LT3592B - Substituted amide derivatives of piperizinylcamphorsulfonyl oxytocin antagonists - Google Patents

Abstract

Compound formula:<IMAGE>Compounds, corresponding to this structural formula, when R<1> is:hydrogen, alkoxycarbonyl or unchanged or changed alkyl, when the mentioned substitute is hydroxyl, alkoxyl, carboxyl, carboxyalkyl, alkylsulfonyl or alkoxycarbonyl;and R<2> ishydrogen, alkoxyl, arylalkoxyl, alkoxycarbonyl, alkoxycarbonylamin, unchanged or changed cycloalkyl, when the mentioned substitute is carboxyl, (7) unchanged or changed phenyl, when the mentioned substitute or several substitutes belong to the group which includes carboxyl, carboxyalkyl or SO3H, unchanged or changed amine, when the mentioned substitute is unchanged or changed alkyl, comprising one or several substitutes, as well as carboxyl, alkylsulfonyl or unchanged pentanomial heterocycle ring with 1 or 2 heteroatoms, when the heteroatom is N,unchanged or changed rings that are expressed in the formulas<IMAGE>when the mentioned substitutes is one or several radicals, including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxygroup or changed amine, when the mentioned substitute is made of one or several radicals including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unchanged or changed alkyl, when the mentioned substitute is made of one or several radicals including hydrocyl, carboxyl, carboxyalkyl phenyl, alkylsulfonyl, amine carbonyl, alkylaminocarbonyl, aryl alkyl, arylalkoxycarbonyl, halogen, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unchanged/changed amine, when the mentioned substitute is one or several radicals, including alkyl, alkyl carbonyl, alkylsulfonyl, carboxyalkyl. Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenyl alkyl or unchanged/changed alkyl carbonyl, when the mentioned substitute is pentanomial heterocycle ring with 1 or 2 heteroatoms and when the heteroatoms herein are N, when Het values provided above for heterocycle rings and when Cyc is changed/unchanged cycloalkyl, when the mentioned substitute is selected from the group including alkoxycarbonyl, carboxyl, hydroxyl, oxygroup or spirodioxolinyl. These compounds are oxytocin antagonist and are useful for treating abortive birth, dysmenorrhea and for trying to stop the preparation for Caesarean sections.

Description

Compounds of the formula:

cAr!

Compounds of this structural formula wherein R ¹ is (1) hydrogen, (2) alkoxycarbonyl, or (3) unsubstituted or substituted alkyl, said substituent being hydroxyl, alkoxyl, carboxyl, carboxyalkyl, alkylsulfonyl or alkoxycarbonyl;

and

R ² is (1) hydrogen, (2) alkoxyl, (3) arylalkoxyl, (4) alkoxycarbonylamino, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl, said substituent being carboxyl, (7) unsubstituted or substituted phenyl, wherein said substituent or substituents are from the group consisting of carboxyl, carboxyalkyl or SO 3 H, (8) an unsubstituted or substituted amine, said substituent being an unsubstituted or substituted alkyl, including carboxyl, alkylsulfonyl or unsubstituted pentavalent a non-heterocyclic ring containing 1 or 2 heteroatoms when the heteroatom is N, (S) unsubstituted or substituted rings having the formula

when the substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted alkyl, the substituent being substituted with one or more radicals , carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkoxycarbonyl, arylalkoxycarbonyl, arylalkoxycarbonyl, Hetarba is an unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, alkylcarbonyl, alkyl, carboxyalkyl. Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl, or unsubstituted or substituted alkylcarbonyl. wherein said substituent is a five-membered non-heterocyclic ring containing 1 or 2 heteroatoms and wherein said heteroatom is N. when Het is represented above for heterocyclic rings and when Cyc is substituted or unsubstituted cycloalkyl, said substituent selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl , oxo or spiro-dioxoliniias. These compounds are oxytocin antagonists and are useful in the treatment of preterm labor, dysmenorrhea and in order to stop birth in preparation for Caesarean section.

i

The present invention relates to novel compounds, novel compositions, methods of use and production. These compounds are generally useful in pharmacology as preparations in obstetrics and gynecology. The aforementioned pharmacological activity is useful in the treatment of mammals. More particularly, the compounds of the present invention may be used in the treatment of preterm labor, in the prevention of delivery, in the preparation of delivery by Caesarean section, and in the treatment of dysmenorrhea. Obstetric and gynecological therapies are currently in short supply.

One of the main problems in the field of obstetrics is preterm labor. Many pregnancies after 30 weeks suffer from birth defects and childbirth, which is the leading cause of morbidity and mortality. Although neonatal care has made great strides, in many cases it is better to keep the fetus in utero.

Currently used tocolytic (uterine-releasing) agents include beta2-adrenergic agonists, magnesium sulfate and ethanol. Rhytodrin, a major beta2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycaemia (and reactive hypoglycaemia in the baby). Other beta2adrenergic agonists, including terbutaline and albuterol, have similar side effects to ritodrine. Magnesium sulfate at plasma levels above the therapeutic level (4-8 mg / dL) may inhibit cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest and is therefore unsuitable for use in patients with decreased renal function. Ethanol is as effective as rhododrine in preventing preterm labor, but atiLT 3592 B does not reliably reduce fetal respiratory distress as with ritodrin.

It has been suggested that the ideal tocolytic agent could be a 5 selective oxytocin antagonist. In recent years, there has been considerable evidence suggesting that the hormone oxytocin is the initiator of preterm birth in some mammalian species, including humans. Oxytocin is thought to act partly by directly undermining the myometrium, partly by stimulating the synthesis and secretion of astringent prostaglandins from the basal membrane of the uterine lining. In addition, prostaglandins may play an important role in cervical maturation. According to these me15 chanisms, labor (normal and premature) is initiated by increased uterine sensitivity to oxytocin; this is due to a reliably proven increase in the number of oxytocin receptors in these tissues. Such regulation of the number of oxytocin receptors and increased uterine sensitivity is caused by trophic effects due to increasing plasma estrogen levels as parturition approaches. By blocking oxytocin, both the uterine (astringent) and indirect (increased prostaglandin synthesis) effects of oxytocin can be blocked. A selective oxytocin blocker or antagonist should be more effective in preterm delivery than current remedies. In addition, oxytocin acts mainly on the uterus during childbirth, so it is expected that such an oxytocin antagonist should have little (or no) side effects.

The compounds of the present invention are also useful in the treatment of di. menorrhea. 'Repeated on <. pains associated with menstruation during the cvulatory cycle. Pain is thought to result from uterine contraction and ischemia caused by the effects of prostaglandins produced in the secretory endometrium. By targeting both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin blocker or antagonist should be more effective in the treatment of dysmenorrhea than is currently the case. A further aspect of the present invention is the use of stopping childbirth in preparation for a Caesarean section.

It is an object of the present invention to provide effective oxytocin-antagonistic agents for use in diseased animals, particularly mammals, and especially human organisms. Another object of the present invention is to provide novel compounds which selectively inhibit the action of oxytocin. It is another object of the present invention to provide a method of counteracting the function of oxytocin for use in a mammalian subject. Purpose of the present invention. are also designed to prevent or treat oxytocin-mediated disorders such as preterm labor and dysmenorrhea by causing oxytocin to counteract.

Compounds of formula I have been shown to be oxytocin antagonists and to bind to oxytocin receptors. When the oxytocin receptor binds a compound of the present invention, the oxytocin is separated from its receptor and cannot exert its biological or pharmacological effects. These compounds are intended for the treatment and prophylaxis of oxytocin-mediated disorders in animals, particularly mammals, and in particular humans. These disorders are primarily premature birth and dysmenorrhea. These compounds will also be useful in stopping birth in preparation for Caesarean section.

The compounds of the Sic invention, or pharmaceutically acceptable salts thereof, have the following general structural formula:

R ²

R

R ¹ p4 D 7 d 8

when

X is (1) C or (2) N;

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

Z is a substituent which may or may not be present; when it is selected from substituted or unsubstituted alkyl, said substituent being carboxyl;

R * is (1) hydrogen (2) alkyl or (3) NH;

R is hydrogen;

R ¹ and R together form an alkyl, bridge of three or three methylenes and form respectively

respectively;

R ³ and R ^{4 are} independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) alkylsulfonyl, (4) alkoxy (5) unsubstituted alkyl or alkyl substituted by hydroxy, alkoxy, alkylsulfonyl, amine, alkylamine or dialkylamine;

R and R are independently selected from one or more groups, including:

(1) hydrogen, (2) alkyl, (3) alkyl substituted with amine, hydroxy, alkoxy, alkylsulfonyl, arylsulfonyl, alkylamine or dialkylamine;

(4) phenylalkyl or (5) oxo;

R 'and R are independently selected from one or more groups including: (1) hydrogen, (i) (2) alkyl, (3) taken together to form unsubstituted cycloalkyl or cycloalkyl substituted by hydroxy or hydroxyalkyl;

10th

R and R taken together form the cyclic epoxy shown below

10th

R and R are independently selected from one or more groups, including:

(1) hydrogen, (2) hydroxyl, (3) halogen, (4) oximino, (5) methyl;

(6) carboxyl, (7) oxo, (8) alkoxycarbonyl, (9) alkylcarbonyloxy, (10) alkoxycarbonylalkoxy, (11) trihaloalkylsulfonyloxy, (12) unsubstituted amine or amine substituted with one or more radicals, including alkyl, carboxyalkyl alkoxycarbonylalkyl;

R ¹¹ , which is attached to the substituent Z when this substituent is present and directly to the camphor ring when Z is absent, is defined as follows:

(1) hydrogen, (2) -N (R ¹² ) -CO-R ¹³ or (3) -CO-N (R ¹⁴ ) -R ¹⁵ ;

_ 12

R is (1) hydrogen, (2) alkoxy, (3) unsubstituted alkyl or alkyl substituted with one or more substituents including carboxyl, hydroxyl, alkoxy, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, (4) alkoxycarbonyl or (5) alkoxycarbonylamine;

'13

R is (1) hydrogen, (2) alkoxy, (3) aralkoxy, (4) carboxyl, (5) alkoxycarbonyl, (6) alkoxycarbonylamine, (7) unsubstituted cycloalkyl or cycloalkyl substituted by carboxyl, (8) unsubstituted phenyl or phenyl , substituted with one or more substituents including carboxyl, carboxyalkyl or SO ₃ H, (9) an unsubstituted amine or an amine substituted with an unsubstituted or substituted alkyl having one or more substituents, including carboxyl, alkylsulfonium or non-LT 3592 B substituted a five-membered heterocyclic ring containing 1 or 2 heteroatoms when the heteroatom is N, (10) the heterocyclic ring being optionally selected from the group consisting of:

unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 members in total and 1, 2, 3 or nitrogen heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings contains one or more radicals, including alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyarylalkyl, aralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, aminoalkylcarbonyl, cyanoradical, alkylsulfonyl, alkoxycarbonyl, non-alkoxycarbonyl, said substituent being one or more radicals, including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (11) unsubstituted or substituted alkyl, wherein said substituent is one or more radicals including hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyl, , cyano radical, sulfate, alkylsulfonyl, acetamidine, formidine, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio radical, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morphclinyl, tetrahydropyranyl, tetrahydrothiapyranyl, alkoxycarbonylpiperidinyl, cyanoradical, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, dialkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a five-membered heterocyclic ring containing 1 or 2 heteroatoms and the N-heteroatoms being substituted, when said substituent is selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het is a heterocyclic ring selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having a total of 5, 6, 7 or 8 members and 1, 2, 3 or 4 nitrogen heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings is one or more radicals including alkyl, amine, carboxyl, carboxyalkyl, aralkyl, carboxyarylalkyl, alkoxycarbonyl, alkoxycarbonyl, substituted with halogen, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, aryloxyalkyl, , an oxo group, SO ₃ H, or an unsubstituted or substituted amine wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl;

R ¹⁴ and R ¹⁵ independently of one another are (1) hydrogen, (2) unsubstituted or substituted alkyl, said substituent being one or more radicals including vanLT 3592 Bio denyl, carboxyl, amine, aminoalkylamine, aminocarbonyl, hydroxyl, alkoxy, alkylthio, thioalkyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl, or unsubstituted five-membered saturated heterocyclic rings having 1 or 2 heteroatoms selected from the group consisting of N and ( unsubstituted or substituted rings having a total of 5, 6, 7 or 8 members and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S and said substituent being one or more radicals including alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; m and n are integers from 0 to 1.

Particularly suitable are compounds having the following general formula:

R ²

R ¹¹ -Z or pharmaceutically acceptable salts thereof, when

X is (1) C or (2) N;

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

Z is a substituent which may or may not be present; when present, it is substituted or unsubstituted alkyl and the substituent is carboxyl;

R ¹ is present

(1) hydrogen, (2) alkyl or (3) NH; R ² is hydrogen; R ¹ and R ² together form an alkyl bridge of three or

four methylenes;

R ³ and one R ⁴ independently of one or more groups, from each other between them: is consisting of (D hydrogen, (2) halogen, (3) alkylsulfonyl, (4) alkoxy group, (5) unchanged or substituted alkyl, when mentioned the substituent is amine, alkylamine arga dialkyl- amine; R ⁵ and R ⁶ independently from each other is consisting of only: s or multiple groups, between them:

(1) hydrogen, (2) alkyl, (3) alkyl substituted with amine, alkylsulfonyl, arylsulf- phenyl, alkylamine or dialkylamine; (4) phenylalkyl or (5) oxo group; R ⁷ and θ R independently of one another are composed of five > or several groups, including: (1) hydrogen, (2) alkyl, (3) taken together to form an unsubstituted cycloalkyl, or cycloalkyl substituted with hydroxyl or hydroxy- sprat; R ⁹ and R ¹⁰ taken together to form a cyclic epoxy; R ⁹ and R ^{10 are} independently of each other five i or several groups, including: (D hydrogen, (2) hydroxyl, (3) halogen, (4) oxyamino group, (5) methyl; (6) carboxyl, (7) oxo group, (8) alkoxycarbonyl, (9) alkylcarbonyloxy, '10) alkoxycarbonylalkoxy, (11) a sulfonyl group;

(12) trihalogenalkylsulfonyloxy, (13) an unsubstituted amine or an amine substituted with one or several radicals, including alkyl, carboxy kilo or alkoxycarbonylalkyl; R ¹¹ , which is connected to the substituent Z when this substituent is, and directly to the camphor ring when Z is absent, is defined as follows: d) hydrogen, (2) -N (R ¹² ) -CO-R ¹³ or (3) -CO-N (R ¹⁴ ) -R ¹⁵ ; 12th R is (1) hydrogen, (2) a1coxycarbonylamine, (3) alkyl or (4) alkylsulfonylalkyl; n ¹³ R is d ') hydrogen, (2) alkoxy group, (3) araikox group, (4) a1coxycarbonyl, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl when mini- mas the substituent is carboxyl, (8) unsubstituted or substituted phenyl when mentioned u a k a it is one or more radicals, including box el, carboxyalkyl or SO ₃ H,

(9) an unsubstituted or substituted amine, said substituent being unsubstituted or substituted alkyl, said substituent being one or more radicals including carboxyl, alkylsulfonyl or an unsubstituted five-membered heterocyclic ring containing 1 or 2 heteroatoms, said heteroatom being N, ( 10) heterocyclic rings optionally selected from the group consisting of:

unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 members in total and 1, 2, 3 or 4 nitrogen heteroatoms; having 5 or 6 members in total and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members, and. two different heteroatoms from the group consisting of N, 0, S; wherein said substituent on any of said heterocyclic rings is one or more radicals, including alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyarylalkyl, aralkyl aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyanoradicale, alkylsulfonyloxy, said substituent being one or more radicals including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or (11) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyalkylphenyl, cyano radical, sulfate, alkyl sulfonyl, acetamidine, formamidine, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio radical, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or a substituted amine wherein said substituent is one or more radicals including alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahyro-pyranyl, tetrahydrothiapyranyl, alkoxycarbonylpiperidinyl, cyano-radical, cyanoalkyl, hydroxyalkyl, haloalkyl, haloalkyl, haloalkyl, , alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a 5-membered heterocyclic ring substituted with 1 or 2 heteroatoms or heteroatoms; unsubstituted cycloalkyl wherein said substituent is selected from the group consisting of 'alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het being heterocyclic rings selected from the group consisting of: unsubstituted or substituted unsaturated rings having 5, 6, 7 or 8 members in total and 1, 2, 3 or 4 nitrogen heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings is one or more radicals including alkyl, amine, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, alkoxycarbonyl, substituted with halogen, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, aryloxyalkyl, aryloxyalkyl, , an oxo group, SO ₃ H, or an unsubstituted or substituted amine wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl;

R 'and F 7 independently of one another are (1) hydrogen, (2) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydrogen, carboxyl, amine, aminoalkylamine, aminocarbonyl, hydroxyl, alkoxy, alkylthio, thioalkyl. , alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl, or unsubstituted five-membered saturated heterocyclic rings containing 1 or 2 heteroatoms, said heteroatom being N or (3) the heterocyclic ring being unsubstituted or substituted with having a total of 5, 6, 7 or 8 members and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and 1 S heteroatoms; or having a total of 6 members and two different heteroatoms selected from the group consisting of N, O, S and said substituent being one or more radicals including alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl;

and m and n are integers from 0 to 1.

