Novel heterocyclic substituted carbonyl derivatives and their use as dopamine D3 receptor

BACKGROUND OF THE INVENTION

[0001] The subject invention relates to novel heterocyclic derivatives that selectively bind to the dopamine D3 receptor. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesireable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347:146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). This receptor is shown in high abundance in brain regions associated with emotional and cognitive functions. Compounds that selectively bind to the dopamine D3 receptor are useful in treating certain central nervous system disorders. These central nervous system disorders include the following indications:

[0002] 1) Psychoses (including schizophrenia)—See, for example, Biochem Pharmacol, 1992, 3(4), 659-66; Clin Neuropharmacol, 1993,16(4), 295-314; Neuropsychopharmacology, 1997, 16(6), 375-84; Am J Psychiatry, 1999,156(4), 610-616; Psychopharmacology (Berl), 1995, 120(1), 67-74.

[0003] 2) Substance dependence and substance abuse—See, for example, Neuroreport,1997, 8(9-10), 2373-2377; J Pharmacol Exp Ther, 1996, 278(3), 1128-37; Brain Res Mol Brain Res, 1997, 45(2), 335-9.

[0004] 3) Mood Disorders (including mania, depressive disorders and bipolar disorders)—See, for example, Clin Neuropharmacol, 1998, 21(3),176-80; Am J Med Genet, 1998, 81(2),192-4; J Clin Psychiatry, 1995,56(11), 514-518; J Clin Psychiatry, 1995, 56(9), 423-429; Am J Med Genet, 1995, 60(3), 234-237; Pharmacopsychiatry, 1999, 32(4), 127-135; J Affect Disord, 1999, 52(1-3), 275-290; Am J Psychiatry, 1999, 156(4), 610-616.

[0005] 4) dyskinetic disorders (including Parkinson's Disease, Parkinsonism, Neuroleptic-Induced Tardive Dyskinesia and Gilles de la Tourette Syndrome)—See, for example, Clin Neuropharmacol, 2000, 23(1), 34-44; Eur J Pharmacol, 1999, 385(1), 39-46.

[0006] 5) sleep disorders (including narcolepsy)—The D3 agonist pramipexole causes narcolepsy. A D3 antagonist would be useful for reversing this undesireable side effect. See Aust Fam Physician, 1999, 28(7), 737; Neurology, 1999, 52(9), 1908-1910.

[0007] 6) anxiety disorders (including obsessive compulsive disorders)—See, for example, Physiol Behav, 1997, 63(1), 137-141; J Clin Psychiatry, 1995, 56(9), 423-429; J Psychiatry Neurosci, 2000, 25(2), 185; J Affect Disord, 1999, 56(2-3), 219-226.

[0008] 7) nausea—Dopamine antagonists are used alone and in combination with 5HT3 antagonists. See, for example, Support Care Cancer, 1998, 6(1), 8-12; Support Care Cancer, 2000, 8(3), 233-237; Eur J Anaesthesiol, 1999, 16(5), 304-307.

[0009] 8) dementia—See, for example, Behav Brain Res, 2000, 109(1), 99-111; Neuroscience, 1999, 89(3), 743-749.

[0010] Dopamine D3 receptor ligands are also useful for the treatment of renal dysfunction. See, for example, WO 200067847.

SUMMARY OF THE INVENTION

[0011] This invention relates to a class of compounds and pharmaceutically acceptable salts thereof which are selective modulators of dopamine D3 receptors. The compounds may act as agonists, partial agonists, antagonists or allosteric modulators of dopamine D3 receptors, and are useful for a variety of therapeutic applications.

[0012] In another aspect, the invention relates to a method for treating central nervous system disorders associated with the dopamine D3 receptor activity in a patient in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound described herein for alleviation of such disorder. The central nervous system conditions or disorders that may be treated with these compounds include Psychotic Disorders, Substance Dependence, Substance Abuse, Dyskinetic Disorders (e.g. Parkinson's Disease, Parkinsonism, Neuroleptic-Induced Tardive Dyskinesia, Gilles de la Tourette Syndrome and Huntington's Disease), Nausea, Dementia, Anxiety Disorders, Sleep Disorders, Circadian Rhythm Disorders and Mood Disorders.

[0013] In yet another aspect, the subject invention is directed toward a pharmaceutical composition comprising an effective amount of a compound described herein with a pharmaceutically-acceptable carrier or diluent optionally in conjunction with one or more dopamine D1, D2, D4, D5 or 5HT receptor antagonists.

[0014] In yet another aspect, the subject invention is directed towards processes for the preparation of the class of compounds described herein.

[0015] Also within the scope of this invention are methods for using these novel compounds as imaging agents for dopamine D3 receptors. Methods of using these compounds as imaging agents are presented, as are intermediates and methods for making the imaging agents.

DETAILED DESCRIPTION OF THE INVENTION

[0016] In accordance with the present invention, there are provided compounds of formula I

[0017] A compound of the formula (I):

[0018] wherein

[0019] A is CH or N;

[0020] n is 1 or 2;

[0021] when n is 1, y is 0 or 2;

[0022] when n is 2, y is 0;

[0023] g is 1 or 2;

[0024] each R3 is independently hydrogen, C1-C6alkyl, or

[0025] wherein w is 1, 2, or 3;

[0026] R is selected from the group consisting of (a)-(w):

[0027] wherein

[0028] each R4, R5, R6, R7, R8, R9, R10, R11, R12 and R18 is independently hydrogen, C1-C6alkyl, halogen, trifluoromethyl, —CO2C1-C6alkyl or —CH2OC1-C6alkyl;

[0029] each R71, R72, R74 and R80 is independently hydrogen, C1-C6alkyl, C1-C6alkoxy, halogen, trifluoromethyl, —CO2C1-C6alkyl or —CH2OC1-C6alkyl;

[0030] R73 is hydrogen, alkyl, pyridyl, benzyl, —CH2CF3, —CO2C1-C6alkyl, phenyl optionally substituted with halogen, trifluoromethyl, trifluoromethoxy or R73 is

[0031] wherein w is 1, 2 or 3 as hereinbefore defined;

[0032] each R75 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0033] each R76 is hydrogen, halogen, —CN or C1-C6alkyl;

[0034] each R77 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0035] each R78 hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0036] each R79 hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0037] p, s and x are 0, 1, or 2;

[0038] each R13 is independently hydrogen, C1-C6alkyl, halogen, benzyl, trifluoromethyl, C1-C6alkoxy, nitro, —CN, or —COC1-C6alkyl;

[0039] R16 is C1-C6alkyl;

[0040] each R14 and R15 is independently hydrogen or C1-C6alkyl;

[0041] R17 is hydrogen, C1-C6alkyl, Ar, —COAr, —CONHAr or —SO2—Ar wherein Ar is a phenyl group which is optionally mono- or di-substituted with substituents independently selected from C1-C6alkyl, halogen, trifluoromethyl, C1-C6alkoxy, nitro, CN and COC1-C6alkyl; and

[0042] m is 0, 1, or 2;

[0043] represents a group selected from (a)-(f):

[0044] wherein

[0045] each R19 and R20 is independently hydrogen, hydroxy or C1-C6alkyl;

[0046] R21, R22, and R23 are each independently hydrogen or C1-C3 linear alkyl; and

[0047] d is 3 or 4;

[0048] R1 is a) hydrogen;

[0049] b) C1-C6alkyl optionally mono- or di-substituted with hydroxy; or

[0050] wherein

[0051] each R24 is independently hydrogen or C1-C6alkyl;

[0052] each R25, and R26 is independently hydrogen or

[0053] C1-C6alkyl;

[0054] t is 0 or 1; and

[0055] q is 0 or 1;

[0056] R2 is a group selected from (a)-(jj):

[0057] wherein

[0058] each R27 and R28 is independently selected from:

[0059] (1) hydrogen;

[0060] (2) C1-C6alkyl;

[0061] (3) C1-C6alkoxy;

[0062] (4) —CO2—R43 wherein R43 is hydrogen or C1-C6alkyl;

[0063] (5) hydroxy;

[0064] (6) —(CH2)a—OR44 wherein a is 1, 2 or 3 and R44 is hydrogen or C1-C6alkyl;

[0065] (7) —(CO)—NR45R46 wherein R45 and R46 are each independently hydrogen, C1-C2alkyl, or R45 and R46 taken together form a 5-membered monocyclic ring;

[0066] z is 0 or 1;

[0067] e is 2, 3, 4, 5, 6 or 7;

[0068] h is 0, 1, 2 or 3;

[0069] u is 0, 1, 2, 3 or 4;

[0070] o is 0 or 1;

[0071] l is 0 or 1;

[0072] j is 0, 1, 2 or 3;

[0073] v is 0, 1, 2, 3 or 4;

[0074] w is 1, 2 or 3 as hereinbefore defined;

[0075] f is 1, 2, 3 or 4;

[0076] t is 0 or 1 as hereinbefore defined;

[0077] b is 0, 1 or 2;

[0078] q is 0 or 1 as hereinbefore defined;

[0079] aa is 0 or 2;

[0080] X is O, S or NR90 wherein R90 is hydrogen, C1-C6alkyl, or

[0081] wherein R143 is hydrogen or alkyl;

[0082] each M and V is a group independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, hydroxy, phenyl, phenoxy, —SO2NH2 or

[0083] or

[0084] —NR48R49 wherein R48 and R49 are each independently hydrogen or C1-C2alkyl;

[0085] each R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R68, and R69 is independently hydrogen or C1-C6alkyl;

[0086] each R29, R30 is independently hydrogen, phenyl or C1-C6alkyl;

[0087] each R83, R84, R86, R87, R88, R89, R92, R93, R98, R99, R94, R95, R100, R101, R103, R104, R105, R106, R108, R109, R110, R111, R113, R114, R115, R116, R117, R118, R119, R120, R122, R123, R124, R125, R127, R128, R130, R131, R133, R134, R135, R136, R137, R138, R139 and R140 is independently hydrogen or C1-C6alkyl;

[0088] each R63, R64 and R65 is independently hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0089] each R66 is independently hydrogen, hydroxy, C1-C6alkyl or C1-C6alkoxy;

[0090] Q is CH2, CHOH or C═O;

[0091] X5 is O or S;

[0092] each R67 is independently hydrogen or C1-C6alkyl;

[0093] R70 is hydrogen, C1-C6alkyl, halogen, nitro or a phenyl group optionally mono-substituted with C1-C6alkyl, halogen or trifluoromethyl;

[0094] R81 is hydrogen, C1-C6alkyl, or —CO2C1-C6alkyl;

[0095] R91 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0096] R96 is hydrogen, C1-C6alkyl or

[0097] wherein R145 and R146 are each independently hydrogen or C1-C6alkyl and b is 0, 1 or 2 as hereinbefore defined;

[0098] R97 is hydrogen or C1-C6alkyl;

[0099] each R102 is independently hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;

[0100] R107 is hydrogen or C1-C6alkyl;

[0101] each R121 is independently hydrogen, halogen,

[0102] C1-C6alkyl or C1-C6alkoxy;

[0103] R127 is hydrogen or C1-C6alkyl;

[0104] R126 is C1-C6alkyl or benzyl;

[0105] R129 is hydrogen or C1-C6alkyl;

[0106] R132 is hydrogen, C1-C6alkyl, halogen or C1-C6alkoxy; X3 is O or —NR127 wherein R127 is hydrogen or C1-C6alkyl;

[0107] X4 is O, S or —NR143 wherein R143 is hydrogen or C1-C6alkyl;

[0108] R141 is hydrogen, C1-C6alkyl or amino;

[0109] R142 is benzyl or phenyl each of which may be optionally substituted with C1-C6alkyl, halogen or C1-C6alkoxy;

[0110] R144 is hydrogen or C1-C6alkyl;

[0111] R85 is hydrogen, C1-C6alkoxy, C1-C6alkyl, —CO2C1-C6alkyl, C(O)C1-C6alkyl or a group selected from the following:

[0112] wherein

[0113] j is 0, 1, 2 or 3 as hereinbefore defined;

[0114] w is 1, 2 or 3 as hereinbefore defined;

[0115] m is 0, 1 or 2 as hereinbefore defined;

[0116] e is 2, 3, 4, 5, 6 or 7 as hereinbefore defined;

[0117] each R147, R148, R150, R151, R152, R153, R156, R157, R159, R160, R162 and

[0118] R163 is independently hydrogen or C1-C6alkyl;

[0119] R149 is hydrogen, halogen, C1-C6alkyl, phenoxy, trifluoromethyl or trifluoromethoxy;

[0120] R155 is hydrogen, halogen or C1-C6alkyl;

[0121] R158 is hydrogen or C1-C6alkyl;

[0122] R161 is hydrogen or C1-C6alkyl;

[0123] R164 is hydrogen, halogen, C1-C6alkyl or trifluoromethyl;

[0124] R165 is hydrogen, C1-C6alkyl or halogen;

[0125] X7 is O or S or —NR167 wherein R167 is hydrogen or C1-C6alkyl;

[0126] R166 is hydrogen or C1-C6alkyl;

[0127] or R1 and R2 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring, and in which the ring is optionally mono- or di-substituted, the substituents independently selected from:

[0128] (1) C1-C6alkyl;

[0129] (2) —CO2—(C1-C6alkyl);

[0130] (3) —NR50R51 wherein R50 and R51 are each independently hydrogen, C1-C6alkyl, or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C1-C6alkyl, halogen or trifluoromethyl;

[0131] (4) —C(O)phenyl wherein the phenyl group is optionally mono- or disubstituted with substituents independently selected from C1-C6alkyl, halogen or trifluoromethyl;

[0132] (5) —(CH2)mOR52 wherein R52 is hydrogen or C1-C2alkyl or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C1-C6alkyl, halogen or trifluoromethyl, and m is 0, 1 or 2 as hereinbefore defined;

[0133] (6) —NR54—COR53 wherein R54 is hydrogen or C1-C6alkyl and R53 is hydrogen or C1-C2alkyl;

[0134] (7) ═O;

[0135] (8) —CN;

[0136] wherein

[0137] b is 0, 1 or 2 as hereinbefore defined;

[0138] w is 1, 2 or 3 as hereinbefore defined;

[0139] t is 0 or 1 as hereinbefore defined;

[0140] i is 0, 1 or 2;

[0141] v is 0, 1, 2, 3 or 4 as hereinbefore defined;

[0142] k is 0 or 1 as hereinbefore defined;

[0143] c are 0, 1 or 2;

[0144] R167 is hydrogen or C1-C6alkyl;

[0145] each R55, R56, R58, R59, R169 and R170 is independently hydrogen or C1-C6alkyl;

[0146] each R57 is independently hydrogen, halogen or C1-C6alkyl;

[0147] each R60 is independently hydrogen, halogen or C1-C6alkyl;

[0148] R61 and R62 are each independently hydrogen or C1-C6alkyl;

[0149] R168 is hydrogen, thienyl or furanyl;

[0150] R171 is hydrogen, C1-C6alkyl, halogen, trifluoromethyl or trifluoromethoxy;

[0151] or R1 and R2 are joined together to form a group of formula X;

[0152] or R1 and R2 are joined together to form the group of formula (Y)

[0153] or R1 and R2 are joined together to form any of the following groups:

[0154] wherein

[0155] g is 1 or 2 as hereinbefore defined;

[0156] p is 0, 1 or 2 as hereinbefore defined;

[0157] R172 is hydrogen, C1-C6alkyl or C1-C6alkoxy;

[0158] R173 is hydrogen, C1-C6alkyl or phenyl optionally mono- or disubstituted with C1-C6alkyl or halogen; and

[0159] R82 is a substituent selected from the following groups:

[0160] (a) C1-C6alkyl optionally substituted with hydroxy;

[0161] (b) C1-C6alkenyl;

[0162] (c) C1-C6alkoxy;

[0163] (d) —(CH2)OC1-C6alkyl;

[0164] wherein X8 is —(CR175R176)h— or —(CR177═CR188)— wherein each R174 is independently hydrogen, C1-C6alkyl, halogen, trifluoromethyl, C1-C6alkoxy or benzyloxy;

[0165] h is 0, 1, 2 or 3 as hereinbefore defined;

[0166] each R175, R176, R177 and R178 is independently hydrogen or C1-C6alkyl; and

[0167] j is 0, 1, 2 or 3 as hereinbefore defined;

[0168] wherein X9 is —(C180R181)j— or

[0169] —(CR184R185CR186═CR187)— or

[0170] —(CR182═CR183)—

[0171] wherein

[0172] aa is 0 or 2 as hereinbefore defined;

[0173] R179 is hydrogen, C1-C6alkyl, halogen, trifluoromethyl,

[0174] C1-C6alkoxy, benzyloxy or phenyl;

[0175] each R180, R181, R182, R183, R184, R185, R186 and R187 is independently hydrogen or C1-C6alkyl;

[0176] j is 0, 1, 2, or 3 as hereinbefore defined;

[0177] wherein w is 1, 2 or 3 as hereinbefore defined;

[0178] each R188 and R189 is independently hydrogen or C1-C6alkyl;

[0179] wherein

[0180] i is 0, 1 or 2 as hereinbefore defined;

[0181] each R190 is independently hydrogen, alkyl or halogen;

[0182] b is 0, 1, or 2 as hereinbefore defined;

[0183] each R191 and R192 is independently hydrogen or C1-C6alkyl;

[0184] wherein

[0185] a is 1, 2 or 3 as hereinbefore defined;

[0186] each R193 and R194 is independently hydrogen or C1-C6alkyl;

[0187] R195 is hydrogen, halogen or C1-C6alkyl;

[0188] wherein

[0189] e is 2, 3, 4, 5 or 6 as hereinbefore defined;

[0190] b is 0, 1 or 2 as hereinbefore defined;

[0191] each R196 and R197 is independently hydrogen or C1-C6alkyl;

[0192] each R198 and R199 is independently hydrogen or C1-C6alkyl;

[0193] wherein

[0194] each R200 and R201 is independently hydrogen or C1-C6alkyl;

[0195] w is 1, 2 or 3 as hereinbefore defined;

[0196] wherein

[0197] each R202, R203, R204 and R205 is independently hydrogen or C1-C6alkyl; and

[0198] w is 1, 2 or 3 is as hereinbefore defined;

[0199] (n)

[0200] —(CR206R207)w—OC1-C6alkyl

[0201] wherein

[0202] C1-C6alkyl is optionally substituted with hydroxy;

[0203] each R206 and R207 is independently hydrogen or C1-C6alkyl; and

[0204] w is 1, 2 or 3 as hereinbefore defined;

[0205] (o)

[0206] —(CR208R209)w—NR210R211

[0207] wherein

[0208] each R208, R209, R210 and R211 is independently hydrogen or C1-C6alkyl;

[0209] w is 1, 2 or 3 as hereinbefore defined;

[0210] with the proviso that when n is 1; and y is 0; and R3 is hydrogen or C1-C6alkyl; and

[0211] is group (a);

[0212] and R is group:

[0213] (a) wherein R4 is hydrogen, halogen or C1-C6alkyl, and R1 is hydrogen or unsubstituted C1-C6alkyl,

[0214] then R2 cannot be a group of the following formula:

[0215] (a) wherein z is 0,

[0216] (b) wherein u is 0 and M is hydrogen, halogen, C1-C6alkyl, or trifluoromethyl,

[0217] (c) wherein o is 0,

[0218] (d) wherein l is 0,

[0219] (e) wherein j is 0,

[0220] (g) wherein v is 0, or

[0221] (i);

[0222] and also when R is the group of formula (a), R1 and R2 cannot be joined together to form the group of formula Y or a 5-, 6-, or 7-membered monocyclic ring wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl;

[0223] (b) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0224] (a),

[0225] (b),

[0226] (c) wherein o is 0,

[0227] (d) wherein l is 0,

[0228] (i),

[0229] (k),

[0230] (l), or

[0231] (m) wherein Q is CH2;

[0232] and also when R is the group of formula (b), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0233] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0234] (c) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0235] (c) wherein o is 0,

[0236] (d) wherein l is 0, or

[0237] (i);

[0238] (d) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0239] (a),

[0240] (b) wherein u is 1,

[0241] (c) wherein o is 0,

[0242] (d),

[0243] (i),

[0244] (k),

[0245] (l), or

[0246] (m) wherein Q is CH2;

[0247] and also when R is the group of formula (d), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0248] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0249] (e) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0250] (a),

[0251] (b),

[0252] (c) wherein o is 0,

[0253] (d),

[0254] (i),

[0255] (k),

[0256] (l), or

[0257] (m) wherein 0 is CH2;

[0258] and also when R is the group of formula (e), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0259] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0260] (f) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0261] (a),

[0262] (b),

[0263] (c) wherein o is 0,

[0264] (d),

[0265] (i),

[0266] (k),

[0267] (l), or

[0268] (m) wherein Q is CH2;

[0269] and also when R is the group of formula (f), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0270] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0271] (g) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0272] (a),

[0273] (b) wherein u is 1,

[0274] (c) wherein o is 0,

[0275] (d),

[0276] (i),

[0277] (k),

[0278] (l), or

[0279] (m) wherein Q is CH2;

[0280] and also when R is the group of formula (g), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0281] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0282] (h) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0283] (a),

[0284] (b),

[0285] (c) wherein o is 0,

[0286] (d),

[0287] (i),

[0288] (k),

[0289] (l), or

[0290] (m) wherein Q is CH2;

[0291] and also when R is the group of formula (h), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0292] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

[0293] (j) then R1 and R2 cannot be joined together to form a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0294] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl.

[0295] The subject invention is directed toward compounds or pharmaceutically acceptable salts of Formula I as depicted above in either racemic or pure stereoisomeric forms.

[0296] Terms used herein have the following meanings:

[0297] a) “Pharmaceutically acceptable salts” means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients for the intended use.

[0298] “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points.

[0299] “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0300] b) “Stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).

[0301] c) “Alkyl” means a branched or straight chain alkyl or alkylene group, as is appropriate to the formula, specified by the amount of carbons in the alkyl, e.g., C1-C6 alkyl means a one, two, three, four, five or six carbon branched or straight chain alkyl or alkylene, as the case may be, or any ranges thereof, for example, but not limited to, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-C6, C3-C4, C3-5, C3-6, C4-5, C4-6, C5-6, etc.

[0302] d) “Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

[0303] e) “Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

[0304] f) “Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.

[0305] g) “Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

[0306] h) “Psychoses” or “Psychotic Disorders” means conditions wherein the patient experiences a major mental disorder of organic and/or emotional origin characterized by derangement of the personality and loss of contact with reality, often with delusions, hallucinations or illusions. Included under the term psychoses are the disorders schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified, and substance-induced psychotic disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., published 1994 by the American Psychiatric Association, Washington D.C. USA, incorporated herein by reference.

[0307] i) “Substance Dependence” means a condition wherein the patient exhibits a maladaptive pattern of substance use, leading to clinically significant impairment or distress. There is a pattern of repeated self-administration that usually results in tolerance, withdrawal, and compulsive drug-taking.

[0308] j) “Substance Abuse” means a condition wherein the patient exhibits a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances. There may be repeated failure to fulfill major role obligations, repeated use in situations in which it is physically hazardous, multiple legal problems, and recurrent social and interpersonal problems. Unlike the criteria for Substance Dependence, the criteria for Substance Abuse do not include tolerance, withdrawal, or a pattern of compulsive use and instead only include the harmful consequences of repeated use.

[0309] k) “Parkinson's Disease” means a slowly progressive neurological condition, characterized by tremor, rigidity, bradykinesia, and postural instability. Other manifestations include depression and dementia.

[0310] l) “Parkinsonism” means a condition where the patient exhibits Parkinsonian signs or symptoms (i.e. tremor, muscular rigidity, or akinesia) that develop in association with the use of neuroleptic medication.

[0311] m) “Neuroleptic-Induced Tardive Dyskinesia” means a disorder characterized by involuntary movements of the tongue, jaw, trunk, or extremities which have developed in association with the use of neuroleptic medication. The involuntary movements may be chloroform, athetoid or rhythmic.

[0312] n) “Gilles de la Tourette Syndrome” means a condition manifested by motor and vocal tics. (A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization.) The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning. The onset is before age eighteen years and the disturbance is not due to the physiological effects of a substance or general medical condition.

[0313] o) “Dementia” means disorders characterized by the development of multiple cognitive deficits that include memory impairment and are due to the direct physiological effects of a general medical condition, to the persisting effects of a substance, or to multiple etiologies (e.g., the combined effects of cerebrovascular disease and Alzheimer's disease). Memory impairment is required to make the diagnosis of a dementia and is a prominent early symptom. Dementia disorders share a common symptom presentation but are differentiated based on etiology. See Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, for diagnostic criteria.

[0314] p) “Anxiety Disorders” means disorders that include Panic Disorder Without Agoraphobia, Panic Disorder with Agoraphobia, Agoraphobia Without History of Panic Disorder, Specific Phobia, Social Phobia, Obsessive-Compulsive Disorder, Post-traumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Anxiety Disorder Due to a General Medical Condition, Substance-induced Anxiety Disorder, and Anxiety Disorder Not Otherwise Specified, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.

[0315] q) “Sleep Disorders” means disorders that include Primary Sleep Disorders, Sleep Disorder Related to Another Mental Disorder, Sleep Disorder Due to a General Medical Condition, and Substance-Induced Sleep Disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Primary Sleep Disorders are those in which none of the etiologies listed below (i.e., another mental disorder, a general medical condition, or a substance) is responsible. Primary Sleep Disorders are presumed to arise from endogenous abnormalities in sleep-wake generating or timing mechanisms, often complicated by conditioning factors. Primary Sleep Disorders in turn are subdivided into Dyssomnias (characterized by abnormalities in the amount, quality, or timing of sleep) and Parasomnias (characterized by abnormal behavioral or physiological events occurring in association with sleep, specific sleep stages, or sleep-wake transitions). A representative example of a Primary Sleep Disorder is Narcolepsy. Narcolepsy is characterized by repeated irresistible attacks of refreshing sleep, cataplexy, and recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition period between sleep and wakefulness.

[0316] r) “Mood Disorders” are disorders that have a disturbance in mood as the predominant feature. As defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Mood Disorders are divided into the Depressive Disorders (“unipolar depression”), the Bipolar Disorders, and two disorders based on etiology—Mood Disorder Due to a General Medical Condition and Substance-induced Mood Disorder. The Depressive Disorders (i.e., Major Depressive Disorder, Dysthymic Disorder, and Depressive Disorder Not Otherwise Specified) are distinguished from the Bipolar Disorders by the fact that there is no history of ever having had a Manic, Mixed, or Hypomanic Episode. The Bipolar Disorders (i.e., Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, and Bipolar Disorder Not Otherwise Specified) involve the presence (or history) of Manic Episodes, Mixed Episodes, or Hypomanic Episodes, usually accompanied by the presence (or history) of Major Depressive Episodes.

[0317] s) “Circadian Rhythm Disorder” means a persistent or recurrent pattern of sleep disruption leading to excessive sleepiness or insomnia that is due to a mismatch between the sleep-wake schedule required by a person's environment and his or her circadian sleep-wake pattern. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The disturbance does not occur exclusively during the course of another Sleep Disorder or other mental disorder. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

[0318] Preferred compounds are those wherein R is group (a) or group (k). When R is group (a), R4 is further preferred to be halogen or CF3. When R is group (k), R12 is further preferred to be hydrogen, C1-C6alkyl, or —CH2OC1-C6alkyl. R2 is preferred to be group (a), (b) or (n). When R2 is group (a), z is further preferred to be 0 or 1; e is further preferred to be 5; and each R27 and R23 is further preferred to be independently selected from hydrogen or C1-C6alkyl. When R2 is group (b), M is further preferred to be hydrogen, C1-C6alkoxy or C1-C6alkyl and u is further preferred to be 0 or 1. When R2 is group (n), R70 is further preferred to be hydrogen and f is further preferred to be 3.

[0319] Specific embodiments of the invention include the compounds set forth in the tables herein.

[0320] Preferred embodiments of the invention are those compounds of Formula I set forth in Table 1 that exhibit enhanced D3 potency. Particularly preferred compounds include the following:

[0321] 2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-trans-cyclopropanecarboxylic acid (trans-4-ethyl-cyclohexyl)-amide

[0322] 2-[4-(2,4-Dimethyl-phenyl)-piperazin-1-ylmethyl]-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-ethyl-cyclohexyl)-amide

[0323] 2-[4-(Chloro-trifluoromethyl-pyridin-2-yl)-piperazin-1-ylmethyl]-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-ethyl-cyclohexyl)-amide

[0324] 2-[4-(2,5-Dimethyl-phenyl)-piperazin-1-ylmethyl]-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-ethyl-cyclohexyl)-amide

[0325] 2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide

[0326] 2-(4-Thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide

[0327] 2-[4-o-Tolyl-piperazin-1-ylmethyl]-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-ethyl-cyclohexyl)-amide

[0328] 4-[4-(6-Fluoro-benzo[b]thiophen-3-yl)-piperazin-1-yl]-N-(trans-4-methyl-cyclohexyl)-butyramide

[0329] 2-(4-Thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-(2R, 3R)-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide

[0330] 2-(4-Thieno[2,3-d]isoxazol-3-yl-piperazin-1-ylmethyl)-(2R, 3R)-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide

[0331] 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperazin-1-ylmethyl]-cyclopropane-1R-carboxylic trans-(4-methyl-cyclohexyl)-amide (AVE1734)

[0332] 2R-[4-(5-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclopropane-1R-carboxylic acid trans-(4-methyl-cyclohexyl)-amide. MDL 834012.

