TITLE QF THE INVENTION

PIPERAZINYL (SULFONYL)AMIDE DERIVATIVES OF CAMPHOR AS OXYTOCIN ANTAGONISTS

FIELD OF THE INVENTION

The present invention provides novel compounds, novel compositions, methods of their use and methods of their . manufacture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy. The aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Cesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.

BACKGROUND OF THE INVENTION In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.

Tocolytic (uterine-relaxing) agents that are currently in use include B2-adrenergic agonists, magnesium sulfate and ethanol. Ritodrine, the leading B2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other B2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can

cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, 5 but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.

It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has accumulated to strongly suggest that the hormone o oxytocin is the physiological initiator of labor in several mammalian species including humans. Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium-and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium decidua. 5 These prostaglandins may, in addition, be important in the cervical ripening process. By these mechanisms, the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This ° "up-regulation" of oxytocin receptors and enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus. A ⁵ selective oxytocin blocker, or antagonist, would likely be more efficacious for treating preterm labor than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few, if any, side effects. ° The compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By

blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antago- nist can be more efficacious for treating dysmenorrhea then current regimens. An additional use for the present invention is for the stoppage of labor preparatory to Cesarean delivery.

It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in animals, preferably mammals, especially in humans. It is another purpose of this invention to prepare novel compounds which more selectively inhibit oxytocin. It is still another purpose of this invention to provide a method of antagonizing the functions of oxytocin in disease states in mammals. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dysmenorrhea by antagonizing oxytocin.

It has now been found that compounds of formula I are antagonists of oxytocin and bind to the oxytocin receptor. When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects. These compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Cesarean delivery.

SUMMARY OF THE INVENTION

The compounds of the present invention are those of the general structural formula:

or the pharmaceutically acceptable salts thereof, wherein

X is

(l) C or

<2) N;

Y is (1) carbonyl or (2) sulfonyl;

Zis an optional substituent that, when present, is substituted or unsubstituted alkyl where said substituent is carboxyl;

Rl is

(1) hydrogen,

(2) alkyl or (3) NH;

R2 is hydrogen;

R! and R^ together are bridged alkyl of three or four methylenes so as to form either

or , respectively;

R3 and R4 are independently one or more of

(1) hydrogen,

(2) halogen,

(3) alkylsulfonyl, (4) alkoxy or

(5) unsubstituted or substituted alkyl wherein said substituent is hydroxyl, alkoxyl, alkylsulfonyl, amino, alkylamino or dialkylamino;

R-5 and R6 are independently one or more of (1) hydrogen,

(2) alkyl,

(3) substituted alkyl where said substituent is amino, hydroxyl, alkoxyl, alkylsulfonyl, arylsulfonyl, alkylamino or dialkylamino,

(4) phenylalkyl or (5) oxo; ^•

R7 and R^ are independently one or more of

(1) hydrogen,

(2) alkyl or (3) joined together to form unsubstituted or substituted cycloalkyl where said substituent is hydroxy or hydroxyalkyl;

R9 and RlO are together joined to form cyclic epoxide of the sort

R9 and RlO are independently one or more of

(1) hydrogen,

(2) hydroxyl,

(3) halogen,

(4) oximino,

(5) methyl,

(6) carboxyl,

(7) oxo,

(8) alkoxycarbonyl,

(9) alkylcarbonyloxy,

(10) alkoxycarbonylalkoxy,

(11) trihaloalkylsulfonyloxo,

(12) unsubstituted or substituted amino where said substituent is one or more of alkyl, carboxyalkyl or alkoxycarbonylalkyl;

Rl 1, which is bonded to substituent Z when Z is present or which is bonded directly to the camphor ring when Z is not present, is defined as

(1) hydrogen,

(2) -N(Rl2)_C0-Rl3 ₀ r (3) -CO-N(R14)-R15 _;

Rl2 is

(1) hydrogen,

(2) alkoxy, (3) substituted or unsubstituted alkyl where said substituent is one or more of carboxyl, hydroxyl, alkoxyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl,

(4) alkoxycarbonyl or

(5) alkoxycarbonylamino;

Rl3 is

(1) hydrogen,

(2) alkoxyl,

(3) aralkoxyl, (4) carboxyl,

(5) alkoxycarbonyl,

(6) a__koxycarbonylamino,

(7) unsubstituted or substituted cycloalkyl, wherein said substituent is carboxyl,

(8) unsubstituted or substituted phenyl wherein said substituent is one or more of carboxyl, carboxyalkyl or SO3H,

(9) unsubstituted or substituted amino, wherein said substituent is unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, alkylsulfonyl or unsubstituted 5-membered heterocyclic rings having 1 or 2 heteroatoms, where said heteroatom is N,

(10) heterocyclic rings selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyaralkyl, aralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyano, alkylsulfonyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted amino wherein said substituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or

(11) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyalkylphenyl, cyano, sulfate, alkylsulfonyl, acetamidine, formamidine, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or substituted amino, wherein said substituent is one or more of alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiapyranyl, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, sulfate, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted alkylcarbonyl, where said substituent is a 5- membered heterocyclic ring having 1 or 2 heteroatoms and where said hetero atom is N, Cyc is defined as substituted or unsubstituted cycloalkyl wherein said substituent is selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het is

defined as heterocyclic rings selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, phenyl, aralkoxycarbonyl, oxo, SO3H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl;

R14 anrj. R15 r independently

(1) hydrogen,

(2) unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, anύnoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N or

(3) heterocyclic rings selected from the group consisting of unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S and wherein said substituent is one or more of alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; and m and n are integers of from 0 to 1.

More particularly preferred compounds are those of the general structural formula:

or the pharmaceutically acceptable salts thereof, wherein

X is (1) C or

(2) N;

Y is

(1) carbonyl or

(2) sulfonyl;

Z is an optional substituent that, when present, is substituted or unsubstituted alkyl where said substituent is carboxyl;

Rl is

(1) hydrogen,

(2) alkyl or

(3) NH;

R2 is hydrogen;

Rl and R2 together are bridged alkyl of three or four methylenes;

R3 and R4 are independently one or more of

(1) hydrogen,

(2) halogen,

(3) alkylsulfonyl,

(4) alkoxy or

(5) unsubstituted or substituted alkyl wherein said substituent is amino, alkylamino or dialkylamino;

R-5 and R6 are independently one or more of

(1) hydrogen,

(2) alkyl,

(3) substituted alkyl where said substituent is amino, alkylsulfonyl, arylsulfonyl, alkylamino or dialkylamino,

(4) phenylalkyl or

(5) oxo;

R? and R& are independently one or more of (1) hydrogen,

(2) alkyl, or

(3) joined together to form unsubstituted or substituted cycloalkyl where said substituent is hydroxy or hydroxyalkyl;

R9 and RlO are together joined to form cyclic epoxide;

R9 and RlO are independently one or more of

(1) hydrogen,

(2) hydroxyl, (3) halogen,

(4) oximino,

(5) methyl,

(6) carboxyl,

(7) oxo, (8) alkoxycarbonyl,

(9) alkylcarbonyloxy,

(10) alkoxycarbonylalkoxy,

(11) sulfonyloxo,

(12) trihaloalkylsulfbnyloxo,

(13) unsubstituted or substituted amino where said substituent is alkoxycarbonylalkyl ;

Rll is (1) hydrogen,

(2) -N(Rl2)-CO-Rl3 or (3) -CO-N(Rl4)-Rl5;

Rl2 i _s o (1) hydrogen,

(2) alkoxycarbonylamino,

(3) alkyl or

(4) alkylsulfonylalkyl;

s Rl3 i _s

(1) hydrogen,

(2) alkoxyl,

(3) aralkoxyl,

(5) alkoxycarbonyl, ⁰ (6) alkoxycarbonylamino,

(7) unsubstituted or substituted cycloalkyl, wherein said substituent is carboxyl,

(8) unsubstituted or substituted phenyl wherein said substituent is one or more of carboxyl, carboxyalkyl or SO3H, ⁵ (9) unsubstituted or substituted amino, wherein said substituent is unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, alkylsulfonyl or unsubstituted 5-membered heterocyclic rings having 1 or 2 heteroatoms, where said heteroatom is N, (10) heterocyclic rings selected from the group consisting of: ° unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1 , 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl,

carboxyalkyl, carboxyaralkyl, aralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyano, alkylsulfonyl, alkoxyc∑ubonylaminoalkylcarbonyl, oxo or unsubstituted or substituted amino wherein said substituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or

(11) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyalkylphenyl, cyano, sulfate, alkylsulfonyl, acetamidine, formamidine, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or substituted amino, wherein said substituent is one or more of alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiapyranyl, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, sulfate, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted alkylcarbonyl, where said substituent is a 5- membered heterocyclic ring having 1 or 2 heteroatoms and where said hetero atom is N, Cyc is defined as substituted or unsubstituted cycloalkyl wherein said substituent is selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het is defined as heterocyclic rings selected from the group consisting of unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, phenyl, aralkoxycarbonyl, oxo, SO3H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl;

Rl4 and R 15 are independently

(1) hydrogen,

(2) unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, aminoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alkylsulfinyl, alkylsufjonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N or (3) heterocyclic rings selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 total members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 total members and 1 or 2 O heteroatoms; having 5 or 6 total members and 1 S heteroatom; or having 6 total members and 2 different heteroatoms from the group consisting of N, O or S and wherein said substituent is one or more of alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; and m and n are integers of from 0 to 1.

Most preferred are those compounds of the general foπnulae

or the pharmaceutically acceptable salts thereof, wherein

Rl is

(1) hydrogen,

(2) alkoxycarbonyl or

(3) alkyl;

R ² is

(1) hydrogen,

(2) alkoxyl,

(3) aralkoxyl,

(4) alkoxycarbonyl,

(5) alkoxycarbonylamino,

(6) unsubstituted or substituted cycloalkyl, wherein said substituent is carboxyl,

(7) unsubstituted or substituted phenyl wherein said substituent is one or more of carboxyl, carboxyalkyl or SO3H,

(8) unsubstituted or substituted amino, wherein said substituent is unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, alkylsulfonyl or unsubstituted 5-membered heterocyclic rings having 1 or 2 heteroatoms, where said heteroatom is N,

(9) unsubstituted or substituted rings of the formulae

where said substituents are one or more of alkyl, carboxyl, carboxyalkyl, carboxyaralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted amino wherein said substituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or

(10) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or substituted amino, wherein said substituent is one or more of alkyl, alkylcarbonyl, alfylsulfonyl, carboxyalkyl, Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted alkylcarbonyl, where said substituent is a 5- membered heterocyclic ring having 1 or 2 heteroatoms and where said hetero atom is N, Cyc is defined as substituted or unsubstituted cycloalkyl wherein said substituent is selected from alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl and Het is defined as unsubstituted or substituted rings of the formulae

^{L IJ} / _N / ^J

where said substituent is one or more of alkyl, amino, carboxyl, carboxyalkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxycarbonyl, oxo, SO3H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl . Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts ofthe compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:

Acetate Lactobionate

Benzenesulfonate Laurate Benzoate Malate Bicarbonate Maleate Bisulfate Mandelate Bitartrate Mesylate Borate Methylbromide Bromide Methylnitrate Calcium Edetate Methylsulfate Camsylate Mucate Carbonate Napsylate Chloride Nitrate 'Clavulanate N-methylglucamine Citrate ammonium salt

Dihydrochloride Oleate Edetate Oxalate Edisylate Pamoate (Embonate) Estolate Palmitate Esylate Pantothenate Fumarate Phosphate/diphosphate Gluceptate Polygalacturonate Gluconate Salicylate Glutamate Stearate Glycollylarsanilate Sulfate Hexylresorcinate Subacetate Hydrabamine Succinate Hydrobromide Tannate Hydrochloride Tartrate Hydroxynaphthoate Teoclate Iodide Tosylate Isothionate Triethiodide Lactate Valerate

The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the

biological or medical response of a tissue, system, ammal or human that is being sought by a researcher or clinician.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range. The term "alkenyl" shall mean straight or branched chain alkenes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.

The term "alkynyl" shall mean straight or branched chain alkynes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range. The term ""aryl" shall mean phenyl, naphthyl or fluorenyl. The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms.

The term "trihaloalkylsulfonyloxo" shall mean the substituent

O

Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl" and "aryl". Designated numbers of carbon atoms (e.g. Ci_iθ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The term "oxo" shall refer to the substituent =0.

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The term "preterm labor" shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.

The term "dysmenorrhea" shall mean painful menstruation.

The term "cesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus. The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.

Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent o moieties, singly or plurally.

The ability of the compounds of formula I to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein oxytocin may be s involved. Examples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery. Because of the known relationship of vasopressin to oxytocin, the compounds of the present invention are also useful as ⁰ vasopressin antagonists. Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their use as diuretics and their use in congestive heart failure.

The compounds of the present invention can be ⁵ administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, ° subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors

including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily deteπnine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.3-6.0 gm/day orally. Intravenously, the most preferred doses will range from 0.1 to about 10 mg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be aclministered-in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen. In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral aα inistration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incoφorated into the mixture. Suitable

binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these

5 dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.

The compounds of the present invention can also be i o administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines .

¹⁵ Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can ⁰ include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamide-phenol, polyhydroxyerhylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be ⁵ coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block ° copolymers of hydrogels .

The compounds of formula I can be prepared readily according to the following reaction Schemes (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make

use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These

5 compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art i o will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.

5

0

5

0

SCHEME1

WhereWisa suitable leaving group

π

30

\_

SCHEME 2

SCHEME 3

SCHEME 4

SCHEME 5

SCHEME6

SCHEME 7

SCHEME 8

Abbreviations used in the Examples are as follows:

TEA = triethylamine

DIEA = diisopropylethylamine

BOP = benzotriazolyloxytris(dimethylamino) . phosphonium hexafluorophosphate

THF = tetrahydrofuran

DMF = dimethylformamide

LAH = lithium aluminum hydride

TFA = trifluoroacetic acid

HPLC Method A = 15 min. linear gradient

95:5 A:B to 0:100 A:B A - H20 containing 0.1 % by vol. TFA B = CH3CN containing 0.1% by vol. TFA 2.0 mL/min flow rate 12 cm Ci8 reverse phase column UV detection (215 nm) TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.

EXAMPLE 1

1 -((7,7-Dimethyl-2-oxo-bicyclo(2.2. l)heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred, 0°C solution of l-(o-tolyl) piperazine hydrochloride (50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) was added (+)-10-camphorsulfbnyl chloride (65.5 g; 260 mmol). The solution was stirred at 0°C for 1 h and then at ambient temperature for 3 h. The solution was extracted with 5% aqueous HCl (2 x 500 mL), water (500 mL), and saturated aqueous NaHC03 (2 x 500 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from methanol to give the title compound, mp 112-114°C (69 g; 75%).

Anal: (C21H30N2O3S) calc: C, 64.57; H, 7.74; N, 7.17 found: C, 64.52; H, 7.68; N, 6.99

TLC: Rf 0.49 (75:25 hexane/ethyl acetate)

HPLC (method A): retention time 10.33 min

FAB MS: m/z 391 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.2 (m, 2H), 7.0 (m, 2H), 3.45 (m,

4H), 3.40 (d, J=16 Hz, IH), 3.0 (m, 4H), 2.57 (m, IH), 2.40 (dt,

Jd=14 Hz, Jt=3 Hz, IH), 2.30 (s, 3H), 2.10 (m, 2H), 1.96 (d, J=14

Hz, IH), 1.67 (m, IH), 1.44 (m, IH), 1.18 (s, 3H), 0.91 (s, 3H)

EXAMPLE 2

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-(l -cyano)ethyl- bicyclo(2.2.1 )-heptan- 1 -yl)methanesulfonyl)-4-(2- methylphenyPpiperazine

To a stirred, -78°C solution of diisopropylamine (21.0 mL; 150 mmol) in THF (350 mL) was added n-butyllithium (60 mL of a 2.5 M solution in hexane; 150 mmol). The solution was warmed to 0°C for 15 min, then cooled to -78°C. A solution of propionitrile (10.1 mL; 141 mmol) in THF (75 mL) was added dropwise, and the resulting solution was stirred at -78°C for 45 min. A -78°C solution of l-((7,7- dimethyl-2-oxo- bicyclo(2.2.1)heptan-l-yl)methane- sulfonyl)-4-(2- methylphenyl)piperazine (50.0 g; 128 mmol) in THF (350 mL) was added via cannula, and the resulting solution was stirred at -78°C for 5 min. A solution of 5:1 THF/water (100 mL) was added and the mixture was warmed to ambient temperature. The mixture was diluted with EtOAc (500 mL) and washed with 5% aqueous citric acid (2 x 500 mL), and brine (250 mL). The organic phase was dried (MgSθ4), filtered, and the solvents were removed under reduced pressure to give a foam. The major isomer by TLC was obtained by crystallization from ether, mp 163-165°C.