The following compounds having the following formula are most suitable:

CH,

or

or a pharmaceutically acceptable salt thereof

R ¹ is (1) hydrogen, (2) alkoxycarbonyl, (3) alkyl;

R ² is (1) hydrogen, (2) alkoxyl, (3) aralkoxyl, (4) alkoxycarbonyl, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl, said substituent being carboxyl, (7) unsubstituted or substituted phenyl, said substituent or substituents being their carboxyl, carboxyalkyl or SO ₃ H, (8) unsubstituted or substituted amine when said substituent is unsubstituted or substituted alkyl, including carboxyl, alkylsulfonyl or unsubstituted five-membered heterocyclic a ring having 1 or 2 heteroatoms when the heteroatom is N, (9) unsubstituted or substituted rings having the formula

.N.

.NO

II

s.

wherein said substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyaralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo, or an unsubstituted or substituted alkyl, the said substituent being one or more radicals, , carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, Het or an unsubstituted or substituted amine where said substituent is one or more radicals including alkyl, -. alkylcarbonyl, alkylsulfonyl, carboxyalkyl, Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a 5-membered heterocyclic ring substituted with 1 or 2 heteroatoms and N heteroatoms cycloalkyl when said substituent <

selected from the group consisting of alkocLT 3592 B sicarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het are unsubstituted or substituted rings of the formulas below

where said substituent is one or more radicals such as alkyl, amino, carboxyl, carboxyalkyl, karboksiaralkilas, alkoxycarbonyl, alkoxycarbonyl substituted by halogen, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoksialkoksialkoksialkilas, aralkylcarbonyl, aralkoxyalkyl, aralkoxycarbonyl, oxo, SO ₃ H, or an unsubstituted or a substituted amine when said substituent is alkyl, carboxyalkyl or alkoxycarbonylalkyl.

Salts, as defined by the term pharmaceutically acceptable, are non-toxic salts of the compounds of this invention, which are usually prepared by reacting the free base with the appropriate organic or inorganic acid. The following salts are typical:

Acetate Lactobionate Benzosulfonate Laurate Benzoate Malat Bicarbonate Maleate Bisulfate Mandelato Bitartrate Me z i1a t a s Borat Methyl bromide Bromide Methylnitrate

Calcium Edetate

Kamzilat

Carbonate

Chloride

Clavulanate

Citrate

Dihydrochloride

Edetat

Edisilat

Estolat

Ezilatas

Fumarat

Gluceptate

Gluconate

Glutamate

Glycolylarsenylate

Hexylresorcinate

Hydrabamine

Hydrobromide

Hydrochloride

Hydroxy naphthoate

Iodide

Isothionates

Lactate

The term pharmacologically elicits a drug or pharmaceutical in tissues, systematizing the response that is elicited.

Methylsulfate

Mukatas

Napsilat

Nitrate

N-methylglucamine ammonium salt

Oleata

Oxalate

Pamoat (Embonato)

Palmitat

Pantothenate

Phosphate / Diphosphate

Polygalacturonate

Salicylate

Stearate

Sulphate

Subacetate

Succinate

Tanat

Tartrate

Theoclate

Tosylate

The effective amount of triethidide valerate refers to the amount of preparation which the investigator or animal can observe or

The term alkyl refers to a straight or branched alkane chain containing 1 to 10 carbon atoms or any number within the range.

The term alkenyl means a straight or branched chain having one or more unsaturated bonds at any position on the chain, an alkene chain having from 2 to 10 carbon atoms, or any number in the range.

The term alkynyl means a straight or branched chain having one or more unsaturated bonds at any position on the chain, an alkyne chain having from 2 to 10 carbon atoms, or any number within that range.

The term aryl means phenyl, naphthyl or fluorenyl.

The term cycloalkyl refers to cyclic aliphatic rings having from 3 to 8 carbon atoms.

The term trihaloalkylsulfonylox means a substituent having the formula below

II

When the terms alkyl and aryl or their prefixes are in the substituent name (e.g., arylalkoxy aryloxy), these substituents are considered to be subject to the same limitations as those for alkyl and aryl above.

A defined number of carbon or ohms (e.g. independently of carbon in a. Or cakio;

Cp. , _(n ) valid for an unsubstituted or substituted alkyl radical.

The term oxo means a substitution = 0.

The term halogen means iodine, bromine, chlorine and fluorine.

The term premature birth refers to the withdrawal of a viable fetus from the uterus before the end of the normal gestation period, and in particular the onset of gestation before the 37th week of pregnancy, accompanied by cervical smoothing and dilation. These may or may not be related to vaginal bleeding or membrane rupture.

The term dysmenorrhea refers to painful menstruation.

The term Caesarean section refers to the incision through the abdominal and uterine wall to produce fetus.

The term substituted includes various degrees of substitution by the aforesaid substituent.

When multiple substituents are described or claimed, the compound may be independently substituted with one or more of the substituents listed above, each one or more times.

The properties of the compounds containing foemula I in contrast to oxytocin make them useful in mammals, especially humans, as pharmacologic agents for the prophylaxis and treatment of disorders that may be affected by oxytocin. Examples of such disorders include preterm labor and especially aismenorrhea. These compounds may also be useful in stopping childbirth in preparation for Caesarean section.

I

Given the relationship between vasopressin and oxyocin, the compounds of the present invention are as useful as vasopressin antagonists. Vasopressin antagonists are used for the prophylaxis and treatment of diseases associated with vasopressin disorders; they are used, for example, as diuretics and in static heart failure.

The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (including sustained-release and sustained-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered intravenously (either as a bolus or .infusion), intraperitoneally, subcutaneously, or intramuscularly, all of which are well known in the art of pharmacy. An effective but non-toxic amount of the desired compound can be used as a tocolytic agent.

The dosage regimen utilized by the compounds of the present invention will be selected according to a variety of factors including the type, species, age, weight, sex and medical condition of the disabled person; the severity of the disease being treated; method of prescribing; patient renal and hepatic function current; the particular compound used or a salt thereof. A prescriber or veterinarian can easily determine and prescribe the effective amount of medicine needed to prevent, treat, or stop the disease.

The oral doses of the present invention, when used to achieve the above effects, are about 0.3-6.0 g / day orally. The most suitable intravenous doses are from about 0.1 to about 10 mg / min at a constant rate, as an advantage, these cuttings of the invention may be administered once a day, or the total daily dose may be divided into two, three or four doses per day. In addition, more preferred compounds of the present invention may be administered intranasally using topical administration of suitable intranasal excipients, or transdermally using those transdermal skin plaques known to those skilled in the art. The transdermal dosage form will, of course, have a continuous delivery, unlike intermittent dosage administration.

The compounds of the present invention may be formulated in accordance with the methods of the present invention to form an active ingredient and are generally administered in admixture with pharmaceutically acceptable diluents, excipients or carriers (collectively referred to as carriers) selected according to their intended forms of administration, e.g. y. oral tablets, capsules, elixirs, syrups and the like, in accordance with known pharmaceutical practice.

For example, the active ingredient of a tablet or capsule for oral administration may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be added to the mixture as required or desired. Suitable binders include starch, gelatin, natural carbohydrates such as glucose or beta-lactose, corn syrups, natural and synthetic resins such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Oils used in dosage forms, oleate, sodium stearate, magnesium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methylcellulose, agar, bentonite, zanthan gum and the like.

Among them is sodium stearate, sodium

The compounds of the present invention may also be used in the form of liposomes, for example, as small unicellular vesicles, large unicellular vesicles, and multilamellar vesicles. Liposomes can be composed of various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of the present invention may also be provided using monoclonal antibodies as individual carriers to which the compound molecules are conjugated. The compounds of the present invention may also be conjugated to soluble polymers as targeting drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethylaspartamide phenol or polyethylenaxaxyllysine substituted with palmitoyl radicals. In addition, the compounds of the present invention may be incorporated into some biodegradable polymers useful for the controlled release of drugs, including, for example, polylactic acid, polepilone caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacephalenes, polydihydropyrans, polycyanoacrylates, and polyisacrylates.

Compounds of Formula I may be readily prepared according to the reaction schemes set forth below (in which all variables have the meanings previously defined) and examples or modifications thereof using readily available starting materials, reagents, and conventional synthesis procedures. These reactions may employ variants known to those skilled in the art but are not mentioned in detail herein.

Most suitable compounds of the present invention are all those set forth in the Examples. However, these compounds need not be construed as constituting the sole sum of viLT 3592 B which is the present invention - any combination of compounds or moieties may form a whole. The following examples of the synthesis of the substituents to be utilized below illustrate the details of the present invention. It will be appreciated by those skilled in the art that known variations in the synthesis procedures and conditions may be employed in the preparation of these compounds. All temperatures are in degrees Celsius unless otherwise stated.

SCHEME 1

Π

SCHEME 2

SCHEME 3

1) Me ₃ -St-CN

2) LAH

3) R ^ Cl

T

O

SCHEME 4

R ²

1) H ₂ CCHMgBr

2) SOC1 ₂

3) H-NR ₂

SCHEME 5

1)

L

m) o

II

R ²

2) Pd (O), CO; MeOH

3) NaOH

4) BOP, H-NR ₂

SCHEME 6

I

SCHEME 8

1)

II ο ^λ

M

O;

2) Pd (O), CO; MeOH

3) Sml ₂ , THF, MeOH

4) NaOH

5) BOP, H-NR ₂

The following abbreviations are used in the examples:

TEA = triethylamine

DIEA - Diisopropylethylamine

BOP = Benzotriazolyloxitrile (dimethylamino) phosphonium hexafluorophosphate

THF = tetrahydrofuran

DMF = dimethylformamide

LAH = lithium aluminum hydride

TFA = trifluoroacetic acid

HPLC method A = 15 min. linear gradient from 95: 5 A: B to 0: 100 A: B

A - H ₂ 0 with 0.1% (v / v) TFA

B - CH ₃ CN with 0.1% (vol) TFA

2.0 ml / min flow rate cm C18 reverse phase column UV detection (215 nrn)

TLC (thin layer chromatography) was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.

EXAMPLE

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

To a stirred solution cooled to 0 ° C, a solution of 1- (o-tolyl) piperazine hydrochloride (50. 0 g,

235 mmol) and TEA (83 mL, 590 mmol) chloroform (1000 mL) were added (+) - 10-camphorsulfonyl chloride (65.5 g, 260 mmol). The solution was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The solution was extracted with 5% HCl (2 x 500 mL), water (500 mL) and saturated aqueous NaHCO ₃ (2 x 500 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The resulting solid is recrystallized from methanol to give the title compound. Vol. 112-114 ° C (69 g, 75%).

Analysis: (C ₂₁ H ₃₀ N ₂ O ₃ S)

Calculated; C, 64.57; y, 7.74; N, 7.17

Found: C, 64.52; K, 7.68; N, 6.99

TLC: R _f 0.49 (75: 25 Hexane / Ethyl acetate)

HPLC (method A): exit time 10.33 min

FAB MS: m / z 391 (M ⁺ + H) ^@ +.

^X H NMR ( 300 MHz, CDCl ₃ ) : d, 7.2 (m, 2H), 7.0 (m, 2H), 3.45 (m, 4H), 3.40 (d, J = 16 Ηζ, ΙΗ), 3.0 (m, 4H), 2.57 (m, 1H), 2.40 (dt, J = 14 Hz, Jt = 3 Hz, 1H), 2.30 (s, 3H), 2.10 (m, 2H), 1.96 (d, J = = 14 Hz, 1H), 1.67 (m, 1H), 1.44

(m, 1H), 1.18 (s, 3H).

EXAMPLE 2

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

To a stirred solution of diisopropylam (21.0 mL, 150 mmol) and THF (350 mL) cooled to -78 ° C was added n-butyllithium (60 mL, 2.5 M in hexane; 150 mmol). The solution is warmed to 0 ° C and held for 15 minutes, 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 minutes. Chilled to -78 ° C 1 - ((7,7,7-dimethyl-2-oxo-bicyclo A solution of (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine (50.0 g, 128 mmol) in THF (350 mL) was poured through a dropping funnel and the resulting solution was stirred for 5 minutes at -78 ° C. C. A 5: 1 solution of THF / water (100 mL) was added and the mixture was warmed to room temperature, diluted with ethyl acetate (500 mL) and washed with 5% aqueous citric acid (2 x 500 mL) and brine (250 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure to give an amorphous mass, the main isomer being obtained by TLC crystallization from ether, m.p. 163-165 ° C.

Analysis: (C24H35N3O3S)

Calculated: C, 64.69; H, 7.92; N, 9.43

Found: C, 64.72; H, 7.99; N, 9.35

TLC: R _f 0.31 (75:25 hexane / ethyl acetate)

HPLC (method A): exit time 10.20 min

FAB MS: m / z 446 (M ⁺ + H) @ ⁺

NMR (300 MHz, CDC1 _3): d 7.19 (m, 2H), 3.70 (d, J = 15

Hz, 1H), 3.68 (s, 1H), 3.49 (m, 4H), 3.38 (d, J = 15 Hz,

1H), 2.75 (q, J = Hz, 1H), 2.30 (s, 2H), 2.05 (m, 2H),

1.7-1.9 (m, 3H), 1.47 (d, J = 7Hz, 3H), 1.41 (d, J = 12Hz,

1H), 1.15 (s, 3H), 1.04 (m, 1H).

EXAMPLE 3

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

To a stirred solution of 1 ((7,7-dimethyl-2-exo-hydroxy-2-endo- (1-cyano) ethylbicyclo (2.2.1) heptan-1-yl) cooled to -78 ° C) methanesulfonyl) -4- (2-methylphenyl) piperazine (25.0 g, 56.2 mmol) and THF (350 mL) was added dropwise to a 1.0 M solution of LAH in THF (170 mL; 170 mmol). The resulting solution was stirred at -78 ° C for one hour and 3 hours. 5M NaOH (35 mL) was added dropwise with ether. The resulting suspension was warmed to room temperature and stirred for 1 hour. Ethyl acetate (250 mL) was added and stirring was continued for another 30 minutes. The solid is removed by filtration through celite and washed The solvent is removed from the filtrate under reduced pressure to give an amorphous mass. The title compound is obtained by recrystallization from methanol (17.2 g, 68%), m.p. 172-174 ° C.

then heated at 0 ° C (300 mL) then slowly

EtOAc. for knowledge

Analysis: (C ₂ 4 H ₃₉ N ₃ 0 ₃ S)

Calculated: C, 64.11; H, 8.74; N, 9.35

Found: C, 64.09; H, 8.88; N, 9.31

TLC: R _f 0.50 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 9.80 min

FAB MS: m / z 450 (M ⁺ H) ³ H NMR (300 MHz, CDC1 _3): d 7.20 (m, 2H), 7:05 (m, 2H);

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

EXAMPLE 4

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (L-propyl) amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) 4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2 -methylphenyl) piperazine (2.0 g;

4.45 mmol) and DMF (30 mL), Na-Fmoc-L-proline (1.58 g; 4.68 mmol), BOP (2.17 g; 4.90 mmol) and DIEA (1.71 mL; 9.80 mmol) were added. After 16 hours, diethylamine (6 mL) was added and the solution was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ₂₉ H ₄₆ N ₄ O ₄ S)

Calculated: C, 52.48; H, 6.50; N, 7.56 Found: C, 52.46; H, 6.50; N, 7.69

1.7 TFA, 0.05 H ₂ O

TLC: R _f 0.45 (90: 10: 1 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 8.60 min FAB MS: m / z 547 (M + H) ^{: 1} H NMR · (400 MHz, CDCl ₃ ): d 7.55 (br t, 1H), 7.18 (m, 2H) , 7.03 (m, 2H), 2.31 (s, 8H), 1.14 (s, 3H), 1.02 (s,

3H0, 0.99 (d, J = 7 EI, m, 3H ').

