Compositions and methods for treating brain injury

Abstract

The present invention provides compounds and compositions, methods and uses thereof for treating brain damage.

Description

Technical Field

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

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

[0003] Brain injury usually has the common characteristics of brain edema and swelling. Brain edema is usually referred to as secondary injury in TBI, is the main cause after primary injury, and is the main factor leading to morbidity and mortality. Left untreated, brain injury can also lead to severe cognitive, learning and memory disorders. In addition, brain injury can lead to loss of motor function. Brain edema can be caused by brain trauma and other non-traumatic causes, such as ischemic stroke, cancer and inflammation of the brain that can be caused by other diseases or conditions (such as meningitis or encephalitis). A treatment that reduces or prevents the effects of moderate to severe TBI is needed to fill this critical care gap, including closed head non-penetrating moderate TBI caused by a single accident (such as a car accident, a fall, etc.). Therefore, there is currently a demand for compounds, compositions and methods for treating brain injury.

[0004] It has been found that the selective arginine vasopressin V1a receptor (V1aR) antagonists described herein are suitable for treating brain injury. It has also been unexpectedly found that the compounds are effective in treating edema and cognitive, memory and learning deficits caused by brain injury. It should be understood that the compositions, methods and uses described herein are not limited by the source of brain injury, which can actually result from a wide variety of causes, including (but not limited to) head impact, rapid acceleration or deceleration, shock waves, chemotherapy (such as CAR-T therapy), or as a comorbidity with another disease.

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

[0006] It has been unexpectedly discovered that the compounds described herein can be administered systemically, including orally, in therapeutically effective doses in the central nervous system (CNS) without clinically significant adverse effects on blood pressure or cardiovascular function. Summary of the invention

[0007] In one illustrative embodiment of the invention, selective V1aR antagonists and compositions and methods using such vasopressin antagonists are described herein. In another illustrative embodiment, selective V1aR antagonists and compositions and methods using such V1aR antagonists are described herein, which are configured to reach or be capable of producing a CNS concentration in the range of 1 nM to at least about 100 nM after administration to a host animal. In another illustrative embodiment, selective V1aR antagonists and compositions and methods using such V1aR antagonists are described herein, which are configured to reach or be capable of producing a CNS concentration in the range of 1 nM to at least about 10 nM, or at least about 1 nM after administration to a host animal. In another illustrative embodiment, highly potent and selective V1aR antagonists and compositions and methods using such V1aR antagonists are described herein, which are configured to reach or be capable of producing a CNS concentration of at least about 100 pM, at least about 10 pM, or at least about 1 pM after administration to a host animal.

[0008] It has been discovered herein that brain damage can be treated with the selective ViaR antagonists described herein. In one embodiment, the vasopressin receptor antagonist has the formula:

[0009]

[0010] and pharmaceutically acceptable salts thereof; wherein

[0011] A is a carboxylic acid, an ester or an amide;

[0012] B is a carboxylic acid, an ester or an amide; or B is an alcohol or a thiol, or a derivative thereof, including an alkyl, aryl or acyl derivative thereof;

[0013] R 1 is hydrogen or C 1 -C 6 alkyl;

[0014] R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl or a group selected from -CO 2 R 8 、-CONR 8 R 8 ' and -NR 8 (COR 9 ) composed of a substituent group; wherein R 8 and R 8 ' are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; or R 8 and R 8 ' together with the connecting nitrogen atom form a heterocyclic group; and wherein R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and R 8 R 8 'N-(C 1 -C 4 alkyl);

[0015] R 3 is amino, amide, acylamide or urea, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclic group attached to a nitrogen atom; and

[0016] R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl or optionally substituted arylalkynyl.

[0017] In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the composition includes a therapeutically effective amount of one or more compounds to treat a host animal with brain damage. It should be understood that the composition may include other components and / or ingredients, including (but not limited to) other therapeutically active compounds and / or one or more carriers, diluents, excipients and the like, and combinations thereof. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating host animals with brain damage are also described herein. In one aspect, the method includes the step of administering one or more of the compounds and / or compositions described herein to the host animal. In another aspect, the method includes administering a therapeutically effective amount of one or more of the compounds and / or compositions described herein to treat brain damage in the host animal. In another embodiment, the use of the compounds and pharmaceutical compositions is also described herein, which is used to manufacture a drug for treating a host animal with brain damage. In one aspect, the drug includes a therapeutically effective amount of one or more of the compounds and / or compositions described herein.

[0018] It is understood that the compounds described herein can be used alone or in combination with other compounds useful for treating brain injury, including those compounds that can be therapeutically effective through the same or different modes of action. In addition, it is understood that the compounds described herein can be used in combination with other compounds administered to treat other symptoms of brain injury, such as pain, inflammation, nausea, vomiting, blurred vision, syncope, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The results of the novel object recognition test are shown; control group (CG), injury group (IG), treatment group (TG); *(p<0.05), **(p<0.01), ***(p<0.001).

[0020] Figure 2A The results of the Barnes Maze Test are shown; control group (CG), injury group (IG), treatment group (TG); *(p<0.05), **(p<0.01).

[0021] Figure 2B The results of the Barnes maze test broken down by day are shown; control group (●), injury group (○), treatment group (□); *(p<0.05), **(p<0.01).

[0022] Figure 3 Shown is the comparison of resting-state functional connectivity between the injury group and the treatment group.

[0023] Figure 4AA glass brain showing 3D organization exhibiting the low connectivity observed in region G of the injury group.

[0024] Figure 4B Shown is a 3D organized glass brain exhibiting the high connectivity observed in region G of the treatment group.

[0025] Figure 5 Scans and volumes of the lateral ventricles are shown; control group (CG), injured group (IG), treated group (TG).

[0026] Figure 6 Shown is a 3D organized glass brain exhibiting the low connectivity observed in region M of the injured and treated groups. DETAILED DESCRIPTION

[0027] Described herein are uses of one or more ViaR antagonists for treating brain injury. The compounds described herein may have the potential to greatly improve the lives of those suffering from brain injury, including but not limited to traumatic brain injury (TBI) (including blast TBI), cerebral edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, concussion, and falls.

[0028] Several illustrative embodiments of the present invention are described by the following description:

[0029] A method for treating brain damage in a host animal is described, wherein the method comprises administering to the host animal a composition comprising one or more selective ViaR antagonists described herein.

[0030] A method for treating brain injury in a host animal is described, wherein the brain injury is caused at least in part by impact, traumatic brain injury (TBI), mild TBI, blast TBI, cerebral edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, ischemic stroke, concussion and fall injury or a combination thereof, and wherein the method comprises administering to the host animal a composition comprising one or more selective ViaR antagonists described herein.

[0031] The method of any of the preceding items, wherein the brain damage is characterized by edema (such as intraventricular edema), cognitive deficits, learning deficits, memory deficits, or motor deficits, or a combination of any of the preceding.

[0032] A method as in any of the preceding items, wherein one or more of the antagonists are selected from compounds of the formula:

[0033]

[0034] and pharmaceutically acceptable salts thereof, wherein

[0035] A is a carboxylic acid, an ester or an amide;

[0036] B is a carboxylic acid, an ester or an amide; or B is an alcohol or a thiol, or a derivative thereof;

[0037] R 1 is hydrogen or C 1 -C 6 alkyl;

[0038] R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl or a group selected from -CO 2 R 8 、-CONR 8 R 8 ' and -NR 8 (COR 9 ) composed of a substituent group; wherein R 8 and R 8 ' are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; or R 8 and R 8 ' together with the connecting nitrogen atom form a heterocyclic group; and wherein R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and R 8 R 8 'N-(C 1 -C 4 alkyl);

[0039] R 3 is amino, amide, acylamide or urea, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclic group attached to a nitrogen atom; and

[0040] R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl or optionally substituted arylalkynyl.

[0041] A method as in any of the preceding items, wherein one or more of the antagonists are selected from compounds of the formula:

[0042]

[0043] and pharmaceutically acceptable salts thereof, wherein

[0044] A and A' are each independently selected from -CO 2 H or its ester or amide derivatives;

[0045] n is an integer selected from 0 to about 3;

[0046] R 1 is hydrogen or C 1 -C 6 alkyl;

[0047] R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl or a group selected from -CO 2 R 8 、-CONR 8 R 8 ' and -NR 8 (COR 9 ) composed of a substituent group; wherein R 8 and R 8 ' are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; or R 8 and R 8 ' together with the connecting nitrogen atom to form a heterocyclic ring; and wherein R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and R 8 R 8 'N-(C 1 -C 4 alkyl);

[0048] R 3 is amino, amide, acylamide or urea, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclic group attached to a nitrogen atom; and

[0049] R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl or optionally substituted arylalkynyl.

[0050] A method as in any of the preceding items, wherein one or more of the antagonists are selected from compounds of the formula:

[0051]

[0052] and pharmaceutically acceptable salts thereof, wherein

[0053] A is -CO 2 H, or an ester or amide derivative thereof;

[0054] Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof;

[0055] n is an integer from 1 to 3;

[0056] R 1 , R 2 , R 3 and R 4 is as defined in Formula I; and

[0057] R 5" is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.

[0058] A method as in any of the preceding items, wherein A is -CO 2 R 5 ; where R 5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aralkyl, heterocyclyl, heterocyclyl (C 1 -C 4 Alkyl) and R 6 R 7 N-(C 2 -C 4 alkyl).

[0059] The method of any of the preceding items, wherein A is a monosubstituted amide group, a disubstituted amide group, or an optionally substituted nitrogen-containing heterocyclic amide group.

[0060] A method as described in any of the preceding items, wherein the heterocyclyl is independently selected from tetrahydrofuranyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidine; wherein the morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidine is an optionally present N-substituted C 1 -C 4 Alkyl or optionally substituted aryl (C 1 -C 4 It is to be understood that at each occurrence of the various embodiments described herein, the heterocyclyl group is independently selected at each instance.

[0061] A method as in any of the preceding clauses, wherein R 6 are independently selected from hydrogen or alkyl; and R 7 is independently selected at each occurrence from alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl. A method as in any of the preceding items, wherein R 6 and R7 Together with the connecting nitrogen atom, it forms an optionally substituted heterocyclic ring, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and homopiperazinyl; wherein the piperazinyl or homopiperazinyl is also an optionally present N-substituted R 13 ; where R 13 is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkyl, and optionally substituted aroyl. It is also understood that at each occurrence in the various embodiments described herein, R 6 and R 7 Each is selected independently in each case.

[0062] A method as in any of the preceding clauses, wherein A and / or A' are amides. A method as in any of the preceding clauses, wherein A and A' are both amides. A method as in any of the preceding clauses, wherein A and / or A' are amides of secondary amines, also referred to herein as secondary amides. A method as in any of the preceding clauses, wherein A and A' are both secondary amides. It is understood that secondary amides include amides of cyclic amines attached to nitrogen.

[0063] A method as in any of the preceding items, wherein A is an amide. A method as in any of the preceding items, wherein A is an amide of a secondary amine, also referred to herein as a secondary amide.

[0064] A method as in any of the preceding items, wherein the antagonist is a diester, acid-ester or diacid, including pharmaceutically acceptable salts thereof, wherein each of A and A' is independently selected. A method as in any of the preceding items, wherein the antagonist is an ester-amide, wherein one of A and A' is an ester and the other is an amide. A method as in any of the preceding items, wherein the antagonist is a diamide, wherein each of A and A' is independently selected from a monosubstituted amide group, a disubstituted amide group and an optionally substituted nitrogen-containing heterocyclic amide group.

[0065] A method as in any of the preceding items, wherein A and / or A' is an independently selected monosubstituted amide group of the formula C(O)NHX-, wherein X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 Alkyl), R 6 R 7 N- and R 6 R 7 N-(C 2 -C 4 alkyl), wherein each heterocyclyl group is independently selected.

[0066] A method as in any of the preceding items, wherein A and / or A' is of the formula C(O)NR14 X-is an independently selected disubstituted amide group, wherein R 14 is selected from the group consisting of hydroxy, alkyl, alkoxycarbonyl and benzyl; and X is selected from the group consisting of alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 Alkyl), R 6 R 7 N- and R 6 R 7 N-(C 2 -C 4 alkyl), wherein each heterocyclyl group is independently selected.

[0067] A method as in any of the preceding items, wherein A and / or A' is an amide of an independently selected optionally substituted nitrogen-containing heterocycle attached to a nitrogen. Illustrative nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperidonyl, 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 optionally present substituents include groups R as defined herein 10 , R 12 , R 6 R 7 N- and R 6 R 7 N-(C 1 -C 4 alkyl).

[0068] A method as in any of the preceding items, wherein A and / or A' is independently an optionally substituted 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl attached to the nitrogen.

[0069] A method as in any of the preceding clauses, wherein A and / or A' is independently an optionally substituted 1,2,3,4-tetrahydroisoquinolin-2-yl attached to nitrogen.

[0070] A method as in any of the preceding items, wherein A and / or A' is an independently selected amide of an optionally substituted piperidinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-、R6 R 7 N-alkyl (including R 6 R 7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 alkyl).

[0071] A method as in any of the preceding clauses, wherein A and / or A' is an independently selected piperidinyl substituted at the 4-position and attached to the nitrogen.

[0072] A method as in any of the preceding items, wherein A and / or A' is an independently selected amide of an optionally substituted piperazinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-, R 6 R 7 N-alkyl (including R 6 R 7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 A method as in any of the preceding clauses, wherein A and / or A' is an independently selected piperazinyl substituted at the 4-position and attached to the nitrogen.

[0073] A method as in any of the preceding items, wherein A and / or A' is an independently selected amide of an optionally substituted homopiperazinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-、R 6 R 7 N-alkyl (including R 6 R7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 alkyl). A method as in any of the preceding items, wherein A and / or A' is an independently selected homopiperazinyl substituted at the 4-position and attached to the nitrogen. A method as in any of the preceding items, wherein A and / or A' is an independently selected homopiperazinyl substituted at the 4-position and attached to the nitrogen. 1 -C 4 alkyl) and attached to the nitrogen.

[0074] A method as in any of the preceding items, wherein A' is a monosubstituted amide group, a disubstituted amide group or an optionally substituted nitrogen-containing heterocyclic amide group. A method as in any of the preceding items, wherein A' is -CO 2 R 5 '; where R 5 ' is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aralkyl, heterocyclic, heterocyclic (C 1 -C 4 Alkyl) and R 6 R 7 N-(C 2 -C 4 alkyl); wherein the heterocyclyl is independently selected at each occurrence from tetrahydrofuranyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidine; wherein the morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidine is optionally C 1 -C 4 Alkyl N-substituted or optionally substituted aryl (C 1 -C 4 alkyl). A method as in any of the preceding items, wherein R 5 ' is an optionally substituted heterocyclylalkyl or an optionally substituted aminoalkyl, including R 6 R 7 N-(C 2 -C 4 alkyl).

[0075] A method as in any of the preceding clauses, wherein A has the formula:

[0076]

[0077] Where R N is hydrogen or an optionally substituted alkyl group or a group forming an amide prodrug; R ais hydrogen or optionally substituted alkyl; and R Ar is hydrogen or one or more aryl substituents such as, but not limited to, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, nitro, and the like. A method as in any of the preceding items, wherein R N , R a and R Ar At least one of is not hydrogen. A method as in any of the preceding items, wherein R N and R a In another embodiment, A has the formula:

[0078]

[0079] Where R N , R a and R Ar is as defined herein.

[0080] A method as in any of the preceding items, wherein A is selected from monosubstituted amide, disubstituted amide and optionally substituted nitrogen-containing heterocyclic amide. A method as in any of the preceding items, wherein A is an amide of optionally substituted 1-tetrahydronaphthylamine.

[0081] A method as in any of the preceding items, wherein A and / or A' is a monosubstituted amide group of the formula C(O)NHX, wherein X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 Alkyl), R 6 R 7 N- and R 6 R 7 N-(C 2 -C 4 alkyl), wherein each heterocyclyl group is independently selected.

[0082] A method as in any of the preceding items, wherein A and / or A' is of the formula C(O)NR 14 X is a disubstituted amide group, wherein R 14 is selected from the group consisting of hydroxy, alkyl, alkoxycarbonyl and benzyl; and X is selected from the group consisting of alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 Alkyl), R 6 R 7 N- and R 6 R 7 N-(C 2 -C 4alkyl), wherein each heterocyclyl group is independently selected.

[0083] A method as in any of the preceding items, wherein A and / or A' is an amide of an optionally substituted nitrogen-containing heterocycle attached to a nitrogen. Illustrative nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperidonyl, 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 optionally present substituents include the group R as defined herein 10 , R 12 , R 6 R 7 N- and R 6 R 7 N-(C 1 -C 4 alkyl).

[0084] A method as in any of the preceding items, wherein A is optionally substituted 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl attached to the nitrogen.

[0085] A method as in any of the preceding clauses, wherein A is optionally substituted 1,2,3,4-tetrahydroisoquinolin-2-yl attached to nitrogen.

[0086] A method as in any of the preceding items, wherein A and / or A' is an amide of an optionally substituted piperidinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-、R 6 R 7 N-alkyl (including R 6 R 7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 A method as in any of the preceding clauses, wherein A and / or A' is piperidinyl substituted at the 4-position and attached to nitrogen.

[0087] The method of any of the preceding items, wherein A and / or A' is an amide of an optionally substituted piperazinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-、R 6 R 7 N-alkyl (including R 6 R 7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 A method as in any of the preceding clauses, wherein A and / or A' is piperazinyl substituted at the 4-position and attached to the nitrogen.

[0088] A method as in any of the preceding items, wherein A and / or A' is an amide of an optionally substituted homopiperazinyl group attached to a nitrogen. Illustrative optionally present substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkoxyalkyl (including (hydroxy (C 2 -C 4 Alkoxy))-(C 2 -C 4 Alkyl)), R 6 R 7 N-、R 6 R 7 N-alkyl (including R 6 R 7 N-(C 1 -C 4 alkyl)), benzhydryl, optionally substituted aryl, optionally substituted aryl (C 1 -C 4 alkyl) and piperidin-1-yl (C 1 -C 4 alkyl). A method as in any of the preceding items, wherein A and / or A' is homopiperazinyl substituted at the 4-position and attached to nitrogen. A method as in any of the preceding items, wherein A and / or A' is homopiperazinyl substituted at the 4-position and attached to nitrogen. 1 -C 4 alkyl) and attached to the nitrogen.

[0089] A method as in any of the preceding clauses, wherein A and / or A' is an amide of a heterocycle attached to nitrogen, wherein the heterocycle is substituted with heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl.

[0090] A method as in any of the preceding items, wherein A and / or A' is an amide of optionally substituted benzyl, optionally substituted 1-naphthylmethyl or optionally substituted 2-naphthylmethylamine. Substituents that may be present 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, 4-methyl, and the like.

[0091] A method as in any of the preceding items, wherein A and / or A' is an amide of an optionally substituted benzyl-N-methylamine. In another embodiment, A in formula (I) or (II) is an amide of an optionally substituted benzyl-N-butylamine (including n-butyl and tert-butyl). A method as in any of the preceding items, wherein A is an amide of an optionally substituted benzyl-N-benzylamine. Optionally present substituents include, but are not limited to, 2,3-dichloro, 3,5-dichloro, 3-bromo, 3-trifluoromethyl, 3-chloro, 3-methyl and the like.

[0092] A method as in any of the preceding items, wherein A and / or A' is an amide of optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl or 1-phenylbenzylamine. A method as in any of the preceding items, wherein A and / or A' is an amide of optionally substituted 1-phenylethyl, 2-phenylethyl, 2-phenylpropyl, 1-phenylbenzylamine-N-methylamine. A method as in any of the preceding items, wherein A and / or A' is an amide of optionally substituted 2-phenyl-β-alanine or a derivative thereof, 1-phenylpropanolamine and the like. Optionally present substituents include, but are not limited to, 3-trifluoromethoxy, 3-methoxy, 3,5-dimethoxy, 2-methyl and the like.