Anal: (C24H35N3O3S) calc. C, 64.69; H, 7.92; N, 9.43

found C, 64.72; H, 7.99; N, 9.35

TLC: Rf 0.31 (75:25 hexane/ethyl acetate) HPLC (method A): retention time 10.20 min FAB MS: m/z 446 (M+ + H) lHNMR (300 MHz, CDCl3): d 7.19 (m, 2H), 3.70 (d, J=15 Hz, IH), 3.68 (s, IH), 3.49 (m, 4 H), 3.38 (d, J=15 Hz, H), 2.75 (q, J=7 Hz, IH), 2.30 (s, 2H), 2.05 (m, 2H), 1.7-1.9 (m, 3H), 1.47 (d, J=7 Hz, 3H), 1.41 (d, J=12 Hz, IH), 1.40 (s, 3H), 1.15 (s, 3H), 1.04 (m, IH)

EXAMPLE 3

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -amino)-propyl- bicyclo(2.2.1)hept -l-yl)memanesulfonyl)-4-2- methylphenyPpiperazine

To a stirred, -78°C solution of l-((7,7- dimethyl-2- exo-hydroxy-2-endo-(l -cyano)ethyl-(2.2.1 ) bicycloheptan- 1 - yl)memanesulfonyl)-4-(2-memyIphenyl)piperazine (25.0 g; 56.2 mmol) in THF (350 mL) was added dropwise a 1.0 M solution of LAH in THF (170 mL; 170 mmol). The resulting solution was stirred at -78°C for 1 h, and then warmed to 0°C for 3 h. Ether (300 mL) was added, followed by the slow drop- wise addition of 5 M NaOH solution (35 mL). The resulting suspension was warmed

to ambient tempera- ture and stirred for 1 h. EtOAc (250 mL) was added and stirring was continued for 30 min. The solids were removed by filtration through Celite and washed with EtOAc. The filtrate sovents were removed under reduced pressure to give a foam. The title compound was obtained by crystallization from methanol (17.2 g; 68%), mp 172-174°C. Anal: (C24H39N3O3S) calc. C, 64.11; H, 8.74; N, 9.35 found C, 64.09; H, 8.88; N, 9.31 TLC: Rf 0.50 (95:5:0.5 CHCl3/MeOH/NH4θH)

HPLC (method A): retention time 9.80 min

FAB MS: m/z 450 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.20 (m, 2H), 7.05 (m, 2H), 2.32

(s, 3H), 1.13 (d, J=6 Hz, 3H), 1.11 (s, 3H), 1.02 (s, 3H)

EXAMPLE 4

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(l-prolyl)- amino)propyl-bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- methylphenylVpiperazine ,

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -amino) propyl-(2.2.1 )bicycloheptan- 1 - yl)methanesulfonyl)- 4-(2-methylphenyl)piperazine (2.00 g; 4.45 mmol) in DMF (30 mL) was added N ^a -Fmoc-L-proline (1.58 g;

4.68 mmol), BOP (2.17 g; 4.90 mmol), and DIEA (1.71 mL; 9.80 mmol). After 16 h, diethylamine (6 mL) was added and the solution was stirred at ambient tempera- ture for 3 h. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C29H46N4O4S) calc. C, 52.48; H, 6.50; N, 7.56 found C, 52.46; H, 6.50; N, 7.69

1.7 TFA, 0.05 H2O

TLC: Rf = 0.45 (90:10:1 CHCl3:MeOH:NH40H) HPLC (method A): retention time 8.60 min FAB MS: m/z 547 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.55 (br t, IH), 7.18 (m, 2H), 7.03 (m, 2H), 2.31 (s, 3H), 1.14 (s, 3H), 1.02 (s, 3H), 0.99 (d, J=7 Hz, 3H)

EXAMPLE 5

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(l-n- (ethoxycarbonyl-propyl)prolyl)amino)propyl-bicyclo(2.2.1 )heptan- l-yl)methanesulfonyl)-4- f2-methylphenyDpiperazine

To a stirred solution of l-((7,7- dimethyl-2-exo- hydroxy-2-endo-2-(l *-(L-prolyl)amino) propyl- (2.2.1 )bicycloheptan- 1 -yl)methane-sulf onyl)-4- (2- methylphenyl)piperazine (1.50 g; FW=679; 2.21 mmol) in DMF (15 mL) was added ethyl 4-bromobutyrate (538 mg; 2.76 mmol), and DIEA (1.15 mL; 6.63 mmol). After 72 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C35H56N4O6S) calc. C, 51.99; H, 6.48; N, 6.17 found C, 52.01; H, 6.33; N, 6.17 2.1 TFA, 0.1 H20

TLC: Rf = 0.40 (95:5 CHCl3:MeOH) HPLC (method A): retention time 10.23 min FAB MS: m/z 661 (M+ + H) iH NMR (400 MHz, CDCI3): d 8.55 (m, IH), 7.20 (m, 2H), 7.08 (m, 2H), 2.35 (s, 3H), 1.25 (t, J=6Hz, 3H), 1.14 (s, 3H), 1.03 (overlapping s and d, 6H)

v

EXAMPLE 6

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(l-n-(3- carboxypropyl)-prolyl)am_no)propyl-bicyclo(2.2.1)heptan-l- y methanesulfonylV4- 2-methylphenyl. piperazine

To a stirred solution of l-((7,7-dimethyl- 2-exo- hydroxy-2-endo-2-(l-(L-N-(ethoxycarbonylpropyl) prolyl)amino)propyl-(2.2.1)bicycloheptan-l-yl)methane- sulfonyl)- 4-(2-methylphenyl)piperazine (1.00 g; FW=909; 1.10 mmol) in THF (15 mL) was added 1 M NaOH solution (1.0 mL; 4.0 mmol) until a pH 10 solution persisted for 1 h. The solution was acidified to pH 7 by addition of citric acid and the solvents were removed under reduced pressure. The residue was dissolved in dichloromethane (75 mL) and washed with water (3 x 25 mL), dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was lyophilized from dioxane-water to give the title compound as a white powder.

Anal: (C33H52N4O6S) calc. C, 59.78; H, 8.25; N, 6.94 found C, 59.86; H, 7.98; N, 6.92 0.1 Na citrate, 1.65 dioxane TLC: Rf = 0.35 (80:20:2 CHCL3:MeOH:NH40H) HPLC (method A): retention time 9.24 min

FAB MS: m/z 633 (M+ + H) iH NMR (400 MHz, CDC13): d 7.55 (br s, IH), 7.18 (m, 2H), 7.03 (m, 2H), 2.31 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 0.98 (d, J=6 Hz, 3H)

EXAMPLE 7

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(4(5)- imidazolylacetyl)-amino)propyl-bicyclo(2.2.1 )heptan- 1 - ⁰ y methanesulfonyl -4-(2-methylpheny piperazine: ■

To a stirred solution of l-((7,7-dimethyl- 2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2.1 )bicyclo- heptan-1 - yl)methanesulfonyl)-4-(2-methylphenyl)piper- azine (1.50 g; 3.34 ⁵ mmol) in DMF (15 mL) was added 4(5)-imidazole acetic acid hydrochloride (679 mg; 4.18 mmol), BOP (1.85 g; 4.18 mmol), and DIEA (2.18 mL; 12.5 mmol). After 16 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCθ3 ° solution (2 x 50 mL) and water (2 x 50 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 (CHCl3:MeOH:NH40H) as eluant. The title compound crystallized from EtOAc, mp 159-163°C.

Anal: (C29H43N5O4S) calc. C, 62.45; H, 7.77; N, 12.56 found C, 62.88; H, 7.68; N, 12.79 TLC: Rf 0.4 (90:10:1 CHCl3/MeOH/NH4θH)

HPLC (method A): retention time 8.72 min FAB MS: m/z 558 (M+ + H) iH NMR (CDCI3): d 7.57 (s, IH), 7.2 (m, 3H), 7.0 (m, 2H), 6.88 (s, IH), 3.55 (m, 2H), 3.4 (m, 5H), 2.95 (m, 4H), 2.87 (d, J=15 Hz, IH), 2.31 (s, 3H), 1.71 (t, J=4 Hz, IH), 1.52 (d, J=13 Hz, IH), 1.15 (s, 3H), 1.03 (s, 3H), 0.97 (d, J=6 Hz, 3H)

EXAMPLE 8

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(quinucUdin-3- yl- carbonyl)amino)propyl-bicyclo(2.2.1)heptan-l- v methanesulfonylV4- 2-methylphenyl.piperazine

To a stirred solution of l-((7,7- dimethyl-2-exo- hydroxy-2-endo-2-(l -amino)propyl- (2.2.1 )bicycloheptan- 1 - yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (2.00 g; 4.45 mmol) in DMF (50 mL) was added quinuclidine-3-carboxyIic acid hydrochloride (938 mg; 4.90 mmol BOP (2.17-g; 4.90 mmol), and

DIEA (2.56 mL; 14.7 mmol). After 16 h, the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% acetic acid. The acetate salt of the title compound (1:1 mixture of diastereomers) was obtained as a lyophilized powder.

Anal: (C32H50N4O4S) calc. C, 60.39; H, 8.58; N; 8.39 found C, 60.41; H, 8.19; N, 8.58

0.8 CH3CO2H, 1.85 H2O

TLC: Rf = 0.65 (80:20:2 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time 8.68 min

FAB MS: m/z 587 (M+ + H) lH NMR (300 MHz, CDCI3): d 7.19 (m, 2H), 7.02

(m, 2H), 2.30 (s, 3H), 1.16 (s, 3H), 1.03 (over¬ lapping s and d, 6H)

EXAMPLE 9

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(l-carboxymeth yl- quinuclidin-3-yl-carbonyl)amino)propyl-bicyclo-(2.2.1)heptan -l- v methanesulfonylV4-( ^' 2-methylphenyl piperazine

To a stirred solution of 1 -((7,7 -dimethyl- 2-exo- hydroxy-2-endo-2-(l -(quinuchdin-3-yI-carbonyl) amino)-propyl- (2.2.1)bicycloheptan-l-yl)methane- sulfonyl)-4-(2- methylphenyl)piperazine (1.50 g; FW=668; 2.25 mmol) in DMF (30 mL) was added iodo- acetic acid (543 mg; 2.92 mmol) and DIEA (0.43 mL; 2.48 mmol). After 16 h, TLC showed complete con- sumption of starting material. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containingl% acetic acid. The title compound, as a 1:1 mixture of diastereomers, was obtained as a lyophilized powder.

Anal: (C34H52N4O4S) calc. C, 60.52; H, 8.18; N, 8.04 found C, 60.52; H, 7.98; N, 8.15

0.55 CH3CO2H, 0.95 H2O

TLC: Rf - 0.20 (80:10:2 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time 8.73 min

FAB MS: m/z 647 (M+ + H) lH NMR (TFA salt; 400 MHz, CDCI3): d 7.46 (br s, IH), 7.19

(m, 2H), 7.02 (m, 2H), 2.30 (s, 3H), 1.13 (s, 3H), 1.02 (s, 3H), 0.98

(d, J=6 Hz, 3H)

EXAMPLE 10

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(2- memoxycarbonylethyl)-amino)propyl-bicyclo(2.2.1)heptan-l-yl) - methanesulfonylV4-r2-methylphenyl.piperazine

H

To a stirred solution of l-((7,7-dimethyl- 2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2.1 ) bicycloheptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.22 mmol) in 1:1 DMF-MeOH (3 mL) was added methyl acrylate (0.020 mL; 0.22 mmol). After 16 h, the solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile*- water gradient containing 0.1% TFA. The TFA salt of the title compound was obtained as a lyophilized powder.

Anal: (C28H45N3O5S) calc. C, 53.03; H, 6.88; N, 6.06 found C, 53.01; H, 6.90; N, 6.01

1.3 TFA, 0.5 H2O TLC: Rf = 0.35 (95:5 (CHCl3:MeOH)

HPLC (method A): retention time 9.04 min

FAB MS: m/z 536 (M+ + H) lH NMR (300 MHz, CDCl3): d 7.20 (m, 2H), 7.03

(m, 2H), 3.72 (s, 3H), 2.32 (s, 3H), 1.19 (d, J=6 Hz, 3H), 1.15 (s, 3H), 0.98 (s, 3H)

EXAMPLE 11

l-((7,7-dimethyl-2-exo-hydroxy-2-endo-2-(l-bis-(2- memoxycarbonyl-emyl)amino)propyl-bicyclo(2.2.1)heptan-l- yl.methanesulfonyIV4-r2-methylphenyl.piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-amino)-propyl-(2.2.1)bicycloheptan-l - yI)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.22 mmol) in 1:1 DMF-MeOH (3 mL) was added methyl acrylate (0.080 mL); 0.89 mmol). After 16 h, the solvents were removed under reduced pressure and the residue was purified by pressurized silica gel chromatography using 3:1 hexane- ethyl acetate as eluant. The title compound was obtained as a foam from hexane.

Anal: (C32H51N3O7S) Calc: C 61.81, H 8.27, N 6.76

Found: C 61.55, H 8.13, N 6.55 TPC: Rf = 0.40 (1:3 EtOAc:hexanes) HPLC (method A): rentention time 9.71 min FAB MS: m/z 622 (M+ + H)

iH NMR (300 MHz, CDC13): d 7.19 (m, 2H), 7.02(m, 2H), 3.66 (s, 6H), 2.31 (s, 3H), 1.13 (s, 3H), 1.00 (overlapping a and d, 6H)

EXAMPLE 12

l-((7,7-dimethyl-2-exo-hydroxy-2-endo-ethenyl- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methyl- phenv piperazine

To a -78°C stirred 1.0 M solution of vinyl magnesium chloride in THF (25 mL; 25 mmol) was added a -78°C solution of l-((7,7-dimethyl-2-oxo-(2.2.1) bicycloheptan- l-yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (5.00 g; 12.8 mmol) in THF (100 mL) via cannula. The resulting solution was stirred under arogn overnight, allowing the cooling bath to warm to ambient temperature. The reaction was quenched by addition of 2% aqueous HCl (50 mL), and the mixture was partitioned between ethyl acetate and water. The organic phase was washed with aqurous NaHCθ3 and brine, dried over MgSθ4, and filtered. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel chromatography using 4:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from ether.

Anal: (C23H34N2O3S) 0.06 H2O

Calc: C 65.82, H 8.19, N 6.67

Found: C 65.99, H 8.42, N 6.63 TLC: Rf - 0.36 (1:5 EtOAc:hexanes) HPLC (method A): rentention time 11.41 min FAB MS: m/z 419 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.02 (m, 2H), 6.48 (dd, IH), 5.30 (d, IH), 5.17 (d, IH), 2.32 (s, 3H), 1.22 (s, 3H), 0.94 (s, 3H). 0

EXAMPLE 13

l-((7,7-dimethyI-2-(2-chloro)ethyHdinebicyclo-(2.2.1)hept an- l-v methanesulfony -4-(2-methyl-pheny piperazine 5

₅ To a 0°C stirred solution of l-((7,7-dimethyl-2- exo-hydroxy-2-endo-ethenyl-(2.2.1)bicycloheptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (2.90 g; 6.94 mmol) in THF (100 mL) was added triethylamine (1.50 mL; 10.7 mmol) and DMF (0.58 mL;7.5 mmol). Thionyl _Q chloride (0.66 mL; 9.1 mmol) was added dropwise, and the resulting solution was stirred for 18 h, allowing the cooling bath to warm ambient temperature. The solvents were removed under reduced pressure and the residue was dissolved in theyl acetate (150 mL) and washed with 5% aqueous HCl (75 mL), water (75 mL) and aqueous NaHCθ3 (100 mL). The organic

phase was dried (MgS04). filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 4:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam.

Anal: (C23H33CIN2O2S) 0.6 H2O Calc: C 65.82, H 8.19, N 6.67 Found: C 65.99, H 8.42, N 6.63

IH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.03 (m, 2H), 5.87 (m, IH), 4.10 (ABX, 2H), 2.32 (s, 3H), 1.00 (s, 3H), 0.82 (s, 3H)

EXAMPLE 14

l-((7,7-dimethyl-2-(2-isobutylamino)ethylidine- bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- metfaylphenvDpiperazine

To a stirred solution of l-((7,7-dimethyl-2-(2- chloro)ethylidine-(2.2.1 )bicycloheptan-l -yl)methanesulfonyl)- 4-(2-methylphenyl)peperazine (200 mg; 0.46 mmol) in MeOH (2 mL) was added isobutylamine (0.5 mL; 5 mmol). After being stirred fro 18 h, the solvents were removed under reduced

pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile- water gradient containing 0.1% TFA. The TFA salt ofthe title compound was obtained as a lyophilized powder.

Anal: (C27H41N3O2S) 2.0 H2O; 1.0 TFA TLC: Rf - 0.30 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): rentention time 9.78 min - FAB MS: m/z 474 (M+ + H) 1H NMR (400 MHz, CD3OD): d 7.20 (m, 3H), 7.03 (t, IH), 5.78 (m, IH), 2.35 (s, 3H), 1.13 (d, J=7 Hz, 6H), 1.12 (s, 3H), 0.88 (s, 3H)

EXAMPLE 15

l-((7,7-dimethyl-2-(2-azido)ethylidine-bicyclo-(2.2.1)hep tan- l-yl methanesulfony -4- 2-methyl-phenyl ^' )piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-(2-chloro)ethylidine-(2.2.1)bicyclo-heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (3.58 g;8.19 mmol) in DMSO (50 mL) and THF (45 mL) was added a solution of sodium azide (5.3 g; 82 mmol) in water (20 mL). After 24 h, the solvents were removed under reduced pressure, the residue was suspended in dichloromethane (100 mL) and washed with water (3 x 50 mL). The organic phase was dried

(MgS04), filtered, and the solvent was removed under reduced pressure to give a solid. Anal: (C23H33N5O2S)

Calc: C 62.27, H 7.50, N 15.79

Found: C 62.41, H 7.54, N 15.60 TLC: Rf 0.75 (70:30 hexane-ethyl acetate) HPLC (method A): rentention time 12.50 min FAB MS: m/z 444 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.20 (m, 2H), 7.02 (m, 2H), 5.79 (m, IH), 3.78 (ABX, 2H), 2.32 (s, 3H), 0.85 (s, 3H)

EXAMPLE 16

1 -((7 ,7-dimethyl-2-(2-amino)ethylidine-bicyclo-(2.2.1 )heptan- l-yDmethanesulfonylV4- 2-methyl-phenyl piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-(2-azido)ethylidine-(2.2.1 )bicyclo-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (3.85 g; 8.69 mmol) in THF (150 mL) and water (3 mL) was added triphenylphosphine (2.50 g; 9.56 mmol). After 14 h, the solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and extracted with 5% aqueous HCl (3 x 75 mL). The combined acid extracts were washed wtih ethyl acetate (50 mL) and then made basic by

adding solid sodium hydroxide to pH 12. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 99:1 to 85:15 chloroform-methanol. The title compound was obtained as a solid.

Anal: (C23H35N3O2S) 0.5 H2O Calc: C 64.75; H 8.51; N 9.85;

Found: C 64.59; H 7.51; N 9.71 TLC: Rf 0.56 (95:5:0.5 CHCl3-MeOH-NH4θH) HPLC (method A): retention time 10.38 min FAB MS: m z 418 (M+ + H) lH NMR (CDCI3): Η NMR (300 MHz, CDC13): 87.16 (m, 2H), 7.00 (m, 2H), 5.61 (m, IH), 3.43 (m, 4H), 3.26 (d, J=6.6Hz, 2H), 1.18 (d, J=14.1 Hz, 1H0, 1.97 (m, 4H), 2.92 (d, J=14.1 Hz, IH), 2.35 (m, IH), 2.31 (s, 3H), 1.7-1.8 (m, 3H), 1.70 (m, IH), 1.25 (m, IH), 0.99 (s, 3H), 0.81 (s, 3H).

EXAMPLE 17

l-((7,7-dimethyl-2-(2-(4(5)-imidazolylacetyl)amino)- ethyIidine-bicyclo(2.2.1 )heptan- 1 -yl)methane-sul onyl)-4-(2- methylphenyl.piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-(2-amino)ethylidine-(2.2.1 )bicyclo-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.20 g;

5 0.48 mmol) in DMF (5 mL) was added BOP (265 mg; 0.60 mmol), 4-imidazoleacetic acid hydrochloride (115 mg; 0.72 mmol) and DIEA (0.38 mL; 2.2 mmol). After 14 h, the solvents were removed under reduced pressure, the residue was suspended in ethyl acetate (50 mL) and washed with aqueous l o NaHC03 (2 x 25 mL) and water (2 x 25 mL). The organic phase was dried (MgS04), filtered and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPCL using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of the title 5 compound was obtained as a lyophilized powder.