EXAMPLE 5

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (Ln (ethoxycarbonyl-propyl) -propyl) -amino) -propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (L-prolyl) -amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine (1.5 g; FW = 679; 2.21 mmol) and DMF (15 mL), ethyl 4-bromobutyrate (538 mg, 2.76 mmol) and DIEA (1.15 mL; 6.63 mmol). After 72 hours at room temperature, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of acetonitrile and water to 0.1%.

TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ^ H ^^ N ^ O ^ S)

Calculated: C, 51.99; H, 6.48; N, 6.17

Found: C, 52.01; H, 6.33; N, 6.17

2.1 TFA. 0.1 H ₂ O

TLC: R _f 0.40 (95: 5 CHCl ₃ : MeOH)

HPLC (method A :): exit time 10.23 min

FAB MS: m / z 661 (M ⁺ H) ^4; H NMR (400 MHz, CDC1 _3): d 8:55 (m, 1H), 7.20 (m, 2H);

7.08 (m, 2H), 2.35 (s, 3H), 1.25 (t, J = 6 Hz, 3H), 1.14 (s, 3H), 1.03 (overlapping s and d, 6H).

Analysis: (C ₃₃ H ₃ N ₂ O ₃ S)

Calculated: C, 51.99; H, 6.48; N, 6.17

Found: C, 52.01; H, 6.33; N, 6.17

2.1 TFA, 0.1 H ₂ O

TLC: R _f 0.40 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 10.23 min

FAB MS: m / z: 661 (M ⁺ H) ^4; H NMR (400 MHz, CDC1 _3): d 8:55 (m, 1H), 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).

EXAMPLE 6

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (1-n-) 3-carboxypropyl) -propyl) amino) -propyl-bicyclo (2.2.1) heptane -

~ T

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (Ln-ethoxycarbonylpropyl) propyl) amino) propylbicyclo- (2.2.1) heptan-1 -yl) methanesulfonyl) 4- (2-methylphenyl) piperazine (1.00 g; FW = 909; 1.10 mmol) and THF (15 mL), 1M NaOH solution (1.0 mL, 4.0 mmol) was added until the pH of the solution was maintained for 1 hour. . The solution is acidified by the addition of citric acid and the solvents are removed under reduced pressure. The residue was dissolved in dichloromethane (75 mL) and washed with water (3 x 25 mL), dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure. The residue is lyophilized from a mixture of dioxane and water to give the title compound (white powder).

Analysis: (C ₃₃ H ₅₂ N ₄ O ₆ S)

Calculated: C, 59.78; H, 8.25; N, 6.94 Found: C, 59.86; H, 7.98; N, 6.92 0.1 Well citrate, 1.65 Dioxane TLC: R _f 0.35 (80: 20: 2 CHCl ₃ : MeOH: NH ₄ OH) HPLC (method A): exit time 9.24 min FAB MS: m / z 633 (M ⁺ + H) ¹ H NMR (400 MHz, CDCl ₃ ): d 7.55 (pi s, 1H), 7.18 (m, 2H), 7.03 (m, 2H) , 2.31 (s, 3H), 1.15 (S, 3H), 1.04 (s,

3H), 0.98 (d, J = 6Hz, 6H)

EXAMPLE 7

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (4 (5) -imidazolylacetyl) amino) propylbicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) - 4- (2-methylphenyl) -piperazine (1.50 g; 3.34 mmol) and DMF (15 mL), 4 (5) imidazolacetic acid hydrochloride (679 mg; 4.18 mmol), BOP (1.85 g, 4.18 mmol) and DIEA ( 2.18 mL; 12.5 mmol). After 16 hours, the solvent is removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution (2 x 50 mL) and water (2 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by silica gel column chromatography (92: 8: 0.8 CHCl ₃ : MeOH: NH ₄ OH). The title compound is crystallized from EtOAc, m.p. 159-163 ° C.

Analysis: (C ₂₉ H ₄₃ N ₅ O ₄ S)

Calculated: C, 62.45; H, 7.77; N, 12.56 Found: C, 62.88; H, 7.68; N, 12.79 TLC: R.- 0.4 (90: 1 0: 1 CHCL · : MeOH: NH ₄ OH) HPLC (method A) ; i S θ ή in IT, O time 8.72 min FAB MS: m / z 553 (M t H) H NMR iCDCl,): G t. O / ( s, 1H), '7.2 (m, 2H), /..38 '2, il · H,. 3.55 (m, 2H), 3.4 (m,

4H), 2.87 (d, J = 15Hz, 1H), 2.31 (s, 3H), 1.71 (t, J = 4Hz, 1H), 1.52 (d, J = 13Hz, 1H), 1.15 (s, 3H), 0.97 (d, J = 6Hz, 3H)

EXAMPLE 8

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1-quinuclidin-3-ylcarbonyl) amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4-i 2-Methylphenyl) -piperazine (2.00 g, 4.45 mmol) and DMF (50 mL), quinuclidine-3-carboxylic acid hydrochloride (938 mg, 4.90 mmol), BOP (2.17 g, 4.90 mmol) and DIEA were added. (2.56 mL; 14.7 mmol). After 16 hours, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 1% acetic acid. The title compound was obtained as the acetate salt (1: 1 mixture of diastereomers; lyophilized powder).

Analysis: (C ₃₂ H ₅₀ N ₄ O ₄ S)

Calculated: C, 60.39; H, 8.58; N, 8.39 Found: C, 60.41; H, 8.19; N, 8.58

0.8 CH ₃ CO ₂ H, 1.85 H ₂ O

TLC: R _f 0.65 (80: 20: 2 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 8.68 min

FAB MS: m / z 587 (M ⁺ H) ^{Χ Η} NMR (300 MHz, CDC1 _3): d 7.19 (m, 2H) 7.02 (m, 2H);

2.30 (s, 3H), 1.16 (s, 3H), 1.03 (overlapping s and d, 6H)

EXAMPLE 9

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo- (1- (1-carboxymethyl-quinuclidin-3-ylcarbonyl) -amino) -propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-quinuclidin-3-ylcarbonyl) amino) propyl-bicyclo (2.2.1) heptane- l-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine (1.50 g; EW = 668; 2.25 mmol) and

DMF (30 mL), iodoacetic acid (543 mg;

2.92 mmol) and DIEA (0.43 mL; 2.48 mmol). After 16 h, TLC showed complete reaction of starting materials. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with ^: 1% acetic acid. The title compound is obtained (1: 1 mixture of diastereomers; lyophilized powder).

Analysis: (C ₃₄ H ₃₂ N ₄ O ₄ S)

Calculated: C, 60.52; H, 8.18; N, 8.04

Found: C, 60.52; H, 7.98; N, 8.15

0.55 CH ₃ CO ₂ H, 0.95 H ₂ 0

TLC: R _f 0.20 (80: 10: 2 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 8.73 min

FAB MS: m / z 647 (M ⁺ H) ^X H NMR (TFA salt, 400 MHz, CDC1 _3): 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 = 6Hz, 3H)

EXAMPLE 10 1 ^- ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (2-methoxycarbonylethyl) amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) - 4- (2-methylphenyl) -piperazine

H

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (100 mg, 0.22 mmol) and DMF-MeOH 1: 1 (3 mL), methyl acrylate (0.020 mL, 0.22 mmol) was added. After 16 hours, the solvent is removed under reduced pressure and the purification of the iLTLT 3592B is carried out by reverse phase preparative HPLC using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ₂ gH 45 N ₃ O ₃ S)

Calculated: C, 53.05; H, 6.88; N, 6.06

Found: C, 53.01; H, 6.90; N, 6.01

1.3 TFA, 0.5 H ₂ O

TLC: R _f 0.35 (95: 5) CHCl ₃ : MeOH)

HPLC (method A): exit time 9.04 min

FAB MS: m / z 536 (M ⁺ H) ¹ H NMR (300 MHz, CDC1 _3): d 7.20 (m, 2H) 7.03 (m, 2H), 3.72 (s, 3H), 2:32 (s , 3H), 1.19 (d, J = 6Hz, 3H), 0.98 (s, 3H)

EXAMPLE 11

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1-bis (2-methoxycarbonylethyl) amino) propylbicyclo (2.2.1) heptane-1)

stirring solution containing 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) -piperazine (100 mg, 0.22 mmol) and DMF-MeOH 1: 1 (3 mL), methyl acrylate (0.080 mL, 0.89 mmol) was added. After 16 hours, the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using a 3: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained as an amorphous material from hexane.

Analysis: (C ₃₂ H ₅₁ N ₃ O ₇ S)

Calculated: C, 61.81; H, 8.27; N, 6.76

Found: C, 61.55; H, 8.13; N, 6.55

TLC: R _f 0.40 (1: 3 EtOAc: Hexane)

HPLC (method A): exit time 9.71 min

FAB MS: m / z 622 (M ⁺ H) ^X H NMR (300 MHz, CDC1 _3): 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

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-ethenyl-bicyclo (2.2.1) heptan-1-ii) methanesulfenyl) -4- (2-methylphenyl) -piperazine

Stir in a cooled solution to - ~ 8 ° C in which; 1M vinylmagnesium chloride solution in THF (25 mL; 25 mmol), added dropwise cooled to -78 ° C, 1 - ((7,7-dimethyl-2-oxo-bicyclo- (2,2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (5 mg; 12.8 mmol) and THF (100 mL). The resulting solution was stirred under argon overnight, allowing the cooling bath to warm to room temperature. The reaction is quenched by the addition of 2% aqueous HCl (50 mL) and the mixture is poured into a mixture of ethyl acetate and water. The organic phase is washed with a saturated solution of sodium bicarbonate and brine, dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a silica gel column using a 4: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained as an amorphous material from hexane.

Analysis: (C ₂₃ H ₃₄ N ₂ 0 ₃ S)

Calculated: C, 65.82; H, 0.06 H ₂ 0 8.19; N, 6.67 Found: C, 65.99; H, 8.42; N, 6.63 TLC: R _f 0.36 (1: 5 EtOAc: hexane)

HPLC (method A): output time 11:41 min FAB MS: m / z 419 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 7.20 (m, 2H) 7.02 (m, 2H);

6.48 (dd, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 2.32 (s,

3H), 1.22 (s, 3H), 0.94 (s, 3H)

EXAMPLE 13

1 - ((7,7-Dimethyl-2- (2-chloro) ethylidenebicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 ((7,7-dimethyl-2-exo-hydroxy-2-endo-ethenyl-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) cooled to 0 ° C) -4- ( 2-methylphenyl) -piperazine (2.90 g; 6.94 mmol) and THF (100 mL), triethylamine (1.50 mL; 10.7 mmol) and DMF (0.58 mL;

7.5 mmol). Thionyl chloride (0.66 ml;

(9.1 mmol), the resulting solution was stirred for 18 hours and allowed to warm to room temperature in a cooling bath. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (150 mL) and washed with 5% aqueous HCl (75 mL), water (75 mL), and aqueous sodium bicarbonate solution (100 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by silica gel column chromatography using a 4: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained as an amorphous material from hexane.

Analysis: (C ₂₃ H ₃₃ ClN ₂ O ₂ S)

Calculated: C, 65.82; H, 0.6 H ₂ O 8.19; N, 6.67 Found: C, 65.99; H, 8.94; N, 6.63 ^{X 1} H NMR (400 MHz, CDCl ₃ ): δ 7.20 (m, 2H), 7.03 (m, 2H),

5.87 (m, 1H), 4.10 (ΑΒΧ, 2H), 2.32 (s, 3H), 1.00 (s,

3H), 0.82 (s, 3H)

EXAMPLE 14

1 ^- ((7,7-Dimethyl-2- (2-isobutylamino) ethylidenebicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2- (2chloro) -ethylidenebicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (200 mg) ; 0.46 mmol) and MeOH (2 mL), isobutylamine (0.5 mL, 5 mmol) was added. After stirring for 18 hours, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ₂₇ H ₄₁ N ₃ O ₂ S)

TLC: R _f 0.30 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.78 min

FAB MS: m / z 474 (M ⁺ H) ² Η NMR (400 MHz, CD ₃ OD) d 7.20 (m, 3H) 7.03 (t, 1H),

5.78 (m, 1H), 2.35 (s, 3H), 1.13 (d, J = 7H, 6H). 1.12 (s, 3H), 0.88 (s, 3H)

EXAMPLE 15

1 - ((7,7-Dimethyl-2- (2-azido) ethylidene-bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2) 2-chloro) -ethylidenebicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) - piperazine (2.58 g;

8.19 mmol), DMSO (50 mL) and THF (45 mL), add a solution of sodium azide (5.3; 82 mmol) in water (20 mL). After 24 hours, the solvent is removed under reduced pressure, the residue is suspended in methylene chloride (100 mL) and washed with water (3 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure to give a solid.

Analysis: (C ₂₃ H ₃₃ N ₅ O ₂ S) 0.06 H, 0

Calculated: C, 62.27; H, 7.50; N, 15.79

Found: C, 62.41; H, 7.54; N, 15.60

TLC: R _f 0.75 (70:30 Hex: EtOAc)

HPLC (method A): exit time 12.50 min

FAB MS: m / z 444 (M ⁺ + H) ^@ +.

NMR (300 MHz, CDCl ₃ ): δ 7.20 (m, 2H), 7.02 (m, 2H),

5.79 (m, 1H), 3.78 (ΑΒΧ, 2H), 2.32 (s, 3H), 0.85 (s, 3H)

EXAMPLE 16

1 - ((7,7-Dimethyl-2- (2-amino) ethylidene-bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy- (2-azido) ethylidenebicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (3.85 g; 8.69 mmol) and THF (150 mL) and water (3 mL) were added triphenylphosphine (2.50 g; 9.56 mmol). After 14 hours, the solvent is removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and extracted with 5% hydrochloric acid (3 x 75 mL). The combined acidic extracts were washed with ethyl acetate (50 mL) and basified by adding solid sodium hydroxide to pH 12. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure. The residue is purified by chromatography on a silica gel column using a gradient elution of chloroform-methanol 99: 1 to 85:15. The title compound (solid) is obtained.

Analysis: (C ₂₃ H ₃₃ N ₃ O ₂ S) 0.5 H ₂ O

Calculated: C, 64.75; H, 8.51; N, 9.85

Found: C, 64.59; H, 7.51; N, 9.71

TLC: R _f 0.56 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 10.38 min

FAB MS: m / z 418 (M ⁺ H) ^X H NMR (300 MHz, CDC1 _3): d 7.16 (m, 2H) 7.00 (m, 2H);

5.61 (m, 1H), 3.43 (m, 4H), 3.26 (d, J = 6.6 Hz, 2H), 1.18 (d, J = 14.1 Hz, 1H), 1.97 (m, 4H), 2.92 (d, J) = 14.1 Hz, 1H), 2.35 (m, 1H), 2.31 (s, 3H), 1.7-1.8 (m, 3H),

1.70 (m, 1H), 1.25 (m, 1H) 0.99 (s, 3H), 0.81 (s, 3H).

EXAMPLE 17

1 - ((7,7-Dimethyl-2- (2- (4- (5) -imidazolylacetylamino) ethylidenebicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

CH ·

SO ₂

N '

H

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

0.48 mmol) and DMF ((5 mL), BOP (265 mg;

0.60 mmol), 4-imidazolactic acid hydrochloride (115 mg, 0.72 mmol) and DIEA (0.38 mL, 2.2 mmol). After 14 hours, the solvent is removed under reduced pressure, the residue is suspended in ethyl acetate (50 mL) and washed with sodium bicarbonate solution (3 x 25 mL) and water (2 x 25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (Csg ^ gNsC? S); 0.5 H ₂ O; 1.7 TFA;

Calculated: C, 50.38; H, 5.55; N, 9.18

Found: C, 50.40; H, 5.55; N, 9.40

TLC: R _f 0.42 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 8.76 min

FAB MS: m / z 526 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 8:40 (s, 1H). 7.58 (br.m, 1H), 7.22 (m, 3H), 7.10 (m, 2H), 5.57 (br t, 1H), 2.37 (s, 3H), 0.97 (s, 3H), 0.76 (s, 3H) ).

EXAMPLE 18

1 - ((7,7-Dimethyl-2-spiro-epoxy-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine; ~ c ·, Ω

chilled to - ⁷ 8 ^O C Isulfide iodide (6 suspension containing 7 8 g; 30.8 mmoi) and

, .d i: H F solution in hexane; 27.7 mmol). After 4 hours at 0 ° C, 1 - ((7,7-dimethyl-2-oxo-bicyclo (2.2.1) heptanyl) methanesulfonyl) -4- (2-methylphenyl) piperazine (8.0 g;

20.5 mmol) in THF (50 mL). The resulting solution was stirred at 0 ° C for 2 hours, then at room temperature for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (150 mL) and washed with water (2 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The resulting solid was recrystallized from ether to give the title compound, mp 131-133 ° C (white needles).