[0093] A method as described in any one of the preceding items, wherein A and / or A' is an amide of an optionally substituted 1-phenylcyclopropyl, 1-phenylcyclopentyl or 1-phenylcyclohexylamine. Optionally present substituents include, but are not limited to, 3-fluoro, 4-methoxy, 4-methyl, 4-chloro, 2-fluoro and the like.

[0094] A method as in any of the preceding items, wherein A and / or A' is an amide of an optionally substituted heteroarylmethylamine, including but not limited to 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like. Optionally present substituents include but are not limited to 5-methyl, 3-chloro, 2-methyl, and the like.

[0095] A method as in any of the preceding items, wherein A and / or A' is an amide of a partially saturated bicyclic aromatic group, including but not limited to 1-, 2-, 4- and 5-indanamine, 1- and 2-tetrahydronaphthylamine, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like, each of which is optionally substituted.

[0096] A method as in any of the preceding items, wherein A and / or A' is an amide of a substituted piperidine or piperazine. The substituents of the piperidine or piperazine include heterocyclyl, heterocyclylalkyl, optionally substituted aryl, and optionally substituted aralkyl. Illustrative piperidines and piperazines include the following formulae:

[0097]

[0098] A method as in any of the preceding items, wherein A' is an amide of a substituted heterocycle attached to a nitrogen. Substituents include alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and aralkyl. A method as in any of the preceding items, wherein A' is an amide of a heterocycle attached to a nitrogen substituted with an alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl.

[0099] A method as in any of the preceding items, wherein A' is an amide of an optionally substituted arylheterocyclic amine, arylalkylheterocyclic amine, heterocyclylalkylamine or heteroarylalkylamine. A method as in any of the preceding items, wherein A' is an amide of a piperidin-1-ylpiperidine or a piperidin-1-ylalkylpiperidine. In another embodiment, alkyl is C 1 -C 2 alkyl.

[0100] A method as in any of the preceding clauses, wherein A is an amide of a substituted piperidine or piperazine.

[0101] A method as in any of the preceding items, wherein B is an alcohol or a thiol, or a derivative thereof, including an alkyl, aryl or acyl derivative thereof.

[0102] A process as in any of the preceding clauses, wherein Q is oxygen or sulfur.

[0103] A method as in any of the preceding clauses, wherein R 5" is an optionally substituted aralkyl group.

[0104] A method as in any of the preceding clauses, wherein R 5" is an optionally substituted aryl group (C 2 -C 4 alkyl). A method as in any of the preceding items, wherein R 5" is an optionally substituted aryl group (C 1 -C 2 alkyl). A method as in any of the preceding items, wherein R 5" is an optionally substituted benzyl group. A method as in any one of the preceding items, wherein R 5" is an optionally substituted alkyl group.

[0105] A method as in any of the preceding clauses, wherein n is 1 or 2. A method as in any of the preceding clauses, wherein n is 1.

[0106] A method as in any of the preceding clauses, wherein R 2 is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl or a group selected from -CO 2 R 8 and-CONR 8 R 8 'A substituent group consisting of 8 and R 8 ' are each independently selected from hydrogen and alkyl. A method as in any of the preceding items, wherein R 2 is hydrogen or alkyl. A method as in any of the preceding items, wherein R 2 For hydrogen.

[0107] A method as in any of the preceding clauses, wherein R 1 is hydrogen. A method as in any of the preceding items, wherein R 1 A method as in any one of the preceding items, wherein R 1 and R 2 All are hydrogen.

[0108] A method as in any of the preceding clauses, wherein R 3 Has the following forms:

[0109]

[0110] Where R 10 and R 11R is each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylalkoxy, optionally substituted aralkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R 12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkyl, optionally substituted aroyl, and the like.

[0111] A method as in any of the preceding clauses, wherein R 3 Has the following forms:

[0112]

[0113] Where R 10 , R 11 and R 12 As defined herein.

[0114] A method as in any of the preceding clauses, wherein R 3 Has the following forms:

[0115]

[0116] Where R 10 , R 11 and R 12 As defined herein.

[0117] A method as in any of the preceding clauses, wherein R 3 Has the following formula:

[0118]

[0119] Where R 10 and R 11 As defined herein.

[0120] A method as in any of the preceding clauses, wherein R 3 Has the following formula:

[0121]

[0122] Where R 10 As defined herein.

[0123] A method as in any of the preceding clauses, wherein R 10 is alkyl, aryl or aralkyl, each of which is optionally substituted; or wherein R 10 is an optionally substituted aryl group.

[0124] A method as in any of the preceding clauses, wherein R4 Has the following formula:

[0125]

[0126] wherein Y is an electron withdrawing group, such as a halogen group, and Y 1 is hydrogen or one or more aryl substituents such as, but not limited to, halo, hydroxy, amino, nitro, optionally substituted alkyl, optionally substituted alkoxy, and the like. It should be understood that the double bonds in the formula may be all or substantially all (E), all or substantially all (Z), or a mixture thereof. A method as in any of the preceding items, wherein the double bonds in the formula are all or substantially all (E). A method as in any of the preceding items, wherein R 4 Has the following formula:

[0127]

[0128] where Y 1 As defined herein. In another embodiment, Y 1 Not hydrogen.

[0129] A method as in any of the preceding items, wherein n is 1, and the stereochemistry of the α-carbon is (S) or (R), or is a dimeric mixture. A method as in any of the preceding items, wherein n is 1, and the stereochemistry of the α-carbon is (R). A method as in any of the preceding items, wherein n is 2, and the stereochemistry of the α-carbon is (S). A method as in any of the preceding items, wherein n is 1 and Q is oxygen, and the stereochemistry of the α-carbon is (R). A method as in any of the preceding items, wherein n is 1 and Q is sulfur, and the stereochemistry of the α-carbon is (S). It should be understood that the compounds of formula (I) and (II) are chiral at the α-carbon, except when A=A' and n=0.

[0130] The method of any of the preceding clauses, wherein at least one compound has a vasopressin V1a receptor binding affinity (IC) of less than about 100 nM, less than about 50 nM, less than about 25 nM, or less than about 10 nM. 50 ).

[0131] The method of any of the preceding clauses, wherein at least one compound is AVN228 (Example 233).

[0132] The method of any of the preceding clauses, wherein at least one compound is AVN246 (Example 224).

[0133] The method of any of the preceding clauses, wherein at least one compound is AVN251 (Example 225).

[0134] The method of any of the preceding clauses, wherein at least one compound is AVN296 (Embodiment 232E).

[0135] The method of any of the preceding clauses, wherein at least one compound is AVN576 (Example 266).

[0136] The method of any of the preceding items, wherein the administering step comprises a total daily dose of about 160 to about 700 mg of one or more compounds of any of the preceding items in single or divided form.

[0137] The method of any of the preceding items, wherein the administering step comprises a total daily dose of about 160 to about 500 mg of one or more compounds of any of the preceding items in single or divided form.

[0138] The method of any of the preceding items, wherein the administering step comprises a total daily dose of about 160 to about 400 mg of one or more compounds of any of the preceding items in single or divided form.

[0139] The method of any of the preceding items, wherein the administering step comprises a total daily dose of about 160 to about 320 mg of one or more compounds of any of the preceding items in single or divided form.

[0140] The method of any of the preceding items, wherein the administering step comprises a total daily dose of about 160 to about 240 mg of one or more compounds of any of the preceding items in single or divided form.

[0141] The method of any of the preceding items, wherein the form is for oral administration.

[0142] A method as in any of the preceding items, wherein the form is for rapid or immediate release oral administration.

[0143] The method of any of the preceding items, wherein the form is for parenteral administration.

[0144] It should be understood that in emergency situations, fast or immediate release oral administration and / or parenteral administration will provide high Cmax with very short Tmax. Without being bound by theory, it is believed herein that fast or immediate release oral administration and / or parenteral administration will prevent downstream damage caused by indwelling untreated brain damage, such as secondary injury events of biochemical cascades generated by cellular processes and occurring 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 neurotransmitter glutamate), calcium and sodium ion influx into neurons, mitochondrial dysfunction, damage to axons in the white matter of the brain separated from its cell body, changes in blood flow to the brain (including ischemia, cerebral hypoxia, brain edema and increased intracranial pressure).

[0145] The method of any of the preceding items, wherein the administering step comprises a qd dosing regimen.

[0146] The method of any of the preceding items, wherein the administering step comprises a bid dosing regimen.

[0147] The method of any of the preceding items, wherein the administering step comprises a sustained release dosing regimen.

[0148] A pharmaceutical composition suitable for or capable of treating brain damage or disorders in a host animal, the composition comprising one or more compounds of any one of the preceding items, and optionally one or more carriers, diluents or adjuvants or a combination thereof.

[0149] A unit dose or unit dosage form suitable for or capable of treating brain damage or disorders in a host animal, the composition comprising one or more compounds of any of the preceding items, and optionally one or more carriers, diluents or adjuvants or a combination thereof.

[0150] A unit dose or unit dosage form as in any of the preceding items, comprising a total of about 80 to about 350 mg of one or more compounds as in any of the preceding items in single or divided form.

[0151] A unit dose or unit dosage form as in any of the preceding items, comprising a total of about 80 to about 250 mg of one or more compounds as in any of the preceding items in single or divided form.

[0152] A unit dose or unit dosage form as in any of the preceding items, comprising a total of about 80 to about 200 mg of one or more compounds as in any of the preceding items in single or divided form.

[0153] A unit dose or unit dosage form as in any of the preceding items, comprising a total of about 80 to about 160 mg of one or more compounds as in any of the preceding items in single or divided form.

[0154] A unit dose or unit dosage form as in any of the preceding items, comprising a total of about 80 to about 120 mg of one or more compounds as in any of the preceding items in single or divided form.

[0155] A unit dose or unit dosage form as in any of the preceding items, suitable for oral delivery.

[0156] A unit dose or unit dosage form as in any of the preceding items, which is suitable for sustained release.

[0157] It is to be understood that in each of the foregoing terms and in each of the embodiments described herein of Formula (I), A, A', Y, Y1 ,n,R 1 , R 2 , R 3 , R 4 , R 5 Different genera, subgenera, and species of each of the foregoing and the like can be combined without limitation, and thus each such other embodiment of the invention is then described by the combination. It is also understood that in each of the foregoing terms and in each of the embodiments described herein of formula (II), A, Q, Y, Y 1 ,n,R 1 , R 2 , R 3 , R 4 , R 5 , R 5" Different genera, subgenera and species of each of the and the like can be combined without limitation, and thus each such other embodiment of the present invention is further described by said combination. For example, a method as in any of the preceding items, wherein a compound of formula (I) is described, wherein

[0158] (a) A has the following formula

[0159]

[0160] Where R N , R a and R Ar As defined herein; and n is 1;

[0161] (b) n is 1, and R 1 is hydrogen;

[0162] (c) A has the following formula

[0163]

[0164] Where R N , R a and R Ar As defined herein; n is 1; and R 1 is hydrogen;

[0165] (d) R 1 and R 3 All are hydrogen;

[0166] (e)R 1 and R 2 are hydrogen; and R 3 Has the following formula:

[0167]

[0168] Where R 10 , R11 and R 12 As defined herein;

[0169] (f) A has the following formula

[0170]

[0171] Where R N , R a and R Ar As defined herein; n is 1; R 1 and R 2 are hydrogen; and R 3 Has the following formula:

[0172]

[0173] Where R 10 and R 11 As defined herein;

[0174] (g) A has the following formula

[0175]

[0176] Where R N , R a and R Ar As defined herein; n is 1; R 1 and R 2 are hydrogen; and A' has the formula:

[0177]

[0178] and its similar ones.

[0179] It should be understood that in the embodiments and embodiments described herein, A and / or A' may include chiral centers and that either of the optically pure enantiomers may be included in the compounds described herein; alternatively, the racemic form may be used. For example, either or both of the following enantiomers may be included in the compounds described herein: (R)-1-(3-methoxyphenyl)ethylamine, (R)-1-(3-trifluoromethylphenyl)ethylamine, (R)-1,2,3,4-tetrahydro-1-naphthylamine, (R)-1-indanamine, (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-indanamine and (S)-α-methylbenzylamine and the like.

[0180] In another embodiment, the compounds described herein cross the blood-brain barrier (BBB) ​​and show high CNS permeability. In another embodiment, the compounds described herein show effective dose levels in the brain for the treatment of brain damage. In another embodiment, the compounds described herein show plasma levels that are located at or exceed those plasma levels required for clinical efficacy in the treatment of brain damage. In another embodiment, the compounds described herein show pharmacokinetics consistent with twice daily (bid) administration. In another embodiment, the compounds described herein show pharmacokinetics consistent with once daily (qd) administration. It should be understood herein that bid and qd administration can be important features in improving patient compliance, 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 show in vivo and in vitro cardiovascular safety profiles consistent with the treatment of brain damage. In another embodiment, the compounds described herein show in vivo respiratory safety.

[0181] In another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing them exhibit high plasma levels and high brain levels, including in the case of oral administration. In another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing them can cross the blood-brain barrier (BBB), including in the case of oral administration. In another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing them, in the case of not significantly or competitively binding with other predetermined GPCRs or other predetermined receptors, exhibit high CNS bioavailability and high affinity, the receptors include, but are not limited to, neurotransmitter-related receptors, steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factors and hormone receptors, other brain and gastrointestinal peptide receptors, other enzymes and the like. In one aspect, the compounds described herein and pharmaceutical compositions and medicaments containing the same are inactive or substantially inactive at 100 nM relative to a standard plot (Novascreen plot) of 64 receptors including 35 GPCRs, including neurotransmitter-related receptors, steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factor receptors, hormone receptors, brain / gut peptides (excluding vasopressin 1), and enzymes.

[0182] Without being bound by theory, it is believed herein that AVP and related peptides represent a series of chemical signals in vertebrates and play an important role in controlling social behavior and emotions. AVP is synthesized in neurons in the hypothalamus of all mammals. AVP is released from nerve endings in the median process and transported to the pituitary gland, where AVP promotes the release of adrenocorticotropic hormone (ACTH) and ultimately promotes the level of stress hormones in the circulation via its action at the pituitary AVP receptors. From nerve endings in the pituitary, AVP also enters the systemic bloodstream, where AVP acts on the heart and blood vessels to affect cardiac performance and on 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 different AVP receptor subtypes have been identified: V1a, V1b, and V2. V1a is the major AVP receptor found in the limbic system and cortex, V1b receptors are located in the limbic system and pituitary gland, but are not as widely distributed as V1a. V2 receptors are located in the kidneys, where they mediate the antidiuretic effect of vasopressin. It is believed herein that V2 is not expressed in the nervous system of adult animals or humans.

[0183] In another embodiment, the compounds described herein are selectively active at the Via AVP receptor. In another embodiment, the compounds described herein are selectively active at the Via AVP receptor and are less active, substantially less active, and / or inactive at other AVP receptors, such as the Vib and / or V2 subtypes of the AVP receptor. In another embodiment, the compounds described herein are 10-fold selective for the Via receptor over the Vib and / or V2 receptor. In another embodiment, the compounds described herein are 100-fold selective for the Via receptor over the Vib and / or V2 receptor. In another embodiment, the compounds described herein are 1000-fold selective for the Via receptor over the Vib and / or V2 receptor. In another embodiment, the compounds described herein are 10,000-fold selective for the Via receptor over the Vib and / or V2 receptor.

[0184] In another embodiment, the compounds described herein are selectively active at the Via AVP receptor over other G protein coupled receptors (GPCRs). In another embodiment, the compounds described herein are selectively active at the Via AVP receptor and are less active, substantially less active, and / or inactive at other GPCRs. In another embodiment, the compounds described herein are 10-fold selective for the Via receptor over other GPCRs. In another embodiment, the compounds described herein are 100-fold selective for the Via receptor over other GPCRs. In another embodiment, the compounds described herein are 1000-fold selective for the Via receptor over other GPCRs. In another embodiment, the compounds described herein are 10,000-fold selective for the Via receptor over other GPCRs.

[0185] In another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing the same have context-dependent specific behavioral effects (see, e.g., Ferris and Potegal Physiology and Behavior, 44: 235-239 (1988)). For example, in another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing the same are effective in regulating neuropsychiatric disorders, but have little or no effect on sexual behavior.

[0186] In each of the foregoing items and each embodiment described herein, it is understood that the formula not only includes and represents all pharmaceutically acceptable salts of the compound, but also includes any and all hydrates and / or solvates of the compound formula. It is understood that certain functional groups (such as hydroxyl, amino and similar groups) form complexes and / or coordination compounds with water and / or different solvents in different physical forms of the compound. Therefore, the above formulas should be understood as descriptions of such hydrates and / or solvates, including pharmaceutically acceptable solvates.

[0187] In each and embodiment described herein, it is also understood that the formula includes and represents 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 each of the following embodiments, it is also understood that the formula includes and represents any and all crystalline forms, partially crystalline forms, and non-crystalline and / or amorphous forms of the compound.

[0188] As used herein, the term "solvate" refers to a compound described herein that is complexed with a solvent molecule. It should be understood that the compounds described herein can form such complexes with a solvent simply by mixing the compound with the solvent, or dissolving the compound in the solvent. It should be understood that when the compound is used as a drug, such solvents are pharmaceutically acceptable solvents. It should also be understood that when the compound is used as a drug, the relative amount of the solvent forming the solvate should be less than the established guidelines for such pharmaceutical use, such as less than the International Conference on Harmonization (ICH) guidelines. It should be understood that the solvate can be separated from the excess solvent by evaporation, precipitation and / or crystallization. In some embodiments, the solvate is amorphous, and in other embodiments, the solvate is crystalline.

[0189] The compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing in multiple stereoisomer forms. It should be understood that, in one embodiment, the invention described herein is not limited to any specific stereochemical requirements, and the compounds and compositions, methods, uses and medicaments comprising them may be optically pure, or may be any of a variety of stereoisomer mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers and their analogs. It should also be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, and a mixture of stereochemical configurations at one or more other chiral centers.

[0190] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E and Z double bonds. It should be understood that, in another embodiment, the invention described herein is not limited to any specific geometric isomer requirements, and the compounds and compositions, methods, uses and medicaments comprising the same may be pure, or may be any of a variety of geometric isomer mixtures. It should also be understood that such a mixture of geometric isomers may include a single configuration at one or more double bonds, and a mixture of geometric shapes at one or more other double bonds.

[0191] As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. As used herein, the terms "alkenyl" and "alkynyl" each include a chain of carbon atoms, which is optionally branched and includes at least one double bond or triple bond, respectively. It should be understood that alkynyl groups may also include one or more double bonds. It should also be understood that in certain embodiments, alkyl groups advantageously have a limited length, including C 1 -C 24 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 and C 1 -C4 and C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 and C 2 -C 4 Illustratively, such specific finite length alkyl groups (including C 1 -C 8 , C 1 -C 6 and C 1 -C 4 and C 2 -C 8 , C 2 -C 6 and C 2 -C 4 and similar groups thereof) may be referred to as low carbon alkyl groups. It is also understood that in certain embodiments, alkenyl and / or alkynyl groups may each advantageously have a limited length, including C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 and C 2 -C 4 and C 3 -C 24 , C 3 -C 12 , C 3 -C 8 , C 3 -C 6 and C 3 -C 4 Illustratively, such specific restricted length alkenyl and / or alkynyl groups (including C 2 -C 8 , C 2 -C 6 and C 2 -C 4 and C 3 -C 8 , C 3 -C 6 and C 3 -C 4and similar groups thereof) may be referred to as lower alkenyl and / or alkynyl. It is understood herein that shorter alkyl, alkenyl and / or alkynyl groups may provide less lipophilicity to the compound, and therefore will have different pharmacokinetic properties. In the embodiments of the invention described herein, it is understood that in each case, the enumeration of alkyl refers to alkyl as defined herein, and is optionally a lower alkyl. In the embodiments of the invention described herein, it is understood that in various cases, the enumeration of alkenyl refers to alkenyl as defined herein, and is optionally a lower alkenyl. In the embodiments of the invention described herein, it is understood that in various cases, the enumeration of alkynyl refers to alkynyl as defined herein, and is optionally a lower alkynyl. Illustrative alkyl, alkenyl and alkynyl groups are, 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, octyl and similar groups thereof, and corresponding groups containing one or more double bonds and / or triple bonds, or combinations thereof.