Anal: (C28H39N5O3S); 0.5 H2O; 2.0 TFA;

Calc: C 50.38; H 5.55; N 9.18

Found: C 50.40; H 5.55; N 9.40

20 TLC: Rf 0.42 (95:5:0.5 CHCl3-MeOH-NH4θH)

HPLC (method A): retention time 8.76 min. FAB MS: m/z 526 (M+ + H) iH NMR (400 MHz, CDCI3): d 8.40 (s, IH), 7.58 (br m, IH), 7.22 (m, 3H), 7.10 (m, 2H), 5.57 (br 5 t, IH), 2.37 (s, 3H), 0.97 (s, 3H), 0.76 (s, 3H)

EXAMPLE 1

1 -((7 ,7-Dimethyl-2-spiro-epoxy-bicyclo(2.2.1 )heptan- 1 - ⁰ yl methane-sulfonv -4-(2-methylphenyl. piperazine

To a stirred 0°C suspension of trimethyl- ₀ sulfoxonium iodide (6.78 g; 30.8 mmol) in THF (100 mL) was added n-butyllithium (11.1 mL of a 2.5 M solution in hexane; 27.7 mmol). After 4 h at 0°C, a solution of l-((7,7-dimethyl-2- oxo-(2.2.1)bjcyclo-heptan-l-yl)methanesuIfonyl)-4-(2- methylphenyl)piperazine (8.00 g; 20.5 mmol) in THF (50 mL). ₅ The resulting solution was stirred at 0°C for 2 h, and then at ambient temperature for 18 h. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (150 mL) and washed with water (2 x 50 mL). The organic phase was dried (MgS04), filtered, and the solvent was o removed under reduced pressure. The resulting solid was recrystallized from ether to give the title compound as white needles, mp l31-133°C.

Anal: (C22H32N2O2S) calc. C, 65.31; H, 7.97; N, 6.92 found C, 65.09; H, 7.99; N, 6.86

0.5 H2O

TLC: Rf0.62 (4:1 hexane-ethyl acetate)

HPLC (method A): retention time 11.50 min FAB MS: m/z405 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.20 (m, 2H), 7.02 (m, 2H),

3.20 (d, J=5.4 Hz, IH), 2.70 (d, J=5.4 Hz, IH), 2.30 (s, 3H),

1.00 (s, 3H), 0.99 (s, 3H)

EXAMPLE 19

1 -((7 ,7-Dimethyl-2-exo-hydroxy-2-endo-isobutylamino-methyl- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyPpiperazine

To a stirred solution of l-((7,7-dimethyl-2- (spiroepoxy)-(2.2.1 )bicycloheptan- 1 -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (200 mg; 0.495 mmol) in MeOH (3 mL) was added isobutyl-unine (0.5 mL; 5 mmol). After being stirred for 18 h, the solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 98:2:0.2 chloroform-methanol- NH4OH as eluant. The product was dissolved in methanol and to it was added several drops of 5% aqueous HCl. The solvents were removed under reduced pressure and the residue was triturated in ether to give the hydrochloride salt of the title compound as a white powder.

Anal: (C26H43N3O3S) calc. C, 57.00; H, 8.76; N, 7.67 found C, 57.03; H, 8.84; N, 7.61 1.0 HCl, 1.8 H20 TLC (free base): Rf 0.20 (3:1 hexane-ethyl acetate)

HPLC (method A): retention time 9.54 min FAB MS: m/z 478 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.20 (m, 2H), 7.02 (m, 2H), 2.30 (s, 3H), 1.10 (s, 3H), 0.95 (s, 3H), 0.90 (two doublets, 6H)

EXAMPLE 20

l-((7,7-Dimethyl-2-methoxycarbbnyl-bicyclo(2.2.1)hept-2-e n- l-y methanesulfony -4- 2-methylphenylVpiperazine

To a stirred, 0°C solution of l-((7,7-dimethyl-2- oxo-bicyclo(2.2. l)heptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (10.0 g; 25.6 mmol) in dichloromethane (500 mL) was added 2,6-di-t-butyl-4- methylpyridine (7.8 g; 38 mmol) and trifluoromethanesulfonic anhydride (5.4 mL; 32 mmol). The cooling bath was removed and the solution was stirred for 18 h. The mixture was filtered and the filtrate was washed with 5% aqueous HCl (2 x 100 mL), water (100 mL), and aqueous NaHC03 (2 x 100 mL). The organic phase was dried (MgS04), filtered and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant The enol triflate product was obtained as a white foam and used as such in the next step. To a stirred solution of l-((7,7-dimethyl-2- trifluoromethanesulfonyloxy-bicyclo(2.2.1)-hep-2-en-l-

yl)methane-sulfonyl)-4-(2-methylphenyl)-piperazine (10.5 g; 20.1 mmol) in 1:1 DMF-MeOH (150 mL) was added triethylamine (5.9 mL; 43 mmol), triphenyl-phosphine (317 mg; 1.21 mmol), and palladium(TI)acetate (135 mg; 0.603 mmol). Carbon monoxide gas was bubbled through the solution for 15 min, and the reaction was kept under atmospheric pressure of CO for 18 h. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from hexane.

Anal: (C23H32N2O4S) calc. C, 62.14; H, 7.50; N 6.30 found C, 61.65; H, 7.17; N, 6.12

0.67 H2θ

TLC: Rf = 0.36 (1:5 EtOAc:hexanes)

HPLC (method A): retention time 11.34 min

FAB MS: m/z 433 (M+ + H) lH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.03

(m, 2H), 6.88 (d, J=3 Hz, IH), 3.72 (s, 3H), 2.33

(s, 3H), 1.09 (s, 3H), 1.01 (s, 3H)

EXAMPLE 21

1 -((7 ,7-Dimethyl-2-carboxy-bicyclo(2.2.1 )hept-2-en- 1 - y methanesulfonylV4-(2-methylphenyl ^' )piperazine

To a stirred solution of l-((7,7-dimethyl-2- methoxycarbonyl-bicyclo (2.2.1 )hep t-2-en- 1 - yI)methanesulfonyl)-4-(2-methylphenyl)-piperazine (1.0 g; 2.3 mmol) in MeOH (10 mL) was added a solution of 4 M aqueous

5 KOH (2.0 mL; 8.0 mmol). After 18 h, the reaction was brought to pH 1 with 5% aqueous HCl, and the solvents were removed under reduced pressure.The residue was taken up in chloroform (50 mL) and washed with water (25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed i o under reduced pressure to give the hydrochloride salt of the title compound as a white foam.

Anal: (C22H30N2O4S) calc. C, 57.51; H, 6.91; N, 6.10 s found C, 57.40; H, 6.87; N, 6.01

1.0 HCl, 0.25 H2O

TPC: Rf = 0.59 (92:8:0.1) CHCl3:MeOH:HOAc)

HPLC (method A): retention time 9.77 min

FAB MS: m/z 419 (M+ + H) 0 lH NMR (400 MHz, CD3OD): d 7.30 (m, 3H), 7.20 (t, IH),

6.89 (d, J=3 Hz, IH), 2.43 (s, 3H), 1.11 (s, 3H), 1.00 (s, 3H)

EXAMPLE 22

⁵ l-((7,7-Dimethyl-2-(4-_midazolyl)ethylaminocarbonyl- bicyclo(2.2.1)hept-2-en-l-yl)methanesulfonyl)-4-(2- methylphenvDpiperazine

0

To a stirred solution of l-((7,7-dimethyl-2- carboxybicyclo-(2.2.1 )hept-2-en- 1 -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (100 mg; FW=460; 0.22 mmol) in DMF (5 mL) was added histamine (30 mg; 0.27 mmol), BOP (115 mg; 0.25 mmol) and DIEA (0.12 mL; 0.69 mmol). After 18 h, the solvent was removed under reduced pressure, the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of the title compound was obtained as a lyophilized powder.

Anal: (C27H37N5O3S) calc. C, 49.35; H, 5.31; N, 9.22 found C, 49.25; H, 5.39; N, 9.20

2.1 TFA, 0.45 H2O

HPLC (method A): retention time 8.16 min

FAB MS: m/z 512 (M+ + H) iH NMR (300 MHz, CD3OD): d 8.80 (s, IH), 7.40 (s, IH), 7.18 (m, 2H), 7.05 (d, IH),

6.99 (t, IH), 6.41 (d, J=3 Hz, IH), 2.31

(s, 3H), 1.08 (s, 3H), 0.98 (s, 3H)

EXAMPLE 23

l-((7,7-Dimethyl-2-endo-methoxycarbonyl-bicyclo- (2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methyl- phenvDpiperazine

To a stirred, -78°C solution of l-((7,7- dimethyl-2- methoxy-carbonyl-bicyclo(2.2. l)hept-2-en-l - yl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine (3.0 g; 6.9 mmol) in 2:1 THF-MeOH (50 mL) was added a solution of 0.1 M s_unarium(H) iodide in THF (250.0 mL; 25.0 mmol). After 1 h, the reaction was warmed to ambient temperature and stirred for another 1 h. The solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were separated and the organic phase was washed with water (50 mL), dried (MgSθ4), filtered, and evaporated to dryness under reduced pressure. By ^A H NMR analysis, a 6:1 ratio of endo:exo products was obtained. The major, lower Rf isomer (endo) was obtained in pure form by pressurized silica gel column chromatography using a gradient elu¬ tion of 98:2 to 95:5 hexane-ethyl acetate, followed by crystallization from ethyl acetate. The title compound was obtained as white needles, mp 156-158°C.

Anal: (C23H34N2O4S)

found C, 63.31; H, 7.83; N, 6.43 calc. C, 63.56; H, 7.89; N, 6.45 TLC: Rf = 0.44 (1:5 EtOAc:hexanes) HPLC (method A): retention time 11.75 min FAB MS: m/z 435 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.05

(m, 2H), 3.72 (s, 3H), 3.29 (ddd, IH), 2.34 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H)

EXAMPLE 24

1 -((7 ,7-Dimethyl-2-endo-carboxy-bicyclo(2.2. l)heptan- 1 - v methane-sulfonyl -Q-methylphenyDpiperazine

To a stirred solution of l-((7,7-dimethyl-2-endo- methoxy-carbonyl-bicyclo(2.2.1 )heptan-l -yl)methanesulf onyl)-

4-(2-methyl-phenyl)piperazine (1.0 g; 2.3 mmol) in THF (10 mL) was added a solution of 4 M aqueous NaOH (1.5 mL; 6.0 mmol). The reaction was heated to reflux for 72 h, cooled, and brought to pH 1 with 5% aqueous HCl. The solvents were removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was separated and washed with water, dried (MgS04), filtered, and the solvent was removed under reduced pressure. The title compound was purified by preparative reverse phase HPLC

using an acetonitrile-water gradient containing 0.1% TFA. The title compound was obtained as a lyophilized powder.

Anal: (C22H32N2O4S) calc. C, 51.92; H, 5.99; N, 4.94 found C, 51.92; H, 5.95; N, 5.17

1.25 TFA, 0.2 H2O

TLC: Rf= 0.22 (95:5:0.5 CHCl3:MeOH:NH40H)

HPLC (method A): retention time 10.67 min ^Q FAB MS: m/z 421 (M+ + H) lHNMR (300 MHz, CD3OD): d 7.18 (m, 2H), 7.05

(d, IH), 6.98 (t, IH), 2.30 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H)

EXAMPLE 25

l-((7,7-Dimethyl-2-endo-(4-intidazoIyl)ethylam__no-carbon yl- bicyclo-(2.2. l)heptan-l -yl)methanesulf onyl)-4-(2- methylphenvDpiperazine

To a stirred solution of l-((7,7-dimethyl-2-endo- carboxy-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (100 mg; 0.238 mmol) in DMF (5 mL) was histamine (35 mg; 0.32 mmol), BOP (142 mg; 0.321

mmol), and DIEA (0.13 mL; 0.75 mmol). After 18 h, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C27H39N5O3S) calc. C, 46.66; H, 5.58; N, 8.58 found C, 46.63; H, 5.23; N, 8.97 2.35 TFA, 1.9 H2θ

HPLC (method A): retention time 8.99 min

FAB MS: m/z 514 (M+ + H) iH NMR (300 MHz, CDCI3): d 8.40 (s, IH), 7.1-7.3

(m, 5H), 2.39 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H)

EXAMPLE 26

Two isomers of l-((7,7-dimethyl-2-exo-hydroxy-2-endo-2-(l- (3 -methoxycarbonyl)-2-pyrrolidinon- 1 -y l)propylbicy clo- (2.2. l)heptan-l -yl)methanesulfonyl)-4-(2- methylphenyDpiperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2. l)bicyclo-heptan-l - yl)methanesuIfonyl)-4-(2-methylphenyl)piperazine (250 mg; 0.557 mmol) in methanol (3 mL) was added dimethyl itaconate (200 mg; 1.27 mmol). The reaction was heated to reflux for 18 h. The solvent was removed under reduced pressure and the redidue was purified by pressurized silica gel column chromatography using 35:65 hexane-ethyl acetate as eluant. The products were obtained as white foams.

Isomer 1:

Anal: (C30H 5N3O6S) calc. -C, 62.58; H, 7.88; N, 7.30 found C, 62.58; H, 8.03; N, 6.95 TLC: Rf 0.34 (35:65 hexane-ethyl acetate) HPLC (method A): retention time 10.23 min FAB MS: m/z 576 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.18 (m, 2H), 7.01

(m, 2H), 3.76 (s, 3H), 2.32 (s, 3H), 1.15 (s, 3H), 1.03 (s, 3H), 0.95 (d, J=6 Hz, 3H)

Isomer 2:

Anal: (C30H45N3O6S) calc. C, 62.58; H, 7.88; N, 7.30 found C, 62.43; H, 8.07; N, 6.95

TLC: Rf 0.23 (35:65 heaxane-ethyl acetate)

HPLC (method A): retention time 10.24 min

FAB MS: m/z 576 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.20 (m, 2H), 7.03 (m, 2H), 3.74 (s, 3H), 2.32 (s, 3H), 1.15 (s, 3H), 1.03 (s, 3H),

0.95 (d, J=6 Hz, 3H)

EXAMPLE 27

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(4- pyridinyl)methylamino)-propyl-bicyclo(2.2.1 )heptan-l ■ vDmemanesulfonylV4-f2-methylphenylVpiperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2.1 )bicycloheptan- 1 - yl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine (50 mg; 0.11 mmol) in DMF (2 mL) was added 4-chloro-methylpyridine hydrochloride (18 mg; 0.11 mmol) and potassium carbonate (50 mg; 0.36 mmol). The reaction was heated to 80°C 18 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C30H44N4O3S) calc. C, 52.07; H, 5.89; N, 7.06 found C, 52.06; H, 5.86; N, 7.20 2.2 TFA, 0.1 H2θ

TLC: Rf = 0.36 (95:5:0-5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time 8.15 min FAB MS: m/z 541 (M+ + H)

iH NMR (300 MHz, CDCI3): d 8.72 (br s, 2H), 7.85 (br s, 2H), 7.20 (m, 2H), 7.03 (m, 2H), 4.27 (AB quartet, 2H), 2.31 (s, 3H), 1.14 (s, 3H), 0.95 (overlapping s and d, 6H)

EXAMPLE 28

l-((7,7-Dimethyl-2-(3-acetamido-3,3 ^, - di(ethoxycarbonyl))propyhdine-bicyclo(2.2. l)heptan-l - yl.methanesulfonylV4- 2-methylphenyl.piperazine

To a stirred solution of diethyl acetamidomalonate (0.69 g; 3.2 mmol) in DMF (20 mL) was added NaH (125 mg of a 60% dispersion in mineral oil; 3.13 mmol). After 30 min, l-((7,7-dimethyl-2-(2-cWoro)-ethyUdine-(2.2.1)bicycloheptan- l-yl)methanesuIfonyl)-4-(2-methylphenyl)-piperazine (0.35 g; 0.80 mmol) was added and the mixture was warmed to 50°C for 3 h. The mixture was cooled and acetic acid (1.5 mL) was added. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (75 mL) and washed with water (3 x 25 mL). The organic phase was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam.

Anal: (C32H47N3O7S)

calc. C, 62.32; H, 7.51; N, 6.81 found C, 61.96; H, 7.71; N, 6.55 TLC: Rf = 0.36 (95:5:0-5 CHCl3_MeOH:NH4θH) HPLC (method A): retention time 11.54 min FAB MS: m/z 618 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.03 (m, 2H),

6.78 (s, IH), 5.38 (br t, IH), 4.22 (m, 4H), 2.32 (s, 3H), 2.00 (s, 3H), 1.27 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H), 0.97 (s, 3H), 0.78 (s, 3H)

EXAMPLE 29

l-((7,7-Dimethyl-2-(3-acetamido-3-carboxy)propylidine- bicyclo(2.2.1 )-heptan- 1 -yl)methanesulfonyl)-4-(2- methylpheny piperazine

To a stirred solution of l-((7,7-dimethyl-2-(3- acetamido-3 ,3'-di(ethoxycarbonyl))propylidine- (2.2.1 )bicycloheptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)-piperazine (0.10 g; 0.16 mmol) in ethanol (2 mL) was added a solution of 2 M NaOH (0.30 mL; 0.60 mmol) and the mixture was heated to reflux for 6 h. The mixture was cooled and brought to pH 2 with 5% aqueous ttCl. The mixture

was heated to reflux for 1 h. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The title compound, as a 1:1 mixture of diastereomers, was obtained as a lyophilized powder.

Anal: (C27H39N3O5S) calc. C, 54.37; H, 6.53; N, 6.56 found C.54.26; H, 6.41; N, 6.59 1.0 TFA, 0.5 H2O

TLC: Rf = 0.39 (92:8:0-1 CHCl3_MeOH:HOAc) HPLC (method A): retention time 9.62 min FAB MS: m/z 518 (M+ + H) lHNMR (400 MHz, CDCl3): d 7.25 (m, 4H), 7.13 (m, 4H), 6.52 (d, IH), 6.40 (d, IH), 5.45 (m, IH), 5.40 (m, IH), 4.67 (m, 2H), 2.40 (s, 6H), 20.5

(s, 3H), 2.04 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.88 (s, 3H), 0.79 (s, 3H)

EXAMPLE 30

1 -((7,7-Dimethyl-2-oxo-bicyclo(2.2.1 )heptan- 1 - yl.metfaanesulfonylV4- 2-methylphenylV3-ρiperazinone

To a stirred solution of l-t-butyloxycarbonyl-4-(2- methyl-phenyl)-3-piperazinone (0.25 g; 0.86 mmol) in dichloromethane (3 mL) was added TFA (1 mL). After 1 hour the solvents were removed under reduced pressure and the

residue was taken up into chloroform and evaporated several times to remove excess TFA. The residue was dissolved in chloroform (5 mL) and added to the stirred solution was 10- camphorsulfonyl chloride (376 mg; 1.50 mmol) and triethylamine (0.38 mL; 2.7 mmol). After 12 hours, the mixture was diluted with chloroform (25 mL) and extracted with 5% aqueous HCl (25 mL), water (25 mL), and aqueous NaHC03 (25 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from ether-hexane.