[0333] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437359)

[0334] 2R-[4-(1-Methyl-7-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 832654)

[0335] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437360)

[0336] 2R-[4-(7-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 833690)

[0337] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(1-methyl-6-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437353)

[0338] 2R-[4-(6-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002287765)

[0339] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002609935)

[0340] 2R-[4-(6-Fluoro-7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 831361)

[0341] 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002436291)

[0342] 2R-{4-[1-(2,2,20Trifluoro-ethyl)-1H-thieno[3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002287767)

[0343] 2R-(4-Thieno[2,3-d]isoxazol-3-yl-piperazin-1-ylmethyl)-1R-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 831493)

[0344] 2R-(4-Benzo[b]thiophen-2-yl-piperidin-1-ylmethyl)-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 831148)

[0345] 2R-[4-(5,6-Dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-piperazin-1-ylmethyl]-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 833699)

[0346] 2R-(4-Thieno[2,3-b]pyridin-3-yl-piperazin-1-ylmethyl)-1R-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 833821)

[0347] 1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 832231)

[0348] The compounds of the present invention may be prepared by various methods. Schemes I through VI show the different ways of preparing the compounds of Formula I.

[0349] The compounds of formula (I) of this invention can be synthesized by following or combining one or more of the steps described below, not necessarily in the order presented. Throughout the description of the synthetic steps, the definitions of R, R1, R2, R3, g, n, y, B and A are as given above unless otherwise stated or indicated, and other nomenclatures appearing below shall have the same meanings defined in their respective first appearances unless otherwise stated or indicated.

[0350] Compounds of the present invention may be prepared according to a process which comprises

[0351] (a) reacting a compound of formula (II):

[0352] wherein R, A, n, y, R3 and g are as defined in formula I with a compound of formula (III)

[0353] wherein

[0354] is as defined in formula I and “LG” is a suitable leaving group selected from chlorine, bromine, iodine, mesyl, tosyl, brosyl, triflyl, nosyl, nonaflyl or tresyl:

[0355] to provide a compound of formula (IV):

[0356] wherein R3, g, R, A, y, n and

[0357] are defined as in formula I;

[0358] (b) hydrolyzing a compound of formula (IV) to provide a compound of formula (V):

[0359] and

[0360] (c) reacting a compound of formula (V) with a compound of formula (VI):

[0361] wherein R1 and R2 are as defined in formula I; to provide a compound of formula (I).

[0362] Typically, the reaction in step (a) is carried out in polar solvent such as, for example, acetonitrile and an amine base such as, for example, triethylamine. The reaction is typically conducted at a temperature of about 80° C. to about 85° C. for about 1 to 3 hours.

[0363] The reaction in step (b) is typically carried out in a water miscible solvent such as, for example, methanol or 1,4-dioxane in the presence of an aqueous hydroxide base such as, for example, 5 N sodium hydroxide. The reaction is typically carried out at a temperature of about 55° C. to about 65° C. for about 2 to 3 hours.

[0364] The reaction in step (c) is typically carried out in a polar solvent such as, for example, N,N′-dimethylformamide, in the presence of a weak base such as, for example, N-methylmorpholine with a suitable coupling reagent. A suitable coupling reagent is, for example, DCC (1,3-dicyclohexylcarbodiimide), EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline) or TOTU {O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′N′-tetramethyluronium tetrafluoroborate}. Typically, the reaction takes place at a temperature of about 20° C. to about 25° C. for about 16 to 20 hours.

[0365] Alternatively, compounds of the present invention may be prepared according to a process which comprises:

[0366] (a) reacting a compound of formula (VII) wherein R1 and R2 are as hereinbefore defined and “LG” is a suitable leaving group selected from chlorine, bromine, iodine, mesyl, tosyl, brosyl, triflyl, nosyl, nonaflyl or tresyl:

[0367] with a compound of formula (II) to provide a compound of formula (I). This reaction is typically carried out in a polar solvent and an amine base such as acetonitrile and triethylamine, at a temperature of about 55° C. to about 65° C. for about 16 to 20 hours.

[0368] Compounds of formula (II) are either commercially available or may be prepared via synthetic methods well known in the art. For example, Scheme I describes the coupling of a benzthiophene with a commercially-available substituted piperazine. The synthesis is analogous for the un-substituted piperazine analogs. The less sterically hindered piperazine nitrogen is more reactive and cleanly gives a single product in the benzo[b]thiophene coupling. The more sterically hindered nitrogen can then be alkylated as before in the un-substituted piperazines.

[0369] Piperidine-substituted compounds may be prepared via syntheses analogous to those shown in the following reaction Schemes II and III.

[0370] The preparation of various substituted aza- and diazacycloheptanes is described by Treiber et al. in WO 9725324.

[0371] The synthesis of compounds of formula (I) wherein the variable designated as

[0372] contains a carbocycle is shown in general reaction Scheme IV. For the sake of simplification, the description of synthetic schemes is presented below for compounds which contain this carbocyclic group, but it will be apparent that compounds which do not contain a carbocyclic group can be prepared by utilizing the synthetic schemes and making necessary modifications.

[0373] wherein R, A, R3, y, g and n are as hereinbefore defined.

[0374] Many of the dicarboxylates or more advanced intermediates that are generically described in scheme IV are commercially available. Several of these are shown in Table 1. This table is used for illustrative purposes only and is not intended to limit the scope of the present invention in any way.

1TABLE IStarting Materials:StructureNameCAS #Supplier

Dimethyl cis-1,2-cyclopropane dicarboxylate826-34-6Acros

Dimethyl trans-1,2-cyclopropane dicarboxylate826-35-7Acros

Dimethyl 1-methyl-trans-1,2- cyclopropane dicarboxylate702-92-1Acros

Dimethyl 3-methyl-trans-1,2- cyclopropane dicarboxylate28363-79-3Acros

trans-Cyclobutane-1,2-dicarboxylic acid dimethylesterSyntec

trans-D,L-1,2-Cyclopentane- dicarboxylic acid1461-97-8Aldrich

trans-2-Carbomethoxy cyclopentane-1-carboxylic acidRieke

trans-1,2-Cyclohexane dicarboxylic acid2305-32-0Aldrich Acros

trans-2-Carbomethoxy cyclohexane-1-carboxylic acidRieke

cis-1,2-Cyclohexane dicarboxylic acid610-09-3Acros

cis-2-Carbomethoxy cyclohexane- 1-carboxylic acidRieke

[0375] When not commercially available, the appropriate starting material may be obtained via standard synthetic methods.

[0376] When a compound of formula (I) is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.

[0377] Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular D3 receptors, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Preferred compounds of the present invention are those which have higher affinity for dopamine D3 than dopamine D2 receptors.

[0378] A major challenge in antipsychotic research is to produce agents with reduced side effects. Orthostatic hypotension is a common side effect in antipsychotics that is associated with the high potency that these agents have at the alpha-1 receptor (hereinafter referred to as “α-1”). A major goal of this work was to find agents with reduced α-1 potency.

[0379] The 6-trifluoromethyl benzo[b]thiophenes described herein have a clear and somewhat surprising advantage over the 6-fluoro benzo[b]thiophenes as is shown in the following table. The 6-fluoro benzo[b]thiophenes are clearly more potent at the alpha-1 receptor than are the 6-trifluoromethyl benzo[b]thiophenes. This is shown by comparing pairs of analogs that only differ in substitution at the 6-position of the benzo[b]thiophene. In every case, the 6-fluoro benzo[b]thiophene is more potent than the corresponding 6-trifluoromethyl analog. In some cases this small structural difference in substitution at the 6-position produces a dramatic change in α-1 potency. There are several examples wherein 6-fluoro analogs exhibited nanomolar potency while the corresponding 6-trifluoromethyl analog exhibited micromolar potency.

2halpha1Ki(nM)halpha1%INUMMOLSTRUCTUREh = humanh = human826844

23.4826804

32.8% Inh @ 1 uM826845

5.44826805

27.8% Inh @ 1 uM826846

93.9826806

10.3% Inh @ 1 uM826849

35.2826809

30.5% Inh @ 1 uM826857

9.82826817

44.4% Inh @ 1 uM826861

9.55826821

1280 24% Inh @ 0.1 nM826847

0.513826807

166000826848

12.3826808

126826850

28.4826810

200826851

18.9826811

223826852

6.16826812

658826853

0.258826813

57826854

0.0713826814

89.3826855

0.889826815

80.5826856

15.3826816

249826858

9.42826818

124826859

4826819

49826860

0.516826820

129826862

0.637826822

32.2826863

32.2826823

148

[0380] Especially preferred compounds of the instant invention are those with a reduced liability for α-1 receptor binding while at the same time having a higher affinity for dopamine D3than dopamine D2 receptors.

[0381] Receptor affinity can be measured using standard methodology such as is described below.

[0382] [N-Methyl-3H]Spiroperidol Binding to Cloned Human Dopamine D3 Receptors

[0383] Purpose

[0384] This assay measures the in vitro activity of compounds on cloned human dopamine (D3) receptors and predicts the direct dopamine-blocking properties of putative neuropsychiatric agents at human dopamine D3 receptors.

[0385] Methods

[0386] A. Cloning

[0387] The D3 gene was isolated from a human striatal cDNA library (Stratagene). The gene was sequenced and sub-cloned into the expression vector RC/RSV (Invitrogen). CHO (Chinese Hamster Ovary) cells were stably transfected with 10 μg of the D3/RSV plasmid using the DOTAP method from Boehringer Mannheim and 72 clones that were G418 resistant were isolated. Using mRNA and binding displacement data a single high expressing clone was identified. This clone was then grown in large batches for the purpose of developing a 96 well format assay.

[0388] B. Cell Culture

[0389] 1. One plate (10 cm) with approximately 2-3 million D3 cells per plate is incubated with 1 ml of Trypsin-EDTA at room temperature for ˜2 min or until cells have lifted off plates. Four ml of Ham's F12+10% Fetal Bovine Serum+1% Penicillin/Streptomycin+G418 (400 μg/ml) medium are added to resuspend cells and 1 ml of this is added to each large plate (15 cm) containing 19 ml of the same medium as mentioned above.

[0390] 2. The 5 large plates are incubated at 37° C. +5% CO2 for ˜3 days or until the cells are confluent.

[0391] 3. After these plates are confluent, they are split into 10 large plates. Medium is aspirated off, 2 ml of Trypsin-EDTA are added to each plate and plates are incubated at RT for 2 min or until cells have lifted off the plate. Eight ml of the F12 medium (same medium as #1 above) are added to each plate (10 ml total) to resuspend the cells and 5 ml are transferred to the 2 new plates containing 15 ml of the F12 media.

[0392] 4. The 10 large plates are incubated at 37° C.+5% CO2 for 2 days or until the cells are confluent.

[0393] 5. The 10 large plates are split into 60 large plates (using Trypsin-EDTA as #3 except 4 ml of F12 medium are added to resuspend cells and 1 ml is aliquoted to 6 new plates containing 19 ml of F12 medium each).

[0394] 6. Plates are incubated at 37° C.+5% CO2 for ˜3 days or until cell are confluent.

[0395] 7. The 60 large plates are then split into 60 roller bottles (100-150 million cells/bottle). Medium is aspirated off, 2 ml of Trypsin-EDTA are added to each plate and incubated at RT for ˜2 minutes or until cells have lifted off plates. Eight ml of F12 medium are added to each plate to resuspend cells and the entire 10 ml are added to 1 roller bottle containing 90 ml of the F12 medium.

[0396] 8. The 60 roller bottles are immediately placed on their sides and transferred to the roller bottle incubator. They are incubated at 37° C.+5% CO2 for ˜3-5 days. Cells are spun at 30-40% motor speed in the Forma incubator.

[0397] 9. Medium is poured off and cells are washed 2× in PBS.

[0398] 10. Cells are then scraped off in 20 ml of PBS and the bottles are rinsed again with 5 ml of PBS to remove any remaining cells. Cells are stored on ice before membrane prepration.

[0399] 11. The yield for 60 D3 roller bottles has varied from ˜260-500 mg.

[0400] Note: All tissue culture reagents are from Gibco-BRL.

[0401] C. Membrane Preparation

[0402] The cells are harvested into 250 ml centrifuge tubes with 100 volumes of cold hosphate buffered saline (PBS) and spun down (1200×G for 10 min at 4° C.). The medium is removed and 100 ml PBS are added to each centrifuge tube, cells are resuspened and spun down again. The PBS is removed and the final pellet is homogenized in an appropriate volume of 10% DMSO with a polytron on ice at a medium setting.

[0403] D. Lowry Protein Assay

[0404] A 200 μl sample membrane homogenate is added to 200 μl of 1% SDS, vortexed and allowed to stand for 5 min. Aliquots (25, 50 and 100 μl) of this mixture are assayed in duplicate following the standard Bio-Rad DC protein assay protocol (kit catalog number 500-0112) and using reagent S. Absorbance readings are made at 750 nm (note: the most accurate protein OD readings are between 0.1-0.5 units). The protein concentration is calculated using a standard curve generated concurrently with bovine serum albumin as standard.

[0405] E. Storage/Freezing Conditions

[0406] Following the determination of the protein concentration and Scatchard analysis, the protein is diluted into distilled water with 10% DMSO to the appropriate volume based on expression levels (Bmax). The concentrated protein is then aliquoted into 1.5 ml screw top cap Eppendorf tubes and placed into a −80° C. freezer.

[0407] F. Binding Assay Reagents

[0408] 1. 0.5M Tris Buffer, pH 7.7

[0409] a) 44.4 g Tris HCl 26.5 g Tris Base q.s. to 1 Liter (0.5 M Tris buffer, pH 7.7 at 37° C.)

[0410] b) make a 1:10 dilution in distilled H2O (0.05 M. Tris buffer, pH 7.7)

[0411] 2. Tris Buffer containing physiological salts

[0412] a) Stock buffer

[0413] NaCl 7.014 g

[0414] KCl 0.372 g

[0415] CaCl2 0.222 g

[0416] MgCl2 0.204 g

[0417] q.s. To 100 ml with 0.5 M. Tris Buffer

[0418] b) Dilute 1:10 in distilled H2O

[0419] This yields 0.05 M. Tris HCl, pH 7.7, containing NaCl (120 mM), KCl (5 mM), CaCl2 (2 mM) and MgCl2 (1 mM)

[0420] Optional: add 0.1% ascorbic acid and check pH (in assays with compounds that may oxidize.

[0421] 3. a) 1.0% polyethyleneimine stock in 0.5M Tris (reagent 1.a) b) Dilute 1:10 in distilled H2O

[0422] 4. [N-methyl-3H]-Spiroperidol (60-90 Ci/mmol) is obtained from New England Nuclear; catalog #NET-856.

[0423] For Ki determinations: [3H]NMSP is made up to a concentration of 2.7 nM in buffer 2b, such that when 150 μl is added to each tube a final concentration of 0.4 nM is attained in the 1 ml assay. Samples of total CPM added are taken for each experiment to calculate the total ligand concentration.

[0424] 5. S(−)-Eticlopride is obtained from Research Biochemicals International (RBI catalog number E-101). A refrigerated stock (good for up to a month) solution of S(−)-eticlopride is made at a concentration of 30 μM in buffer 2b. One hundred microliters are added to 3 wells for the determination of nonspecific binding (this yields a final concentration of 3 μM in the 1 ml assay).

[0425] 6. Test Compounds

[0426] For most assays, a 100 μM stock solution of the test compound is made up in a suitable solvent (usually <0.1% acetic acid) and serially diluted with buffer 2b, such that when 100 μl of drug is combined with the total 1 ml assay, final concentrations ranging from 10−5-10−8 M are attained. Characteristically eight concentrations are studied for each assay; however, higher or lower concentrations may be used, depending on the potency of the drug.

[0427] G. Binding Assay

[0428] 750 μl Tissue

[0429] 150 μl [3H]NMSP

[0430] 100 μl vehicle (for total binding) or 30 μM (−)eticlopride (for nonspecific binding) or appropriate drug concentration.

[0431] The 96-Well Packard Unifilters GF/B are incubated for >1 h at 25° C. in 0.1% polyethylamine (from 3,b). The cold tissue is added last and mixed on a orbital shaker for a few seconds and is then incubated at 37° C. for 30 min in a shaking water bath. The assay is stopped by rapid filtration through Packard Unifilter plates. The filter membranes are then washed with 15 ml of ice-cold 0.05 M Tris buffer. The filters are then dried (˜15 min under a heat lamp or incubated for 15 min in a 60° C. oven) and a bottom seal is applied. Then 40 μl of Packard Microscint 20 scintillation cocktail is added and a permanent topseal (Type P) is applied and heat sealed. The plates are then shaken on an orbital shaker for 1 h and placed in the Packard Topcount and counted for at least 5 minutes for each point.

[0432] Specific binding is defined as the difference between total binding and the binding in the presence of 3 μM S-(−)-eticlopride. Total binding is approximately 10% of the total added ligand. Cheng-Prusoff determination (Ki's) are performed using Prism software using a one-site competition curve analysis where the top and the bottom of the non-linear regression are held constant at 0% and 100% percent inhibition. The percent inhibition at each drug concentration is the mean of duplicate determinations.

[0433] [N-Methyl-3H]Spiroperidol Binding to Cloned Human Dopamine D2Long Receptors

[0434] Purpose:

[0435] This assay measures the in vitro activity of drugs on cloned human dopamine D2Long receptors and predicts the direct dopamine-displacing properties of neuropsychiatric cardiovascular and renal agents at human dopamine D2 receptors.

[0436] Methods:

[0437] A. Cloning

[0438] The D2L gene was isolated from a human striatal (caudate/putamen) cDNA library. The gene was sequenced and sub-cloned into the expression vector pRC/RSV (Invitrogen). CHO (Chinese Hamster Ovary) cells were stably transfected and 72 clones that were geneticin (G418) resistant were isolated. Using mRNA and binding data a single high expressing cell line was identified (#44). This cell line was then grown in suspension culture for the purpose of developing a 96 well format assay.

[0439] B. Cell Culture Conditions

[0440] 1. Medium for adherent CHO cultures:

Ham's F12+10% fetal bovine serum (FBS)+400 μg/ml geneticin (G418)+10 ml/L penicillin-streptomycin (pen-strep)

[0441] 2. Cells are transferred to suspension culture when at least 1.5 million cells are available (this allows for 300,000 cells/ml in a 50 ml spinner flask; this is the ideal suspension density). Cell are removed from flasks with trypsin, spun down (1000×G) and resuspended in fresh medium:

50% CHO-SFM II+50% Ham's F12 w/10% FBS (final FBS conc. 5%)+400 μg/ml G418+pen-strep (10 ml/L)

[0442] 3. After the transfer to suspension culture, growth is monitored and cell viability is assessed using trypan blue exclusion. Total and viable cell count on 5 sectors of the hemocytometer are recorded. When the viable cell density reaches 600,000 cell/ml, the volume is doubled.

[0443] 4. After 1 week of growth in the 50/50 medium, the cells are spun down and transferred to a new spinner flask and replaced with 75% CHO-SFM II/25% Ham's F12+10% FBS plus the pen-strep and G418. Thereafter every 3 days, the medium is replaced with new medium containing a decreasing amount of FBS as follows:

3ml of CHO SFM:ml of Ham'S F12Final % FBS conc.87.50:12.51.2593.75:6.250.62599.00:1.000.1

[0444] 5. The final maintenance culturing medium is made up as follows:

[0445] A stock mixture of 10 ml of pen-strep, 0.5 ml of 400 mg/ml (active; final concentration: 200 mg/ml) G418 and 1 ml of FBS are mixed and filtered and refrigerated. A volume (11.5 ml) of this mixture is added to a freshly opened 1 L bottle of CHO-SFM II.

[0446] C. Membrane Preparation

[0447] The cells are harvested into 250 ml centrifuge tubes with 100 volumes of cold phosphate buffered saline (PBS) and spun down (1200×G for 10 min at 4° C.). The medium is removed and 100 ml PBS are added to each centrifuge tube, cells are resuspened and spun down again. The PBS is removed and the final pellet is homogenized in an appropriate volume of PBS with a polytron on ice at a medium setting.

[0448] D. Lowry Protein Assay

[0449] A 200 μl sample membrane homogenate is added to 200 μl of 1% SDS, vortexed and allowed to stand for 5 min. Aliquots (25, 50 and 100 μl) of this mixture are assayed in duplicate following the standard Bio-Rad DC protein assay protocol (kit catalog number 500-0112) and using reagent S. Absorbance readings are made at 750 nm (note: the most accurate protein OD readings are between 0.1-0.5 units). The protein concentration is calculated using a standard curve generated concurrently with bovine serum albumin as standard.

[0450] E. Storage/Freezing Conditions

[0451] Following the determination of the protein concentration, the protein is diluted into distilled water with 10% DMSO to the appropriate volume based on expression levels (Bmax). The concentrated protein is aliquoted into 1.5 ml screw top eppendorf tubes and placed into a −80° C. freezer.

[0452] F. Binding Assay Reagents

[0453] 1. 0.5M Tris Buffer, pH 7.7

[0454] a) 44.4 g Tris HCl

[0455] 26.5 g Tris Base

[0456] q.s. to 1 Liter (0.5 M Tris buffer, pH 7.7 at 37° C.)

[0457] b) make a 1:10 dilution in distilled H2O (0.05 M. Tris buffer, pH 7.7)

[0458] 2. Tris Buffer containing physiological salts

[0459] a) Stock buffer

[0460] NaCl 7.014 g

[0461] KCl 0.372 g

[0462] CaCl2 0.222 g

[0463] MgCl2 0.204 g

[0464] q.s. To 100 ml with 0.5 M. Tris Buffer

[0465] b) Dilute 1:10 in distilled H2O

[0466] This yields 0.05 M. Tris HCl, pH 7.7, containing NaCl (120 mM), KCl (5 mM), CaCl2 (2 mM) and MgCl2 (1 mM)

[0467] Optional: add 0.1% ascorbic acid and check pH (in assays with compounds that may oxidize.

[0468] 3. a) 1.0% polyethyleneimine stock in 0.5M Tris (reagent 1.a) b) Dilute 1:10 in distilled H2O

[0469] 4. [N-methyl-3H]-Spiroperidol (60-90 Ci/mmol) is obtained from New England Nuclear; catalog #NET-856.

[0470] For Ki determinations: [3H]NMSP is made up to a concentration of 2.7 nM in buffer 2b, such that when 150 μl is added to each tube a final concentration of 0.4 nM is attained in the 1 ml assay. Samples of total CPM added are taken for each experiment to calculate the total ligand concentration.

[0471] 5. S(−)-Eticlopride is obtained from Research Biochemicals International (RBI catalog number E-101). A refrigerated stock (good for up to a month) solution of S(−)-eticlopride is made at a concentration of 30 μM in buffer 2b. One hundred microliters are added to 3 wells for the determination of nonspecific binding (this yields a final concentration of 3 μM in the 1 ml assay).

[0472] 6. Test Compounds

[0473] For most assays, a 100 μM stock solution of the test compound is made up in a suitable solvent (usually <0.1% acetic acid) and serially diluted with buffer 2b, such that when 100 μl of drug is combined with the total 1 ml assay, final concentrations ranging from 10−5-10−8 M are attained. Characteristically eight concentrations are studied for each assay; however, higher or lower concentrations may be used, depending on the potency of the drug.

[0474] G. Binding Assay

[0475] 750 μl Tissue

[0476] 150 μl [3H]NMSP

[0477] 100 μl vehicle (for total binding) or 30 μM (−)eticlopride (for nonspecific binding) or appropriate drug concentration.

[0478] The 96-Well Packard Unifilters GF/B are incubated for >1 h at 25° C. in 0.1% polyethylamine (from 3,b). The cold tissue is added last and mixed on a orbital shaker for a few seconds and is then incubated at 37° C. for 30 min in a shaking water bath. The assay is stopped by rapid filtration through Packard Unifilter plates. The filter membranes are then washed with 15 ml of ice-cold 0.05 M Tris buffer. The filters are then dried (˜15 min under a heat lamp or incubated for 15 min in a 60° C. oven) and a bottom seal is applied. Then 40 μl of Packard Microscint 20 scintillation cocktail is added and a permanent topseal (Type P) is applied and heat sealed. The plates are then shaken on an orbital shaker for 1 h and placed in the Packard Topcount and counted for at least 5 minutes for each point.

[0479] Specific binding is defined as the difference between total binding and the binding in the presence of 3 μM S-(−)-eticlopride. Total binding is approximately 10% of the total added ligand. Cheng-Prusoff determination (Ki's) are performed using Prism software using a one-site competition curve analysis where the top and the bottom of the non-linear regression are held constant at 0% and 100% percent inhibition. The percent inhibition at each drug concentration is the mean of duplicate determinations.