[0192] As used herein, the term "alkylene" includes a divalent chain of carbon atoms, which is optionally branched. As used herein, the terms "alkenylene" and "alkynylene" include a divalent chain of carbon atoms, which is optionally branched and includes at least one double bond or triple bond, respectively. It should be understood that alkynylene may also include one or more double bonds. It should also be understood that in certain embodiments, alkylene advantageously has a limited length, including C 1 -C 24 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 and C 1 -C 4 and C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 and C 2 -C 4 Illustratively, such specific restricted length alkylene groups (including C 1 -C 8 , C 1 -C 6 and C 1 -C 4 and C 2 -C 8 , C 2 -C 6 and C 2 -C4 and similar groups thereof) may be referred to as lower alkylene. It is also understood that in certain embodiments, alkenylene and / or alkynylene may each advantageously have a limited length, including C 2 -C 24 , C 2 -C 12 , C 2 -C 8 , C 2 -C 6 and C 2 -C 4 and C 3 -C 24 , C 3 -C 12 , C 3 -C 8 , C 3 -C 6 and C 3 -C 4 Illustratively, such specific restricted length alkenylene and / or alkynylene groups (including C 2 -C 8 , C 2 -C 6 and C 2 -C 4 and C 3 -C 8 , C 3 -C 6 and C 3 -C 4 and similar groups thereof) may be referred to as lower alkenylene and / or alkynylene. It is understood herein that shorter alkylene, alkenylene and / or alkynylene groups may provide less lipophilicity to the compound and therefore will have different pharmacokinetic properties. In the embodiments of the invention described herein, it is understood that in each case, the enumeration of alkylene, alkenylene and alkynylene refers to alkylene, alkenylene and alkynylene as defined herein, and is optionally lower alkylene, alkenylene and alkynylene. Illustrative alkyl groups are, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene and similar groups thereof.

[0193] As used herein, the term "cycloalkyl" includes a chain of carbon atoms, which is optionally branched, wherein 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. Illustrative cycloalkyls include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and similar groups thereof. As used herein, the term "cycloalkenyl" includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, wherein at least a portion of the chain is cyclic. It should be understood that one or more double bonds may be in the cyclic portion of the cycloalkenyl and / or the non-cyclic portion of the cycloalkenyl. It should be understood that cycloalkenylalkyl and cycloalkylalkenyl are each a subset of cycloalkenyl. It should be understood that cycloalkyl can be polycyclic. Illustrative cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexyleth-2-yl, cycloheptenylpropenyl, and similar groups thereof. It should also be understood that the chains forming the cycloalkyl and / or cycloalkenyl groups are preferably of limited length, including C 3 -C 24 , C 3 -C 12 , C 3 -C 8 , C 3 -C 6 and C 5 -C 6 It is understood herein that shorter alkyl and / or alkenyl chains forming cycloalkyl and / or cycloalkenyl groups, respectively, may render the compound less lipophilic and will therefore have different pharmacokinetic properties.

[0194] As used herein, the term "heteroalkyl" includes a chain of atoms including carbon and at least one heteroatom, and optionally branched. Illustrative heteroatoms include nitrogen, oxygen and sulfur. In some variants, illustrative heteroatoms also include phosphorus and selenium. As used herein, the term "cycloheteroalkyl" (including heterocyclic radicals and heterocycles) includes a chain of atoms including carbon and at least one heteroatom, such as heteroalkyl, and optionally branched, wherein at least a portion of the chain is cyclic. Illustrative heteroatoms include nitrogen, oxygen and sulfur. In some variants, illustrative heteroatoms also include phosphorus and selenium. Illustrative cycloheteroalkyl includes, but is not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl and similar groups thereof.

[0195] As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may be optionally substituted. Illustrative aromatic heterocyclic groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.

[0196] As used herein, the term "amino" includes the group NH 2 , alkylamino and dialkylamino, wherein the two alkyl groups in the dialkylamino group may be the same or different, i.e., alkylalkylamino. Illustratively, amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like. In addition, it should be understood that when amino modifies or is modified by another term, such as aminoalkyl or amido, the above variations of the term amino are included. Illustratively, aminoalkyl includes H 2 The amide group includes acylmethylamino, acylethylamino and the like.

[0197] As used herein, the term "amino and derivatives thereof" includes amino as described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino, heteroalkenylamino, heteroalkynylamino, cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamino, arylalkynylamino, heteroarylamino, heteroarylalkylamino, heteroarylalkenylamino, heteroarylalkynylamino, amide and the like, each of which is optionally substituted. The term "amino derivative" also includes urea, carbamate and the like.

[0198] As used herein, the term "hydroxyl and derivatives thereof" includes OH, and alkoxy, alkenyloxy, alkynyloxy, heteroalkoxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloheteroalkoxy, cycloheteroalkenyloxy, aryloxy, arylalkoxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkoxy, heteroarylalkenyloxy, heteroarylalkynyloxy, acyloxy and the like, each of which is optionally substituted. The term "hydroxyl derivatives" also includes carbamates and the like.

[0199] As used herein, the term "sulfenyl and derivatives thereof" includes SH, and alkylsulfenyl, alkenylsulfenyl, alkynylsulfenyl, heteroalkylsulfenyl, heteroalkenylsulfenyl, heteroalkynylsulfenyl, cycloalkylsulfenyl, cycloalkenylsulfenyl, cycloheteroalkylsulfenyl, cycloheteroalkenylsulfenyl, arylsulfenyl, arylalkylsulfenyl, arylalkenylsulfenyl, arylalkynylsulfenyl, heteroarylsulfenyl, heteroarylalkylsulfenyl, heteroarylalkenylsulfenyl, heteroarylalkynylsulfenyl, arylsulfenyl and the like, each of which is optionally substituted. The term "sulfenyl derivatives" also includes thiocarbamates and the like.

[0200] 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, acylcarbonyl and the like, each of which is optionally substituted.

[0201] As used herein, the term "carbonyl and its derivatives" includes the groups C(O), C(S), C(NH) and substituted amino derivatives thereof.

[0202] As used herein, the term "carboxylic acid and its derivatives" includes the group CO 2 H and its salts, as well as its esters and amides, and CN.

[0203] As used herein, the term "sulfinic acid or its derivatives" includes SO 2 H and its salts, and its esters and amides.

[0204] As used herein, the term "sulfonic acid or its derivatives" includes SO 3 H and its salts, and its esters and amides.

[0205] 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, acylsulfonyl and the like, each of which is optionally substituted.

[0206] As used herein, the term “hydroxyamino and derivatives thereof” includes NHOH, and alkyloxy NH, alkenyloxy NH, alkynyloxy NH, heteroalkyloxy NH, heteroalkenyloxy NH, heteroalkynyloxy NH, cycloalkyloxy NH, cycloalkenyloxy NH, cycloheteroalkyloxy NH, cycloheteroalkenyloxy NH, aryloxy NH, arylalkyloxy NH, arylalkenyloxy NH, arylalkynyloxy NH, heteroaryloxy NH, heteroarylalkyloxy NH, heteroarylalkenyloxy NH, heteroarylalkynyloxy NH, acyloxy and the like, each of which is optionally substituted.

[0207] As used herein, the term “hydrazine group and derivatives thereof” 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, heteroaryl alkyl NHNH, heteroarylalkenyl NHNH, heteroarylalkynyl NHNH, acyl NHNH and the like, each of which is optionally substituted.

[0208] As used herein, the term "optionally substituted" includes replacement of hydrogen atoms with other functional groups on the optionally substituted free radical. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, heteroaryl, heteroaralkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, and the like. Illustratively, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl and / or sulfonic acid is optionally substituted.

[0209] As used herein, the terms "optionally substituted aryl" and "optionally substituted heteroaryl" include replacement of hydrogen atoms with other functional groups on the optionally substituted aryl or heteroaryl. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, and the like. Illustratively, any of amino, hydroxyl, thio, alkyl, haloalkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl and / or sulfonic acid is optionally substituted.

[0210] Illustrative substituents include, but are not limited to, the group -(CH 2 ) x Z X, where x is an integer from 0 to 6, and Z X is selected from halogen, hydroxy, alkanoyloxy, including C 1 -C 6 Alkanoyloxy, optionally substituted aroyloxy, alkyl (including C 1 -C 6 Alkyl), alkoxy (including C 1 -C 6 Alkoxy), cycloalkyl (including C 3 -C 8 Cycloalkyl), cycloalkoxy (including C 3 -C 8 Cycloalkoxy), alkenyl (including C 2 -C 6 alkenyl), alkynyl (including C 2 -C 6 Alkynyl), haloalkyl (including C 1 -C 6 Haloalkyl), haloalkoxy (including C 1 -C 6 Haloalkoxy), halocycloalkyl (including C 3 -C 8 Halogen cycloalkyl), halogen cycloalkoxy (including C 3 -C 8 Halogen cycloalkoxy), amino, C 1 -C 6 Alkylamino, (C 1 -C 6 Alkyl)(C 1 -C 6 alkyl)amino, alkylcarbonylamino, N-(C 1 -C 6 alkyl)alkylcarbonylamino, aminoalkyl, C 1 -C 6 Alkylaminoalkyl, (C 1 -C 6 Alkyl)(C 1 -C 6 alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C 1 -C 6 alkyl)alkylcarbonylaminoalkyl, cyano and nitro; or Z X Selected from -CO 2 R 4 and-CONR 5 R 6 , where R 4 , R 5 and R 6 are independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, Aryl-C1 -C 6 Alkyl and heteroaryl-C 1 -C 6 alkyl.

[0211] As used herein, the term "prodrug" generally refers to any compound that produces a biologically active compound due to one or more spontaneous chemical reactions, enzyme-catalyzed chemical reactions and / or metabolic chemical reactions or a combination thereof when applied to a biological system. In vivo, prodrugs typically work by enzymes (such as esterases, amidases, phosphatases and their analogs), simple biochemical methods or other methods for releasing or regenerating pharmacologically active drugs in vivo. This activation can occur via the action of endogenous host enzymes or non-endogenous enzymes applied to the host before, after or during the application of the prodrug. Other details of the use of prodrugs are described in U.S. Patent No. 5,627,165. It should be understood that once the target is reached, such as target delivery, safety, stability and the like, the prodrug is advantageously converted into the original drug, followed by rapid elimination of the released residues of the group forming the prodrug.

[0212] Prodrugs can be prepared by attaching a group that ultimately decomposes in vivo to one or more functional groups present on the compound, such as -OH-, -SH, -CO 2 H, -NR 2 , and are prepared from the compounds described herein. Illustrative prodrugs include, but are not limited to, carboxylic acid esters, where the groups are alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxy, thiols, and amines, where the linking group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. Illustrative esters (also referred to as active esters) include, but are not limited to: 1-indanyl, N-oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, β-acetoxyethyl, β-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, (1-aminoethyl)carbonyloxymethyl, and the like; alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, β-ethoxycarbonyloxyethyl, and the like; dialkylaminoalkyl groups including di-lower alkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like; 2-(alkoxycarbonyl)-2-enyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl, 2-(ethoxycarbonyl)but-2-enyl, and the like; and lactone groups such as phthalyl, dimethoxyphthalyl, and the like.

[0213] Other illustrative prodrugs contain chemical moieties, such as amide or phosphorus groups, which function to increase the solubility and / or stability of the compounds described herein. Other illustrative prodrugs of amino groups include, but are not limited to: (C3 -C 20 )alkanoyl; halo-(C 3 -C 20 )alkanoyl; (C 3 -C 20 ) alkenoyl; (C 4 -C 7 )cycloalkanoyl; (C 3 -C 6 )-cycloalkyl(C 2 -C 16 )alkanoyl; optionally substituted aroyl, such as unsubstituted aroyl or aroyl substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulfonyloxy, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy, each of which is optionally further substituted with one or more of 1 to 3 halogen atoms; optionally substituted aryl (C 2 -C 16 )alkanoyl and optionally substituted heteroaryl (C 2 -C 16 )alkanoyl, such as aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy, each of which is optionally further substituted with 1 to 3 halogen atoms; and optionally substituted heteroarylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl portion and 2 to 10 carbon atoms in the alkanoyl portion, such as heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulfonyloxy, (C 1 -C 3 ) alkyl and (C 1 -C 3 )alkoxy, each of which is optionally further substituted by 1 to 3 halogen atoms. The groups illustrated are illustrative but not exhaustive and can be prepared by conventional methods.

[0214] It should be understood that the prodrug itself may not have significant biological activity, but on the contrary, after in vivo administration, one or more spontaneous chemical reactions, enzyme-catalyzed chemical reactions and / or metabolic chemical reactions or combinations thereof are carried out to produce compounds described herein of precursors of biologically active or biologically active compounds. However, it should be understood that in some cases, the prodrug is biologically active. It should also be understood that prodrugs can be generally used to improve drug efficacy or safety via improved oral bioavailability, pharmacodynamic half-life and the like. Prodrugs also refer to derivatives of compounds described herein, which include groups that simply cover up undesirable drug properties or improve drug delivery. For example, one or more compounds described herein that may present undesirable properties (the properties should be blocked or minimized) may become pharmacological, pharmaceutical or pharmacokinetic barriers in clinical drug applications, such as low oral drug absorption, insufficient site specificity, chemical instability, toxicity and poor patient acceptance (bad taste, bad smell, pain at injection site and the like), etc. It should be understood herein that prodrugs or other strategies using reversible derivatives may be applicable to the optimization of clinical applications of drugs.

[0215] As used herein, the term "leaving group" refers to a reactive functional group that creates an electrophilic site on the atom to which it is attached, so that a nucleophile can be added to the electrophilic site on the atom. Illustrative leaving groups include, but are not limited to, halogens, optionally substituted phenols, acyloxy groups, sulfonyloxy groups, and the like. It should be understood that such leaving groups can be located on alkyl groups, acyl groups, and the like. Such leaving groups may also be referred to herein as activating groups, such as when the leaving group is present on an acyl group. In addition, conventional peptide, amide and ester coupling agents, such as, but not limited to, PyBop, BOP-Cl, BOP, pentafluorophenol, isobutyl chloroformate, and the like, form various intermediates including leaving groups as defined herein on the carbonyl group.

[0216] It should be understood that in each example disclosed herein, the enumeration of an integer range for any variable describes the enumerated range, each individual member within the range, and each possible subrange of the variable. For example, the enumeration of n as an integer from 0 to 8 describes the range, individual and optional values ​​of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n is 0, or n is 1, or n is 2, etc. In addition, the enumeration of n as an integer from 0 to 8 also describes each and every subrange, each of which can be based on another embodiment, such as n is 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.

[0217] As used herein, the terms "treating," "contacting," or "reacting" when referring to a chemical reaction generally mean that two or more reagents are added or mixed under appropriate conditions, which allow a chemical transformation or chemical reaction to occur, and / or produce a specified and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product may not necessarily be caused directly by the combination of the two reagents initially added. In other words, one or more intermediates may be produced in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0218] As used herein, the term "composition" generally refers to any product containing a specified amount of a specified component, as well as any product obtained directly or indirectly by a combination of specified amounts of specified components. It should be understood that the compositions described herein can be prepared from isolated compounds described herein or salts, solutions, hydrates, solvates, and other forms of compounds described herein. It should also be understood that the compositions can be prepared from different amorphous, crystalline, partially crystalline, crystalline, and / or other morphological forms of the compounds described herein. It should also be understood that the compositions can be prepared from different hydrates and / or solvates of the compounds described herein. Therefore, such pharmaceutical compositions listing the compounds described herein should be understood to include each or any combination of various morphological forms and / or solvates or hydrate forms of the compounds described herein. In addition, it should be understood that the compositions can be prepared from different cocrystals of the compounds described herein.

[0219] Illustratively, the composition may include one or more carriers, diluents and / or excipients. The compounds described herein or compositions containing them may be formulated in therapeutically effective amounts in any conventional dosage form suitable for the methods described herein. The compounds described herein or compositions containing them (including such preparations) may utilize known procedures, by a wide variety of conventional routes for the methods described herein and in a wide variety of dosage forms (generally referring to Remington: The Science and Practice of Pharmacy, (21st edition, 2005)).

[0220] As used herein, the term "therapeutically effective amount" refers to the amount of active compound or agent that causes a biological or medical response (including relieving the symptoms of the disease or condition being treated) sought by researchers, veterinarians, doctors or other clinicians in a tissue system, animal or human. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate the symptoms of a disease or disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage of the compounds and compositions described herein can be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the severity of the condition and condition being treated; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet: the time of administration, route of administration and the excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known to researchers, veterinarians, doctors or other skilled clinicians.

[0221] It will also be appreciated that it is advisable to select a therapeutically effective amount with reference to any toxicity or other undesirable side effects that may occur during administration of one or more of the compounds described herein, whether referring to monotherapy or combination therapy. In addition, it will be appreciated that the co-therapy described herein may allow for the administration of lower doses of compounds that exhibit such toxicity or other undesirable side effects, wherein these lower doses are below the threshold for toxicity or are in the therapeutic window below the amount otherwise administered in the absence of the co-therapy.

[0222] In addition to the illustrative dosages and dosing regimens described herein, it should be understood that the effective amount of any of the compounds described herein or mixtures thereof can be readily determined by the attending diagnostician or physician using known techniques and / or by observing the results obtained under similar circumstances. In determining the effective amount or dosage, the attending diagnostician or physician considers a variety of factors, including, but not limited to, the species of mammal (including human), its size, age and general health, the specific disease or condition involved, the extent or involvement or severity of the disease or condition, the response of the individual patient, the specific compound administered, the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of concomitant drugs, and other relevant circumstances.

[0223] The dosage of each compound in 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 being treated or prevented, and the age, weight, and health of the individual being treated. In addition, information about the pharmacogenomics (the effect of genotype on the pharmacokinetics, pharmacodynamics, or efficacy profile of a treatment) of a particular patient may influence the dosage used.

[0224] It should be understood that in the methods described herein, the individual components or combinations of co-administration can be administered by any suitable means, in the same period, at the same time, in sequence, separately or in the form of a single pharmaceutical preparation. When the co-administered compound or composition is administered in a separate dosage form, the number of doses administered per day of each compound may be the same or different. The compound or composition may be administered via the same or different routes of administration. The compound or composition may be administered in parallel in divided or single forms according to a simultaneous or alternating regimen, at the same or different times during the course of treatment.

[0225] The term "administering" as used herein 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 (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal and the like. The compounds and compositions described herein can be administered in unit dosage form and / or in the form of formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and / or vehicles.

[0226] In making pharmaceutical compositions of the compounds described herein, a therapeutically effective amount of one or more compounds in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed in the carrier, which may be in the form of a capsule, sachet, paper, or other container. An excipient may act as a diluent and may be a solid, semisolid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the formulation composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. The composition may contain any amount of active ingredient from about 0.1% to about 99.9%, depending on the dose and dosage form selected.

[0227] As used herein, the term "antagonist" refers to a full or partial antagonist. Although partial antagonists of any intrinsic activity may be useful, partial antagonists illustratively 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. It should be understood that the illustrative methods described herein require a therapeutically effective amount of a vasopressin receptor antagonist; therefore, a compound that exhibits partial antagonism at one or more vasopressin receptors can be administered at a higher dose that exhibits sufficient antagonist activity to inhibit the effects of vasopressin or a vasopressin agonist.