Anal: (C21H28N2O4S) Calc. C, 62.35; H, 6.98; N, 6.93

Found C, 61.78; H, 6.98; N, 6.82 TLC: Rf 0.30 (1 : 1 hexane-ethyl acetate) HPLC (method A): retention time 8.15 min FAB MS: m/z 405 (M+ + H)

EXAMPLE 31

1 -((7 ,7-Dimethyl-2-oxo-bicyclo(2.2.1 )heptan- 1 -yl)- methanesulfonyl)-4-(2-methylphenyl)-2-methyl-3- piperazinone

To a stirred 78°C solution ofLDA (2.0 mmol) in THF (15 mL) was added a -78°C solution of 1 -t-

butyloxycarbonyl-4-(2-methylphenyl)-3-piperazinone (0.50 g; 1.7 mmol) in THF (5 mL). The resulting solution was stirred for 1 hour, wheniodomethane (0.125 mL; 2.0 mmol) was added. The reaction mixture was stirred at -78°C for 30 minutes, and then the cooling bath was removed and the mixture was stirred at ambient temperature for 3 hours. Water (10 mL) and ethyl acetate (50 mL) were added. The organic layer was separated and washed with water (25 mL) and brine (25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 85:15 hexane-ethyl acetate as eluant. The methylated product had an Rf = 0.47 (70:30 hexane-ethyl acetate) and an HPLC retention time of 8.32 min (Method A). The product (0.40 g; 1.3 mmol) was dissolved in chloroform (3 mL) and TFA (1 mL) was added. After 2 hours, the mixture was diluted with chloroform (50 mL) and extracted with aqueous NaHCθ3 (3 x 25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure to give an on (HPLC retention time 2.95 min, Method A). The residue was dissolved in chloroform (20 mL) and to the stirred solution was added 10-camphorsulfonyl chloride (0.41 g; 1.6 mmol) and triethylamine (0.28 mL; 2.0 mmol). After 12 hours, the mixture was diluted with chloroform (25 mL) and extracted with 5% aqueous HCl (25 mL), water (25 mL), and aqueous NaHCθ3 (2 x 25 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound, as a 1 :1 mixture of diastereomers, was obtained as a white solid from hexane-ether.

Anal: (C22H30N2O4S)

Calc. C, 63.13; H, 7.23; N, 6.69 Found C, 63.46; H, 7.09; N, 6.74

TLC: Rf 0.27 (60:40 hexane-ethyl acetate)

HPLC (method A): retention time 8.52 min

FAB MS: m/z 419 (M+ + H) iH NMR (300 MHz, CDC13): d 7.1-7.3 (m, 8H), 4.62

(overlapping quartets, 2H), 2.21 (s, 3H), 2.20

(s, 3H), 1.68 (overlapping doublets, 6H), 1.13

(s, 3H), 1.11 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H)

EXAMPLE 32

1 -((7 ,7-Dimethyl-2-exo-hydroxy-bicyclo(2.2.1 )heptan- 1 - yl)methane-sulfony -4-(2-methylphenylV2-methyl-piperazine

To a stiiTed, 0°C solution of l-((7,7-dimethyl-2- oxo-bicyclo(2.2.1 )heptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)-2-methyl-3-piperazinone (0.15 g; 0.36 mmol) in THF (5 mL) was added a 1.0 M solution of LAH in THF (1.1 mL; 1.1 mmol). The resulting solution was warmed to ambient temperature and stirred for 3 hours. The reaction was quenched by adding aqueous NaOH to give a white precipitate. The mixture was diluted with ethyl acetate and the solids were removed by filtration through Celite. The filtrate solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant to give l-((7,7-dimethyl-2-exo- hydroxy-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- memylphenyl)-2-methy 1-2,3 -dehydro-piperazine (FAB MS: m/z 405 (M+ + H); olefinic proton at 5.8 ppm in the *H NMR

spectrum). This product (75 mg; 0.19 mmol) was dissolved in triethylsilane (2 mL) and to the stirred solution was added TFA (0.030 mL; 0.38 mmol). After 18 hours, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCθ3 (2 x 10 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The title compound, as a 1:1 mixture of diastereomers, was obtained as a lyophilized powder.

HPLC (method A): retention time 14.33 min FAB MS: m/z 407 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 4H), 7.06 (m, 4H), 4.20 (m, 2H), 2.36 (s, 6H), 1.55 (overlapping doublets, 6H), 1.09 (s, 6H), 0.86 (s, 6H)

EXAMPLE 33

l-((7,7-Dimethyl-2-oximino-bicyclo(2.2.1)heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine _ ^■

To a stirred solution of l-((7,7-dimethyl-2-oxo- bicyclo(2.2.1 )-heptan-l -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (65.0 g; 166 mmol) in pyridine (250 mL) was added hydroxylamine hydrochloride (35.0 g; 0.504

mol). The solution was heated to 70°C for 18 h. The solvent was removed under reduced pressure, the residue was taken up in chloroform (500 mL) and washed with aqueous NaHC03 (2 x 200 mL), water (100 mL), and 5% aqueous HCl (2 x 200 5 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The title compound crystallized from ethyl acetate, giving off-white needles (57 g; 84%), mp 174-175°C.

l o Anal: (C21 H31N3O3S)

Calc. C, 62.19; H, 7.71; N, 10.36 Found C, 62.29; H, 7.63; N, 10.15 TLC: Rf 0.40 (75:25 hexane-ethyl acetate) HPLC (method A): retention time 9.98 min s FAB MS: m/z 406 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.90 (br s, IH), 7.18 (m, 2H), 7.02 (m, 2H), 3.47 (m, 4H), 4.43 (d, J=14.4 Hz, IH), 3.00 (m, 4H), 2.92 (d, J=14.4 Hz, IH), 2.4-2.6 (m, 2H), 2.31 (s, 3H), 2.09 (d, J=16.9 Hz, IH), 1.95 (m, 2H), 1.80 (m, IH), 1.32 (m, ⁰ IH), 1.08 (s, 3H), 0.87 (s, 3H)

EXAMPLE 34

1 -((7,7-Dimethyl-2-endo-amino-bicyclo(2.2.1 )heptan-l - ²⁵ yl)methane-sulfonyl)-4-(2-methylphenyl)-piperazine

0

To a stirred solution of l-((7,7-dimethyl-2- oximino-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (35.0 g; 86 mmol) in 2- methoxyethanol (500 mL) containing Raney Nickel alloy (105.0 g) was added sodium hydroxide solution (17.2 g; 430 mmol dissolved in 75 mL) dropwise over 30 min. During the addition heat and gas was evolved. The mixture was stirred at ambient temperature for 16 h, at which time TLC indicated complete consumption of starting oxime and a ca. 4:1 mixture of endo (lower Rf) and exo (higher Rf) amine products. The mixture was filtered through Celite and the filtercake was washed with methanol and ethyl acetate. The solvents were removed under reduced pressure and the resulting solid was dispersed in water and filtered. The dried solid was purified by pressurized silica gel column chromatography, using a 93:3 to 94:6 A:B gradient elution (A=chlorofoπn, B=5% NELψOH/MeOH). The title compound was obtained as a white foam (24 g; 70%).

FAB MS: m/z 392 (M+ + H)

EXAMPLE 35

1 -((7 ,7-Dimethyl-2-endo-(2S-(tert-butyloxycarbonyl-amino)-4- (methyl-sulfonyl)-butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo- amino-bicyclo(2.2.1 )heptan- 1 -yl)me thanesulf onyl)-4-(2- methylphenyl)piperazine (2.0 g; 5.1 mmol) in DMF (20 mL) was added Boc-L-methionine sulfone (1.5 g; 5.3 mmol), BOP reagent (2.5 g; 5.6 mmol), followed by DIEA (1.85 mL; 10.6 mmol). After being stirred at ambinet temperature for 1 h, more DIEA (ca. 0.1 mL) was added to obtain a pH 8 solution. The solution was stirred for another 1 h, when the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with 5% aqueous HCL (2 x 50 mL), water (2 x 50 mL), and aqueous NaHCθ3 (2 x 75 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using 4:1 EtOAc-hexanes as eluant. The title compound was obtained as a solid from methanol (2.8 g; 85%). Anal: (C31H50N4O7S2)

Calc. C, 55.78; H, 7.76; N, 8.39 0.7-H2O

Found C, 55.57; H, 7.70; N, 8.36 TLC: Rf 0.73 (95:5 CHCl3:MeOH) HPLC (method A): retention time 11.02 min FAB MS: m/z 655 (M+ + H)

iH NMR (300 MHz, CDCI3): d 7.19 (m, 2H), 7.04 (m, 2H), 5.38 (br d, IH), 4.32 (q, J=7.4 Hz, IH), 4.22 (m, IH), 2.94 (s, 3H), 2.32 (s, 3H), 1.45 (s, 9H), 1.00 (s, 3H), 0.98 (s, 3H)

EXAMPLE 36

l-((7,7-Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)- butyramido)-bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- tert-butyloxycarbonylaπ_ o-4-(memylsulfonyl)-butyramido)- bicyclo(2.2.1 )-heptan-l -yl)methane sulf onyl)-4-(2- methylphenyl)piperazine (2.5 g; 3.8 mmol) in dichloromethane (15 mL) was added TFA (5 mL). After 1 h, the solvents were removed under reduced pressure.The residue was dissolved in chloroform (100 mL) and washed with aqueous NaHC03 (2 x 75 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95 :5 :0.5 CHCl3:MeOH:NH4θH as eluant. The title was obtained as a white foam from EtOAc (1.9 g; 90%).

Anal: (C26H42N4O5S2)

Calc. C, 56.14; H, 7.75; N, 9.29 0.55 EtOAc

Found C, 55.94; H, 7.74; N, 9.31 TLC: Rf 0.17 (95:5:0.5 CHCl3_MeOH:NH4θH) HPLC (method A): retention time 8.50 min FAB MS: m/z 455 (M+ + H) *H NMR (300 MHz, CDCI3): d 7.67 (d, J=8.4 Hz, IH), 7.20 (m, 2H), 7.02 (m,2H), 4.43 (m, IH), 2.94 (s, 3H), 2.31 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H)

EXAMPLE 37

1 -((7 ,7-Dimethyl-2-endo-(2s-(imidazol-4-ylacetyl-amino)-4- (methyl-sulf onyl)butyrarnido)-bicyclo(2.2.1 )-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino* -(memylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (250 mg; 0.45 mmol) in DMF (5 mL) was added 4-imidazole acetic acid hydrochloride (110 mg; 0.68 mmol), BOP (265 mg; 0.60 mmol), and DIEA (0.355 mL; 2.0 mmol). The solution was stirrred at ambient temperature for 18 h. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc (100 mL) and filtered through Celite to remove red polymer. The filtrate was washed with 5% aqueous HCl (50 mL). water (50 mL), and aqueous NaHC03

(2 x 50 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as a solid from EtOAc (230 mg; 78%).

Anal: (C31H46N6O6S2)

Calc. C, 53.74; H, 7.32; N, 11.26 0.6 EtOAc, 1.7H20

Found C, 53.74; H, 7.00; N, 11.25 TLC: Rf 0.22 (90:10:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time 8.49 min FAB MS: m/z 663 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.73 (overlapping singlet and broad singlet, 2H), 7.38 (br d, IH), 7.18 (m, 2H), 7.02 (m, 2H), 6.96 (s, IH), 4.68 (br q,

J = ca. 5 Hz, IH), 4.27 (m, IH), 3.62 (br s, 2H), 2.92 (s, 3H), 2.30 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)

EXAMPLE 38

l-((7,7-Dimemyl-2-endo-(2s-(dimemylamino)-4-(methylsulfon yI)- butyramido)-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methyl-phenyl)piperazine

To a stirred solution of 1 -((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo-(2.2.1 )-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (250 mg; 0.45 mmol) in 1:1 HOAc:MeOH (10 mL) was added 37% aqueous formaldehyde (2 mL) and NaBH3CN (60 mg; 0.95 mmol). The solution was stirred at ambient temperature for 4 h. Aqueous NaHCθ3 (2 mL) was added and the solvents were removed under reduced pressure. The residue was suspended in EtOAc (75 mL) and washed with water (2 x 50 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The title compound was obtained as a white foam from EtOAc (190 mg; -72%).

5 Anal: (C28-H46N4O5S2)

Calc. C, 57.56; H, 8.01 ; N, 9.200.3 EtOAc, Found C, 57.41; H, 7.98; N, 9.20 TLC: Rf 0.26 (95:5:0.5 CHCl3_MeOH:NH4θH)

HPLC (method A): retention time 9.10 min o FAB MS: m/z 583 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.62 (Br s, IH), 7.18 (m, 2H),

7.02 (M, 2H), 4.37 (m, IH), 2.92 (s, 3H), 2.36 (s, 6H), 2.30 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H)

EXAMPLE 39 5

1 -((7 ,7-Dimethyl-2-endo-benzyloxycarbonylamino-bi- cyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2-methyl-phenyl)- piperazine

0

To a 0°C stirred solution of l-((7,7-dimethyl-2-endo- amino-bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (1.20 g; 3.07 mmol) in CHC13 (100 mL) was added DIEA (0.80 mL; 4.6 mmol) and benzyl chloroformate (0.58 g; 3.4 mmol). The solution was stirred at 0°C for 1 h and then at ambient temperature for 4 h. The reaction mixture was washed with 5% aqueous HCl (2 x 50 mL) and aqueous NaHC03 (100 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc-hexanes as eluant. The title compound was obtained as a white foam. (1.45 g; 90%).

Anal: (C29H39N3O4S)

Calc. C, 65.75; H, 7.53; N, 7.77 0.15 EtOAc, 0.1 H2O

Found C, 65.90; H, 7.49; N, 7.80 TLC: Rf 0.38 (1:3 EtOAc:hexanes) HPLC (method A): retention time 12.18 min FAB MS: m/z 526 (M+ + H)

EXAMPLE 40

l-((7,7-D_methyl-2-endo-methyl(benzyloxy-carbonyl)amino- bicyclo(2.2.1 )-heptan- 1 -yl)methanesuIfonyl)4-(2-methyl- henyl)piperazine

To a 0°C stirred solution of l-((7,7-dimethyl-2-endo- beι_zyloxycarbonylamino-bicyclo(2.2.1 )-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (1.46 g; 2.78 mmol) in DMF (20 mL) was added iodomethane (0.435 mL; 7.00 mmol) and sodium hydride (0.139 mg of a 60% dispersion in mineral oil; 3.48 mmol). The solution was stirrred at 0°C for 1 h and then at ambient temperature for 18 h. The reaction mixture was treated with HOAc (1 mL) and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aqueous NaHCθ3 (2 x 50 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:5 EtOAc-hexanes as eluant. The title compound was obtained as a white foam. (1.40 g; 93%).

Anal: (C30H41N3O4S)

Calc. C, 66.03; H, 7.70; N, 7.700.33 H2O

Found C, 66.03; H, 7.63; N, 7.68 TLC: Rf 0.44 (1 :4 EtOAc exanes) HPLC (method A): retention time 12.86 min FAB MS: m/z 540 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.25-7.45 (m, 5H), 7.20 (m, 2H), 7.02 (m, 2H), 5.11 (AB quartet, 2H), 4.83 (m, IH), 3.03 (s, 3H), 2.32 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H)

EXAMPLE 41

l-((7,7-ciimethyl-2-endo-methyl(2S-amino-4-(methylsulfony l)- butanoyl)amino-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4- (2- methylphenylj-piperazine

To a stirred, argon purged solution of l-((7,7- dime yl-2-endo-memyl(benzyloxyc-ut)onyl)am__no- bicyclo(2.2.1)heptan-l-yI)methane-sulfonyl)-4-(2- methylphenyl)piperazine (1.1 g; 2.0 mmol) in 96:4 MeOH-HC02H ° (25 mL) was added palladium black (0.4 g). The reaction mixture was stirrred for 16 h at ambient temperature. The catalyst was removed by filtration through Celite, and the filtrate solvents were removed under seduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 s CHCl3:MeOH:NH40H as eluant. The product, l-((7,7-dimethyl- 2-endo-memyl-amino-bicyclo(2.2. l)heptan-l -yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine, was obtained as a white foam. (0.79 g; 95%). To a stirred solution of l-((7,7-dimethyl-2- endo-methylamino-bicyclo(2.2. l)-heptan- 1 -yl)methanesulfonyl)-4- o (2-methylphenyl)-piperazine (0.700 g; 1.73 mmol) in CHC13 (60 mL) was added the acid fluoride of N ^a -Fmoc-L-methionine sulfone (1.23 g; 3.03 mmol) and DIEA (0.52 mL; 3.0 mmol). The mixture was stirred at ambient temperature for 24 h, and then extracted with 5% aqueous HCl (30 mL), water (30 mL), and ⁵ aqueous NaHC03 (2 x 30 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in DMF (10 mL), and to the solution was added diethylamine (2 mL). The mixture was stirred at ambient temperature for 6 h. The solvents were removed under ° reduced pressure and the residue was purified by pressurized sihca gel column chromatography using 95:5:0.5 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as a foam from CHCl3-ether (0.71 g; 61%).

Anal: (C27H44N4O5S2)

Calc. C, 56.26; H, 7.80; N, 9.400.1 CHCI3, 0.2 ether

Found C, 56.21; H, 7.79; N, 9.22

TLC: Rf 0.10 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time 9.01 min FAB MS: m/z 569 (M+ + H) iH NMR (300 MHz, CDCI3): d 7.18 (m, 2H), 7.03 (m, 2H), 5.20 (ddd, IH), 3.95 (dd, J=, 9.3, 4.1 Hz, IH), 3.18 (s, 3H), 2.91 (s, 3H), 2.30 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H)

EXAMPLE 42

l-((7,7-Dimethyl-2-endo-methyl(2s-dimethylanMno-4- (methylsulfonyl)-butanoyl) _unino-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine To a stirred solution of 1 -((7,7-dimethyl-2-endo- memyl(2S-amino-4-(methylsulfonyl)butanoyl)amino- bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (150 mg; 0.264 mmol) in 1:1 HOAc:MeOH (6 mL) was added 37% aqueous formaldehyde (1 mL) and NaBH3CN (30 mg; 0.47 mmol). The solution was stirrred at ambient temperamre for 4 h. Aqueous NaHCθ3 (1 mL) was added and the solvents were removed under reduced pressure. The residue was suspended in EtOAc (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1 % TFA. The TFA salt of the title compound was obtained as a lyophilized powder.

Anal: (C29H48N4O5S2)

Calc. C, 44.88; H, 5.94; N, 6.16 2.5 TFA, 1.5 H2O

Found C, 44.80; H, 5.94; N, 6.18 TLC: Rf 0.45 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time 9.04 min FAB MS: m/z 597 (M+ + H)

iH NMR (400 MHz, CDCI3): d 7.2-7.3 (m, 4H), 5.15 (m, IH), 4.79 (br t, IH), 3.21 (s, 3H), 2.98 (s, 3H), 2.95 (s, 6H), 2.43 (s, 3H), 1.07 (s, 3H), 0.97 (s, 3H)

EXAMPLE 43

l-((7,7-Dimethyl-2-endo-(4-imidazolyl)acetyl)__mino- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methyI- henyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo- amino-bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (1.50 g; 3.84 mmol) in DMF (30 mL) was added 4-imidazole acetic acid hydrochloride (0.938 g; 5.76 mmol), BOP (2.13 g; 4.80 mmol), and DIEA (2.61 mL; 15.0 mmol). The reaction mixture was stiπred for 24 h at ambient temperamre, and the solvent was removed under reduced pressure. The residue was suspended in EtOAc (100 mL) and filtered through Celite to remove red polymer. The filtrate was washed with aqueous NaHC03 (2 x 50 mL) and water (2 x 50 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as white foam.

