Claims for Patent: 8,987,242

Summary for Patent: 8,987,242

Title:	Morpholinone compounds as factor IXA inhibitors
Abstract:	The present invention provides a compound of Formula (I) ##STR00001## as described herein, or a pharmaceutically acceptable salt or a solvate thereof. The present invention also provides pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboses, embolisms, hypercoagulability or fibrotic changes.
Inventor(s):	Chackalamannil; Samuel (Califon, NJ), Chan; Tin-Yau (Edison, NJ), Chelliah; Mariappan V. (Edison, NJ), Clasby; Martin C. (Plainsboro, NJ), Dwyer; Michael (Scotch Plains, NJ), Greenlee; William J. (Teaneck, NJ), Hirabayashi; Tomokazu (Shinjuku-ku, JP), Neelamkavil; Santhosh (Scotch Plains, NJ), Nishida; Hidemitsu (Shinjuku-ku, JP), Saitoh; Fumihiko (Shinjuku-ku, JP), Shah; Unmesh (Green Brook, NJ), Xia; Yan (Edison, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ) Mochida Pharmaceuticals Co., Ltd. (Tokyo, JP)
Application Number:	12/791,464
Patent Claims:	1. A compound of the Formula: ##STR00664## or a pharmaceutically acceptable salt thereof, wherein A is ##STR00665## ##STR00666## ##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672## ##STR00673## ##STR00674## ##STR00675## Y, attached to a carbon or nitrogen ring atom, is 1) halogen, 2) --(C.sub.1-C.sub.6)-alkyl, 3) --(C.sub.1-C.sub.3)-haloalkyl, 4) --(C.sub.3-C.sub.8)-cycloalkyl, 5) --OH, 6) --O--(C.sub.1-C.sub.6)-alkyl, 7) --O--(C.sub.1-C.sub.3)-haloalkyl, 8) .dbd.O (oxo), wherein said --(C.sub.1-C.sub.6)-alkyl part of 2) and 6) of said Y is unsubstituted or substituted independently with the substituents selected from the group consisting of --(C.sub.3-C.sub.8)-cycloalkyl, --C(O)OH, and --C(O)--(C.sub.1-C.sub.6)-alkyl, B is ##STR00676## ##STR00677## provided that when A is ##STR00678## B is not ##STR00679## and when A is ##STR00680## B is not ##STR00681## 2. The compound of claim 1 of the Formula: ##STR00682## or a pharmaceutically acceptable salt thereof, wherein A is ##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## B is ##STR00694## ##STR00695## provided that when A is ##STR00696## B is not ##STR00697## and when A is ##STR00698## B is not ##STR00699## 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the absolute configuration of the Formula is ##STR00700## 4. A compound of claim 1, which is 2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)phenyl)acetate, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(pyrrolidin- e-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(pyrrolidin- e-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)-N-methylbenzamido)acetic acid, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)-N-methylbenzamido)acetate, (S)-1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)- -3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylic acid, 1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)benzoyl)pyrrolidine-2-carboxylate, 3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxom- orpholino)-N-methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzamide, 3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxo- morpholino)-N-methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-methyl-5-(morpholine- -4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-methyl-5-(morpholine- -4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-((R)-3-methoxypyrrol- idine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-((S)-3-methoxypyrrol- idine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-chloro-4-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-- yl)-2-hydroxy-N-(1-iminoisoindolin-5-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-morpholino-2-oxoe- thyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (S)-1-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl- )-3-oxomorpholino)benzoyl)pyrrolidine-2-carboxylic acid, 1-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)benzoyl)pyrrolidine-2-carboxylate, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)acetate, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)acetic