43H]PRAZOSIN BINDING TO CLONED HUMAN ALPHA-1A ADRENERGICRECEPTORS (α1a) EXPRESSED IN CHINESE HAMSTER OVARY CELLS (CHO)Purpose:This in vitro assay is designed as a screen to identify compoundsdisplaying a affinity for the human α1a adrenoceptor subtype expressedin the membrane fragments of CHO cells. The assay measures theability of the test compounds to displace [3H] prazosin from α1a sites.The identification of multiple vascular α1-addrenoceptors (α1a, α1b, α1d)in vitro has provided impetus to define the role(s) of these subtypes incardiovascular regulation in vivo (Vargas and Gorman, 1995).Hemodynamic studies in the unanesthetized rat suggest that vascularα1a receptors are the major subtype involved in the sympatheticregulation of peripheral resistance and systemic arterial pressure(Piascik et al., 1989). Additional evidence for an involvement ofperipheral α1a receptors in the maintenance of arterial pressure wasdemonstrated by the findings that the selective α1a antagonist 5-MUdose dependently lowered resting arterial pressure in awake consciousdogs (Piascik et al., 1989). A demonstrated inability of the irreversibleantagonist, chloroethylclonidine, to reduce arterial pressure in ratswhen administered intravenously, is strong evidence against the role ofα1b and α1d receptors in the acute regulation of arterial pressure(Vargas et al., 1993).Therefore, the binding of compounds to α1a adrenergic receptors isbelieved to be a good measure of a compound's potential to causeorthostatic hypotension and sedation as side effects. Prazosin is apotent antagonist of the human α1a-adrenoceptor subtype, which hasbeen cloned and is expressed in the membrane fragments of CHOcells.hα1areceptor:The cloning of the human α1a cDNA was accomplished first byscreening a human prostate cDNA library (Clontech), from which aportion of the coding region was obtained. This DNA fragment wasthen used to screen a human leukocyte genomic library (Clontech),and the rest of the coding sequence was obtained. Later these twofragments were spliced together. The entire coding sequence wasthen fully sequenced including matching PCR sequence with originalgenomic coding sequence, thus ensuring splice sites were joinedcorrectly (Schwinn et al., 1995). Once sequenced, the gene wassubcloned into the expression vector pcDNA3 (Invitrogen).Plasmid DNA was then used for transfection into CHO cells and G418resistant clones were isolated. A clone expressing high levels of thehα1a receptor (as determined by mRNA and receptor binding data) waschosen and pharmacologically characterized.Culture Media:Media Ingredients for Adherent α1a expressing CHO Culture:A. HAM's F-12 (Cellgro)B. 10% 0.2 micron filtered Fetal Bovine Serum (FBS)(Cellgro)C. 1% 0.2 micron filtered Penicillin-Streptomycin (Cellgro)D. G418 0.2 micron filtered (Geneticin 400 μg/ml)(Cellgro)Cells are cultured using established methods and procedures in either150 × 25 mm culture plates (scale up to 100 plates) or a combination ofthese plates and 70 roller bottles. One culturing/harvest cycle typicallyrequires 2 weeks and yields between 100-400 mg protein. Plates orbottles are incubated at 37° C. + 5% CO2.Storage:Cells are harvested by mechanical scraping, washed using PBS,collected in 250 ml Corning polypropylene centrifuge tubes, spun down(1500 RPM) and resuspended in dH2O 10% DMSO (final volume perharvest is approximately 50 ml). Protein determination is made usingthe Biorad DC Assay Kit. Finally, the appropriate volume is aliquotedinto a 2 ml Corning Cryovial (10 mg/1-1.5 ml) which is stored at −80° C.Current Lot Data:α1a (clone #7)Batch 1/14/98Receptor Concentration2418 fmoles/mg proteinKd0.18 nMVolume1.5 ml/cryovialProtein Concentrationapprox. 10 mg/1.5 mlAssay Requirement:0.5 cryovials per 96 well plate (assay volume = 200 μl/well)[3H]-Ligand:[7-methoxy-3H]-Prazosin: 1.0 nM (NEN, NET-823)70-87 Ci/mmolMaterials:Phentolamine mesylate (Research Biochemicals Int. #P-131)96 well flat bottom plates (Beckman)Unifilter GF/B Plate (Packard)Polyethylenimine (Sigma #P-3134)TomTec or Packard Filtermate 196 Cell HarvestersPackard TopCount Scintillation CounterBuffers:A: 50 mM Tris HCl; 0.1% ascorbate, pH 7.7 (incubation buffer)B: 50 mM Tris HCl; pH 7.7 (wash buffer)Procedure:Assay additions are as follows (in the order indicated):Total Binding = 50 μl buffer A + 50 μl [3H]prazosin + 100 μl membraneNonsp. Bd. = 50 μl 10 μM phentolamine + 50 μl [3H]prazosin + 100 μlmembraneTest Cpd. = 50 μl compound + 50 μl [3H]prazosin + 100 μl membraneCompounds to be evaluated are weighed out to yield a 10 mM stocksolution in DMSO in a 24 well polystyrene plate. This is diluted to a 0.5 mMstock in dH2O. Serial dilutions in Buffer A are made from which 50 μladditions to the plate are made in duplicate in order to achieve thefinal concentrations desired. Typically, one 96 well plate is used toevaluate 11 compounds at 4 concentrations (10−6-10−9 M) in duplicate.Total binding and nonspecific binding are determined in quadruplicate.Usually one standard is run with each assay.[3H]Prazosin is made up in Buffer A such that when 50 μl are addedper well the final concentration is 1.0 nM in a final assay volume of 200 μl.The final concentration should be verified by running a sample in ascintillation counter prior to adding the [3H]prazosin to the 96 well plate.Note: The radioactivity should be prepared just before the additions aremade so that it is not allowed to sit on the bench for very long.Packard GF/B Plate Pretreatment: The filter plates are presoaked forat least 30 min in ice cold Buffer B containing 0.05% polyethyleneimine(200 μl/200 ml) to maximize filtration efficiency and minimize filter blankbinding.Incubation & Filtration: Once buffer, compounds, [3H]prazosin andmembrane have been added (and mixed), the 96 well plates areincubated for 40 min at 37° C. and spaced 3-5 min apart. At 40 min,the plates are filtered using a Tomtec Automated Cell Harvester.Filtration is immediately followed by washes of ice cold Buffer B (totalvol. ˜7 ml).Drying and Counting: Each filter plate is dried under a heat lamp for15 min. The back of the plate is sealed and 40 μl of Packard microscintfluid are added per well. Using Packard film, each plate is heat sealedprior to being counted in a Packard Topcount Scintillation counter. Aprogram has been written that counts each plate twice sending DPM,CPM and TSIS data to disk and printer.Analysis of Results: Raw DPM and CPM data are captured on diskand are imported into one of several software packages (GraphpadPrism Ver 2.0, Excel) residing on the LAN. Specific binding is definedas the difference between total binding and the binding in the presenceof 10 μM phentolamine. Total binding is less than 10% of the totaladded ligand. Software using one-site competition curve analysis isemployed in the calculation of IC50 and KI (Cheng-Prusoff equation,1973). The top and bottom of the non-linear regression are heldconstant at 0% and 100% inhibition. The percent inhibition at eachdrug concentration is the mean of duplicate determinations.References:Vargas, H. M and A. J. Gorman. Life Sciences. Vol. 57, No. 25, pp.2291-2308, 1995.Morrow, A. L. and I. Creese. Mol. Pharmacol. 29: 321-330, 1986.Piascik, M. T., J. W. Kusiak, and K. W. Barron. Eur. J. Pharmacol.11: 101-107, 1989.Vargas, H. M., D. Cunningham, L. Zhou, H. B. Hartman and A. J.Gorman. J. Pharmacol. Exp. Ther. 267: 264-272, 1993.

[0480] The functional activity of compounds of the invention (i.e. whether they are antagonists, agonists or partial agonists) can readily be determined using the microphysiometer test method that follows:

[0481] Chinese Hamster Ovary (CHO) cells, expressing the human dopamine D3 receptor, were grown on the surface of a capsule cup. Cups are assembled and placed on the microphysiometer, and buffer (Dulbecco's Modified Eagle's Medium without sodium bicarbonate and without serum) is perfused through the cup assembly until a stable baseline is achieved (4 hours). Buffer perfusion rate and solution changes are controlled by a computer. Intracellular acidification rate is measured in each of the 8 cup assemblies and recorded by the computer. Buffer containing test compound (10 nM, 100 nM, and 1 uM) was perfused through the cup assembly for 20 min, then buffer containing quinpirole (a D3 agonist) (10 nM) and test compound (same concentrations) is perfused for an additional 1 min. This is followed by a recovery period of 10-60 min where buffer alone is perfused through the cups. Quinpirole increases acidification rate. A D3 antagonist will inhibit this acidification rate in a concentration dependent manner.

[0482] D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression and mania. Conditions which may be treated by D3 agonists include include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety; dementia; circadian rhythm disorders, and drug (e.g. cocaine) dependency.

[0483] D3 receptor ligands are also useful for treating renal dysfunction.

[0484] In accordance with yet another embodiment of the present invention, there is provided a method of modulating the activity of dopamine D3 receptors, said method comprising: contacting cell-associated dopamine D3 receptors with a concentration of a compound of formula IB, or a physiologically acceptable salt thereof, sufficient to modulate the activity of said dopamine D3 receptor. As employed herein, a compound of formula IB shall refer to the compound of formula I except that the proviso therein is deleted therefrom.

[0485] As employed herein, the phrase “modulating the activity of dopamine D3 receptors” refers to a variety of therapeutic applications. Said therapeutic applications refer to the treatment of conditions or disorders which include dyskinetic disorders, psychoses, anxiety disorders, mood disorders, dementia, sleep disorders, nausea substance dependence, substance abuse and nausea.

[0486] The instant invention also provides a method of treating conditions or disorders of the central nervous system comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, IA, or IB or a pharmaceutically acceptable salt thereof. The compounds of formula IA are preferred for this method. As employed herein, a “compound of formula IA” shall refer to the compound of formula I except that the proviso therein i.e. “Proviso A” is deleted therefrom and inserted therefor is the following proviso (hereinafter referred to as “Proviso B”):

[0487] “when n is 1; and y is 0; and R3 is hydrogen or C1-C6alkyl; and

100

[0488] is a group of formula (a), and R is group:

[0489] (a) wherein R4 is hydrogen, halogen or C1-C6alkyl, and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0490] (a) wherein z is 0,

[0491] (b) wherein u is 0 and M is hydrogen, halogen, C1-C6alkyl, or trifluoromethyl,

[0492] (c) wherein o is 0,

[0493] (d) wherein l is 0,

[0494] (e) wherein j is 0,

[0495] (g) wherein v is 0, or

[0496] (i);

[0497] and also when R is the group of formula (a), R1 and R2 cannot be joined together to form the group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0498] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl;

[0499] (b) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0500] (a),

[0501] (b),

[0502] (d) wherein l is 0,

[0503] (k),

[0504] (l), or

[0505] (m) wherein Q is CH2;

[0506] and also when R is the group of formula (b), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0507] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

101

[0508] (d) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0509] (a),

[0510] (b) wherein u is 1,

[0511] (d),

[0512] (k),

[0513] (l), or

[0514] (m) wherein Q is CH2;

[0515] and also when R is the group of formula (d), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0516] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

102

[0517] (e) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0518] (a),

[0519] (b),

[0520] (d),

[0521] (k),

[0522] (l), or

[0523] (m) wherein Q is CH2;

[0524] and also when R is the group of formula (e), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0525] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

103

[0526] (f) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0527] (a),

[0528] (b),

[0529] (d),

[0530] (k),

[0531] (l), or

[0532] (m) wherein Q is CH2;

[0533] and also when R is the group of formula (f), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0534] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

104

[0535] (g) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0536] (a),

[0537] (b) wherein u is 1,

[0538] (d),

[0539] (k),

[0540] (l), or

[0541] (m) wherein Q is CH2;

[0542] and also when R is the group of formula (g), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0543] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

105

[0544] (h) and R1 is hydrogen or unsubstituted C1-C6alkyl, then R2 cannot be a group of the following formula:

[0545] (a),

[0546] (b),

[0547] (d),

[0548] (k),

[0549] (l), or

[0550] (m) wherein Q is CH2;

[0551] and also when R is the group of formula (h), R1 and R2 cannot be joined together to form a group of formula X or a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0552] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl or

106

[0553] (j) then R1 and R2 cannot be joined together to form a group of formula Y or a 5-, 6-, or 7-membered monocyclic ring

[0554] wherein said ring is unsubstituted or mono- or di-substituted with C1-C6alkyl”.

[0555] The instant invention further provides a method of treating conditions or disorders of the central nervous system comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof, in conjunction with one or more D1, D2, D4, DS or 5HT receptor antagonists. Compounds of formula IA are preferred for this method.

[0556] Also provided herein is a method for treating renal dysfunction comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, IA or IB.

[0557] In treating a patient afflicted with a condition or disorder described above, a compound of formula I, IA, or IB can be administered in any form or mode which makes the compound bioavailable in therapeutically effective amounts, including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. One skilled in the art of preparing formulations can determine the proper form and mode of administration depending upon the particular characteristics of the compound selected for the condition or disease to be treated, the stage of the disease, the condition of the patient and other relevant circumstances. For example, see Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990), incorporated herein by reference.

[0558] The compounds of Formula I, IA, or IB can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, standard pharmaceutical practice and other relevant criteria.

[0559] The compounds of formula I, IA, or IB may be administered orally, for example, in the form of tablets, troches, capsules, elixirs, suspensions, solutions, syrups, wafers, chewing gums and the like and may contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[0560] The compounds of Formula I, IA, or IB may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.

[0561] The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials.

[0562] The highly lipophilic esters, amides and carbamates of compounds I, IA, or IB are capable of sustained release in mammals for a period of several days or from about one to four weeks when formulated and administered as depot preparations, as for example, when injected in a properly selected pharmaceutically acceptable oil. The preferred oils are of vegetable origin such as sesame oil, cottonseed oil, corn oil, coconut oil, soybean oil, olive oil and the like, or they are synthetic esters of fatty acids and polyfunctional alcohols such as glycerol or propyleneglycol.

[0563] The depot compositions of formula I, IA, or IB are prepared by dissolving a highly lipophilic ester, amide or carbamate of the instant invention in a pharmaceutically acceptable oil under sterile conditions. The oil is selected so as to obtain a release of the active ingredient over a desired period of time. The appropriate oil may easily be determined by consulting the prior art, or without undue experimentation by one skilled in the art.

[0564] The dosage range at which the compounds of formula I, IA, or IB exhibit their ability to act therapeutically can vary depending upon the particular disease or condition being treated and its severity, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally, the compounds of formula I, IA or IB will exhibit their therapeutic activities at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.

[0565] In a further aspect, the present invention provides novel radiolabeled imaging agents of formula I, IA, or IB useful, inter alia, for imaging dopamine D3 receptors in the CNS to diagnose CNS abnormalities.

[0566] In a further aspect, the present invention provides novel radiolabeled imaging agents of formula I, IA, or IB useful, inter alia, for imaging dopamine D3 receptors in the CNS to diagnose CNS abnormalities.

[0567] The radiolabeled (tritiated and C-14 labeled) forms compounds of formula I, IA, or IB are useful as radioligands to determine the binding of compounds to the dopamine D3 receptor. They are also useful as labeled parent compounds to determine the metabolism of the compound in animals. Preferred for this purpose are compounds of formula I and IA wherein R is group (a) with a radiolabeled 14C in the 3-position of the benzo[b]thiophene ring, R4 is trifluoromethyl, s is 1, R3 is hydrogen, n is 1, y is 0, and A is N. Particularly preferred for this purpose are compounds of formula IC. As employed herein, a “compound of formula IC” shall refer to the compound of formula I wherein R is group (a) with a radiolabeled 14C in the 3-position of the benzo[b]thiophene ring, R4 is trifluoromethyl in the 6-position of the benzo[b]thiophene ring, s is 1, R3 is hydrogen, n is 1, y is 0, and A is N. Compounds of formula IC may be prepared in a manner analogous to that set forth in Example 33.

[0568] Imbalances in dopamine production have been implicated in a variety of mental and physical disorders, such as Parkinson's disease (PD). It is thus desirable to diagnose and monitor such imbalances and to monitor the effectiveness of drugs and substances that affect brain chemistry. New and powerful imaging methods that enable one to assess the living brain in vivo and thereby monitor brain chemistry and the effectiveness of drugs and substances that affect brain chemistry have been developed. Methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) involve administering to a patient a radioactive tracer substance comprising a ligand that binds to the presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays are emitted from the positrons or photons from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control to determine the degree of drug response. Further treatment of the patient with drugs is based on the comparisons made. For these methods to be useful, however, a ligand that has a high specificity and affinity for the desired receptor is required.

[0569] It is believed that certain radioactive ligands may be selective for dopamine transporters and are thus potentially useful in evaluating changes in dopamine function in vivo and in vitro, especially for patients with Parkinson's disease (PD), which is characterized by a selective loss of dopamine neurons in the basal ganglia and substantia nigra.

[0570] Another aspect of this invention relates to methods for utilizing the compounds of the invention as CNS imaging agents. Imaging techniques are non-invasive diagnostic techniques that generally involve administering a compound with marker atoms that can be detected externally to the mammal. Generally, these methods comprise administering to a mammal a compound of the invention, dissolved or dispersed in a suitable pharmaceutical carrier or diluent. The compound of the invention selectively binds to dopamine D3, thus permitting the imaging of CNS receptors and the ability to, inter alia, evaluate brain chemistry, the effectiveness of drugs, and neuronal functions. Imaging techniques suitable for practicing the present invention include, but are not limited to, single photon emission computed tomography (SPECT) and positron emission tomography (PET).

[0571] Radionuclides that are widely used in diagnostic nuclear medicine include technetium [99Tc], iodine [123I], carbon [11C], and fluorine [18F]. The radiolabeled imaging agent specifically exemplified herein contains the radionuclide 11C. It should be noted that the same or similar radiochemistry reactions can be carried out using radionuclides other than 11C.

[0572] The invention is further illustrated by the following non-limiting examples and tabulated information. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: “g” refers to grams; “mmol” refers to millimoles; “ml” refers to milliliters; “C” refers to degrees Celsius; “TLC” refers to thin layer chromatography; “LC/MS” refers to liquid chromatography mass spectrometry; “APCI” refers to atmospheric pressure chemical ionization; “mp” refers to melting point.

EXAMPLES

Example 1

[0573]

107

Example 1(a)

[0574] Preparation of Intermediate 3-benzyl-piperazine

[0575] To a suspension of 3-benzyl-piperazine-2,5-dione (14.98 g, 73 mmol, prepared following generally the procedure of Halpern and Westley, J. Org. Chem. 1968, 33, 864) in dry diethyl ether (500 mL) is added dropwise to a solution of lithium aluminum hydride (400 mL of a 1 M solution in diethyl ether, 400 mmol, 5.4 eq). The suspension is heated at reflux for 23 hours and then cooled to 0° C. Water (70 mL) is then cautiously added and the resulting suspension is warmed to room temperature. After 3 hours the suspension is filtered and the solid washed with diethyl ether (1 L). The filtrate is concentrated under vacuum to provide crude title compound (11.40 g, 88%) as a yellow, crystalline solid. A sample (2 g) is recrystallized from cyclohexane and then from toluene to provide the purified title compound (0.83 g) as a fine, white crystals: mp 80-81° C.

5Anal. Calcd. For C11H16N2:C, 74.96; H, 9.15; N, 15.89;Found:C, 74.84; H, 9.01; N, 16.15.

108

Example 1(b)

[0576] To a solution of LDA (295 mL, 0.59 mol, 2 M in heptane/THF/ethylbenzene) in anhydrous THF (300 mL) cooled to −40° C. was added 2-methylpyrazine (48.5 mL, 0.531 mol) dropwise via an addition funnel. The reaction was allowed to warm to −20° C. and was stirred for 90 minutes when a solution of benzaldehyde (54 mL, 0.531 mol) in anhydrous THF (200 mL) was added dropwise via an addition funnel. After complete addition, the reaction was allowed to warm to room temperature and was stirred for 20 hours. The reaction was then cooled in an ice bath and saturated NH4Cl (500 mL) was added. The resulting mixture was extracted with EtOAc (500 mL, 250 mL). The combined extracts were dried (Na2SO4), filtered and concentrated to a damp, beige solid. The product was triturated with Et2O and collected then dried overnight to yield 56.0 g (53%) of a light brown solid, mp 81-84° C.

[0577] A solution of the above-obtained solid (56.0 g, 0.28 mol) in MeOH (1.1 L) and conc. HCl (290 mL) was stirred at reflux for 24 hours. The reaction was cooled to room temperature and concentrated to a dark liquid. The dark liquid was cooled in an ice bath and water (1 L) was added. The resulting solution was neutralized with a saturated solution of Na2CO3 and the product was extracted with EtOAc (1 L, 2×500 mL). The combined extracts were dried (Na2SO4), filtered and concentrated to yield 46 g of a dark brown solid. The solid was purified via flash column chromatography (40% EtOAc in heptane) yielding 22.7 g of the olefin as a brown foam.

[0578] A 1 L Parr shaker bottle was flushed with nitrogen and charged with 10% Pd/C (4.5 g, Degussa type) and the above-obtained olefin (20.0 g, 0.110 mol) in EtOH (450 mL). The reaction was hydrogenated at 50 psi for 3.5 hours when the reaction was filtered through a celite plug and rinsed with ethanol. The bottle was recharged with fresh 10% Pd/C (4.5 g, Degussa type), the filtrate and conc. HCl (15 mL). The reaction was hydrogenated at 50 psi for 18 hours when the reaction was diluted with warm MeOH and filtered through a plug of celite. The solid was thoroughly washed with hot MeOH and the filtrate was concentrated to yield 11.2 g (39%) of the final product as the di-HCl salt, mp 297-300.

[0579] See: Tetrahedron, 30, 1974 pp667-673 and Tet. Lett. 1979, pp4483-4486

109

Example 1(c)

[0580] DBU (14.0 g, 92 mmol) was added to a solution of the piperazine diacetate (18.2 g, 92 mmol) and aldehyde (12.3 g, 92 mmol) in 92 mL of DMF at ambient temperature. The resulting mixture was stirred at room temperature for 5 h. The precipitated product was collected by filtration, providing 17.1 g of product.

110

[0581] The monoacetate (17.0 g, 62.8 mmol) and hydrazine hydrate (9.4 g, 188.6 mmol) in 125 mL of DMF were stirred at room temperature for 20 h. The precipitated solid was collected by filtration, and washed with water and ethanol, leaving 13.7 g of product.

111

[0582] The olefin (13.6 g, 59.1 mmol) and palladium on carbon (2.7 g, 10% Pd/C, Degussa type, 50% H2O) in 1.2 l of methanol were shaken on a Parr hydrogenation apparatus at 40 psi of hydrogen, until hydrogen uptake ceased. The mixture was diluted with dichloromethane and filtered through celite. Concentration of the filtrate provided 12.1 g of product.

112

[0583] A solution of LAH (156 mL, 156 mmol, 1 M in THF) was added dropwise to a 0° C. solution of the piperazine dione (12.1 g, 52.1 mmol) in 100 ml of THF. The mixture was heated to reflux and stirred overnight. The mixture was cooled to 0° C. and 38 mL of water in 200 mL of THF was carefully added. The resulting mixture stirred for 1 h, then it was filtered, the filter cake was washed with THF, and the filtrate was concentrated in vacuo to give 7.4 g of product.

Example 2

[0584]

113

[0585] 2a: 2-Carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene:

[0586] Equip a 22-L, 3-necked, round-bottom flask with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, charge with 1.20 kg (5.55 mole) of 2-nitro-4-trifluoromethylbenzonitrile, 589.3 g (496 mL, 5.55 mole) of methyl thioglycolate, and 4.3 L of NMP. Cool the resulting yellow solution to 2° C., and add slowly, over a period of 78 min a solution prepared from 466.0 g (11.11 mole, 2.0 eq) of lithium hydroxide monohydrate in 3.36 L of water while maintaining the temperature between 2-20° C. Allow the brown slurry to warm to 21° C. over a 2 h period, and then dilute with 8.0 L of water (observe exotherm->27° C.). Stir for 40 min and cool to 18° C., collect the product by filtration, rinsing with 10 L of water, then air-drying at ambient temperature to give 1.295 kg (84.7% yield) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene, as a light-yellow solid, 99.8% pure by HPLC assay.

[0587] 2b: 1-(6-(trifluoromethyl)-benzo[b]thien-3-yl)-piperazine hydrochloride

[0588] Equip a 12-L, 3-necked, round-bottom flask with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, and charge with 1.14 kg (4.14 mole) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo-[b]thiophene Example 2a, 196.0 g (2.28 mole, 0.55 eq) of pipearazine, 4.0 L of NMP, and 570 mL of xylene. Heat the solution, and hold at 170-180° C. for 4 h, at which time the reaction is ca. 98% complete as determined by HPLC assay. Cool the brown solution to 168° C., and then add 1.605 kg (18.63 mole, 4.5 eq) of piperazine (temp->109° C.) following with 1.575 kg (28.28 mole, 2.0 eq) of p-toluenesulfonic acid monohydrate (observe exotherm, 109->130° C.). Connect a Dean-Stark trap to the condenser, and heat the reaction to collect an azeotrope. Remove a total of 410 mL of an aqueous distillate, while allowing the pot temperature to increase from 145 to 165° C. Monitor the progress of the reaction by GC/MS and HPLC assays. After 14 h at ca. 165° C. (>99% conversion by HPLC and GC/MS assay), cool the reaction to 30-35° C., and then quench into an extractor that contains 5 kg of ice, 12 L of water, and 8.5 L of toluene. Separate the phases, wash the organic extract with 11 L of 0.5 N NaOH, 2 L of saturated aq. NaCl., and then extract with 8 L of 1 N HCl. Dilute the acidic aqueous extract with 1 kg of ice, and basify to pH 11.2 by adding 624 g of 50% NaOH. Extract the resulting mixture with 9.5 L of toluene. Wash the toluene extract with 2 L of saturated aqueous NaCl, dry (Na2SO4), and filter. Charge the filtrate into a 22 L 3-necked, round-bottomed flask (N2, mechanical stirring, temperature control probe), and add a total of 3.7 L of 1 N ethereal HCl at 20-27° C. so that the mixture is positive to Congo Red indicator paper. During the HCl addition, add a total of 2.5 L of toluene to improve the stirring of the thick slurry that results. Stir at ambient temperature for 40 min, filter the slurry and wash with 4.5 L of toluene. After air drying, obtain 1.165 kg (87% yield) of 3-piperazinyl-6-trifluoromethyl-benzo[b]thiophene hydrochloride as a light pink-beige solid, 99.1% pure by GC/MS assay.

Example 3

[0589]

114

[0590] 3a: trans-Cyclopropane-1,2-dicarboxylic acid monomethyl ester

[0591] Suspend trans-cyclopropane-1,2-dicarboxylic acid dimethylester (59.8 g, 0.378 mol) is suspended in 1.0N phosphate buffer (1.5 L, pH=7) add pig liver esterase (2.25 mL, 7500 units), and monitor NaOH consumption with a pH meter to control the reaction. After 3 h the consumption of 189 mL of 2N NaOH indicates the complete hydrolysis of the diester to the monomethylester. Acidified the clear solution by the addition of 5N HCl to a pH=1. Separate the enzyme by addition of dichloromethane (500 mL) and diatomaceous earth (25 g). Stir for 5 min, and then filter the mixture. Saturate the filtrate with NaCl, and extract with ethyl acetate (5 times). Combine the extracts, dry (Na2SO4) and evaporate to obtain 50.8 g (93%) of solid, mp 46-47° C., m/z=145 (M+H)+

[0592] 3b: (S,S)-(+)-Cyclopropane-1,2-dicarboxylic acid monomethyl ester

[0593] Add trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester, Example 3a, (19.46 g) in acetone to quinine (43.8 g) in one portion. Heat the reaction to reflux, and then add methylcyclohexane (150 mL). After crystallization (5 times) from acetone/methylcyclohexane, collect 6.2 g of the diastereomeric salt (αD:+173, c:7.3 CHCl3)

[0594] 3c: (R,R)-(−)-Cyclopropane-1,2-dicarboxylic acid monomethyl ester

[0595] Concentrate the filtrate from 3b above and treat the residue with 1 N KHSO4 solution to yield 12.0 g of the crude (R,R) enatiomer. Dissolve this material in acetone and add 1 equivalent of quinidine in one portion. Heat the reaction to reflux, and then add methylcyclohexane. After crystallization overnight, collect 10.3 g of the diastereomeric salt (αD: −235, c: 8.5 CHCl3)

Example 4

[0596]

115

[0597] 4a: trans-2-Hydroxymethyl-cyclopropanecarboxylic acid methyl ester

[0598] Add borane-methyl sulfide complex (177 mL, 0.354 mol), slowly, by means of a dropping funnel, to a stirring solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (25.5 g, 0.177 mol), trimethyl borate (60.3 mL, 0.531 mol) and tetrahydrofuran (150 mL) at 0° C. After complete addition, allow the reaction to come to ambient temperature and stir for 2 h more. Pour the reaction mixture into a stirring solution of 50% aqueous sodium chloride solution (1.5 L)-concentrated HCl (10 mL). Extract the mixture with ethyl acetate (EtOAc) (3 times), combine the extracts, dry (Na2SO4) and concentrate the solvent to obtain a colorless oil: 22.6 g.

[0599] 4b: (S,S)-(+)-2-Hydroxymethyl-cyclopropanecarboxylic acid methyl ester

[0600] Follow the procedure of Example 4a, and substitute (S,S)-(+)-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3b) therein to obtain the title compound, αD: +54, c: 1.5 CHCl3 (Tetrahedron Asymmetry Vol.6, No.3, pp.683-684, 1995)

[0601] 4c: (R,R)-(−)-2-Hydroxymethyl-cyclopropanecarboxylic acid methyl ester

[0602] Follow the procedure of Example 4a, and substitute (R,R)-(−)-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3c) therein to obtain the title compound (αD: −78.6, c: 4.3 CHCl3)

Example 5

[0603]

116

[0604] 5a: trans-2-Methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester

[0605] Add, dropwise, triethylamine (7.74 mL, 56 mmol) and 4-dimethylaminopyridine (0.013 g, 0.106 mmol) in dichloromethane (30 mL) to a stirred solution of trans-2-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (Example 4a) (2.4 g, 18.64 mmol), at 0-5° C. After 0.5 h, pour the reaction mixture into water and extract the mixture with dichloromethane (3 times). Wash the combined extracts with 1N KHSO4, dry (Na2SO4) and concentrate to yield 4.29 g of a pale yellow oil, which solidifies when stored at 0° C., m/z=209 (M+H)+

[0606] 5b: (S,S)-(+)-2-Methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester

[0607] Follow the procedure of Example 5a, and substitute (S,S)-(+)-2-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (Example 4b) therein to obtain the title compound (αD: +75, c: 4.7 CHCl3)

[0608] 5c: (R,R)-(−)-2-Methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester

[0609] Follow the procedure of Example 5a, and substitute (R,R)-(−)-2-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (Example 4c) therein to obtain the title compound (αD: −74.4, c: 5.9 CHCl3).

Example 6

[0610]

117

[0611] 6a: trans-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester

[0612] Heat at reflux for 16 h, a mixture of 1-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazine, free base of Example 2b, (23.0 g, 71.3 mmol), trans-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (Example 5a) (15.3 g, 73.5 mmol), and triethylamine (40 mL, 288 mmol) in acetonitrile (600 mL). Concentrate the reaction mixture under reduced pressure and dilute the resultant oil with EtOAc (30 mL). Filter the resulting precipitate (unreacted starting piperazine) away and purify the filtrate by column chromatography over silica gel (EtOAc/heptane/MeOH/triethylamine, 20:20:1). Concentration of the appropriate fractions gives 18.0 g of colorless oil, m/z=413 (M+H)+.

[0613] 6b: (S,S)-(+)-2-[r4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester

[0614] Follow the procedure of Example 6a, and substitute (S,S)-(+)-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (Example 5b) therein to obtain the title compound (αD: +48, c: 2.8 EtOH).

[0615] 6c: (R,R)-(−)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester

[0616] Follow the procedure of Example 5, and substitute (R,R)-(−)-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester, Example 5c, therein, to obtain the title compound (αD: −49.3, c: 3.5 CHCl3).

