PYRAZOLO-QUINAZOLINE DERIVATIVES AS CHOLINE KINASE INHIBITORS
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Abstract
The present invention relates to substituted pyrazolo-quinazoline derivatives which modulate the activity of Choline Kinase (ChoK). The compounds of this invention are therefore useful in treating diseases caused by an altered choline metabolism, such as cancer, cell proliferative disorders, infectious diseases of different origin, immune-related disorders and neurodegenerative disorders. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
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Citations
22 Claims
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1. A compound of formula (I)
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 12, 13, 15, 20, 21, 22)
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2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein:
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R2 is hydrogen or an optionally substituted group selected from straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl and heterocyclyl; R3, R4, R3′ and
R4′
are independently hydrogen, straight or branched (C1-C6)alkyl or, taken together with the carbon atom to which they are bonded, R3 and R4 or R3′ and
R4′
form an optionally substituted 3-, 4- or 5-membered cycloalkyl;z and n are independently 0 or 1; A is an optionally substituted ring selected from aryl or heteroaryl; R5 is an optionally substituted group selected from —
CONR6R7, —
NR7COR6, —
NR7CONR6R7, —
OR6 and —
NR6R7;wherein R6 and R7 are as defined in claim 1; provided that R3, R4, R3′ and
R4′
are not simultaneously hydrogen and 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-amino-N, 1,4,4-tetramethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(cyclopentylamino)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride and 8-(cyclopentylamino)-N,1,4,4-tetramethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride are excluded.
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3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 2, wherein:
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R2 is hydrogen or an optionally substituted group selected from straight or branched (C1-C6)alkyl; R3, R4, R3′ and
R4′
are independently hydrogen, straight or branched (C1-C6)alkyl or, taken together with the carbon atom to which they are bonded, R3 and R4 or R3′ and
R4′
form an optionally substituted 4- or 5-membered cycloalkyl;z is 0 and n is 1; L is —
CONR6aR7a or —
NR8COR6a, when y is 0, orL is —
CONR8- or —
NR8CO—
, when y is 1;wherein R6a and R7a are independently hydrogen or an optionally substituted group selected from (C3-C7)cycloalkyl, heterocyclyl, aryl and heteroaryl or, taken together with the nitrogen atom to which they are bonded, R6a and R7a form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S; and R8 is hydrogen; Rc and Rd are independently hydrogen, an optionally substituted straight or branched (C1-C3)alkyl or fluoro; R5 is an optionally substituted group selected from —
CONR6R7, —
NR7COR6, —
OR6;wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl, aryl and heteroaryl or, taken together with the nitrogen atom to which they are bonded, R6 and R7 form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S; provided that R3, R4, R3′ and
R4′
are not simultaneously hydrogen and 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide and 8-(cyclopentylamino)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride are excluded.
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4. A compound of formula (I)7 or a pharmaceutically acceptable salt thereof, according to claim 3, wherein:
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R1 is hydrogen or an optionally substituted straight or branched (C1-C3)alkyl; L is —
CONR6aR7a, when y is 0, orL is —
CONR8, when y is 1;wherein R6a and R7a are independently hydrogen or an optionally substituted group selected from heterocyclyl, aryl and heteroaryl or, taken together with the nitrogen atom to which they are bonded, R6a and R7a form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S; and R8 is hydrogen; Rc and Rd are hydrogen; R5 is an optionally substituted group selected from —
CONR6R7, —
OR6;wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl or, taken together with the nitrogen atom to which they are bonded, R6 and R7 form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S; provided that R3, R4, R3′ and
R4′
are not simultaneously hydrogen and 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide and 8-(cyclopentylamino)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride are excluded.