[0228] The compounds, compositions and methods described herein use one or more compounds described herein to treat or improve one or more effects of brain damage, which can be based on animal models of disease, such as murine, canine, porcine and non-human primate models. For example, it should be understood that brain damage in humans can be characterized by loss of function and / or symptom development, each of which can be induced in animals, such as mice and other alternative test animals. In particular, the mouse models described herein can be used to evaluate the treatment methods and pharmaceutical compositions described herein to determine the therapeutically effective amounts described herein.

[0229] Each of the publications cited herein is hereby incorporated by reference.

[0230] The following examples further illustrate specific embodiments of the present invention; however, the following illustrative examples should not be construed as limiting the present invention in any manner.

[0231] Example

[0232] Method Embodiment

[0233] Example. Controlled cortical impact injury model. Briefly, the experimental animals were anesthetized with isoflurane (4.5%), intubated, and irrigated with N 2 O(66%), O 2 Mechanical ventilation was performed with a mixture of 1% (32%) and isoflurane (1.5-2.0%). Rectal temperature was maintained at 37.0 ± 0.5 °C using an automatically adjustable heating pad. Catheters were placed in the femoral artery and vein. Mean arterial blood pressure (mABP) was continuously monitored using a data reading system, and arterial blood gas parameters (pH, pO) were read at 15-min intervals. 2 , pCO 2 and plasma Na +concentration). The femoral vein is used to administer vehicle, dimethyl sulfoxide (DMSO) or one or more compounds described herein. The animals are fixed in a stereotaxic frame. A midline scalp incision is made, and the skin and periosteum are retracted from the skull surface. A 10 mm diameter craniotomy is performed at the middle position between the right upper anterior bregma and the tip of the lambdoid suture, 1 mm lateral to the midline. A pneumatic impactor (e.g., 5 mm diameter) mounted at a certain angle (e.g., 10°) to the vertical plane is used to produce injury. A single impact (e.g., speed 6 m / s; deformation depth 3.0 mm; dwell time 0.3 s) is delivered to the right cavity wall cortex. After injury, the removed skull portion is replaced with bone wax, sealed, and the skin incision is closed. Sham-operated animals are exposed to the same surgical procedures, but are not subjected to any injury from the pneumatic impactor. Further details are described in Dixon et al., “A fluidpercussion 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 Vireceptor antagonist, SR49059, decreases trauma-induced brain edema” Acta Neurochir 102(Suppl):S425-S429 (2008).

[0234] Example. Momentum exchange impact model. This model features several translational differences that are advantageous over some head injury models, such as the controlled cortical impact injury model. For example, the head, neck, and body can move with the impact, and the velocity and energy transfer of the head movement can be calculated and graded from mild to provide a range of moderate to severe concussions. Moderate impact studies were performed using neuroradiological evidence of contusion. Male rats were concussed 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, the test animals were given vehicle or a test compound, such as a highly selective Via receptor antagonist that crosses the blood-brain barrier. Sham non-concussed test animals were given vehicle or a test compound. The test animals were treated twice daily for 5 consecutive days. Cognitive behavior was assessed two weeks after concussion using, for example, the Barnes maze and / or a novel cognitive model. In addition, motor behavior was assessed using, for example, a balance beam and / or rotarod test. In each case, a neuroradiological MRI was also performed.

[0235] Example. Neuroanatomy Imaging. At the beginning of each imaging session, a high-resolution structural data set was collected using the RARE pulse sequence (20 slices; 1 mm; field of view [FOV] 3.0 cm; 256×256; repetition time [TR] 2.5 sec; echo time [TE] 12.4 ms; NEX 6; 6.5 min acquisition time).

[0236] Example. T2 relaxation measurement of edema. MRI was performed 24-28 days after injury to characterize the volume of edema in the lateral ventricle using the T2 relaxation method. The imaging time was based on the Charles River rat model for TBI assessment. Images were acquired using a multi-slice multi-echo (MSME) pulse sequence. The echo time (TE) was illustratively 11 ms, and 16 echoes were acquired during imaging, with a recovery time (TR) of 2500 ms. A field of view [FOV] of 3 cm was acquired. 2, data matrix = 256 × 256 × 20 slices, thickness = 1 mm images. Longitudinal relaxation time (T2) values ​​were obtained from all slices using ParaVision 5.1 software. T2 was used to characterize the volume of edema in the lateral ventricles. T2 values ​​were used to segment and quantify the ventricular volume. The following equation was used to calculate T2 values; y = A + Cexp (-t / T2) (SD weighted), obtained from Paravision 5.1 software, where A = absolute deviation, C = signal intensity, t = echo time and T2 = spin-spin relaxation time. On the T2 map, the ventricles were identified as high-intensity signals on three 1 mm sections. The volumes were calculated using the snake region growing algorithm in itk-SNAP (www.itksnap.org). The threshold was illustratively set to 6300 to 9000 as absolute pixel intensity. A point was inoculated in the ventricle and the algorithm was run until segmentation was completed.

[0237] Example. Resting-state functional connectivity. Resting-state fMRI scans were collected using a spin-echo three-shot EPI sequence (imaging parameters: matrix size = 96 x 96 x 20, TR / TE = 3000 / 15 msec, voxel size = 0.312 x 0.312 x 0.12 mm, slice thickness = 1 mm). Preprocessing was illustratively achieved 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). Brain tissue masks for resting-state functional images were manually drawn using 3DSlicer (https: / / www.slicer.org / ) and used for skull stripping. Normalization was accomplished by registering the functional data to an MRI rat brain template (Ekam Solutions LLC, Boston, MA) using affine registration via DRAMMS. A region-to-region functional connectivity approach was illustratively performed to measure correlations in spontaneous BOLD fluctuations. The network consists of nodes and edges; nodes are brain regions of interest (ROIs) and edges are connections between regions. Nodes were defined using segmented ROIs from an appropriate MRI rat brain atlas. Illustratively, 171 nodes were defined. Based on residual images, the stereo pixel time series data in each node were averaged using a nuisance regression procedure. Pearson's correlation coefficients were calculated for all pairs of nodes (14535 pairs of 171 nodes) for each individual in all three groups to assess temporal correlations of intervals. Values ​​(in the range of -1 to 1) were z-transformed using Fisher's Z transform to improve normality. For the 171 nodes, a 171×171 symmetric connectivity matrix was constructed, where each entry represents the strength of an edge. Group level analysis was performed to look at the functional connectivity in the control, one hit, and three hit groups.The resulting Z-score matrices from a group t-test were clustered using the K-nearest neighbors clustering method to identify how nodes cluster together and form a resting-state network. For observation purposes, a Z-score threshold of |Z|=2.3 was used to remove impurities or weak node connections.

[0238] Example. Treatment in the momentum exchange impact model using the compounds described herein. Male Sprague Dawley rats (n=19; 250-270 g) aged 65 days were obtained from Charles River (Worcester, MA). The experimental animals were maintained on a 12:12 hour light:dark cycle with lights on at 0700 hours and had ad libitum access to food and water. The protocol used in this study complied with the regulations of the Institutional Animal Care and Use Committee of Northeastern University.

[0239] Pneumatic pressure actuation (50 g indenter) was repeated as described by Viano and described for mild, moderate, and severe head injuries, consistently reproducing 7.4, 9.3, and 11.2 m / s impact velocities, respectively. The data described herein were obtained from a 9.12 m / s impact velocity, as determined using high-speed video recording.

[0240] Beginning at postnatal (P) 70, animals were divided into 3 groups (n=6-7 / group; sham control group (control, CG), injury group (IG), and treatment group (TG) using a custom setup from Animal Imaging Research (AIR; Holden, MA) at P70, and their head impact and drug regimen was initiated. All groups were anesthetized with oxygen containing 4% isoflurane, and the injury group and treatment group received the first of two total head impacts). The day after the first impact (P71), the test compound, such as AVN576, was administered to the treatment group and the sham control group. In addition, only the vehicle control group (VCG) was administered normal saline. All administrations were administered to the control group and the treatment group twice a day at 0700 and 1400 hours (IP, at 10 mg / kg). The drug regimen was continued for 4 days thereafter (5 days total). Two days after the first impact, P72, a second head impact was delivered. Animals were imaged two weeks after the impact, and cognitive and motor behavior were tested. In all assessments performed, there were no differences between the sham control group (CG) receiving test compound and the vehicle-only sham control group (VCG) receiving vehicle.

[0241] Concussed untreated animals (injured group) showed significant cognitive behavioral deficits, functional connectivity pattern changes and anisotropy index localized to the hindbrain and amygdala. Concussed treated animals treated with Example 266 (AVN576) showed no learning and memory deficits and no significant differences compared to the sham control group. Similarly, there were no significant differences in overall motor behavior between the control and treated groups. Even compared to the control group, treated animals showed increased functional connectivity in network circuits associated with learning, cognition, memory and attention.

[0242] Repeated moderate traumatic brain injury using the momentum exchange model produces clear neuroradiological evidence of contusion, signs of inflammation, and white matter damage. Brain injury in untreated animals causes significant cognitive, learning, and memory deficits.

[0243] Brain injury in untreated experimental animals is associated with increased lateral ventricle volume, indicating inflammation and edema. Treatment with the compounds described herein for 5 days reduced edema expansion in the lateral ventricles. The treated animals also showed a significant reduction in injury-induced edema near the impact site. There was no statistical difference between the treated and control groups, indicating complete recovery / healing from the impact. The complete recovery / healing of edema was unexpected. Although a 1-2% reduction in total brain water content has been reported in other studies, a specific reduction in edema or a complete return to baseline levels has not been reported. Kleindienst et al., Acta Neurochir 155: 151-64 (2013); Marmarou et al., Brain Research 1581: 89-102 (2014).

[0244] Brain injury in untreated experimental animals also causes low connectivity in important brain networks (such as hippocampal neural circuits). Treatment with the compounds described herein promotes high connectivity in hippocampal neural circuits. Treatment with the compounds described herein within 24 hours after the first concussion prevents cognitive, learning and memory deficits that occur after brain injury and provides complete recovery therefrom. The treated group showed behavioral measures that were not significantly different from the control group, indicating complete recovery or cure from the impact. The complete recovery / cure from cognitive, learning and memory deficits is unexpected. To date, there has been no report of improving cognitive, learning and memory deficits caused by brain injury by Va1R antagonism.

[0245] Without being bound by theory, it is shown that the compounds described herein can treat the cognitive and neurobiological effects of moderate to severe brain injury by not only reducing inflammation and edema caused by head injury, but also promoting neuroadaptive changes in functional connectivity to compensate for trauma. For example, even compared to undamaged sham control animals that are still treated, the treated group animals show high connectivity. The observed high connectivity is relative to the default mode network represented by the control group, where the injury group shows severe low connectivity. Without being bound by theory, it is shown that the high connectivity caused by treatment with the compounds described herein can reflect the reorganization of the integrated neural network that retains the function of responding to brain injury. In addition, connectivity disruption indicates diffuse axonal damage, and therefore, 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, brain edema, chronic traumatic encephalopathy (CTE), subarachnoid hemorrhage, stroke, ischemic stroke, concussion and fall injuries.

[0246] Example. Novel Object Recognition Test Results. This test assesses intermittent learning and memory related to the recognition of stimuli. Figure 1 The results show that animals in the lesioned group (IG) spent significantly less time investigating the novel object compared to chance (50% of total object investigation) (cognitive index) (t(5) = 3.393, p < 0.05). In contrast, both the control group (CG) (t(6) = 3.08, p < 0.05) and the treated group (TG) (t(5) = 2.61, p < 0.05) spent significantly longer time on the novel object than chance. When compared between groups, all groups spent a significantly longer percentage of time on the novel object compared to the lesioned group (CG: P = 0.0006; TG: P = 0.003; Tukey post hoc analysis after one-way ANOVA, F (3,21) =9.14, P=0.0005). Similarly, the control group (P=0.006) and the treated group (P=0.02) spent significantly more total time on the novel object compared to the injured animals (one-way ANOVA, F (3,21) =5.78, P=0.005). The exploration index (new exploration instances of any object / total exploration instances) showed that the groups expressed differently with AVN576 exposure (one-way ANOVA, F (3,21) =4.48, P=0.01), with only control animals showing a significantly higher number of exploratory instances than lesion animals (P=0.01), and treatment animals only showing a trend toward significance (P=0.06).

[0247] Example. Barnes maze test results. This test assesses spatial learning and memory. The lesioned group had significant deficits in cognitive behavioral measures, while the treated group did not show any learning and memory deficits and was no different from either control group (CG and / or VCG), as shown in Table 1. Figure 2A and Figure 2B As shown in .

[0248] When collapsed on the day of collection, Barnes maze testing demonstrated that IG animals had greater skeletal size than either the control group (VCG: P = 0.03; CG: P = 0.01) and the treated group (P = 0.04; Tukey post hoc analysis of one-way ANOVA, F (3,21) =4.88, P = 0.009)) longer waiting time to find the goal box. Similarly, compared with CG (P = 0.009) and TG animals (P = 0.03), the injured group animals traveled significantly longer distances to search the maze before finding the goal box. Compared with CG animals (P = 0.03) and TG animals (P = 0.03; Tukey post hoc analysis after one-way ANOVA, F (3,21) =3.95, P=0.02), the injured animals also spent significantly more time exploring the wrong hole (error duration). The same results were obtained for the assessment of distance traveled (data not shown). When error duration was broken down across days, there were other differences between groups and between days (mixed design ANOVA, main effect of day: F (3,63) =9.10, P<0.0001; and group: F (3,21) =3.95, P=0.02). Injured animals committed significantly more errors on day 1 compared to CG animals (P=0.07); and on day 2 compared to CG animals (P=0.01) and TG animals (P=0.02). Evaluation of distance traveled and broken down over days yielded the same results (data not shown).

[0249] Example. Resting-state functional connectivity. Figure 3 Shown is a correlation matrix of resting-state functional connectivity (rsFC) of 166 rat brain regions comparing the lesion group to the treatment group. Brain regions with significant correlations often appear in clusters because they are connected in their neuroanatomy and function. Clusters include regions:

[0250] A: Hypothalamus

[0251] B: Dorsal hippocampus CA1, CA3, dentate gyrus

[0252] C: Thalamus

[0253] D: Sensorimotor CTX and dorsal striatum - (motor CTX, anterior cingulate, primary SS CTX), dorsal striatum

[0254] E. Prefrontal CTX and Ventral Striatum - (prelimbic ctx, infralimbic ctx, ventral and lateral orbital), (ventral striatum)

[0255] F. Amygdala and piriform / insula CTX

[0256] G. Ventral hippocampus and temporal CTX-CA1, CA3, dentate gyrus

[0257] H. Cerebellum - all lobes, peduncles 1 and 2, medial cerebellar nucleus, (cerebellar dome)

[0258] I. Reticular Activating System Medulla and Cerebellum - (intermediate nucleus, copula, lobule X), (gigantocellular, parabrachial, parvocellular reticular, nucleus tractus solitarius, vestibular nucleus, principal sensory nucleus of the trigeminal nerve)

[0259] J. Cerebellum and medulla and entorhinal CTX - (paramedian lobule, paraflocculus cerebellum, lobule), (ventral subiculum, entorhinal cortex, exorhinal cortex), (median raphe, locus coeruleus, trapezoid body, dorsomedial tegmentum, facial nucleus, subcoeruleus nucleus, pontine reticular nucleus, cochlear nucleus, dorsal paragigantocellular nucleus)

[0260] K. Midbrain dopamine - substantia nigra pars compacta, substantia nigra pars reticulata, ventral tegmentum

[0261] L. Hypothalamus connection, amygdala

[0262] M. Reticular activating system connections, cerebellar connections, raphe connections, hippocampus, reticular activating system

[0263] N. Amygdala connection, medulla

[0264] O. Midbrain dopamine connections, ventral hippocampus

[0265] P. Midbrain dopamine connections, hypothalamus

[0266] The diagonal separates the different experimental groups, and the pixel positions are mirror images on the diagonal (areas G and M are marked with arrows for illustration). Area AP shows clustered brain regions with functional relationships highlighted, and illustrates the default mode network in the control group (data not shown). Brain regions with significant correlations may also appear in clusters because they are connected in their neuroanatomy and function. Overall, it was observed that the injury group network showed low connectivity, while the treatment group network showed high connectivity. The injury group network also showed low connectivity compared to the control group (data not shown). The treatment group network also showed high connectivity compared to the control group (data not shown).

[0267] refer to Figure 3 In region G, it was observed that the ventral hippocampus in the injury group showed low connectivity compared to the control group (data not shown), while the treatment group showed high connectivity compared to the injury group and the control group. Specific network connections (including the control group) are shown in the table below.

[0268] Region G-hippocampus / amygdala / temporal cortex; control group (CG), injury group (IG), treatment group (TG).

[0269]

[0270]

[0271] Differences in the 3D organization and connectivity of these brain regions are also determined by Figure 4A (Injury group) and Figure 4B Glass brain illustration in (treated group). As shown, connectivity of key nodes of the ventral hippocampus, especially with the amygdala, limbic cortex, and reticular nucleus of the midbrain, was lost in the lesion group and was high in the treated group. High connectivity of the ventral hippocampus with key nodes of the temporal cortex was also observed in the treated group.

[0272] Resting state functional connectivity analysis is suitable for identifying subtle changes in traumatically damaged brain tissue associated with cognitive and emotional symptoms of brain injury. Loss of connectivity and aggregation in the injury group shortens path length or aggregates neural connections, thereby reducing the metabolic cost of signal transduction. In the absence of treatment, the amygdala remains largely disconnected from the ventral hippocampus and adjacent areas. It is recognized that low connectivity is largely associated with cognitive impairment and neurodegeneration. Region G is associated with cognition, learning and memory. The high connectivity observed in the treatment group may reflect the reorganization of integrated neural networks to preserve function in response to brain injury.

[0273] refer to Figure 3 In region M, it was observed that the hippocampus in the injury group showed low connectivity compared to the control group (data not shown), while the treatment group showed high connectivity compared to the injury group and the control group. Specific network connections (including the control group) are shown in the table below.

[0274] Region M-hippocampus / reticular activating system; control group (CG), injury group (IG), treatment group (TG).

[0275]

[0276] (*) Low level of connectivity observed.

[0277] Differences in the 3D organization and connectivity of these brain regions are also determined by Figure 6As shown, the ventral hippocampus had lost connectivity with key nodes of the reticular activating system in the lesioned group and was hyperconnected in the treated group.

[0278] In the absence of treatment, the reticular activating system remains largely disconnected from the ventral hippocampus and adjacent areas. It is well established that low connectivity is largely associated with cognitive impairment, memory, and attention. Region M is associated with cognition, learning, and memory. The high connectivity observed in the treatment group, including compared to the control group, may reflect the reorganization of the integrated neural network to preserve function in response to brain injury and provide a therapeutic benefit leading to functional recovery.

[0279] Example. Edema and ventricular volume. Figure 5 The volume of the lateral ventricles (fimbria / septum) at the level of impact calculated and compared using a one-tailed T test is shown. The ventricular volume in the injured group was significantly increased compared to the control group. The treated group showed a complete response / cure, with the ventricular volume returning to normal levels, without any significant difference between the control and treated groups.

[0280] Example. Motor behavior. Using a standard balance beam performance test, for the balance beam task, the total error frequency (one-way ANOVA, F (3,21) =1.42, P = 0.26) or total beam traversal time (one-way ANOVA, F (3,21) =2.40, P=0.1). However, there were significant differences in errors per wide and middle segment (p<0.0001). Using the standard rotarod performance test, animals in the injured group demonstrated significantly shorter latency to fall (69.8±5.5 seconds) compared to the control group (105.4±7.6 seconds, P=0.01). The treated group demonstrated an improvement in latency to fall (84.0±9.0 seconds), with a significant trend (P=0.2). However, the differences observed in the NOR test did not appear to vary with changes in motor behavior; no significant differences in distance traveled were observed in any group due to any motor impairment. (One-way ANOVA, F (3,21) =1.22, P=0.32).

