Claims for Patent: 9,533,979

Summary for Patent: 9,533,979

Title:	Amino-derivatives as novel inhibitors of histone deacetylase
Abstract:	This invention comprises the novel compounds of formula (I) ##STR00001## wherein n, m, t, R.sup.1, R.sup.2, L, Q, X, Y, Z and ##STR00002## have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
Inventor(s):	Angibaud; Patrick Rene (Fontaine-Bellinger, FR), Van Emelen; Kristof (Sint-Niklaas, BE), Poncelet; Virginie Sophie (Le Manoir sur Seine, FR), Roux; Bruno (Saint Leeger du Bourg-Denis, FR)
Assignee:	Janssen Pharmaceutica NV (Beerse, BE)
Application Number:	14/538,317
Patent Claims:	1. A compound of formula (I), ##STR00088## the N-oxide form, pharmaceutically acceptable addition salt, or stereo-chemically isomeric form thereof, wherein n is 1 and m is 2; t is 0 or 1 and when t is 0 then a direct bond is intended; Q is C; X is N or C; Y is N; Z is --CH.sub.2--; R.sup.1 is --C(O)NR.sup.3R.sup.4, --N(H)C(O)R.sup.7, --C(O)--C.sub.1-6alkanediylSR.sup.7, --NR.sup.8C(O)N(OH)R.sup.7, --NR.sup.8C(O)C.sub.1-6alkanediylSR.sup.7, or --NR.sup.8C(O)C.dbd.N(OH)R.sup.7 wherein R.sup.3 and R.sup.4 are each independently hydrogen, hydroxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl or aminoaryl; R.sup.7 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, arylC.sub.1-6alkyl, C.sub.1-6alkylpyrazinyl, pyridinone, pyrrolidinone, or methylimidazolyl; and R.sup.8 is hydrogen or C.sub.1-6alkyl; R.sup.2 is hydrogen, hydroxy, amino, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC.sub.1-6alkyl, aminocarbonylC.sub.1-6alkyl, hydroxycarbonylC.sub.1-6alkyl, hydroxyaminocarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylaminoC.sub.1-6alkyl, or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; -L- is a bivalent radical that is C.sub.1-6alkanediyl, carbonyl, sulfonyl, or C.sub.1-6alkanediyl substituted with phenyl; ##STR00089## is a radical selected from the group consisting of ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## wherein each s is independently 0, 1, 2, 3, 4 or 5, as allowed; each R.sup.5 and R.sup.6 is independently selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyl substituted with aryl and C.sub.3-10cycloalkyl; C.sub.1-6alkyloxy; C.sub.1-6alkyloxyC.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; cyanoC.sub.1-6alkyl; hydroxyC.sub.1-6alkyl; hydroxyC.sub.1-6alkyloxy; hydroxyC.sub.1-6alkylamino; aminoC.sub.1-6alkyloxy; di(C.sub.1-6alkyl)aminocarbonyl; di(hydroxyC.sub.1-6alkyl)amino; (aryl)(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyloxy; di(C.sub.1-6alkyl)aminoC.sub.1-6alkylamino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkylaminoC.sub.1-6alkyl; aryl sulfonyl; arylsulfonylamino; aryloxy; aryloxyC.sub.1-6alkyl; arylC.sub.2-6alkenediyl; di(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)amino(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)amino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; aminosulfonylamino(C.sub.1-6alkyl)amino; aminosulfonylamino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminosulfonylamino(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminosulfonylamino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; cyano; thiophenyl; thiophenyl substituted with di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, C.sub.1-6alkylpiperazinylC.sub.1-6alkyl, hydroxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl, di(C.sub.1-6alkyl)aminosulfonylpiperazinylC.sub.1-6alkyl, C.sub.1-6alkyloxypiperidinyl, C.sub.1-6alkyloxypiperidinylC.sub.1-6alkyl, morpholinylC.sub.1-6alkyl, hydroxyC.sub.1-6 alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, or di(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkyl; furanyl; furanyl substituted with hydroxyC.sub.1-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C.sub.1-6alkyl; C.sub.1-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylC.sub.1-6alkyloxy; morpholinyl; C.sub.1-6alkylmorpholinyl; morpholinylC.sub.1-6alkyloxy; morpholinylC.sub.1-6alkyl; morpholinylC.sub.1-6alkylamino; morpholinylC.sub.1-6alkylaminoC.sub.1-6alkyl; piperazinyl; C.sub.1-6alkylpiperazinyl; C.sub.1-6alkylpiperazinylC.sub.1-6alkyloxy; piperazinylC.sub.1-6alkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl: C.sub.1-6alkylpiperazinylC.sub.1-6alkyl; C.sub.1-6alkylpiperazinylC.sub.1-6alkylamino; C.sub.1-6alkylpiperazinylC.sub.1-6alkylaminoC.sub.1-6alkyl; C.sub.1-6alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC.sub.1-6alkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminosulfonylpiperazinyl; di(C.sub.1-6alkyl)aminosulfonylpiperazinylC.sub.1-6alkyl; hydroxyC.