Compositions and methods for treating brain injury

Abstract

To provide methods and pharmaceutical compositions for treating brain injury.SOLUTION: A method for treating a brain injury in a host animal is provided, the method comprising administering a composition comprising one or more selective V1a receptor antagonists to the host animal.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention described herein relates to compounds, and compositions, methods, and uses thereof for treating brain injury. For example, the present invention described herein relates to vasopressin receptor modulators for treating brain injury, and compositions, methods, and uses thereof.

Background Art

[0002] It has been reported that 2.5 million Americans suffer traumatic brain injury (TBI) each year. These injuries are reported to cause 50,000 deaths and 275,000 hospitalizations. In addition, according to the report, these injuries are estimated to cost $550,000 per patient up to the average life expectancy, with an annual economic burden of $86 billion. TBI is the third leading cause of injury-related death in the United States and one of the major causes of death and physical disability in people under 35 and over 65 years of age.

Summary of the Invention

[0003] Brain injury often has features common to brain edema and swelling. Brain edema is often referred to as secondary injury in TBI, is associated with a primary insult, and is a major cause of morbidity and mortality. Left untreated, brain injury can also lead to severe cognitive impairment, learning disabilities, and memory impairment. In addition, brain injury can lead to loss of motor function. Brain edema can result from traumatic brain injury, as well as other non-traumatic causes such as ischemic stroke, cancer, and brain inflammation resulting from other diseases or conditions such as meningitis or encephalitis. Treatments that reduce or prevent the effects of moderate to severe TBI, including moderate head closed non-penetrating TBI resulting from a single event such as a motor vehicle accident and a fall, are needed to fill a significant gap in this care. Accordingly, there is a current need for compounds, compositions, and methods for treating brain injury.

[0004] The selective arginine vasopressin V1a receptor (V1aR) antagonists described herein have been found to be useful for treating brain injury. Unexpectedly, the compounds have been found to be effective not only in treating edema, but also in treating cognitive, memory, and learning impairments resulting from brain injury. The compositions, methods, and uses described herein are not limited by, and instead may arise from, various causes including, but not limited to, chemotherapy such as impact, sudden head acceleration or deceleration, shock waves, CAR-T therapy, or as a complication of another disease, or sources of brain injury that may occur as a co-morbidity of another disease.

[0005] Arginine vasopressin (AVP) is a chemical signal in the brain that affects cerebrovascular resistance and brain water permeability. Without being bound by theory, it is suggested herein that AVP is a chemical signal for cerebrovascular resistance and brain water permeability that affects the brain and may contribute to the pathophysiology after head trauma or injury. These cerebrovascular effects are mediated through V1aR receptors that are highly expressed in cortical and subcortical brain regions in all mammals. However, systemic treatment of brain injury has been reported to be accompanied by undesirable side effects resulting from competitive antagonism of peripheral V1aR receptors, such as a decrease in cerebral blood flow, a decrease in blood pressure, or other loss of cardiovascular function. Krieg et al., J. Neurotrauma 32:221-27 (2015).

[0006] The compounds described herein have been found to be capable of systemic administration, including oral administration at therapeutically effective doses in the central nervous system (CNS), without clinically significant adverse effects on blood pressure or cardiovascular function.

Advantages of the Invention

[0007] In one exemplary embodiment of the present invention, selective V1aR antagonists, as well as compositions and methods for using such vasopressin antagonists, are described herein. In another exemplary embodiment, a selective V1aR antagonist configured to achieve or produce a CNS concentration in the range of 1 nM to at least about 100 nM upon administration to a host animal, as well as compositions and methods for using such a V1aR antagonist, are described herein. In another exemplary embodiment, a selective V1aR antagonist configured to achieve or produce a CNS concentration in the range of 1 nM to at least about 10 nM, or at least about 1 nM, upon administration to a host animal, as well as compositions and methods for using such a V1aR antagonist, are described herein. In another exemplary embodiment, a very potent and selective V1aR antagonist configured to achieve or produce a CNS concentration of at least about 100 pM, at least about 10 pM, or at least about 1 pM upon administration to a host animal, as well as compositions and methods for using such a V1aR antagonist, are described herein.

[0008] It has been discovered herein that brain injury is treatable with the selective V1aR antagonists described herein. In one embodiment, the vasopressin receptor antagonist has the formula [Chemical formula] (wherein, A is a carboxylic acid, ester, or amide; B is a carboxylic acid, ester, or amide; or B is an alcohol or thiol, or a derivative thereof including their alkyl, aryl, or acyl derivatives; R 1 is hydrogen or C1-C6 alkyl; R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or -CO2R8 ,-CONR 8 R 8’ 、and -NR 8 (COR 9 ) is a substituent selected from the group consisting of; R 8 and R 8’ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R 8 and R 8’ together with the attached nitrogen atom form a heterocyclyl group; R 9 is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8’ is selected from N-(C1-C4 alkyl); R 3 is an optionally substituted amino, amide, acylamide, or ureido group; or R 3 is a nitrogen-containing heterocyclyl group attached to a nitrogen atom; and R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl) and pharmaceutically acceptable salts thereof.

[0009] In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the composition comprises a therapeutically effective amount of one or more compounds for treating a host animal having a brain injury. The composition may include other therapeutically active compounds and / or one or more carriers, diluents, excipients, etc., and it should be understood that it may include other components and / or ingredients, including but not limited to combinations thereof. In another embodiment, methods of using the compounds and pharmaceutical compositions for treating a host animal having a brain injury are also described herein. In one aspect, the method includes administering to the host animal one or more of the compounds and / or compositions described herein. In another aspect, the method includes administering a therapeutically effective amount of one or more of the compounds and / or compositions described herein for treating the brain injury of the host animal. In another embodiment, the use of the compounds and compositions in the manufacture of a medicament for treating a host animal having a brain injury is also described herein. In one aspect, the medicament comprises a therapeutically effective amount of one or more of the compounds and / or compositions described herein.

[0010] It should be understood here that the compounds described herein can be used alone or in combination with other compounds useful for treating brain injury, including compounds that may be therapeutically effective by the same or different modes of action. In addition, it should be understood here that the compounds described herein can be used in combination with other compounds administered for treating other symptoms of brain injury, such as pain, inflammation, nausea, vomiting, visual impairment, and loss of consciousness. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

Figure 2A

Figure 2B

Figure 3

Figure 4A

Figure 4B

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0012] Described herein is the use of one or more V1aR antagonists for treating brain injury. The compounds described herein may significantly improve the lives of those suffering from brain injuries including, but not limited to, traumatic brain injury (TBI) including blast TBI, brain edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, concussion, and falls.

[0013] Some exemplary embodiments of the present invention are described in the following exemplary clauses.

[0014] Described is a method of treating brain injury in a host animal, the method comprising administering to the host animal a composition comprising one or more of the selective V1aR antagonists described herein.

[0015] A method of treating brain injury in a host animal, wherein the brain injury is at least partially caused by impact, traumatic brain injury (TBI), mild TBI, blast TBI, cerebral edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, ischemic stroke, concussion, fall, or a combination thereof, and administering to the host animal a composition comprising one or more of the selective V1aR antagonists described herein is described.

[0016] The method according to any one of the preceding clauses, wherein the brain injury is characterized by edema such as lateral ventricular edema, cognitive impairment, learning impairment, memory impairment, or motor impairment, or any combination of the foregoing.

[0017] One or more of the antagonists is of the formula: [Chemical formula] (wherein, A is a carboxylic acid, ester, or amide; B is a carboxylic acid, ester, or amide; or B is an alcohol or thiol, or a derivative thereof; R 1 is hydrogen or C1-C6 alkyl; R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or -CO2R 8 , -CONR 8 R 8’ , and -NR 8 (COR 9 ) and is a substituent selected from the group consisting of; R 8 and R 8’ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R 8 and R 8’ together with the attached nitrogen atom form a heterocyclyl group; R 9is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8’ is selected from N-(C1-C4 alkyl); R 3 is an optionally substituted amino, amide, acylamide, or ureido group; or R 3 is a nitrogen-containing heterocyclyl group bonded to a nitrogen atom; and R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl) A method according to any one of the preceding clauses, selected from compounds of and pharmaceutically acceptable salts thereof.

[0018] One or more of the antagonists is of the formula:

Chemical formula

[0019] One or more of the antagonists is of the formula:

Chemical formula

[0020] A is -CO2R 5 (wherein R 5 is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C1-C4 alkyl), and R 6 R 7 is N-(C2-C4 alkyl)) A method according to any one of the preceding clauses.

[0021] A method according to any one of the preceding clauses, wherein A is a mono-substituted amide, a di-substituted amide, or an optionally substituted nitrogen-containing heterocyclylamide.

[0022] Heterocyclyl is independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl, and the morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or is optionally substituted aryl(C1-C4 alkyl). It should be understood that in each occurrence of the various embodiments described herein, heterocyclyl is independently selected in each case.

[0023] R 6 is independently selected from hydrogen or alkyl; and R 7which, independently in each case, is selected from alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, the method according to any one of the preceding claims. R 6 and R 7 together with the attached nitrogen atom form an optionally substituted heterocycle such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; said piperazinyl or homopiperazinyl is also optionally N-substituted by R 13 ; R 13 which, independently in each case, is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aroyl, the method according to any one of the preceding claims. In each occurrence of each of the various embodiments described herein, R 6 and R 7 are to be understood as being independently selected in each case.

[0024] The method according to any one of the preceding claims, wherein A and / or A' is an amide. The method according to any one of the preceding claims, wherein both A and A' are amides. The method according to any one of the preceding claims, wherein A and / or A' is an amide of a secondary amine, also referred to herein as a secondary amide. The method according to any one of the preceding claims, wherein both A and A' are secondary amides. It is to be understood that the secondary amide includes an amide of a cyclic amine bonded at the nitrogen position.

[0025] The method according to any one of the preceding claims, wherein A is an amide. The method according to any one of the preceding claims, wherein A is an amide of a secondary amine, also referred to herein as a secondary amide.

[0026] The method according to any one of the preceding clauses, wherein the antagonist is a diester, an acid ester, or a diacid containing a pharmaceutically acceptable salt thereof, and each of A and A'. is independently selected. The method according to any one of the preceding clauses, wherein the antagonist is an ester-amide, one of A and A' is an ester, and the other is an amide. The method according to any one of the preceding clauses, wherein the antagonist is a diamide, and each of A and A' is independently selected from a mono-substituted amide, a di-substituted amide, and an optionally substituted nitrogen-containing heterocyclic amide.

[0027] A and / or A' is independently selected mono-substituted amide of the formula C(O)NHX-, where X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C1-C4 alkyl), R 6 R 7 N-, and R 6 R 7 selected from N-(C2-C4 alkyl), and each heterocyclyl is independently selected, the method according to any one of the preceding clauses.

[0028] A and / or A' is independently selected di-substituted amide of the formula C(O)NR 14 X-, where R 14 is selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl, and X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C1-C4 alkyl), R 6 R 7 N-, and R 6 R 7 selected from N-(C2-C4 alkyl), and each heterocyclyl is independently selected, the method according to any one of the preceding clauses.

[0029] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of a nitrogen-containing heterocycle bonded at the nitrogen position, independently selected and optionally substituted. Exemplary nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, thiadiazolidinyl, and 1,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted. Such optional substitutions include groups R 10 , R 12 , R 6 R 7 N-, and R 6 R 7 N-(C1-C4 alkyl).

[0030] The method according to any one of the preceding clauses, wherein A and / or A' is 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, independently optionally substituted and bonded at the nitrogen position.

[0031] The method according to any one of the preceding clauses, wherein A and / or A' is 1,2,3,4-tetrahydroisoquinolin-2-yl, independently optionally substituted and bonded at the nitrogen position.

[0032] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of piperidinyl, independently selected, bonded at the nitrogen position, and optionally substituted. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl containing (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 N-(C1-C4 alkyl) containing R 6 R 7It includes N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl).

[0033] The method according to any one of the preceding clauses, wherein A and / or A' is a piperidinyl which is substituted at the 4-position and bonded at the nitrogen position and is independently selected.

[0034] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of piperazinyl which is independently selected, bonded at the nitrogen position and optionally substituted. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl including (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 R including N-(C1-C4 alkyl) 6 R 7 It includes N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl). The method according to any one of the preceding clauses, wherein A and / or A' is a piperazinyl which is substituted at the 4-position and bonded at the nitrogen position and is independently selected.

[0035] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of homopiperazinyl which is independently selected, bonded at the nitrogen position and optionally substituted. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl including (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 R including N-(C1-C4 alkyl) 6 R 7It includes N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl). The method according to any one of the preceding clauses, wherein A and / or A' is a homopiperazinyl which is substituted at the 4-position and bonded at the nitrogen position and is independently selected. The method according to any one of the preceding clauses, wherein A and / or A' is a homopiperazinyl which is substituted with alkyl, aryl, aryl(C1-C4 alkyl) at the 4-position and bonded at the nitrogen position and is independently selected.

[0036] The method according to any one of the preceding clauses, wherein A' is a mono-substituted amide, a di-substituted amide, or an optionally substituted nitrogen-containing heterocyclic amide. A' is -CO2R 5’ wherein R 5’ is hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C1-C4 alkyl), and R 6 R 7 is selected from N-(C2-C4 alkyl), and heterocyclyl is independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl at each occurrence, and the morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or is optionally substituted aryl(C1-C4 alkyl). The method according to any one of the preceding clauses. R 5’ is R 6 R 7 is an optionally substituted heterocyclic alkyl or an optionally substituted aminoalkyl containing N-(C2-C4 alkyl). The method according to any one of the preceding clauses.

[0037] A is of the formula

Chemical formula

Chemical formula

[0038] The method according to any one of the preceding clauses, wherein A is selected from monosubstituted amides, disubstituted amides, and optionally substituted nitrogen-containing heterocyclic amides. The method according to any one of the preceding clauses, wherein A is an amide of optionally substituted 1-tetrahydronaphthylamine.

[0039] The method according to any one of the preceding clauses, wherein A and / or A' is a monosubstituted amide of the formula C(O)NHX, and X is alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C1-C4 alkyl), R 6 R 7 N-, and R 6 R 7 N-(C2-C4 alkyl), and each heterocyclyl is independently selected.

[0040] A and / or A' is a disubstituted amide of the formula C(O)NR 14 X, where R 14 is selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl, X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C1-C4 alkyl), R 6 R 7 N-, and R 6 R 7 N-(C2-C4 alkyl), and each heterocyclyl is independently selected, the method according to any one of the preceding clauses.

[0041] A and / or A' is bonded at the nitrogen position and is an amide of an optionally substituted nitrogen-containing heterocycle. Exemplary nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, thiadiazolidinyl, and 1,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted. Such optional substitutions include the groups R 10 R 12 R 6 R 7 N-, and R 6 R 7 N-(C1-C4 alkyl) as defined herein.

[0042] A is bonded at the nitrogen position and is optionally substituted 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, the method according to any one of the preceding clauses.

[0043] A is bonded at the nitrogen position and is optionally substituted 1,2,3,4-tetrahydroisoquinolin-2-yl, the method according to any one of the preceding clauses.

[0044] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted piperidinyl bonded at the nitrogen position. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl including (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 R including N-(C1-C4 alkyl) 6 R 7 Including N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl). The method according to any one of the preceding clauses, wherein A and / or A' is piperidinyl substituted at the 4-position and bonded at the nitrogen position.

[0045] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted piperazinyl bonded at the nitrogen position. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl including (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 R including N-(C1-C4 alkyl) 6 R 7 Including N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl). The method according to any one of the preceding clauses, wherein A and / or A' is piperazinyl substituted at the 4-position and bonded at the nitrogen position.

[0046] The method according to any one of the preceding clauses, wherein A and / or A’ is an amide of homopiperazinyl bonded at the nitrogen position and optionally substituted. Exemplary optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl containing (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R 6 R 7 N-, R 6 R 7 R including N-(C1-C4 alkyl) 6 R 7 including N-alkyl, diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4 alkyl), and piperidin-1-yl(C1-C4 alkyl). The method according to any one of the preceding clauses, wherein A and / or A’ is homopiperazinyl substituted at the 4-position and bonded at the nitrogen position. The method according to any one of the preceding clauses, wherein A and / or A’ is homopiperazinyl substituted with alkyl, aryl, aryl(C1-C4 alkyl) at the 4-position and bonded at the nitrogen position.

[0047] The method according to any one of the preceding clauses, wherein A and / or A’ is an amide of a heterocycle bonded at the nitrogen position, and the heterocycle is substituted with heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl.

[0048] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted benzyl, optionally substituted 1-naphthylmethyl, or optionally substituted 2-naphthylmethylamine. Optional substitutions include, but are not limited to, 2,3-dichloro, 2,5-dichloro, 2,5-dimethoxy, 2-trifluoromethyl, 2-fluoro-3-trifluoromethyl, 2-fluoro-5-trifluoromethyl, 2-methyl, 2-methoxy, 3,4-dichloro, 3,5-ditrifluoromethyl, 3,5-dichloro, 3,5-dimethyl, 3.5-difluoro, 3,5-dimethoxy, 3-bromo, 3-trifluoromethyl, 3-chloro-4-fluoro, 3-chloro, 3-fluoro-5-trifluoromethyl, 3-fluoro, 3-methyl, 3-nitro, 3-trifluoromethoxy, 3-methoxy, 3-phenyl, 4-trifluoromethyl, 4-chloro-3-trifluoromethyl, 4-fluoro-3-trifluoromethyl, and 4-methyl.

[0049] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted benzyl-N-methylamine. In another embodiment, A of formula (I) or (II) is an amide of optionally substituted benzyl-N-butylamine including n-butyl and t-butyl. The method according to any one of the preceding clauses, wherein A is an amide of optionally substituted benzyl-N-benzylamine. Optional substitutions include, but are not limited to, 2,3-dichloro, 3,5-dichloro, 3-bromo, 3-trifluoromethyl, 3-chloro, and 3-methyl.

[0050] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, or 1-phenylbenzylamine. The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, 1-phenylbenzylamine-N-methylamine. The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted 2-phenyl-β-alanine, or a derivative thereof, and 1-phenylpropanolamine, etc. Optional substitutions include, but are not limited to, 3-trifluoromethoxy, 3-methoxy, 3,5-dimethoxy, and 2-methyl, etc.

[0051] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted 1-phenylcyclopropyl, 1-phenylcyclopentyl, or 1-phenylcyclohexylamine. Optional substitutions include, but are not limited to, 3-fluoro, 4-methoxy, 4-methyl, 4-chloro, and 2-fluoro, etc.

[0052] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of optionally substituted heteroarylmethylamine including, but not limited to, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc. Optional substitutions include, but are not limited to, 5-methyl, 3-chloro, and 2-methyl, etc.

[0053] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of a partially saturated bicyclic aryl including, but not limited to, 1-, 2-, 4-, and 5-indanyl amine, 1- and 2-tetrahydronaphthylamine, indolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl, etc., each of which is optionally substituted.

[0054] The method according to any one of the preceding clauses, wherein A and / or A' is an amide of a substituted piperidine or piperazine. The substituents on the piperidine or piperazine include heterocyclyl, heterocyclylalkyl, optionally substituted aryl, and optionally substituted arylalkyl. Exemplary piperidines and piperazines include the formula;

Table 1

[0055] The method according to any one of the preceding clauses, wherein A' is an amide of a substituted heterocyclic ring bonded at the nitrogen position. The substituents include alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and arylalkyl. The method according to any one of the preceding clauses, wherein A' is an amide of a heterocyclic ring substituted with alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl and bonded at the nitrogen position.

[0056] The method according to any one of the preceding clauses, wherein A' is an amide of an optionally substituted arylheterocyclylamine, arylalkylheterocyclylamine, heterocyclylalkylamine, or heteroarylalkylamine. The method according to any one of the preceding clauses, wherein A' is an amide of piperidin-1-ylpiperidine or piperidin-1-ylalkylpiperidine. In another embodiment, the alkyl is C1-C2 alkyl.

[0057] The method according to any one of the preceding clauses, wherein A is an amide of a substituted piperidine or piperazine.

[0058] The method according to any one of the preceding clauses, wherein B is an alcohol or thiol, or a derivative thereof including their alkyl, aryl, or acyl derivatives.

[0059] The method according to any one of the preceding clauses, wherein Q is oxygen or sulfur.

[0060] R 5” is an optionally substituted arylalkyl, the method according to any one of the preceding clauses.

[0061] R 5” is an optionally substituted aryl(C2-C4 alkyl), the method according to any one of the preceding clauses. R 5” is an optionally substituted aryl(C1-C2 alkyl), the method according to any one of the preceding clauses. R 5” is an optionally substituted benzyl, the method according to any one of the preceding clauses. R 5” is an optionally substituted alkyl, the method according to any one of the preceding clauses.

[0062] n is 1 or 2, the method according to any one of the preceding clauses. n is 1, the method according to any one of the preceding clauses.

[0063] R 2 is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or -CO2R 8 and -CONR 8 R 8’ is a substituent selected from the group consisting of, R 8 and R 8’ are each independently selected from hydrogen and alkyl, the method according to any one of the preceding clauses. R 2 is hydrogen or alkyl, the method according to any one of the preceding clauses. R 2 is hydrogen, the method according to any one of the preceding clauses.

[0064] R 1 is hydrogen, the method according to any one of the preceding clauses. R 1 is methyl, the method according to any one of the preceding clauses. R 1 and R 2 both are hydrogen, the method according to any one of the preceding clauses.

[0065] R 3 is of the formula: [Chemical formula] (wherein, R 10 and R 11 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, and triphenylmethoxy; R 12 is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aroyl, etc.) The method according to any one of the preceding clauses, which is of this kind.

[0066] R 3 is of the formula: [Chemical formula] (wherein R 10 , R 11 , and R 12 are as defined herein) The method according to any one of the preceding clauses, which is of this kind.

[0067] R 3 is of the formula: [Chemical formula] (wherein R 10 , R 11 , and R 12 are as defined herein) The method according to any one of the preceding clauses, which is of this kind.

[0068] R 3 is of the formula: [Chemical formula] (wherein R 10 and R 11 are as defined herein) is one of the methods according to any one of the preceding clauses.

[0069] R 3 is of the formula:

Chemical formula

[0070] R 10 is alkyl, aryl, or arylalkyl, each of which is optionally substituted, or R 10 is optionally substituted aryl, is one of the methods according to any one of the preceding clauses.