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5. A compound (cpd) or a pharmaceutically acceptable salt thereof, according to claim 1, selected from the group consisting of:
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8-amino-N-(3-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
1);8-amino-N-(4-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
2);8-amino-4,4-dimethyl-N-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
3);8-amino-N-(1,3-benzodioxol-5-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
4);ethyl 4-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzoate (cpd
5);8-amino-4,4-dimethyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
6);8-amino-4,4-dimethyl-N-{4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
8);8-amino-1-(3-hydroxypropyl)-4,4-dimethyl-N-{4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
9);8-amino-4,4-dimethyl-N-{3-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
10);8-amino-4,4-dimethyl-N-[4-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
11);8-amino-4,4-dimethyl-N-(4-{[4-(pyrrolidin-1-yl)piperidin-1-yl] carbonyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
13);8-amino-N-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
14);8-amino-N-[4-(cyclohexylcarbamoyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
16);ethyl 3-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzoate (cpd
17);3-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzoic acid (cpd
18);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylcarbonyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
20);8-amino-N-[3-(cyclohexylcarbamoyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
25);8-amino-4,4-dimethyl-N-(3-{[4-(pyrrolidin-1-yl)piperidin-1-yl] carbonyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
26);8-amino-4,4-dimethyl-N-[4-(methylcarbamoyl)phenyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
27);8-amino-N-{4-[(trans-4-hydroxycyclohexyl)carbamoyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
28);8-amino-N-[4-(cyclopentylcarbamoyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
29);8-amino-N-[4-(cyclobutylcarbamoyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
30);8-amino-N-[4-(cyclopropylcarbamoyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
31);8-amino-4,4-dimethyl-N-(4-methyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
32);ethyl (2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl) acetate (cpd
33);8-amino-N-cyclohexyl-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
34);8-amino-N-{4-[2-(cyclohexylamino)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
35);(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl) [4-(pyrrolidin-1-yl)piperidin-1-yl]methanone (cpd
36);8-amino-4,4-dimethyl-N-(4-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
37);(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)(1,4′
-bipiperidin-1′
-yl)methanone (cpd
38);8-amino-N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
39);8-amino-4,4-dimethyl-N-(4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
41);(2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl)acetic acid (cpd
42);tert-butyl {1-[(2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl)acetyl]piperidin-4-yl}carbamate (cpd
43);8-amino-N-{4-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
44);8-amino-4,4-dimethyl-N-{4-[2-oxo-2-(4-oxopiperidin-1-yl)ethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
45);tert-butyl [1-(4-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzoyl) piperidin-4-yl]carbamate (cpd
46);8-amino-N-(4-{2-[4-(azepan-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
47);8-amino-N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
49);8-amino-4,4-dimethyl-N-(4-{[4-(morpholin-4-yl)piperidin-1-yl]carbonyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
50);8-amino-N-{4-[(4,4-difluoro-1,4′
-bipiperidin-1′
-yl)carbonyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
51);8-amino-4,4-dimethyl-N-{4-[(4-methyl-1,4′
-bipiperidin-1′
-yl)carbonyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
52);8-amino-N-[4-({4-[(4-hydroxybutanoyl)amino]piperidin-1-yl}carbonyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
53);8-amino-4,4-dimethyl-N-(4-{[4-(2-oxo-1,3-oxazolidin-3-yl)piperidin-1-yl]carbonyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
56);8-amino-4,4-dimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
58);8-amino-4,4-dimethyl-N-(4-{[4-(piperidin-1-ylmethyl)phenyl]carbamoyl}phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
59);8-amino-4,4-dimethyl-N-(1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
61);8-amino-N-(1,3-benzothiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
62);8-amino-N-(6-methoxy-1,3-benzothiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
63);8-amino-N-(6-chloro-1,3-benzothiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
64);8-amino-4,4-dimethyl-N-(5-methyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
65);8-amino-N-(5-chloro-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
66);2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazole-4-carboxylic acid (cpd
67);8-amino-N-[4-(cyclohexylcarbamoyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
68);8-amino-4,4-dimethyl-N-{4-[(1-methylpiperidin-4-yl)carbamoyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
69);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylcarbonyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
70);8-amino-N-[4-(2-{4-[(tert-butylcarbamoyl)amino]piperidin-1-yl}-2-oxoethyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
71);(2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-5-yl)acetic acid (cpd
72);8-amino-N-{5-[2-(cyclohexylamino)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
73);8-amino-4,4-dimethyl-N-(5-{2-[(1-methylpiperidin-4-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
74);8-amino-N-{5-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
75);8-amino-N-[5-(cyclohexylcarbamoyl)-4-methyl-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
77);8-amino-N-[5-(1,4′
