β-Lactamyl vasopressin V1a Antagonists

A compound having the formula

• wherein:
• n is an integer from 0 to 2;
• A is XNH—, or R5XN—;
• A′ is X′NH—, or R5′X′N—;
• R2 is hydrogen or C1–C6 alkyl;
• R3 is a structure selected from the group consisting of
• R4 is C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C8 cycloalkyl, C3–C9 cycloalkenyl, limonenyl, pinenyl, C1–C3 alkanoyl, optionally-substituted aryl, optionally-substituted aryl(C1–C4 alkyl), optionally-substituted aryl(halo C1–C4 alkyl), optionally-substituted aryl(alkoxy C1–C4 alkyl), optionally-substituted aryl(C2–C4 alkenyl), optionally-substituted aryl(halo C2–C4 alkenyl), or optionally-substituted aryl(C2–C4 alkynyl);
• X is selected from the group consisting of C1–C6 alkyl, C3–C8 cycloalkyl, (C1–C4 alkoxy)-(C1–C4 alkyl), optionally-substituted aryl, optionally-substituted aryl(C1–C4 alkyl), optionally-substituted aryl(C3–C7 cycloalkyl), optionally-substituted indan- l-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C1–C4 alkyl), R7R8N—, and R7R8N—(C2–C4 alkyl);
• and
• R5 is selected from the group consisting of hydroxy, C1–C6 alkyl, C1–C4 alkoxycarbonyl, and benzyl;
• or
• R5 and X are taken together with the attached nitrogen atom to form an optionally substituted heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is optionally substituted with R10, R12, R7R8N—, or R7R8N—(C1–C4 alkyl);
• X′ is selected from the group consisting of C1–C6 alkyl, C3–C8 cycloalkyl, (C1–C4 alkoxy)-(C1–C4 alkyl), optionally-substituted aryl, optionally-substituted aryl(C1–C4 alkyl), optionally-substituted aryl(C3–C7 cycloalkyl), optionally-substituted indan-1-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y′, Y′—(C1–C4 alkyl), R7′R8′N—, and R7′R8′N—(C2–C4 alkyl);
• and
• R5′ is selected from the group consisting of hydroxy, C1–C6 alkyl, C1–C4 alkoxycarbonyl, and benzyl;
• or
• R5′ and X′ are taken together with the attached nitrogen atom to form an optionally substituted heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is optionally substituted with R10, R12′, R7′R8′N—, or R7′R8′N—(C1–C4 alkyl);
• where the heterocycle Y and the heterocycle Y′ are each independently selected from the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl;
• where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1–C4 alkyl or optionally-substituted aryl(C1–C4 alkyl);
• R7 is hydrogen or C1–C6 alkyl;
• and
• R8 is C1–C6 alkyl, C3–C8 cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C1–C4 alkyl);
• or
• R7 and R8 are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
• where said piperazinyl or homopiperazinyl is optionally N-substituted with R12;
• R7′ is hydrogen or C1–C6 alkyl;
• and
• R8′ is C1–C6 alkyl, C3–C8 cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C1–C4 alkyl);
• or
• R7′ and R8′ are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
• where said piperazinyl or homopiperazinyl is optionally N-substituted with R12′;
• R10 and R11 are each independently chosen from the group consisting of hydrogen, C1–C6 alkyl, C3–C8 cycloalkyl, C1–C4 alkoxycarbonyl, C1–C5 alkanoyloxy, benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, and optionally-substituted aryl(C1–C4 alkyl);
• where the C1–C6 alkyl or the C3–C8 cycloalkyl is optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C1–C4 thioalkyl;
• and,
• where the benzyl of said benzyloxy or said benzoyloxy is optionally substituted with one or two substituents independently selected from the group consisting of C1–C4 alkyl, C1–C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1–C4 alkyl)amino, di(C1–C4 alkyl)amino, C1–C4 alkylsulfonylamino, and nitro;
• R12 and R12′ are each independently selected from the group consisting of hydrogen, C1–C6 alkyl, C3–C8 cycloalkyl, C1–C4 alkoxycarbonyl, optionally-substituted aryloxycarbonyl, optionally-substituted aryl(C1–C4 alkyl), and optionally-substituted aryloyl;
• and
• pharmaceutically acceptable acid addition salts thereof;
• and
• providing that when A is XNH— and the integer n is 0, then A′ is not anilinyl, substituted anilinyl, benzylamino, or substituted benzylamino.