acid, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)-N-methylbenzamido)acetate, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)-2-methylpropanoate, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(morpholine-4-carbon- yl)phenyl)-3-oxomorpholin-2-yl)acetamide, 3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-oxo- morpholino)-N-methyl-N-(2-morpholino-2-oxoethyl)benzamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((R)-3-methoxypyr- rolidin-1-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-((S)-3-methoxypyr- rolidin-1-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)-2-methylpropanoate, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)acetate, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(4-methyl-3-oxopiper- azine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenyl)-2-methylpropanoate, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(3-(2-(4-methyl-3-oxopi- perazin-1-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl- )-2-hydroxy-N-(1-iminoisoindolin-5-yl)acetamide, 1-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)benzoyl)piperidine-4-carboxylic acid, 1-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)benzoyl)piperidine-4-carboxylate, 2-(3-((R)-2-((R)-1-acetoxy-2-(1-imino-3-oxoisoindolin-5-ylamino)-2-oxoeth- yl)-3-oxomorpholino)-N-methylbenzamido)acetic acid, (R)--N-(1,3-diiminoisoindolin-5-yl)-2-((R)-4-(3-(2-(dimethylamino)-2-oxoe- thyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)-2-(1-imino-3-oxoisoindolin-5-ylamino)-1-((R)-4-(3-(methyl(2-oxo-2-(py- rrolidin-1-yl)ethyl)carbamoyl)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-fluoro-3-(morp- holine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-((4,4-difluoro- piperidin-1-yl)methyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide), (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxom- orpholino)phenyl)morpholin-2-yl)acetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(2-(difluoromethoxy)phenyl- )-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(2-isopropoxyphe- nyl)-3-oxomorpholin-2-yl)acetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(3-cyanophenyl)-3-oxomorph- olin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholine-4-- carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(4-methyl-3-(mor- pholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(triflu- oromethoxy)phenyl)morpholin-2-yl)acetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(triflu- oromethyl)phenyl)morpholin-2-yl)acetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(1,2,3,4-tetra- hydroisoquinoline-2-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetami- de, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(4,4-difluo- ropiperidine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(3-fluoro-4-(trifluorometh- yl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-ox- omorpholino)phenyl)morpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-imino-7-(trifluoromethyl)isoindolin-5-yl)-2-((R)-3-oxo- -4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetamide, (R)-2-Hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(3-(trifluorometh- oxy)phenyl)morpholin-2-yl)acetamide, Ethyl 2-(3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoindolin-5-ylamino)-2-oxoethyl)-3-- oxomorpholino)phenoxy)acetate, (R)-2-Hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(4-methoxybenzyl)-3-oxo- morpholin-2-yl)acetamide, (R)-2-((R)-4-(3-(Benzyloxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N-(1-im- inoisoindolin-5-yl)acetamide, (R)--N-(1-Aminoisoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbo- nyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, N-(2,3-Dihydro-1-imino-1h-isoindol-5-yl)-4-[2-[(dimethylamino)carbonyl]ph- enyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(2,3-Dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[2-(1-p- yrrolidinylcarbonyl)phenyl]-2(R)-morpholineacetamide, 