Analysis: (C ₂₂ H ₃₂ N ₂ O ₂ S)

Calculated: C, 65.31; H, 7.97; N, 6.92

Found: C, 65.09; H, 7.99; N, 6.86

0.5 H ₂ 0

TLC: R _f 0.62 (4: 1 Hexane / Ethyl acetate)

HPLC (method A): exit time 11.50 min

FAB MS: m / z 405 (M ⁺ + H) ⁴ H NMR (300 MHz, CDCl ₃ ): d, 7.20 (m, 2H), 7.02 (m, 2H),

3.20 (d, J = 5.4 Hz, 1H), 2.70 (d, J = 5.4 Hz, 1H), 2.30 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H).

EXAMPLE 19

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-isobutylaminomethyl-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-spiroepoxy-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (200 mg; 0.495 mmol) ) and MeOH (3 mL), isobutylamine (0.5 mL, 5 mmol) was added. After stirring for 18 hours, the solvent is removed under reduced pressure and the residue is purified by chromatography on a silica gel column using a mixture of chloroform-methanol-NH ₄ OH (98: 2: 0.2) as eluent. The product is dissolved in methanol and a few drops of 5% HCl are added to the solution. The solvent is removed under reduced pressure and the residue is quenched with ether. This gives the hydrochloride (white powder) of the title compound.

Analysis: (C ₂ 6 H _{4 3} N ₃ O ₃ S)

Calculated: C, 57.00; H, 8.76; N, 7.67

Found: C, 57.03; H, 8.84; N, 7.61

1.0 HCl, 1.8 H ₂ 0

TLC (free base): R _f 0.20 (3: 1 Hexane / ethyl acetate) HPLC (method A) ': exit time 9.54 min FAB MS: m / z 478 (M ⁺ + H)

NMR (300 MHz, CDC1 _3): 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

1 - ((7,7-Dimethyl-2-methoxycarbonyl-bicyclo- (2.2.1) hept-2-en-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine

To a stirred solution of 1 ((7,7-dimethyl-2-oxo-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine, cooled to 0 ° C (10.0 g) ; 25.6 mmol) and dichloromethane (500 mL), 2.6-di-t-butyl-4-methylpyridine (7.8 g, 38 mmol) and trifluoromethanesulfonic anhydride (5.4 mL, 32 mmol) were added. The cooling bath is removed and stirred for 18 hours. The mixture was filtered and the filtrate was washed with 5% HCl (2 x 100 mL), water (100 mL) and aqueous sodium bicarbonate solution (2 x 100 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a column of compressed silica gel using hexane / ethyl acetate (9: 1) as eluant. The product, enol triflate, is obtained as a white amide. and used without purification hereafter. To a stirred solution of 1 - ((7,7-dimethyl-2-trifluoromethanesulfonyloxy-bicyclo (2.2.1) hepten-1-ol) methanesulfonyl) -4- (2-methylphenyl) -piperazine (10.5 g;

20.1 mmol) and DMF-MeOH 1: 1 (150 mL), triethylamine (5.9 mL; 43 mmol), triphenylphosphine (317 mg;

1.21 mmol) and palladium (II) acetate (135 mg; 0.603 mmol). Carbon monoxide is bubbled through the solution for 15 minutes and the reaction mixture is kept under CO for 18 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography on a silica gel column using a 9: 1 hexane / ethyl acetate eluent. The title compound is a white amorphous substance which is recrystallized from hexane.

Analysis (C23H ₃₂ N ₂ O ₄ S)

Calculated: C, 62.14; H, 7.50; N, 6.30 Found: C, 61.65; H, 7.17; N, 6.12

0.67 H ₂ O

TLC: R _f 0.36 (1: 5 ethyl acetate / hexane)

HPLC (method A); Exit Time 11:34 min FAB MS: m / z 433 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 7.20 (m, 2H) 7.03 (m, 2H), 6.88 (d, J = 3Hz , 1H), 3.72 (s, 3H), 2.33 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H)

EXAMPLE 21

1 - ((7,7-Dimethyl-2-carboxybicyclo (2.2.1) hept-2-en-1-)

CO-, Η

To a stirred solution of 1 - ((7,7-dimethyl-2-methoxycarbonyl-bicyclo- (2.2.1) hept-2-en-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.0 g; 2.3 mmol) and MeOH (10 mL) were added aqueous 4M KOH (2.0 mL, 8.0 mmol). After 18 hours, the pH of the reaction mixture was adjusted to 1 with 5% HCl and the solvent removed under reduced pressure. The residue was dissolved in chloroform (50 mL) and washed with water (25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The hydrochloride of the title compound is obtained as a white amorphous substance.

Analysis: (C ₂₂ H ₃₀ N ₂ O ₄ S)

Calculated: C, 57.51; H, 6.91; N, 6.10

Found: C, 57.40; H, 6.87; N, 6.01

1.0 HCl, 0.25 H ₂ O

TLC: R _f 0.59 (92: 8: 0.1 CHCl ₃ : MeOH: HOAc)

HPLC (method A): exit time 9.77 min

FAB MS: m / z 419 (M ⁺ H) ^X H NMR (400 MHz, CD ₃ 0D) RF 7.30 (m, 3H), 7.20 (t, 1H), 6.89 (d, J = 3Hz, 1H), 2.43 (s, 3H), 1.11 (s, 3H), 1.00 (s, 3H)

EXAMPLE 22

1 - ((7,7-Dimethyl-2- (4-imidazolyl) ethylaminocarbonyl-bicyclo- (2.2.1) hept-2-en-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine _π 59

V = °

HN

N

N H.

To a stirred solution of 1 - ((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) and DMF (5 mL), histamine (30 mg; 0.27 mmol), BOP (115 mg; 0.25 mmol) and DIEA (0.12 mL; 0.69 mmol) were added. After 18 hours, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ₂₇ H ₃₇ N ₅ O ₃ S)

Calculated: C, 49.35; H, 5.31; N, 9.22

Found: C, 49.25; H, 5.39; N, 9.20

2.1 TFA, 0.45 H ₂ 0

HPLC (method A): exit time 8.16 min

FAB MS: m / z 512 (M ⁺ H) ^{Τ Η} NMR (300 MHz, CD ₃ 0D) d 8.80 (s, IH), 7.18 (m, 2H);

7.05 (d, 1H), 6.99 (t, 1H), 6.41 (d, J = 3Hz, 1H), 2131 (s, 3H), 1.08 (s, 3H), 0.98 (s, 3K)

EXAMPLE 23

1 - ((7,7-Dimethyl-2-endo-methoxycarbonyl-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine

A stirred solution of 1 ((7,7-dimethyl-2-methoxycarbonyl-bicyclo- (2.2.1) hept-2en-1-yl) -methanesulfonyl) -4- (2-methylphenyl) was cooled to -78 ° C. ) -piperazine (3.0 g; 6.9 mmol) and a mixture of THF and MeOH (2: 1, 50 mL) were added 0.1M solution of samar (II) iodide in THF (250.0 mL; 25 mmol). After 1 hour, the reaction mixture was warmed to room temperature and stirred for an additional 1 hour. The solvent is removed under reduced pressure and the residue is poured into a mixture of ethyl acetate (100 mL) and water (50 mL). The layers are separated, the organic phase is washed with water (50 mL), dried (MgSO ₄ ), filtered and evaporated to dryness under reduced pressure. ^The product obtained by ^X H NMR is a 6: 1 mixture of endoegs. The major isomer having a lower R _f (endo) is purified by chromatography on a silica gel column using a gradient elution of a 98: 2 to 95: 5 hexane: ethyl acetate mixture and crystallization from ethyl acetate. The title compound is obtained (white needles en 156-158 ° C).

Analysis: (C ₂₃ H ₃₄ N ₂ O ₄ S)

Calculated: C, 63.31; H, 7.83; N, 6.43

Found: C, 63.56; H, 7.89; N, 6.45

TLC: R _f 0.44 (1: 5 ethyl acetate / hexane)

HPLC (method A): exit time 11.75 min

FAB MS: m / z 435 (M ⁺ H) ^X H NMR (400 MHz, CD ₃ 0D): d 7.20 (m, 2H), 7:05 (m, 2H);

3.72 (s, 3H), 3.29 (ddd, 1H), 2.34 (s, 3H), 1.13 (s,

3H), 1.06 (s, 3H).

EXAMPLE 24

1 - ((7,7-Dimethyl-2-endo-carboxy-bicyclo- (2.2.1) heptanyl-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine

CHCC

A stirred solution of 1 - ((7,7-dimethyl-2-endomethoxycarbonyl-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.0 g; 2.3 mmol) and THF (10 mL), 4M aqueous NaOH (1.5 mL, 6.0 mmol) was added. The reaction mixture is refluxed for 72 hours, cooled and the pH is adjusted to 1 by addition of 5% HCl. The solvent is removed under reduced pressure and the residue is poured into a mixture of chloroform and water. The organic phase is separated off, washed with water, dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The title compound is purified by reverse phase preparative HPLC using 0.1% acetonitrile / water gradient

TFA. The title compound is obtained (lyophilized powder).

Analysis: (C ₂₂ H ₃₂ N ₂ O ₄ S)

Calculated: C, 51.92; H, 5.99; N, 4.94 Found: C, 51.92; H, 5.95; N, 5.17

1.25 TFA, 0.2 H ₂ 0

TLC: R _f 0.22 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A :) exit time 10.67 min

FAB MS: m / z 421 (M ⁺ H) ^X H NMR (300 MHz, CD ₃ OD) d 7.18 (m, 2H), 7:05 (d, 1H), 6.98 (t, 1H), 2.30 (s , 3H), 1.18 (s, 3H), 1.10 (s, 3H)

EXAMPLE 25

1 - ((7,7-Dimethyl-2-endo- (4-imidazolyl) ethylaminocarbonylbicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endocarboxy-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 (2-methylphenyl) -piperazine (100 mg; 0.238 mmol) and DMF (5 mL), histamine (35 mg; 0.32 mmol), BOP (142 mg; 0.321 mmol) and DIEA (0.13 mL; 0.75 mmol) were added. After hours, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Analysis: (C ₂₇ H ₃ gN ₃ O ₃ S)

Calculated: C, 46.66; H, 5.58; N, 8.58

Found: C, 46.63; H, 5.23; N, 8.97

2.35 TFA, 1.9 H ₂ O

HPLC (method A): exit time 8.99 min

FAB MS: m / z 514 (M ⁺ + H) ^@ +.

NMR (300 MHz, CD ₃ OD) d 8.80 (s, 1H), 7.18 (m, 2H);

7.05 (d, 1H), 6.99 (t, 1H), 6.41 (d, J = 3Hz, 1H), 2.31 (s, 3H), 1.08 (s, 3H), 0.98 (s, 3H)

EXAMPLE 26

Two 1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (3-methoxycarbonyl) -2-pyrrolidinon-1-yl) bicyclo (2.2.1) heptan-1) -yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine isomers

To a stirred solution of 1 ((7,7-dimethyl-2-exo-hydroxy-2-endo-2- (1-amino) propylbicyclo- (2.2.1) heptan-1-yl) cooled to -78 ° C ) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (250 mg; 0.557 mmol) and methanol (3 mL) were added dimethyl taconate (200 mg; 1.27 mmol). The reaction mixture was refluxed for 18 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography on a column of compressed silica gel using hexane / ethyl acetate 35:65 as eluent. The resulting products are white amorphous material.

Isomer 1:

Analysis: (C ₃₀ H ₄₅ N ₃ O ₆ S)

Calculated: C, 62.58; H, 7.88; N, 7.30

Found: C, 62.58; H, 8.03; N, 6.95

TLC: R _f 0.34 (35:65 hexane / ethyl acetate)

HPLC (method A): exit time 10.23 min

FAB MS: m / z 576 (M ⁺ + H) ^@ +.

⁴ Η NMR (300 MHz, CDCl ₃ ): d 7.18 (m, 2H), 7.01 (m, 2H), 3.76 (s, 3H), 2.32 (s, 3H), 1.15 0.95 (d, J = 6Hz, 3H) (s, 3H), 1.03 (s, 3H), Isomer 2: Analysis: (C ₃₀ H ₄₅ N ₃ O ₆ S) Calculated: C, 62.58; H, 7.88; N, 7.30

Found: C, 62.43; H, 8.07; N, 6.95

TLC: R _f 12:23 (35:65 hexanes / ethyl acetate) HPLC (method A): output time 24.10 min FAB MS: m / z 576 (M ⁺ H) ^X H NMR (300 MHz, CDC1 ₃₎ 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 = 6Hz, 3H)

EXAMPLE 27 1 ^- ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (4-pyridinyl) -methylamino) -propyl-bicyclo (2.2.1) heptan-1-yl) ) methta n-sulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine (50 mg; 0.11 mmol) and DMF (2 mL), 4-chloromethylpyridine hydrochloride (18 mg; 0.11 mmol) and potassium carbonate (50 mg; 0.36 mmol) were added. The reaction mixture was heated at 80 ° C for 18 hours. The solvent was removed under reduced pressure and the residue was purified by a reverse phase pre-preparative HPLC using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound was obtained.

Anna J. i / -e: (C 3 _C H, i ₄ N _d C ' ₂ o) Calculated: C, 52. C i V ti OU (1 · d In' J 6 f ii f

7.06

2.2 TFA, 0.1 H ₂ O

TLC: R _f 0.36 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 8.15 min

FAB MS: m / z 541 (M ⁺ H) ^{Χ Η} NMR (300 MHz, CDC1 _3): 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

1 - ((7,7, -Dimethyl-2- (3-acetamido-3,3'-di (ethoxycarbonyl)) -propylidin-bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine

To a stirred solution of diethylacetamidomalonate (0.69 g, 3.2 mmol) and DMF (20 mL) was added NaH (125 mg;

60% dispersion in mineral oil; 3.13 mmol). After 30 minutes, 1 - ((7,7-dimethyl-2- (2-chloro) -ethylidinobicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.35) is added. g; 0.8C mmol) and the mixture heated to 50 ° C for 3 hours. The reaction mixture was cooled and acetic acid (1.5 mL) was added. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (75 mL) and washed with water (3 x 25 mL).

The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a column of compressed silica gel using a 2: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained (white amorphous substance).

Analysis: (C ₃₂ H ₄₇ N ₃ O ₇ S)

Calculated: C, 62.32; H, 7.51; N, 6.81

Found: C, 61.96; H, 7.71; N, 6.55

TLC: R _f 0.36 (95: 5: 0.5 CHCl ₃ / MeOH / NH ₄ OH)

HPLC (method A): exit time 11.54 min

FAB MS: m / z 618 (M ⁺ H) ³ H NMR (400 MHz, CDC1 _3): d 7.20 (m, 2H) 7.03 (m, 2H), 6.78 (s, 1H), 5:38 (br t , 1H), 4.22 (m, 4H), 2.32 (s, 3H), 2.00 (s, 3H), 1.27 (t, J = 7Hz, 3H), 1.24 (t, J = 7Hz, 3H), 0.97 (s) , 3H), 0.78 (s, 3H)

EXAMPLE 29

1 - ((7,7-Dimethyl-2- (3-acetamido-3-carboxy) propylidene-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

CHSO;

To a stirred solution of 1 - ((7,7-dimethyl-2- (3acetamido-3 ', 3'-di (ethoxycarbonyl) propylidene-bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4 - (2-Methylphenyl) piperazine (0.10 g, 0.16 mmol) and ethanol (2 mL), 2M NaOH solution (0.30 mL, 0.60 mmol) was added and the mixture was refluxed for 6 h. The mixture was cooled and adjusted to pH 2 with 5% aqueous HCl. The mixture is refluxed for 1 hour, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA to give the title compound (1: 1 diastereomer mixture, lyophilized powder).

Analysis: (C27H39N3O5S)

Calculated: C, 54.37; H, 6.53; N, 6.56

Found: C, 54.26; H, 6.41; N, 6.59

1.0 TFA, 0.5 H ₂ O

TLC: R _f 0.39 (92: 8: 0.1 CHCl ₃ / MeOH / HOAc)

HPLC (method A): exit time 9.62 min

FAB MS: m / z 518 (M ⁺ + H) ^@ +.