[0071] R 4 is of the formula:

Chemical formula

Chemical formula

[0072] The method according to any one of the preceding clauses, wherein n is 1 and the stereochemistry of the α-carbon is (S) or (R), or is an epimer mixture. The method according to any one of the preceding clauses, wherein n is 1 and the stereochemistry of the α-carbon is (R). The method according to any one of the preceding clauses, wherein n is 2 and the stereochemistry of the α-carbon is (S). The method according to any one of the preceding clauses, wherein n is 1, Q is oxygen, and the stereochemistry of the α-carbon is (R). The method according to any one of the preceding clauses, wherein n is 1, Q is sulfur, and the stereochemistry of the α-carbon is (S). It is understood that the compounds of formulas (I) and (II) are chiral at the position of the α-carbon, except when A = A' and n = 0.

[0073] The method according to any one of the preceding clauses, wherein at least one compound has a vasopressin V1a receptor binding affinity (IC 50 ) of less than about 100 nM, less than about 50 nM, less than about 25 nM, or less than about 10 nM.

[0074] The method according to any one of the preceding clauses, wherein at least one compound is AVN228 (Example 233).

[0075] The method according to any one of the preceding clauses, wherein at least one compound is AVN246 (Example 224).

[0076] The method according to any one of the preceding clauses, wherein at least one compound is AVN251 (Example 225).

[0077] The method according to any one of the preceding clauses, wherein at least one compound is AVN296 (Example 232E).

[0078] The method according to any one of the preceding clauses, wherein at least one compound is AVN576 (Example 266).

[0079] The method according to any one of the preceding paragraphs, wherein the administration step comprises one or more compounds according to any one of the preceding paragraphs in a single or divided form, with a total daily dose of about 160 to about 700 mg in total.

[0080] The method according to any one of the preceding paragraphs, wherein the administration step comprises one or more compounds according to any one of the preceding paragraphs in a single or divided form, with a total daily dose of about 160 to about 500 mg in total.

[0081] The method according to any one of the preceding paragraphs, wherein the administration step comprises one or more compounds according to any one of the preceding paragraphs in a single or divided form, with a total daily dose of about 160 to about 400 mg in total.

[0082] The method according to any one of the preceding paragraphs, wherein the administration step comprises one or more compounds according to any one of the preceding paragraphs in a single or divided form, with a total daily dose of about 160 to about 320 mg in total.

[0083] The method according to any one of the preceding paragraphs, wherein the administration step comprises one or more compounds according to any one of the preceding paragraphs in a single or divided form, with a total daily dose of about 160 to about 240 mg in total.

[0084] The method according to any one of the preceding paragraphs, wherein the form is for oral administration.

[0085] The method according to any one of the preceding paragraphs, wherein the form is for rapid or immediate release oral administration.

[0086] The method according to any one of the preceding paragraphs, wherein the form is for parenteral administration.

[0087] In emergencies, it is understood that oral and / or parenteral administration of rapid or immediate release results in high Cmax with a very short Tmax. Without being bound by theory, it is contemplated herein that oral and / or parenteral administration of rapid or immediate release avoids downstream damage caused by untreated brain injury, such as secondary injury events resulting from cellular processes and biochemical cascades that occur within minutes to days after trauma. Secondary injury events include damage to the blood-brain barrier, release of factors that cause inflammation, free radical overload, excitotoxicity (excessive release of the neurotransmitter glutamate), influx of calcium and sodium ions into nerve cells, mitochondrial dysfunction, damaged axons in the white matter of the brain separated from their cell bodies, changes in blood flow to the brain including ischemia, cerebral hypoxia, cerebral edema, and increased intracranial pressure.

[0088] The method according to any one of the preceding clauses, wherein the administration step comprises a once-daily dosing protocol.

[0089] The method according to any one of the preceding clauses, wherein the administration step comprises a twice-daily dosing protocol.

[0090] The method according to any one of the preceding clauses, wherein the administration step comprises a sustained release dosing protocol.

[0091] A pharmaceutical composition adapted to treat or capable of treating a brain injury or disorder in a host animal, comprising one or more compounds according to any one of the preceding clauses, and optionally one or more carriers, diluents, or adjuvants, or combinations thereof.

[0092] A unit dose or unit dosage form adapted to treat or capable of treating a brain injury or disorder in a host animal, comprising one or more compounds according to any one of the preceding clauses, and optionally one or more carriers, diluents, or adjuvants, or combinations thereof.

[0093] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, containing one or more of the compounds described in any one of the preceding paragraphs in a total amount of about 80 to about 350 mg, in single or divided form.

[0094] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, containing one or more of the compounds described in any one of the preceding paragraphs in a total amount of about 80 to about 250 mg, in single or divided form.

[0095] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, containing one or more of the compounds described in any one of the preceding paragraphs in a total amount of about 80 to about 200 mg, in single or divided form.

[0096] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, containing one or more of the compounds described in any one of the preceding paragraphs in a total amount of about 80 to about 160 mg, in single or divided form.

[0097] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, containing one or more of the compounds described in any one of the preceding paragraphs in a total amount of about 80 to about 120 mg, in single or divided form.

[0098] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, adapted for oral delivery.

[0099] A unit dosage or unit dosage form as described in any one of the preceding paragraphs, adapted for sustained release.

[0100] In each of the preceding paragraphs and in each of the embodiments of formula (I) described herein, A, A’, Y, Y 1 , n, R 1 , R 2 , R 3 , R 4 , and R 5Each of the various genera, subgenera, and species such as can be combined without limitation, and thus it should be understood that each such additional embodiment of the present invention is thereby described by the combination. In each of the clauses and in each of the embodiments of formula (II) described herein, A, Q, Y, Y 1 , n, R 1 , R 2 , R 3 , R 4 , R 5 and R 5” Each of the various genera, subgenera, and species such as can be combined without limitation, and thus it should also be understood that each such additional embodiment of the present invention is thereby described by the combination. For example, (a) A is of the formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0101] In the exemplary clauses and embodiments described herein, A and / or A' may contain a chiral center, and either optically pure enantiomers may be included in the compounds described herein, or a racemate may be used, which is understood. For example, any one or both of the following enantiomers: (R)-1-(3-methoxyphenyl)ethylamine, (R)-1-(3-trifluoromethylphenyl)ethylamine, (R)-1,2,3,4-tetrahydro-1-naphthylamine, (R)-1-indanyl-amine, (R)-α,N-dimethylbenzylamine, (R)-α-methylbenzylamine, (S)-1-(3-methoxyphenyl)ethylamine, (S)-1-(3-trifluoromethylphenyl)ethylamine, (S)-1,2,3,4-tetrahydro-1-naphthylamine, (S)-1-indanyl-amine, and (S)-α-methylbenzylamine may be included in the compounds described herein.

[0102] In another embodiment, the compounds described herein cross the blood-brain barrier (BBB) and exhibit high CNS permeability. In another embodiment, the compounds described herein exhibit an in-brain dose level effective for treating brain injury. In another embodiment, the compounds described herein exhibit a plasma level equal to or exceeding the plasma level required for clinical effectiveness in the treatment of brain injury. In another embodiment, the compounds described herein exhibit pharmacokinetics consistent with twice-daily (b.i.d.) dosing. In another embodiment, the compounds described herein exhibit pharmacokinetics consistent with once-daily (q.d.) dosing. It is understood herein that both b.i.d. and q.d. dosing can be important features for improving patient compliance and resulting in an overall enhanced clinical effect. In another embodiment, the compounds described herein are metabolically stable in the stomach and blood. In another embodiment, the compounds described herein exhibit a cardiovascular safety profile consistent with the treatment of brain injury both in vivo and in vitro. In another embodiment, the compounds described herein exhibit respiratory safety in vivo.

[0103] In another embodiment, the compounds described herein, as well as pharmaceutical compositions and medicaments containing them, exhibit high plasma levels and high brain levels, including oral administration. In another embodiment, the compounds described herein, as well as pharmaceutical compositions and medicaments containing them, can pass through the blood-brain barrier (BBB), including oral administration. In another embodiment, the compounds described herein, as well as pharmaceutical compositions and medicaments containing them, do not significantly or competitively bind to other given GPCRs or other given receptors, including but not limited to neurotransmitter-related receptors, steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factor and hormone receptors, other brain and gastrointestinal peptide receptors, and other enzymes, etc., but exhibit high CNS bioavailability and high affinity. In one aspect, the compounds described herein, as well as pharmaceutical compositions and medicaments containing them, are inactive or substantially inactive at 100 nM against a standard panel of 64 receptors, including 35 GPCRs (Novascreen panel) that include neurotransmitter-related receptors, steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factor receptors, hormone receptors, brain / gastrointestinal peptides (excluding vasopressin 1), and enzymes.

[0104] Unconstrained by theory, AVP and related peptides are thought herein to represent a family of chemical signals in vertebrates that play important roles in the control of social behavior and emotion. AVP is synthesized in neurons of the hypothalamus of all mammals. It is released from nerve terminals into the median eminence and transported to the pituitary gland, where it enhances the release of adrenocorticotropic hormone (ACTH) and ultimately increases the levels of circulating stress hormones through its action at pituitary AVP receptors. From nerve terminals in the pituitary gland, AVP also enters the general bloodstream, where it acts on the heart and blood vessels, affects cardiac function, and affects the kidneys to reduce urine output. AVP neurons and nerve fibers are also found throughout the limbic system of the brain. AVP exerts its physiological and behavioral effects by binding to specific G-protein-coupled receptors (GPCRs) in the central nervous system and certain peripheral tissues / sites. Three distinct AVP receptor subtypes, V1a, V1b, and V2, have been identified. V1a is the predominant AVP receptor found in the limbic system and cortex, the V1b receptor is located in the limbic system and pituitary gland but is not as widely present as V1a. The V2 receptor is localized in the kidney and mediates the antidiuretic effect of vasopressin. Generally, V2 is not thought herein to be expressed in the nervous system of adult animals or humans.

[0105] In another embodiment, the compounds described herein are selectively active at the V1a AVP receptor. In another embodiment, the compounds described herein are selectively active at the V1a AVP receptor and have low activity, substantially low activity, and / or inactivity at other AVP receptors such as the V1b and / or V2 subtypes of the AVP receptor. In another embodiment, the compounds described herein are 10-fold selective for the V1a receptor compared to the V1b and / or V2 receptors. In another embodiment, the compounds described herein are 100-fold selective for the V1a receptor compared to the V1b and / or V2 receptors. In another embodiment, the compounds described herein are 1000-fold selective for the V1a receptor compared to the V1b and / or V2 receptors. In another embodiment, the compounds described herein are 10,000-fold selective for the V1a receptor compared to the V1b and / or V2 receptors.

[0106] In another embodiment, the compounds described herein are selectively active at the V1a AVP receptor compared to other G protein-coupled receptors (GPCRs). In another embodiment, the compounds described herein are selectively active at the V1a AVP receptor and have low activity, substantially low activity, and / or inactivity at other GPCRs. In another embodiment, the compounds described herein are 10-fold selective for the V1a receptor compared to other GPCRs. In another embodiment, the compounds described herein are 100-fold selective for the V1a receptor compared to other GPCRs. In another embodiment, the compounds described herein are 1000-fold selective for the V1a receptor compared to other GPCRs. In another embodiment, the compounds described herein are 10,000-fold selective for the V1a receptor compared to other GPCRs.

[0107] In another embodiment, the compounds described herein, and pharmaceutical compositions and medicaments containing them, have certain behavioral effects in a context-dependent manner (see, e.g., Ferris & Potegal Physiology and Behavior, 44:235-239 (1988)). For example, in another embodiment, the compounds described herein, and pharmaceutical compositions and medicaments containing them, are effective in modulating neuropsychiatric disorders but have little or no effect on sexual behavior.

[0108] In each of the foregoing clauses and in each of the embodiments described herein, the formula is understood to include all pharmaceutically acceptable salts of the compound and to represent, not only, any and all hydrates and / or solvates of the formula of the compound. It is understood that certain functional groups, such as hydroxy and amino groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Accordingly, the above formula should be understood as an illustration of such hydrates and / or solvates, including pharmaceutically acceptable solvates.

[0109] In each of the clauses and embodiments described herein, the formula is also understood to include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing embodiments and in each of the following embodiments, the formula is also understood to include and represent any and all crystalline forms, partially crystalline forms, as well as non-crystalline and / or amorphous forms of the compound.

[0110] As used herein, the term "solvate" refers to a compound described herein that is complexed with solvent molecules. It is understood that the compounds described herein can form such complexes with solvents simply by mixing the solvent with the compound or dissolving the compound in the solvent. It is understood that the compound is used as a pharmaceutical and such solvent is a pharmaceutically acceptable solvent. Further, when the compound is used as a pharmaceutical, the relative amount of solvent forming the solvate must be less than the guidelines established for such pharmaceutical use, such as the guidelines of the International Conference on Harmonization (ICH). It is understood that solvates can be isolated from excess solvent by evaporation, precipitation, and / or crystallization. In some embodiments, the solvate is amorphous and in other embodiments, the solvate is crystalline.

[0111] The compounds described herein may contain one or more chiral centers or alternatively may exist as a plurality of stereoisomers. In one embodiment, the invention described herein is not limited to any particular stereochemical requirements and compounds, compositions, methods, uses, and pharmaceuticals containing them can be optically pure or can be any of various mixtures of stereoisomers including racemic mixtures of enantiomers and other mixtures, and other mixtures of diastereomers. It is understood that such mixtures of stereoisomers can include a single stereochemical configuration at one or more chiral centers while including a mixture of stereochemical configurations at one or more other chiral centers.

[0112] Similarly, the compounds described herein may contain geometric centers such as cis, trans, E and Z double bonds. In another embodiment, the invention described herein is not limited to any particular geometric isomer requirements and compounds, compositions, methods, uses, and pharmaceuticals containing them can be pure or can be any of various mixtures of geometric isomers. It is understood that such mixtures of geometric isomers can include a single configuration at one or more double bonds while including a mixture of configurations at one or more other double bonds.

[0113] As used herein, the term "alkyl" includes a chain of carbon atoms that is branched as necessary. As used herein, the terms "alkenyl" and "alkynyl" each include a chain of carbon atoms that is branched as necessary and each includes at least one double bond or triple bond. It should be understood that alkynyl may also include one or more double bonds. Further, in certain embodiments, the advantages of alkyl are C1-C 24 C1-C 12 C1-C8, C1-C6, and C1-C4, as well as C2-C 24 C2-C 12 C2-C8, C2-C6, and C2-C4, etc., and are of limited length. Exemplarily, such specific limited-length alkyl groups including C1-C8, C1-C6, and C1-C4, as well as C2-C8, C2-C6, and C2-C4, etc., may be referred to as lower alkyl. Further, in certain embodiments, the advantages of each of alkenyl and / or alkynyl are C2-C 24 C2-C 12 C2-C8, C2-C6, and C2-C4, as well as C3-C 24 C3-C 12It should be understood that they are of limited length, including C3-C8, C3-C6, and C3-C4, etc. Exemplarily, such particularly limited-length alkenyl and / or alkynyl groups including C2-C8, C2-C6, and C2-C4, as well as C3-C8, C3-C6, and C3-C4, etc., may be referred to as lower alkenyl and / or lower alkynyl. It is understood herein that shorter alkyl, alkenyl, and / or alkynyl groups cannot add much lipophilicity to the compound, and accordingly, have different pharmacokinetic behaviors. In the embodiments of the invention described herein, in each case, the description of alkyl is understood to refer to alkyl as defined herein, optionally lower alkyl. In the embodiments of the invention described herein, in each case, the description of alkenyl is understood to refer to alkenyl as defined herein, optionally lower alkenyl. In the embodiments of the invention described herein, in each case, the description of alkynyl is understood to refer to alkynyl as defined herein, optionally lower alkynyl. Exemplary alkyl, alkenyl, and alkynyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, and octyl, etc., and the corresponding groups containing one or more double and / or triple bonds, or combinations thereof.

[0114] The term "alkylene" as used herein includes a divalent chain of carbon atoms that is branched as necessary. The terms "alkenylene" and "alkynylene" as used herein include a divalent chain of carbon atoms that is branched as necessary and contain at least one double bond or triple bond, respectively. It should be understood that alkynylene may also contain one or more double bonds. Further, in certain embodiments, the advantages of alkylene are C1-C 24 、C1-C 12 、C1-C8, C1-C6, and C1-C4, as well as C2-C 24 、C2-C 12, those having a limited length, such as C2-C8, C2-C6, and C2-C4, should be understood. Exemplarily, such specific limited-length alkylene groups including C1-C8, C1-C6, and C1-C4, as well as C2-C8, C2-C6, and C2-C4, can be called lower alkylene. Further, in certain embodiments, the respective advantages of alkenylene and / or alkynylene are C2-C 24 , C2-C 12 , C2-C8, C2-C6, and C2-C4, and C3-C 24 , C3-C 12 , those having a limited length, such as C3-C8, C3-C6, and C3-C4, should be understood. Exemplarily, such specific limited-length alkenylene groups and / or alkynylene groups including C2-C8, C2-C6, and C2-C4, as well as C3-C8, C3-C6, and C3-C4, can be called lower alkenylene and / or lower alkynylene. Shorter alkylene groups, alkenylene groups, and / or alkynylene groups cannot add much lipophilicity to the compound, and accordingly, it is understood herein that they have different pharmacokinetic behaviors. In the embodiments of the present invention described herein, in each case, the descriptions of alkylene, alkenylene, and alkynylene refer to alkylene, alkenylene, and alkynylene as defined herein, and optionally, lower alkylene, lower alkenylene, and lower alkynylene. Exemplary alkyl groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, and octylene, etc.

[0115] As used herein, the term "cycloalkyl" includes a chain of carbon atoms that is optionally branched and in which at least a portion of the chain is cyclic. It should be understood that cycloalkylalkyl is a subset of cycloalkyl. It should be understood that cycloalkyl can be polycyclic. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, and adamantyl. As used herein, the term "cycloalkenyl" includes a chain of carbon atoms that is optionally branched, contains at least one double bond, and in which at least a portion of the chain is cyclic. It should be understood that one or more double bonds can be in the cyclic portion and / or the acyclic portion of the cycloalkenyl. It should be understood that cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It should be understood that cycloalkyl can be polycyclic. Exemplary cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexylethene-2-yl, and cycloheptenylpropenyl. Further, it should be understood that the chain-forming cycloalkyl and / or cycloalkenyl are of limited length, including C3-C 24 、C3-C 12 、C3-C8, C3-C6, and C5-C6. Shorter alkyl and / or alkenyl chain-forming cycloalkyl and / or cycloalkenyl, respectively, cannot add much lipophilicity to the compound, and accordingly, it is understood herein that they have different pharmacokinetic behaviors.

[0116] As used herein, the term "heteroalkyl" includes chains of atoms containing both carbon and at least one heteroatom, optionally branched. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain embodiments, exemplary heteroatoms also include phosphorus and selenium. As used herein, the term "cycloheteroalkyl", including heterocyclyl and heterocyclic rings, includes chains of atoms containing both carbon and at least one heteroatom, such as heteroalkyl, optionally branched, wherein at least a portion of the chain is cyclic. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain embodiments, exemplary heteroatoms also include phosphorus and selenium. Exemplary cycloheteroalkyls include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, and quinuclidinyl, etc.

[0117] As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Exemplary aromatic carbocyclic groups described herein include, but are not limited to, phenyl, and naphthyl, etc. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may be optionally substituted. Exemplary aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, and benzisothiazolyl, etc.

[0118] As used herein, the term "amino" includes the group NH2, alkylamino, and dialkylamino, where the two alkyl groups in the dialkylamino may be the same or different, i.e., it may be alkylalkylamino. Exemplarily, amino includes methylamino, ethylamino, dimethylamino, and methylethylamino, etc. In addition, when amino is modified or modified by another term such as aminoalkyl or acylamino, it should be understood that the above variations of the term amino are included therein. Exemplarily, aminoalkyl includes H2N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, and methylethylaminoalkyl, etc. Exemplarily, acylamino includes acylmethylamino and acylethylamino, etc.

[0119] As used herein, the term "amino and its derivatives" includes the amino described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino, heteroalkenylamino, heteroalkynylamino, cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamino, arylalkynylamino, heteroaryl amino, heteroarylalkylamino, heteroarylalkenylamino, heteroarylalkynylamino, and acylamino, etc., each of which is optionally substituted. The term "amino derivative" also includes urea, carbamate, etc.

[0120] As used herein, the term "hydroxy and its derivatives" includes OH, and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy, heteroarylalkenyloxy, heteroarylalkynyloxy, and acyloxy, etc., each of which is optionally substituted. The term "hydroxy derivative" also includes carbamate, etc.

[0121] As used herein, the term "thio and its derivatives" includes SH, and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio, arylalkynylthio, heteroarylthio, heteroarylalkylthio, heteroarylalkenylthio, heteroarylalkynylthio, and acylthio, etc., each of which is optionally substituted. The term "thio derivative" also includes thiocarbamate, etc.

[0122] As used herein, the term "acyl" includes formyl, and alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl, heteroalkenylcarbonyl, heteroalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloheteroalkylcarbonyl, cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkynylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, and acylcarbonyl, etc., each of which is optionally substituted.

[0123] As used herein, the term "carbonyl and its derivatives" includes the groups C(O), C(S), C(NH), and their substituted amino derivatives.

[0124] As used herein, the term "carboxylic acid and its derivatives" includes the group CO2H and its salts, as well as its esters and amides, and CN.

[0125] As used herein, the term "sulfinic acid or its derivatives" includes SO2H and its salts, as well as its esters and amides.

[0126] As used herein, the term "sulfonic acid or its derivatives" includes SO3H and its salts, as well as its esters and amides.

[0127] As used herein, the term "sulfonyl" includes alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, heteroalkylsulfonyl, heteroalkenylsulfonyl, heteroalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloheteroalkylsulfonyl, cycloheteroalkenylsulfonyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, arylalkynylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl, heteroarylalkynylsulfonyl, and acylsulfonyl, etc., each of which is optionally substituted.

[0128] As used herein, the term "hydroxylamino and its derivatives" includes NHOH, and alkyloxyl NH, alkenyloxyl NH, alkynyloxyl NH, heteroalkyloxyl NH, heteroalkenyloxyl NH, heteroalkynyloxyl NH, cycloalkyloxyl NH, cycloalkenyloxyl NH, cycloheteroalkyloxyl NH, cycloheteroalkenyloxyl NH, aryloxyl NH, arylalkyloxyl NH, arylalkenyloxyl NH, arylalkynyloxyl NH, heteroaryloxyl NH, heteroarylalkyloxyl NH, heteroarylalkenyloxyl NH, heteroarylalkynyloxyl NH, and acyloxy, etc., each of which is optionally substituted.