4-(2-Cyanophenyl)-N-(2,3-dihydro-1-imino-1h-isoindol-5-yl)-alpha(R)-hydro- xy-3-oxo-2(R)-morpholineacetamide, N-(2,3-Dihydro-1-imino-1h-isoindol-5-yl)-4-[4-fluoro-3-(4-morpholinylcarb- onyl)phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(2,3-Dihydro-1-imino-1h-isoindol-5-yl)-4-[4-fluoro-3-[(3 (R)-methyl-4-morpholinyl)carbonyl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-mor- pholineacetamide, N-(2,3-Dihydro-1-imino-1h-isoindol-5-yl)-4-[4-fluoro-3-[(3 (S)-methyl-4-morpholinyl)carbonyl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-mor- pholineacetamide, N-[4-(Aminoiminomethyl)phenyl]-4-(2-cyanophenyl)-alpha(R)-hydroxy-3-oxo-2- (R)-morpholineacetamide, N-(4-Amino-7-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-a- lpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, [3-[2(R)-[2-[(3-Amino-1,2-benzisoxazol-6-yl)amino]-1 (R)-hydroxy-2-oxoethyl]-3-oxo-4-morpholinyl]phenyl]pentafluorosulfur, [4-[2(R)-[2-[(3-Amino-1,2-benzisoxazol-6-yl)amino]-1 (R)-hydroxy-2-oxoethyl]-3-oxo-4-morpholinyl]phenyl]pentafluorosulfur, N-(3-Amino-5-fluoro-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-(4-morpholinylca- rbonyl)phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(2-Amino-6-quinazolinyl)-4-[4-fluoro-3-(4-morpholinylcarbonyl)phenyl]-a- lpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, (R)-2-((R)-4-(5-fluoro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy- -N-(1-iminoisoindolin-5-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluorometh- yl)phenyl)morpholin-2-yl)acetamide, (R)-2-((R)-4-(2-(difluoromethoxy)phenyl)-3-oxomorpholin-2-yl)-2-hydroxy-N- -(1-iminoisoindolin-5-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(2-isopropoxyphenyl)-3-- oxomorpholin-2-yl)acetamide, (R)-2-hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-3-oxo-4-(2-(trifluorometh- oxy)phenyl)morpholin-2-yl)acetamide, N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[(tetrahydro-2H-pyran-4-y- l)oxy]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-[(3,3-difluoro-1-azetidinyl)carbon- yl]-4-fluorophenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-[(4,4-difluoro-1-piperidinyl)carbo- nyl]-4-fluorophenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, N-(3-amino-1,2-benzisoxazol-6-yl)-4-[4-chloro-3-[3-(1,1-dimethylethyl)-1,- 2,4-oxadiazol-5-yl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide- , N-(3-amino-1,2-benzisoxazol-6-yl)-4-[2-fluoro-5-(trifluoromethyl)phenyl]- -alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof and at least one pharmaceutically acceptable carrier. 6. A pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group consisting of: (a) anticoagulants, (b) anti-thrombin agents, (c) anti-platelet agents, (d) fibrinolytics, (e) hypolipidemic agents, (f) antihypertensive agents, and (g) anti-ischemic agents. 7. A pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group consisting of (a-1) warfarin, (a-2) heparin, (a-3) aprotinin, (a-4) synthetic pentasaccharide, (a-5) direct acting thrombin inhibitors including hirudin and argatroban, (a-6) a factor VIIa inhibitor, (a-7) a factor VIIIa inhibitor, (a-8) a factor IXa inhbitor different from the compounds of Formula (I), (a-9) a factor Xa inhibitor, (a-10) a factor XIa inhibitor, (a-11) a thrombin inhibitor, (a-12) a TAFI, (a-13) a fibrinogen inhibitor, (b-1) a boroarginine derivative, (b-2) a boropeptide, (b-3) heparin, (b-4) hirudin, (b-5) argatroban, (c-1) a NSAID, (c-2) a IIb/IIIa antagonist, (c-3) a thromboxane-A2-receptor antagonist, (c-4) a thromboxane-A2-synthetase inhibitor, (c-5) a PDE-III inhibitor, (c-6) a PDE V inhibitor, (c-7) a ADP receptor antagonist, (c-8) an antagonist of the purinergic receptor P2Y1, (c-9) an antagonist of the purinergic receptor P2Y12, (d-1) tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, (d-2) anistreplase, (d-3) urokinase, (d-4) streptokinase, (d-5) tenecteplase (TNK), (d-6) lanoteplase (nPA), (d-7) a factor VIIa inhibitor, (d-8) a