FAB MS: m/z 500 (M+ + H) 1H NMR (CDC13):

EXAMPLE 44

1 -(( ⁷ ,7-Dimethyl-2-endo-(2-(4-imidazolyl)propanoyl)-amino- bicyclo-(2.2.1 )heptan-l -yl)methanesul onyI)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyI-2-endo- amino-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-

methylphenyl)piperazine (1.1 g; 2.8 mmol) in DMF (25 mL) was added 2-(l-benzyloxymethyl-5-imidazolyl)propionic acid hydrochloride (0.920 g; 3.10 mmol), BOP (1.35 g; 3.05 mmol), and DIEA (1.50 mL; 8.61 mmol). The reaction mixture was stirrred for 1 h at ambient temperature, and more DIEA (ca. 0.2 mL) was added to bring the mixture to pH 8. After another 1 h, the solvent was removed under reduced pressure. The residue was dissolved in CHCI3 (150 mL) and washed with aqueous NaHC03 (2 x 50 mL) and water (2 x 50 mL). The organic phase was dried (MgSθ4), filtered, and the solvent was removed under reduced pressure to give a solid. Recrystallization from EtOAc gave crystals (0.51 g) which, by H NMR analysis, proved to be a 90:10 mixture of isomers (product A). The filtrate was purified by pressurized silica gel column chromatography using 95:5 CHCl3:MeOH as eluant, giving a white foam (1.0 g). iH NMR indicated this material to be a 1:2 mixture of isomers (product B). Products A and B were individually deblocked by hydrogenation for 24 h at ambient temperature in 3:1 MeOH:HOAc using 25 weight % palladium black under 1 atmosphere of hydrogen. The catalyst was removed by filtration through Celite and the solvents were removed under reduced pressure. Catalyst was removed by filtration through Celite, and the filtrate solvents were removed under reduced pressure. The residue derived from product A was purified by preparative reverse phase HPLC using a water- acetonitrile gradient containing 0.1 % TFA. The TFA salt of the title compound (90:10 mixture by ^H NMR) was obtained as a lyophilized powder. Product B was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as white foam from CHCI3 -ether (1 :2 mixture by ^H NMR). The two isomers had identical chromatographic behavior.

Anal: (C27H37N5O3S)

Calc. C, 60.36; H, 7.49; N, 12.460.25 CHCI3, q.25 ether

Found C, 60.49; H, 7.26; N, 12.48

TLC: Rf 0.30 (93:7:0.7 CHCl3:MeOH:NH40H) HPLC (method A): retention time 8.79 min FAB MS: m/z 514 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.75 (br s, IH), 7.20 (m, 2H), 7.0 (m, 3H), 4.40 (m, IH), 2.30, 2.29 (two singlets, ca. 2:1 ratio, 3H), 1.57, 1.53 (two doublets, J=7 Hz, ca. 2:1 ratio, 3H), 1.00 (s, 3H), 0.96 (s, 3H)

Anal: (C27H37N5O3S) Calc. C, 48.91; H, 5.36; N, 9.03 2.3 TFA

Found C, 48.99; H, 5.21; N, 9.03

TLC: Rf 0.30 (93:7:0.7 CHCl3:MeOH:NH40H)

HPLC (method A): retention time 8.79 min

FAB MS: m/z 514 (M+ + H) lH NMR (400 MHz, CDCI3): d 8.43 (s, IH), 7.70 (d, IH), 7.25

(m, 2H), 7.20 (s, IH), 7.15 (m, 2H), 4,40 (m, IH), 4.03 (q, J=7Hhz,

IH), 2.38 (s, 3H), 1.57 (d, J=7Hz, 3H), 1.00 (s, 3H), 0.95 (s, 3H)

EXAMPLE 45

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(1-n- (methoxycarbonyl-ethyl)prolyl)amino)propylbicyclo- (2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methyl- phenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -(L-prolyl)amino)propyl- (2.2.1 )bicycloheptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (1.50 g; 2.74 mmol) in methanol (15 mL) was added methyl acrylate (0.310 mL; 3.43 mmol). After 72 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C33H52N4O6S)

Calc. C, 53.10; H, 6.59; N, 6.82 1.65 TFA

Found C, 53.09; H, 6.58; N, 6.88 TLC: Rf 0.55 (95:5 CHCl3:MeOH)

HPLC (method A): retention time 9.45 min

FAB MS: m/z 633 (M+ + H) iH NMR (400 MHz, CDC13): d 7.18 (m, 2H), 7.03 (m, 2H), 4.55

(m, IH), 3.72 (s, 3H), 2.32 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 1.01

(d, J=6 Hz, 3H)

EXAMPLE 46

1 -((7,7-DimethyI-2-exo-hydroxy-2-endo-2-(l -(l-n-(carboxyethyl)- prolyl)amino)propyl-bicyclo(2.2.1 )-heptan-l -yl)methanesulfonyl)- 4-(2-methyIphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(L-N-(methoxycarbonylethyl)- prolyl)amino)propyl-(2.2.1 )bicyclo-heptan-l -yl)methanesulf onyl)- 4-(2-methylphenyl)piperazine (1.00 g; FW=821; 1.22 mmol) in THF (15 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder. Anal: (C32H50N4O6S)

Calc. C, 51.88; H, 6.34; N, 6.80 1.8 TFA Found C, 51.87; H, 6.28; N, 6.82 TLC: Rf 0.40 (80:20:2 CHCl3_MeOH:NH4θH)

HPLC (method A): retention time 8.88 min FAB MS: m/z 619 (M ⁺ + H) iH NMR (400 MHz, CDCI3): d 8.50 (br s, IH), 7.20 (m, 2H), 7.05 (m, 2H), 2.33 (s, 3H),.1.12 (s, 3H), 1.03 (s, 3H), 0.99 (d, J=6 Hz, 3H)

EXAMPLE 47

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(3- piperidinylcarbonyl)-amino)propyl-bicyclo(2.2. l)heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2.1 )bicycloheptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (2.50 g; 5.57 mmol) in DMF (35 mL) was added N-Fmoc-piperidine-3- carboxylic acid (2.15 g; 6.13 mmol), BOP (2.75 g; 6.20 mmol), and DIEA (2.16 mL; 12.4 mmol). After 16 h, diethylamine (6 mL) was added and the solution was stirred at ambient temperamre for 4 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (150 mL) and washed with aquous NaHCθ3 (2 x 75 mL) and Water (2 x 75 mL). The organic phase

was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized sihca gel column chromatography, using 93:7:0.7 CHCl3:MeOH:NH4θH as eluant. The title compound (1:1 mixture of diastereomers) was obtained as a white foam.

Anal: (C30H48N4O4S)

Calc. C, 56.37; H, 7.49; N, 8.540.8 CHCI3

Found C, 56.49; H, 7.44; N, 8.50 TLC: Rf 0.40 (90:10:1 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time 8.67 min

FAB MS: m/z 561 (M+ + H)

1-H NMR (300 MHz, CDCI3): d 7.50 (br s, IH), 7.20 (m, 2H),

7.02 (m, 2H), 2.30 (s, 3H), 1.17 (s, 3H), 1.00-1.04 (overlapping singlet and doublet, 6H)

EXAMPLE 48

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(3-(l - memoxycarbonyl-ethyl)piperidinylcarbonyl)-amino)propyl- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(3-piperidinylcaιbonyl)-amino)propyl- (2.2.1 )bicycloheptan- 1 -yl)methansulfonyl )-4-(2-

methylphenyl)piperazine (0.50 g; 0.89 mmol) in methanol (10 mL) was added methyl acrylate (0.120 mL; 1.34 mmol). After 72 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of title compound (1:1 mixture of diastereomers) was obtained as a lyophilized powder.

Anal: (C34H54N4O6S) Calc. C, 55.40; H, 7.06; N, 7.08 1.25 TFA, 0.1 H2O

Found C, 55.39; H, 7.05; N, 7.03 TLC: Rf 0.35 (95:5 CHCl3:MeOH)

HPLC (method A): retention time 10.71 min FAB MS: m/z 647 (M+ + H) lH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.02

(m, 2H), 3,72, 3,69 (two singlets, 3H), 2.32, 2.31 (two singlets, 3H), 1.16, 1.15 (two singlets, 3H), 0.98-1.04 (two coincident singlets and two overlapping doublets, 6H)

EXAMPLE 49

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(3-(l -carboxyethyl)- piperidinylcarbonyl)amino)-propylbicyclo(2.2.1 )heptan- 1 - yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine _

O

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -(3-(l -methoxycarbonyl)piperi- ά^ylcaιbonyl)amino)propyl(2.2.1 )-bicycloheptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.30 g; 0.46 mmol) in THF (10 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient o containing 0.1% TFA. The TFA salt oftitle compound (1:1 mixture of diastereomers) was obtained as a lyophilized powder.

Anal: (C33H52N4O6S)

Calc. C, 51.59; H, 6.44; N, 6.54 1.9 TFA, 0.4 H2O s Found C, 51.60; H, 6.44; N, 6.83

TLC: Rf 0.15 (80:20:2 CHC_3:MeOH:NH4θH)

HPLC (method A): retention time 10.27 min

FAB MS: m/z 633 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 2H), 7.05 (m, 2H), 2.39, ° 2.32 (two singlets, 3H), 1.12, 1.11 (two singlets, 3H), 0.95-1.03

(two coincident singlets and two overlapping doublets, 6H)

5 EXAMPLE 50

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(3-(l - ethoxyca__bonyl-memyl)piperidinylcar-bonyl)arnino)propyl- bicyclo(2.2. l)heptan-l -yl)methanesulfonyl)-4-(2- methylphenyl .piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(3-piperidinylcarbonyl)amino)-propyl- (2.2.1 )bicycloheptan-l -yl)methanesulfonyl)-4-(2-methyl- phenyl)piperazine (0.50 g; 0.89 mmol) in DMF (5 mL) was added ethyl bromoacetate (0.110 mL; 0.99 mmol) and DIEA (0.172 mL; 0.99 mmol). After 24 h at ambient temperature, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL) and washed with 5% aqueous citric acid (25 mL), water (25 mL), and aqueous NaHCθ3 (25 mL). The organic phase was dried (MgS04), filtered, and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using 1:1 EtOAc:CHCl3 as eluant. The title compound (1:1 mixture of diastereomers) was obtained as a white foam.

Anal: (C34H54N4O6S)

Calc. C, 58.66; H, 7.77; N, 7.93 0.5 CHCI3

Found C, 58.87; H, 7.83; N, 7.88 TLC: Rf 0.28 (1:1 CHCl3:EtOAc) HPLC (method A): retention time 9.76 min FAB MS: m/z 647 (M+ + H) iH NMR (300 MHz, CDCI3): d 8.2 (very br s, IH), 7.18 (m, 2H), 7.03 (m, 2H), 4.20 (two very closely spaced quartets, 2H), 2.30, 2.31 (two singlets, 3H), 1.28 (t, J=7 Hz, 3H), 1.07, 1.08 (two singlets, 3H), 1.03-1.08 (two coincident singlets and two overlapping doublets, 6H)

EXAMPLE 51

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(3-(l- cart>oxymemyl)-piperidinylcarbonyl)amino)- propylbicyclo(2.2. l)heptan-l -yl)methane-sulfonyl)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(3-(l-methoxycarbonyl)- piperidinylcarbonyl)amino)propyl-(2.2.1)bicycIoheptan-l- yl)methanesulfonyl)-4-(2-methylphenyI)piperazine (0.360 g; 0.555 mmol) in THF (5 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was made acidic by the addition of HO Ac (1 mL) and evaporated under reduced pressure. The residue was suspended in CH2CI2 and filtered. The filtrate was evaporated under reduced pressure several times from CH2CI2 to give the title compound (1:1 mixture of diastereomers) as a white foam. Anal: (C32H50N4O6S) Calc. C, 58.27; H, 7.62; N, 7.99 1.0 NaOAc

Found C, 58.47; H, 7.71; N, 7.90 TLC: Rf 0.55 (85:15 CHCl3:MeOH) HPLC (method A): retention time 8.77 min FAB MS: m/z 619 (M+ + H)

iH NMR (300 MHz, CD3OD): d 7.15 (m, 2H), 7.05 (d, J=7.3 Hz, IH), 6.96 (t, J=7.3 Hz, IH), 2.31 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.98 (d, J=6 Hz, 3H)

EXAMPLE 52

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(l-n-(ethoxy- carboxymethyl)-prolyl)amino)propyl-bicyclo-(2.2.1 )heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -(L-prolyl)amino)propyl(2.2.1 )- bicycloheptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)- piperazine (0.20 g; 0.37 mmol) in DMF (5 mL) was added ethyl bromoacetate (0.045 mL; 0.40 mmol) and DIEA (0.071 mL; 0.41 mmol). After 24 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C33H52N4O6S)

Calc. C, 54.25; H, 6.79; N, 7.07 1.4 TFA Found C, 54.25; H, 6.78; N, 7.02

TLC: Rf 0.50 (1:1 EtOAc:CHCl3)

HPLC (method A): retention time 9.68 min

FAB MS: m/z 633 (M+ + H) iH NMR (400 MHz, CD3OD): d 7.17 (m, 2H), 7.06 (d, J=6Hz,

IH), 6.98 (t, J=6Hz, IH), 4.25 (m, 3H), 4.08 (d J=15 Hz, IH), 2.32

(s, 3H), 1.27 (t, J=7 Hz, 3H), 1.18 (s, 3H), 1.03 (s, 3H), 1.01 (d,

J=6 Hz, 3H)

EXAMPLE 53

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(l-n- (carboxymethyl)-prolyl)am_ino)propyl-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2- exo- hydroxy-2-endo-2-(l-(L-(N-ethoxycarbony_methyl)- prolyl)amino)propyl-(2.2.1 )bicycloheptan- 1 -yl)methane-sulf onyl)- 4-(2-methylphenyl)piperazine (0.20 g; 0.32 mmol) in THF (5 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an aceto- nitrile- water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C31H48N4O6S)

Calc. C, 52.64; H, 6.43; N, 7.22 1.5 TFA

Found C, 52.49; H, 6.51; N, 7.22 TLC: Rf 0.40 (80:20:2 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time 8.79 min

FAB MS: m/z 605 (M+ + H) iH NMR (400 MHz, CD3OD): d 7.17 (m, 2H), 7.07 (d J=5 Hz,

IH), 6.99 (t, J=5 Hz, IH), 4.30 (dd, J=4, 5 Hz, IH), 4.21 (d, J=14

Hz, IH), 4.04 (d, J=14 Hz, IH), 2.32 (s, 3H), 1.18 (s, 3H), 1.03 (s,

3H), 1.01 (d, J=7 Hz, 3H)

EXAMPLE 54

1 -((7 ,7-Dimethyl-2-eχo-hydroxy-2-endo-2-(l -(4- piperidinylcarbonyl)-amino)propyl-bicyclo(2.2.1 )heptan-l • yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -amino)propyl-(2.2.1 )bicycloheptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (1.50 g; 3.34 mmol) in DMF (20 mL) was added N-Fmoc-piperidine-4- carboxylic acid (1.29 g; 3.67 mmol), BOP (1.64 g; 3.70 mmol), and DIEA (1.28 mL; 7.34 mmol). After 16 h, diethylamine (5 mL) was added and the solution was stirred at ambient temperamre for 4 h. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an

acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C30H48N4O4S)

Calc. C, 51.93; H, 6.43; N, 7.15 1.95 TFA, 0.05 H2O

Found C, 51.93; H, 6.36; N, 7.28

TLC: Rf 0.15 (90:10:1 CHCl3:MeOH:NH40H)

HPLC (method A): retention time 8.33 min

FAB MS: m/z 561 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.20 (m, 3H), 7.08 (m, 2H), 2.33

(s, 3H), 1.14 (s, 3H), 1.02 (s, 3H), 1.00 (d, J=6 Hz, 3H)

EXAMPLE 55

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(4-(l- memoxyca_±»onylemyl)-piperio^ylcarbonyl)-amino)propyl- bicyclo(2.2. l)heptan-l -yl)methane-sulf onyl)-4-(2-methyl- phenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(4-piperidmylcarbonyl)amino)-propyl- (2.2.1 )bicycloheptan-l -yl)methane-sulf onyl)-4-(2- methylphenyl)piperazine (0.30 g; 0.53 mmol) in methanol (5 mL) was added methyl acrylate (0.072 mL; 0.80 mmol). After 48 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase

HPLC using an acetonitrile- water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C34H54N4O6S)

Calc. C, 53.04; H, 6.65; N, 6.60 1.75 TFA, 0.15 H2O

Found C, 53.05; H, 6.62; N, 6.69

TLC: Rf 0.25 (95:5 CHCl3:MeOH)

HPLC (method A): retention time 9.02 min

FAB MS: m/z 647 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.45 (br t, IH), 7.21

(m, 2H), 7.09 (m, 2H), 3.72 (s, 3H), 2.33 (s, 3H), 1.15 (s, 3H), 1.00-1.02 (overlapping s and d, 6H)

EXAMPLE 56

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(4-(l-carboxye thyl)- piperidinylcarbonyl)amino)ρropyl-bicyclo-(2.2.1 )heptan-l - yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine ^■

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -(3-(l -methoxycarbonyl)pipe- ridinylcarbonyl)amino)propyl-(2.2.1 )bicycloheptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.15 g; 0.23 mmol) in THF (5 mL) was added 1 M NaOH until a pH 10

solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt oftitle compound was obtained as a lyophilized powder.

Anal: (C33H52N4O6S)

Calc. C, 53.09; H, 6.65; N, 6.84 1.6 TFA, 0.2 H2O

Found C, 53.08; H, 6.66; N, 6.85

TLC: Rf 0.10 (80:20:2 CHCl3:MeOH:NH40H)

HPLC (method A): retention time 8.72 min FAB MS: m/z 633 (M+ + H) lHNMR (400 MHz, CDCl3): d 7.38 (br s, IH), 7.18 (m, 2H), 7.03 (m, 2H), 2.29 (s, 3H), 1.13 (s, 3H), 0.98-1.01 (overlapping s and d, 6H)

EXAMPLE 57

l-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l-(3-(l- ethoxycarbonyl-memyl)piperidinylcar-bonyl)amino)propyl- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l-(3-piperidinylcarbonyl)amino)-propyl- (2.2.1 )bicycloheptan-l -yl)methanesulf onyl)-4-(2-

methylphenyl)piperazine (0.20 g; 0.36 mmol) in DMF (5 mL) was added ethyl bromoacetate (0.044 mL; 0.40 mmol) and DIEA (0.070 mL; 0.40 mmol). After 24 h at ambient temperature, the solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt of title compound was obtained as a lyophilized powder.