[0129] As used herein, the term "hydrazino and its derivatives" includes alkyl NHNH, alkenyl NHNH, alkynyl NHNH, heteroalkyl NHNH, heteroalkenyl NHNH, heteroalkynyl NHNH, cycloalkyl NHNH, cycloalkenyl NHNH, cycloheteroalkyl NHNH, cycloheteroalkenyl NHNH, aryl NHNH, arylalkyl NHNH, arylalkenyl NHNH, arylalkynyl NHNH, heteroaryl NHNH, heteroarylalkyl NHNH, heteroarylalkenyl NHNH, heteroarylalkynyl NHNH, and acyl NHNH, etc., each of which is optionally substituted.

[0130] As used herein, the term "optionally substituted" includes substitution of other functional groups and hydrogen atoms on the optionally substituted radical. Exemplarily, such other functional groups include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. Exemplarily, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted.

[0131] As used herein, the terms "optionally substituted aryl" and "optionally substituted heteroaryl" include substitution of other functional groups and hydrogen atoms on the optionally substituted aryl or heteroaryl. Exemplarily, such other functional groups include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, and carboxylic acid and its derivatives, etc. Exemplarily, any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted.

[0132] Exemplary substituents include the radical -(CH2) X Z X is included, but not limited thereto, wherein x is an integer from 0 to 6, and Z Xis selected from halogen, hydroxy, alkanoyloxy containing C1-C6 alkanoyloxy, optionally substituted aroyloxy, alkyl containing C1-C6 alkyl, alkoxy containing C1-C6 alkoxy, cycloalkyl containing C3-C8 cycloalkyl, cycloalkoxy containing C3-C8 cycloalkoxy, alkenyl containing C2-C6 alkenyl, alkynyl containing C2-C6 alkynyl, haloalkyl containing C1-C6 haloalkyl, haloalkoxy containing C1-C6 haloalkoxy, halocycloalkyl containing C3-C8 halocycloalkyl, halocycloalkoxy containing C3-C8 halocycloalkoxy, amino, C1-C6 alkylamino, (C1-C6 alkyl)(C1-C6 alkyl)amino, alkylcarbonylamino, N-(C1-C6 alkyl)alkylcarbonylamino, aminoalkyl, C1-C6 alkylaminoalkyl, (C1-C6 alkyl)(C1-C6 alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C1-C6 alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Z X is -CO2R 4 and -CONR 5 R 6 is selected from, wherein R 4 , R 5 and R 6 are each independently, in each occurrence, selected from hydrogen, C1-C6 alkyl, aryl-C1-C6 alkyl, and heteroaryl C1-C6 alkyl.

[0133] As generally used herein, the term "prodrug" refers to any compound that, when administered to a living system, results in the production of a biologically active compound as a result of one or more spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), and / or metabolic chemical reaction(s), or combinations thereof. In vivo, prodrugs are typically activated by enzymes (e.g., esterases, amidases, and phosphatases, etc.), simple biochemistry, or other processes in vivo to release or regenerate a more pharmacologically active drug. This activation can occur via the action of endogenous host enzymes or non-endogenous enzymes administered to the host before, after, or during administration of the prodrug. Further details of the use of prodrugs are described in U.S. Patent No. 5,627,165. The advantages of prodrugs are understood to be that, once the objectives such as targeted delivery, safety, and stability are achieved, they are converted to the original drug, and then the remaining prodrug-forming groups are rapidly removed.

[0134] Prodrugs can be prepared from the compounds described herein by attaching a group that is ultimately cleaved in vivo to one or more functional groups present on a compound such as -OH-, -SH, -CO2H, -NR2. Exemplary prodrugs include carboxylic acid esters where the group is alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol and amine where the attached group is an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate, but are not limited thereto. Exemplary esters, also called active esters, include 1-indanyl, N-oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, β-acetoxyethyl, β-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, and β-ethoxycarbonyloxyethyl; dialkylaminoalkyl groups containing di-lower alkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, and diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)penta-2-enyl, and 2-(ethoxycarbonyl)but-2-enyl; and lactone groups such as phthalidyl and dimethoxyphthalidyl, but are not limited thereto.

[0135] Further exemplary prodrugs contain chemical moieties such as amide or phosphorus groups that function to enhance the solubility and / or stability of the compounds described herein. Further exemplary prodrugs for amino groups include (C3-C 20 ) alkanoyl; halo(C3-C 20 ) alkanoyl; (C3-C 20 ) alkenoyl; (C4-C7) cycloalkanoyl; (C3-C6) cycloalkyl(C2-C 16) Alkanoyl; optionally substituted alkanoyl such as aloyl substituted with 1 to 3 substituents selected from the group consisting of unsubstituted aloyl, or halogen, cyano, trifluoromethanesulfonyloxy, (C1-C3) alkyl and (C1-C3) alkoxy (each of which is optionally further substituted with one or more of 1 to 3 halogen atoms); optionally substituted aryl or heteroaryl group such as aryl or heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of halogen, (C1-C3) alkyl and (C1-C3) alkoxy (each of which is optionally further substituted with 1 to 3 halogen atoms) 16 ) Alkanoyl and optionally substituted heteroaryl (C2-C 16 ) Alkanoyl; and optionally substituted heteroarylalkanoyl having 1 to 3 heteroatoms selected from O, S and N in the heteroaryl moiety and having 2 to 10 carbon atoms in the alkanoyl moiety, such as a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulfonyloxy, (C1-C3) alkyl and (C1-C3) alkoxy (each of which is optionally further substituted with 1 to 3 halogen atoms), but not limited thereto. The groups shown are illustrative and not exhaustive and can be prepared by conventional methods.

[0136] Although the prodrug itself does not have significant biological activity, instead, after administration in vivo, it undergoes one or more spontaneous chemical reactions (plural possible), enzyme-catalyzed chemical reactions (plural possible), and / or metabolic chemical reactions (plural possible), or combinations thereof, to produce a compound described herein that has biological activity or is a precursor of a compound with biological activity. However, in some cases, the prodrug is understood to have biological activity. It is also understood that prodrugs can often help improve the effectiveness or safety of a drug, such as through improved oral bioavailability and pharmacokinetic half-life. A prodrug also refers to a derivative of a compound described herein that simply hides undesirable drug properties or contains a group that improves drug delivery. For example, one or more compounds described herein may exhibit undesirable properties that can be pharmacologically, pharmaceutically, or pharmacokinetically barriers in clinical drug applications, such as poor oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at the injection site, etc.), and others. It is understood herein that the use of prodrugs, or other strategies using reversible derivatives, may be useful for optimizing the clinical application of a drug.

[0137] As used herein, the term "leaving group" refers to a reactive functional group that results in an electrophilic site on an atom that is bonded such that a nucleophile can be added to the electrophilic site on the atom. Exemplary leaving groups include, but are not limited to, halogen, optionally substituted phenol, acyloxy group, and sulfonyloxy group. It is to be understood that such leaving groups can be present on, for example, alkyl and acyl. Such leaving groups can also be referred to as activating groups, such as when the leaving group is present on an acyl. In addition, without limitation, conventional peptide, amide, and ester coupling agents such as PyBop, BOP-Cl, BOP, pentafluorophenol, and isobutyl chloroformate form various intermediates that contain a leaving group as defined herein on a carbonyl group.

[0138] In all cases disclosed herein, it should be understood that the description of the integer range of any variable describes the described range, all individual members of the range, and all possible sub-ranges of that variable. For example, the description that n is an integer from 0 to 8 describes that n is 0, or n is 1, or n is 2, etc., which is a range of the individual selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8. In addition, the description that n is an integer from 0 to 8 also describes each and every sub-range, each of which can be the basis for further embodiments such as n being an integer from 1 to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to 3, 2 to 4, etc.

[0139] As used herein, the terms "processing", "contacting", or "reacting" when referring to a chemical reaction generally mean adding or mixing two or more reagents under suitable conditions that cause a chemical transformation or chemical reaction and / or enable the formation of the indicated product and / or the desired product. It should be understood that the reaction that forms the indicated product and / or the desired product may not necessarily occur directly from the combination of the two reagents initially added. In other words, ultimately, there may be one or more intermediates formed in the mixture that lead to the formation of the indicated product and / or the desired product.

[0140] As used herein, the term "composition" generally refers to any product that contains specific components in specific amounts, as well as any product that directly or indirectly results from a combination of specific amounts of specific components. It should be understood that the compositions described herein can be prepared from the isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It should also be understood that the compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the compounds described herein. It should further be understood that the compositions can be prepared from various hydrates and / or solvates of the compounds described herein. Thus, such pharmaceutical compositions listing the compounds described herein should be understood to include each of the various morphological forms and / or solvate or hydrate forms of the compounds described herein, or any combination thereof. In addition, it should be understood that the compositions can be prepared from various co-crystals of the compounds described herein.

[0141] Exemplarily, the composition can include one or more carriers, diluents, and / or excipients. The compounds described herein, or compositions containing them, can be formulated in a therapeutically effective amount in any conventional dosage form appropriate for the methods described herein. The compounds described herein, or compositions containing them such as those formulations, can be administered in various dosage forms by various conventional routes of the methods described herein and using known procedures (see generally Remington: The Science and Practice of Pharmacy, 21st Edition, 2005).

[0142] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or agent that elicits a biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including alleviation of the symptoms of a disease or disorder being treated. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate a disease or the symptoms of a disease with a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily usage of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient depends on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the age, body weight, general health, gender, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound being used; the duration of the treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors well known to researchers, veterinarians, physicians, or other clinicians of ordinary skill.

[0143] Also, regardless of whether reference is made to monotherapy or combination therapy, it is understood that a therapeutically effective amount is conveniently selected with reference to any toxicity or other undesirable side effects that may occur during one or more administrations of the compounds described herein. Also, the co-therapies described herein may enable the administration of lower doses of compounds that exhibit such toxicity or other undesirable side effects, and it is understood that those lower doses are below the toxicity threshold or are lower within the therapeutic window than those administered in the absence of combination therapy in other ways.

[0144] In addition to the exemplary dosages and dosing protocols described herein, it should be understood that an effective amount of any one or a mixture of the compounds described herein can be readily determined by a responsible diagnostician or physician by the use of known techniques and / or by observing the results obtained in similar circumstances. In determining an effective amount or dosage, several factors including, but not limited to, the mammalian species, including human, its size, age, and general health, the particular disease or disorder involved, the degree or involvement or severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dosing regimen selected, the use of concomitant medications, and other relevant circumstances are considered by the responsible diagnostician or physician.

[0145] The dosage of each compound of the claimed combination depends on several factors including the method of administration, the condition being treated, the severity of the condition, whether the condition is to be treated or prevented, the age, weight, and health of the human to be treated. Also, information on pharmacogenomics (the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a treatment) for a particular patient can affect the dosage used.

[0146] It should be understood that in the methods described herein, the individual components, or combinations, of a co-administration can be administered contemporaneously, simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means. When the co-administered compounds or compositions are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The compounds or compositions can be administered via the same or different routes of administration. The compounds or compositions can be administered simultaneously, in divided or single form, at the same or different times during the course of treatment, according to a simultaneous regimen or an alternating regimen.

[0147] As used herein, the term "administering" includes all means of introducing the compounds and compositions described herein into a host animal, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (ssc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, and rectal. The compounds or compositions described herein can be administered in unit dosage forms and / or in preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and / or vehicles.

[0148] In making a pharmaceutical composition of a compound described herein, one or more therapeutically effective amounts of any of the various forms of the compounds described herein can be mixed with one or more excipients, diluted with one or more excipients, or encapsulated within such a carrier that can be present in the form of capsules, sachets, paper, or other containers. Excipients can act as diluents and can be solid, semi-solid, or liquid materials that act as vehicles, carriers, or media for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. The compositions can contain from about 0.1% to about 99.9% by weight of the active ingredient, depending on the dosage selected and the dosage form.

[0149] As used herein, the term "antagonist" refers to a full or partial antagonist. Any partial antagonist with any intrinsic activity can be useful, but partial antagonists, by way of example, exhibit at least about 50% antagonist effect, or at least about 80% antagonist effect. The term also includes compounds that are full antagonists of one or more vasopressin receptors. The exemplary methods described herein require a therapeutically effective amount of a vasopressin receptor antagonist, and thus it is understood that compounds that exhibit partial antagonist activity at one or more vasopressin receptors can be administered at higher doses to exhibit sufficient antagonist activity to inhibit the action of vasopressin or a vasopressin agonist.

[0150] The effective use of the compounds, compositions, and methods described herein to treat or ameliorate one or more effects of brain injury using one or more of the compounds described herein can be based on animal models such as mouse, dog, pig, and non-human primate models of the disease. For example, it is understood that brain injury in humans can be characterized by loss of function and / or onset of symptoms that can each be induced in animals such as mice and other surrogate test animals. In particular, the mouse models described herein can be used to evaluate the treatment methods and pharmaceutical compositions described herein to determine a therapeutically effective amount thereof.

[0151] Each publication cited herein is incorporated herein by reference.

[0152] The following examples further illustrate specific embodiments of the invention. However, the following exemplary examples should in no way be construed as limiting the invention.

[0153] Examples Examples of Methods Example. Controlled Cortical Impact Injury Model. Briefly, test animals are first anesthetized with isoflurane (4.5%), intubated, and mechanically ventilated with a gas mixture of N2O (66%), O2 (32%), and isoflurane (1.5 - 2.0%). Rectal temperature is maintained at 37.0 ± 0.5 °C using a self-regulating heating pad. Catheters are placed in the femoral artery and vein. Mean arterial blood pressure (mABP) is continuously monitored using a data acquisition system, and arterial blood gas parameters (pH, pO2, pCO2, and plasma Na +The concentrations are obtained at 15-minute intervals. Using the femoral vein, the vehicle, dimethyl sulfoxide (DMSO), or one or more of the compounds described herein are administered. The animals are fixed in a stereotaxic frame. A midline scalp incision is made and the skin and periosteum are retracted from the surface of the skull. A craniotomy with a diameter of 10 mm is made midway between the right coronal suture and the lambda suture, 1 mm lateral to the midline. Injury is caused using a pneumatic impactor (e.g., 5 mm in diameter) attached at an angle (e.g., 10°) from the vertical plane. A single impact (e.g., velocity 6 m / sec; depth of deformation 3.0 mm; dwell time, 0.3 sec) is delivered to the right parietal cortex. After injury, the excised skull portion is replaced, sealed with bone wax, and the skin incision is closed. Sham-operated animals are subjected to the same surgical procedure without any injury by the pneumatic impactor. Further details are described in Dixon et al., "A fluid percussion model of experimental brain injury in the rat": J Neurosurg 67:110-119 (1987) and Taya et al., "Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema", Acta Neurochir 102 (Suppl):S425-S429 (2008).

[0154] Example. Momentum exchange impact model. This model features several advantageous translational motion differences that exceed some head injury models such as the controlled cortical impact injury model. For example, the head, neck, and body can move upon impact, and by calculating the speed of head movement and energy transfer and scaling gently, it is possible to cause concussion in the moderate to severe range. The study is conducted with moderate impacts having neuroimaging evidence of contusion. Male rats are vibrated twice a day. Further details are described in Viano et al., "Evaluation of three animal models for concussion and serious brain injury", Ann Biomed Eng. 40(1):213 - 26(2012). Within 24 hours of the first concussion, a test compound such as a vehicle passing through the blood - brain barrier or a highly selective V1a receptor antagonist is administered to the test animals. A vehicle or test compound is administered to sham non - concussion test animals. The test animals are treated twice daily for 5 consecutive days. At the 2 - week time point after concussion, cognitive behavior is evaluated using, for example, the Barnes maze and / or novel recognition models. In addition, motor behavior is evaluated using, for example, the beam walk and / or rotarod tests. In each case, neuroimaging MRI is also performed.

[0155] Example. Imaging neuroanatomy. At the start of each imaging session, a high - resolution anatomical dataset is collected using a RARE pulse sequence (20 slices; 1 mm; field of view [FOV] 3.0 cm; 256×256; repetition time [TR] 2.5 seconds; echo time [TE] 12.4 milliseconds; NEX 6; acquisition time of 6.5 minutes).

[0156] Example. T2 relaxation measurement of edema. To characterize the volume of edema in the lateral ventricle using T2 relaxation measurement, MRI was performed on days 24 - 28 after injury. The imaging time was based on the rat model used for the evaluation of TBI by Charles River. Images were acquired using a multi-slice multi-echo (MSME) pulse sequence. The echo time (TE) was exemplarily 11 milliseconds, 16 echoes were acquired during imaging, and the recovery time (TR) was 2500 milliseconds. Images were acquired with a field of view [FOV] of 3 cm 2 , data matrix = 256×256×20 slices, thickness = 1 mm. Values of the longitudinal relaxation time (T2) were obtained from all slices using ParaVision 5.1 software. T2 was used to characterize the edema volume in the lateral ventricle. The T2 values were used for the segmentation and quantification of the ventricular volume. The T2 values obtained from ParaVision 5.1 software were calculated using the equation: y = A + Cexp(−t / T2) (SD weighted) (where A = absolute bias, C = signal intensity, t = echo time, and T2 = spin - spin relaxation time). The ventricle was identified as the high intensity on the T2 map over three 1 - mm sections. The volume was calculated using the snake region growing algorithm of itk - SNAP (www.itksnap.org). The threshold was set exemplarily at 6300 - 9000 as the absolute pixel intensity. Points within the ventricle were examined and the algorithm was run until the segmentation was complete.

[0157] Example. Functional connectivity at rest. Resting-state fMRI scans are acquired using a spin-echo triple-shot EPI sequence (imaging parameters: matrix size = 96×96×20, TR / TE = 3000 / 15 milliseconds, voxel size = 0.312×0.312×0.12 mm, slice thickness = 1 mm). Preprocessing is achieved, for example, by combining analysis of Functional NeuroImages (AFNI_17.1.12, http: / / afni.nimh.nih.gov / afni / ), FMRIB Software Library (FSL, v5.0.9, http: / / fsl.fmrib.ox.ac.uk / fsl / ), Deformable Registration via Attribute Matching and Mutual-Saliency Weighting (DRAMMS 1.4.1, https: / / www.cbica.upenn.edu. / sbia / software / dramms / index.html) and MATLAB (Mathworks, Natick, MA). A brain tissue mask for the resting-state functional images is manually drawn using 3DSlicer (https: / / www.slicer.org / ) and applied to skull stripping. Normalization is completed by registering the functional data to an MRI rat brain template (Ekam Solutions LLC, Boston, MA) using affine registration via DRAMMS. For example, an inter-regional functional connectivity method is performed to measure the correlation in spontaneous BOLD fluctuations. The network is composed of nodes and edges. Nodes are regions of interest (ROIs) in the brain, and edges are the connections between regions. Nodes are defined using ROIs segmented from an appropriate MRI rat brain atlas. For example, 171 nodes are defined. Voxel time series data are averaged at each node based on artifacts using a nuisance regression procedure.The Pearson correlation coefficients for all pairs of nodes (14,535 pairs for 171 nodes) are calculated for each subject among all three groups to evaluate the temporal correlation between regions. The r-values (in the range of -1 to 1) are Z-transformed using Fisher's Z-transform to improve normality. For 171 nodes, a 171×171 symmetric connectivity matrix is composed of each entry representing the strength of an edge. Group-level analysis is performed to examine functional connectivity in the control group, one-hit group, and three-hit group. To identify how nodes cluster together to form the resting-state network, the Z-score matrix resulting from a one-group t-test is clustered using the K-nearest neighbor clustering method. A Z-score threshold of |Z| = 2.3 is applied to remove connections of false or weak nodes for visualization purposes.

[0158] Example. Treatment in a momentum exchange impact model using the compounds described herein. Male Sprague Dawley rats (n = 19; 250 - 270 g) at 65 days of age are obtained from Charles River (Worcester, MA). The test animals are maintained on a 12:12 hour light:dark cycle with lights on at 0700 and allowed free access to food and water. The protocol used in this study complies with the regulations of the Institutional Animal Care and Use Committee at Northeastern University.

[0159] Replicate the pneumatic drive, a 50 g compactor as described by Viano, and consistently reproduce the impact velocities of 7.4, 9.3, and 11.2 m / s described for mild, moderate, and severe head injuries, respectively. Obtain the data described herein from an impact velocity of 9.12 meters per second as determined using high-speed video recording.

[0160] Starting from 70 days after birth (P70), animals are divided into three groups (n = 6 - 7 / group; sham control group (control, CG), injury group (IG), and treatment group (TG)), and their head impacts and drug regimens are initiated. All groups are anesthetized with 4% isoflurane in oxygen, and the first of two total head impacts is administered to the injury group and treatment group at P70 using custom settings from an Animal Imaging Research (AIR; Holden, MA). The next day after the first impact (P71), a test compound such as AVN576 is administered to the treatment group and sham control group. Additionally, saline is administered to a vehicle-only control group (VCG). All administrations are given twice a day at 0700 and 1400 (IP@10 mg / kg) to the control group and treatment group. The drug regimen is continued for the next 4 days (total of 5 days). The second head impact is delivered at P72, 2 days after the first. At 2 weeks after the impact, the animals are imaged and tested for cognitive and motor behaviors. In all evaluations performed, there was no significant difference between the sham control group (VCG) administered the test compound and the vehicle-only sham control group (CG) administered the vehicle.

[0161] The severely shaken untreated animals (injury group) showed significant deficits in cognitive behavior, changes in the pattern of functional connectivity, and indices of anisotropy localized in the hindbrain and amygdala. The animals in the treatment group, severely shaken and treated with Example 266 (AVN576), showed no deficits in learning and memory and no significant difference compared to the sham control group. Similarly, there was no significant difference in overall motor behavior between the control group and the treatment group. The animals in the treatment group also showed enhanced functional connectivity within the network circuits associated with learning, cognition, memory, and attention compared to the control group.

[0162] Moderate repetitive traumatic brain injury using a momentum exchange model resulted in clear neuroimaging evidence of contusions, signs of inflammation, and white matter injury. The injury to the brain in untreated animals caused significant deficits in cognition, learning, and memory.

[0163] Brain damage in untreated test animals was associated with an increase in the volume of the lateral ventricle, indicating enhanced inflammation and edema. Treatment with the compounds described herein for 5 days reduced the expansion of edema in the lateral ventricle. Animals in the treatment group also showed a significant reduction in injury-induced edema near the site of impact. There was no statistical difference between the treatment and control groups, indicating complete recovery or healing from the impact. Complete recovery / healing of the edema was highly unexpected. A decrease in water content throughout the brain has been reported in other studies to be 1-2%, and neither a specific reduction in edema nor complete recovery to baseline has been reported. Kleindienst et al., Acta Neurochir 155:151-64 (2013); Marmarou et al., Brain Research 1581:89-102 (2014).