PAI-I inhibitor, (d-9) an alpha-2-antiplasmin inhibitor, (d-10) an anisoylated plasminogen streptokinase activator complex, (e-1) a HMG-CoA reductase inhibitor, (e-2) a squalene synthetase inhibitor, (e-3) a fibrate, (e-4) a bile acid sequestrant, (e-5) an ACAT inhibitor, (e-6) a MTP inhibitor, (e-7) a lipooxygenase inhibitor, (e-8) a cholesterol absorption inhibitor, (e-9) a cholesterol ester transfer protein inhibitor, (f-1) an alpha adrenergic blocker, (f-2) a beta adrenergic blocker, (f-3) a calcium channel blocker, (f-4) a diuretics, (f-5) a rennin inhibitor, (f-6) an angiotensin-converting enzyme inhibitor, (f-7) an angiotensin-II-receptor antagonist, (f-8) an ET receptor antagonist, (f-9) a Dual ET/All antagonist, (f-10) a neutral endopeptidase inhibitors, (f-11) a vasopepsidase inhibitor, (g-1) a Class I agent, (g-2) a Class II agent, (g-3) a Class III agent, a (g-4) Class IV agent, (g-5) a K+ cannel opener, (g-6) an IKur inhibitor and (g-7) a cardiac glycoside. 8. A compound of claim 1, which is (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-[4-(- N-methylcarbamimidoyl)phenyl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(1-ox- o-2,3-dihydroisoindol-5-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-1H-quinolin-6-yl)morpholin-2-yl]acetamide, (2R)-2-[(2R)-4-[7-(difluoromethoxy)-2-oxo-1H-quinolin-6-yl]-3-oxomorpholi- n-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide, (2R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quino- lin-6-yl)morpholin-2-yl]acetamide, (2R)--N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo- -1H-quinolin-6-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(1-methyl-2- -oxoquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide, (2R)-2-[(2R)-4-[1-(cyclopropylmethyl)-2-oxoquinolin-7-yl]-3-oxomorpholin-- 2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide, 2-[7-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)amino]-- 2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetate, 2-[7-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)amino]-- 2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxoquinolin-1-yl]acetic acid, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(8-methyl-2- -oxo-1H-quinolin-7-yl)-3-oxomorpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(2-methoxyq- uinolin-7-yl)-3-oxomorpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-quino- lin-7-ylmorpholin-2-yl]acetamide, (2R)--N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-quinoli- n-7-ylmorpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-1H-quinolin-5-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(1-ox- o-3,4-dihydro-2H-isoquinolin-6-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(1-methyl-2- -oxo-3,4-dihydroquinolin-7-yl)-3-oxomorpholin-2-yl]acetamide, (2R)-2-[(2R)-4-[1-(cyclopropylmethyl)-2-oxo-3,4-dihydroquinolin-7-yl]-3-o- xomorpholin-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide, methyl 2-[7-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)- amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]ace- tate, 2-[7-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)am- ino]-2-oxoethyl]-3-oxomorpholin-4-yl]-2-oxo-3,4-dihydroquinolin-1-yl]aceti- c acid, (2R)--N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-[(2R)-3-oxo-4- -(2-oxo-3,4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)--N-(3-amino-1,2-benzoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,- 4-dihydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)--N-(1-aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-di- hydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)--N-(4-aminoquinazolin-7-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dih- ydro-1H-quinolin-7-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-3,4-dihydro-1H-quinolin-5-yl)morpholin-2-yl]acetamide, (2R)-2-hydroxy-2-[(2R)-4-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3-oxomorpho- lin-2-yl]-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-[2-(3-metho- xy-3-methylbutoxy)phenyl]-3-oxomorpholin-2-yl]acetamide, (2R)-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-[2-(2- -oxopiperidin-1-yl)phenyl]morpholin-2-yl]acetamide, (2R)-2-[(2R)-4-[2-(difluoromethoxy)-5-fluorophenyl]-3-oxomorpholin-2-yl]-- 