Example 7

[0617]

118

[0618] 7a: trans-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid

[0619] Add 5N NaOH solution (425 mL, 226 mmol) to a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester, Example 6a, (18.0 g, 45.1 mmol) in dioxane/methanol (400 mL, 3:1) and heat the reaction at 60° C. for 6 h. Selectively remove most of the methanol and acidify the remaining dioxane solution to pH 5-6 with 2N acetic acid. Collect the desired compound, which precipitates from solution, to obtain 14.08 g (81%) of colorless crystals, m/z=385 (M+H)+

[0620] 7b: (S,S)-(+)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid

[0621] Follow the procedure of Example 7a, and substitute (S,S)-(+)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester (Example 6b) therein to obtain the title compound (αD: +55, c: 1.05 EtOH).

[0622] 7c: (R,R)-(−)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid Follow the procedure of Example 7a, and substitute (R,R)-(−)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid methyl ester (Example 5c) therein to obtain the title compound (αD: −40.5, c: 0.79 CHCl3).

Example 8

[0623]

119

[0624] 8a: trans-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide

[0625] Stir a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid (Example 7a) (1.99 g, 5.0 mmol), and O-[(ethoxycarbonyl)-cyanomethylenamino]-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TOTU, 2.05 g, 6.3 mmol) in DMF (50 mL) at 20° C. for 0.5 h. Add N-methylmorpholine (0.58 mL, 5.3 mmol), after which add trans-4-methylcyclohexylamine (1.13 g, 10 mmol), and stir the reaction for 5 h. Concentrate the reaction under reduced pressure to obtain an oil. Purify by column chromatography over silica gel (EtOAc/heptane/methanol/triethylamine, 20:20:1:1) to obtain 1.86, (76%) of colorless crystals LC/MS, m/z=480 (M+H)+.

[0626] 8b: (S,S)-(+)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide

[0627] Follow the procedure of Example 8a, and substitute (S,S)-(+)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid (Example 7b) therein to obtain the title compound, LC/MS, m/z=480 (M+H)+.

[0628] 8c: (R,R)-(−)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide

[0629] Follow the procedure of Example 8a, and substitute (R,R)-(−)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid (Example 7c) therein to obtain the title compound LC/MS, m/z=480 (M+H)+.

Example 9

[0630]

120

[0631] Follow the procedure of Example 8a, and substitute trans-4-amino-cyclohexane carboxylic acid ethyl ester (J.Med.Chem. (1971), 14(7), 600-614) for trans-4-methylcyclohexylamine therein to obtain the title compound LC/MS, m/z=538 (M+H)+.

Example 10

[0632]

121

[0633] Follow the procedure of Example 8a, and substitute trans-4-ethylcyclohexylamine for trans-4-methylcyclohexylamine therein to obtain the title compound LC/MS, m/z=494 (M+H)+.

Examile 11

[0634]

122

[0635] 11a: trans-2-(4-Methyl-cyclohexylcarbamoyl)-cyclopropanecarboxylic acid methyl ester

[0636] Stir a solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (3.0 g, 20.8 mmol) and TOTU (8.5 g, 26 mmol) in DMF (300 mL) at ambient temperature for 20 min at which time add N-methylmorpholine (2.4 mL 22.9 mmol) and trans 4-methylcyclohexylamine 3.06 g, 27.0 mmol). After 3 h, remove the solvent and dissolve the residue in H2O/EtOAc. Extract the aqueous layer 3 more times with EtOAc and combine the extracts. Wash the extract with saturated NaHCO3 solution, brine and dry over MgSO4. Concentrate the solvent to afford the crude product, and purify by column chromatography over silica gel to give 4.76 g (95%) of colorless crystals, m/z=240 (M+H)+.

123

[0637] 11b: trans-2-trans-2-Methylcyclohexylcarbamoyl)-cyclopropanecarboxylic acid

[0638] Stir a solution of trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropane-carboxylic acid monomethyl ester (Example 11a) (4.5 g, 19.8 mmol), 5N NaOH (40 mL) and MeOH/dioxane overnight. Concentrate the reaction mixture under vacuum, cool the resulting solution and acidify to pH 5. Collect the precipitate, wash (H2O) and dry under vacuum at 40° C. to obtain 3.7 g (87%) of solid.

124

[0639] 11c: trans-2-Hydroxymethyl-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide

[0640] Stir a solution, under argon, at 0° C., of trans -2 trans-2-methylcyclohexylcarbamoyl)-cyclopropanecarboxylic acid (Example 11b) (3.69 g, 16.4 mmol), trimethyl borate (5.6 mL, 50 mmol), and add slowly 2N borane dimethylsulfide complex in THF (16.4 mL, 32.8 mmol). Continue to stir the reaction at 0° C. for 1 h, and then at ambient temperature for 2 h. Carefully pour the reaction mixture into ice-H2O and acidify with 2N HCl. Extract the mixture with EtOAc (3 times), wash with brine, dry over MgSO4 and concentrate to obtain 2.85 g (83%) of product as a solid.

125

[0641] 11d: Methane sulfonic acid 2-(trans-4-methylcyclohexylcarbamoyl)-trans-cyclopropylmethyl ester

[0642] Add, dropwise, to a stirring suspension at −20° C. of trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide (Example 11c) (2.85 g, 13.5 mmol), triethylamine (3.74 mL, 27.0 mmol) and 4-(dimethylamino)pyridine (0.1 g, 0.82 mmol) in dichloromethane (100 ml) a solution of methanesulfonic acid (1.59 mL, 20.3 mmol) in DCM (10 mL). When the reaction is complete, pour the mixture into ice water and extract the mixture with DCM. Combine the extracts, wash with 0.1N KHSO4, brine, dry over MgSO4 and concentrate under vacuum. Treat the residue with a mixture of isopropanol/heptane and collect the precipitate by filtration to obtain 2.91 g (74%) of solid, MS m/z=290 (M+H)+.

[0643] 11e: trans-2-[4-(3-Chloro-phenyl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide

[0644] Reflux a solution of methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 11d) (30.0 mg, 0.1 mmol), t-(3-chloro-phenyl)-piperazine hydrochloride (29.0 mg, 0.13 mmol) triethylamine (0.05 mL, 0.4 mmol) in acetonitrile (5 ml) for 15 h. Concentrate the reaction mixture under vacuum and chromatograph the residue over silica gel to obtain 11.3 mg (28%) of solid, LC/MS, m/z=390 (M+H)+.

Example 12

[0645]

126

[0646] Follow the procedure of Example 11e, and substitute 1-(pyrazin-2-yl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=358 (M+H)+.

Example 13

[0647]

127

128

[0648] 13a: trans-2-(4-Ethyl-cyclohexylcarbamoyl)-cyclopropanecarboxylic acid methyl ester

[0649] Follow the procedure of Example 11a, and substitute trans-(4-ethylcyclohexylamine) for trans-(4-methylcyclohexylamine) therein to obtain the title compound, m/z=254 (M+H)+.

129

[0650] 13b: trans-2-(trans-2-Ethylcyclohexylcarbamoyl)-cyclopropanecarboxylic acid

[0651] Follow the procedure of Example 11b, and substitute trans-2-(4-ethyl-cyclohexylcarbamoyl)-cyclopropanecarboxylic acid monomethyl ester (Example 13a) for trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropanecarboxylic acid monomethyl ester therein to obtain the title compound.

130

[0652] 13c: trans-2-Hydroxymethyl-cyclopropanecarboxylic acid trans-(4-ethylcyclohexyl)-amide

[0653] Follow the procedure of Example 11c, and substitute trans-2-(4-ethylyclohexylcarbamoyl)-cyclopropanecarboxylic acid (Example 13b) for trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropane carboxylic acid therein to obtain the title compound.

131

[0654] 13d: Methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester

[0655] Follow the procedure of Example 11d, and substitute trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-ethylcyclohexyl)-amide, Example 13c for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester therein, to obtain the title compound, m/z=304 (M+H)+.

[0656] 13e: trans-2-[4-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-ylmethyl)-cyclopropanecarboxylic acid trans-(4-ethylcyclohexyl)-amide

[0657] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS m/z=473 (M+H)+.

Example 14

[0658]

132

[0659] Follow the procedure of Example 11e, and substitute 1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound MS, m/z=424 (M+H)+, 85.2% pure by HPLC assay.

Example 15

[0660]

133

[0661] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-trifluoromethyl-phenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound MS m/z=438 (M+H)+, 78.5% pure by HPLC assay.

Example 16

[0662]

134

[0663] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester, Example 13d for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-chlorophenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=404 (M+H)+.

Example 17

[0664]

135

[0665] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3,4-dichlorophenyl)-piperazino hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=438 (M+H)+.

Example 18

[0666]

136

[0667] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(2,5-dimethylphenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=398 (M+H)+.

Example 19

[0668]

137

[0669] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(2,5-dimethylphenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=398 (M+H)+.

Example 20

[0670]

138

[0671] Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(2-methylphenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=384 (M+H)+.

Example 21

[0672]

139

140

[0673] 21a: 4-(3-Bromo-thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester

[0674] Stir a solution, under nitrogen, of 3-bromothiophene (21.0 mL, 0.224 mol) in tetrahydrofuran (1.0 L) at −78° C., and add a 2.0 M solution of lithium disopropylamide in heptane/tetrahydrofuran/ethylbenzene (112 mL, 0.224 mol) for 45 min. Add, dropwise, over 2 h, a solution of 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (prepared according to U.S. Pat. No. 5,134,139) (79.4 g, 0.291 mol) in tetrahydrofuran (800 mL). Stir for 2 h, add a saturated ammonium chloride solution, and stir for an additional 0.5 h. Filter the resulting solid, and pour the filtrate into water (800 mL). Extract the aqueous mixture with ether and concentrate to obtain a dark liquid. Pour the liquid into water (400 mL), add NaCl and extract the aqueous mixture with ether. Wash the extract with water, brine, and dry over Na2SO4 Filter and concentrate to obtain the crude product. Chromatograph the product over silica gel (pet.ether/ether, 4:1) to obtain 41.5 g (50%) of white solid.

141

[0675] 21b: 4-[(3-Bromo-thiophen-2-yl)-hydroxyimino-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0676] Stir a mixture of 4-(3-bromo-thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 21a) (41.5 g, 0.11 mol), hydroxylamine hydrochloride (15.4 g, 0.23 mol) and pyridine (190 mL) at ambient temperature overnight. Pour the reaction into water (500 mL) and extract with dichloromethane (3 times). Wash the combined extracts with saturated CuSO4 solution (2 times), dry (MgSO4) and concentrate to a green solid. Dissolve the solid in toluene (175 mL) and let stand at ambient temperature for 3 h. Collect the resulting crystals that form and wash with toluene (60 mL). Concentrate the filtrate and again dissolve the residue in toluene and proceed to collect additional crystals to obtain a total yield of 25 g (58%) of the title compound as a light, green solid.

142

[0677] 21c: 4-Thieno[2,3-d]isoxazol-3-yl-piperidine-1-carboxylic acid tert-butyl ester

[0678] Add to a stirring solution of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]piperidine-1-carboxylic acid tert-butyl ester (Example 21b) (25 g., 64.2 mmol) in 2-methoxyethanol (200 mL), a solution of potassium hydroxide (7.2 g, 128.4 mmol) in water (20 mL). Heat the reaction to 60° C. and then add copper powder (1.25 g). Stir at 60-70° C. for 6 h and then at ambient temperature overnight. Pour the reaction mixture into water (500 mL) and extract with EtOAc (3 times). Concentrate to a dark residue and purify by column. chromatography over silica gel (heptane/EtOAc, 4:1) to provide 9.8 g (50%) of a white solid.

[0679] 21d: 3-Piperidinyl-4-yl-thieno[2,3-d]isoxazole hydrochloride Add ethereal HCl (10 mL) to 4-thieno[2,3-d]isoxazol-3-yl-piperidine-1-carboxylic acid_tert-butyl ester (Example 21c) (1.0 g, 3.2 mmol) and then methanol (1 mL) to effect solution. Permit to stand at ambient temperature for 1 h and then collect 0.34 g of white solid, mp 240-241° C. From the filtrate collect 0.25 g of additional white solid, mp 263-265° C. Both samples: MS, m/z=209 (M+H)+.

[0680] Analysis (sample mp 263-265° C.):

6Calc. For: C10H12N2OS.HCl:49.08% C5.35% H11.45% NFound:49.03% C5.29% H11.25% N

Example 22

[0681]

143

[0682] 22a: trans-2-(4-Thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cycloproranecarboxylic acid methyl ester

[0683] Reflux a solution of 3-piperidinyl-4-yl-thieno[2,3-d]isoxazole trifluoroacetate, (trifluoroacetic acid salt of Example 21d) (6.0 g, 18.6 mmol), trans-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (Example 5a) (3.99 g, 19.2 mmol) and triethylamine (7.6 g, 75 mmol) in acetonitrile (100 mL) for 15 h. Concentrate and purify the residue by column chromatography over silica gel (dichloromethane/EtOAc/diethylamine (8:2:1). Further purify by another chromatography dichloromethane/MeOH (95:5) to obtain 1.4 g (24%) of product, MS, m/z=321(M+H)+.

[0684] 22b: trans-2-(4-Thieno[2,3d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid ethyl ester

[0685] Add 5N NaOH (4.4 mL, 21.9 mmol) to a solution of trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid methyl ester, Example 22a (1.4 g, 4.37 mmol) in dioxane/methanol (24 mL, 3:1), and heat to 60° C. for 3 h. Concentrate the reaction and treat the residue with acetic acid. After 36 h dilute the acetic acid solution with dichloromethane and wash the organic phase with 5% aqueous HCl, water and brine. Dry the organic phase and concentrate to a yellow oil. Evacuate the oil at high vacuum and 60° C. for 20 h to obtain 0.191 g of oil.

[0686] Treat the aqueous washings with NaCl and collect an additional 1.0 g of the product as a solid. MS, m/z 307 (M+H)+.

Example 23

[0687]

144

[0688] Add TOTU (415 mg, 1.06 mmol) to a solution of trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid methyl ester (Example 22b) (300 mg, 1.0 mmol), in dimethylformamide (approximately 10 mL), and allow the reaction to stir at ambient temperature for 0.5 h. Add N-methylmorpholine (107 mg, 1.26 mmol) and trans-4-ethylcyclohexylamine (254 mg, 2.0 mmol), and stir for 6 h. Add additional equivalents of N-methylmorpholine and TOTU and continue to stir for overnight. I think again I didn't write it down Concentrate the reaction and purify the residue by column chromatography over silica gel (dichloromethane/MeOH, gradient 0→30%) to obtain 270 mg (65%), LC/MS, m/z=416 (M+H)+.

Example 24

[0689]

145

[0690] Dissolve racemic-trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid trans-(4-ethyl-cyclohexyl)-amide (Example 23) (14 mg) in heptane/ethanol (1.5 mL, ˜1:1) and make 20 separate injections of 50 μL each on to a preparative HPLC apparatus (Chiralpak AD 10μ 250×4.6 mm, heptane/ethanol, 85:15). Collect and combine fractions that elute at tR=14.2 min and obtain 3.0 mg of enatiomer with an enatiomeric excess >99%.

Example 25

[0691]

146

[0692] Follow the procedure of Example 24, but collect and combine the fractions that elute at tR=23.6 min to obtain 6.0 mg of enatiomer with opposite chirality and an enatiomeric excess >99%.

Example 26

[0693]

147

[0694] The cyclobutane carboxylic acid (26-1)(1.43 g, 9.05 mmol) and TOTU (3.7 g, 9.5 mmol) were combined in 90 mL of DMF and stirred at ambient temperature for 0.5 h. N-Methylmorpholine (0.96 g, 9.5 mmol) and the amine (26-2) (1.53 g, 13.5 mmol) were added and the mixture stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and the organic phase was sequentially washed with saturated sodium bicarbonate solution (3×), 10% HCl solution and brine (2×), then dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and the mixture filtered. Concentration of the filtrate provided 1.5 g of the product (26-3).

[0695] Lithium borohydride 93.0 mL, 5.93 mmol, 2M in THF) was added dropwise to a solution of the ester (26-3) (1.5 g, 5.93 mmol) in 20 mL of THF at ambient temperature. The solution was stirred at room temperature for 20 h, and tehn lit was quenched by the careful addition of water. The product was extracted into ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to leave 1.1 g of product. Chromatography on silica gel (40 g Biotage column) eluting with ethyl acetate and dichloromethane gave 618 mg of the alcohol (26-4).

[0696] Methanesulfonyl chloride (0.276 g, 2.41 mmol) was added dropwise to a solution of the alcohol (26-4) (0.493 g, 2.19 mmol) and triethylamine (0.332 g, 3.29 mmol) in 11 mL of dichloromethane at 0° C. The mixture was stirred at 0° C. for 1 h, and then it was stirred at ambient temperature for 2 h. The resulting solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, water, and brine and then filtered and the filtrate was concentrated to provide 627 mg of the product (26-5).

148

[0697] In Scheme V, R is as hereinbefore defined. For example, the mesylate (26-5) (75 mg, 0.025 mmol), potassium carbonate (52 mg, 0.038 mmol) and the amine (Example 2) (72 mg, 0.025 mmol) in 2 mL of acetonitrile were heated at 80° C. in a JKEM reaction block for 20 h. The mixture was cooled to room temperature, diluted with 6 mL of dichloromethane and 400 mg of polymer supported isocyanate resin was added (Argonaut Technologies, resin loading 1.49 mmol/gram) and the mixture shaken at ambient temperature for 20 h. The reaction mixture was deposited on a 2 g Varian strong cation exchange (SCX) column. The resin was washed twice with 4 mL ethyl acetate and thrice with 4 mL of dichloromethane. The column was further washed with 15 mL of ethyl acetate. The product was next eluted using a 4:1 mixture of 2% triethyl amine in ethyl acetate and methanol. The volatiles were removed in vacuo and the residue was chromatographed on silica gel, eluting with methanol/ethyl acetate. Concentration of the fractions containing the product provided 67 mg of product.

[0698] The following compounds were prepared using this method.

7CompoundCPD #

149

829997

150

829998

151

829999

152

830000

153

829996

[0699] Characterizing data for the compounds is as follows:

8MOLAmtR.T.MS %CPD #WTobtyieldbasepeak(min.)area829997457.650.05145458.31.6100829998493.630.06754494..31.64100829999443.630.06256444.31.57100830000430.610.04037431.31.44100829996416.590.05250417.31.43100

Example 27

[0700]

154

[0701] 27a. 3-Amino-6-fluoro-benzo[b]thiophene-2-carboxylic acid

[0702] At 50° C., add to a stirring solution of 2-carbomethoxy-3-amino-6-fluoro-benzo[b]thiophene (prepared according to U.S. Pat. No. 5,143,923), (90.1 g, 0.4 mol) in H2O (450 mL), a 50% aqueous solution of NaOH (64 g, 0.8 mol) over 2-3 min. Heat the reaction to 70-73° C. and continue to stir for 3 h. Add 10% aqueous isopropanol (45 mL) and bring to reflux. Remove the isopropanol under N2 and add H2O (300 mL). Cool the reaction mixture to between 7-10° C. and add concentrated HCl (80 mL). Add H2O (650 mL), cool to 5-7° C., filter the resulting solid, and wash the filter cake with H2O (2×150 mL). Dry the solid under vacuum at 35° C. to obtain 80.6 g (94.7%) of solid mp 160-163° C., TLC on silica gel (dichloromethane/methanol, 3:1), Rf=0.69.

[0703] 27b. 1-(6-Fluoro-benzo[b]thiophen-3-yl)-1,4]diazepane

[0704] Heat a solution of 3-amino-6-fluoro-benzo[b]thiophene-2-carboxylic acid (5.0 g, 24 mmol) in 1-methyl-2-pyrrolidinone (5 ml) to 100° C. for 2 h., and then, introduce a stream of nitrogen, to cool the solution to room temperature. Add homopiperazine (9.5 g, 95 mmol) and p-toluene sulfonic acid monohydrate (9.0 g, 47 mmol) and heat the mixture to 145° C. for 4 h. After that time, cool the reaction mixture to room temperature, dilute with ethyl acetate (30 mL) and wash with brine (3×15 mL). Separate the organic layer and dry over Mg SO4. Evaporate the solvent and purity the crude product by column chromatography (SiO2, 100 g CH2Cl2(MeOH 9:2, then CH2Cl2/MeOH/NH4OH 9:2:0.15) to give 3.9 g (65%) of yellowish oil LC/MS (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water-gradient 20%→100% (25 min), Flow: 1.5 mL/min) tR=10.74 min, m/z=250.3.

Example 28

[0705]

155

[0706] 28a: 4-(6-Fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

[0707] Add a solution of di-tert-butyl dicarbonate (5.15 g, 23.6 mmol) in CHCl3 (15 mL), dropwise, over 45 min to a solution at −65° C. of 1-(6-fluorobenzo[b]thiophen-3-yl)-piperazine (prepared according to U.S. Pat. No. 5,143,923), (2.8 g, 11.8 mmol), 4-(dimethyl-amino)pyridine (0.1 g, 1.3 mmol), and diisopropylethylamine (4.3 mL, 3.2 g, 24.8 mmol) in CHCl3 (50 mL). Following complete addition, stir the reaction at ambient temperature for 20 h, and then pour the reaction into a mixture of cold (5° C.) 5% aqueous NaOH/EtOAc (150/150 mL). Extract the product into EtOAc, wash the extract with H2O, brine and concentrate to a red oil. Purify the crude oil over silica gel (EtOAc), to obtain 3.6 g, of red oil, LC/MS m/z=337 (M+H)+.

156

[0708] 28b: 4-(2-Bromo-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

[0709] Add N-bromosuccinimide (0.59 g, 3.3 mmol) to a stirring solution of 4-(6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 28a) (1.00 g, 2.97 mmol) in CHCl3 (32.8 mL) and reflux for 30 min. Allow cooling to room temperature and filter. Evaporate the solvent and purify the residue by chromatography over silica gel (EtOAc/heptane, 9:1) to obtain 0.53 g (43%) of oil, MS, m/z=416 (M+H)+.

[0710] In an alternative procedure, add N-bromosuccinimide (1.319 g, 6.62 mmol) to a stirring solution of 4-(6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 46a) (2.226 g, 6.62 mmol) in CCl4 and reflux for 2 h. Allow cooling to room temperature and filter. Evaporate the solvent and purify the residue by chromatography over silica gel (EtOAc/heptane, 9:1) to obtain 2.34 g (94%) of oil.

157

[0711] 28c: 4-(2-Fluoro-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

[0712] At a temperature of −65° C. stir, under nitrogen, a solution of the 4-(2-bromo-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 28b) (15.59 g, 37.55 mmol) in anhydrous THF (247 mL) and add, dropwise, n-butyllithium in hexane (2.5M, 19.53 mL, 48.82 mmol). Stir for 30 min and then add, dropwise, N-fluorobenzenesulfonimide (17.76 g, 56.33 mmol) dissolved in anhydrous THF. Stir overnight at ambient temperature, cool the reaction to 0° C., add saturated NaCl solution and then water. Extract the mixture with EtOAc (3×'s), combine the extracts and wash with water and brine. Dry the extract (MgSO4), and concentrate to obtain 11.0 g of oil. Chromatograph the oil over silica gel (ether/pet. ether, 9:1) and obtain 6.28 g (52%) of red oil, MS, m/z, 354 (M+H)+.

[0713] 28d: 1-(2,6-Difluoro-benzo[b]thien-3-yl)-piperazine trifluoroacetate

[0714] Stir a solution of 4-(2-fluoro-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 28c) (250 mg, 0.70 mmol) in trifluoroacetic acid (2.2 mL) at ambient temperature for 30 min. Evaporate the trifluoroacetic acid and treat the residue with ether. Stir the suspension at ambient temperature for 2 h, and filter the resulting white solid to obtain 191 mg (56%) of the trifluoroacetate salt. MS, m/z=255 (M+H)+.

Examples 29-31

[0715] The following HPLC conditions are referred to in examples 29-31:

[0716] HPLC Condition I:

[0717] A) 95/5/0.1% Water/Acetonitrile/Formic Acid,

[0718] B) 5/95/0.1% Water/Acetonitrile/Formic Acid.

[0719] Column: YMC ODS-A 4×50 mm, Flow rate: 2 mL/minute.

[0720] The initial HPLC conditions consisted of 100% (A) flowing at 2 mL/minute. After the initial injection a linear gradient was performed so that at 2 minutes the HPLC conditions were 100% B. These conditions were then held for 3.4 minutes at which time the system switched back to initial conditions and equilibrated for the next analysis.

[0721] HPLC Condition II:

[0722] A) 95/5/0.1% Water/Acetonitrile/Formic Acid,

[0723] B) 5/95/0.1% Water/Acetonitrile/Formic Acid.

[0724] Column: YMC ODS-A 2×50 mm, Flow ratel mL/minute.

[0725] The initial HPLC conditions consisted of 100% (A) flowing at 0.1 mL/minute. After the initial injection a linear gradient was performed so that at 2 minutes the HPLC conditions were 100% B. These conditions were then held for 3.5 minutes at which time the system switched back to initial conditions and equilibrated for the next analysis.

Example 29

[0726]

158

[0727] 29a: Preparation of 4-[1-(3-bromo-4-methyl-thiophen-2-yl)-methanoyl]-1-piperidine-1-carboxylic acid tert-butyl ester:

[0728] Under inert conditions, add a 2.0 M solution (in tetrahydrofuran/n-heptane) of lithium diisopropylamide (29.65 mmol, 14.83 mL, 1.05 equivalents) to a cold (−78° C.) solution of 3-bromo-4-methylthiophene (28.24 mmol, 5.00 g, 1.00 equivalents) in dry tetrahydrofuran (27.33 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (28.24 mmol, 7.69 g, 1.00 equivalents), dropwise. Continue stirring at −78° C. for 3 hours. Quench the reaction mixture with saturated ammonium chloride (aqueous, 55 mL) and allow to warm to room temperature. Extract the reaction mixture with a mixture of ethyl acetate: diethyl ether (1:1,3 times 40 mL). Combine the extracts and dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography using a mixture of n-heptane:ethyl acetate (4:1) to yield a yellow, crystalline solid (9.84 g).

[0729] MS (Cl, methane) m/e 388 (MH+), LC/MS (APCI), m/e 288 (M-100), retention time 2 min. 43 sec. Condition I.

159

[0730] 29b: Preparation of 4-[l-(3-bromo-4-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester:

[0731] Add ammonium hydroxide hydrochloride (50.68 mmol, 3.52 g, 2.00 equivalents) to a stirred solution of 4-[1-(3-bromo-4-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester (25.54 mol, 9.84 g, 1.00 equivalents) in pyridine (47.5 mL). Stir at room temperature overnight and at 70° C. for 4 hours. Cool the reaction mixture and add hydrochloric acid (3 M solution, 115 mL). Extract the reaction mixture with dichloromethane (115 mL), filter the organic layer, wash with water (100 mL), dry over magnesium sulfate, filter and evaporate. Recrystallize the resulting residue from toluene to yield a white solid (4.84 g). LC/MS (APCI), m/e 403 (MH+), retention time 2 min. 32 sec. Condition I.

160

[0732] 29c: Preparation of 4-(6-methyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester:

[0733] Add cesium carbonate (3.72 mmol, 1.21 g, 1.50 equivalents) and copper iodide (0.25 mmol, 47 mg, 0.10 equivalents) to a stirred solution of 4-[1-(3-bromo-4-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.48 mmol, 1.00 g, 1.00 equivalents) in 2-methoxy ethanol (25 mL). Stir the resulting mixture at room temperature overnight and filter to remove the inorganic material. Concentrate the filtrate and partition the resulting oil between ethyl acetate (75 mL) and water (25 mL). Extract the aqueous layer with ethyl acetate (2×75 mL) and wash the combined organic layers with saturated sodium chloride (aqueous, 25 mL), dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with n-heptane: ethyl acetate (4:1) to yield a white solid (588 mg). MS (Cl, methane) m/e 323 (MH+), LC/MS (ESI), m/e 345 (MNa+), retention time 2.05 minutes. Condition II.

[0734] 29d: Preparation of 6-methyl-3-piperidin-4-yl-thieno[2,3-d]isoxazole hydrochloride:

161

[0735] Stir a solution of 4-(6-methyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.84 mmol, 2.85 g, 1.00 equivalents) in hydrochloric acid (48.75 mL, 1 M solution in diethyl ether) and methanol (2.00 mL) at room temperature for 3.5 hours. Filter the suspension, collect the white solid and dry to yield the desired product (659 mg). Allow the mother liquor to age overnight, filter, collect the white solid and dry to yield additional desired product (1.252 g). LC/MS (ESI), m/e 223 (MH+), retention time 1.14 minutes. Condition II.