BN IR (400 MHz, CI DC1 ₃ ) 1: d 7.25 (m, 4H), 7.13 (m, 4H) 52 (d , 1H) , 6.40 (d, 1H), 5.45 (m, 1H), 5.40 (m, 1H) 67 (m , 2H) , 2.40 (s, 6H), 2.05 (s, 3H), 2.04 (s, 3H) 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) methanesulfonyl) -4- (2-methylphenyl) -3-piperazinone

TFA (1 mL) was added to a stirred solution of l-t-butyloxycarbonyl-4- (2-methylphenyl) -3-piperazinone (0.25 g, 0.86 mmol) and dichloromethane (3 mL). After 1 hour, the solvent is removed under reduced pressure and the residue is dissolved in chloroform and evaporated several times to remove excess TFA. The residue was dissolved in chloroform (5 mL) and added to a stirred solution of 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 NaHCO ₃ (25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a column of compressed silica gel using a 2: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained (a white amorphous substance from a mixture of ether and hexane).

Analysis: (C ₂₁ H ₂₈ N ₂ O ₄ S)

Calculated: C, 62.35; H, 6.98; N, 6.93

Found: C, 61.78; H, 6.98; N, 6.82

TLC: R _f 0.30 (1: 1 Hexane Ethyl Acetate) sPLo (Method n): Output Kss 8.is mm

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, cooled to -78 ° C solution of LDA (2.0 mmol) and THF (15 mL) was added chilled to -78 ° C tert -butyloxycarbonyl-4- (2-methylphenyl) -3-piperazinone (0.50 g) ; 1.7 mmol) in THF (5 mL). The solution was stirred for 1 h before iodomethane (0.125 mL, 2.0 mmol) was added. The reaction mixture was stirred at -78 ° C for 30 minutes, then the cooling bath was removed and the mixture was stirred for 3 hours at room temperature. 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 is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a column of compressed silica gel using hexane / ethyl acetate 85:15 as eluent. Methylated product Rf = 0.47 (70:30 hexane-ethyl acetate). and HPLC exit time 8.32 minutes (Method A). The product (0.40 g, 1.3 mmol) was dissolved in chloroform (3 mL) and TFA (1 mL) was added. After two hours, the mixture was diluted with chloroform (50 mL) and extracted with aqueous NaHCO ₃ ( ₃ x ₂₅ mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. Obtained an oil (HPLC exit time 2.95 minutes (Method A)). The residue was dissolved in chloroform (20 ml) and 10 camphorsulfonyl chloride (0.41 g, 1.6 mmol) and triethylamine (0.28 ml, 2.0 mmol) were added to the stirred solution. After 12 hours, the mixture was extracted with chloroform (25 mL), extracted with 5% aqueous HCl (25 mL), water (25 mL), and aqueous NaHCO ₃ (2 x 25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a column of compressed silica gel using a 2: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained (1: 1 mixture of diastereomers, white solid, hexane: ether).

Analysis: (^ 22 ^ 3 (^ 2048)

Calculated: C, 63.13; H, 7.23; N, 6.69

Found: C, 63.46; H, 7.09; N, 6.74

TLC; R _f 0.27 (60:40 Hexane - Ethyl acetate)

HPLC (Method A): Output FAB MS: m / z 419 (M ⁺ + H) ^Χ Η NMR (300 MHz, CDCl ₃ ) overlapping quartets, 3H), 1.68 (overlapping)

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

EXAMPLE 32 Time 8.52 min: d 7.1-7.3 (m, 8H), 4.62

2H), 2.21 (s, 3H), 2.20 (s doublets, 6H), 1.13 (s, 3H) , 0.89 (s, 3H)

I ^- ((7,7-Dimethyl-2-exo-hydroxy-bicyclo- (2.2.1) heptanyl-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -2-methyl-piperazine

To a stirred solution cooled to -78 ° C containing 1 ((7,7-dimethyl-2-oxo-bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -2-Methyl-3-piperazinone (0.15 g, 0.36 mmol) and THF (5 mL) were added 1.0 M LAH in tetrahydrofuran (1.1 mL; 1.1 mmol). The resulting solution was warmed to room temperature and stirred for 3 hours. The reaction is quenched by the addition of aqueous sodium hydroxide solution and a white precipitate precipitates. The mixture was diluted with ethyl acetate and the solid removed by filtration through celite. The solvent is removed under reduced pressure. The residue was purified by chromatography on a silica gel column using a 9: 1 hexane / ethyl acetate eluent. 1 - ((7,7-Dimethyl-2-exo-hydroxybicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -2-methyl-2,3-dehydro- is obtained. piperazine (FAB MS: m / z 405 (M ⁺ + H); olefin proton 5.8 ppm in NMR spectrum).

The product (75 mg, 0.19 mmol) was dissolved in triethylsilane (2 mL) and TFA (0.030 mL, 0.38 mmol) was added to the stirred solution. After 18 hours, the solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. a (20 mL) and washed with aqueous NaHCO ₃ (23 * 1025 mL). The organic phase is dried (MgSO ₄ ), and the filtered ic solvent is removed under reduced pressure. The residue was purified by reverse phase preparative HPLC using a gradient of acetonitrile and water

0.1% TFA. The title compound is obtained (1: 1 mixture of diastereomers, lyophilized powder).

HPLC (method A): exit time 14.33 min

FAB MS: m / z 407 (M ⁺ + H) ¹ H NMR (400 MHz, CDC1 ₃ ): d 7.20 (m, 4H), 7.06 (m, 4H), 4.20 (m, 2H), 2. 36 (s, 6H), 1.55 (overlapping dub slowly, 6H), 1.09 (s, 6H) , 0.86 (s, 6H) EXAMPLE 33

1 - ((7,7-Dimethyl-2-oximino-bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine

A stirred solution of 1 ((7,7-dimethyl-2-oxo-bicyclo- (2.2.1) heptan-1-yl) - (methanesulfonyl) -4- (2-methylphenyl) cooled to -78 ° C. ) -piperazine (65.0 g; 166 mmol) and pyridine (250 mL), hydroxylamine hydrochloride (35.0 g, 0.504 mol) was added and the solution was heated at 70 ° C for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in chloroform (500 mL). and washed with aqueous NaHCO 3 (2 x 200 mL), water (200 mL), and 5% HCl (2 x 200 mL). The organic phase was dried (MgSO 4), filtered and the solvent removed under reduced pressure to give the title compound as a white needle. 57 g, 84%) mp 174-175 ° C.

Analysis: (C ₂ iH ₃₁ N ₃ O3S)

Calculated: C, 62.19; H, 7.71; N, 10.36 Found: C, 62.29; H, 7.63; N, 10.15 TLC: R _f 0.40 (75:25 Hexane - Ethyl acetate) HPLC (method A): exit time 9.98 min FAB MS: m / z 406 (M ⁺ + H)

1 H NMR (3 00 MHz, CDC1 _3): d 7.90 (br s, 1H), 7.18 (m, 2H), 7.02 (m, 2H), 3.47 (m, 4H), 4.43 (d, J = 14.4) Hz, 1H), 3.00 (m, 4H), 2.92 (d, J = 14.4Hz, 1H), 2.4-2.6 (m, 2H), 2.31 (s, 3H), 2.09 (d, J = 16.9Hz, 1H), 1.95 (m, 2H), 1.80 1 i m, 1H), 1.32 (m, 1H), 1.08 (s, 3H), 0.87 (s, 3H) EXAMPLE 34

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

To a stirred solution of 1 - ((7,7-dimethyl-2-oximino-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 (2-methylphenyl) -piperazine (35.0 g, 86 mmol) , 2-methoxyethanol (500 mL) and Renee nickel (105.0 g) are added dropwise over 30 minutes with sodium hydroxide solution (17.2 g; 430 mmol dissolved in 75 mL). There is a difference between heat and gas as it drips. The mixture was stirred at room temperature for 16 hours. TLC data indicates that the parent oxime is no longer present and a 4: 1 mixture of endo- (lower R _f ) and exo-amine (higher R _f ) is formed. The mixture is filtered through celite and the material is washed with methanol and ethyl acetate on the filter. The solvent is removed under reduced pressure, the resulting solid is dispersed in water and filtered. The dried material was purified by chromatography on a compressed silica gel column using a gradient elution of 93: 3 to 94: 6 A: B (A = chloroform, B = 5% NH ₄ OH / MeOH). The title compound is obtained (white amorphous substance, 24 g; 70%).

FAB MS: m / z 392 (M ⁺ + H) ^@ +.

EXAMPLE 35

1 - ((7,7-Dimethyl-2-endo- (2S- (t-butyloxycarbonylamino) 4-methylsulfonylbutyramido) -bicyclo (2.2.1) heptan-1-yl) -

2.0 g; 0.1 rrimol) / Boc-L-methionine sulfone (1.5 g, 5.3 mmol), BOP reagent (2.5 g, 5.6 mmol) and DIEA (1.85 mL;

10.6 mmol). Stir at room temperature for 1 hour, then add more DIEA (about 0.1 mL) to pH 8. The solution is stirred for another 1 hour, and the solvent is removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with 5% aqueous HCl (2x50 mL), water (2x50 mL), and aqueous NaHCO ₃ (2x75 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a silica gel column using a 1: 4 hexane / ethyl acetate eluent. The title compound is obtained (methanol solid; 2.8 g, 85%).

Analysis: (C ₃₁ H ₅₀ N ₄ O ₇ S)

Calculated: C, 55.78; H, 7.76; N, 8.39

Found: C, 55.57; H, 7.70; N, 8.36

TLC: R _f 0.73 (95: 5 CHCl ₃ / methanol)

HPLC (method A): exit time 11.02 min

FAB MS: m / z 655 (M ⁺ + H)

^X H NMR (300 MHz, CDCl ₃ ) : d 7.19 (m, 2H), 7.04 (m, 2H), 5.38 (br d, 1H), 4.32 J = 7.4Hz, 1H), 4.22 (m, 1H), 2.94 (s, 3H) , 2.32 (s, 3H), 1.45 (s, 9H), 1.00 (s, 3H),

0.98 (s, 3H)

EXAMPLE 36

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S- (t-butyloxycarbonylamino) -4-methylsulfonylbutyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine (2.5 g, 3.8 mmol) and dichloromethane (15 mL), TFA (5 mL) was added. After 1 hour, the solvent is removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with aqueous NaHCO ₃ (2 x 75 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a silica gel column using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (white amorphous material from EtOAc (1.9 g; 90%)).

Analysis: (C ₂ gH ₄₂ N ₄ O ₃ S ₂ )

Calculated; C, 56.14; H, 7.75; N, 9.29

Found: C, 55.94; H, 7.74; N, 9.31

TLC: R _f 0.17 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.50 min

FAB MS m / z 455 (Μ ^τ + H) NMR (300 MHz, CDCl ₃ ): d 7.67 (d, J = 8.4'Hz, IH), ' 7.20 (m, 2H) , 7.02 (m, 4 H), -, 4 3 (m, 1H), 2.94 (s, 3 H), 2.31 (s, 3H) , 1.03 (s, 3H), 7.97 (ε, 3H)

EXAMPLE 37

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) -piperazine (250 mg; 0.45 mmol) and DMF (5 mL), 4-imidazolacetic acid hydrochloride (110 mg; 0.68 mmol), BOP (265 mg, 0.60 mmol) and DIEA (0.355 mL; 2.0) were added. mmol). The solution was stirred at room temperature for 18 hours. The solvent is removed under reduced pressure, the residue is suspended in ethyl acetate (100 mL) and filtered through celite to remove the red polymer. The filtrate was washed with 5% aqueous HCl (50 mL), water (50 mL), and aqueous NaHCO ₃ (2x50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a column of compressed silica gel, eluting with a 92: 8: 0.8 CHCl ₃ : MeOH: NH ₄ OH mixture. The title compound is obtained (EtOAc solid; 230 mg; 78%).

Analysis: (C ₃₁ H ₄₆ N ₆ O ₆ S ₂ )

Calculated: C, 53.74; H, 7.32; N, 11.26

Found: C, 53.74; H, 7.00; N, 11.25

0.6 EtOAc, 1.7 H ₂ O

TLC: R _f 0.22 (90: 10: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.49 min

FAB MS: m / z 663 (M ⁺ H) ^t H NMR (300 MHz, CDC1 _3): d 7.73 (overlapping singlet and broad singlet, 2H), 7.38 (br d, 1H), 7.18 (m, 2H), 7.02 (m, 2H), 6.96 (s, 1H), 4.68 (br q, J = about 5Hz, 1H), 4.27 (m, 1H), 3.62 (br s, 2H), 2.92 (s, 3H),

2.30 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)

EXAMPLE 38

1 - ((7,7-Dimethyl-2-endo (2S- (dimethylamino) -4-methylsulfonyl) -butyramido-bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) ) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (250 mg; .0.45 mmol) and 1: 1 HOAc with MeOH (10 mL) were added 37% aqueous formaldehyde solution (2 mL) and NaBH ₃ CN (60 mg; 0.95 mmol). ). The solution was stirred at room temperature for 4 hours. NaHCO ₃ solution (2 ml) is added and the solvent is removed under reduced pressure. The residue was suspended in ethyl acetate (75 mL) and washed with water (2 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The title compound is obtained (white amorphous material from EtOAc; 190 mg; 72%).

Analysis: (C ₂₈ H ₄₆ N ₄ O ₅ S 2)

Calculated: C, 57.56; H, 8.01; N, 9.20

Found: C, 57.41; H, 7.98; N, 9.20

0.3 EtOAc

TLC: R _f 0.26 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.10 min

FAB MS: m / z 583 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 7.62 (br s, 1H), 7.18 (m,

2H), 7.02 (m, 2H), 4.37 (m, 1H), 2.92 (s, 3H), 2.36 (s,

6H), 2.30 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H)

EXAMPLE 39

1 - ((7,7-Dimethyl-2-endo-benzyloxycarbonylamino-bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine

HN H

To a stirred solution of 1 ((7,7-dimethyl-2-endo-aminobicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) cooled to 0 ° C -piperazine (1.20 g; 3.07 mmol) and CHCl ₃ (100 mL) were 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 hour and at room temperature for a further 4 hours. The reaction mixture was washed with 5% aqueous HCl (2 x 50 mL) and aqueous NaHCO ₃ (100 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a column of compressed silica gel using a 4: 1 mixture of hexane and ethyl acetate as eluent. The title compound is obtained (white amorphous material, 1.45 g, 90%).

Analysis: (C ₂₉ H ₃₉ N ₃ O ₄ S)

Calculated: C, 65.75; H, 7.53; N, 7.77

Found: C, 65.90; H, 7.49; N, 7.80

0.15 EtOAc, 0.1 H ₂ O

TLC: R _f 0:38 (1: 3 EtOAc / hexanes)

HPLC (method A): exit time 12.18 min

FAB MS: / m / z 526 (M ⁺ + H)

EXAMPLE 40

1 - ((7,7-Dimethyl-2-endo-methyl (benzyloxycarbonyl) aminobicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution cooled to 0 ° C containing 1 ((7,7-dimethyl-2-endo-benzyloxycarbonylamino-bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) ) piperazine (1.46 g; 2.78 mmol) and DMF (20 mL) were added iodomethane (0.435 mL; 7.00 mmol) and sodium hydride (0.139 mg, 60% dispersion in mineral oil;

3.48 mmol). The solution was stirred at 0 ° C for 1 hour and 18 hours at room temperature. 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 NaHCO ₃ (2x50 mL). The organic phase is dried (MgSO4, filtered and the solvent is removed under reduced pressure. The residue is purified by chromatography on a silica gel column using 5: 1 hexane: ethyl acetate as the eluent to give the title compound (white amorphous material, 1.40 g, 93%). ).