2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide, methyl 2-(difluoromethoxy)-3-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydro-iso- indol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoate, 2-(difluoromethoxy)-3-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoi- ndol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzoic acid, 2-(difluoromethoxy)-3-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoi- ndol-5-yl)amino]-2-oxoethyl]-3-oxomorpholin-4-yl]-N,N-dimethylbenzamide, 2-(difluoromethoxy)-3-[2-[(1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl- )amino]-2-oxoethyl]-3-oxomorpholin-4-yl]benzamide, methyl 2-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)amino]-2-o- xoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoate, 2-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)amino]-2-o- xoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzoic acid, 2-[(2R)-2-[(1R)-1-hydroxy-2-[(1-imino-2,3-dihydroisoindol-5-yl)amino]-2-o- xoethyl]-3-oxomorpholin-4-yl]-5-(trifluoromethoxy)benzamide, (2R)--N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-- 1H-quinolin-6-yl)morpholin-2-yl]acetamide, (2R)--N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-- 1H-quinolin-7-yl)morpholin-2-yl]acetamide, or (2R)--N-(3-amino-1,2-benzisoxazol-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-- 1H-quinolin-5-yl)morpholin-2-yl]acetamide, or a pharmaceutically acceptable salt thereof. 9. A compound of claim 1, which is (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(3-((S)-2-methylpyrroli- dine-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(morpholine- -4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-(pyrrolidin- e-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-(azetidine-1-carbonyl)-5-fluorophenyl)-3-oxomorpholin-2-y- l)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide, (R)-2-((R)-4-(3-(azetidine-1-carbonyl)-2-methylphenyl)-3-oxomorpholin-2-y- l)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide, (R)-2-((R)-4-(5-(azetidine-1-carbonyl)-2-methylphenyl)-3-oxomorpholin-2-y- l)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(6-(trifluorometh- yl)pyridin-2-yl)morpholin-2-yl)acetamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(pyrrolidin- e-1-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (R)-2-((R)-4-(3-(azetidine-1-carbonyl)-5-methylphenyl)-3-oxomorpholin-2-y- l)-N-(4-carbamimidoylphenyl)-2-hydroxyacetamide, (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-5-(morpholine- -4-carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, (S)-1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)- -3-oxomorpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylic acid, 1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate, 1-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)-5-fluorobenzoyl)pyrrolidine-2-carboxylate, 2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)-5-fluoro-N-methylbenzamido)acetic acid, 2-(3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)-5-fluoro-N-methylbenzamido)acetate, 3-((R)-2-((R)-2-(4-carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-oxom- orpholino)-N-(2-(dimethylamino)-2-oxoethyl)-5-fluoro-N-methylbenzamide, (R)--N-(1,3-diiminoisoindolin-5-yl)-2-hydroxy-2-((R)-4-(3-(2-(4-methyl-3-- oxopiperazin-1-yl)-2-oxoethyl)phenyl)-3-oxomorpholin-2-yl)acetamide, N-(2-(dimethylamino)-2-oxoethyl)-3-((R)-2-((R)-1-hydroxy-2-(1-iminoisoind- olin-5-ylamino)-2-oxoethyl)-3-oxomorpholino)-N-methylbenzamide, 2-((S)-hydroxy((R)-3-oxo-4-p-tolylmorpholin-2-yl)methyl)-4-oxo-1,4-dihydr- oquinazoline-6-carboximidamide, 1,1-dioxo-3-((S)-hydroxy((R)-3-oxo-4-p-tol(Example