Example 30

[0736]

162

[0737] 30a: Preparation of 4-[1-(3-bromo-5-methyl-thiophen-2-yl)-methanoyl]-1-piperidine-1-carboxylic acid tert-butyl ester:

[0738] Prepared essentially as in 29a except that 2-bromo-5-methyl thiophene is used as the starting material. In addition, 1.20 equivalents of lithium diisopropylamide and 1.24 equivalents of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester are used for the reaction. Accordingly, stirring time of the reaction mixture may vary. Purification of the residue via flash column chromatography uses a gradient with a mixture of ethyl acetate: n-heptane (1:9) to ethyl acetate: n-heptane (2:8) to yield a yellow oil. LC/MS (ESI), m/e 332 (M-56) and 388 (MH+), retention time 2.15 minutes. Condition II.

163

[0739] 30b: Preparation of 4-[1-(3-bromo-5-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester:

[0740] Prepared essentially as 29b except that 4-[1-(3-Bromo-5-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material and the reaction mixture was stirred at 70° C. for 6 hours. LC/MS (ESI), m/e 347 (M-56) and 403 (MH+), retention time 2.03 minutes. Condition II.

164

[0741] 30c: Preparation of 4-(5-methyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid:

[0742] Prepared essentially as in 29c except that 4-[1-(3-bromo-5-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material. Two other differences are: 1) 0.05 equivalents of copper iodide is used, and 2) no partition between ethyl acetate and water accompanied by subsequent extraction with ethyl acetate is required. Purification of the residue via flash column chromatography uses a mixture of ethyl acetate: n-heptane (1:4) to yield a white solid. LC/MS (ESI), m/e 345 (MNa+), retention time 2.12 minutes. Condition II.

Example 31

[0743]

165

[0744] 31a: Preparation of (4-bromo-thiophen-2-yl)-methanol:

[0745] Under inert conditions, add sodium borohydride (13.82 mmol, 0.523 g, 2.08 equivalents) in absolute ethanol (16 mL) dropwise over a period of 15 minutes to a stirred mixture of 4-bromothiophene-2-carboxaldehyde (26.58 mmol, 5.08 g, 1.00 equivalents) in cold (0° C.) absolute ethanol (32 mL). Stir the resulting mixture at room temperature for 2.5 hours and add glacial acetic acid dropwise until the effervescence ceases. Evaporate the resulting solution, take the residue up in diethyl ether (75 mL), wash with water (15 mL) and brine (15 mL) and dry over magnesium sulfate. Filter and evaporate to yield the product as a colorless oil (5.13 g).

166

[0746] 31b: Preparation of 4-bromo-2-methoxymethyl-thiophene:

[0747] Add sodium hydride (737 mg, 29.23 mmol, 1.10 equivalents, 95%) to a solution containing methyl iodide (1.65 mL, 26.57 mmol, 1.00 equivalents) and (4-bromo-thiophen-2-yl)-methanol (5.13 g, 26.57 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 25 mL). Stir the resulting mixture at room temperature overnight and evaporate. Partition the residue between water (100 mL) and dichloromethane (100 mL). Extract the aqueous layer with dichloromethane (100 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil.

167

[0748] 31c: Preparation of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester:

[0749] Add lithium diisopropyl amide (13.20 mL, 26.37 mmol, 1.05 equivalents) to a stirred, cold (−78° C.) solution of 4-bromo-2-methoxymethyl-thiophene (5.20 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 24.30 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (6.84 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 16.40 mL), dropwise. Stir the resulting solution at −78° C. for 3 hours. Quench the reaction mixture with saturated sodium chloride (aqueous, 50 mL). Allow the resulting mixture to warm to room temperature and extract with a mixture of ethyl acetate: diethyl ether (1:1, 3×35 mL). Combine the extracts, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of n-heptane: ethyl acetate (4:1) to yield the desired product as a yellow oil (9.47 g). LC/MS (ESI), m/e 362 (M-56) and 418 (MH+), retention time 2.08 minutes. Condition II.

168

[0750] 31d: Preparation of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester:

[0751] Add hydroxylamine hydrochloride (2.29 g, 45.27 mmol, 2.00 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester (9.47 g, 22.64 mmol, 1.00 equivalents) in pyridine (42.40 mL). Stir the resulting solution at room temperature overnight and then at 70° C. for 4 hours. Cool the reaction mixture slightly, add hydrochloric acid (3N, 100 mL) and extract the resulting mixture with dichloromethane (100 mL). Wash the extract with water (100 mL), dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil (9.48 g).

169

[0752] 31e: Preparation of 4-(5-methoxymethyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester:

[0753] Add cesium carbonate (1.13 g, 3.46 mmol, 1.50 equivalents) and copper iodide (44 mg, 0.23 mmol, 0.10 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.31 mmol, 1.00 equivalents) in 2-methoxy ethanol (23.30 mL). Stir the resulting mixture at room temperature overnight or up to 3 days and filter through celite. Evaporate the filtrate, partition the residue between ethyl acetate (70 mL) and water (23 mL) and separate. Extract the aqueous layer with ethyl acetate (3×70 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of hexane: ethyl acetate (4:1) to yield the desired product as a yellow oil. LC/MS (ESI), m/e 375 (MNa+), retention time 1.98 minutes. Condition II.

170

[0754] 31f: Preparation of 5-methoxymethyl-3-piperidin-4-yl-thieno[2,3-d]isoxazole Hydrochloride:

[0755] Stir a solution of 4-(5-methoxymethyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.21 g, 6.68 mmol, 1.00 equivalents) and hydrochloric acid (1.0 M in diethyl ether, 35 mL) overnight to form a suspension. Add additional hydrochloric acid (1.0 M in diethyl ether, 10 mL). Stir the suspension overnight, filter and wash the solid with ether. Collect the solid and dry to yield the desired product as a dark blue solid. LC/MS (ESI), m/e 253 (MH+), retention time 1.17 minutes. Condition II.

Example 32

[0756]

171

[0757] Synthesis of BOC Protected Piperazine-thienylisoxazole

[0758] 3-Bromothiophene-2-carbaldehyde oxime

[0759] 3-Bromothiophene-2-carbaldehyde (Maybridge) (28.7 gm, 0.15 mol) in ethanol (50 ml) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 gm, 0.2 mole), sodium hydroxide (8 gm, 0.2 mol) in water (30 ml) and ethanol (100 ml). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight. The reaction mixture was diluted with cold water (600 ml), and the precipitated solids were collected by filtration to provide 20.5 gm, (67%) of product. The aqueous layer was further extracted with ethyl acetate and, the combined organic layers were washed with brine, dried with magnesium sulfate filtered and concentrated in vacuo to leave an additional 6.9 g of product.

[0760] 3-bromothiophene-2-hydroximidoyl chloride

[0761] To a solution of 3-bromothiophene-2-carbaldehyde oxime (10.8 gm, 52.4 mmol), hydrogen chloride (14.5 ml, 4M in dioxane) in DMF (100 ml) was added oxone (16.9 gm, 1.05 eqiv) in one portion at room temperature. The mixture was stirred at ambient temperature overnight.

[0762] At the end of the reaction, DMF solution was poured into water and product was extracted into ethyl acetate. The organic solution was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to 12.68 gm of product which was used in the next reaction without further purification.

[0763] (4-t-Butoxycarbonylpiperazinyl)-3-bromo-2-thienyl methanone oxime

[0764] 3-bromothiophene-2-hydroximidoyl chloride (16.4 gm, 68 mmol) in tetrahydrofuran (THF, 70 ml) was added dropwise to a solution of N-(t-butoxycarbonyl)piperazine (14 gm, 1.1 equiv.), DABCO (9.5 gm, 1.25 eqiv.) in DMF (100 ml) at 0° C. over 25 minutes. The mixture was stirred for 3.5 hrs. At the end, the mixture was poured into water and was extracted with ethyl acetate. The organic was washed with brine and dried over magnesium sulfate. The solvent was removed on a rotary evaporator. The crude product (30.5 gm) was purified by chromatography on a Biotage cartridge (400 gm of silica gel), eluting with methanol in dichloromethane (0-5% of MeOH). The product thus obtained weighed 24.6 gm (85%).

[0765] (t-BOC-piperazine)3-thienylbenzisoxazole

[0766] A mixture of (4-t-Butoxycarbonylpiperazinyl)-3-bromo-2-thienyl methanone oxime (10.3 gm, 26.4 mmol), cesium carbonate (10.7 gm, 32.7 mmol), and copper iodide (500 mg) in methoxyethanol (200 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, the washed with water. The aqueous solution was extracted three times with ethyl acetate. the organic solution (total 600 ml) was washed with brine and was dried over magnesium sulfate then concentrated to an oil (˜10 gm). This material was purified by chromatography using a Biotage cartridge (120 gm of silica gel, eluting with 0-8% Methanol in dichloromethane). The product thus obtained as light oil (5.1 gm, 62%).

Example 33

[0767] Synthesis of radiolabeled C14 intermediate useful for the preparation of certain compounds within the scope of the present invention.

172

[0768] General: Analytical thin layer chromatography (TLC) was performed on E. Merck TLC plates with silica gel 60 F254 (0.25 mm). TLC plates used in the analysis of radioactive samples were scanned on a BIOSCAN system 2000 Imaging Scanner using P-10 gas (10% methane, 90% argon). Identity of the intermediates was established by co-migration in radio-TLC and/or radio-HPLC with the standard samples of unlabeled analogues. Flash chromatography was performed using silica gel with a particle size of 40-63 μm. Specific activity was determined on a Packard Minaxi Tri-Carb Liquid Scintillation Analyzer (Model 1600 TR) using Bio-Safe II as scintillation cocktail.

[0769] Purification of compounds VI-2, VI-3, VI-4, VI-5, and VI-6 was monitored by HPLC (conditions:A) which was carried out on Waters 600 Controller, Waters 996 Photodiode Array Detector, Millennium Chromatography Manager and Beta-Ram Radioactive Flow Through Monitor System, Model 2 (IN/US Systems Inc.). Final purity determination of VI-7 by HPLC (conditions:B) was performed on Waters Model 510 Pumps, Waters 680 Gradient Controller, Waters 715 Ultra Wisp Autosampler, Waters 484 Tunable Absorbance Detector and Beta-Ram Radioactive Flow-Through Monitor System, Model 2 (IN/US Systems Inc.).

[0770] Conditions A: YMC Basic 5 μm, C18, 4.6×250 mm, mobile phase A: (v/v) 50/50 acetonitrile/0.1N ammonium formate, mobile phase B: (v/v) 75/25 acetonitrile/0.1N ammonium formate, flow rate 1.0 mL/min, uv detection at 254 nm.

9Gradient:Time (minutes)% MP: A% MP: B01000151000250100300100351000

[0771] Conditions B: Ultremex 5 μm, C8, 4.6×150 mm, mobile phase (v/v/v) 50/50/0.25 acetonitrile/0.05 M potassium phosphate buffer, pH 3.0/triethylamine, flow rate 1.0 mL/min, uv detection at 210 nm.

[0772] [14C] Copper (I) Cyanide (VI-1):

[0773] A solution of copper (II) sulfate pentahydrate

[0774] (4.16 g, 16.67 mmol) in water (13.3 mL) was heated to 70° C. and a solution of sodium metabisulfite (1.94 g, 6.28 mmol) in water (3.3 mL) at 70° C. was added in one minute. Immediately a solution of [14C] potassium cyanide (245.5 mg, 200 mCi, 3.77 mmol, S.A. 53.0 mCi/mmol) and unlabeled potassium cyanide (0.84 g, 12.9 mmol) in water (3.3 mL) at 70° C. was added in one minute. A white solid precipitated out of solution and blue color of the solution was discharged. After stirring for 10 min at 70° C., the mixture was filtered hot and the solid was washed with hot water (15 mL) and ethanol (15 mL). The white solid was dried under vacuum (0.1 mm Hg) for 27 h 45 min to prove VI-1 (1.393 g, 186.6 mCi) in 93.3% yield.

[0775] 2-Nitro-4-(trifluoromethyl)-[7-14C]benzonitrile (VI-2):

[0776] To a suspension of [14C]copper (I) cyanide (VI-1) (1.393 g, 15.55 mmol, 186.6 mCi) in 1-methyl-2-pyrrolidinone (NMP, 10 mL) was added 4-bromo-3-nitrobenzotrifluoride (6.33 g, 23.45 mmol) and the mixture was heated at 190-195° C. for 1 h. Ethyl acetate (25 mL) and water (20 mL) were added at room temperature and the mixture was filtered through celite. To the filtrate more water (20 mL) and ethyl acetate (25 mL) were added and the aqueous layer was extracted with ethyl acetate (90 mL). The organic extract was washed with iron (III) chloride solution (50 mL) prepared by dissolving iron (III) chloride (7.468 g, 46.04 mmol) in water (50 mL).The organic extract was further washed with water (30 mL), sat. sodium chloride (15 mL), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate, 9/1-7/3) to provide an oil which was dissolved in hexane (70 mL). The solvent was removed under reduced pressure and residue was dried under vacuum for 15 h 40 min to provide VI-2 (3.01 g, 167.13 mCi, 89.6% yield) as a yellow solid. Radio-TLC (hexane/ethyl acetate, 9/1), Rf=0.21;HPLC (System A), RCP 99.86% (ret. time, 9.2 min).

[0777] [3-14C]-3-Amino-2-carbomethoxy-6-trifluoromethylbenzo[b]thiophene (VI-3):

[0778] Nitrile (VI-2) (3.01 g, 13.9 mmol, 167.13 mCi) was dissolved in DMF (14 mL) and methyl thioglycolate (1.78 g, 15.94 mmol, 95%) was added in one minute. The mixture was cooled to 0-5° C. and a solution of lithium hydroxide (0.689 g, 28.77 mmol) in water (9.2 mL) was added dropwise in 12 minutes. After the addition, cooling bath was removed and the mixture was stirred at room temperature for 4 hours. Water (70 mL) was added at 0-5° C. and the mixture was stirred for 15 min at 0-5° C. the solid was collected on a filter, washed with water (20 mL) and dried under vacuum (0.1 mm Hg) for 40 h 15 min to provide VI-3 (3.469 g, 151.24 mCi, 90.49% yield). Radio-TLC (CH2Cl2), Rf=0.372; HPLC (system A), RCP 99.92% (ret. time, 16.722 min).

[0779] [3-14C]-3-Amino-6-trifluoromethylbenzo[b]thiophene (VI-4):

[0780] To a solution of benzo[b]thiophene (VI-3) (3.469 g, 12.6 mmol, 151.2 mCi) in NMP (14 mL) was added 1-methylpiperazine (6.69 g, 66.79 mmol) and the mixture was heated at 140-145° C. for 5 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with ethyl acetate (140 mL). The organic extract was washed with water (30 mL), sat. sodium chloride (10 mL), dried (Na2So4) and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate, 1/1) to yield a greenish solid which was dried under vacuum (0.1 mm HG) for 14 h to provide VI-4 (w.66 g, 146.95 mCi, 97.16% yield). ). Radio-TLC (hexane/ethyl acetate, 1/5), Rf=0.407; HPLC (system A), RCP 99.44% (ret. time, 10.552 min).

[0781] 1-[6-(trifluoromethyl)benzo[b]thien-3-yl-[3-14C]piperazine (VI-5):

[0782] To a solution of benzo[b]thiophene (VI-4) (2.66 g, 12.24 mmol, 146.95 mCi) in NMP (17 mL) was added piperazine (4.309 g, 50.02 mmol) and p-toluenesulfonic acid (4.76 g, 25.02 mmol) at room temperature. The mixture was heated at 17° C. for 20 m h 24 min, allowed to cool to room temperature and poured into a solution of sodium carbonate (4.70 g, 44.3 mmol) in water (60 mL). The mixture was extracted with ethyl acetate (20 mL), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 9/1/0.2) and product was dried under vacuum (0.1 mm Hg) for 11 h 50 min. Ethanol (absolute, 30 mL) was added to the product and solvent was removed under reduced pressure. The residue was dried under vacuum (0.1 mm Hg) for 24 h 55 min to provide VI-5 (3.44 g, 144.18 mCi, 98.1% yield) as an oil. Radio-TLC (CH2Cl2/MeOH/NH4OH, 9/1/0.2), Rf=0.46; HPLC (system A), RCP 99.88% (ret. time, 5.807 min).

Example 34

[0783]

173

174

[0784] 3-Bromo-thiophene-2-carboxylic acid. To a solution of 3-bromothiophene (600.0 g, 3.68 mol) in THF (3 L) cooled to −72° C. was added LDA (1.93 L, 3.86 mol, 2 N) slowly over 2 hours. The rate of LDA addition is such that the reaction temperature never exceeded 68° C. After complete addition, the solution is stirred for an additional 40 minutes. Diethyl ether (3 L) is then added via an addition funnel such that the temperature is maintained below −65° C. The addition funnel is then replaced with a dispersion tube and CO2 gas is bubbled through the solution for 3 hours. Dry ice (500 g) is then added and the mixture is stirred overnight. The reaction flask is then placed in an ice bath and 6 N HCl is added slowly to prevent excessive bubbling until the pH of the solution is adjusted to 1-2. The resulting mixture is then extracted with EtOAc. The extract is washed with brine then dried over MgSO4, filtered and evaporated. The product is dried under vacuum at room temperature yielding 585.15 g (77%) as an off-white solid.

175

[0785] 1-(3-Bromo-thiophene-2-carboxylic acid)-2-(4-toluenesulfonyl)-hydrazine.

[0786] To a stirred suspension of the acid (285.53 g, 1.38 mol) in DCM (1.5 L) was added a catalytic amount of NMP (2 mL). Thionyl chloride (105.8 mL, 1.45 mol) is then added and the solution is refluxed until the solids have completely dissolved. The solution is further refluxed for 1 hour, cooled to room temperature and evaporated to afford a light, brown solid. The crude material is dried under vacuum overnight. The brown solid is taken up in toluene (3.5 L) and p-toluenesulfonhydrazine (402.25 g, 2.16 mol) is added. The mixture is stirred at 100° C. for 8 hours then at room temperature overnight. The resulting mixture was cooled with an ice bath and the resulting solids were collected by filtration and washed with toluene. The solids were then stirred as a slurry in 1 N HCl for 1 hour. The solids were collected by filtration and washed with copious amounts of water. The solid were dried under vacuum at 40° C. then recrystallized from toluene/isoproyl alcohol yielding 484.28 g (93%) of the desired product.

176

[0787] N-((4-Methylphenyl)-sulfonyl)-3-bromo-thiophene-2-carbohydrazonyl chloride. 1-(3-Bromo-thiophene-2-carboxylic acid)-2-(4-toluenesulfonyl)-hydrazine (60.80 g, 0.161 mol) was added to thionyl chloride (70.5 mL, 0.966 mol). The resulting mixture was stirred at 80° C. until the mixture becomes homogenous. The solution is then stirred at 70° C. for 30 minutes and heptane (300 mL) is added over a period of 20 minutes. The solution was cooled slowly to room temperature then cooled further to 5° C. The solids are collected by filtration, washed with heptane (3×100 mL) and dried under vacuum yielding 62.1 g (98%) of the desired product as an off-white solid.

177

[0788] 3-(4-Benzyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-thieno[3,2-c]pyrazole.

[0789] To a stirred solution of DABCO (14.18 g, 112.18 mol) and benzylpiperazine (35.35 g, 0.200 mol) in DMF (200 mL) cooled to −30° C. was added via cannula a solution of N-((4-Methylphenyl)-sulfonyl)-3-bromo-thiophene-2-carbohydrazonyl chloride (62.1 g, 0.158 mol) in THF (100 mL). The addition is controlled to prevent the reaction temperature from exceeding −30° C. After complete addition precipitation occurs and the mixture is then allowed to stir at room temperature overnight when K2CO3 (65.41 g, 0.473 mol) and CuCl (1.0 g, 0.010 mol) was added. The resulting mixture is heated to 110° C. and the THF is removed by distillation at this point. The temperature is then increased to 140° C. and the mixture is stirred for 6 hours, cooled to room temperature and stirred overnight. The mixture was then poured over water (100 mL) and EtOAc (100 mL). The EtOAC layer is then separated and the aqueous layer is extracted with EtOAC (3×500 mL). The combined EtOAC layers were washed with water (500 mL) and then filtered through celite and concentrated. The solids were collected by filtration and washed with cold water then EtOAc/heptane (1:4) and dried under vacuum yielding 66.05 g (95%) of the desired product as an off-white solid.

178

[0790] 3-(4-Benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole. To a stirred mixture of KOH(s) (56.09 g, 2.66 mol) in methyl alcohol (1.33 L) is added 3-(4-benzyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-thieno[3,2-c]pyrazole (241 g, 0.532 mol). The mixture is heated at reflux for 1.25 hours, cooled to room temperature and evaporated. The residue is taked up in EtOAc (1 L) washed with water (2 L), dried (MgSO4) filtered and evaporated. The residue was recrystallized from EtOAc/Heptane yielding 129 g (81%).

179

[0791] 3-(4-Benzyl-piperazin-1-yl)-1-methyl-1H-thieno[3,2-c]pyrazole. To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and Mel (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.

180

[0792] 1-Methyl-3-piperazin-1-yl-1H-thieno[3,2-c]pyrazole. To a solution of a mixture of 3-(4-Benzyl-piperazin-1-yl)-1-methyl-1H-thieno[3,2-c]pyrazole and the 2-methyl analog (189.0 g, 0.60 mol) is dissolved in DCM (1.25 L) is added 1-chloroethylchloroformate (78.6 mL, 0.72 mol). The solution is heated at reflux for 1 hour when the mixture is cooled and the solvent is removed by evaporation. The residue is taken up in methanol (1 L) and heated at reflux for 30 minutes. After cooling, the solution is treated with 1 N HCl in ether (200 mL) and an additional 1 L of ether to afford the precipitation of the product. The solid is collected via filtration and washed with cold ether. The solid is recrystallized from methanol (1 L) and the HCl salt is collected by filtration, washed with ether and dried under vacuum yielding 123.04 g (80%) of the desired product as an 80:1 mixture of regioisomers in favor of the desired regioisomer as seen by NMR.

181

[0793] 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperazin-1-ylmethyl]-cyclopropane-1R-carboxylic acid methyl ester. A mixture of 1-methyl-3-piperazin-1-yl-1H-thieno[3,2-c]pyrazole (2.75 g, 12.37 mmol), 2R-bromomethyl-cyclopropane-1R-carboxylic acid methyl ester (2.41 g, 12.5 mmol) and K2CO3 (3.46 g, 25.0 mmol) in acetonitrile (75 mL) was heated at reflux for 1 hour and then at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and then poured into water (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (9:1; EtOAc/MeOH) yielding 3.65 g (88%) of the desired product.

182

[0794] 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperazin-1-ylmethyl]-cyclopropane-1R-carboxylic trans-(4-methyl-cyclohexyl)-amide. To a solution of 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperazin-1-ylmethyl]-cyclopropane-1R-carboxylic acid methyl ester (10.0 g, 29.9 mmol) and trans-4-methylcyclohexylamine (6.77 g, 60.0 mmol) in toluene (100 mL) was added sodium methoxide (9.72 g, 45.0 mmol, 25% in MeOH). The resulting mixture was heated to 80° C. for 21 hours. Upon cooling to room temperature, the mixture was partitioned between water (800 mL) and EtOAc (200 mL) and separated. The aqueous layer is salted out with the addition of NaCl then extracted with EtOAc (200 mL). The combined organic layers are washed with brine (50 mL), dried (Na2SO4), filtered and evaporated. The residue was recrystallized from toluene (100 mL) and EtOAc (20 mL) to yield 9.30 g (75%) of the desired product as a white solid, MP 185-186° C. Anal. Calcd. for C22H33N5OS: C, 63.58; H, 8.00; N, 16.85. Found: C, 63.68; H, 8.24; N, 16.62.

Example 35

[0795]

183

[0796] Trityloxymethyl-(1R, 2R)-cyclopropanecarboxylic acid ethyl ester. To a suspension of sodium hydride (15.20 g, 380 mmol, 60% oil dispersion) in xylenes (300 mL) was added triethylphosphonoacetate (85.07 g, 379 mmol) in a controlled manner to avoid the excessive evolution of gas and to maintain the internal temperature less than 55° C. After the complete addition, the mixture was stirred for 20 minutes when the yellow solution was added via cannula to a solution of (R)-trityl glycidyl ether (100.0 g, 316 mmol) in xylenes (300 mL). The resulting solution was heated to 125° C. for 2 hours. The resulting solution was cooled to room temperature, acidified with the addition of 10% HCl (320 mL) and extracted with EtOAc (2×300 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and evaporated yielding a 175 g of a crude product as an oil. The material was carried on crude.

184

[0797] 2R-bromomethyl-cyclopropane-1R-carboxylic acid methyl ester. A solution of triphenylphosphine (124.7 g, 1.34 mol) in CH2Cl2 (260 mL) was cooled to 5° C. when a solution of bromine (24.4 mL, 1.34 mol) in CH2Cl2 (65 mL) was added over 20 minutes while the temperature was maintained below 12° C. The mixture was stirred at 5° C. for 1 hour when 2 M HCl/Et2O (16 mL, 32 mmol) was added followed by the addition of crude trityloxymethyl-(1R, 2R)-cyclopropane carboxylic acid ethyl ester (124 g, 0.32 mol). The resulting mixture was stirred at room temperature overnight when saturated NaHCO3 (600 mL) was added. The mixture was separated and the aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were washed with water (400 mL), dried (MgSO4), filtered and evaporated. The residue was diluted with heptane (200 mL) and evaporated two times to remove excess CH2Cl2. The residue was allowed to stand for 30 minutes when the solid impurities were removed by filtration. The filter cake was washed with heptane (2×400 mL). The combined organic layers were evaporated to provide 92.68 g of a crude yellow liquid. The crude liquid was distilled (BP=80-85° C./1.5 torr) to provide 55.19 g (84% yield for the two steps) of a colorless liquid.

Example 36

[0798]

185

[0799] 4-(2-Fluoro-5-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-fluorobenzotrifluoride (25 g, 0.152M) in anhydrous THF (300 mi) was cooled to −60° C. (IPA/CO2 bath) and treated with n-butyl lithium (84 mL of a 2.0M solution in Hexane, 0.168M-1.1 eq) with a maximum rate so not to exceed 60° C. The reaction was stirred for 3 hours (temperature maintained) and then treated with a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (51.86 g, 0.190M-1.25 eq, in 130 mL of anhydrous THF) with a maximum rate so as not to exceed −55° C. The mixture was stirred for a further two hours before allowing to warm to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (75 mL) and the THF removed under reduced pressure. The residue was dissolved in ethylacetate (800 mL), washed with 1 N Hydrochloric acid (400 ml), 5% aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively. The organics were dried over MgSO4, filtered and concentrated to give a brown oil, which on triturating in ethyl acetate gave a white solid 27.6 g (48%).

186

[0800] 4-[(2-Fluoro-5-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-(2-fluoro-5-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 0.013M) in pyridine (25 mL) was treated with hydroxylamine hydrochloride (1.11 g, 0.015 M-1.2 eq). The reaction was stirred under N2 at room temperature for 14 hours and then poured onto ice water (250 mL). The mixture was stirred at 0° C. for 1 hour, the product was then filtered off, washed with cold water (3×15 mL) and dried in a vacuum oven at 50° C. A white solid was obtained (5.03 g, 97%).

187

[0801] 4-(5-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-[(2-Fluoro-5-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.969 g, 0.013 M) in anhydrous THF (59 mL) was treated with Potassium tert-butoxide (13.4 mL of a 1M solution in THF, 0.0133 M-1.05 eq). The mixture was stirred at ambient temperature for 1 hour and. then heated to 65° C. for 2 hours. The THF was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with H2O (50 mL) and brine (50 mL) respectively. It was then dried over MgSO4, filtered and concentrated to give a solid (5 g) which was purified on silica 120 g, (eluting with ethylacetate/heptane (30:70) to give the product as a white solid (2.69 g, 57%).

188

[0802] 3-Piperidin-4-yl-5-trifluoromethyl-benzo[d]isoxazole. 4-(5-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.69 g, 0.007M) was suspended in a 50:50 mixture of DCM/Trifluoroacetic acid (4 mL). The mixture was heated for 30 minutes at 50° C. and then concentrated to give the product as the TFA salt. This was dissolved in dichloromethane (10 mL), washed with saturated Na2CO3 solution (3×3 mL), dried over MgSO4, filtered and concentrated to give the product as an oil (0.91 g, 46%)

Example 37

[0803]

189

[0804] 2R-[4-(5-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclopropane-1R-carboxylic acid trans-(4-methyl-cyclohexyl)-amide. A solution 3-Piperidin-4-yl-5-trifluoromethyl-benzo[d]isoxazole (0.1 g, 0.37 mM) was dissolved in acetonitrile (4.5 mL) and treated with potassium carbonate (0.06 g, 0.46 mM) dissolved in water (0.5 mL). The reaction was stirred at ambient temperature for 10 minutes and then treated with methane sulfonic acid 2-(4-methyl-cyclohexyl carbomyl)-transcyclopropyl methyl ester (0.11 g, 0.38 mM-1.04 eq). Heated mixture at 56° C. for 14 hours. Product filtered off and washed with hexanes (2 mL). Dried product under vacuum to obtain the product as a white solid (0.1 18 g, 91%).

