A method of treating thrombosis associated with ischemia, viral infections, stroke, cancer, restenosis, myocardial infarction, disseminated intramuscular coagulopathy which occurs during septic shock, unstable angina, disseminated intramuscular coagulation caused by trauma, coronary artery bypass, hip replacement, thrombolytic therapy, sepsis, hemodialysis, adult respiratory distress syndrome, rheumatoid arthritis, ulcerative colitis, induration, metastasis, hypercoagulability during chemotherapy, Alzheimer's disease, Down's syndrome, fibrin formation in the eye, wound healing, or inflammation in a mammal, comprising administering to the mammal a compound of Formula I:
- 22
- or a hydrate or pharmaceutically acceptable salt thereof;
- wherein:
- W is hydrogen, R1, R1OCO, R1CO, R1(CH2)sNHCO, or (R1)2CH(CH2)sNHCO,
- wherein s is 0-4;
- R1 is
- R2,
- R2(CH2)tC(R12)2, where t is 0-3, and each R12 can be the same or different,
- (R2)(OR12)CH(CH2)p, where p is 1-4,
- (R2)2(OR12)C(CH2)p, where p is 1-4,
- R2C(R12)2(CH2)t, wherein t is 0-3, and each R12 can be the same or different, wherein (R12)2 can also form a ring with C represented by C3-7 cycloalkyl,
- R2CF2C(R12)2(CH2)q, wherein q is 0-2, and each R12 can be the same or different, wherein (R12)2 can also form a ring with C represented by C3-7cycloalkyl,
- R2CH2C(R12)2(CH2)q, wherein q is 0-2, and each R12 can be the same or different, wherein (R12)2 can also form a ring with C represented by C3-7 cycloalkyl,
- (R2)2CH(CH2)r, where r is 0-4 and each R2 can be the same or different, and wherein (R2)2 can also form a ring with CH represented by C3-7 cycloalkyl, C7-,2 bicyclic alkyl, C10-16 tricyclic alkyl, or a 5- to 7-membered mono- or 9- or 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
- R2O(CH2)p, wherein p is 2-4,
- (R2)2CF(CH2)r, wherein r is 0-4 and each R2 can be the same or different, wherein (R2)2 can also form a ring with C represented by C3-7 cycloalkyl, C7-12 bicyclic alkyl, C10-16 tricyclic alkyl, or a 5- to 7-membered mono- or 9- or 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
- 23
- R2CF2C(R12)2;
- R2 is
- phenyl, naphthyl, or biphenyl, each of which is unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, CF3, OCF3, COOH, CONH2, or SO2NH2,
- a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, each of which is optionally substituted with halogen or hydroxy, and wherein the heterocyclic or non-heterocyclic ring is unsubstituted or substituted with halogen or hydroxy,
- C1-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, C3-7 cycloalkyl, CF3, N(CH3)2, or C1-3 alkylaryl,
- CF3,
- C3-7 cycloalkyl, unsubstituted or substituted with aryl,
- C7-12 bicyclic alkyl, or
- C10-16 tricyclic alkyl;
- R3 is
- hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, optionally substituted C6-10 aryl, optionally substituted C6-10 ar(C1-6)alkyl, trifluoromethyl, halogen, C1-6 hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx,
- where Rx, in each instance, is independently one of hydrogen, C1-6 alkyl or C3-7 cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
- R4 is
- hydrogen or halogen;
- R12 is
- hydrogen,
- phenyl, naphthyl, or biphenyl, each of which is unsubstituted or substituted with one or more of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, CF3, OCF3, COOH, or CONH2,
- a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,
- C1-4 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, or aryl,
- CF3,
- C3-7 cycloalkyl,
- C7-12 bicyclic alkyl, or
- C10-16 tricyclic alkyl;
- R5 is hydrogen, C1-4alkyl, or C2-4 alkenyl;
- A is one of
- 24
- Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw, where
- Rw is alkyl, cycloalkyl, phenyl, benzyl,
- 25
- where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
- each n is from zero to 4;
- each m is from zero to 4;
- and
- each j is from zero to 4;
- provided that n, m and j are not all zero.