Analysis: (C ₃₀ H ₄₁ N ₃ O ₄ S)

Calculated: C, 66.03; H, 7.70; N, 7.70 Found: C, 66.03; H, 7.63; N, 7.68 0.33 H ₂ O

TLC: R _f 0.44 (1: 4 EtOAc / Hexane)

HPLC (method A): exit time 12.86 min

FAB MS: m / z 540 (M + H) ^{Χ Η} NMR (300 MHz, CDC1 _3): d 7:25 to 7:45 (m, 5H), 7.20 (m, 2H) 7.02 (m, 2H), 5.11 (AB quartet, 2H), 4.83 (m, 1H),

3.03 (s, 3H), 2.32 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H)

EXAMPLE 41

1 - ((7,7-Dimethyl-2-endo-methyl (2S-amino-4- (methylsulfonyl) butanol) aminobicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- ( 2-methylphenyl) -piperazine

To a stirred solution through which argon was passed containing 1 - ((7,7-dimethyl-2-endo-methyl- (benzyloxycarbonyl) amino-bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (1.1 g; 2.0 mmol) and 96: 4 MeOH / HCOOH (25 mL) were added palladium black (0.4 g). The reaction mixture was stirred for 16 hours at room temperature. The catalyst is removed by filtration through celite and the solvent is removed from the filtrate under reduced pressure. The residue is purified by chromatography. passing through a column of compressed silica gel using 95: 5: 0.5 CHCl ₃ : MeOH as eluent; NH ₄ OH. The product -. 1 - ((7,7-dimethyl-2-endo-methyl-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine is obtained as a white solid. amorphous material. (0.79 g, 95%). to a stirred solution of 1 - ((7,7-dimethyl-2LT 3592B endo-methylaminobicyclo (2.2.1) -heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.700 g; 1.73 mmol) and chloroform (60 mL) were added acid N ^a -Fmoc-Lmethioninesulfonium fluoride (1.23 g; 3.03 mmol) and DIEA (0.52 mL; 3.0 mmol). The mixture was stirred for 24 hours at room temperature, then extracted with 5% aqueous HCl (30 mL) water (30 mL) and aqueous NaHCO ₃ (2x30 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was dissolved in DMF (10 mL) and diethylamine (2 mL) was added. The mixture was stirred for 6 hours at room temperature. The solvent is removed under reduced pressure. The residue was purified by chromatography on a column of compressed silica gel using 95: 5: 0.5 as eluent.

CHCl ₃ : MeOH: NH ₄ OH. The title compound is obtained (amorphous material from chloroform-ether; 0.71 g, 61%).

Analysis: C2 ₇ H ₄₄ N ₄ O ₃ S2)

Calculated: C, 56.26; H, 7.80; N, 9.40

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

0.1 CHCl ₃ , 0.2 ether

TLC: R _f 0.10 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.01 min

FAB MS: m / z 569 (M ⁺ H) ^X H NMR (300 MHz, CDC1 _3): d 7.18 (m, 2H) 7.03 (m, 2H), 5.20 (ddd, 1H), 3.95 (dd, J = 9.3, 4.1 Hz, 1H), 3.18 (s, 3H),

2.91 (s, 3H), 2.30 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H)

EXAMPLE 42

1 - ((7,7-Dimethyl-2-endo-methyl (2S-dimethylamino-4- (methylsulfonyl) butanol) aminobicyclo (2.2.1) heptan-1-yl) sulfonyl) -4- (2 -methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endomethyl- (2S-amino-4- (methylsulfonyl) butanoyl) aminobicyclo (2.2.1) -heptan-1-yl) methanesulfonyl ) -4- (2-methylphenyl) piperazine (150 g; 0.264 mmol) and 1: 1 HOAc: MeOH (6 mL), 37% aqueous formaldehyde solution (1 mL) and NaBH ₃ CN (30 mg; 0.47) were added. mmol). The solution was stirred at room temperature for 4 hours. NaHCO ₃ solution (1 mL) was added and the solvent removed under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and washed with water (2 x 25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₂₉ H ₄₈ N ₄ O ₅ S ₂ )

Calculated: C, 44.88; H, 5.94; N, 6.16 Found: C, 44.80; H, 5.94; N, 6.18

2.5 TFA 1.5 H-0

TLC: R _f 0.45 (95: 5: 0.5 0HCl,: MeOH: NH ₄ OH) HPLC (methocis Ai: exit time 9.04 min.

FAB MS: m / z 5 97 (bf + H +)

NMR (400 MHz, CDCl ₃ ): d 7.2-7.3 (m, 4H), 5.15 (m, 1H) , 4. 79 (br t, 1H), 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

1 - ((7,7-Dimethyl-2-endo- (4-imidazolyl) acetyl) amino-bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endoamino-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.50 g, 3.84 mmol) ) and DMF (30 mL), 4-imidazolacetic acid hydrochloride (0.938 g, 5.76 mmol), BOP (2.13 g, 4.80 mmol) and DIEA (2.61 mL, 15.0 mmol) were added. The solution was stirred at room temperature for 24 hours. The solvent is removed under reduced pressure, the residue is suspended in ethyl acetate (100 mL) and filtered through celite to remove the red polymer. The filtrate was washed with aqueous NaHCO ₃ solution (2 x 50 mL), water (2 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a silica gel column using 92: 8: 0.8 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (white amorphous substance).

FAB MS: m / z 500 (M ⁺ H) ^X H NMR (CDC1 _3):

EXAMPLE 44

1 - ((7,7-Dimethyl-2-endo- (2- (4-imidazolyl) popopanoyl) amino-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endoamino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.1 g; 2.8 mmol) and DMF (25 mL), 2- (1-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) were added. After stirring for 1 hour at room temperature, additional DIEA (about 0.2 ml) was added until the mixture reached pH 8. After another 1 hour, the solvent was removed under reduced pressure. The residue was dissolved in chloroform (150 mL) and washed with aqueous NaHCO ₃ solution (2x50 mL), water (2x50 mL). The organic phase is dried (MgSO4, filtered and the solvent removed under reduced pressure.) To give a solid. Recrystallization from EtOAc yields crystals (0.51 g), which is 90:10 isomer mixture (product A) in ^X NMR. The filtrate is purified. chromatography allowing through compressed silica gel column with eluent - chloroform-MeOH 95: 5, gaunaLT 3592 B ma white amorphous solid (1.0 g). ¹ NMR indicated that this material is a mixture of isomers 1: 2 (product B). Products A and B were each deprotected by reduction at room temperature with hydrogen in a mixture of MeOH and HOAc (3: 1) using 25% (w / w) palladium on carbon at 1 atm of hydrogen and removing the catalyst by filtration under reduced pressure. The product A residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile and water, 0.1% TFA TFA salt of the title compound is obtained (90:10 mixture by ¹ NMR spectrum, lyophilized powder). Purify product B by chromatography on a compressed silica gel column using eluent 95: 5: 0.5

CHCl ₃ : MeOH: NH ₄ OH. To yield the title compound as a white amorphous solid and chloroform - ether (a mixture of 1: 2 according to ¹ NMR spectrum). Both isomers behave identically when purified by chromatography.

Analysis: (C ₂₇ H ₃₇ N ₅ O ₃ S)

Calculated: C, 60.36; H, 7.49; N, 12.46 Found: C, 60.49; H. 7.26; N, 12.48 0.25 CHCl ₃ , 0.25 ether TLC: R _f 0.30 (93: 7: 0.7 CHCl ₃ : MeOH; NH ₄ OH) HPLC (method A): exit time 8.79 min FAB MS: m / z 514 (M ⁺ +) H) 1 H NMR (400 MHz, CDCl ₃ ): δ 7.75 (br s, 1H), 7.20 (m, 2H), 7.00 (m, 3H), 4.40 (m, 1H), 2.30.2.29 (two sin- flutes in a ratio of about 2: 1, 3H), 1.57.11.53 (two dub at a slow ratio of about 2: 1, J = 7Hz, 3H), 1.00 (s, 3H),

0.96 (s, 3H)

Analysis: (C ₂₇ H ₃₇ N ₅ O ₃ S)

Calculated: C, 48.91; H, 5.36; N, 9.03

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

2.3 TFA

TLC: R _f (93: 7: 0.7 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.79 min

FAB MS: m / z 514 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 8:43 (s, 1H), 7.70 (d, 1H),

7.25 (m, 2H), 7.20 (s, 1H), 7 .15 (m, 2H) , 4.40 (m, 1H), 4.03 <q. J = 7Hz, 1H) , 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- (1- (1-n-methoxycarbonylethyl) propyl-bicyclo (2.2.1) heptan-1-yl) - methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (L-prolylamino) -propylamino-bicyclo (2.2.1) -heptan-1) -yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.50 g, 2.74 mmol) and methanol (15 mL) were added methyl acrylate (0.310 mL, 3.43 mmol) and after 72 hours at room temperature the solvent was removed under reduced pressure. and the residue is purified by preparative

HPLC reversed phase gradient using acetonitrile / water gradient with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₃ H ₅₂ N ₄ O gS)

Calculated: C, 53.10; H, 6.59; N, 6.82

Found: C, 53.09; H, 6.58; N, 6.88

1.65 TFA

TLC: R _f 0.55 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 9.45 min

FAB MS: m / z 633 (M ⁺ H) ^4; H NMR (400 MHz, CDC1 _3): d 7.18 (m, 2H) 7.03 (m, 2H);

4.55 (m, 1H), 3.72 (s, 3H), 2.32 (s, 3H), 1.15 (s, 3H),

1.04 (s, 3H), 1.01 (d, J = 6Hz, 3H)

EXAMPLE 46

1 ^- ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (1-n-carboxyethyl) prolylamino) propyl-bicyclo (2.2.1) heptanyl) - methanesulfonyl) -4- (2-methylphenyl) -piperazine

CH

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (L-N-methoxycarbonylethyl) prolylamino) -propyl-bicyclo- (2.2.1 ) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.00 g; FW = 821;

1.22 mmol) and THF (15 mL), 1M NaOH was added until the pH of the solution was stable for 1 hour. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₂ H ₅₀ N ₄ O ₆ S)

Calculated: C, 51.88; H, 6.34; N, 6.80

Found: C, 51.87; H, 6.28; N, 6.82

1.8 TFA

TLC: R _f 12:40 (80: 20: 2 OLC1 _3: MeOH: NH ₄ OH)

HPLC (method A): exit time 8.88 min

FAB MS: m / z 619 (M ⁺ H) ^{Χ Η} NMR (400 MHz, CDC1 _3): 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 = 6Hz, 3H)

EXAMPLE 47

1 '((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (3-piperidinylcarbonyl) amino) propyl-bicyclo (2.2.1) heptane-1

i!

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (2.50 g, 5.57 mmol) and DMF (35 mL) were added N-Fmocpiperidine-3-carboxylic acid (2.15 g, 6.13 mmol). After 16 hours, diethylamine (6 mL) was added and the solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (150 mL) and washed with aqueous NaHCO ₃ (2x75 mL), water. (2x75 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by chromatography on a silica gel column using 93: 7: 0.7 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (1: 1 mixture of diastereomers, white amorphous).

Analysis: (C ₃₀ H ₄₈ N ₄ O ₄ S)

Calculated: C, 56.37; H, 7.49; N, 8.54

Found: C, 56.49; H, 7.44; N, 8.50

0.8 CHCl ₃

TLC: R _f 0.40 (90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.67 min

FAB MS: m / z 561 (M ⁺ H) ^X H NMR (300 MHz, CDC1 _3): d 7:50 (br s, 1H), 7.20 (m, 2H) 7.02 (m, 2H), 2.30 (s , 3H), 1.17 (s, 3H), 1.001.04 (overlapping singlet and doublet, 6H)

EXAMPLE 48

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (3- (1-methoxycarbonylethyl) piperidinylcarbonyl) amino) propylbicyclo (2.2.1)) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3-piperidinylcarbonyl) -amino) propyl-bicyclo (2.2.1) -heptane) -1-yl) -methanesulfonyl) -4 (2-methylphenyl) -piperazine (0.50 g, 0.89 mmol) and methanol (10 mL), methyl acrylate (0.120 mL;

1.34 mmol). After 72 hours at room temperature, the solvent is removed under reduced pressure and the residue purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. TFA salt (1: 1 mixture of diastereomers, freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₄ H ₅₄ N ₄ O ₆ S)

Calculated: C 55.40; H, 7.06; N, 7.08 Found: C, 55.39; H, 7.05; N, 7.03

1.25 TFA, 0.1 H ₂ O

TLC: R _f 0.35 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 10.71 min

FAB MS : m / z 647 (M ⁺ + H) • 1 H NMR (400 MHz, CDCl ₃ ): d 7.20 (m, 2H) , 7.02 (m, 2H), 3.72,. 3.69 {two singlet i, 3K), 2.32, 3.31 (two singles- Slowly, 3H), 'i.l6, 1.15 (two singles, 3H), 0.98-1.04

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

EXAMPLE 49

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

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3- (1-methoxycarbonyl) piperidine carbonyl) amino) -propyl-bicyclo- (2.2.1) -heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.30 g, 0.46 mmol) and THF (10 mL) were added with 1M NaOH until the pH of the solution was stable for 1 hour. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% ⁿ FA. TFA salt (1: 1 mixture of astereomers, freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₃ H ₅₂ N ₄ O ₆ S)

Calculated: C, 51.59; H, 6.44; N, 6.54

Found: C, 51.60; H, 6.44; N, 6.83

1, 9 TFA. 0.4 H ₂ O

TLC: R _f 0.15 (80: 20: 2 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 10.27 min

FAB MS: m / z 633 (M ⁺ H) ^{Σ Η} NMR (400 MHz, CDC1 _3): 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 overlapping singlets and two overlapping doublets, 6H)

Example 50

1 '((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (3- (1-ethoxycarbonylmethyl) piperidinylcarbonyl) amino) propylbicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3-piperidinylcarbonyl) amino) propyl-bicyclo (2.2.1) -heptane- 1-yl) -methanesulfonyl) -4 (2-methylphenyl) -piperazine (0.50 g, 0.89 mmol) and DMF (5 mL) were added ethyl bromoacetate (0.110 mL; 0.99 mmol) and DIEA (0.172 mL; 0.99 mmol). After 2-4 hours at room temperature, the solvent is removed under reduced pressure, the residue is dissolved in EtOAc (50 mL) and washed with 5% aqueous citric acid (25 mL), water (25 mL), and aqueous NaHCO ₃ (25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure and the residue is purified by chromatography on a silica gel column using a 1: 1 mixture of EtOAc and CHCl _{3 to give the} title compound as TFA salt (1: 1 mixture of diastereomers). , amorphous white matter.

Analysis: (C ₃₄ H ₅₄ N ₄ O ₆ S)

Calculated: C, 58.66; H, 7.77; N, 7.93 Found: C, 58.87; H, 7.83; N, 7.88 0.5 CHCl ₃

TLC: R _f 0.28 (1: 1 CHCl ₃ : ETOAc)

HPLC (method A): exit time 9.76 min FAB MS: m / z 647 (M ⁺ + H)

NMR (300 MHz, CDCl ₃ ): δ 8.20 (very broad s, 1H), 7.18 (m, 2H), 7.03 (m, 2H), 4.20 (two very close quartets, 2H), 2.30, 2.31 (two singlets, 3H), 1.28 (t, J = 7Hz, 3H), 1.07, 1.08 (two singlets, 3H), 1.03-1.08 (two overlapping singlets and two overlapping doublets, 6H)

EXAMPLE 51

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

ch ₃

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3- (1-methoxycarbonyl) -piperidinyl-carbonyl) amino) -propyl-bicyclic) - (2.2.1) -heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.360 g, 0.555 mmol) and THF (5 mL) was added with 1M NaOH until the pH of the solution was stable for 1 hour. .

The solution was acidified by adding HOAc (1 mL) and evaporated under reduced pressure. The residue is suspended in methylene chloride and filtered. The filtrate was evaporated several times under reduced pressure to give the title compound (1: 1 mixture of diastereomers, amorphous white solid).

Analysis: (C ₃ 2 H ₃ gN ₄₀ O gS)

Calculated: C, 58.27; H, 7.62; N, 7.99

Found: C, 58.47; H, 7.71; N, 7.90

1.0 NaOAc

TLC: R _f 0.55 (85:15 CHCl ₃ : MeO.H)

HPLC (method A): exit time 8.77 min

FAB MS: m / z 619 (M ⁺ + H) ^{: 1} H NMR (300 MHz, CD ₃ OD) d 7.15 (m, 2H), 7.05 (d, J = 7.3

Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 2.31 (s, 3H), 1.17 (s,

3H), 1.03 (s, 3H), 0.98 (d, J = 6Hz, 3H).