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl; C.sub.1-6alkyloxypiperidinyl; C.sub.1-6alkyloxypiperidinylC.sub.1-6alkyl; piperidinylaminoC.sub.1-6alkylamino; piperidinylaminoC.sub.1-6alkylaminoC.sub.1-6alkyl; (C.sub.1-6alkylpiperidinyl)(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkylamin- o; (C.sub.1-6alkylpiperidinyl)(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkylam- inoC.sub.1-6alkyl; hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl; (hydroxyC.sub.1-6alkyl)(C.sub.1-6alkyl)amino; (hydroxyC.sub.1-6alkyl)(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; hydroxyC.sub.1-6alkylaminoC.sub.1-6alkyl; di(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkyl; pyrrolidinylC.sub.1-6alkyl; pyrrolidinylC.sub.1-6alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from the group consisting of C.sub.1-6alkyl and trihaloC.sub.1-6alkyl; pyridinyl; pyridinyl substituted with C.sub.1-6alkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC.sub.1-6alkyl; quinolinyl; indolyl; phenyl; phenyl substituted with one, two, or three substituents independently selected from the group consisting of halo, amino, nitro, C.sub.1-6alkyl, C.sub.1-6alkyloxy, hydroxyC.sub.1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC.sub.1-4alkyloxy, C.sub.1-4alkylsulfonyl, C.sub.1-4alkyloxyC.sub.1-4alkyloxy, C.sub.1-4alkyloxycarbonyl, aminoC.sub.1-4alkyloxy, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyloxy, di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkylaminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)amino(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)amino(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, aminosulfonylamino(C.sub.1-4alkyl)amino, aminosulfonylamino(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminosulfonylamino(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminosulfonylamino(C.sub.1-4alkyl)aminoC.sub.1-6alkyl, cyano, piperidinylC.sub.1-4alkyloxy, pyrrolidinylC.sub.1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminosulfonylpiperazinyl, di(C.sub.1-4alkyl)aminosulfonylpiperazinylC.sub.1-4alkyl, hydroxyC.sub.1-4alkylpiperazinyl, hydroxyC.sub.1-4alkylpiperazinylC.sub.1-4alkyl, C.sub.1-4alkyloxypiperidinyl, C.sub.1-4alkyloxypiperidinylC.sub.1-4alkyl, hydroxyC.sub.1-4alkyloxyC.sub.1-4alkylpiperazinyl, hydroxyC.sub.1-4alkyloxyC.sub.1-4alkylpiperazinylC.sub.1-4alkyl, (hydroxyC.sub.1-4alkyl)(C.sub.1-4alkyl)amino, (hydroxyC.sub.1-4alkyl)(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(hydroxyC.sub.1-4alkyl)amino, di(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkyl, furanyl, furanyl substituted with --CH.dbd.CH--CH.dbd.CH--, pyrrolidinylC.sub.1-4alkyl, pyrrolidinylC.sub.1-4alkyloxy, morpholinyl, morpholinylC.sub.1-4alkyloxy, morpholinylC.sub.1-4alkyl, morpholinylC.sub.1-4alkylamino, morpholinylC.sub.1-4alkylaminoC.sub.1-4alkyl, piperazinyl, C.sub.1-4alkylpiperazinyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkyloxy, piperazinylC.sub.1-4alkyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkylamino, C.sub.1-4alkylpiperazinylC.sub.1-4alkylaminoC.sub.1-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC.sub.1-4alkyl, piperidinylaminoC.sub.1-4alkylamino, piperidinylaminoC.sub.1-4alkylaminoC.sub.1-4alkyl, (C.sub.1-4alkylpiperidinyl)(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkylamin- o, (C.sub.1-4alkylpiperidinyl)(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkylam- inoC.sub.1-4alkyl, pyridinylC.sub.1-4alkyloxy, hydroxyC.sub.1-4alkylamino, hydroxyC.sub.1-4alkylaminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC.sub.1-4alkyloxy, and thiophenylC.sub.1-4alkylamino; each R.sup.5 and R.sup.6 can be placed on the nitrogen in replacement of the hydrogen; wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl. 2. A compound of formula (I), ##STR00095## the N-oxide form, pharmaceutically acceptable addition salt, or stereo-chemically isomeric form thereof, wherein n is 1; m is 2; t is 0; Q is C; X is N or C; Y is N; Z is --CH.sub.2--; R.sup.1 is --C(O)NR.sup.3R.sup.4, --C(O)--C.sub.1-6alkanediylSR.sup.7, --NR.sup.8C(O)N(OH)R.sup.7, --NR.sup.8C(O)C.sub.1-6alkanediylSR.sup.7, or --NR.sup.8C(O)C.dbd.N(OH)R.sup.7 wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyC.sub.1-6alkyl, and aminoC.sub.1-6alkyl; R.sup.2 is hydrogen, hydroxy, amino, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyl, aminocarbonyl, aminoC.sub.1-6alkyl, C.sub.1-6alkylaminoC.sub.1-6alkyl, or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; -L- is a bivalent radical selected from the group consisting of C.sub.1-6alkanediyl, carbonyl and sulfonyl; ##STR00096## is a radical selected from the group consisting of ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## s is 0, 1, 2, 3 or 4, as allowed; R.sup.5 is selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; hydroxyC.sub.1-6alkyl; aryloxy; di(C.sub.1-6alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyC.sub.1-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C.sub.1-6alkyl; C.sub.1-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; C.sub.1-6alkylmorpholinyl; piperazinyl; C.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkylpiperazinyl; C.sub.1-6 alkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from the group consisting of C.sub.1-6alkyl and trihaloC.sub.1-6alkyl; pyridinyl; pyridinyl substituted with C.sub.1-6alkyloxy, aryloxy, or aryl; pyrimidinyl; quinolinyl; indolyl; phenyl; and phenyl substituted with one or two substituents independently selected from the group consisting of halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, and trifluoromethyl; and R.sup.6 is selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; hydroxyC.sub.1-6alkyl; aryloxy; di(C.sub.1-6alkyl)amino; cyano; pyridinyl; phenyl; and phenyl substituted with one or two substituents independently selected from the group consisting of halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, and trifluoromethyl; wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl. 3. The compound as claimed in claim 1, wherein R.sup.1 is --C(O)NH(OH); R.sup.2 is hydrogen; -L- is a bivalent radical that is carbonyl, sulfonyl, or C.sub.1-6alkanediyl substituted with phenyl; ##STR00102## is a radical that is (a-1), (a-20), or (a-43); s is 0 or 1; and each R.sup.5 is hydrogen or phenyl. 4. The compound as claimed in claim 1, wherein R.sup.1 is --C(O)NH(OH); R.sup.2 is hydrogen; -L- is a bivalent radical that is carbonyl or sulfonyl; ##STR00103## is a radical that is (a-1) or (a-20); each s is independently 0 or 1; and each R.sup.5 is independently selected from the group consisting of hydrogen and phenyl. 5. The compound according to claim 1 that is ##STR00104## 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1. 7. A process of preparing a pharmaceutical composition as claimed in claim 6 comprising intimately mixing the pharmaceutically acceptable carrier and the compound. 8. A process for preparing a compound as claimed in claim 1, comprising reacting an intermediate of formula (II) ##STR00105## with an appropriate acid, yielding a hydroxamic acid of formula (I-a) ##STR00106## 9. The method of claim 8 wherein the acid is trifluoroacetic acid. 10. A method of detecting or identifying a histone deactylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim 1 and a HDAC. 11. A composition comprising a compound of claim 1 and an additional anti-cancer agent that is cisplatin, carboplatin, oxalyplatin, paclitaxel, docetaxel, irinotecan, topotecan, etoposide, teniposide, vinblastine, vincristine, vinorelbine, 5-fluorouracil, gemcitabine, capecitabine, cyclophosphamide, chlorambucil, carmustine, lomustine, daunorubicin, doxorubicin, idarubicin, mitoxantrone, trastuzumab, tamoxifen, toremifene, droloxifene, faslodex, raloxifene, exemestane, anastrozole, letrazole, vorozole, vitamin D, accutane, azacytidine, flavoperidol, imatinib mesylate, gefitinib, butyrate, 4-phenylbutyrate or valproic acid, suberoylanilide hydroxamic acid (SAHA), biaryl hydroxamate A-161906, bicyclic aryl-N-hydroxycarboxamides, pyroxamide, CG-1521, PXD-101, sulfonamide hydroxamic acid, LAQ-824, trichostatin A (TSA), oxamflatin, scriptaid, m-carboxy cinnamic acid bishydroxamic acid, trapoxin-hydroxamic acid analogue, trapoxin, apidicin, depsipeptide, MS-275, CI-994, or depudecin.

Details for Patent 9,533,979

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2022-03-13
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2022-03-13
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2022-03-13