[0281] Example. Human vasopressin V 1a Receptor binding assay. Expression of human V in CHO cells 1a The cell line of the receptor (hereafter referred to as hV 1a Cell lines) were obtained from Dr. Michael Brownstein, NIMH, Bethesda, MD, USA. 1aThe cDNA sequence is described by Thibonnier et al., Journal of Biological Chemistry, 269, 3304-3310 (1994), and the expression method is the same as described by Morel et al. (1992). 1a The cell line was grown in α-MEM with 10% fetal bovine serum and 250ug / ml G418 (Gibco, Grand Island, NY, USA). For competitive binding assays, hV1a cells were seeded into 6-well culture plates from confluent flasks at a 1:10 dilution and maintained in culture for at least two days. The culture medium was then removed and the cells were washed with 2ml binding buffer (25mM Hepes, 0.25% BSA, 1×DMEM, pH=7.0). 990μl binding buffer containing 1nM 3H-AVP was added to each well, followed by 10μl of serially diluted example compounds dissolved in DMSO. All incubations were performed in triplicate, and the dose inhibition curve consisted of total binding (DMSO) and 5 concentrations (0.1, 1.0, 10, 100 and 1000nM) of the test agent, including IC 50 . 100 nM cold AVP (Sigma) was used to assess nonspecific binding. Cells were incubated at 37°C for 45 minutes, the assay mixture was removed and each well was washed three times with PBS (pH = 7.4). 1 ml of 2% SDS was added to each well, and the culture plate was allowed to stand for 30 minutes. The entire contents of the wells were transferred to a scintillation vial. Each well was rinsed with 0.5 ml PBS, which was then added to the corresponding vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, Georgia) was then added at 3 ml per vial. Samples were counted in a liquid scintillation counter (Beckman LS3801). IC was calculated by Prism curve fitting software 50 value.

[0282] In this assay, all alkanedioates and amides exemplified in the previous examples were tested dissolved in DMSO. Binding curves were generated according to the method described by Thibonnier et al. (1994). 3 H]-AVP was added to hV1a cell cultures, followed by 10-fold dilutions of each test compound. All active compounds showed dose-dependent competition binding curves, IC 50 and K i The value is characterized by the expression V 1a V in the recipient CHO cells (hV1a cell line) 1a For example, Example 225 shows high affinity binding to the IC 50 (1.86-2.13 nM) and Ki Dose-dependent competition binding curve with values ​​of (1.14-1.30 nM).

[0283] Binding affinities (IC 50 ) and inhibition constant (K i ) are shown in the table below.

[0284]

[0285]

[0286]

[0287]

[0288] Example. Human vasopressin V 1b Receptor expressing cells. Human vasopressin receptor 1b (hV1b) 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 mammalian cell expression vector pCI-neo (Promega) at the EcoR1 site. Recombinant plasmids carrying hV1b cDNA were identified from transformed E. coli clones and used to transfect Chinese hamster ovary cells (CHO-K1, ATCC). Two micrograms of hV1b receptor DNA were introduced into 10 cells cultured in 6-well culture plates using Fugene-6 mediated transfection technology (Boehringer Mannheim). 5The cells were then cultured in 100% 1% 1% CHO cells. Twenty-four hours after transfection, the cells were then cultured under G-418 (0.25 mg / ml) supplemented to the culture medium. Three days later, limiting dilutions were performed to obtain single cell clones in 96-well culture plates. After a 2-week growth period, the single clones were expanded into two sets of 12-well culture plates. When confluence was reached, a set of wells was analyzed for its ability to bind tritiated arginine-vasopressin (NEN). Nine positive clones were initially identified from the 60 clones screened, and the clone that confirmed the highest AVP binding was saved as a permanent cell line for hV1b affinity screening.

[0289] Example. Based on human or rat vasopressin V 1b Receptor binding assay of cells. V1b cell lines (expressing human or rat V 1b Receptor cells) at 75cm 2Flasks were grown in α-MEM medium supplemented with 10% fetal bovine serum and 250ug / ml G418 (Gibco, Grand Island, NY). For competitive binding assays, hV1b cells were dissociated using an enzyme-free, PBS-based cell dissociation solution (Specialty Media, Phillipursburg, NJ) following the manufacturer's protocol. Cells were seeded into 12-well culture plates at a ratio of one flask to 18 plates (ratio should be adjusted based on confluence) and maintained in culture for 2-3 days. The medium was then removed and the cells were washed once with 2ml binding buffer (25mM Hepes, 0.25% BSA, 1×DMEM, pH=7.0) at room temperature. 990μl of binding buffer containing 1nM 3H-AVP was added to each well, followed by 10μl of serially diluted test compound or cold AVP, all dissolved in DMSO. All incubations were performed in triplicate, and dose inhibition curves consisted of total binding (DMSO only) and 5 concentrations (0.1, 1.0, 10, 100, and 1000 nm) of test agent or cold AVP, including the IC50. Cells were incubated at 37°C in a humidified incubator for 30 min. The assay mixture was then removed and each well was washed three times with PBS (pH = 7.4). After washing, 1 ml of 2% SDS was added to each well, and the culture plate was allowed to stand at room temperature for 15 minutes. The plate was gently tapped to ensure that the lysed cells were detached. The entire contents of the well were transferred to a scintillation vial. Each well was then rinsed with 0.5 ml PBS and added to the corresponding vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, Georgia) was then added at 3 ml per vial. Samples were counted in a liquid scintillation counter (Beckman LS3801). IC50 and Ki values ​​were calculated using Prism curve fitting software. The illustrative compounds shown in the preceding tables exhibit binding constants greater than 100 nM or greater than 1000 nM. Illustrative inhibition data (Ki, nM) for selected example compounds are shown in the following table.

[0290]

[0291] Example. Phosphatidylinositol conversion (V 1a ) inhibition. The physiological effects of vasopressin are mediated by specific G protein-coupled receptors. q / G 11The agonist or antagonist characteristics of the compounds of the present invention can be determined by their ability to inhibit vasopressin-mediated phosphatidylinositol conversion by the procedure described in the following paragraphs. In this analysis, illustrative compound examples 35, 44, 88, 110 and 133 were tested and found to be vasopressin V 1a Antagonist.

[0292] Example. Vasopressin V 1b Inhibition of phosphatidylinositol conversion mediated by vasopressin V, a functional assay for antagonist activity. The physiological actions of vasopressin are mediated via specific G protein-coupled receptors. 1b The receptor is coupled to a G protein which is coupled to cAMP. The agonist or antagonist characteristics of the compounds described herein can be determined by their ability to inhibit vasopressin-mediated phosphatidylinositol turnover using conventional methods, including the procedures described in the following paragraphs.

[0293] Cell culture and labeling of cells. Three days prior to analysis, subconfluent cultures of hV1a or hV1b cells were dissociated and seeded in 6-well tissue culture plates from 75 cm 2 The flask was inoculated with approximately 100 wells (equivalent to a 12:1 split ratio). Each well contained 1 mL of 2 μCi [ 3 H] myo-inositol (American Radiolabeled Chemicals, St. Louis, MO, USA) in the growth medium.

[0294] Expressing human or rat V 1b The recipient cells were grown in alpha-modified minimal essential medium containing 10% fetal bovine serum and 0.25 mg / ml G418. Three days before the assay, subconfluent cells were dissociated and seeded in 6-well tissue culture plates, one from each 75 cm 2 The flask was inoculated with approximately 100 wells (equivalent to a 12:1 split ratio). Each well contained 1 ml of 2 μCi [ 3 H] myo-inositol (American Radiolabeled Chemicals, St. Louis, MO) in the growth medium.

[0295] Cultivation (V 1a and V 1bAll assays were performed in triplicate, except for basal and 10 nM AVP (n=6 for both). AVP ((arginine vasopressin), Peninsula Labs, Belmont, CA, USA (No. 8103)) was dissolved in 0.1 N acetic acid. The test agent was dissolved in DMSO and diluted in DMSO to 200 times the final assay concentration. The test agent and AVP (or the corresponding volume of DMSO) were added as 5 μL in DMSO to 12×75 mm glass tubes containing 1 mL of assay buffer (Tyrode's balanced salt solution containing 50 mM glucose, 10 mM LiCl, 15 mM HEPES pH 7.4, 10 μM phosphono dipeptide and 100 μM bacitracin). The incubation order was randomized. Incubation was initiated by removing the pre-labeled medium, washing the monolayer once with 1 mL 0.9% NaCl and transferring the contents of the assay tube to the corresponding well. The plates were incubated at 37° C. for 1 hour. Incubations were terminated by removing the incubation medium and adding 500 μL of ice-cold 5% (w / v) trichloroacetic acid and allowing the wells to stand for 15 min.

[0296] [ 3 H] inositol phosphate (V 1a and V 1b ) measurement. BioRad Poly-Prep Econo-columns were filled with 0.3mL AG 1 X-8 100-200 formate resin. The resin was mixed with water 1:1, and 0.6mL was added to each column. The column was then washed with 10mL water. A scintillation bottle (20mL) was placed under each column. For each well, the contents were transferred to a microcolumn, followed by washing the well with 0.5mL distilled water, which was also added to the microcolumn. The column was then washed twice with 5mL 5mM myo-inositol to elute free myo-inositol. An aliquot (1mL) was transferred to a 20mL scintillation bottle and 10mL Beckman Ready ProteinPlus was added. After the myo-inositol wash was completed, an empty scintillation bottle was placed under the column and eluted with three additions of 1mL 0.5M ammonium formate containing 0.1N formic acid. 3H] inositol phosphate. Elution conditions are optimized to recycle inositol mono-, di- and triphosphates, without eluting metabolically more inert tetra-, penta- and hexaphosphates. 10 mL of high salt capacity scintillation fluid, such as Tru-Count High Salt Capacity or Packard Hionic-Fluor, is added to each sample. By adding 1 mL of 2% sodium dodecyl sulfate (SDS) to each well, the well is allowed to stand for at least 30 min, and the solution is transferred to a 20 mL scintillation bottle, 10 mL of Beckman Ready Protein Plus scintillation fluid is subsequently added thereto, to measure inositol lipids. Samples are counted for 10 min in a Beckman LS 3801 liquid scintillation counter. The total inositol incorporation in each well is calculated as the sum of free inositol, inositol phosphates and inositol lipids.

[0297] Data analysis (V 1a and V 1b ): Concentration inhibition experiments. The concentration-response curves of AVP and the concentration-inhibition curves of the test agents relative to 10 nM AVP were analyzed by nonlinear least squares curve fitting with a 4-parameter logistic function. Parameters of basal and maximum inositol phosphates EC 50 or IC 50 and the Hill coefficient were varied to achieve the best fit. Curve fits were weighted under the assumption that the standard deviation is proportional to the dpm of radioactivity. A complete concentration-response curve for AVP was plotted in each experiment. IC 50 Value converted to K i value, which is based on the EC of AVP in the same experiment by applying the Cheng-Prusoff equation 50 Reflects the antagonistic activity of the signal transduction molecule IP3 relative to AVP. Inositol phosphates are expressed as dpm / 10 6 dpm total inositol incorporated.

[0298] Data analysis (V 1a and V 1b ): Competitive experiment. Test the V of the test agent 1a Competition experiments consist of concentration-response curves of AVP in the absence and presence of two or more concentrations of the test agent. 1b Competition experiments 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 the following competition logistic equation:

[0299]

[0300] where Y is the dpm of inositol phosphate, B is the basal inositol phosphate concentration, M is the maximum increase in inositol phosphate concentration, A is the concentration of the agonist (AVP), and E is the EC of the agonist. 50 , D is the concentration of the antagonist (test agent), K is the K of the antagonist i , and Q is the cooperativity (Hill coefficient).

[0301] Compound Example 225 50 (2.68 nM) and K i (0.05 nM) produced a dose-dependent inhibition of the effect of AVP. These values ​​are consistent with the high affinity binding of Example 225 and its ability to bind to human V 1a The results were consistent with inhibition of inositol lipid synthesis at the receptor.

[0302] Example. Pharmacokinetics. The compounds described herein are rapidly absorbed after oral administration. The compounds described herein cross the blood-brain barrier and reach therapeutically effective concentrations in the CNS. The compounds described herein can be administered according to a wide variety of regimens, including, but not limited to, qd, bid, and the like. When administered according to various regimens, including, but not limited to, qd, bid, the compounds described herein exhibit dose-related increases in Cmax and AUC. For example, bid administration exhibited 1.7-fold accumulation and improved T for AVN246. 1 / 2 .

[0303] Examples. General synthetic pathways A proximal amide approach that permits synthetic variation at distal sites; the proximal amide is set first, followed by the distal amide diversity through parallel synthesis.

[0304]

[0305] A distal amide approach permits synthetic variation at the proximal site; the distal amide is set first, followed by the proximal amide diversity through parallel synthesis.

[0306]

[0307] The synthesis of AVN251 (SRX251) and AVN251.HCl is shown below. All other compounds were prepared in a similar manner with appropriate selection of starting materials.

[0308]

[0309] Additional details and alternative syntheses for preparing the compounds described herein are described in U.S. Pat. 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 methods described in U.S. Pat. No. 7,119,083. Additional details are described in Guillon, CD et al. Azetidinones as vasopressin Via antagonists. Bioorg Med Chem, 15(5): 2054-80 (2007).

[0310] Compound Examples

[0311] Example 1. (4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride. A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (Evans, U.S. Pat. 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 / milliequivalent of the acetic acid derivative), resulting in vigorous gas evolution. After 45 minutes, all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to give the title compound as an off-white solid after drying in vacuo for 2 h.

[0312] Example 1A. (4(R)-phenyloxazolidin-2-on-3-yl)acetyl chloride. Example 1A was prepared following the procedure of Example 1, except that (4(R)-phenyloxazolidin-2-on-3-yl)acetic acid was used in place of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (see Evans & Sjogren, Tetrahedron Lett. 26:3783 (1985)).

[0313] 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) (prepared according to Evans in U.S. Pat. No. 4,665,171) in 20 mL of anhydrous methanol was treated with 5 equivalents of acetyl chloride per hour 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 CHCl. 2 Cl 2 and 50 mL of Na 2 CO 3 The organic layer was evaporated and dried (MgSO 4 ) to give the title compound (1.001 g, 94%) as a colorless oil; 1 H NMR (CDCl 3)δ3.37(d,J==18.0Hz,1H),3.69(s,3H),4.13(t,J=8.3Hz,1H),4.28(d,J=18.0Hz,1H ), 4.69 (t, J = 8.8Hz, 1H), 5.04 (t, J = 8.4Hz, 1H), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).

[0314] 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 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred at about -70°C for 1 h before the addition of MeI (1.59 mL, 25.51 mmol). After complete conversion of the azetidinone, the mixture was heated to 40 ℃ with NH 4 The reaction was quenched with saturated aqueous Cl solution and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite solution and saturated aqueous NaCl solution. The resulting organic layer was dried (MgSO 4 ) and evaporated to give the title compound (mixture of diastereomers) (1.06 g, 93%) as a white solid; 1 H NMR (CDCl 3 )δ1.07 / 1.53(d / d,J=7.5Hz,3H),3.59 / 3.74(s / s,3H),3.85 / 4.48(q / q,J=7.5Hz,1H),4.10-4.1 4(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).

[0315] 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 at 0°C was added 14.3 mL (12.04 mmol) of a 0.84 M solution of LiOH in water. The reaction mixture was then stirred at ambient temperature for 3 h. After complete hydrolysis of the azetidinone, the MeOH was removed by evaporation and the crude residue was dissolved in CH 2 Cl 2 The organic layer was dried (MgSO 4) and evaporated to give the title compound (racemic mixture) (0.906 g, 96%) as a white solid; 1 HNMR (CDCl 3 )δ1.13 / 1.57(d / d,J=7.5Hz,3H),3.75 / 4.50(q / q,J=7.5Hz,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).

[0316] Example 1E. 2-(4(S)-phenyloxazolidin-2-one-3-yl)propanoyl chloride. 1 equivalent of Example 1D and 1.3 equivalents of oxalyl chloride were dissolved in 200 mL of CH 2 Cl 2 A solution of 4-(1-(4-(4-piperidin-2-yl)-4-yl)-4-nitropropionic acid derivative (150 mL / g propionic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 μl / mmol propionic acid derivative), resulting in vigorous gas evolution. After 45 min, all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to give the title compound as an off-white solid after drying in vacuo for 2 h.

[0317] Example 2. General procedure for forming amides from activated ester derivatives. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of anhydrous 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 a saturated aqueous solution of sodium bicarbonate. The organic layer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1 H NMR (CDCl 3 )δ1.39(s,9H),2.61(dd,J=6.5Hz,J=17.2Hz,1H),2.98(dd,J=3.7Hz,J=17.0Hz,1H),4.41(dd,J=5.9Hz,J=15.3Hz,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).

[0318] Examples 2A-2C and 3-5 were prepared according to the procedure of Example 2, except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester was replaced with an appropriate amino acid derivative and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine.

[0319] Example 2A. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazineamide. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave 5.89 g (quantitative yield) of the title compound as an off-white oil; 1 H NMR (CDCl 3 )δ1.40(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).

[0320] Example 2B. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3-(trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) to give 5.41 g (98%) of the title compound as an off-white solid; 1 H NMR (CDCl 3 )δ1.40(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).

[0321] Example 2C. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazineamide. N-Benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitative yield) of the title compound as an off-white oil; 1 H NMR (CDCl 3 )δ1.43(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).

[0322] Example 3. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazineamide. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave 5.89 g (quantitative yield) of the title compound as an off-white oil; 1 H NMR (CDCl 3 )δ1.40(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).

[0323] Example 4. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3-(trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) to give 5.41 g (98%) of the title compound as an off-white solid; 1 H NMR (CDCl 3)δ1.40(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).

[0324] Example 5. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazineamide. N-Benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitative yield) of the title compound as an off-white oil; 1 HNMR (CDCl 3 )δ1.43(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).

[0325] Example 5A. N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine tert-butyl ester. At 0°C, dichloromethane (8 mL) containing N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmol) was treated with tert-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask. After completion (TLC), the reaction was quenched with dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane / methanol) to give the title compound (0.292 g, 77%) as a colorless oil; 1 H NMR (CDCl 3)δ1.44(s,9H);3.68(dd,J=2.9Hz,J=9.3Hz,1H);3.87(dd,J=2.9Hz,J=9.3Hz,1H);4.22(t,J=7.1Hz, 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).

[0326] Example 5B. O-(Benzyl)-D-serine tert-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 resulting mixture was washed twice with phosphate buffer (pH=5.5), once with saturated aqueous potassium bicarbonate solution, and evaporated to give 0.329 g (quantitative yield) of the title compound as an off-white solid; 1 H NMR (CD 3 OD)δ1.44(s,9H);3.48(dd,J=J'4.2Hz,1H);3.61(dd,J=4.0Hz,J=9.2Hz,1H);3.72(dd,J =4.6Hz, J=9.2Hz, 1H); 4.47 (d, J=12.0Hz, 1H); 4.55 (d, J=12.0Hz, 1H); 7.26-7.33 (m, 5H).

[0327] Example 6. General procedure for the formation of amides from carboxylic acids. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated sequentially by the 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. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane / methanol eluent), the reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate and distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1 H NMR (CDCl 3) δ1.39 (s, 9H); 2.61 (dd, J = 6.5Hz, J = 17.2Hz, 1H); 2.98 (dd, J = 4.2Hz, J = 17.2Hz, 1H); 4.41 (dd, J = 5.9Hz, J = 15.3Hz, 1H); 4.5 0-4.57(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).