Example 38

[0805]

190

[0806] 4-(2-Fluoro-3-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester. To a stirred solution of 2-fluoroanisole (6.00 g, 47.6 mmol) and anhydrous THF (125 mL) at −78° C. under nitrogen was added butyllithium (35 mL of a 1.6 M solution in hexanes, 56.0 mmol). After stirring for 13 min, N,N,N′,N′,N″-Pentamethyidiethylenetriamine (12.9 mL, 61.8 mmol) was added dropwise and the reaction stirred at −78° C. After 168 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (16.8 g, 61.7 mmol) in anhydrous THF (40 mL) was added dropwise over 25 min. The reaction was stirred at −78° C. for 35 min and at room temperature for 65 min. The reaction was diluted with ethyl acetate (400 mL) and washed with cold 0.5 N aqueous HCl (2×200 mL), 5% aqueous potassium carbonate (200 mL), water (200 mL), and brine (200 mL) successively. The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give 20.1 g of a yellow oil. The product was chromatographed on silica gel (350 g), using a step gradient elution of 20% ethyl acetatejheptane to 30% ethyl acetate/heptane, to afford 12.0 g (75%) of the desired product as a white solid.

191

[0807] 4-[(2-Fluoro-3-methoxy-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 4-(2-Fluoro-3-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (11.6 g, 34.4 mmol), hydroxylamine hydrochloride (2.87 g, 41.3 mmol) and pyridine (50 mL) was stirred at room temperature under nitrogen overnight. The yellow reaction solution was poured into cold water (500 mL) and the mixture aged at 0° C. for 15 min. The product was collected by filtration, washed with water, and dried under vacuum at 50° C. to afford 11.6 g (96%) of the desired product as a white powder. Proton NMR showed product to be a 2:1 mixture of Z- to E-isomers.

192

[0808] 4-(7-Methoxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 831478). To a room temperature mixture of 4-[(2-Fluoro-3-methoxy-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 14.2 mmol) in THF (50 mL) under nitrogen was added potassium tert-butoxide (15.0 mL of a 1M THF solution, 15.0 mmol) rapidly and the reaction refluxed for 4 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (250 mL) and washed with water (100 mL) and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give a waxy solid. Recrystallization of the solid did not remove impurities so the crude product was chromatographed on silica using a step gradient elution of 10% ethyl acetate/dichloromethane to 40% ethyl acetate/dichloromethane to afford 3.04 g (64%) of the desired product as a white powder, mp:130-132° C.

193

[0809] 7-Methoxy-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride (MDL 831587A). A mixture of 4-(7-Methoxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.00 g, 9.03 mmol), HCl (35 mL of a 1 M ether solution, 35.0 mmol), and methanol (25 mL) was stirred at room temperature under nitrogen for 18 h. Ether (75 mL) was added, the mixture stirred at room temperature for 15 min, and the product collected by filtration to afford 2.37 g (98%) of the desired product as a white powder, mp: >250° C.

Example 39

[0810]

194

[0811] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437359). The target was synthesized via the method analogous to the one described previously. 3R-Imidazol-1-ylmethyl-piperidine was obtained via the method describe by Guzi, et.al. WO 0037458.

Example 40

[0812]

195

[0813] 4-(2-Fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester.

[0814] To a stirred solution of 2-fluorobenzotrifluoride (19.4 g, 118 mmol) and anhydrous THF (300 mL) at −78° C. under nitrogen was added was added LDA (65.0 mL of a 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 130 mmol) dropwise over 25 min. After 165 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (40.1 g, 147 mmol) in anhydrous THF (100 mL) was added dropwise over 50 min and the reaction stirred at −78° C. for 20 min and at room temperature for 85 min. The reaction was quenched with saturated ammonium chloride (40 mL) and the mixture concentrated. The residue was taken up in ethylacetate (400 mL) and washed successively with 1 N HCl (200 mL), 5% aqueous potassium carbonate, water (200 mL), and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give an amber oil. The product was chromatographed on silica gel (300 g), using a step gradient elution of 20% ethyl acetate/heptane to 60% ethyl acetate/heptane, to afford 23.2 g (52%) of the desired product as an off-white solid.

196

[0815] 4-(1-Methyl-7-trifluoromethyl-1H-indazol-3-yl)-piperidine-1-carboxylic acid tert-butyl esters (MDL 832782). A solution of 4-(2-Fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (7.00 g, 18.6 mmol), methylhydrazine (1.13 g, 24.4 mmol), and n-butanol (50 mL) was heated at reflux for 135 min. The reaction was cooled to room temperature and diluted with ethyl acetate (250 mL). The oganics were washed with 5% aqueous potassium carbonate (150 mL), water (150 mL), and brine (150 mL) successively, dried over magnesium sulfate, filtered, and the solvent partially removed to give a viscid liquid. The remaining solvent was removed under high vacuum at 65° C. to provide an off-white solid. The product was chromatographed on silica, eluting with 30% ethyl acetate/heptane, to afford 6.63 g (93%) of the desired product as an off-white solid, mp: 104.7° C.

197

[0816] 1-Methyl-3-piperidin-4-yl-7-trifluoromethyl-1H-indazole hydrochloride (832641A).

[0817] Added 1N HCl (100 mL) to a solution of 4-(1-methyl-7-trifluoromethyl-1H-indazol-3-yl)-piperidine-1-carboxylic acid tert-butyl esters (6.50 g, 16.9 mmol) in ethanol (25 mL) and the reaction stirred at room temperature overnight. The mixture was diluted with ether (350 mL) and cooled 0° C. for 20 min. The solid was collected, washed with ether, and dried at 45° C. under high vacuum to afford 4.66 g (86%) of the desired product as a white powder.

Example 41

[0818]

198

[0819] 2R-[4-(1-Methyl-7-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 832654). The target was synthesized via the method analogous to the one described previously.

Example 42

[0820]

199

[0821] 4-[(2-Fluoro-3-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (MDL 832163). A mixture of 4-(2-Fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), hydroxylamine hydrochloride (2.00 g, 28.8 mmol) and pyridine (50 mL) was stirred at room temperature under nitrogen overnight. The yellow reaction solution was poured into cold water (500 mL) and the mixture aged at 0° C. for 1 h. The product was collected by filtration, washed with water, and dried under vacuum at 50° C. to afford 9.54 g of a white solid. Trituration of the solid with hot 25% ethyl acetate/heptane afforded 8.50 g (91%) of the desired product as a white solid. Proton NMR showed product to be a 3.8 to 1 mixture of isomers.

200

[0822] 4-(7-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 832159). To a room temperature mixture of 4-[(2-fluoro-3-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.40 g, 3.59 mmol) in THF (20 mL) under nitrogen was added potassium tert-butoxide (3.60 mL of a 1 M THF solution, 3.60 mmol) in one portion and the reaction heated at 60° C. for 1.5 h. After standing at room temperature overnight, the solvent was removed and the residue diluted with ethyl acetate (60 mL). The organics were washed with water (30 mL) and brine (30 mL) successively, dried over magnesium sulfate, filtered, and concentrated to give an amber solid. The crude product was chromatographed on silica using 40% ethyl acetateiheptane as eluent to afford 0.97 g (73%) of the desired product as a white solid, mp:111-113° C.

201

[0823] 3-Piperidin-4-yl-7-trifluoromethyl-benzo[d]isoxazole (MDL 832106A). A mixture of 4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.00 g, 21.6 mmol), HCl (100 mL of a 1 M ether solution, 100 mmol), and methanol (50 mL) was stirred at room temperature under nitrogen overnight. The reaction was concentrated and the solid triturated with methanovether to afford 5.84 g (88%) of the desired product as a white powder, mp: 242-243° C.

Example 43

[0824]

202

[0825] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-[2R-[4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437360). The target was synthesized via the method analogous to the one described previously. 3R-Imidazol-1-ylmethyl-piperidine was obtained via the method describe by Guzi, et.al. WO 0037458.

Example 44

[0826]

203

[0827] 4-(3-Hydroxy-2-methoxycarbonyl-7-trifluoromethyl-2,3-dihydro-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 832712). To a room temperature solution of 4-(2-fluoro-3-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetate/heptane afforded 6.20 g (56%) of the desired product as a white powder.

204

[0828] 3-Piperidin-4-yl-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester. To a room temperature solution of 4-(3-hydroxy-2-methoxycarbonyl-7-trifluoromethyl-2,3-dihydro-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (6.00 g, 13.0 mmol) in DCM (30 mL) was added TFA (30 mL) causing rapid gas evolution. After 5 min, the reaction was stirred at 40° C. for 5.5 h. After cooling to room temperature, the reaction was poured into 20% aqueous potassium carbonate (400 mL) and extracted with DCM (2×200 mL). The combined extracts were dried over magnesium sulfate, filtered, and the solvent removed to give a thick oil. After drying under high vacuum 4.37 g (98%) of the desired product was obtained as a white foam.

205

[0829] 3-(1-Acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester. To a room temperature solution of 3-piperidin-4-yl-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (4.37 g, 12.7 mmol), triethylamine (2.70 mL. 19.4 mmol), and anhydrous THF (80 mL) under nitrogen was added acetyl chloride (1.10 mL, 15.5 mmol) in one portion and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate (300 mL) and washed with water (150 mL) and brine (150 mL) successively. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed. The residue was chromatographed on silica, eluting with 10% methanol/ethyl acetate, to afford 4.28 g (88%) of the desired product as a white solid, mp: 155.2° C.

206

[0830] 3-(1-Acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid.

[0831] To a solution of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (4.10 g, 10.6 mmol) in THF (25 mL) was added 0.5 N aqueous sodium hydroxide (23.4 mL, 11.7 mmol) and the reaction stirred at room temperature. After 18 h, the reaction was acidified with 1 N HCl (200 mL) and the mixture extracted with DCM (2×100 mL). The organics were washed with water (100 mL), dried over magnesium sulfate, filtered, and concentrated to give 4.13 g of the desired product as a white foam.

207

[0832] 1-[4-(7-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-ethanone (MDL 832823). A mixture of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (4.13 g, 11.1 mmol), Cu powder (0.706 g, 11.1 mmol), and quinoline (20 mL) was heated to 200° C. under nitrogen. After 10 min, no gas evolution was observed and the reaction cooled at room temperature. The mixture was diluted with ethyl acetate (100 mL), filtered through a Celite bed and the filtrate washed with 1 N HCl (2×100 mL), 5% aqueous potassium carbonate (100 mL), water (100 mL), and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give an amber oil. The oil was chromatographed on silica, eluting with 10% methanol/ethyl acetate to afford 2.69 g (74%) of the desired product as a tan solid.

208

[0833] 4-(7-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine. A mixture of 1-[4-(7-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-yl]-ethanone (2.95 g, 9.01 mmol), concentrated HCl (30 mL), and ethanol was heated at 80° C. for 18 h. After cooling to room temperature, the reaction was basified with 20% aqueous potassium carbonate (150 mL) and the mixture extracted with DCM (2×100 mL). The organics were washed with water (100 mL), dried over potassium carbonate, filtered, and concentrated to give 2.42 g (94%) the desired product as an amber waxy solid.

Example 45

[0834]

209

[0835] 2R-[4-(7-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 833690).

[0836] The target was synthesized via the method analogous to the one described above.

Example 46

[0837]

210

[0838] 1-Dimethoxymethyl-2-fluoro-4-trifluoromethyl-benzene. A solution of 2-fluoro-4-trifluoromethylbenzaldehyde (10.0 g, 52.0 mmol), trimethyl orthoformate (55.0 g, 520 mmol) and a catalytic amount of p-toluene sulfonic acid (5 mol %) was stirred at room temperature for 24 hours. The resulting solution was saturated with the addition of solid Na2CO3 and stirred for 15 minutes. The mixture was then filtered and the solution was evaporated. The residue was diluted with ether and evaporated yielding 12.1 g (98%) of the desired product as an oil.

211

[0839] [(2-Fluoro-4-trifluoromethyl-phenyl)-methoxy-methyl]-phosphinic acid diethyl ester. To a solution of the 1-dimethoxymethyl-2-fluoro-4-trifluoromethyl-benzene (5.0 g, 21.0 mmol) and P(OEt)3 (4.18 g, 25.2 mmol) in CH2Cl2 (42 mL) cooled to −78° C. was added titanium tetrachloride (42 mL, 42 mmol, 1 M in DCM) portion-wise. The resulting solution was stirred at −78° C. for 2 hours when the reaction is quenched with the addition of water (10 mL). The mixture was warmed to room temperature and separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and evaporated. The residue is separated via chromatography (1:1; EtOAc/DCM) yielding 6.1 g (85%) of the desired product.

212

[0840] 1-Benzyl-4-[(2-fluoro-4-trifluoromethyl-phenyl)-methoxy-methylene]-piperdine. To a solution of [(2-fluoro-4-trifluoromethyl-phenyl)-methoxy-methyl]-phosphinic acid diethyl ester (16.1 g, 46.5 mmol) in THF (200 mL) cooled to −78° C. was added n-Butyl lithium (32.1 mL, 51.5 mmol) drop-wise. To the resulting solution was added a solution of 1-benzyl-4-piperidone (9.71 g, 51.5 mmol) in THF (20 mL) drop-wise. The mixture was stirred at −78° C. for 3 hours and then was allowed to slowly warm to room temperature overnight. The reaction mixture was partitioned between water (50 mL) and EtOAc (200 mL) and separated. The aqueous layer was extracted with EtOAc (100 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was purified via chromatography (gradient elution, heptane to 40% EtOAc in heptane) to obtain 9.9 g (56%) of the desired product as an oil.

213

[0841] (1-Benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone. A solution of the 1-benzyl-4-[(2-fluoro-4-trifluoromethyl-phenyl)-methoxy-methylene]-piperidine (9.9 g, 26.1 mmol) in acetone (100 mL) and conc. HCl (10 mL) in a sealed vessel was heated at 60° C. for 2 hours. Upon cooling to room temperature the solution was basified with the addition of 3 N NaOH. The resulting mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated yielding 8.8 g (92%) of the desired product as a solid.

214

[0842] 3-(1-Benzyl-piperidin-4-yl)-1-methyl-6-trifluoromethyl-1H-indazole (MDL 833796). A solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (2.0 g, 5.46 mmol), methylhydrazine (327 mg, 7.10 mmol), and n-butanol (22 mL) was heated at 120° C. in a seal vessel for 18 hours. The reaction was cooled to room temperature and basified with NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated. The product was chromatographed on silica, eluting with 1:1 ethyl acetate/heptane, to afford 1.68 g (82%) of the desired product as an oil.

215

[0843] 1-Methyl-3-piperidin-4-yl-6-trifluoromethyl-1H-indazole hydrochloride (MDL 833799A). To the 3-(1-benzyl-piperidin-4-yl)-1-methyl-6-trifluoromethyl-1H-indazole (1.41 g, 3.78 mmol) in DCM (20 mL) was added 1-chloroethyl chloroformate (0.49 mL, 4.50 mmol). The resulting solution was stirred at room temperature overnight when the volitiles were removed in vacuo. The residue was taken un in methanol (20 mL) and the resulting solution was heated at reflux for 1 hour. The mixture was cooled to room temperature and the solution was evaporated. The residue was taken up in EtOAc and the solid product was collected by filtration yielding 1.03 g (86%) of the HCl salt as a white solid.

Example 47

[0844]

216

[0845] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(1-methyl-6-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002437353). The target was synthesized via the method analogous to the one described previously. 3R-Imidazol-1-ylmethyl-piperidine starting material was obtained via the method describe by Guzi, et.al. WO 0037458.

Example 48

[0846]

217

[0847] (1-Benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone oxime. A mixture of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (5.0 g, 13.66 mmol), hydroxylamine hydrochloride (1.1 g, 16.39 mmol) and pyridine (50 mL) was stirred at room temperature overnight when the mixture was distilled to remove pyridine (35 mL). The solid residue was washed with heptane then ether. The resulting solid was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The solid residue was washed with 3:1 heptane/EtOAc and dried under vacuum to obtain 2.1 g (40%) of the desired product as a white solid.

218

[0848] 3-(1-Benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]isoxazole. To a room temperature mixture of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone oxime (2.1 g, 5.51 mmol) in THF (20 mL) under nitrogen was added potassium tert-butoxide (5.78 mL of a 1M THF solution, 5.78 mmol) in one portion. The resulting solution was stirred at room temperature for 6 hours when the mixture was partitioned between water (60 mL) and ethyl acetate (60 mL). The aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to give 1.9 g (96%) as the desired product.

219

[0849] 3-Piperidin-4-yl-6-trifluoromethyl-benzo[d]isoxazole hydrochloride. To the 3-(1-Benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]isoxazole (1.9 g, 5.27 mmol) in DCM (26 mL) was added 1-chloroethyl chloroformate (0.69 mL, 6.33 mmol). The resulting solution was stirred at room temperature overnight when the volitiles were removed in vacuo. The residue was taken un in methanol (25 mL) and the resulting solution was heated at reflux for 1 hour. The mixture was cooled to room temperature and the solution was evaporated. The residue was taken up in EtOAc and the solid product was collected by filtration yielding 1.2 g (74%) of the HCl salt as a white solid.

Example 49

[0850]

220

[0851] 2R-[4-(6-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002287765). The target was synthesized via the method analogous to the one described previously.

Example 50

[0852]

221

[0853] 3-(1-Benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (MDL 833803). To a room temperature solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (7.5 g, 20.5 mmol), methyl thioglycolate (2.0 mL, 22.5 mmol), and DMF (100 mL) was added K2CO3 (5.65 g, 41.0 mmol). The reaction was stirred at 60° C. for 24 hours, cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (2×300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford an oil. The oil was purified via chromatography (30% EtOAc in heptane) yielding 5.91 g (67%) as a solid.

222

[0854] 4-(2-Methoxycarbonyl-6trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester. To a solution of 3-(1-benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (5.9 g, 13.6 mmol) in DCM (50 mL) was added methyl chloroformate (1.26 mL, 16.3 mmol) drop-wise. The resulting solution was stirred overnight when the volatiles were removed in vacuo. The residue was washed with heptane to yield 4.2 g (77%) of the desired product as a white solid.

223

[0855] 4-(2-Carboxy-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester. To a stirred solution of 4-(2-Methoxycarbonyl-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (1.1 g, 2.7 mmol) in THF (7.0 mL) was added 1 N NaOH (2.97 mL). The resulting mixture was stirred at room temperature overnight when the mixture was diluted with water (50 mL) and washed with ether (100 mL). The aqueous layer was acidified with the addition of 3 N HCl and the product was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated yielding 960 mg (92%) of the desired product as a white solid.

224

[0856] 4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester. A mixture of 4-(2-carboxy-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (4.3 g, 11.1 mmol) and copper (705 mg, 11.1 mmol) in quinoline (28 mL) was heated at 200° C. for 45 minutes. Upon cooling to room temperature the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with 5% HCl (2×20 mL), water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was separated via chromatography (30% EtOAc in heptane) yielding 3.14 g (82%) of the desired product as a white solid.

225

[0857] 4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine hydrobromide. A mixture of 4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (3.1 g, 9.0 mmol) in HBr (45 mL, 30% in acetic acid) was stirred at room temperature for 20 hours when the volatiles were removed in vacuo. The residue was washed with EtOAc and the product was collected by filtration yielding 3.09 g (94%) of the desired product as a white solid.

Example 51

[0858]

226

[0859] (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone (A002609935). The target was synthesized via the method analogous to the one described previously. 3R-Imidazol-1-ylmethyl-piperidine starting material was obtained via the method describe by Guzi, et.al. WO 0037458.

Example 52

[0860]

227

[0861] 4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 811778). To a stirred suspension of 4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine (1.00 g, 454 mmol) in dry dichloromethane (10.0 mL) was added triethylamine (0.95 mL, 6.82 mmoles), 4-dimethylaminopyridine (55 mg, 0.454 mmoles) and di-tert-butyl dicarbonate (1.98 g, 9.09 mmoles). Gas spontaneously evolved for several minutes upon the addition of di-tert-butyl dicarbonate. The resulting solution was stirred at room temperature for 1 hour when the solution was diluted with CH2Cl2 (50 mL) and washed with water (10 mL), 10% HClaq(10 mL), water (10 mL), saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL) and dried (MgSO4), filtered and evaporated. The residue was recrystallized from diethyl ether yielding 1.31 g (90%) as a white, crystalline solid, mp 117-188° C. Analysis calculated for C17H21N2FO3: 63.74% C, 6.61% H, 8.74% N. Found: 63.66% C, 6.64% H, 8.73% N.

228

[0862] 4-(6-Fluoro-7-hydroxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 811820). To a stirred solution of 4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.13 mmol) in dry tetrahydrofuran (31.3 mL) cooled to −78° C. was added lithium diisopropylamide (1.72 mL, 3.35 mmoles). The resulting solution was stirred at −78° C. for 2 hours when trimethylborate (0.44 mL, 3.84 mmoles) was added. The resulting solution was stirred at −78° C. for 1 hour then was allowed to warm to room temperature over 3 hours when hydrogen peroxide (2.00 mL) and acetic acid (1.00 mL) were added. The resulting mixture was stirred at room temperature overnight when the mixture was quenched with saturated NH4Claq (20 mL) and 10% HClaq (20 mL). The resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 0.619 g (59%) of the phenol as a white, crystalline solid, mp 169-170° C. Analysis calculated for C17H21N2FO4; 60.70% C, 6.29% H, 8.33% N. Found: 60.72% C, 6.15% H, 8.22% N.

229

[0863] 4-(6-Fluoro-7-methoxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (MDL 811841). To a stirred solution of 4-(6-fluoro-7-hydroxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 3.80 mmol) in N-methyl-2-pyrrolidone (33 mL) was added potassium tertbutoxide (2.09 g, 17.12 mmoles). To the resulting deep red solution was added iodomethane (1.20 mL, 19.02 mmoles). The resulting yellow solution was stirred at room temperature for 6 hours when the reaction was quenched with water (55 mL) and acidified with HClaq. The resulting mixture was extracted with Et2O (4×110 mL). The combined extracts were washed with brine (110 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 1.2 g of the methyl ether. The white, solid product was further purified via recrystallization from 1:1; Et2O/Pet. ether yielding 963 mg (72%) as a white, crystalline solid, mp 94-96° C. Analysis calculated for C18H23N2FO4: 61.70% C, 6.62% H, 7.99% N. Found: 61.75% C, 6.73% H, 7.94% N.

230

[0864] 6-Fluoro-7-methoxy-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride (MDL 811998). To a stirred solution of 4-(6-fluoro-7-methoxy-benzo[doisoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 11.43 mmol) in dry hydrochloric acid in diethyl ether (100 mL) was added methanol (7.62 mL). The resulting solution was stirred at room temperature for 5 hours when a white solid precipitate formed. The resulting.suspension was filtered and the white solid was wash thoroughly with ether yielding 1.76 g of the desired product as a white solid. The mother liquor precipitated yielding an additional 0.94 g of product providing a total of 2.70 g (83%) of the desired product as a pure, white solid, mp 246-248° C.

Example 53

[0865]

231

[0866] 2R-[4-(6-Fluoro-7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 831361). The target was synthesized via the method analogous to the one described above.

Example 54

[0867]

232

[0868] 4-[(3-Bromo-thiophen-2-yl)-(methyl-hydrazono)-methyl]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 4-(thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, 5.2 mmol) in methylhydrazine (2 mL) was heated at 75° C. overnight. The excess methyl hydrazine was then removed with a vacuum pump. The residue was purified by chromatography (eluted with 0-8% of MeOH in DCM) yielding 0.95 g (45%) of the desired product.

233

[0869] 4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester. 4-[(3-Bromo-thiophen-2-yl)-(methyl-hydrazono)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.74 mmol) was mixed with Cul (20 mg), CsCO3 (650 mg, 1.15 eq) in methoxyethanol (10 mL). The mixture was heated to 70° C. for 2 hr. then stirred overnight at room temperature. The solvent was stripped on rotary evaporator. The residue was extracted into EtOAc then washed with brine and concentrated down to an oil. This oil was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 520 mg (68%) of the desired product.

234

[0870] 1-Methyl-3-piperidin-4-yl-1H-thieno[3,2-c]pyrazole hydrochloride (A002436287A). 4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (520 mg, 1.6 mmol) was stirred at room temperature in a solution of HCl (5 mL, 4N HCl in dioxane) for 4 hours. The volatiles were removed in. vacuo and the residue was triturated with ether (twice) to yield off white solids 304 mg (74%) as the desired hydrochloride salt.

Example 55

[0871]

235

[0872] 2R-[4-(1-Methyl-1H-thieno[3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002436291). The target was synthesized via the method analogous to the one described previously.

Example 56

[0873]

236

[0874] 4-{(3-Bromo-thiophen-2-yl)-[(2,2,2-trifluoro-ethyl)-hydrazono]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. To a mixture of 4-(thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 6.24 mmol) in n-butanol (20 mL) was added trifluoroethylhydrazine (2.43 g, 12.4 mmol). The resulting mixture was heated at 110° C. overnight. The volatiles were then removed in vacuo. The residue was purified by chromatography (eluted with 0-10% MeOH in DCM) yielding 2.41 g (92%) of the desired product.

237

[0875] 4-[1-(2,2,2-Trifluoro-ethyl)-1H-thieno[3,2-c]pyrazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester. 4-{(3-Bromo-thiophen-2-yl)-[(2,2,2-trifluoro-ethyl)-hydrazono]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 4.98 mmol) was mixed with Cul (50 mg), CsCO3 (1.9 g, 1.2 eq) in methoxyethanol (25 mL). The mixture was heated to 75° C. for 1 hour. The mixture was then diluted with EtOAc and filtered. The filtrate was evaporated and the residue was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 2.03 g (>95%) of the desired product.

238

[0876] 3-Piperidin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-thieno[3,2-c]pyrazole hydrochloride (833906). 4-[1-(2,2,2-Trifluoro-ethyl)-1H-thieno[3,2-c]pyrazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 4.87 mmol) was stirred at room temperature in a solution of HCl (6 mL, 4N HCl in dioxane) for 4 hours. The volatiles were removed in vacuo and the residue was triturated with ether (twice) to yield off white solids 2.1 g (74%) as the desired hydrochloride salt.

Example 57

[0877]

239

[0878] 2R-{4-[1-(2,2,20Trifluoro-ethyl)-1H-thieno(3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (A002287767). The target was synthesized via the method analogous to the one described previously.

Example 58

[0879]

240

[0880] 3-Bromo-thiophene-2-carbaldehyde oxime. 3-Bromothiophene-2-carbaldehyde (28.7 g, 0.15 mol) in ethanol (50 mL) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 g, 0.2 mol), sodium hydroxide (8 g, 0.2 mol) in water (30 mL) and ethanol (100 mL). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight when a precipitate formed. The mixture was diluted with cold water (600 ml) and the solid was collected by filtration yielding 20.5 g, (67%). The aqueous solution was further extracted with ethyl acetate. The organic solution was washed with brine, dried with magnesium sulfate, filtered and evaporated yielding 6.9 g of additional product as a light yellow solid. The total yield was 27.4 g (89%).

241

[0881] 3-Bromo-thiophene-2-(chloro-carbaldehyde) oxime. To the solution of 3-bromo-thiophene-2-carbaldehyde oxime (10.8 g, 52.4 mmol), hydrogen chloride (14.5 mL, 4M in dioxane) in DMF (100 mL) was charged with oxone (16.9 g, 1.05 eqiv) in one portion at room temperature. The mixture was stirred at room temp overnight when the solution was poured in to water and extracted with ethyl acetate. The organic solution was washed with brine and dried over magnesium sulfate, filtered and evaporated to dryness to give a yellow solid (12.68 g, quantitative by weight) which was used in the next reaction without further purification.

242

[0882] 4-[(3-Bromo-thiophen-2-yl)-hydroxyimino-methyl]-piperazine)-1-carboxylic acid tert-butyl ester. A solution of 3-bromo-thiophene-2-(chloro-carbaldehyde) oxime (16.4 g, 68 mmol) in THF (70 mL) was added drop-wise to a solution of N-(t-butoxycarbonyl)piperazine (14 g, 1.1 equiv.), DABCO (9.5 g, 1.25 eqiv.) in DMF (100 mL) at 0° C. over 25 minutes. The mixture was stirred at 0° C. for 3.5 hours when the mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate, filtered and evaporated. The crude product (30.5 g) was purified via chromatography (eluted with 0-5% of MeOH in DCM) yielding 24.6 g (85%) of the desired product.