[0164] Brain damage in untreated test animals also resulted in low connectivity within important brain networks such as the hippocampal neural circuit. Treatment with the compounds described herein promoted high connectivity in the hippocampal neural circuit. Treatment with the compounds described herein within 24 hours after the first brain concussion prevented and led to complete recovery from cognitive, learning, and memory impairments that occur after brain injury. The treatment group showed behavioral measurements that were not significantly different from those of the control group, indicating complete recovery or healing from the impact. Complete recovery / treatment from cognitive, learning, and memory deficits was highly unexpected. Improvement of cognitive, learning, or memory deficits resulting from brain injury by a Va1R antagonist has not been reported previously.

[0165] Without being bound by theory, the compounds described herein not only reduce inflammation and edema caused by head injury, but also treat the cognitive and neurobiological effects of moderate to severe brain injury by promoting neural adaptive changes in functional connectivity to compensate for trauma. For example, animals in the treatment group showed high connectivity compared to sham control animals that were not injured but received treatment. The high connectivity observed was with respect to the default mode network represented by the control group, and the injury group showed severe low connectivity. Without being bound by theory, it is suggested that the high connectivity resulting from treatment with the compounds described herein may reflect the reorganization of an integrated neural network that retains function in response to brain injury. Furthermore, disruption of connectivity is an indicator of diffuse axonal injury, and thus the results obtained herein for impact models such as rmTBI are applicable to other brain injuries including, but not limited to, traumatic brain injury, blast TBI, cerebral edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, ischemic stroke, concussion, and falls.

[0166] Example. Results of the novel object recognition test. In this test, the recognition of stimuli related to episodic learning and memory is evaluated. Figure 1 shows that animals in the injury group (IG) spent significantly less time (recognition rate) investigating a novel object (t(5)=3.393, p<0.05) compared to the opportunity to investigate novel objects (50% of all object investigations). In contrast, both the control group (CG) (t(6)=3.08, p<0.05) and the treatment group (TG) (t(5)=2.61, p<0.05) spent significantly more time on novel objects than chance. When compared between groups, all groups spent a significantly greater proportion of time on novel objects compared to the injury group (CG: P=0.0006, TG: P=0.003; one-way ANOVA followed by Tukey's post hoc test, F (3.21) =9.14, P=0.0005). Similarly, both the control group (P=0.006) and the treatment group (P=0.02) spent significantly more total time on novel objects compared to injury group animals (one-way ANOVA, F (3,21)= 5.78, P = 0.005). The exploration index (new exploration instances of any object / total exploration instances) indicates that the groups behave differently as a function of AVN576 exposure (one-way ANOVA, F (3,21) = 4.48, P = 0.01), only the control group animals showed a significantly greater number of exploration instances than the damaged group animals (P = 0.01), and the treated group animals showed only a trend towards significance (P = 0.06).

[0167] Example. Results of the Barnes maze test. In this test, spatial learning and memory are evaluated. As shown in FIGS. 2A and 2B, the damaged group has significant deficits in behavioral measures of cognition, while the treated group shows no deficits in learning and memory and does not differ from either control group (CG and / or VCG).

[0168] If debilitated by the acquisition date, the Barnes maze test showed that IG animals took significantly longer to find the goal box than either the control group (VCG: P = 0.03, CG: P = 0.01) and the treated group (P = 0.04; one-way ANOVA followed by Tukey post hoc test, F (3.21) = 4.88, P = 0.009). Similarly, animals in the damaged group moved significantly longer distances exploring the maze before finding the goal box compared to both CG (P = 0.009) and TG animals (P = 0.03). Animals in the damaged group also spent significantly more time (error period) exploring incorrect holes compared to CG animals (P = 0.03) and TG animals (P = 0.03; one-way ANOVA followed by Tukey post hoc test, F (3,21) = 3.95, P = 0.02). The same results were obtained by evaluating the distance traveled (data not shown). When the error period was separated over several days, additional differences occurred between the groups and days (mixed design ANOVA, main effect of day: F (3,63) = 9.10, P < 0.0001; group: F (3,21)= 3.95, P = 0.02). Animals in the injury group made significantly more errors on day 1 compared to CG animals (P = 0.07), and on day 2 compared to both CG animals (P = 0.01) and TG animals (P = 0.02). The same results were obtained from the evaluation of movement distance and over several days (data not shown).

[0169] Example. Resting-state functional connectivity. Figure 3 shows the correlation matrix of 166 rat brain regions of resting-state functional connectivity (rsFC) comparing the injury group and the treatment group. Since they are adjacent in neuroanatomy and function, brain regions with significant correlations often appear as clusters. The clusters include regions: A: Hypothalamus B: Dorsal hippocampus - CA1, CA3, dentate C: Thalamus D: Sensorimotor CTX & dorsal striatum - (motor CTX, anterior cingulate, primary SS CTX), dorsal striatum E. Prefrontal CTX & ventral striatum - (prelimbic ctx, infralimbic ctx, ventral & transverse tract), (ventral striatum) F. Amygdala & piriform / insula CTX G. Ventral hippocampus & temporal CTX - CA1, CA3, dentate H. Cerebellum - all lobes, crus 1 & 2, medial cerebellar nuclei, (fastigial) I. Medulla of the reticular activating system & cerebellum - (interposed nuclei, copula, lobule X), (giant cell, juxtarestiform body, parvicellular reticular, solitary nucleus, vestibular nucleus, main sensory nucleus, trigeminal nerve) J. Cerebellum & medulla & entorhinal CTX - (paramedian nucleus, paraflocculus, flocculus), (ventral hippocampal formation, entorhinal ctx, ectorhinal ctx), (midline raphe, locus coeruleus, trapezoid body, dorsomedial tegmentum, facial nucleus, subcoeruleus, pontoreticular nucleus, cochlear nucleus, dorsal paragigantocellular) K. Midbrain dopamine - substantia nigra pars compacta, substantia nigra reticularis, ventral tegmentum L. Hypothalamic connections, amygdala M. Reticular activating system connections, cerebellar connections, raphe connections, hippocampus, reticular activating system N. Amygdala connections, medulla O. Midbrain dopamine connections, ventral hippocampus P. Mesencephalic dopamine connection, hypothalamus is included.

[0170] The diagonal line separates different experimental groups, and the position of each pixel is a mirror image with respect to the diagonal line (regions G and M marked with arrows for illustration). Regions A - P have a functional relationship and show a cluster of highlighted brain regions that represent the default mode network in the control group (data not shown). Brain regions with significant correlations can also appear as clusters because they are close in neuroanatomy and function. Generally, it is observed that the damaged group network shows low connectivity, while the treated group network shows high connectivity. The damaged group network also shows lower connectivity compared to the control group (data not shown). The treated group network also shows higher connectivity compared to the control group (data not shown).

[0171] Referring to region G in Figure 3, the ventral hippocampus shows lower connectivity in the damaged group compared to the control group (data not shown), while the treated group is observed to show higher connectivity compared to the damaged group and the control group. Specific network connections including the control group are shown in the table.

[0172] Region G - hippocampus / amygdala / temporal cortex; control group (CG), damaged group (IG), treated group (TG). [Table 2]

[0173] Differences in the 3D organization and connectivity of these brain regions are also shown by the glass brains in Figure 4(A) (damaged group) and Figure 4(B) (treated group). As shown, there is a loss of connectivity in the damaged group, and there is high connectivity in the treated group for the main nodes of the ventral hippocampus, particularly the amygdala, limbic cortex, and reticular nucleus of the midbrain. In the treated group, high connectivity is also observed for the main nodes of the ventral hippocampus and temporal cortex.

[0174] Functional connectivity analysis at rest is useful for identifying subtle changes in traumatic brain tissue associated with cognitive and emotional symptoms of brain injury. Loss of connectivity and clustering in the injury group shortens path length or convergent neural connections and reduces the metabolic cost of signal transmission. If untreated, the amygdala will mainly be disconnected from the ventral hippocampus and adjacent regions. It has been well established that low connectivity is strongly associated with cognitive impairment and neurodegeneration. Region G is associated with cognition, learning, and memory. The low connectivity observed in the treatment group may reflect the reorganization of integrated neural circuitry to maintain function in response to brain injury.

[0175] Referring to region M in Figure 3, the hippocampus shows low connectivity in the injury group compared to the control group (data not shown), but the treatment group is observed to show higher connectivity compared to the injury group and the control group. Specific network connections including the control group are shown in the table.

[0176] Region M - hippocampus / reticular activating system; control group (CG), injury group (IG), treatment group (TG). [Table 3]

[0177] Differences in the 3D organization and connectivity of these brain regions are also shown by the glass brain of Figure 6. As shown, there is a loss of connectivity in the injury group and high connectivity for the main nodes of the ventral hippocampus and the reticular activating system in the treatment group.

[0178] If left untreated, the reticular activating system will mainly be disconnected from the ventral hippocampus and adjacent areas. It has been well established that low connectivity is strongly associated with cognitive impairment, memory, and attention. Area M is associated with cognition, learning, and memory. The high connectivity observed in the treatment group may reflect the reorganization of integrated neural circuits to maintain function in response to brain injury, including comparison with the control group, and provide therapeutic benefits leading to functional recovery.

[0179] Example. Edema and ventricular volume. Figure 5 shows the volume of the lateral ventricles (hippocampal formation / adjacent septum) at the impact level calculated and compared using a single two-sided T-test. There is a significant increase in ventricular volume in the injury group compared to the control group. The treatment group showed complete remission / cure with the ventricular volume returning to normal levels, but there was no significant difference between the control group and the treatment group.

[0180] Example. Motor behavior. Using a standard balance beam performance test, for the balance beam task, there was no difference in the total number of foot faults (one-way ANOVA, F (3,21) = 1.42, P = 0.26) or total beam passage time (one-way ANOVA, F (3,21) = 2.40, P = 0.1). However, there was a significant difference in faults per broad central segment (p < 0.0001). Using a standard rotarod performance test, injured group animals showed a significantly shorter latency to fall (69.8 ± 5.5 seconds) compared to the control group (105.4 ± 7.6 seconds, P = 0.01). The treatment group had a trend towards significance (P = 0.2) and showed improvement in the latency to fall (84.0 ± 9.0 seconds). However, the differences observed in the NOR test were not considered a function of changes in motor behavior, and no significant difference in movement distance was observed in either group due to motor impairment (one-way ANOVA, F (3,21) = 1.22, P = 0.32).

[0181] Example. Human vasopressin V 1a receptor binding assay. A cell line expressing the human V 1a receptor in CHO cells (hereinafter hV1a a cell line (referred to as the cell line) was obtained from Dr. Michael Brownstein, NIMH, Bethesda, MD, USA. hV 1a The cDNA sequence has been described by Thibonnier et al., Journal of Biological Chemistry, 269, 3304 - 3310 (1994), and the expression method was the same as that described by Morel et al. (1992). hV 1a The cell line was grown in alpha MEM with 10% fetal bovine serum and 250 μg / ml of G418 (Gibco, Grand Island, NY, USA). For the competitive binding assay, hV 1a cells were seeded from confluent flasks at a 1:10 dilution into 6 - well culture plates and maintained in culture for at least 2 days. Then, the medium was removed and the cells were washed with 2 ml of binding buffer (25 mM Hepes, 0.25% BSA, 1×DMEM, pH = 7.0). To each well, 990 μl of binding buffer containing 1 nM of 3H - AVP was added, and 10 μl of the serially diluted Example compound dissolved in DMSO was added. All incubations were performed in triplicate, and the dose - inhibition curve consisted of five concentrations (0.1, 1.0, 10, 100, and 1000 nM) of the test agent including total binding (DMSO) and IC 50 Non - specific binding was evaluated using 100 nM cold AVP (Sigma). The cells were incubated at 37 °C for 45 minutes, the assay mixture was removed, and each well was washed 3 times with PBS (pH = 7.4). 1 ml of 2% SDS was added per well and the plates were left for 30 minutes. The total contents in the wells were transferred to scintillation vials. Each well was rinsed with 0.5 ml of PBS and then added to the corresponding vial. Then, scintillation liquid (Ecoscint, National Diagnostics, Atlanta, Georgia) was added at 3 ml per vial. The samples were counted in a liquid scintillation counter (Beckman LS3801). IC 50 values were calculated using Prism curve - fitting software.

[0182] All of the alkane diacid esters and amides exemplified in the foregoing examples dissolved in DMSO were tested in this assay. Binding curves were generated according to the method described by Thibonnier et al. (1994). 3 [[H]]-AVP was added to the hV1a cell culture, and then each test compound was serially diluted 10-fold. All active compounds 1a showed dose-dependent competitive binding curves with IC 1a and K 50 values characteristic of high affinity binding to the V i receptor in CHO cells expressing the human V 50 receptor (hV1a cell line). For example, Example 225 showed a dose-dependent competitive binding curve with IC i (1.86 - 2.13 nM) and K

[0183] (1.14 - 1.30 nM) values. 50 The binding affinities (IC i ) and inhibition constants (K

Table 4

[0184] Example. Human vasopressin V 1b receptor-expressing cells. Human vasopressin receptor 1b (hV 1b)cDNA (see Lolait et al., "Extrapituitary expression of the rat V1b vasopressin receptor gene," Proc. Natl. Acad. Sci. USA 92:6783-7 (1995); de Keyzer et al., "Cloning and characterization of the human V3(V1b) pituitary vasopressin receptor," FEBS Lett. 356:215-20 (1994); Sugimoto et al., "Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor," J. Biol. Chem. 269:27088-92 (1994)) was inserted into the EcoR1 site of the mammalian cell expression vector PCI-neo (Promega). The recombinant plasmid carrying hV1b cDNA was identified from transformed E. coli clones and used for transfection of Chinese hamster ovary cells (CHO-K1, ATCC). 2 micrograms of hV1b receptor DNA was cultured in a 6-well plate using the Fugene-6 mediated transfection technique (Boehringer Mannheim) and 10 5It was introduced into individual CHO cells. Then, at 24 hours after transfection, the cells were cultured under selection with G-418 (0.25 mg / ml) supplemented in the medium. Three days later, limiting dilution was performed to obtain single cell clones in 96-well plates. Two weeks after growth, the monoclonal clones were expanded into two sets of 12-well plates. When confluence was reached, one set of wells was assayed for the ability to bind tritiated arginine-vasopressin (NEN). First, 9 positive clones were identified from the 60 clones screened, and the clone demonstrating the highest AVP binding was preserved as a permanent cell line for hV1b affinity screening.

[0185] Example. Human or rat vasopressin V 1b Cell-based receptor binding assay. V1b cell line (human or rat V 1b cells expressing either receptor) were grown in α-MEM medium supplemented with 10% fetal bovine serum and 250 μg / ml of G418 (Gibco, Grand Island, NY) in 75 cm 2 flasks. For the competitive binding assay, hV1b cells were dissociated with an enzyme-free PBS-based cell dissociation solution (Specialty Media, Phillipursburg, NJ) according to the manufacturer's protocol. The cells were seeded into 12-well culture plates at a ratio of one flask per 18 plates (the rate should be adjusted according to the degree of confluence) and maintained in culture for 2 - 3 days. Then, the medium was removed and the cells were washed once with 2 ml of binding buffer (25 mM Hepes, 0.25% BSA, 1×DMEM, pH = 7.0) at room temperature. To each well, 1 nM of 3Add 990 μl of binding buffer containing H-AVP, add 10 μl of serially diluted test compound or cold AVP, and dissolve everything in DMSO. All incubations were performed in triplicate, and the dose-inhibition curve consisted of the test agent, including the IC50, or total binding of cold AVP (DMSO only) and five concentrations (0.1, 1.0, 10, 100, and 1000 nM). The cells were incubated at 37 °C for 30 minutes in a humidified incubator. Then, the assay mixture was removed, and each well was washed three times with PBS (pH = 7.4). After washing, 1 ml of 2% SDS was added per well, and the plate was left at RT for 15 minutes. The plate was gently tapped to confirm that the lysed cells had detached. The entire contents of the well were transferred to a scintillation vial. Then, each well was rinsed with 0.5 ml of PBS and added to the corresponding vial. Thereafter, scintillation liquid (Ecoscint, National Diagnostics, Atlanta, Georgia) was added at 3 ml per vial. The samples were counted in a liquid scintillation counter (Beckman LS3801). The IC50 and K i values were calculated using Prism curve-fitting software. The exemplary compounds shown in the previous table exhibit binding constants greater than 100 nM or greater than 1000 nM. Exemplary inhibition data (Ki, nM) for the selected example compounds are shown in the following table.

Table 5

[0186] Example. Inhibition of phosphatidylinositol metabolic turnover (V 1a ). The physiological effects of vasopressin are mediated via specific G-protein coupled receptors. V1aR is the G of the G protein q / G 11It binds to the family and mediates phosphatidylinositol metabolism turnover. The agonist or antagonist characteristics of the compounds of the present invention can be determined by their ability to inhibit the vasopressin-mediated metabolism turnover of phosphatidylinositol by the procedures described in the following paragraphs. Examples 35, 44, 88, 110, and 133 of exemplary compounds were tested in this assay, and vasopressin V 1a was found to be an antagonist.

[0187] Example. Vasopressin V 1b Inhibitory functional assay for vasopressin-mediated phosphatidylinositol metabolism turnover and antagonist activity. The physiological effects of vasopressin are mediated via specific G-protein coupled receptors. Vasopressin V 1b receptor binds to the G protein, which in turn binds to cAMP. The agonist or antagonist characteristics of the compounds described herein can be determined by their ability to inhibit the vasopressin-mediated metabolism turnover of phosphatidylinositol using conventional methods including the procedures described in the following paragraphs.

[0188] Cell culture and cell labeling. Three days prior to the assay, cultures near confluence of hV1a or hV1b cells were dissociated and seeded into 6-well tissue culture plates, with approximately 100 wells seeded from each 75 cm 2 flask (corresponding to a split ratio of 12:1). Each well contained 1 mL of growth medium with 2 μCi of 3 [3H]myo-inositol (American Radiolabeled Chemicals, St. Louis, MO, USA).

[0189] Cells expressing human or rat V 1b receptors are grown in alpha-modified minimal essential medium containing 10% fetal bovine serum and 0.25 mg / ml of G418. Three days prior to the assay, cultures near confluence were dissociated and seeded into 6-well tissue culture plates, with approximately 100 wells seeded from each 75 cm 2seeded from the flask (equivalent to a split ratio of 12:1). Each well contained 1 mL of growth medium with 2 μCi of 3 [[H]]myo-inositol (American Radiolabeled Chemicals, St. Louis, MO, USA).

[0190] Incubation (V 1a and V 1b ). All assays were performed in triplicate except for the basal and 10 nM AVP (both n = 6). AVP (arginine vasopressin), Peninsula Labs, Belmont, Ca, USA (#8103) was dissolved in 0.1 N acetic acid. Test agents were dissolved in DMSO and diluted with DMSO to a final test concentration of 200-fold. Test agents and AVP (or the corresponding volume of DMSO) were added separately as 5 μL in DMSO to 12 × 75 mm glass tubes containing 1 mL of assay buffer (Tyrode's solution containing 50 mM glucose, 10 mM LiCl, 15 mM HEPES pH 7.4, 10 μM phosphoramidone, and 100 μM bacitracin). The order of incubation was randomized. The pre-labeled medium was removed, the monolayer was washed once with 1 mL of 0.9% NaCl, and incubation was initiated by transferring the contents of the assay tube to the corresponding well. The plates were incubated at 37 °C for 1 hour. Incubation was stopped by removing the incubation medium, adding 500 μL of ice-cold 5% (w / v) trichloroacetic acid, and leaving the wells for 15 minutes.

[0191] 3 [[H]]inositol phosphate (V 1a and V 1b ​Measurement of (). A BioRad Poly-Prep Econo-Column was filled with 0.3 mL of AG1-X8 100-200 formate-forming resin. The resin was mixed with water at a ratio of 1:1, and 0.6 mL was added to each column. Then, the column was washed with 10 mL of water. A scintillation vial (20 mL) was placed under each column. For each well, the contents were transferred to the mini-column, and then the well was washed with 0.5 mL of distilled water, which was also added to the mini-column. Then, the column was washed twice with 5 mL of 5 mM myo-inositol to elute free inositol. An aliquot (1 mL) was transferred to a 20 mL scintillation vial, and 10 mL of Beckman's Ready Protein Plus was added. After the washing of myo-inositol was completed, an empty scintillation vial was placed under the column, and 1 mL of 0.5 M ammonium formate containing 0.1 N formic acid was added three times to 3 elute [H] inositol phosphates. The elution conditions were optimized to recover inositol monophosphate, inositol diphosphate, and inositol triphosphate without eluting more metabolically inert tetrakisphosphate, pentakisphosphate, and hexakisphosphate. To each sample, 10 mL of a high-salt capacity scintillation fluid such as Tru-Count High Salt Capacity or Packard Hionic-Fluor was added. Inositol lipids were measured by adding 1 mL of 2% sodium dodecyl sulfate (SDS) to each well, leaving the well for at least 30 minutes, transferring the solution to a 20 mL scintillation vial, and then adding 10 mL of Beckman's Ready Protein Plus scintillation fluid thereto. The samples were counted on a Beckman LS3801 liquid scintillation counter for 10 minutes. The total inositol uptake for each well was calculated as the sum of free inositol, inositol phosphates, and inositol lipids.

[0192] Data analysis (V 1a and V 1b): Concentration-inhibition experiment. The concentration-response curve of AVP and the concentration-inhibition curve of the test agent against 10 nM AVP were analyzed by a non-linear least-squares curve fitted to a four-parameter logistic function. The parameters of basal and maximal inositol phosphate, EC 50 or IC 50 , and the Hill coefficient were varied to achieve the best fit. Curve fitting was weighted under the assumption that the standard deviation is proportional to the dpm of radioactivity. A complete concentration-response curve of AVP was generated for each experiment. Based on the EC 50 of AVP in the same experiment, by applying the Cheng-Prusoff equation, the K i value reflecting the antagonistic activity against AVP in the production of the signaling molecule IP3 was converted to the IC 50 value. Inositol phosphate was expressed as dpm per dpm of total inositol uptake of 10 6 .

[0193] Data analysis (V 1a and V 1b ): Competition experiment. The experiment for testing the V 1a competition of the test agent consisted of concentration-response curves of AVP in the absence and presence of two or more concentrations of the test agent. The experiment for testing the V 1b competition by the test agent consisted of concentration-response curves of AVP in the absence and presence of at least five concentrations of the test agent. The data were fitted to a competitive logistic equation:

Equation

[0194] Compound Example 225 has an IC50 (2.68 nM) and K i (0.05 nM) dose-dependently inhibits the action of AVP. These values are consistent with its inhibition of high-affinity binding and inositol lipid synthesis via the human V 1a receptor in Example 225.