Anal: (C34H54N4O6S) Calc. C, 52.81; H, 6.67; N, 6.57 1.75 TFA, 0.35 H2O Found C, 52.80; H, 6.64; N, 6.69 TLC: Rf 0.35 (95:5 CHCl3:MeOH)

HPLC (method A): retention time 9.26 min FAB MS: m/z 647 (M+ + H) lH NMR (400 MHz, CDCI3): d 7.19 (m, 2H), 7.04 (m, 2H), 4.26 (q, J=7 Hz, 2H), 3.85 (s, 2H), 2.32 (s, 3H), 1.29 (t, J=7 Hz, 3H), 1.14 (s, 3H), 1.02-1.05 (overlapping s and d, 6H)

EXAMPLE 58

1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(l -(4-(l • carboxymethyl)-piperidinylcarbonyl)amino)propyl- bicyclo(2.2.1 )heptan- 1 -yl)methane-sulfonyl)-4-(2- methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-exo- hydroxy-2-endo-2-(l -(3-(l -methoxycarbonylmethyl)- piperidinylcarbonyl)amino)propyl-(2.2.1 )bicycloheptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.15 g; 0.23 mmol) in THF (5 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1 % TFA. The TFA salt ^" of title compound was o obtained as a lyophilized powder.

Anal: (C32H50N4O6S)

Calc. C, 53.23; H, 6.82; N, 7.18 1.3 TFA, 0.75 H2O

Found C, 53.20; H, 6.81; N, 7.18 5 TLC: Rf 0.15 (80:20:2 CHCl3:MeOH;NH4θH)

HPLC (method A): retention time 8.59 min FAB MS: m/z 619 (M+ + H) iH NMR (400 MHz, CDCI3): d 7.35 (br s, IH), 7.17 (m, 2H), 7.02 (m, 2H), 3.90 (s, 2H), 2.30 (s, 2H), 1.13 (s, 3H), 1.01 (s, 3H), o 0.97 (d, J=6 Hz, 3H)

EXAMPLE 59

l-((7,7-Dimemyl-2-endo-(2s-diethylamino-4-(methyl- sulfonyl)butyramido)-bicyclo(2.2.1)heptan-l -yl)methanesulfonyl)- 4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (100 mg; 0.18 mmol) in methanol containing 1 % acetic acid (2 mL) was added acetaldehyde (0.033 mL; 0.6 mmol) and sodium cyanoborohydride (10 mg; 0.18 mmol). After 2 h, the reaction was quenched with sodium bicarbonate solution (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), brine (2 x 25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 95:5:0.5 CHCl3:CH3θH:NH4θH. The title compound was obtained as a white foam by evaporation under reduced pressure from ether-chloroform in 85% yield.

Analysis: C30H50N4O5S2, 0.7 CHCI3, 0.2 (CH3CH2)2θ calc. C 53.65 H 7.51 N 8.01 found 53.64 7.50 8.13 TLC: Rf = 0.38 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 9.66 min, purity = 95% FAB MS: m/z = 611 (M + H+)

EXAMPLE 60

l-((7,7-Dimemyl-2-endo-(2s-emoxycarbonylmemyl-amino-4- (memyl-suIfonyl)butyramido)-bicyclo(2.2.1)-heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- _fflήno*4-(memylsulfonyl)butyramido)-bicyclo(2.2.1)-heptan- l- yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (200 mg; 0.36 mmol) in DMF (3 mL) was added DIEA (0.070 mL; 0.40 mmol) and ethyl bromoacetate (0.044 mL; 0.40 mmol). After 24 h, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with 5 wt% aqueous citric acid (2 x 25 mL) and saturated sodium bicarbonate solution (2 x 25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by sihca gel flash column chromatography eluting with 95:5 CHCl3:CH3θH. The title compound was obtained as a white foam by evaporation under reduced pressure from EtOAc-hexane in 75% yield.

Analysis: C30H48N4O7S2, 0.4 EtOAc, 0.05 hexane calc. C 56.30 H 7.69 N 8.23

found C 56.22 H 7.70 N 8.25 TLC: Rf = 0.35 (95:5 CHCl3_MeOH) HPLC (method A): retention time = 9.67 min, purity = 99+% FAB MS: m/z = 641 (M + H+)

EXAMPLE 61

1 -((7 ,7-Dimethyl-2-endo-(2s-caιi3θxymethylamino-4- (methylsulf onyl)-butyramido)-bicyclo(2.2.1 )heptan- 1 - o yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- ₅ ethoxycarbonyl-memylamino-4-(methyl-sulf onyl)butyramido)- bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine (50 mg; 0.08 mmol) in ethanol, was added 1 N aqueous sodium hydroxide to obtain a pH 13 reaction solution. After 24 h, the reaction was acidified to pH 2 with 5% o aqueous HCl and the solvent was removed under reduced pressure.

The residue was taken up in methylene chloride (25 mL), washed with brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was triturated in ether and filtered to give the title compound as a white solid in 75% yield.

Analysis: C28-H44N4O7S2, 0.5 NaCl calc. C 52.38 H 6.91 N 8.73 found C 52.43 H 6.55 N 8.80 TLC: Rf = 0.2 (90:10:0.2:0.2 CHCl3:MeOH:H2θ:HOAc)

HPLC (method A): retention time = 8.91 min, purity = 99% FAB MS: m/z = 613 (M + H+)

EXAMPLE 62

1 -((7 ,7-Dimethyl-2-endo-(2s-aπ_ino-4-(methylsulf onyl)- butyramido)-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methyl-5-fluorophenyl)-piperazine

The title compound was prepared from l-((7,7- dimemyl-2-endo-_unino-bicyclo(2.2.1)heptan-l-yl)methane- sulfonyl)-4-(2-methyl-5-fluoro-phenyl)piperazine and Boc-L- methionine sulfone using the procedures set forth in Examples 35 and 36. The crude product was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in 85% yield.

Analysis: C26H41FN4O5S2, 0.3H20, 1.7 CF3COOH calc. C 45.74 H 5.65 N 7.26

found C 45.74 H 5.65 N 7.50 TLC: Rf = 0.18 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.86 min, purity = 99% FAB MS: m/z = 573 (M + H+)

EXAMPLE 63

1 -((7 ,7-Dimethyl-2-endo-(2s-dimethylamino-4-(methyl-sulf onyl)- butyramido)-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methyl-5-fluorophenyl.piperazine

The title compound was prepared from l-((7,7- dimemyl-2-endo-(2S-_unino-4-(methylsulfonyl)-butyramido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methyl-5- fluorophenyl)piperazine using the procedure set forth in Example 38. The crude product was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in 90% yield.

Analysis: C28H45FN4O5S2, 0.05 H2O, 1.65 CF3COOH calc. C 47.59 H 5.97 N 7.09 found C 47.56 H 5.91 N 7.15 TLC: Rf = 0.39 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.82 min, purity = 99% FAB MS: m/z = 601 (M + H+)

EXAMPLE 64

l-((7,7-Dimethyl-2-endo-(2s-(l-piperidinyl)-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- aπ__ino* -(me ylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)mem_mesulfonyl)-4-(2-methyl-phenyl)piperazine (100 mg; 0.18 mmol) in methanol containing 1% by volume of acetic acid in methanol (5 mL) was added glutaraldehyde (25 wt% in water; 0.005 mL; 0.22 mmol) and sodium cyanoboro-hydride (30 mg; 0.54 mmol). After 3 h, the reaction was quenched with aqueous sodium bicarbonate solution (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), brine (2 x 25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title compound was obtained as a white foam in 90% yield.

Analysis: C31H50N4O5S2, 0.85 H2θ, calc. C 58.33 H 8.17 N 8.78 found C 58.31 H 7.77 N 8.67 TLC: Rf = 0.45 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.72 min, purity = 99+% FAB MS: m/z = 623 (M + H+)

EXAMPLE 65

1 -((7,7-Dimethyl-2-endo-(2s-(2-hydroxyethyl)amino-4- (methylsulfonyl)-butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine

A stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)-iperazine (310 mg, 0.56 mmol) in ethanol (10 mL) was cooled to 0°C. Ethylene oxide was bubbled through the solution, the reaction vessel was sealed, and the reaction mixture was warmed to 70°C. After 48 h, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient elution of 97:3 to 93:7 CHCl3:MeOH to separate the faster running bis- alkylated product from the mono-alkylation product. The title compound was obtained as a white foam by evaporation under reduced pressure from CHCl3-MeOH in 60% yield.

Analysis: C28-H46N406S2, 0.4 CHCI3, 0.15 MeOH, calc. C 52.64 H 7.27 N 8.60 found C 52.67 H 7.27 N 8.37 TLC: Rf = 0.15 (93:7 CHCl3:MeOH) HPLC (method A): retention time = 8.72 min, purity = 99% FAB MS: m/z = 599 (M + H+)

EXAMPLE 66

l-((7,7-Dimethyl-2-endo-(2s-(4-morphoIinyl)-4-(methyl-sul fonyl)- butyramido)-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenv piperazine

To a solution of l-((7,7-dime yl-2-endo-(2S-amino- 4-(methylsulfonyl)butyramido)-bicyclo(2.2.1)heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg, 0.18 mmol) in DMF (3 mL) was added bis(2-chIoroethyl)-ether (0.029 mL; 0.25 mmol), sodium iodide (75 mg; 0.5 mmol), and sodium carbonate (80 mg; 0.75 mmol). The mixture was flushed with argon and heated at 130°C for 6 h. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and washed with water (2 x 25 mL), saturated

aqueous sodium bicarbonate (2 x 25 mL), brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in 25% yield.

Analysis: C30H48N4O6S2, 3.O CF3CO2H, 0.5 H2O calc. C 44.31 H 5.37 N 5.74 found C 44.20 H 5.04 N 6.10 TLC: Rf = 0.63 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 9.08 min, purity = 100% FAB MS: m z = 625 (M + H+)

EXAMPLE 67

1 -((7 ,7-Dimethyl-2-endo-(2s-cy -momethylamino-4- (methylsulf onyl)-butyramido)-bicyclo(2.2.1 )heptan- 1 • yl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine

C— N

To a solution of l-((7,7-dimethyl-2-endo-(2S-amino- 4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )hep tan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg, 0.18

mmol) in chloroform (5 mL) was added DIEA (0.037 mL; 0.21 mmol) followed by iodoacetonitrile (0.015 mL; 0.21 mmol). After 24 h, the reaction was diluted with chloroform (50 mL) and washed with water (25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography using 97:3 dichloromethane:methanol as eluant. The title compound was obtained as a white foam in 70% yield.

Analysis: C28H43N5O5S2, 0.5 H2O calc. C 55.79 H 7.36 N 11.67 found C 56.15 H 7.42 N 11.32 TLC: Rf = 0.45 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 9.78 min, purity = 100% FAB MS: m/z = 594 (M + H+)

EXAMPLE 68

1 -((7,7-D_-metliyl-2-endo-(2s-(4-tetra-hydropyranyl)amino-4- (methylsulfonyl)-butyramido)-bicyclo(2.2. l)heptan-l - v methanesulfonylV4-r2-methyl-phenyl piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1)-heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (200 mg; 0.36 mmol) in methanol containing 1 % by volume of acetic acid (4 mL) was added 4-5 molecular sieves (3A), tetrahydropyran-4-one (0.037 mL, 0.37 mmol) and sodium cyanoborohydride (20 mg; 0.36 mmol). After 2 h, the reaction was quenched with aqueous sodium bicarbonate (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 o mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title compound was obtained in 90% yield as a white foam.

5 Analysis: C31H50N4O6S2, 0.45 EtOAc, calc. C 58.05 H 7.96 N 8.26 found C 57.81 H 7.71 N 8.28 TLC: Rf = 0.27 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 8.29 min, purity = 99% o FAB MS: m/z = 639 (M + H+)

EXAMPLE 69

1 -((7,7-Dimethyl-2-endo-(2s-(2-ammoethyl)amino-4- ⁵ (methylsulfonyl)-butyramido)-bicyclo(2.2.1 )heptan- 1 - v methanesulfonyl ^' )-4-(2-methyl-phenyl piperazine

0

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo (2.2.1 )-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg; 0.36 mmol) in methanol containing 1% by volume of acetic acid (4 mL) was added 4-5 molecular sieves (3A), N-Boc-glycinal (62 mg, 0.39 mmol) and sodium cyanoboro-hydride (20 mg; 0.36 mmol). After 2 h, the reaction was quenched with aqueous sodium bicarbonate (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 95:5 chloroform:methanol as eluant to give l-((7,7-dimethyl-2-endo- (2S-(2-(tert-butyloxycar-bonylamino)ethyl)amino-4- (memylsulfonyl)butyramido)-bicyclo(2.2.1)heptan-l- yl)methanesulfonyl)-4-(2-methylphenyI)piperazine in 80% yield. This compound was dissolved in methylene chloride (7 mL) and to the solution was added trifluoroacetic acid (7 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in methylene chloride (70 mL) and washed with saturated aqueous sodium bicarbonate (3 x 100 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title compound was

lyophilized from dioxane-water to give a white powder in 90% yield.

Analysis: C28H47N5O5S2, 0.5 C4H8O2, 1.5 H2O calc. C 53.87 H 8.14 N 10.47 found C 54.04 H 8.96 N 10.44 TLC: Rf = 0.08 (90:10:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.30 min, purity = 99% FAB MS: m/z = 598 (M + H+)

EXAMPLE 70

l-((7,7-Dimethyl-2-endo-(2r-amino-4-(methylsulfonyl)- butyramido)-bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenv piperazine

l-((7,7-Dimethyl-2-endo-(2R-(tert-butyloxy- carbonyl)amino-4-(methylthio)butyramido)-bicyclo(2.2.1 )-heptan- 1 -yl)methanesulf onyl)-4-(2-methy lphenyl)-piperazine was prepared from Boc-D-methionine and 1 -((7,7-dimethyl -2-endo- amino-bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine using the procedure set forth in Example 35. l-((7,7-Dimethyl-2-endo-(2R-(tert-butyloxycarbonyl)amino-4- (methylthio)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg; 0.32

mmol) was dissolved in 3:1 MeOH:water (25 mL) and to the solution was added sodium acetate (200 mg; 2.6 mmol) and Oxone® (0.80 g; 1.3 mmol). After 24 h, the solvents were removed under reduced pressure and the residue was purified by sihca gel flash column chromatography using 90: 10: 1

CHCl3:MeOH:NH4θH as eluant to give l-((7,7-dimethyl-2-endo-

(2R-(tert-butyloxycarbonyl)amino-4-(methylsulfonyl)butyra mido)- bicyclo(2.2. l)heptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine-4-N-oxide as a foam from chloroform in 70% yield. This product was dissolved in THF (3 mL) and treated with triphenylphosphine (79 mg; 0.35 mmol). After 24 h the solvent was removed under reduced pressure and the residue was purified by sihca gel flash column chromatography using 1 :1 EtOAc:hexane as eluant to give l-((7,7-dimethyI-2-endo-(2R-(tert- butyloxycarbonyl)-amino-4-(methylsulfonyl)butyramido)- bicyclo(2.2.1 )heptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine as a white foam in 90% yield. This product was dissolved in dichloromethane (5 mL) and treated with TFA (4 mL). After 1 h, the solvents were removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (4 x 25 mL), brine (25 mL), dried (MgSθ4), filtered, and the solvents were removed under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient elution of 98:2:0.2 to 95:5:0.5 CHCl3:MeOH:NH4θH. The title compound was obtained as a white foam by evaporation under reduced pressure from ether in 90% yield.

Analysis: C26H42N54O5S2, 0.9 H20, 0.3 ether calc. C 55.07 H 7.95 N 9.44 found C 55.08 H 7.57 N 9.17

TLC: Rf= 0.33 (94:6:0.5 CHCl3_MeOH:NH4θH)

HPLC (method A): retention time = 8.85 min, purity = 99% FAB MS: m/z = 555 (M + H+)

EXAMPLE 71

l-((7,7-Dimethyl-2-endo-(4-(methylsulfonyl)butyramido)- bicyclo(2.2.1 )-heptan- 1 -yl)methanesulf ony l)-4-(2- methylphenyl)piperazine

To a stirred solution of 4-(methylsulfonyl)-butyric acid (370 mg; 2.23 mmol), in DMF (25 mL) was added BOP (986 mg; 2.23 mmol), l-((7,7-dimemyl-2-endo-amino-bicyclo(- 2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (960 mg; 2.45 mmol), and DIEA (7.84 mL; 4.5 mmol). After 16 h, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic solution was washed with 5 wt% aqueous citric acid (2 x 50 mL), saturated aqueous sodium bicarbonate (3 x 50 mL), and brine. The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography using 1:1 ethyl acetate:hexane as eluant. The title compound was obtained as a white foam in 90% yield.

Analysis: C26H41N3O5S2, 0.25 C2H5CO2CH3, 0.25 H2O calc. C 57.26 H 7.74 N 7.42 found C 57.26 H 7.54 N 7.32 TLC: Rf = 0.18 (1:1 EtOAc:Hexane) HPLC (method A): retention time = 10.62min, purity = 99.7%

FAB MS: m/z = 548 (M + H+)

EXAMPLE 72

l-((7,7-Dimethyl-2-endo-(2s-bis(hydroxyethyl)amino-4- (memylsulf onyl)-butyramido)-bicyclo(2.2. l)heptan- 1 - yl)methanesulfonyl)-4-(2-methyl-ρhenyl)piperazine

A stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsul onyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (310 mg, 0.56 mmol) in ethanol (10 mL) was cooled to 0°C. Ethylene oxide was bubbled through the solution, the reaction vessel was sealed, and the reaction mixture was warmed to 70°C. After 48 h, the reaction was cooled to 0°C and ethylene oxide was bubbled through the solution. The reaction vessel was sealed and heated at 70°C for 48 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in 55% yield.

Analysis: C30H5 ON4O7S2, 2.2 CF3CO2H, 0.35 H2O calc. C 45.90 H 5.92 N 6.23 ^• found C 45.90 H 5.89 N 6.33

TLC: Rf = 0.62 (90:10:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 8.93 min, purity = 98+%

FAB MS: m/z = 643 (M + H+)

EXAMPLE 73

l-((7,7-Dimethyl-2-endo-(2s-(4-tetrahydrothiopyranyl)-ami no-4- (methyl-sulfonyl)butyramido)-bicyclo-(2.2.1)heptan-l- v methanesulfonylV4-(2-methylphenyl.piperazine

The title compound was prepared from 4-tetra- hydrothio-pyranone and l-((7,7-dimethyl-2-endo-(2S-amino-4- (methylsulfonyl)-butyramido)-bicyclo-(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine using the procedure set forth in Example 68. The crude product was purified by silica gel flash chromatography eluting with 97:3:0.3 CHCl3:CH3θH:NH4θH. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 95% yield.

Analysis: C31H50N4O5S3, 0.75 CHCI3 calc. C 51.22 H 6.87 N 7.53 found 51.29 6.83 7.27

TLC: Rf = 0.44 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.91 min, purity = 99%

FAB MS: m/z = 655 (M + H+)

EXAMPLE 74

l-((7,7-DimethyI-2-endo-(2s-(l,l-dioxo-4-tetrahydrothio- pyranyl)an____no-4-(memylsulfonyl)bu^amido)-bicyclo- (2.2.1)heptan-l-yl)methanesuIfonyl)-4-(2-methylphenyl)- iperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- (4-tefrahycho opy__anyl)ainino-4-(methylsulfonyl)-butyramido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2- methylphenyl)piperazine (90 mg, 0.12 mmol) in 1:9 H2θ:acetone (3 mL) was added 4-methylmorpholine-N-oxide (43 mg, 0.36 mmol) and Osθ4 (0.013 mL of 2.4 wt% solution). After 17 h the reaction was quenched with saturated aqueous NaHS03 (0.05 mL), and the solvent was removed under reduced pressure. The residue was taken up in methylene chloride (25 mL) and washed with IN NaHS03 (3 x 25 mL), brine (2 x 25mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase

HPLC using an acetonitrile-water gradient containing 0.1 % trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in 80% yield.