243

[0883] 4-Thieno[2,3-d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester. A mixture of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]-piperazine)-1-carboxylic acid tert-butyl ester (10.3 g, 26.4 mmol), cesium carbonate (10.7 g, 32.7 mmol), copper iodide (500 mg) in methoxyethanol (200 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous solution was extracted three times with ethyl acetate. The combined organic layers (total 600 ml) were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (120 gm of silica gel, eluted with 0-8% Methanol in dichloromethane) yielding 5.1 g (62%) of the desired product as light oil.

244

[0884] 3-Piperazin-1-yl-thieno[2,3-d]isoxazole. 4-Thieno[2,3-d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 16.2 mmol) was stirred at room temperature in a solution of HCl (25 mL, 4N HCl in dioxane) for 4 hours. The volatiles were removed in vacuo and the residue was triturated with ether (twice) to yield off white solids 3.3 g (84%) as the desired hydrochloride salt.

Example 59

[0885]

245

[0886] 2R-(4-Thieno[2,3-d]isoxazol-3-yl-piperazin-1-ylmethyl)-1R-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 831493). The target was synthesized via the method analogous to the one described previously.

Example 60

[0887]

246

[0888] 2R-(4-Benzo[b]thiophen-2-yl-piperidin-1-ylmethyl)-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 831148). The target was synthesized via the method analogous to the one described above. 4-Benzo[b]thiophen-2-yl-piperidine was obtained via the method described by Bernasconi, DE 2456246.

Example 61

[0889]

247

[0890] 2R-[4-(5,6-Dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-piperazin-1-ylmethyl]-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide (MDL 833699). The target was synthesized via the method analogous to the one described above. 2-Piperazin-1-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline was obtained via the method described by Glamkowski and Freed, EP 95-113849.

Example 62

[0891]

248

[0892] 2R-(4-Thieno[2,3-b]pyridin-3-yl-piperazin-1-ylmethyl)-1R-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 833821). The target was synthesized via the method analogous to the one described above. 3-Piperazin-1-yl-thieno[2,3-b]pyridine was obtained via the method described by Hrib and Jurcak, U.S. Pat. No. 92-942,232.

Example 63

[0893]

249

[0894] Cyclopropanecarboxylic acid tert-butyl ester. To a stirred suspension of 12.0 g (107.1 mmol) of potassium t-butoxide in 200 mL ether at 0° C. under nitrogen was added 13.4 g (128.6 mmol) of cyclopropanecarboxylic acid chloride over 5 min. After 30 min at 0° C. the mixture was stirred at ambient temperature for an additional 30 min. The reaction mixture was poured into aqueous saturated sodium bicarbonate and extracted with ether. The organic layer was dried and carefully concentrated to deliver 15.0 g (99%) of a yellow oil as the desired ester product.

250

[0895] 1-Allyl-cyclopropanecarboxylic acid tert-butyl ester. Lithium diisopropyl amide was generated from 7.5 g (58.1 mmol) diisopropyl amine and 23.2 mL of 2.5 M n-butyl lithium in 200 mL THF at 0° C. under nitrogen. After stirring for 30 minutes at 0° C. the solution was taken to −78° C. where 7.5 g (52.8 mmol) of cyclopropanecarboxylic acid tert-butyl ester in 30 mL of THF was added dropwise over 5 min. After 4 h 12.8 g (106 mmol) of allyl bromide in 30 mL THF was added drop-wise over 10 min. to the clear golden solution. The reaction was allowed to slowly warm to room temperature. After 19 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with ether, dried and concentrated to deliver an oil which was purified via Kugelrohr distillation (approx. 20 mm Hg; 60-75° C. oven) to deliver 5.4 g (56%) of the desired product as a clear colorless oil.

251

[0896] 1-(2-Oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester. A solution of 5.7 g (31.3 mmol) of 1-allyl-cyclopropanecarboxylic acid tert-butyl ester in 50 mL methanol and 50 mL dichloromethane under nitrogen was taken to −78° C. where ozone was bubbled in for 1 hour. Nitrogen was bubbled in until the familiar blue color dissipated. Three drops of pyridine followed by 2 mL of dimethyl sulfide were added and the cooling bath removed. After 2 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with dichloromethane, dried and concentrated to deliver a quantitative yield of the desired aldehyde as an oil.

Example 64

[0897]

252

[0898] 1-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl)-cyclopropanecarboxylic acid tert-butyl ester. To a solution of 4.2 g (14.7 mmol) of 1-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazine in 100 mL of dichloromethane under nitrogen was added 3.5 g (19.1 mmol) of 1-(2-Oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester. After stirring 10 minutes at room temperature 6.5 g (30.7 mmol) of sodium triacetoxyborohydride was added portion-wise. After 30 minutes 100 mL of 0.5 N aqueous sodium hydroxide was added and the reaction was stirred for 15 minutes. The organic layer was separated, dried and concentrated to deliver a paste. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 6.6 g (13.4 mmol) of the desired product as a white powder mp=187-9° C.

253

[0899] 1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid. 1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid tert-butyl ester, 0.7 g (1.54 mmol), was stirred in 10 mL of trifluoroacetic acid. After 2 hours the reaction mixture was concentrated to an oil. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 0.4 g (60%) of white powder as the desired carboxylic acid mp=255-7° C.

254

[0900] 1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide (MDL 832231). A suspension of 0.17 g (0.39 mmol) of 1-{2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid in 10 mL dichloromethane under nitrogen was treated with 1 mL of oxalyl chloride followed by 3 drops of DMF. After 2 hours the reaction was concentrated to a slurry, diluted with 10 mL DMF and treated with 0.10 g (0.78 mmol) of 1-(3-aminopropyl)imidazole followed by 0.12 g (1.2 mmol) of triethylamine. After 12 hours the reaction was poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to deliver an oil. Chromatographic purification gave 0.075 g (38%) of the desired final product as an oil.

10TABLE 2

255

No.Rn

256

R1AR2R3d3Ki827055 (racemic)

257

258

259

CH2Ph792827071 (racemic)

260

261

262

(CH2)2Ph454827074 (racemic)

263

264

CH3N

265

(CH2)2Ph267827079 (racemic)

266

267

CH3N

268

(CH2)3Ph126827085 (racemic)

269

270

271

CH2Ph126827086 (racemic)

272

273

274

CH2Ph334827087 (racemic)

275

276

277

CH2Ph178827088 (racemic)

278

279

280

CH2Ph284827089 (racemic)

281

282

CH3N

283

CH2Ph307827090 (racemic)

284

285

CH3CH2N

286

CH2Ph346827101 (racemic)

287

288

289

CH2Ph148827102 (racemic)

290

291

292

CH2Ph218827105 (racemic)

293

294

295

(CH2)3Ph117827106 (racemic)

296

297

298

(CH2)3Ph317827107 (racemic)

299

300

301

(CH2)3Ph489827108 (racemic)

302

303

304

(CH2)3Ph302827109 (racemic)

305

306

CH3N

307

(CH2)3Ph78.6827110 (racemic)

308

309

CH3CH2N

310

(CH2)3Ph208827111 (racemic)

311

312

HO(CH2)2N

313

(CH2)3Ph143817047 (racemic)

314

315

316

H2.86817048 (racemic)

317

318

319

H2.85817049 (racemic)

320

321

322

H7.02817050 (−)-R,R

323

324

325

H2.15817051 (−)-R,R

326

327

328

H3.47817244 (racemic)

329

330

HO(CH2)2N

331

H817569A (−)-R,R

332

333

334

H5.38818499 (racemic)

335

336

337

H22.1818497 (racemic)

338

339

340

H5.52818673 (Isomer 1)

341

342

CH2PhN

343

H818674 (Isomer 2)

344

345

CH2PhN

346

H827196 (racemic)

347

348

349

H2.35817037 (racemic)

350

351

352

H0.98817038 (racemic)

353

354

355

H0.952817039 (racemic)

356

357

358

H14.8817040 (racemic)

359

360

361

H0.804817045 (racemic)

362

363

364

H5.36817041 (racemic)

365

366

367

H0.776817042 (racemic)

368

369

370

H0.615817043 (racemic)

371

372

373

H7.2817044 (racemic)

374

375

376

H1.1817046 (racemic)

377

378

379

H1.92817090 (−)-R,R

380

381

382

H2.17817091 (−)-R,R

383

384

385

H3.98817092 (−)-R,R

386

387

388

H3.39817094

389

390

391

H8.89817095

392

393

394

H0.671817096

395

396

397

H9.09817097

398

399

400

H0.636817098

401

402

403

H1.06817099

404

405

406

H1.1817100

407

408

409

H0.75817101

410

411

412

H0.547817102 (−)-R,R

413

414

415

H7.75827253

416

417

418

H15.8827254

419

420

421

H8.66817039A (racemic)

422

423

424

H35817090A (racemic)

425

426

427

H5.04817571A (racemic)

428

429

430

H11.5817092A (racemic)

431

432

433

H22.3817570A (racemic)

434

435

436

H5.04817478A (racemic)

437

438

439

H1.99817043A (racemic)

440

441

442

H18.6817091A (−)-R,R

443

444

445

H4.04817102A (−)-R,R

446

447

448

H7.57818675DA (−)-R,R

449

450

451

H5.69827201 (racemic)

452

453

454

H126817093 (−)-R,R

455

456

457

H5.97817480A (−)-R,R

458

459

460

H5.33817566

461

462

463

H2.46817565

464

465

466

H1.73817198

467

468

469

H161818427 (racemic)

470

471

472

H6.07817892 (−)-R,R

473

474

475

H5.47817893 (+)-S,S

476

477

478

H245817892A (−)-R,R

479

480

481

H3.02818574 (racemic)

482

483

484

H9.6817787 (−)-R,R

485

486

487

H5.81817786 (+)-S,S

488

489

490

H125817787A (−)-R,R

491

492

493

H1.76817272 (racemic)

494

495

496

H1.72817273 (racemic)

497

498

499

H3.05817260 (racemic)

500

501

502

H12.5817261 (racemic)

503

504

505

H9.23827731 (racemic)

506

507

508

H19.5827732 (racemic)

509

510

511

H10.5817567 (racemic)

512

513

514

H80.6817568 (racemic)

515

516

517

H36.3827733 (racemic)

518

519

520

H1.19818498 (racemic)

521

522

523

H25.6827800 (racemic)

524

525

526

H19.7814648

527

528

CH3(CH2)2N

529

H39.6814649

530

531

532

533

H38.9814650A

534

535

CH3N

536

H18813384

537

538

539

H74822129

540

541

CH3N

542

H38822130

543

544

CH3CH2N

545

H51822131

546

547

CH3N

548

H61822132

549

550

CH3CH2N

551

H18822133

552

553

CH3N

554

H17822134

555

556

557

H82822135

558

559

560

H3.6822136

561

562

563

H207822137

564

565

566

H36822138

567

568

CH3N

569

H81822139

570

571

CH3N

572

H21.2822140

573

574

CH3N

575

H112.8822142

576

577

CH3N

578

H39.1822143

579

580

581

582

H338826804

583

584

585

H67.4826805

586

587

588

H14.2826806

589

590

591

H40826807 (racemic)

592

593

594

H43826808

595

596

CH3N

597

H17.4826809

598

599

CH3CH2N

600

H71826810

601

602

HO(CH2)2N

603

H86.7826820

604

605

606

H52.8826821

607

608

609

H70.1826824

610

611

612

H34.2826825

613

614

615

H74.9826826

616

617

618

H27.4826827 (racemic)

619

620

621

H39.5826828

622

623

CH3N

624

H14.4826829

625

626

CH3CH2N

627

H15826830

628

629

HO(CH2)2N

630

H25.1826840

631

632

633

H11826841

634

635

636

H22822144

637

638

CH3N

639

H144822145

640

641

642

H176822147

643

644

645

H217822148

646

647

648

H41.4826844

649

650

651

H0.591826845

652

653

654

H4.42826846

655

656

657

H17.6826847

658

659

660

H1.01826848

661

662

CH3N

663

H4.35826849

664

665

CH3CH2N

666

H54.2826850

667

668

HO(CH2)2N

669

H18.8826860

670

671

672

H3.48826861

673

674

675

H2.89825857 Racemic

676

677

678

H137825860 Racemic

679

680

681

H130825870 Racemic

682

683

684

H100825871 Racemic

685

686

687

H137825872 Racemic

688

689

690

H104825881

691

692

693

H189825882

694

695

696

H186825883

697

698

699

H140825886

700

701

702

H40.2825886

703

704

705

H40.2825887

706

707

708

H90.4825888

709

710

711

H89.4825893

712

713

714

H73.8825894

715

716

717

H59825895

718

719

720

H31.7825896

721

722

723

H53.3825897

724

725

726

H140825898

727

728

729

H49825899

730

731

732

H42.9826065

733

734

735

H175822202

736

737

738

H8.1826066

739

740

741

H60.3826067

742

743

744

H19.3826068

745

746

747

H54.6826069

748

749

750

H27.2826070

751

752

753

H12.6826071

754

755

756

H165822203

757

758

759

H30826072

760

761

762

H62.6826073

763

764

765

H32.3826074

766

767

768

H72.6826075

769

770

771

H55.6826076

772

773

774

H15826077

775

776

777

H88.9826078

778

779

780

H162822204

781

782

783

H12.6826079

784

785

786

H106826080

787

788

789

H14.8815916

790

791

792

H5(+)- 816589 (S,S)

793

794

795

H1070(−)- 817569 (R,R)

796

797

798

H2.62815917

799

800

801

H18815918

802

803

804

H15826655

805

806

807

H31826656

808

809

810

H45826658

811

812

813

H17826884

814

815

816

H15.2826885

817

818

CH3N

819

H20.3826886

820

821

822

823

H136826887

824

825

826

H83.8826888

827

828

829

H37.2826889

830

831

832

H36.2826890

833

834

835

H38826891

836

837

838

H263826892

839

840

841

H25.9826893

842

843

844

H20.4826894

845

846

CH3CH2N

847

H35826895

848

849

HO(CH2)2N

850

H48.8826897

851

852

853

H128826898

854

855

856

H50.5816078A HCl salt

857

858

859

H89.7826678

860

861

862

H15826679

863

864

865

H9.1826680

866

867

868

H58826681

869

870

871

H48826682

872

873

874

H103826684

875

876

877

H7.9826665

878

879

880

H1.9826666

881

882

883

H6.3826667

884

885

886

H2.5826668

887

888

889

H3.9826670

890

891

892

H4.2826677

893

894

895

H2.3826864

896

897

898

H2.16826865

899

900

901

H3.68826866

902

903

904

H1.24826867

905

906

907

H1.89826868

908

909

CH3N

910

H3.49826869

911

912

CH3CH2N

913

H6.75826870

914

915

HO(CH2)2N

916

H7.4826880

917

918

919

H2.86826881

920

921

922

H2.38825825

923

924

925

H152825826G (Malcate Salt)

926

927

928

H32.5825827

929

930

931

H54.8825828

932

933

934

H21.8825829G (Malcate Salt)

935

936

937

H40.1825830

938

939

940

H64.6825831

941

942

943

H48.1825832

944

945

946

H60.3825834G (Malcate Salt)

947

948

949

H6.9825900

950

951

952

H22.4826057

953

954

955

H90.9826058

956

957

958

H45.2826059

959

960

961

H27.1826060

962

963

964

H40.2826061

965

966

967

H826062

968

969

970

H826063

971

972

973

H826064

974

975

976

H826086

977

978

979

H103826092

980

981

982

H293826098

983

984

985

H451826100

986

987

988

H193826102

989

990

991

H210826104

992

993

994

H16.8826105

995

996

997

H690826106

998

999

1000

H230826108

1001

1002

1003

H100826113

1004

1005

1006

H200826114

1007

1008

1009

H133826115

1010

1011

1012

H72.3826116

1013

1014

1015

H59.9826117

1016

1017

1018

H241826118

1019

1020

1021

H568826120

1022

1023

1024

H487826121

1025

1026

1027

H502826122

1028

1029

1030

H130816592

1031

1032

1033

H11816593

1034

1035

1036

H7.47827173

1037

1038

1039

H2.78827174

1040

1041

1042

H8.7827176

1043

1044

1045

H1.18827177

1046

1047

1048

H1827178

1049

1050

1051

H12.4827179

1052

1053

1054

H1.04827180

1055

1056

1057

H2.47827181

1058

1059

1060

H97.2827182

1061

1062

1063

H73827183

1064

1065

1066

H3.29827185

1067

1068

1069

H4.89827186

1070

1071

1072

H8.21827187

1073

1074

1075

H10.6827189

1076

1077

1078

H126827190

1079

1080

1081

H2.42827191

1082

1083

1084

H0.724827193

1085

1086

1087

H40.6827194

1088

1089

1090

H24.4827195

1091

1092

1093

H8.18827175

1094

1095

1096

H4.0827197

1097

1098

1099

H27.6827199

1100

1101

1102

H4.34827200

1103

1104

1105

H119827205

1106

1107

1108

H200827206

1109

1110

1111

H59.7827212

1112

1113

1114

H1.2827213

1115

1116

1117

H11.1827215

1118

1119

1120

H0.229827216

1121

1122

1123

H2.16827218

1124

1125

1126

H1.22827219

1127

1128

1129

H2.63817480 (Racemic)

1130

1131

1132

H3.07827221

1133

1134

1135

H99.2827222

1136

1137

1138

H2.09828393

1139

1140

1141

H3.45817570 (Racemic)

1142

1143

1144

H6.24827226

1145

1146

1147

H16.1827228

1148

1149

1150

H62827229

1151

1152

1153

H1.71827230

1154

1155

1156

H2.09817571 (racemic)

1157

1158

1159

H2.85827233

1160

1161

1162

H27.7827234

1163

1164

1165

H3.15827235

1166

1167

1168

H4.49827214

1169

1170

1171

H6.13827236

1172

1173

1174

H12.9827238

1175

1176

1177

H2.48827239

1178

1179

1180

H90.8827244

1181

1182

1183

H197827245

1184

1185

1186

H43818675 (Racemic)

1187

1188

1189

H0.771817478 (Racemic)

1190

1191

1192

H1.46

[0901]

11

CMPD NUMBER
R
n

1193

A
R1R2N
R3
d3Ki

826811

1194

1195

1196

H
40.4

826816

1197

1198

1199

H
26.3

826817

1200

1201

1202

H
20

826818

1203

1204

1205

H
29.3

826819

1206

1207

1208

H
11.6

826822

1209

1210

1211

H
2.79

826823

1212

1213

1214

H
19

826831

1215

1216

1217

H
2.55

826832

1218

1219

1220

H
16.1

826833

1221

1222

1223

H
0.872

826834

1224

1225

1226

H
8.01

826835

1227

1228

1229

H
2.12

826836

1230

1231

1232

H
2.23

826837

1233

1234

1235

H
8.8

826838

1236

1237

1238

H
14.6

826839

1239

1240

1241

H
9.37

826842

1242

1243

1244

H
3.66

826843

1245

1246

1247

H
126

826851

1248

1249

1250

H
2.77

826852

1251

1252

1253

H
3.54

826853

1254

1255

1256

H
0.128

826854

1257

1258

1259

H
0.116

826855

1260

1261

1262

H
0.58

826856

1263

1264

1265

H
1.8

826857

1266

1267

1268

H
0.817

826858

1269

1270

1271

H
3.71

826859

1272

1273

1274

H
3.53

826862

1275

1276

1277

H
0.951

825868

1278

1279

1280

H
13

825891

1281

1282

1283

H
118

826081

1284

1285

1286

H
18.6

826657

1287

1288

1289

H
14

826659

1290

1291

1292

H
140

826660

1293

1294

1295

H
53

826661

1296

1297

1298

H
25

826662

1299

1300

1301

H
69

826664

1302

1303

1304

H
9.4

826896

1305

1306

1307

H
89.5

826899

1308

1309

1310

H
45.5

826900

1311

1312

1313

H
181

826901

1314

1315

1316

H
42.4

826902

1317

1318

1319

H
13.1

826903

1320

1321

1322

H
7.47

826904

1323

1324

1325

H
39.4

826905

1326

1327

1328

H
14.5

826906

1329

1330

1331

H
39.5

826907

1332

1333

1334

H
18.8

826908

1335

1336

1337

H
7.06

826909

1338

1339

1340

H
28.9

826910

1341

1342

1343

H
17.5

826911

1344

1345

1346

H
93

826912

1347

1348

1349

H
58.5

826913

1350

1351

1352

H
86.1

826914

1353

1354

1355

H
101

826916

1356

1357

1358

H
157

826917

1359

1360

1361

H
196

826918

1362

1363

1364

H
30.3

826919

1365

1366

1367

H
329

826920

1368

1369

1370

H
67.6

826921

1371

1372

1373

H
183

826922

1374

1375

1376

H
183

826923

1377

1378

1379

H
141

826924

1380

1381

1382

H
256

826926

1383

1384

1385

H
86.5

826928

1386

1387

1388

H
11.2

826683

1389

1390

1391

H
3.7

826685

1392

1393

1394

H
154

826686

1395

1396

1397

H
26

826687

1398

1399

1400

H
132

826688

1401

1402

1403

H
217

826689

1404

1405

1406

H
674

826691

1407

1408

1409

H
35

826669

1410

1411

1412

H
0.24

826671

1413

1414

1415

H
6.8

826672

1416

1417

1418

H
0.64

826673

1419

1420

1421

H
7.9

826674

1422

1423

1424

H
48

826675

1425

1426

1427

H
8

826676

1428

1429

1430

H
2

826871

1431

1432

1433

H
10.7

826872

1434

1435

1436

H
3.66

826873

1437

1438

1439

H
1.31

826874

1440

1441

1442

H
1.72

826875

1443

1444

1445

H
2.79

826876

1446

1447

1448

H
2.72

826877

1449

1450

1451

H
4.72

826878

1452

1453

1454

H
7.95

826879

1455

1456

1457

H
1.59

826882

1458

1459

1460

H
2.93

826883

1461

1462

1463

H
13.4

826056

1464

1465

1466

H
5.4

826119

1467

1468

1469

H
219

826812

1470

1471

1472

H
7.29

826813

1473

1474

1475

H
5.16

826814

1476

1477

1478

H
10.3

826815

1479

1480

1481

H
31.7

826863

1482

1483

1484

H
26.6

827064

1485

1486

1487

PhCH2
245

827065

1488

1489

1490

PhCH2
168

827066

1491

1492

1493

PhCH2
209

827067

1494

1495

1496

PhCH2
268

827068

1497

1498

1499

PhCH2
197

827063

1500

1501

1502

PhCH2
373

827082

1503

1504

1505

Ph(CH2)3
303

827084

1506

1507

1508

Ph(CH2)3
266

827092

1509

1510

1511

PhCH2
316

827093

1512

1513

1514

PhCH2
84

827094

1515

1516

1517

PhCH2
34.6

827095

1518

1519

1520

PhCH2
37.8

827096

1521

1522

1523

PhCH2
44.7

827097

1524

1525

1526

PhCH2
51.5

827098

1527

1528

1529

PhCH2
82.9

827099

1530

1531

1532

PhCH2
144

827100

1533

1534

1535

PhCH2
63.5

827103

1536

1537

1538

PhCH2
81.7

827104

1539

1540

1541

PhCH2
141

827112

1542

1543

1544

Ph(CH2)3
126

827113

1545

1546

1547

Ph(CH2)3
95

827114

1548

1549

1550

Ph(CH2)3
120

826690 (racemic)

1551

1552

1553

H
83% Inh @0.1 nM

[0902]