[0195] Example. Pharmacokinetics. The compounds described herein are rapidly absorbed after oral administration. The compounds described herein pass through the blood-brain barrier and achieve therapeutically effective concentrations in the CNS. The compounds described herein can be administered according to various protocols including, but not limited to, once daily and twice daily. The compounds described herein show dose-related increases in Cmax and AUC when administered according to various protocols including, but not limited to, once daily and twice daily. For example, twice-daily dosing shows a 1.7-fold accumulation and improvement in T for AVN246 1 / 2 of.

[0196] Example. General synthetic route. The proximal amide method allows for synthetic variation at the distal amide site. Once the proximal amide is set first, subsequent distal amide diversity by parallel synthesis follows.

Chemical formula

[0197] The distal amide method that allows for synthetic variation at the proximal site; once the distal amide is set first, subsequent proximal amide diversity by parallel synthesis follows.

Chemical formula

[0198] The synthesis of AVN251 (SRX251) and AVN251·HCl is shown below. All other compounds are prepared in a similar manner by appropriate selection of starting materials.

Chemical formula

[0199] Further details and alternative syntheses for preparing the compounds described herein are described in U.S. Patent No. 7,119,083, the disclosure of which is incorporated herein by reference in its entirety. The compounds described herein can be formulated and administered according to the processes described in U.S. Patent No. 7,119,083. Further details are described in Guillon, C.D. et al., Azetidinones as vasopressin V1a antagonists. Bioorg Med Chem, 15(5):2054 - 80(2007).

[0200] Examples of Compounds Example 1. Acetyl (4(S)-phenyloxazolidin-2-one-3-yl)chloride. A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (Evans, U.S. Patent No. 4,665,171) and 1.3 equivalents of oxalyl chloride in 200 mL of dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 μL / 1 milliequivalent of acetic acid derivative), and vigorous gas evolution occurred. After 45 minutes, all gas evolution ceased, and the reaction mixture was concentrated under reduced pressure and dried under vacuum for 2 hours, providing the title compound as an off-white solid.

[0201] Example 1A. Acetyl (4(R)-phenyloxazolidin-2-one-3-yl)chloride. Example 1A was prepared according to the procedure of Example 1, except that (4(R)-phenyloxazolidin-2-one-3-yl)acetic acid was used instead of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (see Evans & Sjogren, Tetrahedron Lett. 26:3783(1985)).

[0202] Example 1B. Methyl (4(S)-phenyloxazolidin-2-one-3-yl)acetate. A solution of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (1 g, 4.52 mmol) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of MeOH was redissolved in 30 mL of CH2Cl2 and treated with 50 mL of saturated aqueous Na2CO3. The organic layer was evaporated, dried (MgSO4), and the title compound (1.001 g, 94%) was obtained as a colorless oil; 1 1H NMR (CDCl3) δ 3.37 (d, J == 18.0 Hz, 1H), 3.69 (s, 3H), 4.13 (t, J = 8.3 Hz, 1H), 4.28 (d, J = 18.0 Hz, 1H), 4.69 (t, J = 8.8 Hz, 1H), 5.04 (t, J = 8.4 Hz, 1H), 7.26 - 7.29 (m, 2H), 7.36 - 7.42 (m, 3H).

[0203] Example 1C. Methyl 2-(4(S)-phenyloxazolidin-2-one-3-yl)propanoate. A solution of methyl (4(S)-phenyloxazolidin-2-one-3-yl)acetate (1 g, 4.25 mmol) in 10 mL of anhydrous THF at -78 °C was treated with a 1 M solution of 4.68 mL (4.68 mmol) of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred at about -70 °C for 1 h and MeI (1.59 mL, 25.51 mmol) was added. After complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4Cl and partitioned between EtOAc and water. The organic layer was washed successively with saturated aqueous sodium bisulfite and saturated NaCl solutions. The resulting organic layer was dried (MgSO4) and evaporated to give the title compound (a mixture of diastereomers) as a white solid (1.06 g, 93%). 11H NMR (CDCl3) δ 1.07 / 1.53 (d / d, J = 7.5 Hz, 3H), 3.59 / 3.74 (s / s, 3H), 3.85 / 4.48 (q / q, J = 7.5 Hz, 1H), 4.10 - 4.14 (m, 1H), 4.60 - 4.64 / 4.65 - 4.69 (m / m, 1H), 4.88 - 4.92 / 4.98 - 5.02 (m / m, 1H), 7.24 - 7.40 (m, 5H).

[0204] Example 1D. 2-(4(S)-Phenyloxazolidin-2-one-3-yl)propanoic acid. To a solution of methyl 2-(4(S)-phenyloxazolidin-2-one-3-yl)propanoate (1 g, 4.01 mmol) in 35 mL of MeOH was added 14.3 mL (12.04 mmol) of 0.84 M LiOH solution in water at 0 °C. The reaction mixture was then stirred at ambient temperature for 3 h. After complete hydrolysis of the azetidinone, MeOH was removed by evaporation, the crude residue was dissolved in CH2Cl2 and treated with saturated NaCl aqueous solution. The obtained organic layer was dried (MgSO4) and evaporated to give the title compound (racemic mixture) (0.906 g, 96%) as a white solid; 1 1H NMR (CDCl3) δ 1.13 / 1.57 (d / d, J = 7.5 Hz, 3H), 3.75 / 4.50 (q / q, J = 7.5 Hz, 1H), 4.10 - 4.16 (m, 1H), 4.62 - 4.72 (m, 1H), 4.92 - 5.03 (m, 1H), 7.32 - 7.43 (m, 5H).

[0205] Example 1E. 2-(4(S)-Phenyloxazolidin-2-one-3-yl)propanoyl chloride. A solution of 1 equivalent of Example 1D and 1.3 equivalents of oxalyl chloride in 200 mL of CH2Cl2 (150 mL / 1 g of the propionic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 μL / 1 mmol of the propanoic acid derivative), and vigorous gas evolution occurred. After 45 min, all gas evolution ceased, and the reaction mixture was concentrated under reduced pressure and dried under vacuum for 2 h to afford the title compound as an off-white solid.

[0206] Example 2. General procedure for amide formation from activated ester derivatives. N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzylamine. After completion (TLC, 60:40 hexane / ethyl acetate), the mixture was evaporated and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1 1H NMR (CDCl3) δ 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, 1H), 2.98 (dd, J=3.7 Hz, J=17.0 Hz, 1H), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, 1H), 4.50-4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, 1H), 6.95 (s, 1H), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

[0207] Examples 2A - 2C and 3 - 5 were prepared according to the procedure of Example 2, except that N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-N-hydroxysuccinimide ester was replaced with the appropriate amino acid derivative and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine.

[0208] Example 2A. N - Benzyloxycarbonyl - L - aspartic acid β - t - butyl ester α - [4 - (2 - phenylethyl)]piperazine amide. From N - benzyloxycarbonyl - L - aspartic acid β - t - butyl ester α - N - hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4 - (phenylethyl)piperazine 2.27 mL (11.9 mmol), 5.89 g (quantitative yield) of the title compound was obtained as an off - white oil; 1 H NMR (CDCl3) δ 1.40 (s, 9H), 2.45 - 2.80 (m,10H), 3.50 - 3.80 (m, 4H), 4.87 - 4.91 (m, 1H), 5.08 (s, 2H), 5.62 - 5.66 (m, 1H), 7.17 - 7.33 (m, 10H).

[0209] Example 2B. N - Benzyloxycarbonyl - L - glutamic acid γ - t - butyl ester α - (3 - trifluoromethyl)benzyl amide. From N - benzyloxycarbonyl - L - glutamic acid β - t - butyl ester α - N - hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3 - (trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol), 5.41 g (98%) of the title compound was obtained as an off - white solid; 1 H NMR (CDCl3) δ 1.40 (s, 9H), 1.88 - 1.99 (m, 1H), 2.03 - 2.13 (m, 1H), 2.23 - 2.33 (m, 1H), 2.38 - 2.47 (m,1H), 4.19 - 4.25 (s, 1H), 4.46 - 4.48 (m, 2H), 5.05 - 5.08 (m, 2H), 5.67 - 5.72 (m, 1H), 7.27 - 7.34 (m, 5H), 7.39 - 7.43 (m, 2H), 7.48 - 7.52 (m, 2H).

[0210] Example 2 C. N - Benzyloxycarbonyl - L - glutamic acid γ - t - butyl ester α - [4 - (2 - phenylethyl)]piperazine amide. From N - benzyloxycarbonyl - L - glutamic acid γ - t - butyl ester α - N - hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4 - (phenylethyl)piperazine 2.19 mL (11.5 mmol), 5.87 g (quantitative yield) of the title compound was obtained as an off - white oil; 1 H NMR (CDCl3) δ 1.43 (s, 9H); 1.64 - 1.73 (m,1H);1.93 - 2.01 (m, 1H); 2.23 - 2.40 (m, 2H); 2.42 - 2.68 (m, 6H); 2.75 - 2.85 (m, 2H); 3.61 - 3.74 (m, 4H); 4.66 - 4.73 (m, 1H); 5.03 - 5.12 (m, 2H); 5.69 - 5.72 (m, 1H); 7.16 - 7.34 (m, 10H).

[0211] Example 3. N - Benzyloxycarbonyl - L - aspartic acid β - t - butyl ester α - [4 - (2 - phenylethyl)]piperazine amide. From N - benzyloxycarbonyl - L - aspartic acid β - t - butyl ester α - N - hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4 - (phenylethyl)piperazine 2.27 mL (11.9 mmol), 5.89 g (quantitative yield) of the title compound was obtained as an off - white oil; 1 H NMR (CDCl3) δ 1.40 (s, 9H), 2.45 - 2.80 (m,10H), 3.50 - 3.80 (m, 4H), 4.87 - 4.91 (m, 1H), 5.08 (s, 2H), 5.62 - 5.66 (m, 1H), 7.17 - 7.33 (m, 10H).

[0212] Example 4. N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid β-t-butyl ester α-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3-(trifluoromethyl)benzylamine (1.63 mL, 11.4 mmol), 5.41 g (98%) of the title compound was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.40 (s, 9H), 1.88-1.99 (m, 1H), 2.03-2.13 (m, 1H), 2.23-2.33 (m, 1H), 2.38-2.47 (m,1H), 4.19-4.25 (s, 1H), 4.46-4.48 (m, 2H), 5.05-5.08 (m, 2H), 5.67-5.72 (m, 1H), 7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

[0213] Example 5. N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazine amide. From N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine (2.19 mL, 11.5 mmol), 5.87 g (quantitative yield) of the title compound was obtained as an off-white oil; 1 H NMR (CDCl3) δ 1.43 (s, 9H); 1.64-1.73 (m,1H);1.93-2.01 (m, 1H); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.66-4.73 (m, 1H); 5.03-5.12 (m, 2H); 5.69-5.72 (m, 1H); 7.16-7.34 (m, 10H).

[0214] Example 5A. N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine t-butyl ester. N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmol) in dichloromethane (8 mL) was treated with t-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0 °C. After completion (TLC), the reaction was quenched with dichloromethane (10 mL) and saturated aqueous potassium hydrogen carbonate (15 mL). The organic layer was washed with distilled water and evaporated. The residue obtained was purified by flash column chromatography (98:2 dichloromethane / methanol) to give the title compound as a colorless oil (0.292 g, 77%); 1 1H NMR (CDCl3) δ 1.44 (s, 9H); 3.68 (dd, J = 2.9 Hz, J = 9.3 Hz, 1H); 3.87 (dd, J = 2.9 Hz, J = 9.3 Hz, 1H); 4.22 (t, J = 7.1 Hz, 1H); 4.30 - 4.60 (m, 5H); 5.64 - 5.67 (m, 1H); 7.25 - 7.39 (m, 9H); 7.58 - 7.61 (m, 2H); 7.73 - 7.76 (m, 2H).

[0215] Example 5B. O-(Benzyl)-D-serine t-butyl ester. Example 5A (0.620 g, 1.31 mmol) in dichloromethane (5 mL) was treated with tris(2-aminoethyl)amine (2.75 mL) for 5 h. The mixture obtained was washed twice with phosphate buffer (pH = 5.5), once with saturated aqueous potassium hydrogen carbonate, and evaporated to give 0.329 g (quantitative yield) of the title compound as an off-white solid; 11H NMR (CD3OD) δ 1.44 (s, 9H); 3.48 (dd, J=J′=4.2 Hz, 1H); 3.61 (dd, J=4.0 Hz, J=9.2 Hz, 1H); 3.72 (dd, J=4.6 Hz, J=9.2 Hz, 1H); 4.47 (d, J=12.0 Hz, 1H); 4.55 (d, J=12.0 Hz, 1H); 7.26-7.33 (m, 5H).

[0216] Example 6. General procedure for amide formation from carboxylic acids. N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of 1-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate and distilled water until completion was determined by thin layer chromatography (95:5 dichloromethane / methanol eluent) after at least 12 h at ambient temperature. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1 1H NMR (CDCl3) δ 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, 1H); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, 1H); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, 1H); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, 1H); 6.91-7.00 (m, 1H); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).

[0217] Examples 7 - 7H were prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with an appropriate amino acid derivative and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine.

[0218] Example 7. N-Benzyloxycarbonyl-D-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid γ-t-butyl ester (1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) of 3-(trifluoromethyl)benzylamine, 1.67 g (quantitative yield) of Example 7 was obtained as an off-white solid. Example 7 showed an 1 H NMR spectrum consistent with the assigned structure.

[0219] Example 7A. N-Benzyloxycarbonyl-L-glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide. From N-benzyloxycarbonyl-L-glutamic acid α-t-butyl ester (1.36 g, 4.03 mmol) and 0.746 g (4.43 mmol) of 1-cyclohexylpiperazine, 1.93 g (98%) of Example 7A was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.02 - 1.12 (m, 5H); 1.43 (s, 9H), 1.60 - 1.64 (m, 1H); 1.80 - 1.93 (m, 5H); 2.18 - 2.52 (m, 8H); 3.38 - 3.60 (m,4H); 4.20 - 4.24 (m, 1H); 5.03 - 5.13 (m, 2H); 5.53 - 5.57 (m, 1H); 7.28 - 7.34 (m, 5H).

[0220] Example 7B. N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL of (2-fluoro-3-trifluoromethyl)benzylamine, 0.365 g (quantitative yield) of Example 7B was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.38 (s, 9H); 2.59 (dd, J=6.5 Hz, J=17.0 Hz, 1H); 2.95 (dd, J=4.3 Hz, J=17.0 Hz, 1H); 4.46-4.56 (m, 3H); 5.11 (s, 2H); 5.94-5.96 (m, 1H); 7.15 (t, J=8.0 Hz, 1H); 7.30-7.36 (m, 5H); 7.47-7.52 (m, 2H).

[0221] Example 7C. N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(S)-α-methylbenzyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (S)-α-methylbenzylamine, 0.281 g (90%) of Example 7C was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.41 (s, 9H); 1.44 (d, J=7.0 Hz, 3H); 2.61 (dd, J=7.0 Hz, J=17.0 Hz, 1H); 2.93 (dd, J=4.0 Hz, J=17.5 Hz, 1H); 4.50-4.54 (m, 1H); 5.04-5.14 (m, 3H); 5.94-5.96 (m, 1H); 6.76-6.80 (m, 1H); 7.21-7.37 (m, 10H).

[0222] Example 7D. N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(R)-α-methylbenzyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (R)-α-methylbenzylamine, 0.281 g (90%) of Example 7D was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.38 (s, 9H); 1.43 (d, J=6.9 Hz, 3H); 2.54 (dd, J=7.3 Hz, J=17.2 Hz, 1H); 2.87 (dd, J=4.1 Hz, J=17.3 Hz, 1H); 4.46-4.50 (m, 1H); 4.99-5.15 (m, 3H); 5.92-5.96 (m, 1H); 6.78-6.82 (m, 1H); 7.21-7.33 (m, 10H).

[0223] Example 7E. N-Benzyloxycarbonyl-D-aspartic acid γ-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. From N-benzyloxycarbonyl-D-aspartic acid γ-t-butyl ester (0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol) of N-methyl-N-(3-trifluoromethylbenzyl)amine, 0.287 g (65%) of Example 7E was obtained as an off-white solid; 1 H NMR (CDCl3) δ 1.40 (s, 9H); 2.55 (dd, J=5.8 Hz, J=15.8 Hz, 1H); 2.81 (dd, J=7.8 Hz, J=15.8 Hz, 1H); 3.10 (s, 3H); 4.25 (d, J=15.0 Hz, 1H); 4.80 (d, J=15.5 Hz, 1H); 5.01-5.13 (m, 3H); 5.52-5.55 (m, 1H); 7.25-7.52 (m, 10H).

[0224] Example 7F. N - Benzyloxycarbonyl - D - aspartic acid β - t - butyl ester α - [(S)-1-(3 - trifluoromethylphenyl)ethyl]amide. From N - benzyloxycarbonyl - D - aspartic acid β - t - butyl ester monohydrate (Novabiochem) (84 mg, 0.25 mmol) and 47 mg of (S)-1-(3 - trifluoromethylphenyl)ethylamine, 122 mg (quantitative yield) of Example 7F was obtained as an off - white solid. Example 7F was consistent with the specified structure. 1 showed an H NMR spectrum.

[0225] Example 7G. N - Benzyloxycarbonyl - D - aspartic acid β - t - butyl ester α - [(R)-1-(3 - trifluoromethylphenyl)ethyl]amide. From N - benzyloxycarbonyl - D - aspartic acid β - t - butyl ester monohydrate (Novabiochem) (150 mg, 0.44 mmol) and 83 mg of (R)-1-(3 - trifluoromethylphenyl)ethylamine, 217 mg (quantitative yield) of Example 7G was obtained as an off - white solid. Example 7G was consistent with the specified structure. 1 showed an H NMR spectrum.

[0226] Example 7H. N - Benzyloxycarbonyl - D - glutamic acid α - methyl ester γ-(3 - trifluoromethyl)benzylamide. From N - benzyloxycarbonyl - D - glutamic acid α - methyl ester (508 mg, 1.72 mmol) and 317 mg (1.81 mmol) of 3 - (trifluoromethyl)benzylamine, 662 mg (85%) of Example 7H was obtained as an off - white solid. Example 7H was consistent with the specified structure. 1 showed an H NMR spectrum.

[0227] Example 8. General procedure for the hydrogenation of benzyloxycarbonylamine. L-Aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide. A suspension of 2.23 g (4.64 mmol) of N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide and palladium (5 wt% on activated carbon, 0.642 g) in 30 mL of methanol was maintained under a hydrogen atmosphere until complete conversion was determined by thin layer chromatography (95:5 dichloromethane / methanol eluent). The reaction mixture was filtered to remove the palladium carbon, and the filtrate was evaporated to give 1.52 g (96%) of the title compound as an oil; 1 H NMR (CDCl3) δ 1.42 (s, 9H); 2.26 (brs, 2H); 2.63-2.71 (m, 1H); 2.82-2.87 (m, 1H); 3.75-3.77 (m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.90 (brs, 1H).

[0228] Examples 9 to 13P were prepared according to the procedure of Example 8, except that the N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with an appropriate amino acid derivative.

[0229] Example 9. L-Aspartic acid β-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide. From 5.89 g (11.9 mmol) of N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide, 4.24 g (98%) of Example 9 was obtained as an off-white oil; 1 H NMR (CDCl3): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, 1H); 7.17-7.29 (m, 5H).

[0230] Example 10. D-Aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol), 0.973 g (96%) of Example 10 was obtained as an off-white oil: δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J = 7.1 Hz, J = 16.8 Hz, 1H); 2.84 (dd, J = 3.6 Hz, J = 16.7 Hz, 1H); 3.73 - 3.77 (m, 1H); 4.47 - 4.50 (m, 2H); 7.41 - 7.52 (m, 4H); 7.83 - 7.87 (m, 1H).

[0231] Example 11. L-Glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol), 3.94 g (quantitative yield) of Example 11 was obtained as an off-white oil; 1 1H NMR (CDCl3): δ 1.41 (s, 9H); 1.73 - 1.89 (m, 3H); 2.05 - 2.16 (m, 1H); 2.32 - 2.38 (m, 2H); 3.47 (dd, J = 5.0 Hz, J = 7.5 Hz, 1H); 4.47 - 4.49 (m, 2H); 7.36 - 7.54 (m, 4H); 7.69 - 7.77 (m, 1H).

[0232] Example 12. L-Glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazine amide. From N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazine amide (5.86 g, 11.50 mmol), 4.28 g (99%) of Example 12 was obtained as an off-white oil; 11H NMR (CDCl3) δ 1.39 (s, 9H); 2.00 - 2.08 (m, 1H); 2.38 - 2.46 (m, 1H); 2.55 - 2.90 (m, 9H); 3.61 - 3.82 (m, 4H); 4.48 - 4.56 (m, 1H); 7.17 - 7.26 (m, 5H).

[0233] Example 13. D-Glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. 1.15 g (94%) of Example 13 was obtained as an off-white oil from N-benzyloxycarbonyl-D-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol); 1 1H NMR (CDCl3) δ 1.41 (s, 9H); 1.80 - 2.20 (m, 4H); 2.31 - 2.40 (m, 2H); 3.51 - 3.59 (m, 1H); 4.47 - 4.49 (m, 2H); 7.39 - 7.52 (m, 4H); 7.71 - 7.79 (m, 1H).

[0234] Example 13A. L-Glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide. 1.30 g (93%) of Example 13A was obtained as an off-white oil from N-benzyloxycarbonyl-L-glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide (1.93 g, 3.96 mmol); 1 1H NMR (CDCl3) δ 1.02 - 1.25 (m, 5H); 1.41 (s, 9H); 1.45 - 1.50 (m, 1H); 1.56 - 1.60 (m, 1H); 1.69 - 1.80 (m, 6H); 3.30 (dd, J = 4.8 Hz, J = 8.5 Hz, 1H); 3.44 (t, J = 9.9 Hz, 2H); 3.56 (t, J = 9.9 Hz, 2H).

[0235] Example 13B. D-Aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol), 0.256 g (92%) of Example 13B was obtained as an off-white oil; 1 H NMR (CDCl3) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, 1H); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, 1H); 7.48 (t, J=7.3 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.97-8.02 (m, 1H).

[0236] Example 13C. D-Aspartic acid β-t-butyl ester α-[(S)-α-methyl]benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(S)-α-methylbenzyl]amide (0.275 g, 0.65 mmol), 0.17 g (90%) of Example 13C was obtained as an off-white oil; 1 H NMR (CDCl3) δ 1.40 (s, 9H); 1.47 (d, J=6.9 Hz, 3H); 1.98 (brs, 2H); 2.49 (dd, J=7.9 Hz, J=17.7 Hz, 1H); 2.83 (dd, J=3.6 Hz, J=16.7 Hz, 1H); 3.69 (brs, 1H); 4.99-5.10 (m, 1H); 7.19-7.33 (m, 5H); 7.65-7.68 (m, 1H).