Analysis: C31H50N4O7S3, 2.05 CF3CO2H, 0.35 H2O . calc.C 45.47 H 5.74 N 6.04 found 45.47 5.72 5.89 TLC: Rf = 0.33 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 9.02 min, purity = 99% FAB MS: m/z = 687 (M + H+)

EXAMPLE 75

l-((7,7-Dimethyl-2-endo-(2s-acetamido-4-(methyl- sulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 -yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine .

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- am o-4-(memylsulfonyl)butyramido)-bicyclo(2.2.1)-heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (160 mg, 0.29 mmol) in chloroform (5 mL) was added acetic anhydride (1 mL), and dnsopropylethylamine (0.03 mL). After 2 h the solvent was

removed under reduced pressure. The residue was dissolved in chloroform (25 mL) and washed with 5% aqueous HCl (2 x 10 mL), water (10 mL), saturated aqueous sodium bicarbonate (2 x 10 mL), brine (10 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure to give the title compound as a foam in 90% yield.

Analysis: C28H44N4O6S2, 0.5 CHC13, calcC 55.89 H 7.37 N 9.30 found 55.90 7.36 9.22

TLC: Rf = 0.21 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.01 min, purity = 99% FAB MS: m/z = 597 (M + H+)

EXAMPLE 76

1 -((7 ,7-Dimemyl-2-endo-(2s-(2-cyanoethyl)amino-4- (memylsuιfonyl)-butyramido)-bicyclo(2.2.1 )heptan- 1 - yl metfaanesulfony -4-r2-methyIphenv piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in MeOH was added aciylonitrile (0.026 mL, 0.40 mmol).

After 16 h, an additional amount of acrylonitrile (0.010 mL, 0.15 mmol) was added. After 24 h the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 1 :3 EtOAc:hexanes as eluant. The solvent was removed under reduced pressure and the residue was triturated in EtOAc and hexanes. The solid was dried in vacuo for 16 h to give the title compound as a white powder in 55% yield.

Analysis: C29H45N5O5S2, 0.32 EtOAc calc.C 57.18 H 7.54 N 11.01 found 56.86 7.74 11.01 TLC: Rf = 0.2 (1 :4 EtOAc±exanes) HPLC (method A): retention time = 8.99 min, purity = 99% FAB MS: m/z= 608 (M + H+)

EXAMPLE 77

l-((7,7-Dimethyl-2-endo-(2s-(2-hydroxy-2,2-dimethyl- emyl)amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan- l-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- an_ino-4-(memylsuh ^c onyl)butyramido)-bicycloj(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36

mmol) in EtOH (5 mL) was added isobutylene oxide (0.026 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath. After 16 h, an additional amount of isobutylene oxide (0.026 mL, 0.36 mmol) was added and heating was continued. After 24 h, an additional amount of isobutylene oxide (0.026 mL, 0.36 mmol) was added and heating was continued. After 24 h the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The trifluoroacetate salt ofthe title compound was obtained by lyophihzation to yield a white powder in 48% yield.

Analysis: C30H50N4O6S2, 1.7 CF3CO2H, 0.4 H2O calcC 48.45 H 6.39 N 6.77 found 48.46 6.37 6.78

TLC: Rf =0.3 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 8.56 min, purity = 97% FAB MS: m/z= 627 (M + H+)

EXAMPLE 78

l-((7,7-Dimethyl-2-endo-(2s-(2r-hydroxypropyl)amino-4- (methylsulf onyl)-butyramido)-bicyclo(2.2. l)heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in EtOH (5 mL) was added R-(+)-propylene oxide (0.025 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath. After 16 h, an additional amount of R-(+)-propylene oxide (0.010 mL, 0.15 mmol) was added and heating was continued. After 72 h the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1 % trifluoroacetic acid. The faster running of two products was isolated and lyophilized to give the trifluoroaeetate salt of the title compound as a white powder in 42% yield.

Analysis: C29H48 4O6S2, 1.75 CF3CO2H, 0.5 H2O calc.C 47.52 H 6.23 N 6.82 found 47.50 6.22 6.90 TLC: Rf = 0.2 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.34 min, purity = 99% FAB MS: m/z= 613 (M + H+)

EXAMPLE 79

1 -((7,7-Dimethyl-2-endo-(2s-bis(2r-hydroxypropyl)amino-4- (methyl-sulf onyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

The slower running of two products isolated from the preparative HPLC purification of the crude product from Example 78 was lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 2% yield.

Analysis: C32H54N4O7S2, 1.9 CF3CO2H, 0.15 H2O calcC 48.49 H 6.36 N 6.29 found 48.31 6.35 6.52 TLC: Rf = 0.2 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.74 min, purity = 95% FAB MS: m/z= 671 (M + H+)

EXAMPLE 80

1 -((7 ,7-Dimethyl-2-endo-(2s-(2s-hydroxypropyl)amino-4-(methyl- sul bnyl)butyramido)-bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)- 4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in EtOH (5 mL) was added S-(-)-propylene oxide (0.025 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath. After 16 h, an additional amount of S-(-)-propylene oxide (0.010 mL, 0.15 mmol) was added and heating was continued. After 72 h the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1 % trifluoroacetic acid. The faster ninning of two products was isolated and lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 24% yield.

Analysis: C29H48N4O6S2, 1.8 CF3CO2H, 0.3 H2O calc.C 47.54 H 6.17 N 6.80 found 47.55 6.16 6.90 TLC: Rf = 0.2 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.40 min, purity = 99% FAB MS: m/z= 613 (M + H+)

EXAMPLE 81

l-((7,7-Dimethyl-2-endo-(2s-bis(2s-hydroxypropyl)amino-4- (memyl-sulfonyl)butyramido)-bicyclo(2.2.1)heptan-l- yl)methanesuIfonyl)-4-(2-methylphenyl)piperazine

The slower runiring of two products isolated from the preparative HPLC purification ofthe crude product from Example 80 was lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 5% yield.

Analysis: C32H54N4O7S2, 1.9 CF3CO2H, 0.15 H2O calc.C 48.37 H 6.41 N 6.32 found 48.36 6.42 6.52 TLC: Rf = 0.2 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.78 min, purity = 97% FAB MS: m/z= 671 (M + H+)

EXAMPLE 82

l-((7,7-Dimethyl-2-endo-(2s-(2-propyl)amino-4-(methyl- sulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 -yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in EtOH (5 mL) was added acetone (0.026 mL, 0.40 mmol) and activated, crushed 3A sieves. After 5 h, NaBH3CN (11 mg, 0.36 mmol) was added. After 16 h an additional amount of NaBH3CN (5 mg, 0.15 mmol) was added. After 24 h one drop of water was added and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophihzation to give a white powder in 35% yield.

Analysis: C29H48N4O5S2, 1.7 CF3CO2H, 0.8 H2O calc. C 48.33 H 6.42 N 6.96 found 48.33 6.42 7.14

TLC: Rf = 0.6 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.68 min, purity = 99%

FAB MS: m/z= 597 (M + H+)

EXAMPLE 83

1 -((7 ,7-D__memyl-2-endo-(2s-(4-pyridyl)amino-4- (methylsul onyl)butyramido)-bicyclo(2.2. l)heptan-l - yl)methanesuIfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in DMF (10 mL) was added 4-bromo-pyridine (70 mg, 0.36 mmol) and the reaction was heated to 120°C for 16 h. Much degradation occurred. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The trifluoro-acetate salt of the title compound was obtained by lyophihzation to give a white powder in 2.5% yield.

Analysis: C31H45N4O5S2, 2.05 CF3CO2H, 1.35 H2O

calc. C 47.37 H 5.63 N 7.87 found 47.36 5.93 7.48

TLC: Rf = 0.4 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.23 min, purity = 93% FAB MS: m/z= 632 (M + H+)

EXAMPLE 84

. l-((7,7-Dimethyl-2-endo-(2s-(2-fluoroethyl)amino-4- i o (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- ammo-4-(memylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - 5 yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in DMF (5 mL) was added 1 ,2-bromo-fluoroethane (0.025 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath. After 16 h the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using 0 an acetonitrile-water gradient containing 1 % trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophihzation to give a white powder in 18% yield.

Analysis: C28FH45N4O5S2, 1.8 CF3CO2H calc. C 47.08 H 5.85 N 6.95

found 47.09 5.86 7.04

TLC: Rf = 0.4 (95:5 CHCl3:MeOH) HPLC (method A): retention time = 8.50 min, purity = 99% FAB MS: m/z= 601 (M + H+)

EXAMPLE 85

l-((7,7-Dimethyl-2-endo-(2s-emylamino-4-(methyl- suhOnyl)butyramido)-bicyclo(2.2.1)heptan-l-yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- _ i__no-4-(memylsulfonyl)butyramido)-bicyclo(2.2.1)-heptan-l- yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.206 g; 0.371 mmol) in DMF (30 mL) was added iodoethane (0.015 mL; 0.19 mmol) followed by DIEA (0.097 mL, 0.56 mmol). The reaction was stirred at ambient temperature for 48 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (3 x 50 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 98:2:0.2 CH2Cl2:MeOH:NH4θH. The resulting oil was dissolved in CH3CN and H2O containing 0.1% TFA and

lyophylized to give the trifluoroacetate salt of the title compound as a white powder in 40% yield.

Analysis: C28H46N4O5S2 0.15 H20, 0.85 TFA

FW = 682.451 calc. C 52.57 H 6.96 N 8.21 found C 52.30 H 6.92 N 8.19

TLC: Rf = 0.46 (96:4:0.4 CH2Cl2:MeOH:NH4θH)

HPLC (method A): retention time = 8.43 min, 99% purity FAB MS: m/z = 583 (M + H+)

EXAMPLE 86

1 -((7 ,7-Dimethyl-2-endo-(2s-(tert-butyloxycarbony 1)- methylamino-4-(methylsulfonyl)butyramido)-bicyclo- (2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2-me t hylphenyl)- iperazine

A solution of N-Boc-N-methyl-L-methionine sulfone (0.899 g; 3.04 mmol) and BOP (1.35 g, 3.00 mmol) in DMF (50 mL) was stirred for 10 min. A solution of l-((7,7-dimethyl-2- endo-amino-bicy clo(2.2.1 )heptan- 1 -yl)methane-sulfonyl)-4-(2- methylphenyl)piperazine (1.80 g; 2.77 mmol) in DMF (15 mL) was added dropwise to the reaction followed by DIEA (5.2 mL; 3.0

mmol) to bring the reaction mixture to pH 8 (as judged by spotting an aliquot on wetted E. Merck pH paper). After 16 h the DMF was removed under reduced pressure and the residue was dissolved in EtOAc (100 m ) and washed with 5 wt% aqueous citric acid (lOOmL) and saturated aqueous sodium bicarbonate (2 x 100 mL). The organic layer was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 40:60 hexane:EtOAc. The title compound was obtained as a white foam in 90% yield.

Analysis: C32H52N4O7S2 0.25 EtOAc FW = 690.95 calc. C 57.36 H 7.88 N 8.11 found C 57.68 H 7.84 N 8.13

TLC: Rf = 0.27 (40:60 hexane:EtOAc)

HPLC (method A): retention time = 11.21 min, 99+% purity

FAB MS: m/z = 669 (M + H+)

EXAMPLE 87

l-((7,7-Dimetiιyl-2-endo-(2s-memylamino-4-(methyl- sulfonyl)butyramido)-bicyclo(2.2.1)heptan-l-yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- (tert-butyloxycarbonyl)methylamino-4-(methylsulf- onyl)butyramido)-bicyclo(2.2.1)heptan-l-yl)methane-sulfonyl) -4- (2-methylphenyl)piperazine (1.0 g; 1.5 mmol) in DCM (25 mL) was added TFA (25 mL). The reaction was stirred at ambient temperature for 1 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate (4 x 50 mL). The organic layer was dried (MgSθ4), filtered, and the solvent was ° removed under reduced pressure to give the title compound as a foam in 95% yield.

Analysis: C27H44N4O5S2 0.40 EtOAc 0.45 H2O FW = 612.15 s calc. C 56.11 H 7.92 N 9.15 found C 56.14 H 7.78 N 9.16 TLC: Rf = 0.16 (97:3 DCM:MeOH) HPLC (method A): retention time = 8.23 min, 99+% purity

FAB MS: m/z = 569 (M + H+) 0

5

EXAMPLE 88

l-((7,7-Dimethyl-2-endo-(2s-trideuteromethylamino-4- (methylsulfonyl)butyramido)-bicyclo(2.2. l)heptan-l - yl)metfaanesuIfonyl)-4-(2-methylphenyl)piperazine

The title compound was prepared from N-Boc-N- trideuteromemyl-L-metMonine sulfone and l-((7,7-dimethyl-2- endo-amino-bicyclo(2.2.1)heptan-l-yl)methane-sulfonyl)-4-(2- methylphenyl)piperazine using die procedures set forth in Examples 86 and 87. The title compound was obtained as a white foam by evaporation under reduced pressure from EtOAc-hexane.

Analysis: C27D3H41N4O5S2 0.35 EtOAc, 0.20 H2θ FW = 606.22 calc. C 56.26 H 7.28 N 9.24 found C 55.93 H 7.67 N 9.18 TLC: Rf = 0.16 (97:3 DCM.MeOH) HPLC (method A): retention time = 8.23 min, 99+% purity FAB MS: m/z = 572 (M + H+)

EXAMPLE 89

1 -((7 ,7-Dimethyl-2-endo-(2s-bis(trideuteromethyl)amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2. l)heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

A stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.433g, 0.781 mmol) and DIEA (0.203 mL; 1.17 mmol) in DMF (10 mL) was cooled to 0°C. Iodomethane-d3 (0.50 mL, 0.786 mmol) was added dropwise via syringe. The reaction was gradually warmed to ambient temperature and then stirred for 16 h. The reaction was cooled to 0°C and an additional 0.5 eq of CD3I and DIEA were added, and the reaction was stirred for 16 h. at ambient temperature. The solvent was removed under reduced pressure and the residue was dissloved in EtOAc (50 mL). The EtOAc solution was washed with saturated aqueous sodium bicarbonate (2 x 25 mL), dried (MgS04), filtered, and the solvent was removed under reduced pressure. HPLC analysis of the crude product indicated the presence of unreacted L-368,899, mono-, bis-, and tris- alkylated products. The desired bis-alkylated product was isolated by silica gel flash column chromatography eluting with 98:2

CH2Cl2:MeOH. Pure fractions were combined and the solvent was removed under reduced pressure to give an oil. The oil was lyophilized from 1:2 CH3CN:H2θ containing 0.1% TFA to give the trifluoroacetate salt ofthe title compound as a white powder.

Analysis: C28 D 6H 40N 4O 5S 2 0.80 HWA, =2.45 H2

724.256 calc. C 49.08 H 6.36 N 7.74 found C 49.12 H 6.55 N 7.43

TLC: Rf = 0.43 (95:5:0.5 DCM:MeOH:NH4θH)

HPLC (method A): retention time = 8.33 min, 99+% purity

FAB MS: m/z = 589 (M + H+)

EXAMPLE 90

l-((7,7-Dimethyl-2-endo-(2s-tris(trideuteromemyl)amino-4- (methylsulf onyl)butyramido)-bicyclo(2.2. l)heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine trifluoroacetate

A stirred solution of l-((7,7-dimethyl-2-endo-(2S- anuno-4-(me ylsuhonyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)memanesulfonyl)-4-(2-methylρhenyl)piperazine (0.426 g, 0.768 mmol) and DIEA (0.40 mL; 2.3 mmol) in DMF (20 mL) was cooled to 0°C Iodomethane-d3 (0.16 mL; 2.5 mmol) was added

dropwise via syringe. The reaction was gradually warmed to ambient temperature and stirred for 48 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse-phase HPLC using a water: acetonitrile gradient containg 0.1% TFA. The title compound was obtained by lyophihzation to give a white powder in 50% yield.

Analysis: C31H4D9F30N4O7S2 0.6 TFA FW = 788.284 calc. C 49.06 H 6.34 N 7.11 found C 49.13 H 6.61 N 6.96

TLC: Rf = 0.11 (90:10:0.5 DCM:MeOH:NH4θH)

HPLC (method A): retention time = 8.51 min, 99+% purity FAB MS: m/z = 606 (M+)

EXAMPLE 91

1 -((7 ,7-Dimethyl-2-endo-(2s-n,n-dimethylf ormamidinyl-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )-heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.18 mmol) in DMF (2 mL) was added dimethyl-formamide-

dimethylacetal (xx mL; 0.54 mmol). After 24 h, the solvent was removed under reduced pressure. The resulting oil was dissolved in EtOAc (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgS04), filtered, and the solvent was removed under reduced pressure. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 90% yield.

Analysis: C29H47N5O5S2 0.4 CHC13 calc. C 53.70 H 7.27 N 10.65 found C 53.87 H 7.27 N 10.66

TLC: Rf = 0.35 (95:5:0.5 DCM:MeOH:NH4 H)

HPLC (method A): retention time = 8.34 min, 99+% purity

FAB MS: m/z = 610 (M + H+)

EXAMPLE 92

l-((7,7-Dimethyl-2-endo-(2s-acetamidinyl-4-(methyl- sulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 -yl)methane- sulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-l -

yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.18 mmol) in DMF (4 mL) was added methyl acetimidate hydrochloride (100 mg; 0.91 mmol) and sodium carbonate (150 mg; 1.5 mmol). After 48 h, the mixture was filtered through Celite and the solvent was removed under reduced pressure. The resulting dark oil was purified by silica gel flash column chromatography using a gradient elution of 95:5:0.5 CHCl3:MeOH:NH4θH to 85:15:0.75 CHCl3:MeOH:NH4θH. The trifluoroacetate salt of the title compound was obtained as a white powder in 25% yield by lyophihzation from 1 :3 CH3CN:H2θ containing 0.1 % TFA.

Analysis: C28-H45N5O5S2 1.0 TFA, 1.5 H2O calc. C 48.90 H 6.70 N 9.50 found C 48.71 H 6.45 N 9.62

TLC: Rf = 0.29 (85:15:0.75 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 9.05 min, 97.9% purity FAB MS: m/z = 596 (M + H+)

EXAMPLE 93

l-((7,7-Dimethyl-2-endo-(2s-(4-(l-tert-butyloxycarbony)- piperidinyl)amino-4-(methylsulfonyl)butyramido)-bicyclo- (2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)- piperazine

v_

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- ammo* -(memylsulfonyl)butyramido)-bicyclo(2.2.1)-heptan-l- yl)methanesuIfonyl)-4-(2-methylphenyl)piperazine (200 mg; 0.36 mmol) in methanol containing 1% by volume of acetic acid (4 mL) was added 4-5 molecular sieves (3A), l-tert-butyloxycarbonyl-4- piperidinone (78 mg, 0.39 mmol) and sodium cyanoborohydride (20 mg; 0.36 mmol). After 5 h, the reaction was quenched with aqueous sodium bicarbonate (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by sihca gel flash coumn chromatography using 95:5 CHCl3:MeOH as eluant. The resulting oil was lyophilized from H2θ:CH3CN containing 0.1 % TFA. The trifluoroacetate salt ofthe title compound was obtained in 85% yield as a white powder.