1554

MDL #
D3 KI (nM)
Chirality
n
X
R1
R2
R3

817274
4.49
Racemic
1
N

1555

1556

817275
3.34
Racemic
1
N

1557

1558

827184
237
Racemic
1
N
t-Boc
H

1559

827192
150
Racemic
1
N

1560

1561

827202
177
Racemic
1
N
—CH2Ph
H

1562

827209
30.4
Racemic
1
CH
—CH2Ph
H

1563

827211
353
Racemic
1
CH

1564

1565

827223
159
Racemic
1
N
t-Boc
H

1566

827226
16.1
Racemic
1
N

1567

1568

827229
1.71
Racemic
1
N

1569

1570

827231
60.6
Racemic
1
N

1571

CH3

1572

827237
153
Racemic
1
N
—CH2CH2Ph
H

1573

827240
152
Racemic
1
N

1574

1575

827241
89.5
Racemic
1
N
—CH2Ph
H

1576

827248
19.4
Racemic
1
CH
—CH2Ph
H

1577

827250
45.2
Racemic
1
CH

1578

1579

828716
2.38
R,R
1
N

1580

1581

829006DA
12.4
R,R
1
N

1582

1583

829363
63.9
Racemic
1
CH

1584

1585

830046
16.5
Racemic
1
N

1586

1587

830112
54
Racemic
1
CH

1588

1589

830114
5.42
Racemic
1
N

1590

1591

830116
13.1
Racemic
1
N

1592

1593

830121
47.1
Racemic
1
N

1594

1595

830122
67.6
Racemic
2
N

1596

1597

830123
73.8
Racemic
2
N

1598

1599

830124
1.84
Racemic
1
N

1600

1601

830128
69.7
Racemic
2
N

1602

1603

830129
4.16
Racemic
1
N

1604

1605

830131
34.1
Racemic
2
N

1606

1607

830132
9.26
Racemic
1
CH

1608

1609

830133
176
Racemic
1
CH

1610

1611

830134
0.602
Racemic
1
CH

1612

1613

830439
17.6
Racemic
1
N

1614

1615

831147
40.8
S,S
1
CH

1616

1617

831148
0.454
R,R
1
CH

1618

1619

831226
26.7
R,R
1
N

1620

1621

831269
4.08
R,R
1
N

1622

1623

831270
17.8
R,R
1
N

1624

H
—NH—(CH2)3—Ph

831271
6.57
R,R
1
N

1625

1626

831309
40.6
R,R
1
CH

1627

1628

831310
103
R,R
1
CH

1629

H
—NH—(CH2)3—Ph

831311
38.7
R,R
1
CH

1630

1631

831312
214
R,R
1
CH

1632

H
—NH—(CH2)3—Ph

831313
134
R,R
1
N

1633

1634

831314
133
R,R
1
N

1635

H
—NH—(CH2)3—Ph

831360
17.1
S,S
1
CH

1636

1637

831361
1.75
R,R
1
CH

1638

1639

831488
0.725
R,R
1
CH

1640

1641

831489
16.9
R,R
1
CH

1642

H
—NH—(CH2)3—Ph

831491
0.187
R,R
1
N

1643

1644

831492
0.432
R,R
1
N

1645

1646

831768
0.904
R,R
1
N

1647

1648

831808
3.84
R,R
1
N

1649

1650

831809
0.0284
R,R
1
CH

1651

1652

831810
124
R,R
1
CH

1653

1654

831878
189
R,R
1
CH

1655

1656

831880
100
R,R
1
CH

1657

1658

831881
109
R,R
1
N

1659

1660

831882
57.3
R,R
1
N

1661

1662

831883
48.1
R,R
1
N

1663

1664

831884
1.94
R,R, (R,S)
1
N

1665

1666

831885
35.3
R,R
1
N

1667

1668

831886
16.8
R,R
1
N

1669

1670

831887
6.5
R,R
1
N

1671

1672

831888
17.5
R,R
1
N

1673

1674

831949
29
R,R
1
N

1675

1676

831950
5.48
R,R
1
CH

1677

1678

831952
42.8
R,R
1
CH

1679

1680

831953
37.4
R,R
1
CH

1681

1682

831958
13
R,R
1
N

1683

1684

832102
81.5
R,R
1
CH

1685

H
—NH—(CH2)3—Ph

832104
619.7
R,R
1
CH

1686

1687

832108
178
R,R
1
CH

1688

1689

832203
4.76
R,R
1
CH

1690

1691

832216
76.5
R,R,R
1
N

1692

1693

832217
44.1
R,R,S
1
N

1694

1695

832268
2.62
R,R, (R,S)
1
N

1696

1697

832271
112.29
R,R
1
CH

1698

1699

832272
144.72
R,R
1
CH

1700

1701

832273
205
R,R
1
CH

1702

1703

832274
52.4
R,R
1
CH

1704

1705

832494
25
R,R
1
N

1706

1707

832495
63.6
R,R
1
N

1708

1709

832496
3.66
R,R
1
N

1710

1711

832497
38
R,R
1
N

1712

1713

832498
70.3
R,R
1
N

1714

1715

832499
19.7
R,R
1
N

1716

1717

832500
161
R,R (R,S)
1
N

1718

1719

832501
41.4
R,R (R,S)
1
N

1720

1721

832502
2.67
R,R
1
N

1722

1723

832503
11.1
R,R (R,S)
1
N

1724

1725

832504
5.77
R,R (R,S)
1
N

1726

1727

832510
25
R,R
1
N

1728

1729

832511
12.3
R,R
1
N

1730

1731

832512
15.7
R,R
1
N

1732

1733

832577
1.85
R,R
1
N

1734

1735

832578
25.8
R,R, (R,S)
1
N

1736

1737

832759
6.29
R,R
1
N

1738

1739

832580
28.83
R,R
1
N

1740

1741

832581
67.35
R,R
1
N

1742

1743

832852
25
R,R
1
N

1744

1745

832583
1.61
R,R
1
N

1746

1747

832654
4.72
R,R
1
CH

1748

1749

832714
12.4
R,R
1
CH

1750

1751

832715
166.46
R,R
1
CH

1752

1753

832716
7.54
R,R
1
CH

1754

1755

832734
9.85
R,R
1
N

1756

1757

832735
36.8
R,R
1
N

1758

1759

832736
2.74
R,R
1
N

1760

1761

832737
5.42
R,R
1
N

1762

1763

832738
3.26
R,R
1
N

1764

1765

832739
2.89
R,R
1
N

1766

1767

832740
30.2
R,R
1
N

1768

1769

832741
6.03
R,R
1
N

1770

1771

832742
5.75
R,R
1
N

1772

1773

832743
2.36
R,R
1
N

1774

1775

832744
1.37
R,R
1
N

1776

1777

832745
15.04
R,R
1
N

1778

1779

832747ES
1.05
R,R
1
N

1780

1781

832748FH
79.07
R,R
1
N

1782

1783

832789
3.05
R,R
1
N

1784

1785

832833
18.2
R,R
1
N

1786

1787

832834
12.2
R,R
1
N

1788

1789

832835
18.1
R,R
1
N

1790

1791

832859
14.3
R,R
1
N

1792

1793

833062
55.4
R,R
1
N

1794

1795

833064
28.8
R,R, (R,S)
1
N

1796

1797

833065
692.37
R,R
1
N

1798

1799

833080
22.9
R,R
1
CH

1800

1801

833090
41.85
R,R
1
CH

1802

1803

833091
117.7
R,R
1
CH

1804

1805

833092
33.47
R,R
1
CH

1806

1807

833097
0.9
R,R,S
1
N

1808

1809

833098
8.84
R,R,R
1
N

1810

1811

833120
138
R,R
1
N

1812

1813

833121
26.5
R,R
1
N

1814

1815

833122
52.89
R,R
1
N

1816

1817

833123
26.26
R,R
1
N

1818

1819

833124
26.83
R,R
1
N

1820

1821

833125
70.76
R,R
1
N

1822

1823

833136
14.3
R,R
1
N

1824

1825

833151
11.2
R,R
1
CH

1826

1827

833157
43.88
R,R
1
CH

1828

1829

833197
45.38
R,R
1
N

1830

1831

833277
16.7
R,R
1
N

1832

1833

833278
7.04
R,R
1
N

1834

1835

833305
8.81
R,R
1
CH

1836

1837

833322
12.8
R,R
1
N

1838

1839

833323
3.46
R,R
1
N

1840

1841

833512
2.17
R,R
1
N

1842

1843

833513
43.1
R,R
1
N

1844

1845

833514
0.36
R,R
1
N

1846

1847

833515
48.3
R,R
1
N

1848

1849

833516
21.7
R,R
1
N

1850

1851

833585ES
5.86
R,R
1
CH

1852

1853

833625
22.2
R,R,R
1
N

1854

1855

833626
2.17
R,R
1
N

1856

1857

833627
1.63
R,R
1
N

1858

1859

833628
95.82
R,R
1
N

1860

1861

833629
2.69
R,R
1
N

1862

1863

833630
52.09
R,R,R
1
N

1864

1865

833631
31.3
R,R
1
N

1866

1867

833632
4.06
R,R,R
1
N

1868

1869

833686
7.22
R,R
1
CH

1870

1871

833690
7.97
R,R
1
CH

1872

1873

833692
72.9
R,R
1
CH

1874

1875

833693
18.4
R,R
1
CH

1876

1877

833694
46.9
R,R
1
CH

1878

1879

833695
176
R,R
1
CH

1880

1881

833696
268
R,R
1
CH

1882

1883

833697
105
R,R
1
CH

1884

1885

833698
134
R,R
1
CH

1886

1887

833699
7.2
R,R
1
N

1888

1889

833700
3.24
R,R
1
N

1890

1891

833701
1.28
R,R
1
N

1892

1893

833702
0.495
R,R
1
N

1894

1895

833703
1.92
R,R
1
CH

1896

1897

833704
2.3
R,R
1
N

1898

1899

833769
1.63
R,R
1
CH

1900

1901

833821
6.91
R,R
1
N

1902

1903

833822
0.64
R,R
1
N

1904

1905

833701
1.28
R,R
1
N

1906

1907

833702
0.495
R,R
1
N

1908

1909

833703
1.92
R,R
1
CH

1910

1911

833704
2.3
R,R
1
N

1912

1913

833769
1.63
R,R
1
CH

1914

1915

833821
6.91
R,R
1
N

1916

1917

833822
0.64
R,R
1
N

1918

1919

833823
0.637
R,R
1
N

1920

1921

833834
0.333
R,R
1
N

1922

1923

833835
0.499
R,R
1
N

1924

1925

833836
1.36
R,R
1
N

1926

1927

833910
1.09
R,R, (R,S)
1
CH

1928

1929

833911
1.26
R,R (R,S)
1
CH

1930

1931

833934
0.633
R,R
1
CH

1932

1933

833941
8.98
R,R
1
CH

1934

1935

834003
3.51
R,R
1
CH

1936

1937

834012
0.241
R,R
1
CH

1938

1939

834015
1.24
R,R
1
CH

1940

1941

834016
1.63
R,R
1
CH

1942

1943

834017
1.62
R,R
1
CH

1944

1945

834054
13.8
R,R
1
CH

1946

1947

834055
62
R,R
1
CH

1948

1949

834056
93.2
R,R
1
CH

1950

1951

834057
89.4
R,R
1
CH

1952

1953

834058
91.4
R,R
1
CH

1954

1955

834059
2.76
R,R
1
CH

1956

1957

834129
6.75
R,R
1
CH

1958

1959

834171
65.2
R,R
1
CH

1960

1961

834172
0.837
R,R
1
N

1962

1963

834173
5.15
R,R (R,S)
1
N

1964

1965

A002200835
0.4
R,R (R,S)
1
CH

1966

1967

A002200836
1.51
R,R
1
CH

1968

1969

A002200837
0.368
R,R
1
CH

1970

1971

A002200838
0.807
R,R
1
CH

1972

1973

A002243383
25.09
R,R
1
N

1974

1975

A002243384
133.36
R,R
1
N

1976

1977

A002287512
0.647
R,R, (R,S)
1
CH

1978

1979

A002287513
3.57
R,R
1
CH

1980

1981

A002287764
0.48
R,R
1
CH

1982

1983

A002287765
0.011
R,R
1
CH

1984

1985

A002287766
126.3
R,R,S
1
CH

1986

1987

A002328939
201.16
R,R
1
CH

1988

1989

A002328940
26.8
R,R
1
CH

1990

1991

A002328941
23.88
R,R
1
CH

1992

1993

A002329092
321.2
R,R
1
CH

1994

1995

A002329093
411.4
R,R
1
CH

1996

1997

A002329094
7.08
R,R
1
CH

1998

1999

A002329095
26.47
R,R
1
CH

2000

2001

A002329097
101.2
R,R
1
CH

2002

2003

A002329098
345.2
R,R
1
CH

2004

2005

A002329099
2.06
R,R (R,S)
1
CH

2006

2007

A002329100
6.32
R,R
1
CH

2008

2009

A- 002436288A
105.69
R,R
1
CH

2010

2011

A002437094
91.93
R,R
1
N

2012

2013

A002437350
16.2
R,R
1
N

2014

2015

A002437351
32.68
R,R
1
N

2016

2017

A002437353
0.937
R,R,S
1
CH

2018

2019

A002437354
1.03
R,R,S
1
CH

2020

2021

A002437355
1.87
R,R,S
1
CH

2022

2023

A002437357
14.03
R,R (R,S)
1
N

2024

2025

A002437358
8.858
R,R (R,S)
1
N

2026

2027

A002437359
0.541
R,R,S
1
CH

2028

2029

A002437360
0.239
R,R,S
1
CH

2030

2031

A002437517
10.51
R,R
1
CH

2032

2033

A002437802
0.251
R,R,S
1
N

2034

2035

A002438636
13.04
R,R,S
1
N

2036

2037

A002438637
21.18
R,R,R
1
N

2038

2039

A002438638
3.28
R,R,R
1
N

2040

2041

A002438639
97.32
R,R
1
CH

2042

2043

A002438663
1.37
R,R,S
1
N

2044

2045

A002438664
6.49
R,R
1
CH

2046

2047

A002439099
4.91
R,R
1
N

2048

2049

A002439100
551.94
R,R
1
N

2050

2051

A002439258
34.08
R,R
1
CH

2052

2053

A002439259
39.05
R,R
1
CH

2054

2055

A002439260
0.303
R,R,S
1
CH

2056

2057

A002439261
55.3
R,R
1
CH

2058

2059

A- 002440433A
180.18
R,R
1
CH

2060

2061

A- 002440437A
41.24
R,R
1
CH

2062

2063

A002609935
0.142
R,R,S
1
CH

2064

2065

[0903]

2066

MDL #
D3 Ki (nM)
Chirality
X
Y
R1
n
R2

827393
391
Racemic
O
CH
H
1

2067

827394
391
Racemic
O
CH
H
1

2068

827395
31.4
Racemic
O
CH
H
1

2069

827397
111
Racemic
O
CH
H
1

2070

829460
158
R,R
O
CH
H
1

2071

829461
306
R,R
O
CH
H
1

2072

829462
9.65
R,R, (R,S)
O
CH
H
1

2073

829463
4.76
Racemic
O
CH
H
1

2074

829464
22.4
R,R
O
CH
H
1

2075

829465
80.3
R,R
O
CH
H
1

2076

829466
24.8
R,R
O
CH
H
1

2077

829467
9.01
R,R
O
CH
H
1

2078

829590
109
Racemic
O
CH
H
1

2079

829591
72.4
Racemic
O
CH
H
1

2080

829592
42.3
Racemic
O
CH
H
1

2081

829593
350
Racemic
O
CH
H
1

2082

829594
364
Racemic
O
CH
H
1

2083

829595
201
Racemic
O
CH
H
1

2084

829596
4.41
R,R
O
CH
H
1

2085

829597
226
Racemic
O
CH
H
1

2086

830126
23.8
Racemate
O
N
H
2

2087

830127
1.66
Racemate
O
N
H
1

2088

830250
48.6
R,R
O
CH
H
1

2089

830251
11.4
R,R
O
CH
H
1

2090

830252
110
R,R
O
CH
H
1

2091

830827
9.85
R,R
O
CH
3-CH3
1

2092

830828
8.57
R,R
O
CH
H
1
—N—(CH2)3-Ph

830829
5.3
R,R
O
CH
H
1
—N—(CH2)2-Ph

830830
2.58
R,R
O
CH
H
1

2093

830831
3.19
R,R
O
CH
H
1

2094

830832
67.7
R,R
O
CH
H
1

2095

831045
335
R,R
O
CH
H
1

2096

831046
15.5
R,R
O
CH
H
1

2097

831047
2.87
R,R
O
CH
H
1
—N—(CH2)4-Ph

831048
11.3
R,R
O
CH
H
1
—N—(CH2)3—N(CH3)2

831082
38.2
S,S
O
N
H
1

2098

831083
3.2
R,R
O
N
H
1

2099

831192
3.44
R,R
O
CH
H
1

2100

831193
23.8
R,R
O
CH
H
1

2101

831194
5.06
R,R
O
CH
H
1

2102

831195
1.84
R1R
O
CH
H
1

2103

831196
7.81
R,R
O
CH
H
1

2104

831197
4.17
R,R
O
CH
H
1

2105

831198
1.76
R,R
O
CH
H
1

2106

831199
2.78
R,R
O
CH
H
1

2107

831215
5.92
R,R
O
CH
H
1

2108

831267
28.3
R,R
N-Ts
N
H
1

2109

831272
6.22
R,R
O
CH
H
1

2110

831273
68.6
R,R
O
CH
H
1

2111

831274
17.4
R,R
O
CH
H
1

2112

831275
5.15
R,R
O
CH
H
1

2113

831276
3.85
R,R
O
CH
H
1

2114

831277
5.38
R,R
O
CH
H
1

2115

831278
18.1
R,R
O
CH
H
1

2116

831315
29.3
R,R
NH
N
H
1

2117

831343
13.7
R,R
O
CH
H
1

2118

831344
22.1
R,R
O
CH
H
1

2119

831345
34.4
R,R
O
CH
H
1

2120

831374
1.12
R,R
O
CH
CH3
1

2121

831375
2.9
R,R
O
CH
CH3
1
—N—(CH2)3-Ph

831376
40.3
R,R
O
CH
H
1

2122

831377
4.68
R,R
O
CH
H
1

2123

831378
35.6
R,R
O
CH
H
1

2124

831379
46.7
R,R
O
CH
H
1

2125

831385
22.7
Racemic
O
CH
H
1

2126

831390
0.861
Racemic
O
CH
H
1

2127

831453
18.3
Racemic
O
CH
H
1

2128

831454
1.86
Racemic
O
CH
H
1

2129

831455
6.79
Racemic
O
CH
H
1

2130

831456
6.21
Racemic
O
CH
H
1

2131

831457
1.83
Racemic
O
CH
H
1

2132

831458
7.43
Racemic
O
CH
H
1

2133

831493
4.95
R,R
O
N
H
1

2134

831494
28.3
R,R
O
N
H
1
—N—(CH2)3-Ph

831599
49.8
Racemic
O
CH
H
1

2135

831602
19.6
Racemic
O
CH
H
1

2136

831603
20.9
Racemic
O
CH
H
1

2137

831621
70.3
Racemic
O
CH
H
1

2138

831622
34.6
Racemic
O
CH
H
1

2139

831649
173
Racemic
O
CH
H
1

2140

831673
23.5
Racemic
N-Me
N
H
1

2141

831686
25.3
Racemic
O
CH
H
1

2142

831687
277
Racemic
O
CH
H
1

2143

831689
16.4
Racemic
O
CH
H
1

2144

831701
55.7
Racemic
O
CH
H
1

2145

831702
27.9
Racemic
O
CH
H
1

2146

831703
45
Racemic
O
CH
H
1

2147

831704
47.5
Racemic
O
CH
H
1

2148

831735
81.3
Racemic
O
CH
H
1

2149

831736
291
Racemic
O
CH
H
1

2150

831737
1.25
Racemic
O
CH
H
1

2151

831738
223
Racemic
O
CH
H
1

2152

831740
2.96
Racemic
O
CH
H
1

2153

831741
125
Racemic
O
CH
H
1

2154

831794
27.3
Racemic
O
CH
H
1

2155

831795
1.82
Racemic
Q
CH
H
1

2156

831798
46.3
Racemic
O
CH
H
1

2157

831799
12.1
Racemic
O
CH
H
1

2158

831800
5
Racemic
O
CH
H
1

2159

831801
11.2
Racemic
O
CH
H
1

2160

831802
13.4
Racemic
O
CH
H
1

2161

831803
7.44
Racemic
O
CH
H
1

2162

831804
9.89
Racemic
O
CH
H
1

2163

831805
10.2
Racemic
O
CH
H
1

2164

831818
0.117
Racemic
O
CH
H
1

2165

831819
0.1
Racemic
O
CH
H
1

2166

831820
6.54
Racemic
O
CH
H
1

2167

831821
24.1
Racemic
O
CH
H
1

2168

831822
1.38
Racemic
O
CH
H
1

2169

831823
2.37
Racemic
O
CH
H
1

2170

831830
0.76
R,R
N-Me
N
H
1

2171

831831
6.31
Racemic
O
CH
H
1

2172

831835
234
Racemic
O
CH
H
1

2173

831836
94.3
Racemic
O
CH
H
1

2174

831837
491
Racemic
O
CH
H
1

2175

831838
141
Racemic
O
CH
H
1

2176

831936
34.7
R,R, (R,S)
O
CH
H
1

2177

831937
35
R,R
O
CH
H
1

2178

831938
33
R,R
O
CH
H
1

2179

831951
36.7
R,R
N-Ts
N
H
1

2180

831954
15.6
R,R
O
CH
CH3
1

2181

831955
47.3
R,R
O
N
H
1

2182

831956DA
5.91
R,R
N-Me
N
H
1

2183

831957
63.2
R,R
O
CH
H
1

2184

831991
0.722
Racemic
O
CH
H
1

2185

831992
4.81
Racemic
O
CH
H
1

2186

831993
2.51
Racemic
O
CH
H
1

2187

831994
2.68
Racemic
O
CH
H
1

2188

831995
4.73
Racemic
O
CH
H
1

2189

831996
7.97
Racemic
O
CH
H
1

2190

831997
3.55
Racemic
O
CH
H
1

2191

831998
7.46
Racemic
O
CH
H
1

2192

831999
473
Racemic
O
CH
H
1

2193

832000
79.6
Racemic
O
CH
H
1

2194

832001
157
Racemic
O
CH
H
1

2195

832044
657
Racemic
O
CH
H
1

2196

832045
22
Racemic
O
CH
H
1

2197

832046
35.5
Racemic
O
CH
H
1

2198

832047
25.8
Racemic
O
CH
H
1

2199

832049
6.54
Racemic
O
CH
H
1

2200

832055
112
Racemic
O
CH
H
1

2201

832057
21.7
Racemic
O
CH
H
1

2202

832058
24.2
Racemic
O
CH
H
1

2203

832059
4.13
Racemic
O
CH
H
1

2204

832153
30.74
Racemic
O
CH
H
1

2205

832154
21.86
Racemic
O
CH
H
1

2206

832155
0.434
Racemic
O
CH
H
1

2207

832156
0.315
Racemic
O
CH
H
1

2208

832157
0.226
Racemic
O
CH
H
1

2209

832158
0.37
Racemic
O
CH
H
1

2210

832164
6.6
Racemic
O
CH
H
1

2211

832165
30.13
Racemic
O
CH
H
1

2212

832185
7.87
Racemic
O
CH
H
1

2213

832186
16.06
Racemic
O
CH
H
1

2214

832187
19.14
Racemic
O
CH
H
1

2215

832188
10.1
Racemic
O
CH
H
1

2216

832189
58.47
Racemic
O
CH
H
1

2217

832190
94.61
Racemic
O
CH
H
1

2218

832191
8.06
Racemic
O
CH
H
1

2219

832192
7.81
Racemic
O
CH
H
1

2220

832193
13.1
Racemic
O
CH
H
1

2221

832194
23
Racemic
O
CH
H
1

2222

832195
22.8
Racemic
O
CH
H
1

2223

832196
22.9
Racemic
O
CH
H
1

2224

832197
17.1
Racemic
O
CH
H
1

2225

832198
5.81
Racemic
O
CH
H
1

2226

832199
18.7
Racemic
O
CH
H
1

2227

832207
54.84
R,R
N-Me
N
H
1

2228

832269
5.1
R,R, (R,S)
O
CH
H
1

2229

832340
11.54
Racemic
O
CH
H
1

2230

832341
2.63
Racemic
O
CH
H
1

2231

832342
0.077
Racemic
O
CH
H
1

2232

832343
0.718
Racemic
O
CH
H
1

2233

832344
2.76
Racemic
O
CH
H
1

2234

832345
1.46
Racemic
O
CH
H
1

2235

832346
12.88
Racemic
O
CH
H
1

2236

832347
1.88
Racemic
O
CH
H
1

2237

832348
0.465
Racemic
O
CH
H
1

2238

832349
0.843
Racemic
O
CH
H
1

2239

832391
77.93
Racemic
O
CH
H
1

2240

832392
2.29
Racemic
O
CH
H
1

2241

832393
8.44
Racemic
O
CH
H
1

2242

832394
8.32
Racemic
O
CH
H
1

2243

832395
30.2
Racemic
O
CH
H
1

2244

832397
51.94
Racemic
O
CH
H
1

2245

832464
12.8
Racemic
O
CH
H
1

2246

832487
66.1
Racemic
O
CH
H
1

2247

832488
39.5
Racemic
O
CH
H
1

2248

832489
95
Racemic
O
CH
H
1

2249

832505
40.6
Racemic
O
CH
H
1

2250

832513
55.4
R,R (Isomer 1)
O
CH
H
1

2251

832514
114.6
S,S, (Isomer 2)
O
CH
H
1

2252

832527
45.4
R,R
O
CH
H
1

2253

832528
48.5
R,R
O
CH
H
1

2254

832529
145.6
R,R
O
CH
H
1

2255

832530
16
R,R
O
CH
H
1

2256

832531
67.67
R,R
O
CH
H
1

2257

832532
14.4
R,R
O
CH
H
1

2258

832533
4.12
R,R, (R,S)
O
CH
H
1

2259

832565
1.45
R,R

2260

N
H
1

2261

832566
1.76
R,R

2262

N
H
1

2263

832573FH
4.52
Racemic
O
CH
H
1

2264

832574FH
57.34
R,R
O
CH
H
1

2265

832575ES
4.06
Racemic
O
CH
H
1

2266

832576ES
17.5
Racemic
O
CH
H
1

2267

832634
7.63
R,R

2268

N
H
1

2269

832648
20.8
R,R

2270

N
H
1

2271

832692
7.29
R,R
N-Ph
N
H
1

2272

832723
54
R,R
O
CH
H
1

2273

832724
1.44
R,R
O
CH
H
1

2274

832725
4.22
R,R
O
CH
H
1

2275

832726
7.05
R,R
O
CH
H
1

2276

832727
1.19
R,R
O
CH
H
1

2277

832728
3.12
R,R
O
CH
H
1

2278

832729
1.67
R,R
O
CH
H
1

2279

832730
3.62
R,R
O
CH
H
1

2280

832731
0.699
R,R
O
CH
H
1

2281

832732
0.74
R,R
O
CH
H
1

2282

832733
0.656
R,R
O
CH
H
1

2283

832788
1.84
R,R
O
CH
H
1

2284

832816
2.57
R,R
N-Ph
N
H
1

2285

832849
1.12
R,R
N-Ph
N
H
1

2286

832850
0.264
R,R

2287

N
H
1

2288

832881
37.86
R,R

2289

N
H
1

2290

833333
8.11
R,R

2291

N
H
1

2292

833372
1.04
Racemic
O
CH
H
1

2293

833373
65.46
R,R,S
O
CH
H
1

2294

833374
30.6
R,R (R,S)
O
CH
H
1

2295

833375
24.2
R,R
O
CH
H
1

2296

833382
2.32
R,R
O
CH
H
1

2297

833383
2.57
R,R
O
CH
H
1

2298

833384
5.68
R,R,R
O
CH
H
1

2299

833385
3.31
R,R (R,S)
O
CH
H
1

2300

833386
36.46
R,R
O
CH
H
1

2301

833482
0.962
R,R
O
CH
H
1

2302

833483
0.93
R,R
O
CH
H
1

2303

833485
2.99
R,R
O
CH
H
1

2304

833509
41.53
R,R
O
CH
H
1

2305

833714
4.16
R,R
O
CH
H
1

2306

833715
5.7
R,R
O
CH
H
1

2307

833748
1.38
R,R
O
CH
H
1

2308

833855
12.4
R,R

2309

N
H
1

2310

833856
3.01
R,R

2311

N
H
1

2312

833876
50.3
R,R

2313

N
H
1

2314

833909
1.86
R,R
N-Ph
CH
H
1

2315

834205
90.47
R,R

2316

N
H
1

2317

834206
88.82
R,R

2318

N
H
1

2319

834207
71.4
R,R

2320

N
H
1

2321

A002201942
30.2
R,R

2322

N
H
1

2323

A002202401
205.3
R,R
N—(CH2)3—CH3
N
H
1

2324

A002202402
47.33
R,R
N-Me
N
H
1

2325

A002202403
86.78
R,R
N-Me
N
H
1

2326

A002243385
660.86
R,R

2327

N
H
1

2328

A002243404
492.34
R,R

2329

N
H
1

2330

A002287757
2.41
R,R
N-Me
N
H
1

2331

A002287758
139.32
R,R

2332

N
H
1

2333

A002287767
3.3
R,R
N—CH2—CF3
CH
H
1

2334

A002328969
137.1
R,R
N—CH2—CF3
CH
H
1

2335

A002328970
36.2
R,R
N—CH2—CF3
CH
H
1

2336

A002329040
159.9
R,R
N-Me
N
H
1

2337

A002350369
100.28
R,R
N-Me
N
H
1

2338

A002350370
81.25
R,R
N-Me
N
H
1

2339

A002436290
520.47
R,R
N-Me
CH
H
1

2340

A002436291
0.629
R,R
N-Me
CH
H
1

2341

A002436292
128.56
R,R
N-Me
CH
H
1

2342

A002436428
2.17
R,R
N-Me
N
H
1

2343

A002436429
4.16
R,R
N-Me
N
H
1

2344

A002437082
9.23
R,R

2345

N
H
1

2346

A002437083
11.03
R,R

2347

N
H
1

2348

A002437084
7.105
R,R

2349

N
H
1

2350

A002437352
1.22
R,R,S
N-Me
CH
H
1

2351

A002438640
104.16
R,R
N-Me
CH
H
1

2352

A002438641
62.76
R,R
N-Me
CH
H
1

2353

A002439262
28.3
R,R
N-Ph
CH
H
1

2354

A002439263
30.6
R,R
N-Ph
CH
H
1

2355

A002439265
87.98
R,R
N—CH2—CF3
CH
H
1

2356

A002439266
66.04
R,R
N—CH2—CF3
CH
H
1

2357

A002440434A
462.13
R,R
N-Me
CH
H
1

2358

A002440435A
304.55
R,R
N—CH2—CF3
CH
H
1

2359

A002440436A
11.38
R,R
N-Ph
CH
H
1

2360

833127
79.63
R,R
O
CH
H
1

2361

833128
28.69
R,R
O
CH
H
1

2362

833129
95.34
R,R
O
CH
H
1

2363

833130
8.85
R,R
O
CH
H
1

2364

833131
16.8
R,R
O
CH
H
1

2365

833132
107.5
R,R
O
CH
H
1

2366

833133
113.7
R,R
O
CH
H
1

2367

833160
2.09
R,R
O
CH
H
1

2368

833163
17.5
R,R
O
CH
H
1

2369

833164
52.55
R,R
O
CH
H
1

2370

833165
1.07
R,R
O
CH
H
1

2371

833166
1.72
R,R
O
CH
H
1

2372

833167
1.57
R,R
O
CH
H
1

2373

833168
3.11
R,R
O
CH
H
1

2374

834126
4.9
R,R
N-Bn
N
H
1

2375

[0904]

2376

(All Compounds Racemic)

MDL #
D3 Ki (nM)
R

831452
115
Bn

831811
819

2377

831812
453

2378

[0905]

2379

MDL #
D3 KI (nM)
Chirality
n
X
Ar

829997
10.4
Racemic
2
N

2380

829830
65.3
Racemic
1
CH

2381

829996
277
Racemic
1
N

2382

830000
286
Racemic
2
N

2383

[0906]

2384

MDL #
D3 KI (nM)
Chirality
X
Y
R1
R2

830557
97.4
S
CH
O
OH

2385

830558
34.2
R
CH
O
OH

2386

830573
547
R
CH
O
OH

2387

832212
301.8
n.a.
N
O
H

2388

A002201941
119
n.a.
N
N—CH3
H

2389

[0907]

2390

MDL #
D3 KI (nM)
X
Ar
R

832171
4.9
CH

2391

2392

832180
91
CH

2393

—NH—(CH2)2-Ph

832231
6.93
N

2394

2395

832239
206.8
CH

2396

2397

832240
185.96
CH

2398

2399

832241A
51.8
CH

2400

2401

832242A
436.2
CH

2402

2403

832317
943
CH

2404

2405

832517
172.58
N

2406

2407

832518
98.2
N

2408

2409

832519
97.51
N

2410

—NH—(CH2)2-Ph

832520
140.93
N

2411

2412

833330
72.69
CH

2413

2414

833365
166.4
CH

2415

2416

833378
23.7
CH

2417

2418

833475
22.45
N

2419

2420

833476
131.37
CH

2421

2422

[0908]

2423

MDL #
D3 KI (nM)
Chirality
Ar

832831DA
153.74
Racemic

2424

833953A
88.82
Racemic

2425

[0909]

2426

MDL #
D3 KI (nM)
Chirality
X
R

830115
45.3
Racemic
H
Me

830130
6.68
Racemic
F
Et

	Number	Date	Country
Parent	10078225	Feb 2002	US
Child	10819037	Apr 2004	US

Novel heterocyclic substituted carbonyl derivatives and their use as dopamine D3 receptor

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Priority Claims (1)

Provisional Applications (1)

Continuations (1)