ylmorpholin-2-yl)methyl)-4H-benzo[e][1,2,4]thiadiazine-7-carboximidamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-((R)-4-(4-chloro-3-(morpholinomet- hyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-4-(3-(morpholine-4- -carbonyl)phenyl)-3-oxomorpholin-2-yl)acetamide, 3-((R)-2-((R)-2-(4-carbamimidoyl-3-fluorophenylamino)-1-hydroxy-2-oxoethy- l)-3-oxomorpholino)benzoic acid, (R)--N-(4-carbamimidoyl-3,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(- 3-oxomorpholino)phenyl)morpholin-2-yl)acetamide, (R)--N-(4-carbamimidoyl-2,3-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(- 3-oxomorpholino)phenyl)morpholin-2-yl)acetamide, (R)--N-(4-carbamimidoyl-2,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(- 3-oxomorpholino)phenyl)morpholin-2-yl)acetamide, (R)--N-(3-(aminomethyl)-4-cyano-5-(trifluoromethyl)phenyl)-2-hydroxy-2-((- R)-3-oxo-4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)acetamide, (R)-2-Hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(2-methyl-1-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide, (R)-2-Hydroxy-N-(1-iminoisoindolin-5-yl)-2-((R)-4-(2-methyl-3-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide hydrochloride, (R)-2-((R)-4-(2-(Cyclopropylmethyl)-3-oxoisoindolin-5-yl)-3-oxomorpholin-- 2-yl)-2-hydroxy-N-(1-iminoisoindolin-5-yl)acetamide, (R)--N-(4-(Aminomethyl)-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-ox- omorpholino)phenyl)morpholin-2-yl)acetamide, (R)--N-(4-Guanidinophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)p- henyl)morpholin-2-yl)acetamide, (R)--N-(4-(Aminomethyl)phenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbony- l)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)-2-(4-Carbamoylphenylamino)-1-((R)-4-(4-fluoro-3-(morpholine-4-carbony- l)phenyl)-3-oxomorpholin-2-yl)-2-oxoethyl acetate, (R)-2-((R)-4-(4-Fluoro-3-(morpholine-4-carbonyl)phenyl)-3-oxomorpholin-2-- yl)-2-hydroxy-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)acetamide, (R)--N-(4-(Aminomethyl)-3-fluorophenyl)-2-((R)-4-(4-fluoro-3-(morpholine-- 4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(4-((R)-1-Aminoethyl)phenyl)-2-((R)-4-(4-fluoro-3-(morpholine-4-ca- rbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N--((R)-1-amino-2,3-dihydro-1H-inden-5-yl)-2-((R)-4-(4-fluoro-3-(mor- pholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N--((S)-1-Amino-2,3-dihydro-1H-inden-5-yl)-2-((R)-4-(4-fluoro-3-(mor- pholine-4-carbonyl)phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, (R)--N-(2-Aminoquinolin-6-yl)-2-((R)-4-(4-fluoro-3-(morpholine-4-carbonyl- )phenyl)-3-oxomorpholin-2-yl)-2-hydroxyacetamide, N-(7-fluoro-2,3-dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-- 4-[3-(3-oxo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide, N-(4-chloro-2,3-dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-- 4-[3-(3-oxo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide, 3-[2(R)-[2-[(2,3-Dihydro-1-imino-1h-isoindol-5-yl)amino]-1(R)-hydroxy-2-o- xoethyl]-3-oxo-4-morpholinyl]benzoic acid, Methyl 3-[2(R)-[2-[(2,3-dihydro-1-imino-1H-isoindol-5-yl)amino]-1(R)-- hydroxy-2-oxoethyl]-3-oxo-4-morpholinyl]benzoate, Methyl 2-[2(R)-[2-[(2,3-dihydro-1-imino-1h-isoindol-5-yl)amino]-1(R)-hydroxy-2-o- xoethyl]-3-oxo-4-morpholinyl]benzoate, N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[4-fluoro-3-[2,2,2-trifluoro-1-(4-mor- pholinyl)ethyl]phenyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, (R)-2-((R)-4-(5-chloro-2-isopropoxyphenyl)-3-oxomorpholin-2-yl)-2-hydroxy- -N-(1-iminoisoindolin-5-yl)acetamide, N-(3-Amino-1,2-benzisoxazol-6-yl)-4-[3-(difluoromethoxy)-4-fluorophenyl]-- alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide, or a pharmaceutically acceptable salt thereof.

Details for Patent 8,987,242

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bayer Healthcare Pharmaceuticals Inc.	TRASYLOL	aprotinin	Injection	020304	12/29/1993		2028-12-05
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2028-12-05
Genentech, Inc.	TNKASE	tenecteplase	For Injection	103909	06/02/2000		2028-12-05