Analysis: C36H59N5O7S2, 0.45 H2θ, 2.5 TFA calc. C 47.75 H 6.10 N 6.79 found 47.76 6.07 7.12

TLC: Rf = 0.27 (95:5 CHCl3:MeOH)

HPLC (method A): retention time = 10.72 min, purity = 99+%

FAB MS: m/z = 738 (M + H+)

EXAMPLE 94

1 -((7 ,7-Dimethyl-2-endo-(2s-(4-piperidinyl)amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

To a stirred solution of l-((7,7-dimethyl-2-endo-(2S- (4-(l-tert-butyloxycarbony)piperidinyl)amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-l - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.10 g; 0.14 mmol) in dichloromethane (20 mL) was added TFA (15 mL). After 1 h, the solvents were removed under reduced pressure and the residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (4 x 25 mL), brine (25 mL), dried (MgSθ4) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel flash column chromatography using 90:10:1 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as a white foam in 90%

yield by evaporation under reduced pressure from dichloromethane.

Analysis: C31H51N5O5S2, 0.6 CH2CI2 calc. C 55.13 H 7.70 N 9.79 found 55.09 7.64 10.07

TLC; Rf = 0.11 (90:10:1 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 8.13 min, purity = 99+% FAB MS: m/z = 638 (M + H+)

EXAMPLE 95

l-((7,7-D_methyl-2-Endo-(2s-Amino-4-Hydroxybutyramido)- Bicyclo(2.2.1)Heptan-l-Yl)Methanesulfonyl)-4-(2- Methylphenyl)Piperazine

H N

To a stirred solution of l-((7,7-dimethyl-2-endo-amino- bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (2.0 g; 5.1 mmol) in DMF (20 mL) was added N-Boc-L-homoserine, O- benzyl ether (1.73 g; 5.61 mmol), hydroxybenzotriazole hydrate (0.87 g; 5.7 mmol), DIEA (2.0 mL; 11.5 mmol), and EDC (1.09 g; 5.7 mmol). After 24 h, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (2 x 25 mL), water (25 mL), saturated aqueous sodium

bicarbonate (2 x 50 mL), dried (MgSθ4) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel flash column chromatography using 1:1 ethyl acetate:hexane as eluant. 1 - ((7,7-Dimethyl-2-endo-(2S-tert-butyloxycarbonylamino-4- (benzyloxy)butyramido)-bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine was obtained as a white foam in 90% yield. This compound was N-deprotected by dissolving in dichloromethane (15 mL) and adding TFA (10 mL). After 1 h, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (4 x 50 mL), dried (MgSθ4), and filtered. The solvent was removed under reduced pressure to give ((7,7-dimemyl-2-endo-(2S-amino-4-(benzyloxy)butyramido)- bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine as a white foam in 95% yield. This compound was O-deprotected by dissolving in methanol containing 5% by volume of acetic acid (50 mL) and stirring with palladium black (150 mg) under an atmosphere of hydrogen (ambient pressure). After 24 h, the reaction was flushed with argon, the catalyst was removed by filtration through Celite, and the solvents were removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 90:10:1

CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as a white foam in 90% yield after evaporation under reduced pressure from chloroform-ether.

Analysis: C25H40N4O4S, 0.15 CHCI3, 0.15 ether calc. C 59.28 H 8.05 N 10.74 found 59.42 8.02 10.72

TLC: Rf = 0.18 (90:10:1 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.31 min, purity = 99+% FAB MS: m/z = 493 (M + H+)

EXAMPLE 96

l-((7,7-Dimethyl-2-Endo-(2s-(4-Piperidinyl)Amino-4- Hydroxybutyramido)-Bicyclo(2.2. l)Heptan-l - Yl)Methanesulfonyl)-4-(2-Methylphenyl)Piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-am_ino-4-hydroxybutyramido)- bicyclo(2.2.1)heptan-l-yl)memanesulfonyl)-4-(2-methylphenyl) piperazine with l-tert-butyloxycarbonyl-4-piperidinone followed by TFA N- deprotection using procedures analogous to those set forth in Example 93 and Example 94. The crude product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1 % by volume of TFA. The trifluoroacetate of the title compound was obtained as a white lyophilized powder in 50% yield.

Analysis: C30H49N5O4S, 3.9 TFA, 1.15 H2O calc. C 43.60 H 5.34 N 6.73 found 43.61 4.95 7.12

TLC: Rf = 0.10 (90:10:1 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 7.85 min, purity = 99+% FAB MS: m/z = 576 (M + H+)

EXAMPLE 97

l-((7,7-Dimethyl-2-Endo-(2s-(4-Tetrahydropyranyl)-Amino-4 - Hydroxybutyramido)-Bicyclo(2.2.1 )Heptan- 1 - Yl)Methanesulfonyl)-4-(2-Methylphenyl)Piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-amino-4-hydroxybutyramido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 68. The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:NH4θH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform-methanol.

Analysis: C30H48N4O5S, 0.2 CHCI3, 0.3 CH3OH calc. C 60.02 H 8.16 N 9.18 found 60.04 8.09 9.14

TLC: Rf = 0.35 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.82 min, purity = 96% FAB MS: m/z = 577 (M + H+)

EXAMPLE 98

l-((7,7-Dimethyl-2-Endo-(2s-(l,l-Dioxo-4- Tetι^ydroMopyranyl)Aπuιιo-4-Hydroxybutyramido)- Bicyclo(2.2.1)Heptan-l-Yl)Methanesulfonyl)-4-(2- Methylphenyl)Piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S--unino-4-hydroxybutyramido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with 4-tetrahydrothiopyranone foUowed by oxidation to the sulfone using procedures analogous those set forth in Example 73 and Example 74. The cmde product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:NH4θH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform.

Analysis: C30H48N4O6S2, 0.4 CHCI3, 0.1 H2O calc. C 54.13 H 7.26 N 8.31 found 54.15 6.91 8.15

TLC: Rf = 0.30 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.79 min, purity = 97% FAB MS: m/z = 625 (M + H+)

EXAMPLE 99

l-((7,7-dinιethyl-2-endo-(2s-amino-3-hydroxypropionamido )- bicyclo(2.2.1 )heptan-l -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine

The title compound was prepared from 1 -((7,7-dimethyl-2- endo-amino-bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2- methylphenyl)piperazine and Boc-L-serine followed by TFA N- deprotection using procedures analogous to those set forth in Example 35 and Example 36. The cmde product was purified by silica gel flash column chromatography using 95:5:0.5 CHCl3:MeOH:NH4θH as eluant. The title compound was obtained as a white foam in 90% yield after evaporation under reduced pressure from chloroform.

Analysis: C24H38N4O4S, 0.35 CHCI3 calc. C 56.19 H 7.43 N 10.77 found 56.24 7.50 10.86

TLC: Rf = 0.32 (95:5:0.5 CHCl3:MeOH:NH4θH)

HPLC (method A): retention time = 8.23 min, purity = 99+% FAB MS: m/z = 479 (M + H+)

EXAMPLE 100

1 -((7,7-dimethyl-2-endo-(2s-(4-piperidinyl)amino-3 - hydroxypropionamido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-amino-3-hydroxypropionamido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with l-tert-butyloxycarbonyl-4-piperidinone foUowed by TFA N- deprotection using procedures analogous to those set forth in Example 93 and Example 94. The cmde product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1% by volume of TFA. The trifluoroacetate of the title compound was obtained as a white lyophilized powder in 80% yield.

Analysis: C29H47N5O4S, 4 TFA, 0.9 CH3CN calc. C 44.20 H 5.14 N 7.89 found 44.63 4.62 7.88

TLC: Rf = 0.05 (90:10:1 CHCl3:MeOH:NH40H) HPLC (method A): retention time = 7.99 min, purity = 99+% FAB MS: m/z = 562 (M + H+)

EXAMPLE 101

l-((7,7-dimethyl-2-endo-(2s-(4-tetrahydropyranyl)amino-3- hydroxypropionamido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimethyl-2-endo-(2S-amino-3-hydroxypropionamido)- bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2-methylpheny l)piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 68. The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:NH4θH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from ethyl acetate in 90% yield.

Analysis: C29H46N4O5S, 0.45 ethyl acetate calc. C 61.40 H 8.30 N 9.30 found 61.03 8.13 9.54

TLC: Rf = 0.30 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.76 min, purity = 98% FAB MS: m/z = 563 (M + H+)

EXAMPLE 102

l-((7,7-dimethyl-2-endo-(2s-(l,l-choxo-4- teti-ihydrot opyranyl)aπ_ino-3-hydroxypropionamido)- bicyclo(2.2. l)heptan-l -yl)meώanesulfonyl)-4-(2- methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-aιnino-3-hydroxypropionamido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with 4-tetrahydrothiopyranone followed by oxidation to the sulfone using procedures analogous those set forth in Example 73 and Example 74. The cmde product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:NH4θH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform.

Analysis: C29H46N4O6S2, 1.25 H2O calc. C 54.99 H 7.72 N 8.85 found 55.01 7.99 8.76

TLC: Rf = 0.35 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.88 min, purity = 99% FAB MS: m/z = 611 (M + H+)

EXAMPLE 103

1 -((7 ,7-dimethyl-2-endo-(2s-amino-3r-hydroxybutyramido)- bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine

The title compound was prepared from l-((7,7-dimethyl-2- endo-amino-bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine and Boc-L-threonine followed by TFA N- deprotection using procedures analogous to those set forth in Example 35 and Example 36. The cmde product was purified by silica gel flash column chromatography using 95:5:0.5 CHCl3:MeOH:NH4θH as eluant. The trifluoroacetate salt of the title compound was obtained as a white powder by lyophihzation from H2θ:CH3CN containing 0.1% by volume of TFA.

Analysis: C25H40N4O4S, 1.75 TFA, 0.1 H2O calc. C 49.32 H 6.09 N 8.07 found 49.35 6.01 7.93

TLC: Rf = 0.15 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.51 min, purity = 99+% FAB MS: m/z = 493 (M + H+)

EXAMPLE 104

l-((7,7-dimethyl-2-endo-(2s-(4-piperid_nyl)-imino-3s- hydroxybutyramido)-bicyclo(2.2. l)heptan-l -yl)methanesulfonyl)- 4-(2-methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-amino-3S-hydroxybutyraιnido)- bicyclo(2.2.1)heptan-l-yl)mem- esulfonyl)-4-(2-memylphenyl)piperazine with l-tert-butyloxycarbonyl-4-piperidinone followed by TFA N- deprotection using procedures analogous to those set forth in Example 93 and Example 94. The cmde product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1% by volume of TFA. The trifluoroacetate of the title compound was obtained as a white lyophilized powder in 80% yield.

Analysis: C30H49N5O4S, 2.5 TFA, 0.2 H2O calc. C 46.87 H 6.24 N 7.81 found 46.88 6.01 8.00

TLC: Rf = 0.09 (90:10:1 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.10 min, purity = 99+% FAB MS: m/z = 576 (M + H+)

EXAMPLE 105

l-((7,7-dimethyl-2-endo-(2s-(4-tetrahydropyranyl)amino-3s - hydroxybutyramido)-bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)- 4-(2-methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimethyl-2-endo-(2S-amino-3S-hydroxybutyramido)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 68. The cmde product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:NH4θH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 90% yield.

Analysis: C30H48N4O5S, 0.35 CHC13 calc. C 58.92 H 7.88 N 9.06 found 59.07 7.87 9.13

TLC: Rf = 0.44 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC (method A): retention time = 8.96 min, purity = 99% FAB MS: m/z = 577 (M + H+)

EXAMPLE 106

l-((7,7-dimethyl-2-endo-(2s-(4-emoxycarbonyl)cyclohexylam ino- 4-(methylsulf onyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

The title compound was prepared by reductive alkylation of 1 - ((7,7-dimemyl-2-endo-(2S-aπ_ino-4-(methylsulfonyl)butyramid o)- bicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl )piperazine with 4-ethoxycarbonylcyclohexanone using a procedure analogous that set forth in Example 68. The cmde product was purified by silica gel flash column chromatography using 2:1 ethyl acetate:hexane as eluant. Two isomers ofthe title compound differing in configuration at the point of attachment ofthe ethoxycarbonyl substituent were obtained as a white foams.

Isomer Number 1

Analysis: C35H56N4O7S2, 1.55 CH30H calc. C 57.86 H 8.26 N 7.39 found 57.85 7.95 7.62

TLC: Rf = 0.13 (2:1 ethyl acetate:hexane) HPLC (method A): retention time = 10.24 min, purity = 99% FAB MS: m/z = 709 (M + H+)

Isomer Number 2

Analysis: C35H56N4O7S2, 0.2 ethyl acetate, 0.9 CH2CI2 . calc. C 54.89 H 7.46 N 6.98

found 54.95 7.51 7.00

TLC: Rf = 0.26 (2:1 ethyl acetate :hexane)

HPLC (method A): retention time = 10.27 min, purity = 99% FAB MS: m/z = 709 (M + H+)

EXAMPLE 107

l-((7,7dimethyl-2-endo-(2s-(4-carboxy)cyclohexylamino-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine

The title compound was prepared by saponification of the lower Rf isomer from Example 106. 1 -((7,7-Dimethyl-2-endo-(2S-(4- ethoxycarbonyl)cyclohexylamino-4-(merhylsulfonyl)butyramido) - bicyclo(2.2.1 )heptan- 1 -yl)methanesulf onyl)-4-(2-methylphenyl)piperazine (50 mg; 0.071 mmol) was dissolved in THF (2 mL) containing 2 N NaOH (1 mL). After the reaction had been stirred at ambient temperature for 2 days, aqueous citric acid was added to obtain a pH 3 solution and the product was extracted into ethyl acetate. The solvent was removed under reduced pressure to give the title compound as a foam.

Analysis: C33H52N4O7S2, 0.55 ethyl acetate, 0.85 CH2CI2 calc. C 54.01 H 7.31 N 6.99 found 54.12 7.18 6.99

TLC: Rf = 0.42 (90:10:0.5 CHCl3:MeOH:HOAc) HPLC (method A): retention time = 9.06 min, purity = 99% FAB MS: m/z = 781 (M + H+)

EXAMPLE 108

l-((7,7-dimethyl-4-(memylsulfonyl)-butyramido)- bicyclo(2.2.1)heptan-l-yl)memanesulfonyl)-4~(2- methylphenyl)piperazine

The title compound was prepared by saponification of the higher Rf isomer from Example 106. l-((7,7-Dimethyl-2-endo-(2S-(4- ethoxycarbonyl)cyclohexylam o-4-(methylsulfonyl)butyramido)- bicyclo(2.2.1)heptan-l-yl)memanesulfonyl)-4-(2-methylphenyl) piperazine (50 mg; 0.071 mmol) was dissolved in THF (2 mL) containing 2 N NaOH (1 mL). After the reaction had been stirred at ambient temperamre for 2 days, aqueous citric acid was added to obtain a pH 3 solution and the product was extracted into ethyl acetate. The solvent was removed under reduced pressure to give the title compound as a foam.

Analysis: C33H52N4O7S2, 0.65 ethyl acetate, 0.95 CHC13 calc. C 53.60 H 7.27 N 6.84 found 53.64 7.15 6.85

TLC: Rf = 0.44 (90:10:0.5 CHCl3:MeOH:HOAc) HPLC (method A): retention time = 9.39 min, purity = 99% FAB MS: m/z = 781 (M + H+)

TABLE

In addition to those compounds specifically exemplified above, additional compounds of the present invention 5 are set forth in tabular form below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue . experimentation. All variables listed in the Tables below are with i° reference to the following generic structure:

Variable

In this generic structure, all values for V are for a substituted 5 carbon atom which is to be understood to be in the 2 position of the camphor ring; therefore, in the following table, said substituted carbon atom generally only shows two valence bonds, the other two valence bonds being understood to be part of the camphor ring. When said substituted carbon atom only shows one valence o bond, it is to be understood that a double bond is present between the 2 and 3 positions of the camphor ring.

TABLE OF SUBSTT UENTS REPRESENTED BY "V"

v= C- _N .OH

TABLE (Continued

/ \

^" N NH

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O II

10 O ^ F

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TABLE (Continued)

H H

\_

Additional examples of species covered by this invention include the following non-limiting hst:

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EXAMPLE 109 RADIOGLIGAND BINDING ASSAYS

The high affinity binding of [3H] Oxytocin (OT)([tyrosyl, 3,5-[3H]OT; 30-60 Ci/mmol; New England Nuclear. Boston, MA) to uterine OT receptors was based on an assay (Fuchs, A-R; Fuchs, F; Soloff, MS. 1985 J. Clin. Endocrinol. Metab. 60:37) using a cmde membrane preparation of uteri taken from diethylstilbestrol dipropionate (DES)-treated (0.3 mg/kg, ip; 18-24) rats. Competition studies were conducted at

equilibrium (60 minutes; 22°C) using 1 nM[3H]OT in the following assay buffer: 50 mM Tris-HCI, 5 mM MgCl2, and 0.1% BSA, pH 7.4. Nonspecific binding (10% of the total binding) was determined using 1 mM unlabeled OT and the binding reaction was terminated by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, Inc., Sterling, VA). IC50 (the concentration of tested compound that inhibits 50% of OT) was reported, unless otherwise noted.

The measurement of [3H]Vasopressin (AVP) ([phenylalanyl-3,4,5-3H] AVP; 80-90 Ci/mmol; New England

Nuclear)binding to a crade membrane preparation of male rat liver (AVP-Vl sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al. (Butlen, D; Guillon, G; Rajerison, R.M.;Jard, S; Sawyer, W.H.;Manning, M. 1978 Mol Pharmacol 14:1006).

Competition assays were conducted at equilibrium (30 minutes at 30°C) using 1 nM [3H]AVP (liver) or 2 nM [3H]AVP (kidney) in the following assay buffer: 100 mM Tris-HCI, 5 mM MgCl2, 0.1% BSA, 50 mM phenylmethylsulfonylfluoride, and 50 mg/ml bacitracin, pH 8.0. Nonspecific binding (5-10% of the total binding) was determined using 10 mM unlabeled AVP, and the binding reaction was terminated by filtration as described above for the [3H]OT binding assay.

Kj values were obtained for each compound from three to six separate determinations of the IC50 values (Ki = IC50/1 + c/Kd) (Cheng, Y-C; Prusoff, W.H.; 1973 Biochem Pharmacol 22:3099) using Kd values obtained from a saturation binding assay: [3H]OT (utems), 0.7 nM; [3H]AVP (liver), 0.4 nM; [3H] (kidney), 1.4 nM.

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While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for prevention of preterm labor, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended,

therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.