[0328] Examples 7-7H were prepared according to the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with an appropriate amino acid derivative and 3-(trifluoromethyl)benzylamine was replaced with an appropriate amine.

[0329] Example 7. N-Benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester (1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) 3-(trifluoromethyl)benzylamine gave 1.67 g (quantitative yield) of Example 7 as an off-white solid. Example 7 showed consistent with the specified structure. 1 H NMR spectroscopy.

[0330] Example 7A. N-Benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester (1.36 g, 4.03 mmol) and 0.746 g (4.43 mmol) of 1-cyclohexylpiperazine gave 1.93 g (98%) of Example 7A as an off-white solid; 1 H NMR (CDCl 3 )δ1.02-1.12(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).

[0331] Example 7B. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL (2-fluoro-3-trifluoromethyl)benzylamine gave 0.365 g (quantitative yield) of Example 7B as an off-white solid; 1 H NMR (CDCl 3 )δ1.38(s,9H);2.59(dd,J=6.5Hz,J=17.0Hz,1H);2.95(dd,J=4.3Hz,J=17.0Hz,1H);4.46-4.56(m ,3H); 5.11 (s, 2H); 5.94-5.96 (m, 1H); 7.15 (t, J = 8.0Hz, 1H); 7.30-7.36 (m, 5H); 7.47-7.52 (m, 2H).

[0332] Example 7C. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-α-methylbenzyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL (S)-α-methylbenzylamine gave 0.281 g (90%) of Example 7C as an off-white solid; 1 H NMR (CDCl 3 )δ1.41(s,9H);1.44(d,J=7.0Hz,3H);2.61(dd,J=7.0Hz,J=17.0Hz,1H);2.93(dd,J=4.0Hz,J=17.5Hz ,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).

[0333] Example 7D. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-α-methylbenzyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL (R)-α-methylbenzylamine gave 0.281 g (90%) of Example 7D as an off-white solid; 1 H NMR (CDCl 3)δ1.38(s,9H);1.43(d,J=6.9Hz,3H);2.54(dd,J=7.3Hz,J=17.2Hz,1H);2.87(dd,J=4.1Hz,J=17.3Hz ,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).

[0334] Example 7E. N-Benzyloxycarbonyl-D-aspartic acid γ-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. N-Benzyloxycarbonyl-D-aspartic acid γ-tert-butyl ester (0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol) of N-methyl-N-(3-trifluoromethylbenzyl)amine gave 0.287 g (65%) of Example 7E as an off-white solid; 1 H NMR (CDCl 3 )δ1.40(s,9H);2.55(dd,J=5.8Hz,J=15.8Hz,1H);2.81(dd,J=7.8Hz,J=15.8Hz,1H);3.10(s,3H);4.2 5(d,J=15.0Hz,1H); 4.80(d,J=15.5Hz,1H); 5.01-5.13(m,3H); 5.52-5.55(m,1H); 7.25-7.52(m,10H).

[0335] Example 7F. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (84 mg, 0.25 mmol) and 47 mg of (S)-1-(3-trifluoromethylphenyl)ethylamine gave 122 mg (quantitative yield) of Example 7F as an off-white solid. Example 7F exhibited a structure consistent with the assigned 1 H NMR spectroscopy.

[0336] Example 7G. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (150 mg, 0.44 mmol) and 83 mg of (R)-1-(3-trifluoromethylphenyl)ethylamine gave 217 mg (quantitative yield) of Example 7G as an off-white solid. Example 7G exhibited a structure consistent with the specified 1 H NMR spectroscopy.

[0337] Example 7H. N-Benzyloxycarbonyl-D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-glutamic acid α-methyl ester (508 mg, 1.72 mmol) and 317 mg (1.81 mmol) of 3-(trifluoromethyl)benzylamine gave 662 mg (85%) of Example 7H as an off-white solid. Example 7H showed a structure consistent with the specified 1 H NMR spectroscopy.

[0338] Example 8. General procedure for the hydrogenation of benzyloxycarbonylamine. L-Aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide. A suspension of 2.23 g (4.64 mmol) of N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide and palladium (5 wt.% on activated carbon, 0.642 g) in 30 mL of methanol was maintained under a hydrogen atmosphere until complete conversion as determined by thin layer chromatography (95:5 dichloromethane / methanol eluent). The reaction 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 (CDCl 3 )δ1.42(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).

[0339] Examples 9-13P were prepared according to the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide was replaced with the appropriate amino acid derivative.

[0340] Example 9. L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g (98%) of Example 9 as an off-white oil; 1 H NMR (CDCl 3 ): δ1.42(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).

[0341] Example 10. D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide (1.41 g, 2.93 mmol) gave 0.973 g (96%) of Example 10 as an off-white oil; 1 H NMR (CDCl 3 ): δ1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J = 7.1Hz, J = 16.8Hz, 1H); 2.84 (dd, J = 3.6Hz, J = 16.7Hz,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).

[0342] Example 11. L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide (5.41 g, 10.9 mmol) was used to obtain 3.94 g (quantitative yield) of Example 11 as an off-white oil; 1 H NMR (CDCl 3 ): δ1.41(s,9H); 1.73-1.89(m,3H); 2.05-2.16(m,1H); 2.32-2.38(m,2H); 3.47(dd , J=5.0Hz, J=7.5Hz, 1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).

[0343] Example 12. L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 12 as an off-white oil; 1 H NMR (CDCl 3 )δ1.39(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).

[0344] Example 13. D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide (1.667 g, 3.37 mmol) to give 1.15 g (94%) of Example 13 as an off-white oil; 1 H NMR (CDCl 3 )δ1.41(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).

[0345] Example 13A. L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) to give 1.30 g (93%) of Example 13A as an off-white oil; 1 H NMR (CDCl 3 )δ1.02-1.25(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 = 4.8Hz, J = 8.5Hz, 1H); 3.44 (t, J = 9.9Hz, 2H); 3.56 (t, J = 9.9Hz, 2H).

[0346] Example 13B. D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide (0.36 g, 0.72 mmol) gave 0.256 g (92%) of Example 13B as an off-white oil; 1 H NMR (CDCl 3 )δ1.39(s,9H);2.50(brs,2H);2.74(dd,J=7.0Hz,J=16.5Hz,1H);2.86(dd,J=4.8Hz,J=16.8Hz,1H);3.89(brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J = 7.8Hz, 1H); 7.48 (t, J = 7.3Hz, 1H); 7.56 (t, J = 7.3Hz, 1H); 7.97-8.02 (m, 1H).

[0347] Example 13C. D-aspartic acid β-tert-butyl ester α-[(S)-α-methyl]benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-α-toluenemethyl]amide (0.275 g, 0.65 mmol) gave 0.17 g (90%) of Example 13C as an off-white oil; 1 H NMR (CDCl 3 )δ1.40(s,9H);1.47(d,J=6.9Hz,3H);1.98(brs,2H);2.49(dd,J=7.9Hz,J=17.7Hz,1H);2.83(dd, J=3.6Hz, J=16.7Hz,1H); 3.69(brs,1H); 4.99-5.10(m,1H); 7.19-7.33(m,5H); 7.65-7.68(m,1H).

[0348] Example 13D. D-aspartic acid β-tert-butyl ester α-[(R)-α-methylbenzyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-α-toluenemethyl]amide (0.273 g, 0.64 mmol) gave 0.187 g (quantitative yield) of Example 13D as an off-white oil; 1 H NMR (CDCl 3 )δ1.38(s,9H);1.46(d,J=6.9Hz,3H);1.79(brs,2H);2.51(dd,J=7.8Hz,J=17.5Hz,1H);2.87(dd, J=3.6Hz, J=16.9Hz, 1H); 4.19 (brs, 1H); 4.99-5.11 (m, 1H); 7.18-7.34 (m, 5H); 7.86-7.90 (m, 1H).

[0349] Example 13E. D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave 0.195 g (95%) of Example 13E as an off-white oil. Example 13E showed a structure consistent with the assigned 1 H NMR spectroscopy.

[0350] Example 13F. L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g (98%) of Example 13F as an off-white oil;1 H NMR (CDCl 3 ): δ1.42(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).

[0351] Example 13G. D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide (1.41 g, 2.93 mmol) gave 0.973 g (96%) of Example 13G as an off-white oil; 1 H NMR (CDCl 3 ): δ1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J = 7.1Hz, J = 16.8Hz, 1H); 2.84 (dd, J = 3.6Hz, J = 16.7Hz,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).

[0352] Example 13H. L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide (5.41 g, 10.9 mmol) was used to give 3.94 g (quantitative yield) of Example 13H as an off-white oil; 1 H NMR (CDCl 3 ): δ1.41(s,9H); 1.73-1.89(m,3H); 2.05-2.16(m,1H); 2.32-2.38(m,2H); 3.47(dd , J=5.0Hz, J=7.5Hz, 1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).

[0353] Example 13I. L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 13I as an off-white oil; 1 H NMR (CDCl 3)δ1.39(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).

[0354] Example 13J. D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide (1.667 g, 3.37 mmol) to give 1.15 g (94%) of Example 13J as an off-white oil; 1 H NMR (CDCl 3 )δ1.41(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).

[0355] Example 13K. L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) to give 1.30 g (93%) of Example 13K as an off-white oil; 1 H NMR (CDCl 3 )δ1.02-1.25(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 = 4.8Hz, J = 8.5Hz, 1H); 3.44 (t, J = 9.9Hz, 2H); 3.56 (t, J = 9.9Hz, 2H).

[0356] Example 13L. D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide (0.36 g, 0.72 mmol) gave 0.256 g (92%) of Example 13L as an off-white oil; 1 H NMR (CDCl 3)δ1.39(s,9H);2.50(brs,2H);2.74(dd,J=7.0Hz,J=16.5Hz,1H);2.86(dd,J=4.8Hz,J=16.8Hz,1H);3.89(brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J = 7.8Hz, 1H); 7.48 (t, J = 7.3Hz, 1H); 7.56 (t, J = 7.3Hz, 1H); 7.97-8.02 (m, 1H).

[0357] Example 13M. D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide (120 mg, 0.24 mmol) gave 91 mg (91%) of Example 13M as an off-white oil and was consistent with the specified structure. 1 H NMR spectroscopy.

[0358] Example 13N. D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide (217 mg, 0.44 mmol) gave 158 mg (quantitative yield) of Example 13N as an off-white oil and exhibited a structure consistent with the specified 1 H NMR spectroscopy.

[0359] Example 13O. D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave 0.195 g (95%) of Example 13O as an off-white oil and appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0360] Example 13P. D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzamide. N-Benzyloxycarbonyl-D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzamide (764 mg, 1.69 mmol) gave 516 mg (96%) of Example 13P as an off-white oil and showed consistent with the specified structure. 1 H NMR spectroscopy.

[0361] Example 14. General procedure for the formation of 2-azetidinones from imines and acetyl chloride.

[0362] Step 1: General procedure for the formation of imines from amino acid derivatives. A solution of 1 equivalent of an α-amino acid ester or amide in dichloromethane is treated sequentially with 1 equivalent of an appropriate aldehyde and a drying agent such as magnesium sulfate or silica gel in an amount of about 2 grams of drying agent per gram of starting α-amino acid ester or amide. The reaction is stirred at ambient temperature until all reactants are consumed as measured by thin layer chromatography. The reaction is typically complete within one hour. The reaction mixture is then filtered, the filter cake is washed with dichloromethane, and the filtrate is concentrated under reduced pressure to give the desired imine which is used directly in the subsequent step.

[0363] Step 2: General procedure for the 2+2 cycloaddition of imines and acetyl chloride. A solution of the imine in dichloromethane (10 mL dichloromethane / 1 g imine) is cooled to 0°C. To this cooled solution is added 1.5 equivalents of an appropriate amine, typically triethylamine, followed by dropwise addition of 1.1 equivalents of an appropriate acetyl chloride in dichloromethane, such as that described in Example 1 (10 mL dichloromethane / 1 g appropriate acetyl chloride). The reaction mixture is allowed to warm to ambient temperature within 1 h and is subsequently quenched by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture is partitioned between water and dichloromethane. The layers are separated and the organic layer is washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue can be used directly in other reactions or, if necessary, purified by chromatography or 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 rotation dispersion (CD / ORD). Illustratively, (αR,3S,4R) and (αS,3S,4R) β-lactam platform examples from previous syntheses can be used as CD / ORD standards.

[0364] Example 15. tert-Butyl [3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetate. Using the procedure of Example 14, the 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 (recrystallized, n-chlorobutane); mp 194-195°C.

[0365] Example 16. General procedure for 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 equiv). The resulting anion was treated with the appropriate acyl halide (1.1 equiv). 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 sequentially with 1N 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 with an appropriate eluent, such as 3:2 hexane / ethyl acetate.

[0366] Example 17. 2(RS)-(tert-Butyloxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid 2,2,2-trichloroethyl ester.

[0367] 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; mp 176-178°C.

[0368] Example 18. 2(RS)-(tert-Butyloxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. 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 under reflux. After complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform / hexanes) to give 0.17 g (82%) of Example 18 as a white solid; mp 182-184°C.

[0369] Example 18A. 2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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%) and appeared consistent with the specified structure. 1 H NMR spectroscopy.

[0370] Examples 19-25AF were prepared according to the procedure of Example 14, wherein the appropriate amino acid derivative and aldehyde were used in step 1, and the appropriate acetyl chloride was used in step 2.

[0371] Example 19. 2(S)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.52 g (4.39 mmol) of L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 2.94 g of an orange-brown oil which after flash column chromatography purification (70:30 hexanes / ethyl acetate) gave 2.06 g (70%) of Example 19 as a white solid; 1 H NMR (CDCl 3 )δ1.39(s,9H);2.46(dd,J=11.1Hz,J=16.3Hz,1H);3.18(dd,J=3.8Hz,J=16.4Hz,1H);4.12-4.17(m ,1H); 4.26 (d, J=5.0Hz, 1H); 4.45 (dd, J=6.0Hz, J=14.9Hz, 1H); 4.54 (dd, J=5.3Hz, J=9.8Hz, 1H); 4.5 8-4.66 (m, 3H); 4.69-4.75 (m, 1H); 4.81 (dd, J = 3.8Hz, J = 11.1Hz, 1H); 6.25 (dd, J = 9.6Hz, J = 15.8Hz, 1H); 6.70 (d, J = 15.8Hz, 1H); 7.14-7.17 (m, 2H); 7.28-7.46 (m, 11H); 7.62 (s, 1H); 8.27-8.32 (m, 1H).

[0372] Example 19A. 2(S)-(tert-Butyloxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-phenylvinyl)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%); 1 H NMR (CDCl 3)δ1.37(s,9H);3.11(dd,J=3.7Hz,J=17.8Hz,1H);3.20(dd,J=10.6Hz,J=17.8Hz,1H ); 4.02 (dd, J = 3.7Hz, J = 10.6Hz, 1H); 4.10-4.17 (m, 1H); 4.24 (d, J = 4.9Hz, 1H); 4.465 2-4.574(dd,J=5.9Hz,J=15.1Hz,1H); 4.58-4.76(m,4H); 6.27(dd,J=9.6Hz,J=15.8 Hz, 1H); 6.79 (d, J = 15.8Hz, 1H); 7.23-7.53 (m, 13H); 7.63 (s, 1H); 8.51-8.55 (m, 1H).

[0373] Example 20. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 3.94 g (10.93 mmol) of L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 5.53 g (75%) of Example 20 after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.36(s,9H);1.85-1.96(m,1H);2.18-2.49(m,3H);4.14-4.19(m,1H);4 .30(d,J=4.9Hz,2H); 4.44(dd,J=6.1Hz,J=14.9Hz,1H); 4.56-4.67(m,4H); 4.71-4.75(m,1H); 6.26(dd,J=9.6Hz,J=15.8Hz,1H); 6.71(d,J=15.8Hz,1 H);7.16-7.18(m,2H);7.27-7.49(m,11H);7.60(s,1H);8.08-8.12(m,1H).

[0374] Example 21. 2(S)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The imine prepared from 4.20 g (11.6 mmol) of L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 4.37 g (55%) of Example 21 after flash column chromatography purification (50:50 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.34(s,9H);2.26-2.32(m,1H);2.46-2.63(m,4H);2.75-2.89(m,4H);3.2 4-3.32(m,1H); 3.49-3.76(m,3H); 4.07-4.13(m,1H); 4.30(d,J=4.6Hz,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=9.3Hz,J=15.9Hz,1H); 6.63(d,J=15.8Hz,1H); 7.18-7.42(m,15H).

[0375] Example 22. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 3.55 g (76%) of Example 22 after flash column chromatography purification (50:50 hexanes / ethyl acetate); 1 H NMR (CDCl 3)δ1.32(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 = 8.9Hz, J = 16.0Hz, 1H); 6.62 (d, J = 16.0Hz, 1H); 7.16-7.42 (m, 15H).

[0376] Example 23. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.973 g (2.81 mmol) of D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 1.53 g (82%) of Example 23 after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.37(s,9H);3.10(dd,J=3.7Hz,J=17.8Hz,1H);3.20(dd,J=10.7Hz,J=17.8Hz,1H); 4.02(dd,J=3.6Hz,J=10.6Hz,1H); 4.11-4.17(m,1H); 4.24(d,J=4.9Hz,1H); 4.46(dd,J =5.8Hz, J=15.1Hz, 1H); 4.58-4.67 (m, 3H); 4.70-4.76 (m, 1H); 6.27 (dd, J=9.5Hz, J=15 .8Hz, 1H); 6.79 (d, J = 15.8Hz, 1H); 7.25-7.50 (m, 13H); 7.63 (s, 1H); 8.50-8.54 (m, 1H).

[0377] Example 23A. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-phenylvinyl)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 (CDCl 3 )δ1.39(s,9H);2.47(dd,J=11.2Hz,J=16.3Hz,1H);3.18(dd,J=3.8Hz,J=16.3Hz,1H);4.15(t,J=8.25,Hz 1H); 4.26 (d, J = 5.0Hz, 1H); 4.45 (dd, J = 6.0Hz, J = 15.0Hz, 1H); 4.52-4.57 (m, 3H); 4.63 (t, J = 9Hz, 1H); 4.70 (t, J = 8Hz, 1H); 4.81 (dd, J = 3.8Hz, J = 10.8Hz, 1H); 6.25 (dd, J = 9.8Hz, J = 15.8Hz, 1H); 6.70 (d, J = 15.8Hz, 1H); 7.15-7.17 (m, 2H); 7.27-7.51 (m, 11H); 7.62 (s, 1H); 8.27-8.32 (m, 1H).

[0378] Example 24. 2(R)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.15 g (3.20 mmol) of D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 1.84 g (85%) of Example 24 after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3)δ1.37(s,9H);2.23-2.39(m,4H);3.71-3.75(m,1H);4.13-4.18(m,1H);4.31(d,J=4.9Hz,1H);4.44-4.51(m,2H);4.56-4.68(m,2H ); 4.71-4.76 (m, 1H); 6.26 (dd, J = 9.5Hz, J = 15.8Hz, 1H); 6.71 (d, J = 15.8Hz, 1H); 7.25-7.52 (m, 13H); 7.63 (s, 1H); 8.25-8.30 (m, 1H).

[0379] Example 25. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. The imine prepared from 2.58 g (5.94 mmol) of L-glutamic acid γ-tert-butyl ester α-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 3.27 g (94%) of Example 25 after flash column chromatography purification (95:5 dichloromethane / methanol); 1 H NMR (CDCl 3 )δ1.32(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=8.3Hz,1H); 4.27(d,J=5.0Hz,1H); 4.31-4.55(m,4H); 4.71(t,J=8.3Hz,1 H); 4.83-4.90 (m, 1H); 6.18 (dd, J = 9.1Hz, J = 15.9Hz, 1H); 6.67 (d, J = 15.9Hz, 1H); 7.25-7.44 (m, 10H); 8.22 (brs, 1H).

