Claims for Patent: 8,969,336

Summary for Patent: 8,969,336

Title:	Diamino heterocyclic carboxamide compound
Abstract:	Provided is a compound useful as an inhibitor against the kinase activity of EML4-ALK fusion protein. As a result of intensive and extensive studies on compounds having inhibitory activity against the kinase activity of EML4-ALK fusion protein, the present inventors found that the diamino heterocyclic carboxamide compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein. By this finding, the present invention was completed. The compounds of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, such as lung cancer, non-small cell lung cancer, and small cell lung cancer.
Inventor(s):	Shimada; Itsuro (Tokyo, JP), Kurosawa; Kazuo (Tokyo, JP), Matsuya; Takahiro (Tokyo, JP), Iikubo; Kazuhiko (Tokyo, JP), Kondoh; Yutaka (Tokyo, JP), Kamikawa; Akio (Tokyo, JP), Tomiyama; Hiroshi (Nagano, JP), Iwai; Yoshinori (Nagano, JP)
Assignee:	Astellas Pharma Inc. (Tokyo, JP) Kotobuki Pharmaceutical Co., Ltd. (Hanishina-gun, JP)
Application Number:	13/266,164
Patent Claims:	1. A compound of formula (I) or a salt thereof: ##STR01354## wherein the symbols are as defined below: --X-- is a group of formula (II): ##STR01355## A is chloro, ethyl, or isopropyl; R.sup.1 is phenyl in which the carbon at the 4-position is substituted with --W--Y--Z and the carbon at the 3-position may be substituted with a group selected from the group consisting of halogen, R.sup.00, and --O--R.sup.00; R.sup.00 is lower alkyl which may be substituted with one or more halogens; --W-- is a bond, piperidine-1,4-diyl, or piperazine-1,4-diyl; --Y-- is a bond; Z is a non-aromatic heterocyclic ring which may be substituted with one or more R.sup.00; R.sup.2 is (i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of --N(lower alkyl).sub.2, lower alkyl, --COO-lower alkyl, --OH, --COOH, --CONH--R.sup.ZB, and morpholinyl, or (ii) a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of lower alkyl, --CO-lower alkyl, oxo, --CO--R.sup.ZB, and benzyl; R.sup.ZB is phenyl which may be substituted with a group selected from the group consisting of halogen and --O-lower alkyl; and R.sup.3 is --H. 2. The compound according to claim 1 or a salt thereof, wherein R.sup.1 is phenyl in which the carbon at the 4-position is substituted with a group selected from the group consisting of 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl, and 4-isopropylpiperazin-1-yl, and the carbon at the 3-position may be substituted with a group selected from the group consisting of fluoro, methyl, trifluoromethyl, and methoxy. 3. The compound according to claim 1 or a salt thereof, wherein R.sup.2 is 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, or tetrahydropyran-4-yl. 4. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-y- l)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-- 1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin- -1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-- 1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamid- e, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methy- lpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpipera- zin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carbox- amide, 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-- [4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxam- ide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpipera- zin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}a- mino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methyl- piperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(- tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}- amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)- -5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydr- o-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetr- ahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-- pyran-4-ylamino)pyrazine-2-carboxamide, or 6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}a- mino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 5. A pharmaceutical composition, which comprises the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable excipient. 6. An inhibitor against the kinase activity of EML4-ALK fusion protein, which comprises the compound according to claim 1 or a salt thereof. 7. A pharmaceutical composition for preventing or treating cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide-positive cancer, EML4-ALK fusion polynucleotide-positive lung cancer, or EML4-ALK fusion polynucleotide-positive non-small cell lung cancer, which comprises the compound according to claim 1 or a salt thereof. 8. The compound according to claim 1 or a salt thereof, wherein said compound is: 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpipera- zin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carbox- amide. 9. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(- 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide. 10. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}- amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 11. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)- -5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 12. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}a- mino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.