-bipiperidin-1′
-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
78);8-amino-4,4-dimethyl-N-{4-methyl-5-[(1-methylpiperidin-4-yl)carbamoyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
79);8-amino-1,4,4-trimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
80);ethyl 2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazole-5-carboxylate (cpd
81);2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazole-5-carboxylic acid (cpd
82);8-amino-N-[5-(1,4′
-bipiperidin-1′
-ylcarbonyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
84);1,4,4-trimethyl-8-(methylamino)-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
85);8-amino-4,4-dimethyl-N-(4-{2-[(1-methylpiperidin-4-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
86);8-amino-N-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
87);8-amino-N-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
88);8-amino-N-(4-{2-[4-(dimethylamino)piperidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
89);8-amino-N-{4-[2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
90);8-amino-N-(4-{2-[4-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
91);8-amino-N-{4-[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
92);8-amino-N-(4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
93);8-amino-N-[4-(2-amino-2-oxoethyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
94);8-amino-N-[4-(2-{[3-(dimethylamino)propyl] amino}-2-oxoethyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
95);ethyl (4-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}phenyl)acetate (cpd
96);8-amino-N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
98);8-amino-N-(4-hydroxyphenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
105);8-amino-N-[3-(1,3-dioxan-2-yl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
106);8-amino-N-(3-formylphenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
107);8-amino-N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
108);8-amino-N-[3-(1,4′
-bipiperidin-1′
-ylmethyl)phenyl]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
109);8-amino-N-[3-(1,4′
-bipiperidin-1′
-ylmethyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
110);8-amino-1,4,4-trimethyl-N-{3-[(4-methyl-1,4′
-bipiperidin-1′
-yl)methyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
111);8-amino-4,4-dimethyl-N-{3-[(4-methyl-1,4′
-bipiperidin-1′
-yl)methyl]phenyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
112);tert-butyl [1-(3-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzyl) piperidin-4-yl]carbamate (cpd
114);8-amino-N-(4-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
116);8-amino-N-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
117);8-amino-N-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
118);8-amino-4,4-dimethyl-N-(4-{2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
119);8-amino-N-{3-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
120);N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-8-(methylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
121);4,4-dimethyl-8-(methylamino)-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
122);8-amino-N,4,4-trimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
123);8-amino-N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-N, 1,4,4-tetramethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
124);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylmethyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide bistrifluoroacetate (cpd
125);8-amino-N-[4-({[4-(1,4′
-bipiperidin-1′
-ylmethyl)phenyl] amino}methyl)phenyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide bistrifluoroacetate (cpd
126);methyl 1-(2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl) cyclopropanecarboxylate (cpd
127);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylmethyl)phenyl]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
128);1-(2-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl) cyclopropanecarboxylic acid (cpd
129);8-amino-N-[4-(1-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}cyclopropyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
130);8-amino-N-{4-[1-(1,4′
-bipiperidin-1′
-ylcarbonyl)cyclopropyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
131);tert-butyl [1-(4-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}benzyl)piperidin-4-yl]carbamate (cpd
133);(3-{[(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)carbonyl]amino}phenyl)acetic acid (139); 8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylmethyl)-1,3-thiazol-2-yl]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
141);8-amino-N-(3-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-oxoethyl}phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
142);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylmethyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
143);8-amino-N-(1H-imidazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
144);8-amino-N-(4-{2-[(1-cyclohexylpiperidin-4-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
145);8-amino-N-(3-{2-[4-(dimethylamino)piperidin-1-yl]-2-oxoethyl}phenyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
146);8-amino-N-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
147);8-amino-N-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide dihydrochloride (cpd
148);8-amino-N-{3-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]phenyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide hydrochloride (cpd
149);8-amino-N-{4-[2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
150);8-amino-4,4-dimethyl-N-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide dihydrochloride (cpd
151);8-amino-N-{4-[(4-aminopiperidin-1-yl)methyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide dihydrochloride (cpd
152);8-amino-1,4,4-trimethyl-N-(4-{2-[4-(1-oxidopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (153); 8-amino-N-(4-{2-[(3R)-3-(dimethylnitroryl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
154);8-amino-1,4,4-trimethyl-N-(4-methyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