[0237] Example 13D. D-Aspartic acid β-t-butyl ester α-[(R)-α-methylbenzyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(R)-α-methylbenzyl]amide (0.273 g, 0.64 mmol), 0.187 g (quantitative yield) of Example 13D was obtained as an off-white oil; 1 H NMR (CDCl3) δ 1.38 (s, 9H); 1.46 (d, J=6.9 Hz, 3H); 1.79 (brs, 2H); 2.51 (dd, J=7.8 Hz, J=17.5 Hz, 1H); 2.87 (dd, J=3.6 Hz, J=16.9 Hz, 1H); 4.19 (brs, 1H); 4.99-5.11 (m, 1H); 7.18-7.34 (m, 5H); 7.86-7.90 (m, 1H).

[0238] Example 13E. D-Aspartic acid β-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol), 0.195 g (95%) of Example 13E was obtained as an off-white oil. Example 13E showed an H NMR spectrum consistent with the assigned structure 1 H NMR spectrum was shown.

[0239] Example 13F. L-Aspartic acid β-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide. From N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide (5.89 g, 11.9 mmol), 4.24 g (98%) of Example 13F was obtained as an off-white oil; 1 H NMR (CDCl3): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, 1H); 7.17-7.29 (m, 5H).

[0240] Example 13G. D-Aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide. 0.973 g (96%) of Example 13G was obtained as an off-white oil from N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol); 1 H NMR (CDCl3): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, 1H); 2.84 (dd, J=3.6 Hz, J=16.7 Hz, 1H); 3.73-3.77 (m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, 1H).

[0241] Example 13H. L-Glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. 3.94 g (quantitative yield) of Example 13H was obtained as an off-white oil from N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol); 1 H NMR (CDCl3): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, 1H); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz, 1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).

[0242] Example 13I. L-Glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide. 4.28 g (99%) of Example 13I was obtained as an off-white oil from N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazineamide (5.86 g, 11.50 mmol); 11H NMR (CDCl3) δ 1.39 (s, 9H); 2.00 - 2.08 (m, 1H); 2.38 - 2.46 (m, 1H); 2.55 - 2.90 (m, 9H); 3.61 - 3.82 (m, 4H); 4.48 - 4.56 (m, 1H); 7.17 - 7.26 (m, 5H).

[0243] Example 13J. D-Glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide. 1.15 g (94%) of Example 13J was obtained as an off-white oil from N-benzyloxycarbonyl-D-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol); 1 1H NMR (CDCl3) δ 1.41 (s, 9H); 1.80 - 2.20 (m, 4H); 2.31 - 2.40 (m, 2H); 3.51 - 3.59 (m, 1H); 4.47 - 4.49 (m, 2H); 7.39 - 7.52 (m, 4H); 7.71 - 7.79 (m, 1H).

[0244] Example 13K. L-Glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide. 1.30 g (93%) of Example 13K was obtained as an off-white oil from N-benzyloxycarbonyl-L-glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide (1.93 g, 3.96 mmol); 1 1H NMR (CDCl3) δ 1.02 - 1.25 (m, 5H); 1.41 (s, 9H); 1.45 - 1.50 (m, 1H); 1.56 - 1.60 (m, 1H); 1.69 - 1.80 (m, 6H); 3.30 (dd, J = 4.8 Hz, J = 8.5 Hz, 1H); 3.44 (t, J = 9.9 Hz, 2H); 3.56 (t, J = 9.9 Hz, 2H).

[0245] Example 13L. D-Aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol), 0.256 g (92%) of Example 13L was obtained as an off-white oil; 1 1H NMR (CDCl3) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, 1H); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, 1H); 7.48 (t, J=7.3 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.97-8.02 (m, 1H).

[0246] Example 13M. D-Aspartic acid β-t-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide (120 mg, 0.24 mmol), 91 mg (91%) of Example 13M was obtained as an off-white oil, which showed an 1H NMR spectrum consistent with the assigned structure 1 and showed an 1H NMR spectrum consistent with the assigned structure.

[0247] Example 13N. D-Aspartic acid β-t-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide (217 mg, 0.44 mmol), 158 mg (quantitative yield) of Example 13N was obtained as an off-white oil, which showed an 1H NMR spectrum consistent with the assigned structure 1 and showed an 1H NMR spectrum consistent with the assigned structure.

[0248] Example 13 O.D-Aspartic acid β-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. From N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol), 0.195 g (95%) of Example 13 O was obtained as an off-white oil, which was consistent with the specified structure. 1 The 1H NMR spectrum was shown.

[0249] Example 13 P.D-Glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide (764 mg, 1.69 mmol), g (516 mg, 96%) of Example 13 P was obtained as an off-white oil, which was consistent with the specified structure. 1 The 1H NMR spectrum was shown.

[0250] Example 14. General procedure for forming 2-azetidinone from imine and acetyl chloride Step 1: General procedure for forming imine from amino acid derivatives. A solution of 1 equivalent of an α-amino acid ester or amide in dichloromethane is sequentially treated with 1 equivalent of an appropriate aldehyde and a drying agent such as magnesium sulfate or silica gel in an amount of about 2 g of the drying agent per 1 g of the starting α-amino acid ester or amide. The reaction mixture is stirred at ambient temperature until all of the reactants are consumed as measured by thin layer chromatography. The reaction typically is complete within 1 hour. The reaction mixture is then filtered, the filter cake is washed with dichloromethane, and the filtrate is concentrated under reduced pressure to afford the desired imine, which is used as such in the next step.

[0251] Procedure 2: General procedure for the 2+2 cycloaddition of imines and acetyl chloride. A solution of imine (10 mL of dichloromethane / 1 g of imine) in dichloromethane is cooled to 0 °C. To this cooled solution, 1.5 equivalents of the appropriate amine, typically triethylamine, is added, and a solution of 1.1 equivalents of the appropriate acetyl chloride, such as that described in Example 1 (10 mL of dichloromethane / 1 gm of the appropriate acetyl chloride), is added dropwise. The reaction mixture is warmed to ambient temperature over 1 hour and then quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture is partitioned between water and dichloromethane. The layers are separated, and the organic layer is washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue can be used directly for further reaction or, if necessary, purified by chromatography or by crystallization from an appropriate solvent system. In each case, after the 2+2 reaction, the stereochemistry of the β-lactam can be confirmed by circular dichroism / optical rotatory dispersion (CD / ORD). Exemplarily, examples of the (αR,3S,4R) and (αS,3S,4R) β-lactam platform stereochemical configurations from the previous synthesis can be used as CD / ORD standards.

[0252] Example 15. tert-Butyl [3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. Using the procedure of Example 14, an imine prepared from 4.53 g (34.5 mmol) of glycine tert-butyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 5.5 g (30%) of Example 15 as colorless crystals (recrystallization, n-chlorobutane); melting point 194-195 °C.

[0253] Example 16. General procedure for the acylation of azetidin-2-one-1-yl acetate. A solution of (azetidin-2-one-1-yl) acetate in tetrahydrofuran (0.22 M in azetidinone) was cooled to -78 °C and treated with lithium bis(trimethylsilyl)amide (2.2 equivalents). The resulting anion was treated with the appropriate acyl halide (1.1 equivalents). After complete conversion of the azetidinone, the reaction was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The resulting organic layer was dried (magnesium sulfate) and evaporated. The residue was purified by silica gel chromatography using an appropriate eluent such as 3:2 hexane / ethyl acetate.

[0254] Example 17. 2,2,2-Trichloroethyl 2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate Using the procedure of Example 16, 9.0 g (20 mmol) of Example 15 was acylated with 4.2 g (20 mmol) of trichloroethyl chloroformate to give 7.0 g (56%) of Example 17; melting point 176-178 °C.

[0255] Example 18. N-(3-Trifluoromethylbenzyl)-2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetamide. A solution of 0.20 g (0.32 mmol) of Example 17 and 52 μL (0.36 mmol) of (3-trifluoromethylbenzyl)amine in THF was heated to reflux. After complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform / hexane) to give 0.17 g (82%) of Example 18 as a white solid; melting point 182-184 °C.

[0256] Example 18A.2 (RS)-(tert-Butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. Example 18A was prepared according to the procedure of Example 18 using 2-fluoro-3-(trifluoromethyl)benzylamine instead of (3-trifluoromethylbenzyl)amine. Example 18A was obtained as a white solid (140 mg, 41%), which was consistent with the assigned structure. 1 showed an H NMR spectrum.

[0257] Examples 19 to 25AF were prepared according to the procedure of Example 14, using appropriate amino acid derivatives and aldehydes in Step 1 and appropriate acetyl chlorides in Step 2.

[0258] Example 19.2(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 1.52 g (4.39 mmol) of L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 2.94 g of an orange-brown oil, which, after purification by flash column chromatography (70:30 hexane / ethyl acetate), gave 2.06 g (70%) of Example 19 as a white solid; 11H NMR (CDCl3) δ 1.39 (s, 9H); 2.46 (dd, J=11.1 Hz, J=16.3 Hz, 1H); 3.18 (dd, J=3.8 Hz, J=16.4 Hz, 1H); 4.12 - 4.17 (m, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.45 (dd, J=6.0 Hz, J=14.9 Hz, 1H); 4.54 (dd, J=5.3 Hz, J=9.8 Hz, 1H); 4.58 - 4.66 (m, 3H); 4.69 - 4.75 (m, 1H); 4.81 (dd, J=3.8 Hz, J=11.1 Hz, 1H); 6.25 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.14 - 7.17 (m, 2H); 7.28 - 7.46 (m, 11H); 7.62 (s, 1H); 8.27 - 8.32 (m, 1H).

[0259] Example 19A.2 (S)-(tert-Butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 19A was prepared according to the method of Example 19, except that 2-(4(R)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1A) was used instead of 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride. Example 19A was obtained as a white solid (41 mg, 13%); 11H NMR (CDCl3) δ 1.37 (s, 9H); 3.11 (dd, J=3.7 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.6 Hz, J=17.8 Hz, 1H); 4.02 (dd, J=3.7 Hz, J=10.6 Hz, 1H); 4.10 - 4.17 (m, 1H); 4.24 (d, J=4.9 Hz, 1H); 4.4652 - 4.574 (dd, J=5.9 Hz, J=15.1 Hz, 1H); 4.58 - 4.76 (m, 4H); 6.27 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.79 (d, J=15.8 Hz, 1H); 7.23 - 7.53 (m, 13H); 7.63 (s, 1H); 8.51 - 8.55 (m, 1H).

[0260] Example 20.2 (S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 3.94 g (10.93 mmol) of L-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 5.53 g (75%) of Example 20 was obtained; 11H NMR (CDCl3) δ 1.36 (s, 9H); 1.85 - 1.96 (m, 1H); 2.18 - 2.49 (m, 3H); 4.14 - 4.19 (m, 1H); 4.30 (d, J = 4.9 Hz, 2H); 4.44 (dd, J = 6.1 Hz, J = 14.9 Hz, 1H); 4.56 - 4.67 (m, 4H); 4.71 - 4.75 (m, 1H); 6.26 (dd, J = 9.6 Hz, J = 15.8 Hz, 1H); 6.71 (d, J = 15.8 Hz, 1H); 7.16 - 7.18 (m, 2H); 7.27 - 7.49 (m, 11H); 7.60 (s, 1H); 8.08 - 8.12 (m, 1H).

[0261] Example 21.2 (S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazine amide. An imine prepared from 4.20 g (11.6 mmol) of L-aspartic acid β-t-butyl ester α-[4-(2-phenylethyl)]piperazine amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (50:50 hexane / ethyl acetate), 4.37 g (55%) of Example 21 was obtained; 11H NMR (CDCl3) δ 1.34 (s, 9H); 2.26 - 2.32 (m, 1H); 2.46 - 2.63 (m, 4H); 2.75 - 2.89 (m, 4H); 3.24 - 3.32 (m, 1H); 3.49 - 3.76 (m, 3H); 4.07 - 4.13 (m, 1H); 4.30 (d, J = 4.6 Hz, 1H); 4.22 - 4.48 (m, 1H); 4.55 - 4.61 (m, 1H); 4.69 - 4.75 (m, 1H); 5.04 - 5.09 (m, 1H); 6.15 (dd, J = 9.3 Hz, J = 15.9 Hz, 1H); 6.63 (d, J = 15.8 Hz, 1H); 7.18 - 7.42 (m, 15H).

[0262] Example 22.2 (S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazine amide. An imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-t-butyl ester α-[4-(2-phenylethyl)]piperazine amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (50:50 hexane / ethyl acetate) to give 3.55 g (76%) of Example 22; 1 1H NMR (CDCl3) δ 1.32 (s, 9H); 1.96 - 2.07 (m, 1H); 2.15 - 2.44 (m, 6H); 2.54 - 2.62 (m, 2H); 2.69 - 2.81 (m, 3H); 3.28 - 3.34 (m, 1H); 3.59 - 3.68 (m, 1H); 4.08 - 4.13 (m, 1H); 4.33 - 4.44 (m, 2H); 4.48 - 4.60 (m, 2H); 4.67 - 4.77 (m, 1H); 6.14 (dd, J = 8.9 Hz, J = 16.0 Hz, 1H); 6.62 (d, J = 16.0 Hz, 1H); 7.16 - 7.42 (m, 15 H).

[0263] Example 23.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.973 g (2.81 mmol) of D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 1.53 g (82%) of Example 23 was obtained; 1 H NMR (CDCl3) δ 1.37 (s, 9H); 3.10 (dd, J=3.7 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.7 Hz, J=17.8 Hz, 1H); 4.02 (dd, J=3.6 Hz, J=10.6 Hz, 1H); 4.11-4.17 (m, 1H); 4.24 (d, J=4.9 Hz, 1H); 4.46 (dd, J=5.8 Hz, J=15.1 Hz, 1H); 4.58-4.67 (m, 3H); 4.70-4.76 (m, 1H); 6.27 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.79 (d, J=15.8 Hz, 1H); 7.25-7.50 (m, 13H); 7.63 (s, 1H); 8.50-8.54 (m, 1H).

[0264] Example 23A.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23A was prepared according to the method of Example 23, except that 2-(4(R)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1A) was used instead of 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride. Example 23A was obtained as a white solid (588 mg, 49%); 1 H NMR (CDCl3) δ 1.39 (s, 9H); 2.47 (dd, J=11.2 Hz, J=16.3 Hz, 1H); 3.18 (dd, J=3.8 Hz, J=16.3 Hz, 1H); 4.15 (t, J=8.25, Hz 1H); 4.26 (d, J=5.0 Hz, 1H); 4.45 (dd, J=6.0 Hz, J=15.0 Hz, 1H); 4.52-4.57 (m, 3H); 4.63 (t, J=9 Hz, 1H); 4.70 (t, J=8 Hz, 1H); 4.81 (dd, J=3.8 Hz, J=10.8 Hz, 1H); 6.25 (dd, J=9.8 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.15-7.17 (m, 2H); 7.27-7.51 (m, 11H); 7.62 (s, 1H); 8.27-8.32 (m, 1H).

[0265] Example 24.2 (R)-(tert-Butyl butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.15 g (3.20 mmol) of D-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (70:30 hexane / ethyl acetate) to give 1.84 g (85%) of Example 24; 1 H NMR (CDCl3) δ 1.37 (s, 9H); 2.23-2.39 (m, 4H); 3.71-3.75 (m, 1H); 4.13-4.18 (m, 1H); 4.31 (d, J=4.9 Hz, 1H); 4.44-4.51 (m, 2H); 4.56-4.68 (m, 2H); 4.71-4.76 (m, 1H); 6.26 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.25-7.52 (m, 13H); 7.63 (s, 1H); 8.25-8.30 (m, 1H).

[0266] Example 25.2 (S)-(tert-Butyl butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(4-cyclohexyl)piperazineamide. The imine prepared from 2.58 g (5.94 mmol) of L-glutamic acid γ-t-butyl ester α-(4-cyclohexyl)piperazineamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (95:5 dichloromethane / methanol) to give 3.27 g (94%) of Example 25; 11H NMR (CDCl3) δ 1.32 (s, 9H); 1.10 - 1.18 (m, 1H); 1.20 - 1.31 (m, 2H); 1.38 - 1.45 (m, 2H); 1.61 - 1.66 (m, 1H); 1.84 - 1.89 (m, 2H); 1.95 - 2.01 (m, 1H); 2.04 - 2.14 (m, 3H); 2.20 - 2.24 (m, 1H); 2.29 - 2.35 (m, 1H); 2.85 - 2.92 (m, 1H); 3.24 - 3.32 (m, 1H); 3.36 - 3.45 (m, 2H); 3.80 - 3.86 (m, 1H); 4.08 (t, J = 8.3 Hz, 1H); 4.27 (d, J = 5.0 Hz, 1H); 4.31 - 4.55 (m, 4H); 4.71 (t, J = 8.3 Hz, 1H); 4.83 - 4.90 (m, 1H); 6.18 (dd, J = 9.1 Hz, J = 15.9 Hz, 1H); 6.67 (d, J = 15.9 Hz, 1H); 7.25 - 7.44 (m, 10H); 8.22 (brs, 1H).

[0267] Example 25 A. tert-Butyl 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-Phenyloxazolidin-2-one-3-yl)-4(R)-(2-Styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 1.282 g (3.63 mmol) of L-Glutamic acid α-t-butyl ester γ-(4-cyclohexyl)piperazine amide and cinnamaldehyde was combined with 2-(4(S)-Phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (50:50 hexane / ethyl acetate) to give 1.946 g (80%) of Example 25 A; 11H NMR (CDCl3) δ 1.15 - 1.26 (m, 6H); 1.39 (s, 9H); 1.55 - 1.64 (m, 2H); 1.77 - 1.83 (m, 3H); 2.22 - 2.35 (m, 2H); 2.40 - 2.50 (m, 6H); 2.75 - 2.79 (m, 1H); 3.43 - 3.48 (m, 1H); 3.56 - 3.60 (m, 2H); 3.75 - 3.79 (m, 1H); 4.10 (t, J = 8.3 Hz, 1H); 4.31 - 4.35 (m, 2H); 4.58 (t, J = 8.8 Hz, 1H); 4.73 (t, J = 8.4 Hz, 1H); 6.17 (dd, J = 8.6 Hz, J = 16.0 Hz, 1H); 6.65 (d, J = 16.0 Hz, 1H); 7.27 - 7.42 (m, 10H).

[0268] Example 25B.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. An imine prepared from 0.256 g (0.70 mmol) of D-aspartic acid β-t-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 0.287 g (60%) of Example 25B was obtained; 11H NMR (CDCl3) δ 1.38 (s, 9H); 3.12 (dd, J = 4.0 Hz, J = 17.8 Hz, 1H); 3.20 (dd, J = 10.4 Hz, J = 17.8 Hz, 1H); 4.05 (dd, J = 3.9 Hz, J = 10.4 Hz, 1H); 4.14 (dd, J = J′ = 8.2 Hz, 1H); 4.25 (d, J = 4.9 Hz, 1H); 4.59 - 4.67 (m, 4H); 4.74 (t, J = 8.3 Hz, 1H); 6.36 (dd, J = 9.6 Hz, J = 15.8 Hz, 1H); 6.83 (d, J = 15.8 Hz, 1H); 7.02 - 7.07 (m, 1H); 7.28 - 7.55 (m, 12H); 8.44 - 8.48 (m, 1H).

[0269] Example 25C.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. An imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-t-butyl ester [(S)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 0.219 g (63%) of Example 25C was obtained; 11H NMR (CDCl3) δ 1.35 (s, 9H); 1.56 (d, J=7.0 Hz, 3H); 2.97 (dd, J=3.5 Hz, J=18.0 Hz, 1H); 3.15 (dd, J=11.0 Hz, J=17.5 Hz, 1H); 4.01 (dd, J=3.0 Hz, J=11.0 Hz, 1H); 4.14 (t, J=8.5 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.57 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.64 (t, J=8.8 Hz, 1H); 5.07 (t, J=8.5 Hz, 1H); 5.03 - 5.09 (m, 1H); 6.43 (dd, J=9.5 Hz, J=16.0 Hz, 1H); 6.83 (d, J=16.0 Hz, 1H); 7.16 - 7.20 (m, 1H); 7.27 - 7.49 (m, 14H); 8.07 - 8.10 (m, 1H).

[0270] Example 25D. 2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. An imine prepared from 0.187 g (0.46 mmol) of D-aspartic acid β-t-butyl ester [(R)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 0.25 g (64%) of Example 25D was obtained; 11H NMR (CDCl3) δ 1.36 (s, 9H); 1.59 (d, J=7.1 Hz, 3H); 3.10 (dd, J=3.5 Hz, J=17.8 Hz, 1H); 3.22 (dd, J=10.9 Hz, J=17.8 Hz, 1H); 3.93 (dd, J=3.5 Hz, J=10.8 Hz, 1H); 4.14 (t, J=8.1 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.58 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.65 (t, J=8.7 Hz, 1H); 4.74 (t, J=8.2 Hz, 1H); 5.06-5.14 (m, 1H); 6.32 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.74 (d, J=15.8 Hz, 1H); 7.19-7.43 (m, 15H); 8.15-8.18 (m, 1H).

[0271] Example 25E.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-t-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 0.253 g (69%) of Example 25E was obtained; 11H NMR (CDCl3) δ 1.36 (s, 9H); 2.53 (dd, J=4.0 Hz, J=17.0 Hz, 1H); 3.06 (dd, J=10.8 Hz, J=16.8 Hz, 1H); 3.13 (s, 3H); 4.12 (dd, J=8.0 Hz, J=9.0 Hz, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.38 (d, J=15.0 Hz, 1H); 4.46 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.56 (t, J=6.8 Hz, 1H); 4.70 - 4.79 (m, 2H); 5.27 (dd, J=4.0 Hz, J=11.0 Hz, 1H); 6.22 (dd, J=9.3 Hz, J=15.8 Hz, 1H); 6.73 (d, J=15.8 Hz, 1H); 7.33 - 7.45 (m, 14H).

[0272] Example 25F.2 (S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-chlorostyryl-2-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-t-butyl ester α-(3-trifluoromethyl)benzylamide and α-chlorocinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / ethyl acetate), 0.708 g (22%) of Example 25F was obtained; 11H NMR (CDCl3) δ 1.35 (s, 9H); 1.68(brs, 1H); 2.19 - 2.35(m, 2H); 2.40 - 2.61 (m, 2H); 4.13 (dd, J = 7.5 Hz, J = 9.0 Hz, 1H); 4.22 (t, J = 7.0 Hz, 1H); 4.34 (d, J = 4.5 Hz, 1H); 4.45 (dd, J = 5.5 Hz, J = 15.0 Hz, 1H); 4.51 - 4.60 (m, 3H); 4.89 (dd, J = 7.5 Hz, J = 8.5 Hz, 1H); 6.89 (s, 1H); 7.28 - 7.54 (m, 14H).

