carboxamide;
e) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-(2-methoxyethoxy)-1H-indole-4-carbonitrile;
f) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-cyclopropyl-1H-indole-4-carboxamide;
g) N-benzyl-2-[2-methyl-4-(1H-1,2,3,4-tetrazol-5-yl)-1H-indol-1-yl]-5,6,7,8-tetrahydroquinazolin-4-amine;
h) 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
i) 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
j) 1-(4-{[(3-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
k) 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-carboxylic acid;
l) 1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
m) 1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
n) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-sulfonamide;
o) N-benzyl-2-(4-methanesulfonyl-2-methyl-1H-indol-1-yl)-5,6,7,8-tetrahydroquinazolin-4-amine;
p) 1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-N-methyl-2-methyl-1H-indole-4-carboxamide; and,
q) 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-N,2-dimethyl-1H-indole-4-carboxamide.
10. A pharmaceutical composition according to claim 9 wherein the fused pyrimidine compound is selected from any one of the following names:
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl 1H-indole-4-carboxamide,
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-(4-{[(3-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyridino[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
and
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide.
11. A pharmaceutical composition according to claim 10 wherein the fused pyrimidine compound has the name 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide.
12. A method for treatment of cancer, comprising administering to a human patient, who has a cancer selected from the group consisting of colorectal cancer, non-small cell lung cancer, multiple myeloma, skin cancer, breast cancer, liver cancer, kidney cancer, head and neck cancer and leukemia, an effective amount of the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fused pyrimidine compound of Formula IA
or a pharmaceutically acceptable salt thereof, wherein:
A is CH 2 , NR 1 or O;
m is an integer of 1-3;
n is 0 or an integer of 1-2;
the ring containing A is a six member ring and the sum of m and n is 2;
Y is selected from the group consisting of, CO 2 H, CON(R c ) 2 , wherein each R c is hydrogen;
Z is selected from the group consisting of methyl or methoxy,
R 1 is hydrogen; and,
Ar is phenyl or fluorophenyl.
13. A method for treatment of cancer in a human patient in need of such treatment according to claim 12 wherein the pharmaceutical composition is administered orally at a dose of up to 2000 mg of the fused pyrimidine compound per day and the patient's serum concentration of the fused pyrimidine compound is monitored to adjust the dosage or timing of administration or both.
14. A method according to claim 12 wherein the cancer is multiple myeloma, colorectal cancer or non-small cell lung cancer.
15. A method according to claim 12 wherein the fused pyrimidine compound of Formula IA is selected from any one of the compounds having the following names:
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxylic acid;
1-(4-{[(4-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-(4-{[(2-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-(4-{[(3-fluorophenyl)methyl]amino}-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide;
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methoxy-1H-indole-4-carboxamide; and
1-[4-(benzylamino)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxylic acid.
16. A method according to claim 12 wherein the fused pyrimidine compound is 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide.
17. A method of decreasing Valosin Containing Protein-Proteosome pathway activity in a patient with cancer comprising administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fused pyrimidine compound of Formula IA
or a pharmaceutically acceptable salt thereof, wherein:
A is CH 2 , NR 1 or O;
m is an integer of 1-3;
n is 0 or an integer of 1-2;
the ring containing A is a six member ring and the sum of m and n is 2;
Y is selected from the group consisting of, CO 2 H, CON(R c ) 2 , wherein each R c is hydrogen;
Z is selected from the group consisting of methyl or methoxy;
R 1 is hydrogen; and,
Ar is phenyl or fluorophenyl.
18. A method according to claim 17 wherein the patient with cancer is a human.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fused pyrimidine compound of Formula IB
or a pharmaceutically acceptable salt thereof, wherein:
A is CH 2 , NR 1 , O or S;
m is an integer of 1-3;
n is 0 or an integer of 1-2;
the ring containing A is a five or six member ring and the sum of m and n is no greater than 2;
Y is selected from the group consisting of halogen, OR c , CN, CO 2 H, CON(R c ) 2 , C(NR c )N(R c ) 2 , CH 2 N(R c ) 2 , SO 2 N(R c ) 2 , tetrazolyl, SO 2 R c and SO 3 H wherein each R c is independently selected from the group consisting of hydrogen and alkyl of 1 to 4 carbons;
Z is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxymethoxy, methoxyethoxy, morpholinyl, piperidinyl, piperazinyl, pyrrolidonyl, pyrrolidinyl, trifluoromethyl, pentafluoroethyl;
R 1 is selected from a group consisting of hydrogen and unsubstituted alkyl of 1 to 6 carbons; and,
Ar is phenyl or fluorophenyl.
20. A pharmaceutical composition according to according to claim 19 wherein R c of Y is hydrogen or methyl.
21. A pharmaceutical composition according to claim 19 wherein Y is selected from the group consisting of carboxyl, sulfo, methylsulfonyl, carboxamido sulfonamido, N-alkyl carboxamido, N,N-dialkylcarboxamido, N-alkylsulfonamido, N,N-dialkylsulfonamido, wherein the alkyl group is 1 to 4 carbons.
22. A pharmaceutical composition according to claim 19 wherein Ar is an unsubstituted phenyl.
23. A pharmaceutical composition according to claim 19 , wherein A is CH 2 .
24. A pharmaceutical composition according to claim 19 , wherein A is NR 1 .
25. A pharmaceutical composition according to claim 19 , wherein A is O.