155);8-amino-N-(4-{[(1-cyclohexylpiperidin-4-yl)amino]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide dihydrochloride (cpd
156);8-amino-N-(4-{[(1-cyclohexylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
157);8-amino-4,4-dimethyl-N-{4-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
160);(8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl)(4-phenylpiperazin-1-yl)methanone (cpd
161);8-amino-N-[4-(1,4′
-bipiperidin-1′
-ylcarbonyl)benzyl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
165);8-amino-4,4-dimethyl-N-{4-[(1-methylpiperidin-4-yl)carbamoyl]benzyl}-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
166);8-amino-4,4-dimethyl-N-[4-({[trans-4-(4-methylpiperidin-1-yl)cyclohexyl]oxy}methyl)-1,3-thiazol-2-yl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
170);8-amino-1-(2-hydroxyethyl)-4,4-dimethyl-N-(4-methyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
182);8-amino-N-{4-[2-(1,4′
-bipiperidin-1′
-yl)-1,1-difluoro-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
183);8-amino-N-[4-({[1-(4,4-difluorocyclohexyl)piperidin-4-yl]oxy}methyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
189);8-amino-N-[4-({[1-(4,4-dimethylcyclohexyl)piperidin-4-yl]oxy}methyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
190);8-amino-N-{4-[1,1-difluoro-2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
191);8-amino-N-(4-{[(1-cycloheptylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
209);8-amino-2,4,4-trimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
211);8-amino-N-[4-({[1-(cyclohexylmethyl)piperidin-4-yl]oxy}methyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
212);8-amino-N-(4-{[(1-benzylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
213);8-amino-N-(4-{[(1-cycloheptylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
217);8-amino-N-{4-[2-(4,4-dimethyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (cpd
218);8-amino-N-{4-[2-(3,3-dimethyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
219);8-amino-N-(4-{2-[(2,6-dimethyl-4-oxohept-5-en-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
220);8-amino-N-[4-({[1-(4,4-dimethylcyclohexyl)piperidin-4-yl]oxy}methyl)-1,3-thiazol-2-yl]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide trihydrochloride (cpd
221);8-amino-N-{4-[2-(3,3-difluoro-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
222);8-amino-N-(4-{[(1-cycloheptylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide trihydrochloride (cpd
223);8-amino-4,4-dimethyl-N-{4-[2-(3-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
224);8-amino-1,5,5-trimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
225);8-amino-N-(4-{[(1-cycloheptyl-4-methylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide (cpd
226);8-amino-N-{4-[2-(4,4′
-dimethyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
227);8-amino-4,4-dimethyl-N-{6-[(4-methyl-1,4′
-bipiperidin-1′
-yl)carbonyl]-1,3-benzothiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
228);8-amino-N-{4-[2-(4,4-difluoro-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
229);8-amino-4,4-dimethyl-N-[4-({[1-(spiro[2.5]oct-6-yl)piperidin-4-yl]oxy}methyl)-1,3-thiazol-2-yl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
230);8-amino-5,5-dimethyl-N-{4-[2-(4-methyl-1,4′
-bipiperidin-1′
-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (cpd
231); and8-amino-N-(4-{[(1-cycloheptylpiperidin-4-yl)oxy]methyl}-1,3-thiazol-2-yl)-5,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide trihydrochloride (cpd
232).
-
-
6. A process for preparing a compound or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:
-
either SEQUENCE A; Step a) reacting an intermediate compound of formula (V);
-
-
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier or diluent.
-
8. A pharmaceutical composition according to claim 7, further comprising one or more chemotherapeutic agents.
-
12. A method for treating a diseases caused by and/or associated with altered choline metabolism, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof according to claim 1.
-
13. The method according to claim 12, which is for treating a disease selected from the group consisting of a cancer, a cell proliferative disorder, an infectious disease, an immune-related disorder and an neurodegenerative disorder.
-
15. to claim 13, wherein the cancer is selected from the group consisting of:
- carcinomas;
hematopoietic tumors of lymphoid lineage;
hematopoietic tumors of myeloid lineage;
tumors of mesenchymal origin;
tumors of the central and peripheral nervous system;
melanoma;
seminoma;
teratocarcinoma;
osteosarcoma;
xeroderma pigmentosum;
keratoxanthoma;
thyroid cancers; and
Kaposi'"'"'s sarcoma.
- carcinomas;
-
20. The method according to claim 12, wherein said mammal is a human.
-
21. The method according to claim 13, wherein the cancer is selected from the group consisting of:
- bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma, leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, hairy cell lymphoma, Burkitt'"'"'s lymphoma, acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma neuroblastoma, glioma and schwannomas.
-
22. The method according to claim 13, further comprising subjecting said mammal to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.
-
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein:
-
9. (canceled)
-
10. (canceled)
-
11. (canceled)
-
14. (canceled)
-
16. (canceled)
-
17. (canceled)
-
18. (canceled)
-
19. (canceled)
Specification
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Current AssigneeNerviano Medical Sciences SRL (NMS Group SpA)
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Original AssigneeNerviano Medical Sciences SRL (NMS Group SpA)
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InventorsBADARI, Alessandra, CASALE, Elena, NESI, Marcella, QUARTIERI, Francesca
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current
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CPC Class CodesA61K 31/519 ortho- or peri-condensed wi...A61P 35/00 Antineoplastic agentsC07D 487/04 Ortho-condensed systems