EXAMPLE 52

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (1-n- (ethoxycarboxymethyl) prolyl) amino) propylbicyclo (2.2.1) heptane) l-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

ch ₂ ch ₃

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (L-prolyl) -amino) -propyl-bicyclo (2.2.1) -heptan-1- il) -methanesulfonyl) -4- (2-methylphenyl) piperazine (0.20 g, 0.37 mmol) and DMF (5 mL), ethyl bromoacetate (0.045 mL, 0.40 mmol) and DIEA (0.071 mL, 0.41 mmol) were added. After 24 hours at room temperature, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (1: 1 mixture of diastereomers, freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₃ H ₅₂ N ₄ O ₆ S)

Calculated: C, 54.25; H, 6.79; N, 7.07 Found: C, 54.25; H, 6.73; N, 7.02

1.4 TFA

TLC: R _f 0.50 (1: 1 EtOAc: CHCl ₃ )

HPLC (method A): exit time 9.68 min FAB MS: m / z 633 (Μ ^τ + H) ² H NMR (400 MHz, CD ₃ OD) d 7.17 (m, 2H), 7.06 (d, J = 6 Hz) ,

1H), 6.98 (t, u-6 Hz, 1H), 4.25 (m, 3H), 4.08 (d, J = 15 Hz, 1H), 2.32 (s, 3H), 1.27 (t, J = 7 Hz, 3H), 1.18 (s, 3H), 1.03 (s, 3H), 1.01 (d, J = 6Hz, 3H)

EXAMPLE 53

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (1-n- (carboxymethyl) propyl) amino) propylbicyclo (2.2.1) heptanil) yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (L- (N-ethoxycarbonylmethyl) prolyl) amino) propyl-bicyclo (2.2. 1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.20 g, 0.32 mmol) and THF (5 mL) was started with 1M NaOH until the pH of the solution was stable for 1 hour. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₁ H ₄₈ N ₄ O ₆ S)

Calculated: C, 52.64; H, 6.43; N, 7.22 Found: C, 52.49; H, 6.51; N, 7.22

TFA

100

TLC: R _f 0.40 (80: 20: 2 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.79 min

FAB MS: m / z 605 (M ⁺ H) ^X H NMR (400 MHz, CD ₃ OD) d 7.17 (m, 2H) 7.07 (d, J = 5Hz, 1H), 6.99 (t, J = 5 Hz, 1H), 4.30 (dd, J = 4.5 Hz, 1H),

4.21 (d, J = 14 Hz, 1H), 4.04 (d, J = 14 Hz, 1H), 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-exo-hydroxy-2-endo-2- (1- (4-piperidinylcarbonyl) amino) propylbicyclo (2.2.1) ) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

CHNH

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1-amino) propyl-bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.50 g, 3.34 mmol) and DMF (20 mL), N-Fmocpiperidine-4-carboxylic acid (1.29 g, 3.67 mmol), BOP (1.64 g, 3.70 mmol) was added and DIEA (1.28 mL, 7.34 mmol). After 16 hours, diethylamine (5 mL) was added and the solution was stirred at room temperature for 4 hours. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA.

101

TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₀ H ₄₈ N ₄ O ₄ S)

Calculated: C, 51.93; H, 6.43; N, 7.15 Found: C, 51.93; H, 6.36; N, 7.28 1.95 TFA, 0.05 H ₂ 0

TLC: R _f 0.15 (90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH) HPLC (method A): exit time 8.33 min FAB MS: m / z 561 (M ⁺ + H)

1 H NMR (400 MHz, CDCl ₃ ): δ 7.20 (m, 3H), 7.08 (m, 2H),

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

EXAMPLE 55

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (4- (1-methoxycarbonyl-ethyl) -piperidine-1-carbonyl) -amino) -propyl) -bicyclo (2.2.1 ) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

Γ a stirred solution of i - ({7,7-dimethyl-2-exohydro-2-endo-2 - (1- (4-pyper 5. dinylcarbcni 1) - a in iho) pro pi1-o icyclo- (2.2.1) -heptan-1 H * -methanesulfonyl; ..... 4- (2-oeriltenyl) -piperazine (0.30 p; C.53 mmol) and mer 102 O (5 ml), methyl acrylate ( 0.072 ml; 0.80 mmol) After 48 hours at room temperature the solvent is removed under reduced pressure and the residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA to afford the title compound as a TFA salt (lyophilized powder).

Analysis: (C ₃₄ H ₅₄ N ₄ O ₆ S) Calculated: C, 53.04; H, 6.65; N, 6.60

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

1.75 TFA, 0.15 H ₂ O

TLC: R _f 0.25 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 9.02 min

FAB MS: m / z 647 (M ⁺ H) ^t; H NMR (400 MHz, CDC1 _3): d 7:45 (br t, 1H), 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

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (4- (1-carboxyethyl) piperidinylcarbonyl) amino) propylbicyclo (2.2.1) heptane-1) -yl) -methanesulfonyl) -4- (2-methylphenyl) piperazine

CH

OH

103

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3- (1-methoxycarbonyl) piperidinylcarbonyl) amino) -propyl-bicyclo (2.2 .1) -Heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.15 g, 0.23 mmol) and THF (5 mL) was added with 1M NaOH until the pH of the solution was stable for 1 hour. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA.

TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₃ H ₃ 2 N ₄ O g S)

Calculated: C, 53.09; H, 6.65; N, 6.84

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

1.6 TFA, 0.2 H ₂ O

TLC: R _f 0.10 (80: 20: 2 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.72 min

FAB MS: m / z 633 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): d 7:38 (br s, 1H), 7.18 (m, 2H) 7.03 (m, 2H), 2.29 (s , 3H), 1.13 (s, 3H), 0.981.01 (overlapping s and d, 6H)

EXAMPLE 57

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (3- (1-ethoxycarbonylmethyl) piperidinylcarbonyl) amino) propylbicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

104

n ^ y ° 'ch ₂ ch ₃

O

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3-piperidinylcarbonyl) amino) propyl-bicyclo (2.2.1) -heptane- l-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.20 g, 0.36 mmol) and DMF (5 mL), ethyl bromoacetate (0.044 mL, 0.40 mmol) and DIEA (0.070 mL, 0.40 mmol) were added. After 24 hours at room temperature, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₄ H ₅₄ N ₄ O ₆ S)

Calculated: C, 52.81; H, 6.67; N, 6.57

Found: C, 52.80; H, 6.64; N, 6.69

1.75 TFA, 0.35 H ₂ O

TLC: R _f 0.35 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 9.26 min

FAB MS: m / z 647 (M ⁺ H) ^X H NMR (400 MHz, CDC1 _3): 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 = 7Hz, 3H), 1.14 (s, 3H), 1.02-1.05 (overlapping s and d, 6H)

105

EXAMPLE 58

1 - ((7,7-Dimethyl-2-exo-hydroxy-2-endo-2- (1- (4- (1-carboxymethyl) piperidinylcarbonyl) amino) propyl-bicyclo (2.2.1) heptane-1 -yl) -methanesulfonyl) -4- (2-methylphenyl) piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-exohydroxy-2-endo-2- (1- (3- (1-methoxycarbonylmethyl) piperidinylcarbonyl) amino) propyl-bicyclo (2.2. 1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (0.15 g, 0.23 mmol) and THF (5 mL) was added with 1M NaOH until the pH of the solution was stable for 1 hour. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. TFA salt (freeze-dried powder) of the title compound is obtained.

Analysis: (C ₃₂ H ₅₀ N ₄ O ₆ S)

Calculated: C, 53.23; H, 6.82; N, 7.18

Found: C, 53.20; H, 6.81; N, 7.18

1.3 TFA, 0.75 H ₂ 0

TLC: R _f 0.15 (80: 20: 2 CHCl ₃ : MeOH: NH ₄ GH)

HPLC (method A): exit time 8.59 min

FAB MS: m / z 619 (M ⁺ + H) ^@ +.

106 ^X H NMR (400 MHz, CDC1 _3): 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), 0.97 (d, J = 6Hz, 3H)

EXAMPLE 59

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

Λ h ₃ c ch ₃

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (100 mg, 0.18 mmol) and methanol containing 1% acetic acid (2 mL) were added acetaldehyde (0.033 mL, 0.6 mmol) and sodium cyanoborohydride (10 mg; 0.18 mmol). After 2 hours, the reaction was quenched by the addition of sodium bicarbonate solution (0.5 mL) and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution (2 x 25 mL), brine (2 x 25 mL), dried (MgSO ₄ ) and filtered. The solvent is removed under reduced pressure. The residue was purified by flash chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (white amorphous substance on evaporation)

107 under reduced pressure from a mixture of ether and chloroform, 85% yield).

Analysis: (C ₃₀ H ₅₀ N ₄ O ₅ S 2)

Calculated: C, 53.65; H, 7.51; N, 8.01

Found: C, 53.64; H, 7.50; N, 8.13

0.7 CHCl ₃ , 0.2 (CH ₃ CH ₂ ) ₂ O

TLC: R _f 0.38 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.66 min, 95% purity FAB MS: m / z 611 (M ⁺ + H)

EXAMPLE 60 1 ^- ((7,7-Dimethyl-2-endo- (2s-ethoxycarbonylmethyl-amino-4- (methylsulfonyl) -butyramido) -bicyclo (2.2.1) heptane-11-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine.

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo) - (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and DMF (3 mL) were added with DIEA (0.070 mL; 0.40 mmol) and ethyl bromoacetate (0.044 mL; 0.40 mmol). After 24 hours at room temperature, the solvent is removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 5% aqueous citric acid (2 x 25 mL) and saturated NaHCO _3.

108 (2x25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 95: 5 CHCl ₃ : MeOH as eluent. The title compound is obtained (white amorphous material, evaporated under reduced pressure from a mixture of ethyl acetate and hexane, 75% yield).

Analysis: (C ₃ q H ₄ q N ₄ O-7S 2)

Calculated: C, 56.30; H, 7.69; N, 8.23

Found: C, 56.22; H, 7.70; N, 8.25

0.4 EtOAc, 0.05 Hexane

TLC: R _f 0.35 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 9.67 min, purity 99 +% FAB MS: m / z 641 (M ⁺ + H)

EXAMPLE 61

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

To a stirred solution of 1 - ((7,7-dimethyl-2endo (23-ethoxycarbonylmethylamino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) T ' ~ "'

109

4- (2-Methylphenyl) -piperazine (50 mg, 0.08 mmol) and ethanol were added to pH 13 of 1N aqueous sodium hydroxide solution. After 24 hours, the mixture was acidified to pH 2 with 5% aqueous HCl and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride (25 mL), washed with brine (25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was triturated with ether and filtered to give the title compound (white solid, 75% yield).

Analysis: (C ₂ gH ₄₄ N ₄ O ₇ S ₂ )

Calculated: C, 52.38; H, 6.91; N, 8.73.

Found: C, 52.43; H, 6.55; N, 8.80

0.5 NaCl

TLC: R _f 0.2 (90: 10: 0.2: 0.2 CHCl ₃ : MeOH: H ₂ O: HOAc)

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

EXAMPLE 62

1 - ((7,7-Dimethyl-2-endo- (2s-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) 4- ( 2-methyl-5-fluorophenyl) -piperazine

NH,

110

The title compound is synthesized from 1 - ((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-5-fluorophenyl) -piperazine and Boc-Lmethionine sulfone using the procedures described in Examples 35 and 36. The product was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA.

Lyophilization yields the TFA salt of the title compound (white powder, 85% yield).

Analysis: (C ₂₆ H ₄₁ FN ₄ O ₅ S ₂ )

Calculated: C, 45.74; H, 5.65; N, 7.26

Found: C, 45.74; H, 5.65; N, 7.50

0.3 H ₂ O, 1.7 CF 3 COOH

TLC: R _f 0.18 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.86 min, purity 99% FAB MS: m / z 573 (M ⁺ + H)

EXAMPLE 63

1 ^- ((7,7-Dimethyl-2-endo- (2s-dimethylamino-4- (methylsulfonyl) -butyramido) -bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2- methyl-5-fluorophenyl) -piperazine

SO ₂ CH ₃

111

The title compound is synthesized from 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) butyramido) bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2 -methyl-15-fluorophenyl) -piperazine according to the procedure described in Example 38. The product was purified by reverse phase preparative HPLC using 0.1% TFA in acetonitrile and water. Lyophilization yields the TFA salt of the title compound (white powder, 90.5% yield).

Analysis: (C ₂₈ H ₄₅ FN ₄ O ₅ S ₂ )

Calculated: C, 47.59; H, 5.97; N, 7.09

Found: C, 47.56; H, 5.91; N, 7.15

0.05 H ₂ O, 1.65 CF ₃ COOH

TLC: R _f 0.39 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

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

EXAMPLE 64

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

CH

O '

112

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (100 mg, 0.18 mmol) and methanol containing 1% acetic acid (5 mL) were added glutaric aldehyde (25 wt% in water; 0.005 mL; 0.22 mmol) and sodium cyanoborohydride (30 mL). mg; 0.54 mmol). After 3 hours, quench the reaction with aqueous sodium bicarbonate solution (0.5 mL) and remove the solvent under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution (2 x 25 mL), brine (2 x 25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The title compound is obtained (white amorphous material, 90% yield).

Analysis: (C ₃₄ H ₃ qN ₄ O ₃ S 2)

Calculated: c, 58.33; H, 8.17; N, 8.78 Found: C, 58. 0.85 H ₂ O 31; H, 7.77; N, 8.67 TLC: R _f 0.45 (95 : 5: -0.5 CHCl ₃ : MeOH: NH ₄ OH) HPLC (Method A): exit time 8.72 min, purity 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-methylphenyl) -piperazine

113

SO ₂ CH ₃

OH

A stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (310 mg; 0.56 mmol) and ethanol (10 mL) ·, cooled to 0 ° C. Ethylene oxide was passed through the solution, the reaction vessel was sealed, and the reaction mixture was heated to 70 ° C. After 48 hours, the solvent is removed under reduced pressure. The residue was purified by flash chromatography over a silica gel column using a gradient elution of 97: 3 to 93: 7 CHCl ₃ : MeOH to separate the faster-leaving dialkylation product from the monoalkylation product. To yield the title compound (white amorphous solid after evaporation under reduced pressure, CHCI _3: MeOH, 60% yield).

Analysis: (C ₂₈ H ₄₆ N ₄ O ₆ S ₂ )

Calculated: C, 52.64; H, 7.27; N, 8.60

Found: C, 52.67; H, 7.27; N, 8.37

0.4 CHCl ₃ , 0.15 MeOH

TLC: R _f 0.15 (93: 7 CHCl ₃ : MeOH)

HPLC (method A): exit time 8.72 min, purity 99% FAB MS: m / z 599 (M ⁺ + H)

114

EXAMPLE 66

1 - ((7,7-Dimethyl-2-endo- (2s- (4-morpholinyl) -4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4 - (2-Methylphenyl) -piperazine

HN

0 '

N.

To a solution of 1 - ((7,7-dimethyl-2-endo- (2Samino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (100 mg; 0.18 mmol) and DMF (3 mL), bis (2-chloroethyl) 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 purged with argon and heated to 130 ° C for 6 hours. The solvent is removed under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and washed with water (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), brine (25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. Lyophilization yields the TFA salt of the title compound (white powder, 25% yield).

Analysis: (C ₃₀ H ₄₈ N ₄ O ₆ S ₂ )

Calculated: C, 44.31; H, 5.37; N, 5.74

115

Found: C, 44.20; H, 5.04; N, 6.10

3.0 CF3COOH, 0.3 H ₂ O

TLC: R _f 0.63 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.08 min, purity 100% FAB MS: m / z 625 (M ⁺ + H)

EXAMPLE 67

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

CH ·

H

HN

O '

HN.

C ^ N

To a solution of 1 - ((7,7-dimethyl-2-endo- (2Samino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (100 mg; 0.18 mmol) and chloroform (5 mL), DIEA (0.037 mL; 0.21 mmol) and iodacetonitrile (0.015 mL, 0.21 mmol) were added. After 24 hours, the reaction mixture was diluted with chloroform (50 mL) and washed with water (25 mL), saturated sodium bicarbonate solution (2 x 25 mL), brine (25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography over silica gel using 97: 3 'dichloromethane: MeOH as eluent. The title compound is obtained (white amorphous material, 70% yield).

116

Analysis: (C ₂₈ H ₄₃ N ₅ O ₅ S ₂ )

Calculated: C, 55.79; H, 7.36; N, 11.67

Found: C, 56.15; H, 7.42; N, 11.32

0.5 H ₂ O

TLC: R _f 0.4 5 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.78 min, purity 100% FAB MS: m / z 594 (M ⁺ + H)

EXAMPLE 68

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

To a stirred solution of 1 - {(7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and methanol containing 1% acetic acid (4 mL) were added with 4-5 molecular sieves (3 A), tetrahydropyran-4-one (0.037 mL; 0.37 mL). mmol). After 2 hours, quench the reaction with aqueous sodium bicarbonate solution (0.5 mL) and remove the solvent under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (2x50 mL), brine (2x50 mL), dried over magnesium sulfate and filtered. Solvent Feed 3592 B

117 under reduced pressure. The title compound is obtained (white amorphous material, 90% yield).