[0380] Example 25A. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetate. The imine prepared from 1.282 g (3.63 mmol) of L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 1.946 g (80%) of Example 25A after flash column chromatography purification (50:50 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.15-1.26(m,6H);1.39(s,9H);1.55-1.64(m,2H);1.77-1.83(m,3H);2.22-2.35(m,2 H); 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=8.3Hz,1H);4.31-4.35(m,2H);4.58(t,J=8.8Hz,1H);4.73(t,J=8. 4Hz, 1H); 6.17 (dd, J = 8.6Hz, J = 16.0Hz, 1H); 6.65 (d, J = 16.0Hz, 1H); 7.27-7.42 (m, 10H).

[0381] Example 25B. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. The imine prepared from 0.256 g (0.70 mmol) of D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.287 g (60%) of Example 25B after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3)δ1.38(s,9H);3.12(dd,J=4.0Hz,J=17.8Hz,1H);3.20(dd,J=10.4Hz,J=17.8Hz, 1H); 4.05 (dd, J=3.9Hz, J=10.4Hz, 1H); 4.14 (dd, J=J'8.2Hz, 1H); 4.25 (d, J=4.9Hz ,1H);4.59-4.67(m,4H);4.74(t,J=8.3Hz,1H);6.36(dd,J=9.6Hz,J=15.8Hz,1H); 6.83(d,J=15.8Hz,1H); 7.02-7.07(m,1H); 7.28-7.55(m,12H); 8.44-8.48(m,1H).

[0382] Example 25C. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. The imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-tert-butyl ester [(S)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.219 g (63%) of Example 25C after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.35(s,9H);1.56(d,J=7.0Hz,3H);2.97(dd,J=3.5Hz,J=18.0Hz,1H);3.15(dd,J=11.0Hz,J=17.5 Hz, 1H); 4.01 (dd, J = 3.0Hz, J = 11.0Hz, 1H); 4.14 (t, J = 8.5Hz, 1H); 4.24 (d, J = 5.0Hz, 1H); 4.57 (dd, J = 5 .0Hz, J=9.5Hz, 1H); 4.64 (t, J=8.8Hz, 1H); 5.07 (t, J=8.5Hz, 1H); 5.03-5.09 (m, 1H); 6.43 (dd, J=9.5 Hz, J=16.0Hz, 1H); 6.83 (d, J=16.0Hz, 1H); 7.16-7.20 (m, 1H); 7.27-7.49 (m, 14H); 8.07-8.10 (m, 1H).

[0383] Example 25D. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. The imine prepared from 0.187 g (0.46 mmol) of D-aspartic acid β-tert-butyl ester [(R)-α-methylbenzyl]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.25 g (64%) of Example 25D after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.36(s,9H);1.59(d,J=7.1Hz,3H);3.10(dd,J=3.5Hz,J=17.8Hz,1H);3.22(dd,J=10.9Hz,J= 17.8Hz, 1H); 3.93 (dd, J=3.5Hz, J=10.8Hz, 1H); 4.14 (t, J=8.1Hz, 1H); 4.24 (d, J=5.0Hz, 1H); 4.5 8(dd,J=5.0Hz,J=9.5Hz,1H);4.65(t,J=8.7Hz,1H);4.74(t,J=8.2Hz,1H);5.06-5.14(m,1H);6 .32(dd,J=9.5Hz,J=15.8Hz,1H); 6.74(d,J=15.8Hz,1H); 7.19-7.43(m,15H); 8.15-8.18(m,1H).

[0384] Example 25E. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.253 g (69%) of Example 25E after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 HNMR (CDCl 3)δ1.36(s,9H);2.53(dd,J=4.0Hz,J=17.0Hz,1H);3.06(dd,J=10.8Hz,J=16.8Hz,1H);3.13( s, 3H); 4.12 (dd, J = 8.0Hz, J = 9.0Hz, 1H); 4.26 (d, J = 5.0Hz, 1H); 4.38 (d, J = 15.0Hz, 1H); 4.46 (dd, J=5.0Hz, J=9.5Hz, 1H); 4.56 (t, J=6.8Hz, 1H); 4.70-4.79 (m, 2H); 5.27 (dd, J=4.0Hz, J= 11.0Hz, 1H); 6.22 (dd, J = 9.3Hz, J = 15.8Hz, 1H); 6.73 (d, J = 15.8Hz, 1H); 7.33-7.45 (m, 14H).

[0385] Example 25F. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyrene-2-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzamide and α-chlorocinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.708 g (22%) of Example 25F after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.35(s,9H);1.68(brs,1H);2.19-2.35(m,2H);2.40-2.61(m,2H);4.13(dd,J=7.5Hz,J=9.0Hz,1H);4.22(t,J=7.0Hz,1H);4.34(d, J=4.5Hz, 1H); 4.45 (dd, J=5.5Hz, J=15.0Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5Hz, J=8.5Hz, 1H); 6.89 (s, 1H); 7.28-7.54 (m, 14H).

[0386] Example 25G. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2'-methoxystyrene-2-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid β-tert-butyl ester α-(3-trifluoromethylbenzyl)amide and 2'-methoxycinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.402 g (59%) of Example 25G after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.35(s,9H);1.68(brs,1H);2.19-2.35(m,2H);2.40-2.61(m,2H);4.13(dd,J=7.5Hz,J=9.0Hz,1H);4.22(t,J=7.0Hz,1H);4.34(d, J=4.5Hz, 1H); 4.45 (dd, J=5.5Hz, J=15.0Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, J=7.5Hz, J=8.5Hz, 1H); 6.89 (s, 1H); 7.28-7.54 (m, 14H).

[0387] Example 25H. tert-butyl (2R)-(benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetate. The imine prepared from 0.329 g (1.31 mmol) of tert-butyl O-(benzyl)-D-serinate (Example 5B) and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to afford 0.543 g (73%) of Example 25H after flash column chromatography purification (90:10 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.39(s,9H);3.56(dd,J=2.7Hz,J=9.5Hz,1H);3.82(dd,J=4.8Hz,J=9.5Hz,1H);4.11(t,J=8.3Hz,1H);4.21-4.29(m,2H);4.50- 4.58 (m, 3H); 4.71-4.78 (m, 2H); 6.19 (dd, J = 9.1Hz, J = 16.0Hz, 1H); 6.49 (d, J = 16.0Hz, 1H); 7.07-7.11 (m, 1H); 7.19-7.40 (m, 14H).

[0388] Example 25I. tert-Butyl 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetate. The 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) to give 464 mg (80%) of Example 25I after flash column chromatography purification (50:50 hexanes / ethyl acetate). Example 25I appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0389] Example 25J. tert-butyl 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(styrene-2-yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)benzylaminocarbonyl]propanoate. The imine prepared from 0.307 g (0.89 mmol) of D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide (Example 20) and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)propanoyl chloride (Example 1E) to give 120 mg (20%) of Example 25J after flash column chromatography purification (hexanes 70% / EtOAc 30%); 1 H NMR (CDCl 3 )δ1.25(s,3H),1.38(s,9H);3.09(dd,J=3.0Hz,J=18.0Hz,1H);3.33(dd,J=12.5Hz,J=18 .0Hz, 1H); 4.01 (dd, J = 3.0Hz, J = 11.5Hz, 1H); 4.04 (dd, J = 3.5Hz, J = 8.8Hz, 1H); 4.42 (d, J =9.0Hz,1H);4.45-4.51(m,3H);4.61-4.66(m,1H);4.75(dd,J=3.5Hz,J=8.5Hz,1H);6.2 3(dd, J=9.0Hz, J=15.5Hz, 1H); 6.78 (d, J=15.5Hz, 1H); 7.23-7.53 (m, 13H); 7.64 (s, 1H).

[0390] Example 25K. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(prop-1-enyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 0.289 g (0.83 mmol) of D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide and crotonaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) and purified by flash column chromatography (99:1 CH 2 Cl 2 / MeOH) to give 381 mg (76%) of Example 25K; 1 H NMR (CDCl 3 )δ1.36(s,9H),1.69(dd,J=2Hz,J=6.5Hz,3H);3.08(dd,J=3.3Hz,J=17.8Hz,1H);3.18(dd,J=11 Hz, J=17.5Hz, 1H); 3.94 (dd, J=3.5Hz, J=11Hz, 1H); 4.12 (d, J=5Hz, 1H); 4.15 (dd, J=7Hz, J=8Hz, 1 H); 4.35 (dd, J = 4.8Hz, J = 9.8Hz, 1H); 4.44 (dd, J = 6Hz, J = 15Hz, 1H); 4.61 (dd, J = 6Hz, J = 15Hz, 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).

[0391] Example 250. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-one-1-yl]acetate. The imine prepared from 433 mg (1.99 mmol) of L-glutamic acid γ-tert-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 682 mg (64%) of Example 250 after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 HNMR (CDCl 3)δ1.32(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=7.5Hz,J=9Hz,1H);4.38(dd,J=5Hz,J=9Hz,1H);4.55(d,J=5Hz 1H); 4.61 (t, J = 9Hz, 1H); 4.86 (dd, J = 7.5Hz, J = 9Hz, 1H); 6.00 (dd, J = 9Hz, J = 16Hz, 1H); 6.60 (d, J = 16Hz, 1H); 7.26-7.43 (m, 10H).

[0392] Example 25M. tert-butyl 2(S)-(methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-one-1-yl]acetate. The imine prepared from 428 mg (1.97 mmol) of L-glutamic acid γ-tert-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 864 mg (82%) of Example 25M after flash column chromatography purification (70:30 hexanes / ethyl acetate); 1 H NMR (CDCl 3 )δ1.40(s,9H);2.12-2.27(m,1H);2.32-2.55(m,3H);3.50(s,3H);3.72(dd,J=4.6Hz,J=10.4Hz,1H);4.12-4.17(m,1H);4.34(dd,J=5Hz,J=9 Hz, 1H); 4.50 (d, J = 5Hz, 1H); 4.60 (t, J = 8.9Hz, 1H); 4.81-4.86 (m, 1H); 6.06 (dd, J = 9Hz, J = 16Hz, 1H); 6.59 (d, J = 16Hz, 1H); 7.25-7.42 (m, 10H).

[0393] Example 25P. 2(S)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-one-1-yl]acetate. The imine prepared from 424 mg (2.09 mmol) of L-aspartic acid γ-tert-butyl ester α-methyl ester and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) and heated to 40 ℃ in a humidified atmosphere. 2 Cl 2 After recrystallization from / hexane, 923 mg (85%) of Example 25P was obtained; 1H NMR (CDCl 3 )δ1.41(s,9H);2.77(dd,J=7.5Hz,J=16.5Hz,1H);3.00(dd,J=7Hz,J=16.5Hz,1H);4.16(dd,J=7.5Hz,J=9Hz,1H);4.41-48(m,2H);4.55(d,J= 5Hz, 1H); 4.60 (t, J = 8.8Hz, 1H); 4.86 (dd, J = 7.5Hz, J = 9Hz, 1H); 5.93 (dd, J = 9.5Hz, J = 15.5Hz, 1H); 6.61 (d, J = 15.5Hz, 1H); 7.25-7.43 (m, 10H).

[0394] Example 25L. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. The imine prepared from 160 mg (0.44 mmol) of D-aspartic acid β-tert-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) to give 166 mg (55%) of Example 25L after flash column chromatography purification (70:30 hexanes / EtOAc). Example 25L appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0395] Example 25N. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. The imine prepared from 120 mg (0.22 mmol) of D-aspartic acid β-tert-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) to give 75 mg (50%) of Example 25N after flash column chromatography purification (70:30 hexanes / EtOAc). Example 25N appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0396] Example 25Q. Methyl 2(R)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-on-1-yl]acetate. The imine prepared from 517 mg (1.62 mmol) of D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 527 mg (51%) of Example 25Q after flash column chromatography purification (50:50 hexanes / EtOAc). Example 25Q appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0397] The following compounds were prepared according to the methods described herein:

[0398]

[0399]

[0400]

[0401] Example A 25V (R)-1,2,3,4-Tetrahydro-1-naphthylamide 25W 1-Phenyl-cyclopentylamide

[0402]

[0403]

[0404]

[0405] Example A 25Z 1-phenyl-cyclopent-1-ylamino 25AA (R)-1-phenylethyl-1-amino

[0406]

[0407]

[0408] Example 25AF. tert-Butyl 2(S)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetate.

[0409] Example 26. General procedure for the hydrolysis of tert-butyl esters. A solution of the tert-butyl ester derivative in formic acid, typically 1 g in 10 mL, is stirred at ambient temperature until the ester is no longer detected by thin layer chromatography (dichloromethane 95% / methanol 5%), a typical reaction time of about 3 hours. The formic acid is evaporated under reduced pressure; the resulting solid residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer is evaporated to give an off-white solid which can be used directly in other reactions or, if necessary, recrystallized from an appropriate solvent system.

[0410] Examples 27-34AE were prepared according to the procedure used for Example 26 from the appropriate tert-butyl ester.

[0411] Example 27. 2(R,S)-(Carboxy)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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 H NMR (CDCl 3 )δ4.17-5.28(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).

[0412] Example 28. 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. 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 (CDCl 3 )δ2.61(dd,J=9.3Hz,J=16.6Hz,1H);3.09-3.14(m,1H);4.10-4.13(m,1H);4.30(d,J=4.5Hz,1H);4.39-4.85(m,6H);6.20( dd, J=9.6Hz, J=15.7Hz, 1H); 6.69 (d, J=15.8Hz, 1H); 7.12-7.15 (m, 2H); 7.26-7.50 (m, 11H); 7.61 (s, 1H); 8.41-8.45 (m, 1H).

[0413] Example 28A. 2(S)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(S)-(2-phenylvinyl)azetidin-2-on-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 (CDCl 3 )δ2.26(d,J=7Hz,1H);4.03(t,J=7Hz,1H);4.16(t,J=8Hz,1H);4.26(d,J=4.3Hz,1H);4.46(dd,J=5.7Hz,J=15.1,1H);4.53- 4.75 (m, 5H); 6.25 (dd, J = 9.5Hz, J = 15.7Hz, 1H); 6.77 (d, J = 15.7Hz, 1H); 7.28-7.53 (m, 13H); 7.64 (s, 1H); 8.65-8.69 (m, 1H).

[0414] Example 29. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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 (CDCl 3 )δ1.92-2.03(m,1H);2.37-2.51(m,3H);4.13-4.19(m,1H);3.32(d,J=4.9Hz,1H);4.35-4.39(m,1H);4.44(dd,J=5.9Hz,J=14.9Hz,1H); 4.50-4.57 (m, 2H); 4.61-4.67 (m, 1H); 4.70-4.76 (m, 1H); 6.24 (dd, J = 9.6Hz, J = 15.8Hz, 1H); 6.70 (d, J = 15.8Hz, 1H); 7.18-7.47 (m, 14H).

[0415] Example 30. 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g (60%) of Example 30 as an off-white solid; 1H NMR (CDCl 3 )δ2.63(dd,J=6.0Hz,J=16.5Hz,1H);2.75-2.85(m,1H);3.00(dd,J=8.2Hz,J=16.6Hz ,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=5.0Hz,1H);4.46-4.66(m,1H);4.65-4.70(m,1H);5.10-5.15(m,1H);6.14(d d, J=9.3Hz, J=15.9Hz, 1H); 6.71 (d, J=15.9Hz, 1H); 7.22-7.41 (m, 15H); 12.02 (s, 1H).

[0416] Example 31. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylphenyl)azetidin-2-one-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. 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 H NMR (CDCl 3 )δ1.93-2.01(m,1H);2.07-2.36(m,6H);2.82-2.90(m,1H);3.00-3.20(m,4H);3.3 6-3.54(m,4H);3.74-3.82(m,1H);4.06-4.11(m,1H);4.29(d,J=4.9Hz,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= 9.2Hz, J=16.0Hz, 1H); 6.67 (d, J=15.9Hz, 1H); 7.19-7.42 (m, 15H); 8.80 (brs, 1H).

[0417] Example 32. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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.

[0418] Example 32A. 2(R)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-phenylvinyl)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 exhibited a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0419] Example 33. 2(R)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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.

[0420] Example 34. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492 g (quantitative yield) of Example 34 as an off-white solid; 1 H NMR (CDCl 3 )δ1.09-1.17(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=8.3Hz,1H);4.28(d,J=5.0Hz,1H);4.33-4.56(m,4H);4.70(t,J=8.3Hz,1H); 4.83-4.91 (m, 1H); 6.17 (dd, J = 9.1Hz, J = 15.9Hz, 1H); 6.67 (d, J = 15.9Hz, 1H); 7.25-7.44 (m, 10H); 8.22 (brs, 1H).

[0421] Example 34A. 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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; 1 H NMR (CDCl 3 )δ1.05-1.13(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); 3.4 8-3.52(m,1H); 3.64-3.69(m,1H); 4.06-4.14(m,2H); 4.34-4.43(m,2H); 4.56(t,J=8.8Hz,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).

[0422] Example 34B. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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 H NMR (CDCl 3 )δ3.27(d,J=7.2Hz,1H);4.06(t,J=7.2Hz,1H);4.15(t,J=8.1Hz,1H);4.27(d,J=4.8Hz,1H);4.56-4.76(m,5H);6.34( dd, J=9.5Hz, J=15.7Hz, 1H); 6.80 (d, J=15.7Hz, 1H); 7.06 (t, J=7.7Hz, 1H); 7.31-7.54 (m, 12H); 8.58 (t, J=5.9Hz, 1H).

[0423] Example 34C. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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 (CDCl 3 )δ1.56(d,J=7.0Hz,1H);3.10(dd,J=4.5Hz,J=17.9Hz,1H);3.18(dd,J=9.8Hz, J=17.9Hz, 1H); 4.00 (dd, J=4.5Hz, J=9.7Hz, 1H); 4.14 (t, J=8.2Hz, 1H); 4.26 (d ,J=4.7Hz,1H);5.02-5.09(m,1H);6.41(dd,J=9.4Hz,J=15.8Hz,1H);6.78(d,J =15.8Hz, 1H); 7.18 (t, J = 7.3Hz, 1H); 7.26-7.43 (m, 12H); 8.29 (d, J = 8.2Hz, 1H).

[0424] Example 34D. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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; 1 H NMR (CDCl 3 )δ1.59(d,J=7.0Hz,1H); 3.25(d,J=7.0Hz,2H); 3.92(t,J=7.3Hz,1H); 4.15(t, J=8.3Hz, 1H); 4.26 (d, J=5.0Hz, 1H); 4.52 (dd, J=4.8Hz, J=9.3Hz, 1H); 4.65 (t, J=8.8Hz, 1H); 4.72 (t, J=8.3Hz, 1H); 5.07-5.28 (m, 1H); 6.29 (dd, J=9.5Hz, J=1 5.6Hz, 1H); 6.71 (d, J = 16.0Hz, 1H); 7.20-7.43 (m, 13H); 8.31 (d, J = 8.0Hz, 1H).

[0425] Example 34E. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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 H NMR (CDCl 3 )δ3.07-3.15(m,4H);4.13(t,J=8.2Hz,1H);4.30(d,J=4.9Hz,1H);4.46-4.78(m,5H);5.23(dd,J=4 .6Hz, J=9.7Hz, 1H); 6.20 (dd, J=9.4Hz, J=15.9Hz, 1H); 6.73 (d, J=15.9Hz, 1H); 7.25-7.43 (m, 15H).

[0426] Example 34F. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyrene-2-yl)azetidin-2-on-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 (CDCl 3 )δ2.22-2.28(m,2H); 2.49-2.64(m,2H); 4.09(t,J=8.0Hz,1H); 4.25-4.62(m,6H); 4.87(t,J=8.0Hz,1H); 6.88(s,1H); 7.25-7.66(m,15H).