[0273] Example 25G.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2'-methoxystyryl-2-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid β-t-butyl ester α-(3-trifluoromethylbenzyl)amide and 2'-methoxycinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (70:30 hexane / ethyl acetate) to give 0.402 g (59%) of Example 25G; 1 1H NMR (CDCl3) δ 1.35 (s, 9H); 1.68 (brs, 1H); 2.19 - 2.35 (m, 2H); 2.40 - 2.61 (m, 2H); 4.13 (dd, J = 7.5 Hz, J = 9.0 Hz, 1H); 4.22 (t, J = 7.0 Hz, 1H); 4.34 (d, J = 4.5 Hz, 1H); 4.45 (dd, J = 5.5 Hz, J = 15.0 Hz, 1H); 4.51 - 4.60 (m, 3H); 4.89 (dd, J = 7.5 Hz, J = 8.5 Hz, 1H); 6.89 (s, 1H); 7.28 - 7.54 (m, 14H).

[0274] Example 25H. tert-Butyl (2R)-(benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 0.329 g (1.31 mmol) of O-(benzyl)-D-serine tert-butyl ester (Example 5B) and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (90:10 hexane / ethyl acetate), 0.543 g (73%) of Example 25H was obtained; 1 H NMR (CDCl3) δ 1.39 (s, 9H); 3.56 (dd, J=2.7 Hz, J=9.5 Hz, 1H); 3.82 (dd, J=4.8 Hz, J=9.5 Hz, 1H); 4.11 (t, J=8.3 Hz, 1H); 4.21-4.29 (m, 2H); 4.50-4.58 (m, 3H); 4.71-4.78 (m, 2H); 6.19 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.49 (d, J=16.0 Hz, 1H); 7.07-7.11 (m, 1H); 7.19-7.40 (m, 14H).

[0275] Example 25I. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 0.3 g (0.88 mmol) of L-aspartic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (50:50 hexane / ethyl acetate), 464 mg (80%) of Example 25I was obtained as a white solid. Example 25I showed an H NMR spectrum consistent with the assigned structure. 1 The H NMR spectrum was shown.

[0276] Example 25 J. tert-Butyl 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(stil-2-yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoate. An imine prepared from 0.307 grams (0.89 millimoles) of D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide (Example 20) and cinnamaldehyde was combined with 2-(4(S))-phenyloxazolidin-2-one-3-yl)propanoyl chloride (Example 1E), and after purification by flash column chromatography (hexane 70% / EtOAc 30%), 120 mg (20%) was obtained; 1 H NMR (CDCl3) δ 1.25 (s, 3H), 1.38 (s, 9H); 3.09 (dd, J = 3.0 Hz, J = 18.0 Hz, 1H); 3.33 (dd, J = 12.5 Hz, J = 18.0 Hz, 1H); 4.01 (dd, J = 3.0 Hz, J = 11.5 Hz, 1H); 4.04 (dd, J = 3.5 Hz, J = 8.8 Hz, 1H); 4.42 (d, J = 9.0 Hz, 1H); 4.45 - 4.51 (m, 3H); 4.61 - 4.66 (m, 1H); 4.75 (dd, J = 3.5 Hz, J = 8.5 Hz, 1H); 6.23 (dd, J = 9.0 Hz, J = 15.5 Hz, 1H); 6.78 (d, J = 15.5 Hz, 1H); 7.23 - 7.53 (m, 13H); 7.64 (s, 1H).

[0277] Example 25K.2 (R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(prop-1-enyl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.289 g (0.83 mmol) of D-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide and crotonaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1), and after purification by flash column chromatography (99:1 CH2Cl2 / MeOH), 381 mg (76%) of Example 25K was obtained; 1 H NMR (CDCl3) δ 1.36 (s, 9H), 1.69 (dd, J=2 Hz, J=6.5 Hz, 3H); 3.08 (dd, J = 3.3 Hz, J = 17.8 Hz, 1H); 3.18 (dd, J = 11 Hz, J = 17.5 Hz, 1H); 3.94 (dd, J = 3.5 Hz, J = 11 Hz, 1H); 4.12 (d, J=5 Hz, 1H); 4.15 (dd, J = 7 Hz, J = 8 Hz, 1H); 4.35 (dd, J = 4.8 Hz, J=9.8Hz, 1H); 4.44 (dd, J=6 Hz, J=15 Hz, 1H); 4.61 (dd, J=6 Hz, J=15 Hz, 1H); 4.67-4.75 (m, 2H); 5.52-5.58 (m, 1H); 5.92-6.00 (m, 1H); 7.33-7.60 (m, 9H); 8.47-8.50 (m, 1H).

[0278] Example 25O. Methyl 2(S)-(tert-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 433 mg (1.99 mmol) of L-glutamic acid γ-t-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (70:30 hexane / ethyl acetate) to give 682 mg (64%) of Example 25O; 1 H NMR (CDCl3) δ 1.32 (s, 9H); 2.10-2.26 (m, 1H); 2.30-2.41 (m, 3H); 3.66 (s, 3H); 3.95-3.99 (m, 1H); 4.16 (dd, J=7.5 Hz, J=9 Hz, 1H); 4.38 (dd, J=5 Hz, J=9 Hz, 1H); 4.55 (d, J= 5 Hz 1H); 4.61 (t, J= 9 Hz, 1H); 4.86 (dd, J=7.5 Hz, J=9 Hz, 1H); 6.00 (dd, J=9 Hz, J=16 Hz, 1H); 6.60 (d, J=16 Hz, 1H); 7.26-7.43 (m, 10H).

[0279] Example 25M. tert-Butyl 2(S)-(methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 428 mg (1.97 mmol) of L-glutamic acid γ-t-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (70:30 hexane / ethyl acetate) to give 864 mg (82%) of Example 25M; 11H NMR (CDCl3) δ 1.40 (s, 9H); 2.12 - 2.27 (m, 1H); 2.32 - 2.55 (m, 3H); 3.50 (s, 3H); 3.72 (dd, J = 4.6 Hz, J = 10.4 Hz, 1H); 4.12 - 4.17 (m, 1H); 4.34 (dd, J = 5 Hz, J = 9 Hz, 1H); 4.50 (d, J = 5 Hz, 1H); 4.60 (t, J = 8.9 Hz, 1H); 4.81 - 4.86 (m, 1H); 6.06 (dd, J = 9 Hz, J = 16 Hz, 1H); 6.59 (d, J = 16 Hz, 1H); 7.25 - 7.42 (m, 10H).

[0280] Example 25P. Methyl 2(S)-(tert-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 424 mg (2.09 mmol) of L-aspartic acid γ-t-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1), and after recrystallization from CH2Cl2 / hexane, 923 mg (85%) of Example 25P was obtained; 1 1H NMR (CDCl3) δ 1.41 (s, 9H); 2.77 (dd, J = 7.5 Hz, J = 16.5 Hz, 1H); 3.00 (dd, J = 7 Hz, J = 16.5 Hz, 1H); 4.16 (dd, J = 7.5Hz, J = 9 Hz, 1H); 4.41 - 48 (m, 2H); 4.55 (d, J = 5 Hz, 1H); 4.60 (t, J = 8.8 Hz, 1H); 4.86 (dd, J = 7.5 Hz, J = 9 Hz, 1H); 5.93 (dd, J = 9.5 Hz, J = 15.5 Hz, 1H); 6.61 (d, J = 15.5 Hz, 1H); 7.25 - 7.43 (m, 10H).

[0281] Example 25L. 2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. An imine prepared from 160 mg (0.44 mmol) of D-aspartic acid β-t-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / EtOAc), 166 mg (55%) of Example 25L was obtained. Example 25L showed an 1 H NMR spectrum.

[0282] Example 25N. 2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. An imine prepared from 120 mg (0.22 mmol) of D-aspartic acid β-t-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and, after purification by flash column chromatography (70:30 hexane / EtOAc), 75 mg (50%) of Example 25N was obtained. Example 25N showed an 1 H NMR spectrum.

[0283] Example 25Q. Methyl 2(R)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 517 mg (1.62 mmol) of D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combined with acetyl 2-(4(S)-phenyloxazolidin-2-one-3-yl) (Example 1), and after purification by flash column chromatography (50:50 hexane / EtOAc), 527 mg (51%) of Example 25Q was obtained. Example 25Q was consistent with the specified structure. 1 showed an H NMR spectrum.

[0284] The following compounds were prepared according to the processes described herein:

Chemical formula

Table 6

Chemical formula

Table 7

Chemical formula

Table 8

Chemical formula

Table 9

Chemical formula

Table 10

[0285] Example 25. AF. t-Butyl 2(S)-(2-(3-Trifluoromethylbenzyl)aminocarbonyl)ethyl-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate.

[0286] Example 26. General procedure for hydrolysis of tert-butyl esters. Typically, a solution of 1 g of a tert-butyl ester derivative in 10 mL of formic acid is stirred at ambient temperature for about 3 hours, a typical reaction time, until no ester is detected by thin layer chromatography (95% dichloromethane / 5% methanol). The formic acid is evaporated under reduced pressure, and the resulting solid residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer is evaporated to give an off-white solid, which can be used directly in further reactions if necessary or recrystallized from a suitable solvent system.

[0287] Examples 27 - 34 AE were prepared from the appropriate tert-butyl esters according to the procedure used in Example 26.

[0288] Example 27. 2(R,S)-(Carboxy)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 18 (0.30 g, 0.46 mmol) was hydrolyzed to give 0.27 g (quantitative yield) of Example 27 as an off-white solid; 1 1H NMR (CDCl3) δ 4.17 - 5.28 (m, 9H); 6.21 - 6.29 (m, 1H), 6.68 - 6.82 (m, 1H); 7.05 - 7.75 (m, 13H); 9.12 - 9.18 (m, 1H).

[0289] Example 28.2 N-(3-Trifluoromethylbenzyl)-2-(S)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetamide. Example 19 (1.72 g, 2.59 mmol) was hydrolyzed to give 1.57 g (quantitative yield) of Example 28 as an off-white solid; 1 H NMR (CDCl3) δ 2.61(dd, J=9.3 Hz, J=16.6 Hz, 1H); 3.09-3.14 (m, 1H); 4.10-4.13 (m, 1H); 4.30 (d, J=4.5 Hz, 1H); 4.39-4.85(m, 6H); 6.20(dd, J=9.6 Hz, J=15.7 Hz, 1H); 6.69 (d, J=15.8 Hz, 1H); 7.12-7.15 (m, 2H); 7.26-7.50(m, 11H); 7.61(s, 1H); 8.41-8.45(m, 1H).

[0290] Example 28A.2 (S)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 19A (41 mg, 0.06 mmol) was hydrolyzed to give 38 mg (quantitative yield) of Example 28A as an off-white solid; 1 H NMR (CDCl3) δ 2.26 (d, J=7 Hz, 1H); 4.03 (t, J=7 Hz, 1H); 4.16 (t, J=8 Hz, 1H); 4.26 (d, J=4.3 Hz, 1H); 4.46 (dd, J=5.7 Hz, J=15.1, 1H); 4.53-4.75 (m, 5H); 6.25 (dd, J=9.5 Hz, J=15.7 Hz, 1H); 6.77 (d, J=15.7 Hz, 1H); 7.28-7.53 (m, 13H); 7.64 (s, 1H); 8.65-8.69 (m, 1H).

[0291] Example 29.2 (S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 20 (4.97 g, 7.34 mmol) was hydrolyzed to give 4.43 g (97%) of Example 29 as an off-white solid; 1 H NMR (CDCl3) δ 1.92-2.03 (m,1H); 2.37-2.51(m, 3H); 4.13-4.19 (m, 1H); 3.32 (d, J=4.9 Hz, 1H); 4.35-4.39 (m, 1H); 4.44 (dd, J=5.9 Hz, J=14.9 Hz, 1H); 4.50-4.57 (m, 2H); 4.61-4.67 (m, 1H); 4.70-4.76 (m, 1H); 6.24 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18-7.47 (m, 14H).

[0292] Example 30.2 (S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazine amide. Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g (60%) of Example 30 as an off-white solid; 11H NMR (CDCl3) δ 2.63 (dd, J = 6.0 Hz, J = 16.5 Hz, 1H); 2.75 - 2.85 (m, 1H); 3.00 (dd, J = 8.2 Hz, J = 16.6 Hz, 1H); 3.13 - 3.26 (m, 4H); 3.37 - 3.56 (m, 4H); 3.86 - 4.00 (m, 1H); 4.05 - 4.11 (m, 1H); 4.24 (d, J = 5.0 Hz, 1H); 4.46 - 4.66 (m, 1H); 4.65 - 4.70 (m, 1H); 5.10 - 5.15 (m, 1H); 6.14 (dd, J = 9.3 Hz, J = 15.9 Hz, 1H); 6.71 (d, J = 15.9 Hz, 1H); 7.22 - 7.41 (m, 15H); 12.02 (s, 1H).

[0293] Example 31.2 (S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazine amide. Example 22 (0.383 g, 0.55 mmol) was hydrolyzed to give 0.352 g (quantitative yield) of Example 31 as an off-white solid; 1 1H NMR (CDCl3) δ 1.93 - 2.01 (m, 1H); 2.07 - 2.36 (m, 6H); 2.82 - 2.90 (m, 1H); 3.00 - 3.20 (m, 4H); 3.36 - 3.54 (m, 4H); 3.74 - 3.82 (m, 1H); 4.06 - 4.11 (m, 1H); 4.29 (d, J = 4.9 Hz, 1H); 4.33 - 4.46 (m, 2H); 4.50 - 4.58 (m, 2H); 4.67 - 4.72 (m, 1H); 4.95 - 5.00 (m, 1H); 6.18 (dd, J = 9.2 Hz, J = 16.0 Hz, 1H); 6.67 (d, J = 15.9 Hz, 1H); 7.19 - 7.42 (m, 15H); 8.80 (brs, 1H).

[0294] Example 32.2 (R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23 (1.51 g, 2.27 mmol) was hydrolyzed to give 1.38 g (quantitative yield) of Example 32 as an off-white solid.

[0295] Example 32A.2 (R)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 23A (550 mg, 0.83 mmol) was hydrolyzed to give 479 mg (95%) of Example 32A as an off-white solid. Example 32A showed an 1 H NMR spectrum consistent with the assigned structure.

[0296] Example 33.2 (R)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 24 (0.604 g, 0.89 mmol) was hydrolyzed to give 0.554 g (quantitative yield) of Example 33 as an off-white solid.

[0297] Example 34.2 (S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(4-cyclohexyl)piperazine amide. Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492 g (quantitative yield) of Example 34; 11H NMR (CDCl3) δ 1.09 - 1.17 (m, 1H); 1.22 - 1.33 (m, 2H); 1.40 - 1.47 (m, 2H); 1.63 - 1.67 (m, 1H); 1.85 - 1.90 (m, 2H); 1.95 - 2.00 (m, 1H); 2.05 - 2.15 (m, 3H); 2.20 - 2.24 (m, 1H); 2.30 - 2.36 (m, 1H); 2.85 - 2.93 (m, 1H); 3.25 - 3.33 (m, 1H); 3.36 - 3.46 (m, 2H); 3.81 - 3.87 (m, 1H); 4.08 (t, J = 8.3 Hz, 1H); 4.28 (d, J = 5.0 Hz, 1H); 4.33 - 4.56 (m, 4H); 4.70 (t, J = 8.3 Hz, 1H); 4.83 - 4.91(m, 1H); 6.17 (dd, J = 9.1 Hz, J = 15.9 Hz, 1H); 6.67 (d, J = 15.9 Hz, 1H); 7.25 - 7.44 (m, 10H); 8.22 (brs, 1H).

[0298] Example 34A. 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25A (0.787 g, 1.28 mmol) was hydrolyzed to give 0.665 g (92%) of Example 34A as an off-white solid; 11H NMR (CDCl3) δ 1.05 - 1.13 (m, 1H); 1.20 - 1.40 (m, 5H); 1.60 - 1.64 (m, 1H); 1.79 - 1.83 (m, 2H); 2.00 - 2.05 (m, 2H); 2.22 - 2.44 (m, 3H); 2.67 - 2.71(m, 1H); 2.93 - 3.01(m, 4H); 3.14 - 3.18 (m, 1H); 3.38 - 3.42 (m, 1H); 3.48 - 3.52 (m, 1H); 3.64 - 3.69 (m, 1H); 4.06 - 4.14 (m, 2H); 4.34 - 4.43 (m, 2H); 4.56 (t, J = 8.8 Hz, 1H); 4.73 (t, J = 8.4 Hz, 1H); 6.15 (dd, J = 9.1 Hz, J = 16.0 Hz, 1H); 6.65 (d, J = 16.0 Hz, 1H); 7.25 - 7.42 (m, 10H).

[0299] Example 34B.2 (R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. Example 25B (0.26 g, 0.38 mmol) was hydrolyzed to give 0.238 g (quantitative yield) of Example 34B as an off-white solid; 1 1H NMR (CDCl3) δ 3.27 (d, J = 7.2 Hz, 1H); 4.06 (t, J = 7.2 Hz, 1H); 4.15 (t, J = 8.1 Hz, 1H); 4.27 (d, J = 4.8 Hz, 1H); 4.56 - 4.76 (m, 5H); 6.34 (dd, J = 9.5 Hz, J = 15.7 Hz, 1H); 6.80 (d, J = 15.7 Hz, 1H); 7.06 (t, J = 7.7 Hz, 1H); 7.31 - 7.54 (m, 12H); 8.58 (t, J = 5.9 Hz, 1H).

[0300] Example 34C. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. Example 25C (0.215 g, 0.35 mmol) was hydrolyzed to give 0.195 g (quantitative yield) of Example 34C as an off-white solid; 1 H NMR (CDCl3) δ 1.56 (d, J=7.0 Hz, 1H); 3.10 (dd, J=4.5 Hz, J=17.9 Hz, 1H); 3.18 (dd, J=9.8 Hz, J=17.9 Hz, 1H); 4.00 (dd, J=4.5 Hz, J=9.7 Hz, 1H); 4.14 (t, J=8.2 Hz, 1H); 4.26 (d, J=4.7 Hz, 1H); 5.02-5.09 (m, 1H); 6.41(dd, J=9.4 Hz, J=15.8 Hz, 1H); 6.78 (d, J=15.8 Hz, 1H); 7.18 (t, J=7.3 Hz, 1H); 7.26-7.43 (m, 12H); 8.29 (d, J=8.2 Hz, 1H).

[0301] Example 34D. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. Example 25D (0.22 g, 0.35 mmol) was hydrolyzed to give 0.20 g (quantitative yield) of Example 34D as an off-white solid; 11H NMR (CDCl3) δ 1.59 (d, J = 7.0 Hz, 1H); 3.25 (d, J = 7.0 Hz, 2H); 3.92 (t, J = 7.3 Hz, 1H); 4.15 (t, J = 8.3 Hz, 1H); 4.26 (d, J = 5.0 Hz, 1H); 4.52 (dd, J = 4.8 Hz, J = 9.3 Hz, 1H); 4.65 (t, J = 8.8 Hz, 1H); 4.72 (t, J = 8.3 Hz, 1H); 5.07 - 5.28 (m, 1H); 6.29 (dd, J = 9.5 Hz, J = 15.6 Hz, 1H); 6.71 (d, J = 16.0 Hz, 1H); 7.20 - 7.43 (m, 13H); 8.31 (d, J = 8.0 Hz, 1H).

[0302] Example 34E.2 (R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. Example 25E (0.253 g, 0.37 mmol) was hydrolyzed to give 0.232 g (quantitative yield) of Example 34E as an off-white solid; 1 1H NMR (CDCl3) δ 3.07 - 3.15 (m, 4H); 4.13 (t, J = 8.2 Hz, 1H); 4.30 (d, J = 4.9 Hz, 1H); 4.46 - 4.78 (m, 5H); 5.23 (dd, J = 4.6 Hz, J = 9.7 Hz, 1H); 6.20 (dd, J = 9.4 Hz, J = 15.9 Hz, 1H); 6.73 (d, J = 15.9 Hz, 1H); 7.25 - 7.43 (m, 15H).

[0303] Example 34F. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-chlorostyryl-2-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 25F (0.707 g, 0.99 mmol) was hydrolyzed to give 0.648 g (99%) of Example 34F as an off-white solid; 1 H NMR (CDCl3) δ 2.22-2.28 (m,2H); 2.49-2.64 (m, 2H); 4.09 (t, J=8.0 Hz, 1H); 4.25-4.62 (m, 6H); 4.87 (t, J=8.0 Hz, 1H); 6.88 (s, 1H); 7.25-7.66 (m, 15H).

[0304] Example 34G. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2'-methoxystyryl-2-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 25G (0.268 g, 0.39 mmol) was hydrolyzed to give 0.242 g (98%) of Example 34G as an off-white solid; 1 H NMR (CDCl3) δ 3.26 (d, J=7.1 Hz, 1H); 3.79 (s, 3H); 4.14 (t, J=8.2 Hz, 1H); 4.25 (d, J=4.5 Hz, 1H); 4.51(dd, J=5.9 Hz, J=15.5 Hz, 1H); 4.53-4.66 (m, 4H); 6.36 (dd, J=9.4 Hz, J=15.8 Hz, 1H); 8.88 (t, J=8.2 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18 (d, J=6.5 Hz, 1H); 7.25-7.48 (m, 10H); 7.48 (s, 1H); 8.66-8.69 (m, 1H).

[0305] Example 34H. (2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25H (0.16 g, 0.28 mmol) was hydrolyzed to give 0.144 g (quantitative yield) of Example 34H as an off-white solid; 1 H NMR (CDCl3) δ 3.65 (dd, J=4.0 Hz, J=9.5 Hz, 1H); 3.82 (dd, J=5.5 Hz, J=9.5 Hz, 1H); 4.11-(dd, J=7.8 Hz, J=8.8 Hz, 1H); 4.33 (s, 2H); 4.50 (d, J=5.0 Hz, 1H); 4.57 (t, J=9.0 Hz, 1H); 4.67 (dd, J=4.0 Hz, J=5.0 Hz, 1H); 4.69 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.75 (t, J=8.0 Hz, 1H); 6.17 (dd, J=9.3 Hz, J=15.8 Hz, 1H); 6.55 (d, J=16.0 Hz, 1H); 7.09-7.12 (m, 2H); 7.19-7.42 (m, 13H).

[0306] Example 34I. 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25I (737 mg, 1.12 mmol) was hydrolyzed to give 640 mg (95%) of Example 34I as an off-white solid. Example 34I showed an H NMR spectrum consistent with the assigned structure. 1 The H NMR spectrum was shown.

[0307] Example 34J. 3(R)-[3(S)-(4(S)-Phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(stil-2-yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the general method of Example 26, 120 mg (0.18 mmol) of Example 25J was hydrolyzed to give 108 mg (98%) of Example 34J as an off-white solid; 1 H NMR (CDCl3) δ 1.22 (s, 3H); 3.25 (dd, J = 3.5 Hz, J = 18.0 Hz, 1H); 3.36 (dd, J = 10.8 Hz, J = 18.2 Hz, 1H); 4.01-(dd, J = 4.0 Hz, J = 10.5 Hz, 1H); 4.05 (dd, J = 3.8 Hz, J = 8.8 Hz, 1H); 4.33 (d, J = 9.0 Hz, 1H); 4.44-4.51(m, 3H); 4.61-4.66 (m, 1H); 4.73 (dd, J = 3.8 Hz, J = 8.8 Hz, 1H); 6.19 (dd, J = 9.0 Hz, J = 16.0 Hz, 1H); 6.74 (d, J = 16.0 Hz, 1H); 7.22-7.54 (m, 13H); 7.65 (s, 1H).

[0308] Example 34K. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(prop-1-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Using the general method of Example 26, 160 mg (0.27 mmol) of Example 25K was hydrolyzed to give 131 mg (90%) of Example 34K as an off-white solid; 11H NMR (CDCl3) δ 1.69 (dd, J = 1 Hz, J = 6.5 Hz, 3H); 3.23 (d, J = 7 Hz, 1H); 3.93 (t, J = 7.3 Hz, 1H); 4.14 - 4.20 (m, 3H); 4.29 (dd, J = 5 Hz, J = 9.5 Hz, 1H); 4.43 (dd, J = 6 Hz, J = 15 Hz, 1H); 4.61 (dd, J = 6.5 Hz, J = 15 Hz, 1H); 4.66 - 4.74 (m, 2H); 5.50 - 5.55 (m, 1H); 5.90 - 5.98 (m, 1H); 7.32 - 7.60 (m, 9H); 8.60 - 8.64 (m, 1H).

[0309] Example 34L. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. Example 25L (166 mg, 0.24 mmol) was hydrolyzed to give 152 mg (quantitative yield) of Example 34L as an off-white solid, which was consistent with the assigned structure 1 and showed an 1H NMR spectrum.

[0310] Example 34M. 2(S)-(Methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25M (875 mg, 1.64 mmol) was hydrolyzed to give 757 mg (97%) of Example 34M as an off-white solid, which was consistent with the assigned structure 1 and showed an 1H NMR spectrum.

[0311] Example 34N. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. Example 25N (38.5 mg, 0.057 mmol) was hydrolyzed to give 35 mg (quantitative yield) of Example 34N as an off-white solid, which was consistent with the assigned structure 1 showed an H NMR spectrum.

[0312] Example 34O. 2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25O (97 mg, 0.18 mmol) was dissolved in methanol / tetrahydrofuran (2.5 mL / 2 mL) and reacted with lithium hydroxide (0.85 mL of a 0.85 M solution in water; 0.72 mmol) at room temperature for 6 hours. The reaction was diluted with 15 mL of dichloromethane and aqueous hydrochloric acid (1 M) was added until the pH of the aqueous layer was 5 (measured with standard pH paper). The organic layer was then separated and evaporated to dryness to give 84 mg (89%) of Example 34O as an off-white solid, which was consistent with the assigned structure 1 showed an H NMR spectrum.

[0313] Example 34P. 2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. Example 25P (200 mg, 0.39 mmol) was hydrolyzed according to the method used for Example 34O to give 155 mg (88%) of Example 34P as an off-white solid, which was consistent with the assigned structure 1 showed an H NMR spectrum.

[0314] Example 34Q. 2(R)-(2-((3-(Trifluoromethyl)benzyl)amino)-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. According to the method used for Example 34O, 150 mg (0.24 mmol) of Example 25Q was hydrolyzed to give 143 mg (97%) of Example 34Q as an off-white solid, which was consistent with the assigned structure. 1 showed an H NMR spectrum.

[0315] Example 34R. 2(R)-(tert-Butoxycarbonylmethyl)-2-[3(RS)-2-thienylmethyl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 290 mg (0.84 mmol) of the β-t-butyl ester α-(3-trifluoromethyl)benzylamide of D-aspartic acid and cinnamaldehyde was combined with 2-thiopheneacetyl chloride and purified by flash column chromatography (70:30 hexane / ethyl acetate) to give 42 mg (8%) of Example 34R, which was consistent with the assigned structure. 1 showed an H NMR spectrum.

[0316] The following compounds were prepared according to the methods described herein:

Chemical formula

Table 11

Chemical formula

Table 12

Chemical formula

Table 13

Chem.

Table 14

Chem.

Table 15

[0317] Examples 36 to 42A shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 27 and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine. All of the enumerated examples were consistent with the specified structures. 1 The 1H NMR spectra were shown.

Chem.

Table 16

[0318] Examples 43 to 86A shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 28 and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine. All of the enumerated examples were consistent with the specified structures. 1 The 1H NMR spectra were shown.

Chem.

Table 17

[0319] Example 86B. Example 63 (44 mg, 0.06 mmol) was dissolved in 4 mL of dichloromethane and reacted with 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) until the reaction was complete as evaluated by TLC (94% dichloromethane / 6% methanol, UV detection). The reaction mixture was quenched with an aqueous sodium sulfite solution, and the dichloromethane layer was washed with a 5% aqueous sodium hydrogen carbonate solution and distilled water. The dichloromethane layer was evaporated to give Example 86B as an off-white solid (35 mg, 78%), which was consistent with the designated structure. 1 The 1H NMR spectrum was shown.

[0320] Examples 121 to 132 shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 30 and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the listed examples were consistent with the designated structure. 1 The 1H NMR spectrum was shown. [Chemical formula] [Table 18]

[0321] Examples 132A to 132B shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34I and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the listed examples were consistent with the designated structure. 1 The 1H NMR spectrum was shown. [Chemical formula] [Table 19]

[0322] Example 132C.2 (S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(4-cyclohexyl)piperazine amide. Example 132C was prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34P and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexylpiperazine. Example 132C showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0323] The compounds shown in the following table were prepared according to the processes described herein.

Chemical formula

Table 20

[0324] Examples 133 to 134G shown in the following table were prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 32 and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the enumerated examples showed an 1 H NMR spectrum that was consistent with the assigned structure.

Chemical formula

Table 21

[0325] Example 134H. Example 134H was prepared according to the procedure of Example 86B, except that Example 133 was replaced with Example 110. Example 134H was obtained as an off-white solid (48 mg, 94%) that was consistent with the assigned structure. 1The 1H NMR spectrum was shown.

[0326] Example 134I.2 (R)-[[4-(Piperidinyl)piperidinyl]carboxymethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 134I was prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with that of Example 32A, and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and it is consistent with the specified structure 1 The 1H NMR spectrum was shown.

[0327] The compounds shown in the following table were prepared according to the processes described herein.

Chemical formula

Table 22

[0328] Example 222.2 (R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. Example 222 was prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with that of Example 34B, and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 222 is consistent with the specified structure 1 The 1H NMR spectrum was shown.

[0329] Example 223. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. Example 223 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34C and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 223 showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0330] Example 224

Chemical formula

[0331] Example 225

Chemical formula

[0332] Example 225 hydrochloride. Example 225 (212.5 mg) was dissolved in 30 mL of dry Et2O. Dry HCl gas was bubbled through this solution, and an off-white precipitate rapidly formed. When the formation of the precipitate was no longer observed (after about 5 minutes), the addition of HCl was stopped. The solid was isolated by suction filtration, washed twice with 15 mL of dry Et2O, and dried to give 213.5 mg (96% yield) of an off-white solid; C 43 H 49 Calculated for C28H34ClF3N5O5: C, 63.89; H, 6.11; N, 8.66; Cl, 4.39; Found: C, 63.41; H, 5.85; N, 8.60; Cl, 4.86.

[0333] Example 225A. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. Example 225A was prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34C and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225A showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0334] Example 225B. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. Example 225B was prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34D and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225B showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0335] Example 225C. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. Example 225C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34L and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 225C showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0336] Example 225D. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. Example 225D was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34N and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 225D showed an 1 H NMR spectrum that was consistent with the assigned structure.

[0337] Examples 87 to 120E shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 29 and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine. All of the enumerated examples showed an 1 H NMR spectrum that was consistent with the assigned structure. [Chemical formula] [Table 23]

[0338] Example 120F. Example 120F was prepared using the procedure of Example 86B, except that Example 63 was replaced with Example 110, to give an off-white solid (54.5 mg, 98%). Example 120F was consistent with the assigned structure 1 and showed an 1H NMR spectrum.

[0339] Example 120G. N-(3-Trifluoromethylbenzyl)-2(S)-(methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetamide. Example 120G was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34M, and it was consistent with the assigned structure 1 and showed an 1H NMR spectrum.

[0340] Example 35. N-(3-Trifluoromethylbenzyl)-2(S)-[4-(2-phenylethyl)piperazinyl-carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetamide. The title compound was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with the carboxylic acid of Example 29 and 3-(trifluoromethyl)benzylamine was replaced with 4-(2-phenylethyl)piperazine; 11H NMR (CDCl3) δ 2.21 - 2.23 (m, 1H); 2.25 - 2.45 (m, 6H); 2.52 - 2.63 (m, 3H); 2.72 - 2.82 (m, 2H); 3.42 - 3.48 (m, 2H); 3.52 - 3.58 (m, 1H); 4.13 - 4.18 (m, 1H); 4.26 (dd, J = 5.1 Hz, J = 8.3 Hz, 1H); 4.29 (d, J = 5.0 Hz, 1H); 4.44 (dd, J = 6.0 Hz, J = 15.0 Hz, 1H); 4.54 (dd, J = 6.2 Hz, J = 14.9 Hz, 1H); 4.61 - 4.68 (m, 2H); 4.70 - 4.75 (m, 1H); 6.27 (dd, J = 9.6 Hz, J = 15.8 Hz, 1H); 6.73 (d, J = 15.8 Hz, 1H); 7.16 - 7.60 (m, 19H); 8.07 - 8.12 (m, 1H); FAB + (M + H) + / z 794; C 45 H 46 Elemental analysis calculated for C41H35F3N5O5: C, 68.08; H, 5.84; N, 8.82; Found: C, 67.94; H, 5.90; N, 8.64.

[0341] Examples 141 - 171 shown in the following table were prepared using the procedure of Example 6, except that N - benzyloxycarbonyl - D - aspartic acid β - t - butyl ester monohydrate was replaced with that of Example 34 and 3 - (trifluoromethyl) benzylamine was replaced with the appropriate amine. All of the enumerated examples showed 1 1 1H NMR spectra that were consistent with the specified structures.

Chemical Structure

Table 24

[0342] Examples 172 to 221R shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34A and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the enumerated examples were consistent with the specified structure. 1 showed an H NMR spectrum.

Chemical formula

Table 25

[0343] The compounds shown in the following table were prepared according to the process described herein.

Chemical formula

Table 26

[0344] Examples 135 to 140 shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 33 and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the enumerated examples were consistent with the specified structure. 1 showed an H NMR spectrum.

Chemical formula

Table 27

[0345] Example 140A.2 (R)-(2-((3-(Trifluoromethyl)benzyl)amino)-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetate N-(4-cyclohexyl)piperazine amide. Example 140A was prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34Q and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexyl-piperazine, and it is consistent with the specified structure. 1 The 1H NMR spectrum was shown.

[0346] Examples 226 to 230C shown in the following table were prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34F and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All of the enumerated examples are consistent with the specified structure. 1 The 1H NMR spectrum was shown. [Chemical formula] [Table 28]

[0347] The following compounds were prepared according to the methods described herein: [Chemical formula] [Table 29]

[0348] Example 86C.2(S)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 86C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with that of Example 28A and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and it is consistent with the designated structure 1 showed an H NMR spectrum.

[0349] Example 231.2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2'-methoxystyryl-2-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 231 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with that of Example 34G and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and it is consistent with the designated structure 1 showed an H NMR spectrum.

[0350] Examples 232 to 233A shown in the following table were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with that of Example 34H and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine. All the examples listed are consistent with the designated structure 1 showed an H NMR spectrum. [Chemical formula] [Table 30]

[0351] Example 234. (2RS)-[4-(Piperidinyl)piperidinylcarbonyl]-2-methyl-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. [Chem.]

[0352] Example 37 (50 mg, 0.067 mmol) in tetrahydrofuran (4 mL) was treated successively with sodium hydride (4 mg, 0.168 mmol) and methyl iodide (6 μL, 0.094 mmol) at -78 °C. The resulting mixture was slowly warmed to ambient temperature and evaporated. The resulting residue was partitioned between dichloromethane and water, and the organic layer was evaporated. The resulting residue was purified by silica gel chromatography (95:5 chloroform / methanol) to give 28 mg (55%) of the title compound as an off-white solid; MS (ES + ): m / z = 757 (M + ).

[0353] Example 234A. 4-(Piperidinyl)-piperidinyl 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(stil-2-yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl)propanoic acid. [Chem.]

[0354] The title compound was prepared in quantitative yield using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with the carboxylic acid of Example 34J and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine; MS (m+H) + 772.

[0355] The compounds shown in the following table were prepared according to the method described in this specification: [Chemical formula] [Table 31]

[0356] Example 235. 2(S)-[[(1-Benzylpiperidin-4-yl)amino]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 235 was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 63 (50 mg, 0.064 mmol), and 40 mg (80%) of Example 235 was obtained as an off-white solid. Example 235 was consistent with the specified structure 1 showed an H NMR spectrum.

[0357] Example 236. (2S)-[(4-Cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 236 was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 110 (50 mg, 0.065 mmol), and 42 mg (84%) of Example 236 was obtained as an off-white solid. Example 236 was consistent with the specified structure 1 showed an H NMR spectrum.

[0358] Example 236A. (2S)-[(4-Cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-one-1-yl]acetic acid N-[(R)-1,2,3,4-tetrahydronaphth-1-yl]amide. Example 236A was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with Example 215 (76 mg, 0.10 mmol), and 69 mg (90%) of Example 236A was obtained as an off-white solid. Example 236A showed an 1 H NMR spectrum consistent with the assigned structure.

[0359] Example 237. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(prop-1-yl)azetidin-2-one-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 237 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with Example 34K and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 237 showed an 1 H NMR spectrum consistent with the assigned structure.

[0360] Example 238. N-[4-[2-(Piperid-1-yl)ethyl]piperidin-1-yl]amide of (2S)-(benzylthiomethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one-1-yl]acetic acid. This example was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate was replaced with the corresponding benzyl-protected cysteine analog, and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperid-1-yl)ethyl]piperidine.

[0361] Step 1. N-t-butyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidinamide. From N-t-butyloxycarbonyl-(S)-benzyl-N-(t-butyloxycarbonyl)-D-cysteine (0.289 g, 0.93 mmol) and 4-[2-(1-piperidyl)ethyl]piperidine (0.192 g, 0.98 mmol) in dichloromethane (20 mL), 0.454 g (quantitative yield) of Example X was obtained as an off-white solid. 1 H NMR (CDCl3) δ 0.89-1.15 (m, 2H); 1.39-1.44 (m, 16H); 1.54-1.61 (m, 4H); 1.62-1.71 (m, 1H); 2.21-2.35 (m, 5H); 2.49-2.58 (m, 2H); 2.66-2.74 (m, 1H); 2.79-2.97 (m, 1H); 3.67-3.76 (m, 3H); 4.48-4.51 (m, 1H); 4.72-4.75 (m, 1H); 5.41-5.44 (m, 1H); 7.19-7.34 (m, 5H).

[0362] Step 2. (S)-(Benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)piperidine amide dihydrochloride. N-t-Butyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidine amide (0.453 g, 0.93 mmol) was reacted overnight with acetyl chloride (0.78 mL, 13.80 mmol) in anhydrous methanol (15 mL). The title compound was obtained as an off-white solid (0.417 g, 97%) by evaporating the reaction mixture until dry. 1 H NMR (CD3OD) δ 0.94-1.29 (m, 2H); 1.49-1.57 (m, 1H); 1.62-1.95 (m, 10H); 2.65-2.80 (m, 2H); 2.81-2.97 (m, 4H); 3.01-3.14 (m, 2H); 3.50-3.60 (m, 3H); 3.81-3.92 (m, 2H); 4.41-4.47 (m, 2H); 7.25-7.44 (m, 5H).

[0363] Step 3. Using the general procedure described herein, an imine prepared from (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidine amide, dihydrochloride (0.417 g, 0.90 mmol) and cinnamaldehyde in the presence of triethylamine (0.26 mL, 1.87 mmol) was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1), and 0.484 g (76%) of Example 238 was obtained as an off-white solid after recrystallization from dichloromethane / hexane. 11H NMR (CDCl3) δ 0.89 - 1.06 (m, 2H); 1.40 - 1.44 (m, 5H); 1.57 - 1.67 (m, 6H); 2.25 - 2.43 (m, 6H); 2.45 - 2.59 (m, 2H); 2.71 - 2.88 (m, 2H); 3.55 - 3.70 (m, 3H); 4.11 - 4.17 (m, 1H); 4.37 - 4.47 (m, 2H); 4.54 - 4.61 (m, 1H); 4.64 - 4.69 (m, 1H); 4.76 - 4.84 (m, 2H); 6.05 - 6.19 (m, 1H); 6.66 - 6.71 (m, 1H); 7.12 - 7.40 (m, 15H).

[0364] The following compounds are described. [Chemical formula] [Table 32] TIFF0007699634000094.tif80162 Example 266 (AVN576) [Chemical formula]

[0365] The following compounds are described. [Chemical formula] [Table 33]

[0366] The following compounds are described. [Chemical formula] [Table 34]

[0367] The following compounds are described.

Chem.

Table 35

[0368] The following compounds are described.

Chem.

Table 36

[0369] The following compounds are described.

Chem.

Table 37

[0370] The following table shows the corresponding (M+H) + parent ions, which are further characterized by FAB + mass spectrometry used for observation.

Table 38

Claims

1. An orally administrable pharmaceutical composition for treating cognitive impairment, learning disorder, or memory disorder in traumatic brain injury in a host animal, wherein the pharmaceutical composition comprises a selective vasopressin V1a receptor antagonist, and the selective vasopressin V1a receptor antagonist has the formula: 【Chemical 1】 and 【Chemical 2】 (wherein, A and A' are each independently selected from amides, each amide being of the formula C(O)NHX or of the formula C(O)NR １４ X amide, or an amide of a nitrogen-containing heterocycle optionally substituted and bonded at the nitrogen position; R １４ is selected from alkyl and benzyl; X is alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C １ ~C ４ alkyl), and R ６ R ７ N-(C ２ ~C ４ alkyl) is selected from; and each heterocyclyl is independently selected; R ６ is independently selected from hydrogen or alkyl; and R ７ is independently, in each case, selected from alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R ６ and R ７ together with the nitrogen atom to which they are attached form an optionally substituted heterocycle; Q is oxygen or sulfur; R ５” is an optionally substituted arylalkyl; n is 1 or 2; R １ is hydrogen; R ２ is hydrogen ‘‘ ; R ３ is the formula: [Chemical Formula 3] (wherein, R １０ and R １１ are each independently selected from hydrogen and optionally substituted aryl); and R ４ is an optionally substituted arylalkyl or an optionally substituted arylalkenyl) A pharmaceutical composition selected from the compounds of formula and pharmaceutically acceptable salts thereof.

2. The antagonist is selected from the compounds of the formula: 【Chemical Formula 4】 (wherein, A is of the formula C(O)NHX or the formula C(O)NR １４ X; and A' is an amide of a nitrogen-containing heterocyclic ring bonded at the nitrogen position, independently selected and optionally substituted) The pharmaceutical composition according to claim 1, selected from the compounds of formula and pharmaceutically acceptable salts thereof.

3. R １４ The pharmaceutical composition according to claim 2, wherein R is alkyl; and X is optionally substituted aryl or optionally substituted arylalkyl.

4. A is of the formula 【Chemical Formula 5】 (wherein, R Ｎ is hydrogen or optionally substituted alkyl; R ａ is hydrogen or optionally substituted alkyl; R Ａｒ is hydrogen or one or more aryl substituents) The pharmaceutical composition according to claim 2.

5. The antagonist is selected from the compounds of the formula: 【Chemical Formula 6】 (wherein, A is an amide of a nitrogen-containing heterocyclic ring bonded at the nitrogen position, independently selected and optionally substituted) The pharmaceutical composition according to claim 1, selected from the compounds of formula and pharmaceutically acceptable salts thereof.

6. R ５” is an optionally substituted aryl(C ２ ~C ４ alkyl), the pharmaceutical composition according to claim 5.

7. R ５” The pharmaceutical composition according to claim 5, wherein R is benzyl which is optionally substituted.

8. Each nitrogen-containing heterocyclic ring is independently selected from pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, and 1,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted. The pharmaceutical composition according to any one of claims 1 to 7.

9. Each nitrogen-containing heterocyclic ring is R １０ 、R １２ 、R ６ R ７ N-, or R ６ R ７ N-(C １ ~C ４ alkyl) and is independently selected from piperidinyl and piperazinyl substituted with; R １２ is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aroyl, etc., The pharmaceutical composition according to claim 8.

10. The substituted piperidine or piperazine is substituted with heterocyclyl, heterocyclylalkyl, optionally substituted aryl, and optionally substituted arylalkyl. The pharmaceutical composition according to claim 9.

11. The substituted piperidine or piperazine is of the formula: 【Table 1】 The pharmaceutical composition according to claim 9.

12. n is 1. The pharmaceutical composition according to any one of claims 1 to 7.

13. R ４ is given by the formula: 【Chemical Formula 7】 (wherein Y is halogen, and Y １ is hydrogen or one or more aryl substituents), the pharmaceutical composition according to any one of claims 1 to 7.

14. The antagonist is [Chemical Formula 8] [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 The pharmaceutical composition according to claim 1, selected from the group consisting of and pharmaceutically acceptable salts thereof.

15. The antagonist is 【Chemical Formula 9】 [Chemical] The pharmaceutical composition according to claim 1, selected from the group consisting of and combinations thereof.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the traumatic brain injury (TBI) is blast TBI, repetitive mild TBI (rmTBI), cerebral edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, ischemic stroke, or concussion.

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