[0427] Example 34G. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2'-methoxystyrene-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 (CDCl 3)δ3.26(d,J=7.1Hz,1H);3.79(s,3H);4.14(t,J=8.2Hz,1H);4.25(d,J=4.5Hz,1H);4.51(dd,J=5.9Hz,J=15.5Hz,1H);4.53-4.66(m,4H);6.36(dd, J=9.4Hz, J=15.8Hz, 1H); 8.88 (t, J=8.2Hz, 1H); 6.70 (d, J=15.8Hz, 1H); 7 .18(d,J=6.5Hz,1H);7.25-7.48(m,10H);7.48(s,1H);8.66-8.69(m,1H).

[0428] Example 34H. (2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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 (CDCl 3 )δ3.65(dd,J=4.0Hz,J=9.5Hz,1H); 3.82(dd,J=5.5Hz,J=9.5Hz,1H); 4.11(dd,J=7.8Hz ,J=8.8Hz,1H);4.33(s,2H);4.50(d,J=5.0Hz,1H);4.57(t,J=9.0Hz,1H);4.67(dd,J=4 .0Hz, J=5.0Hz, 1H); 4.69 (dd, J=5.0Hz, J=9.5Hz, 1H); 4.75 (t, J=8.0Hz, 1H); 6.17 (dd, J =9.3Hz, J=15.8Hz, 1H); 6.55 (d, J=16.0Hz, 1H); 7.09-7.12 (m, 2H); 7.19-7.42 (m, 13H).

[0429] Example 34I. 2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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 exhibited a structure consistent with the specified 1 H NMR spectroscopy.

[0430] Example 34J. 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(styrene-2-yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)benzylaminocarbonyl]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 (CDCl 3 )δ1.22(s,3H);3.25(dd,J=3.5Hz,J=18.0Hz,1H);3.36(dd,J=10.8Hz,J=18.2Hz,1H) ;4.01(dd,J=4.0Hz,J=10.5Hz,1H); 4.05(dd,J=3.8Hz,J=8.8Hz,1H); 4.33(d,J=9.0H z,1H);4.44-4.51(m,3H);4.61-4.66(m,1H);4.73(dd,J=3.8Hz,J=8.8Hz,1H);6.19( dd, J=9.0Hz, J=16.0Hz, 1H); 6.74 (d, J=16.0Hz, 1H); 7.22-7.54 (m, 13H); 7.65 (s, 1H).

[0431] Example 34K. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(propen-1-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Using the general procedure of Example 26, 160 mg (0.27 mmol) of Example 25K were hydrolyzed to give 131 mg (90%) of Example 34K as an off-white solid. 1 HNMR (CDCl 3 )δ1.69(dd,J=1Hz,J=6.5Hz,3H); 3.23(d,J=7Hz,1H); 3.93(t,J=7.3Hz,1H); 4.14-4.20(m,3H); 4.29(dd,J=5Hz,J=9.5Hz,1H); 4.43(dd,J=6Hz ,J=15Hz,1H);4.61(dd,J=6.5Hz,J=15Hz,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).

[0432] Example 34L. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. Example 25L (166 mg, 0.24 mmol) was hydrolyzed to afford 152 mg (quantitative yield) of Example 34L as an off-white solid; and the resulting product was consistent with the specified structure. 1 H NMR spectroscopy.

[0433] Example 34M. 2(S)-(Methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid. Example 25M (875 mg, 1.64 mmol) was hydrolyzed to afford 757 mg (97%) of Example 34M as an off-white solid and exhibited a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0434] Example 34N. 2(R)-(carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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 and exhibited a structure consistent with the specified 1 H NMR spectroscopy.

[0435] Example 34O.2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylphenyl)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 aqueous solution; 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 reached 5 (as measured by 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 and exhibited a structure consistent with the specified structure. 1 H NMR spectroscopy.

[0436] Example 34P. 2(S)-(tert-Butyloxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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; and it appeared consistent with the specified structure. 1 H NMR spectroscopy.

[0437] Example 34Q. 2(R)-(2-(3-trifluoromethylbenzyl)amino-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid. Example 25Q (150 mg, 0.24 mmol) was hydrolyzed according to the method used for Example 34O to give 143 mg (97%) of Example 34Q as an off-white solid and appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0438] Example 34R. 2(R)-(tert-Butyloxycarbonylmethyl)-2-[3(RS)-2-thienylmethyl)-4(R)-(2-phenylvinyl)azetidin-2-one-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The imine prepared from 290 mg (0.84 mmol) of D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide and cinnamaldehyde was combined with 2-thiophene-acetyl chloride to give 42 mg (8%) of Example 34R after flash column chromatography purification (70:30 hexanes / ethyl acetate) and appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0439] The following compounds were prepared according to the methods described herein:

[0440]

[0441]

[0442]

[0443] Example A 34V (R)-1,2,3,4-Tetrahydro-1-naphthylamide 34W 1-Phenyl-cyclopentylamide

[0444]

[0445]

[0446]

[0447] Example A 34Z 1-phenyl-cyclopent-1-ylamino 34AA (R)-1-phenylethyl-1-amino

[0448]

[0449]

[0450] Examples 36-42A shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 27, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0451]

[0452] Example A' 36 2-(Piperidinyl)ethylamino 37 4-(Piperidinyl)piperidinyl 38 4-(2-Phenylethyl)piperazinyl 39 1-Benzylpiperidin-4-ylamino 40 4-Butylpiperazinyl 41 4-Isopropylpiperazinyl 42 4-Cyclohexylpiperazinyl 42A 4-[2-(Piperidinyl)ethyl]piperidinyl

[0453] Examples 43-86A shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 28, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0454]

[0455]

[0456]

[0457] 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 assessed by TLC (dichloromethane 94% / methanol 6%, UV detection). The reaction was quenched with aqueous sodium sulfite solution and the dichloromethane layer was washed with 5% aqueous sodium bicarbonate solution and distilled water. The dichloromethane layer was evaporated to give Example 86B (35 mg, 78%) as an off-white solid and exhibited a structure consistent with the specified structure. 1 H NMR spectroscopy.

[0458] Examples 121-132 shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 30, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0459]

[0460] Example A' 121 3-Trifluoromethylbenzylamino 122 Morpholin-4-ylamino 123 2-(Dimethylamino)ethylamino 124 3-(Dimethylamino)propylamino 125 Cyclohexylamino 126 Piperidinyl 127 2-Methoxyethylamino 128 Isopropylamino 129 Isobutylamine 130 Ethylamino 131 Dimethylamino 132 Methylamino

[0461] Examples 132A-132B shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34I, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples presented were consistent with the designated structures 1 H NMR spectroscopy.

[0462]

[0463] Example A' 132A (2,3-Dichlorobenzyl)amino 132B 1-Phenylcyclohexylamino

[0464] Example 132C. 2(S)-(tert-Butyloxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-(4-cyclohexyl)piperazineamide. Example 132C was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34P and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexyl-piperazine. Example 132C presented a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0465] The compounds shown in the table below were prepared according to the methods described herein.

[0466]

[0467] Example A A' 132D 1-phenyl-cyclopent-1-ylamino 4-(Piperidinyl)piperidinyl 132E 1-phenyl-cyclopent-1-ylamino 1-Benzylpiperidin-4-ylamino 132F (R)-1-phenylethyl-1-amino 4-(Piperidinyl)piperidinyl

[0468] Examples 133-134G shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 32, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0469]

[0470] Example A' 133 4-(Piperidinyl)piperidinyl 134 4-(2-Phenylethyl)piperazinyl 134A 4-[2-(Piperidinyl)ethyl]piperidinyl 134B 4-(Pyrrolidinyl)piperazinyl 134C 1-Benzylpiperidin-4-ylamino 134D (Pyridin-3-ylmethyl)amino 134E 3-(Dimethylamino)propylamino 134F 3-(S)-(1-Benzylpyrrolidin-3-yl)amino 134G 4-[(Piperidinyl)methyl]piperidinyl 134H 4-(Piperidinyl)piperidinyl N-oxide

[0471] Example 134H. Example 134H was prepared using 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%) and appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0472] Example 134I. 2(R)-[[4-(Piperidinyl)piperidinyl]carboxymethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 134I was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 32A and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and the resulting product was consistent with the assigned structure. 1 H NMR spectroscopy.

[0473] The compounds shown in the table below were prepared according to the methods described herein.

[0474]

[0475]

[0476] Example 222. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. Example 222 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34B and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine; Example 222 appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0477] Example 223. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 34C and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine; Example 223 appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0478] Example 224.

[0479]

[0480] 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. Example 224 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34D and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine; Example 223 presented a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0481] Example 225.

[0482]

[0483] 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-one-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. Example 225 was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34E and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine; Example 223 presented a structure consistent with the assigned structure. 1 H NMR spectroscopy; C 43 H 48 F 3 N 5 O 5 Calculated values: C, 66.91; H, 6.27; N, 9.07; Found. C, 66.68; H, 6.25; N, 9.01.

[0484] Example 225. Hydrochloride salt. Example 225 (212.5 mg) was dissolved in 30 mL of anhydrous Et 2 O. Anhydrous HCl gas was bubbled through the solution, resulting in the rapid formation of an off-white precipitate. The HCl addition was discontinued when no more precipitate formation was observed (approximately 5 minutes). The solid was isolated by suction filtration and washed with 15 mL of anhydrous Et 2 O was washed twice and dried to 213.5 mg (96% yield) of off-white solid; C 43 H 49 CIF 3 N 5 O 5 Calculated values: 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.

[0485] Example 225A. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 34C, and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225A presented a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0486] Example 225B. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 34D and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperidinyl)ethyl]piperidine. Example 225B presented a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0487] Example 225C. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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-tert-butyl ester monohydrate was replaced with Example 34L, and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 225C exhibited a structure consistent with the assigned structure. 1 H NMR spectroscopy.

[0488] Example 225D. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenylvinyl)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-tert-butyl ester monohydrate was replaced with Example 34N and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 225D appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0489] Examples 87-120E shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 29, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0490]

[0491]

[0492]

[0493] 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 appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0494] Example 120G. 2(S)-(Methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Example 120G was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34M, and the resulting product was consistent with the assigned structure. 1 H NMR spectroscopy.

[0495] Example 35. 2(S)-[4-(2-phenylethyl)piperazinyl-carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the carboxylic acid of Example 29 and 3-(trifluoromethyl)benzylamine was replaced with 4-(2-phenylethyl)piperazine, the title compound was prepared; 1 H NMR (CDCl 3 )δ2.21-2.23(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=5.1Hz,J=8.3Hz,1H);4.29(d,J=5.0Hz,1H);4.44(dd ,J=6.0Hz,J=15.0Hz,1H);4.54(dd,J=6.2Hz,J=14.9Hz,1H);4.61-4.68(m,2H);4.70-4.75(m,1H);6 .27(dd,J=9.6Hz,J=15.8Hz,1H); 6.73(d,J=15.8Hz,1H); 7.16-7.60(m,19H); 8.07-8.12(m,1H); FAB + (M+H) + / z 794; Elemental analysis C 45 H 46 F 3 N 5 O 5 Calculated values: C, 68.08; H, 5.84; N, 8.82; Found values: C, 67.94; H, 5.90; N, 8.64.

[0496] Examples 141-171 shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0497]

[0498]

[0499]

[0500] Examples 172-221R shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34A, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures 1 H NMR spectroscopy.

[0501]

[0502]

[0503]

[0504]

[0505] The compounds shown in the table below were prepared according to the methods described herein.

[0506]

[0507]

[0508]

[0509] Examples 135-140 shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 33, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples present structures consistent with the indicated structures. 1 H NMR spectroscopy.

[0510]

[0511] Example A' 135 4-(Piperidinyl)piperidinyl 136 4-(2-Phenylethyl)piperazinyl 137 4-Butylpiperazinyl 138 4-Isopropylpiperazinyl 139 4-Cyclohexylpiperazinyl 140 4-(Cyclohexylmethyl)piperazinyl

[0512] Example 140A. 2(R)-(2-(3-trifluoromethylbenzyl)amino-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. Example 140A was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34Q and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexyl-piperazine, and the resulting product was consistent with the assigned structure. 1 H NMR spectroscopy.

[0513] Examples 226-230C shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34F, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples presented were consistent with the designated structure 1 H NMR spectroscopy.

[0514]

[0515]

[0516]

[0517] The following compounds were prepared according to the methods described herein:

[0518]

[0519]

[0520] Example 86C. 2(S)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 28A and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and was presented consistent with the assigned structure. 1 H NMR spectroscopy.

[0521] Example 231. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2'-methoxystyrene-2-yl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 34G and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, and the resulting product was consistent with the assigned structure. 1 H NMR spectroscopy.

[0522] Examples 232-233A shown in the table below were prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with Example 34H, and 3-(trifluoromethyl)benzylamine was replaced with the appropriate amine; all listed examples presented were consistent with the designated structure 1 H NMR spectroscopy.

[0523]

[0524] Example A' α 232 4-(Piperidinyl)piperidinyl D 232A (3-Trifluorobenzyl)amino D 232B 4-(3-Trifluoromethylphenyl)piperazinyl D or L 232C 4-(3-Trifluoromethylphenyl)piperazinyl D or L 232D 4-Cyclohexylpiperazinyl DL 232E 4-(Piperidinylmethyl)piperidinyl D 233 4-[2-(Piperidinyl)ethyl]piperidinyl D 233A 4-[(1-Piperidinyl)methyl]piperidinamide D

[0525] Example 234. (2RS)-[4-(Piperidinyl)piperidinylcarbonyl]-2-methyl-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide.

[0526]

[0527] Tetrahydrofuran (4 mL) containing Example 37 (50 mg, 0.067 mmol) was treated with sodium hydride (4 mg, 0.168 mmol) and iodomethane (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 + ).

[0528] Example 234A. 4-(Piperidinyl)-piperidinyl 3(R)-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-3-methyl-4(R)-(phenylvinyl-2-yl)azetidin-2-on-1-yl]-3-[(3-trifluoromethyl)benzylaminocarbonyl]propanoic acid.

[0529]

[0530] Using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the carboxylic acid of Example 34J and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, the title compound was prepared in quantitative yield; MS (m+H) + 772.

[0531] The compounds shown in the table below were prepared according to the methods described herein.

[0532]

[0533]

[0534] Example 235. 2(S)-[[(1-Benzylpiperidin-4-yl)amino]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-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-tert-butyl ester α-(3-trifluoromethyl)benzamide was replaced with Example 63 (50 mg, 0.064 mmol) to afford 40 mg (80%) of Example 235 as an off-white solid; Example 235 appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0535] Example 236. (2S)-[(4-cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-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-tert-butyl ester α-(3-trifluoromethyl)benzamide was replaced with Example 110 (50 mg, 0.065 mmol) to afford 42 mg (84%) of Example 236 as an off-white solid; Example 236 appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0536] Example 236A. (2S)-[(4-cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-1-yl]acetic acid N-[(R)-1,2,3,4-tetrahydronaphthalen-1-yl]amide. Example 236A was prepared using the procedure of Example 8, except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzamide was replaced with Example 215 (76 mg, 0.10 mmol) to afford 69 mg (90%) of Example 236A as an off-white solid. Example 236A appeared consistent with the assigned structure. 1 H NMR spectroscopy.

[0537] Example 237. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(propen-1-yl)azetidin-2-on-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-tert-butyl ester monohydrate was replaced with Example 34K and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine. Example 237 appears consistent with the assigned structure. 1 H NMR spectroscopy.

[0538] Example 238. (2S)-(Benzylthiomethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenylvinyl)azetidin-2-on-1-yl]acetic acid N-[4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl]amide. This example was prepared using the procedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the corresponding benzyl protected cysteine ​​analog, and 3-(trifluoromethyl)benzylamine was replaced with 4-[2-(piperidin-1-yl)ethyl]piperidine.

[0539] Step 1. N-tert-Butoxycarbonyl-(S)-(phenylmethyl)-D-cysteine-[4-(2-(1-piperidinyl)ethyl)]piperidineamide. N-tert-Butoxycarbonyl-(S)-phenylmethyl-N-(tert-butoxycarbonyl)-D-cysteine ​​(0.289 g, 0.93 mmol) and 4-[2-(1-piperidinyl)ethyl]piperidine (0.192 g, 0.98 mmol) in dichloromethane (20 mL) gave 0.454 g (quantitative yield) of Example X as an off-white solid. 1 H NMR (CDCl 3 )δ0.89-1.15(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).

[0540] Step 2. (S)-(Benzyl)-D-cysteine-[4-(2-(1-piperidinyl)ethyl)]piperidinamide dihydrochloride. N-tert-Butyloxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidinyl)ethyl)]piperidinamide (0.453 g, 0.93 mmol) was reacted with acetyl chloride (0.78 mL, 13.80 mmol) in anhydrous methanol (15 mL) overnight. The title compound (0.417 g, 97%) was obtained as an off-white solid by evaporation of the reaction mixture to dryness. 1 H NMR (CD 3 OD)δ0.94-1.29(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,4 H); 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).

[0541] Step 3. Using the general procedure described herein, the imine prepared from (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidinyl)ethyl)]piperidinamide dihydrochloride (0.417 g, 0.90 mmol) and cinnamaldehyde was combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) in the presence of triethylamine (0.26 mL, 1.87 mmol) to afford 0.484 g (76%) of Example 238 as an off-white solid after recrystallization from dichloromethane / hexanes. 1 HNMR (CDCl 3 )δ0.89-1.06(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).

[0542] Describe the following compound:

[0543]

[0544]

[0545]

[0546] Example 266 (AVN576)

[0547] Describe the following compound:

[0548]

[0549] Example Ar 257 Benzothiophene-7-yl 254 Furan-2-yl 255 Thiophene-2-yl

[0550] Describe the following compound:

[0551]

[0552]

[0553] Describe the following compound:

[0554]

[0555]

[0556]

[0557] Describe the following compound:

[0558]

[0559] Example <![CDATA[R N ]]> <![CDATA[R a ]]> <![CDATA[R Ar ]]> 599 Me H <![CDATA[3-CF 3 ]]> 601 H (R)-Me H

[0560] Describe the following compound:

[0561]

[0562] Example <![CDATA[R N ]]> <![CDATA[R a ]]> <![CDATA[R Ar ]]> 670 Me H <![CDATA[3-CF 3 ]]> 672 H (R)-Me H

[0563] The following table illustrates selected compounds that were further characterized by mass spectrometry using FAB + Observation correspondence (M+H) + Parent ion.

[0564]

[0565]

Claims

1. Use of a composition comprising one or more selective vasopressin V1a receptor antagonists in the preparation of a medicament for treating traumatic brain injury (TBI) in a host animal, wherein the one or more antagonists are selected from compounds of the following formula: AVN576, AVN246, and AVN251, and pharmaceutically acceptable salts thereof.

2. The use according to claim 1, wherein the compound is: AVN246, or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, wherein the compound is: AVN251, or a pharmaceutically acceptable salt thereof.

4. The use according to claim 1, wherein the compound is: AVN576, or a pharmaceutically acceptable salt thereof.

5. The use according to any one of claims 1 to 4, wherein the traumatic brain injury (TBI) is blast TBI, repeated mild TBI, cerebral edema, chronic traumatic encephalopathy (CTE) or concussion.

6. The use according to claim 5, wherein the TBI comprises edema.

7. The use according to any one of claims 1 to 4, wherein the TBI is spatial learning dysfunction, memory dysfunction or intermittent learning dysfunction.

8. The use according to any one of claims 1 to 4, wherein the TBI comprises loss of connectivity of key nodes of the ventral hippocampus, reticular activating system, temporal cortex, amygdala, limbic cortex, or reticular nucleus of the midbrain.

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