Analysis: (C ₃₃ H ₃ QN _{4 0} gS ₂ )

Calculated: C, 58.05; H, 7.96; N, 8.26 Found: C, 57.81; H, 7.71; N, 8.28 0.45 EtOAc

TLC: R _f 0.27 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.29 min, purity 99%

FAB MS: m / z 639 M ⁺ + H)

EXAMPLE 69

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2s-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and methanol containing 1% acetic acid (4 mL) were added with 4-5 molecular sieves (3 A), N-Boc-glycinal (62 mg; 0.39 mmol) and sodium cia.ni

118 borohydride (20 mg; 0.36 mmol). After 2 hours, quench the reaction with aqueous sodium bicarbonate solution (0.5 mL) and remove the solvent under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (2x50 mL), brine (2x50 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 95: 5 CHCl ₃ : MeOH as eluant to give 1 - ((7,7-dimethyl-2-endo (2S- (2- (t-butyloxycarbonylamino) -ethyl)) amino-4-). (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (80% yield). This compound was dissolved in methylene chloride (7 mL) and TFA (7 mL) was added. After 30 minutes, the solvent is removed under reduced pressure. The residue was dissolved in methylene chloride (70 mL) and washed with saturated sodium bicarbonate solution (3 x 100 mL), brine (2 x 50 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. Lyophilization from a mixture of dioxane and water gives the title compound (white powder, 90% yield).

Analysis: (C ₂₈ H ₄₇ N ₅ O ₅ S ₂ )

Calculated: C, 53.87; H, 8.14; N, 10.47

Found: C, 54.04; H, 8.96; N, 10.44

0.5 C ₄ H ₈ O ₂ , 1.5 H ₂ O

TLC: R _f 0.08 (90: 10: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

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

119

EXAMPLE 70

1 ^- ((7,7-Dimethyl-2-endo- (2R-amino-4- (methylsulfonyl) butyramido) -bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine

1 - ((7,7-Dimethyl-2-endo- (2R- (t-butyloxycarbonyl) amino4- (methylthio) -butyramido) -bicyclo (2.2.1) -heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) -piperazine was synthesized from Boc-D-methionine and 1 - ((7,7-dimethyl-2-endoamino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4 - (2-methylphenyl) -piperazine according to the procedures of Example 35. 1 - ((7,7-Dimethyl-2-endo- (2R- (t-butyloxycarbonyl) -amino-4- (methylthio) -butyramido) -bicyclo- (2.2.1) 25 Heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (200 mg, 0.32 mmol) was dissolved in a 3: 1 mixture of methanol and water (25 mL) and added to the solution. sodium acetate (200 mg; 2.6 mmol) and Oxone ^R (0.80 g;

1.3 mmol). After 24 hours, the solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH as the eluent to give 1 - ((7,7-dimethyl-2-endo- (2R- (2- (t-butyloxycarbonyl)) ) amino) -4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) 35 methanesulfonyl) -4- (2-methylphenyl) -piperazine N-oxide (amorphous substance from chloroform) , 70% yield). This material was dissolved in THF (3 mL) and treated with trifenriLT 3592 B

120 phosphine (79 mg, 0.35 mmol). After 24 hours, the solvent is removed under reduced pressure. The residue is purified by flash column chromatography over silica gel using 1: 1 ethyl acetate / hexane as eluant to give 1 - ((7,7-dimethyl-2-endo- (2R- (2- (t-butyloxycarbonyl) amino)) - 4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine (amorphous white material, yield 90%). This product was dissolved in dichloromethane (5 mL) and treated with TFA (4 mL). After 1 hour, the solvent is removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (4 x 25 mL), brine (25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using a gradient elution of 98: 2: 0.2 to 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH. The title compound is obtained (white amorphous material, evaporated under reduced pressure from ether, 90% yield).

Analysis: (C2gH 2N5O _{4 3} S2)

Calculated: C, 55.07; H, 7.95; N, 9.44

Found: C, 55.08; H, 7.57; N, 9.17

0.9 H ₂ O, 0.3 ether

TLC: R _f 0.33 (94: 6: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

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

EXAMPLE 71

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

121

To a stirred solution of 4- (methylsulfonyl) butyric acid (370 mg; 2.23 mmol ·) and DMF (25 mL) was added BOP (986 mg; 2.23 mmol), 1 - ((7,7-dimethyl-2-) endo-aminobicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methyl-5-fluorophenyl) -piperazine (960 mg; 2.45 mmol) and DIEA (7.84 mL; 4.5 mmol). After 16 hours, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with 5% aqueous citric acid (2 x 50 mL) and saturated NaHCO ₃ ( ₃ x 50 mL) and brine. The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 1: 1 ethyl acetate-hexane as eluent. The title compound is obtained (white amorphous material, 90% yield).

Analysis: (C ₂₆ H ₄₁ N ₃ O ₅ S ₂ )

Calculated: C, 57.26; H, 7.74; N, 7.42

Found: C, 57.26; H, 7.54; N, 7.32

0.25 EtOAc, 0.25 water

TLC: R _f 0.18 (1: 1 EtOAc: Hexane)

HPLC (method A): output time of 10.62, 99.7% purity FAB MS: m / z 54 8 (M ^'? + H)

122

EXAMPLE 72

1 - ((7,7-Dimethyl-2-endo- (2s-bis (hydroxyethyl) amino-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) methane n-sulfonyl ) -4- (2-Methylphenyl) -piperazine

A stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (310 mg; 0.56 mmol) and ethanol (10 mL) cooled to 0 ° C. Ethylene oxide was passed through the solution, the reaction vessel was sealed, and the reaction mixture was heated to 70 ° C. After 48 hours, the reaction mixture is cooled to 0 ° C, ethylene oxide is passed through the solution, the reaction vessel is sealed, and the reaction mixture is heated to 70 ° C for 48 hours. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. Lyophilization yields the TFA salt of the title compound (white powder, 55% yield).

Analysis: (C ₃₀ H ₅₀ N ₄ O ₇ S ₂ )

Calculated: C, 45.90; H, 5.92; N, 6.23 Found: C, 45.90; H, 5.89; N, 6.33

2.2 TFA, 0.35 H ₂ O

123

TLC : R _f 0.62 (90 : 10: 0.5 CHCl ₃ : MeOH: NH ₄ OH) HPLC (method A): exit time 8.93 min, purity 98 +% FAB MS: m / z 643 (M + H ⁺ )

EXAMPLE 73

1 - ((7 _r 7-Dimethyl-2-endo- (2S- (4-tetrahydrothiopyranyl) amino-4- (methylsulfonyl) -butyramide) -biciklo- (2.2.1) heptan-l-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine

The title compound is synthesized from 1 - ((7,7-dimethyl-2-endo- (2S-amino-4- (methylsulfonyl) butyramido) bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- ( 2-Methyl-5-fluorophenyl) -piperazine according to the procedure described in Example 68. The crude product was purified by flash column chromatography over silica gel using 97: 3: 0.3 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (white amorphous material after evaporation under reduced pressure from chloroform in 90% yield).

Analysis: (C _3i H ₅₀ N ₄ O ₅ S ₃₎

Calculated: C, Found: C, 51.29;

0.75 CHCl3

51.22; H, 6.87; N, 7.53 E, 6.83; N, 7.27

TLC: R _£ 00:44 (95: 5: 0..5 CHC1 _3: MeOH: NH ₄ OH)

124

HPLC (method A): exit time 9.91 min, purity 99% FAB MS: m / z 655 (M + H ⁺ )

EXAMPLE 74

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

stirring solution containing 1 - ((7,7-dimethyl-2-endo (2s- (4-tetrahydrothiopyranyl) amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 (2-methylphenyl) -piperazine (90 mg; 0.12 mmol) and a 1: 9 mixture of water and acetone (4 mL), 4-methylmorpholine-N-oxide (43 mg; 0.36 mmol) and OsO _{4 were added.} (0.013 mL;

2.4 (wt%) solution). After 17 hours, quench the reaction with saturated aqueous NaHSO ₃ (0.05 mL), remove the solvent under reduced pressure. The residue was dissolved in methylene chloride (25 mL), washed with IN NaHSO ₃ ( ₃ x 25 mL), brine (2 x 25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. Lyophilization yields the TFA salt of the title compound (white powder, 80% yield).

125

Analysis: (C ₃₄ H ₃ qN ₄ O ₇ S ₃ )

Calculated: C, 45.47; H, 5.74; N, 6.04

Found: C, 45.47; H, 5.72; N, 5.89

2.05 TFA, 0.35 H ₂ 0

TLC: R _f 0.33 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.02 min, purity 99% FAB MS: m / z 687 (M + H)

EXAMPLE 75

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2s-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (160 mg; 0.29 mmol) and chloroform (5 mL) were added with acetic anhydride (1 mL) and diisopropylethylamine (0.03 mL). After 2 hours, the solvent is 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 solution (2 x 10 mL), brine (10 mL), dried over magnesium sulfate and filtered. Solvent Feed 3592 B

126 is applied under reduced pressure. The title compound is obtained (amorphous material, 90% yield).

Analysis: (C _{2 a} H ₄₄ N ₄ O ₆ S ₂ )

Calculated: C, 55.89; H, 7.37; N, 9.30

Found: C, 55.90; H, 7.36; N, 9.22

0.5 CHCl ₃

TLC: R _f 0.21 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

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

EXAMPLE 76

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (200 mg, 0.36 mmol) and methanol, acrylonitrile (0.026 mL, 0.40 mmol) was added. After 16 hours, additional acrylonitrile (0.010 mL, 0.15 mmol) was added. After 24 hours, the solvent is removed under reduced pressure. The residue is flash chromatography

T

Method 127 on a silica gel column using a 1: 3 mixture of ethyl acetate and hexane as eluent. The solvent is removed under reduced pressure and the residue is taken up in ethyl acetate and hexane. The solid is dried in vacuo to give the title compound (white powder, 55% yield).

Analysis: (C ₂₉ H ₄₅ N ₅ O ₅ S ₂ )

Calculated: C, 57.18; H, 7.54; N, 11.01

Found: C, 56.86, 7.74; N, 11.01

0.32 EtOAc

TLC: R _f 0.2 (1: 4 EtOAc: hexane)

HPLC (method A): exit time 8.99 min, purity 99% FAB MS: m / z 608 (M + H ⁺ )

EXAMPLE 77

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

HN H

SO ₂ CH ₃

OH

128

To a stirred solution of 1 - ((7,7-dimethyl-2endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) piperazine (200 mg, 0.36 mmol) and ethanol (5 mL), isobutylene oxide (0.026 mL, 0.36 mmol) was added and the reaction mixture was sealed and heated on a steam bath. After 16 hours, additional isobutylene oxide (0.026 mL, 0.36 mmol) was added and heating was continued. After 24 hours, additional isobutylene oxide (0.026 mL, 0.36 mmol) was added and heating was continued. After 24 hours, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA. Lyophilization yields the TFA salt of the title compound (white powder, 48% yield).

Analysis: (C ₃₀ H ₅ O ₄ O ₆ S ₂ )

Calculated: C, 48.45; H, 6.39; N, 6.77

Found: C, 48.46; H, 6.37; N, 6.78

1.7 TFA, 0.4 H ₂ O

TLC: R _f 0.3 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

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

EXAMPLE 78

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

129

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and ethanol (5 mL) were added R - (+) - propylene oxide (0.025 mL; 0.36 mmol), the reaction mixture was sealed and heated on a steam bath. After 16 hours, an additional amount of R - (+) 20 propylene oxide (0.010 mL; 0.15 mmole) isobutylene oxide was added and heating was continued. After 72 hours, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water with 0.1% TFA.

A more mobile product is isolated which is lyophilized to give the title compound TFA salt (white powder, 42% yield).

Analysis: (C ₂₉ H ₄₈ N ₄ O ₆ S ₂ )

3C Calculated: C, 47.52; H, 6.23; N, 6.82 Found: C, 47.50; H, 6.22; N, 6.90

1.7 5 TFA, 0.5 H ₂ O

TLC: R _f 0.2 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 3.31 min, purity 99%

FAB MS: m / a 613 (M-HA

130

EXAMPLE 79

1 - ((7,7-Dimethyl-2-endo- (2s-bis (2R-hydroxypropyl) amino-4- (methylsulfonyl) butyramido) -bicyclo (2.2.1) hept-n-1-yl) - methanesulfonyl) -4- (2-methylphenyl) -piperazine

Subsequently, the product isolated by reverse-phase preparative HPLC purification of the crude product according to Example 78 was lyophilized to give the TFA salt of the title compound (white powder, 2% yield).

Analysis: (C ₃ 2 H ₃₄ N ₄ O ₃ S 2)

Calculated: C, 48.49; H, 6.36; N, 6.29

Found: C, 48.31; H, 6.35; N, 6.52

1.9 TFA, 0.15 H ₂ O

TLC: R _f 0.2 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.74 min, 95% purity FAB MS: m / z 671 (M + H ⁺ )

EXAMPLE 80 i - ((7,7-Dimethyl-2-endo- (2s- (2s-hydroxypropyl) -amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) hept.an-1'-yl) -methanesulfonyl ) -4- (2-Methylphenyl) -piperazine

131

H

HN

SO ₂ CH ₃

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (200 mg; 0.36 mmol) and ethanol (5 mL) were added.

S - (-) - propylene oxide (0.025 mL, 0.36 mmol). The reaction vessel is sealed and the reaction mixture is heated on a steam bath. After 16 hours, an additional amount is added

S - (-) - propylene oxide (0.010 mL; 0.15 mmol) and continue heating. After 72 hours, the solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 1% TFA. A more mobile product is isolated which, upon lyophilization, affords the TFA salt of the title compound (white powder, 24% yield).

Analysis: (C ₂₉ H ₄₈ O ₆ S ₂ )

Calculated: C, 47.54; H, 6.17; N, 6.80

Found: C, 47.55; H, 6.16; N, 6.90

1.8 TFA, 0.3 H ₂ O

TLC: R _f 0.2 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.40 min, purity 99%

FAB MS: m / z 613 (Mi-H ^r)

132

EXAMPLE 81

1 - ((7,7-Dimethyl-2-endo- (2s-bis (2S-hydroxypropyl) amino-4- (methylsulfonyl) butyramido) -bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) -piperazine

Subsequently, the product isolated by preparative HPLC reverse phase purification of the crude product according to Example 80 was lyophilized to give the TFA salt of the title compound (white powder, 5% yield).

Analysis: (C ₃₂ H ₅₄ N ₄ O ₇ S ₂ )

Calculated: C, 48.37; H, 6.41; N, 6.32

Found: C, 48.36; H, 6.42; N, 6.52

1.9 TFA, 0.15 H ₂ O

TLC: R _f 0.2 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.78 min, purity 97% FAB MS: m / z 671 (M + H ⁺ )

EXAMPLE 82

1 - ((7,7-Dimethyl-2-endo- (2s- (2-propyl) -amino-4- (methylphonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine

133

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine (200 mg, 0.36 mmol) and ethanol (5 mL), acetone (0.026 mL, 0.40 mmol) and activated, crushed sieves (3A) were added. After 5 hours, NaBH ₃ CH (11 mg, 0.36 mmol) was added. After 16 hours, additional NaBH ₃ CN (5 mg; 0.15 mmol) was added. After 24 hours, one drop of water was added and the solvent removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 1% TFA. Lyophilization gives the title compound as TFAdd salt (white powder, 35% yield).

Analysis: (C ₂₉ H ₄₈ N ₄ O ₅ S ₂ )

Calculated: C, 48.33; H, 6.42; N, 6.96

Found: C, 48.33; H, 6.42; N, 7.14. 7 TFA, 0.8 H ₂ O

TLC: R _f 0.6 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.68 min, purity 99 '%

FAB MS: m / z 5 97 (M + H ⁺ ).

134

EXAMPLE 83

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

so ₂

HN.

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and DMF (10 mL) were added 4-bromopyridine (70 mg; 0.36 mmol) and the reaction mixture was heated to 120 ° C for 16 h. Many degradants are formed. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 1% TFA. Lyophilisation yields the TFA salt of the title compound (white powder,

2.5% yield).

Analysis: (C ₃₁ H ₄₅ N ₄ O ₅ S ₂ )

Calculated: C, 47.37; H, 5.63; N, 7.87

Found: C, 47.36; H, 5.93; N, 7.48

2.05 TFA, 1.35 H ₂ O

TLC: R _f 0.4 (95: 5: 0.5 CHCl ₃ : MeOH: NH, OH)

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

135

EXAMPLE 84

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

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (200 mg; 0.36 mmol) and DMF (5 mL) were added 1,2-bromofluoroethane (0.025 mL; 0.36 mmol) and the reaction mixture was sealed and heated on a steam bath. After 16 hours, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 1% TFA. Lyophilization gives the TFA salt of the title compound (white powder, 18% yield).

Analysis: (C _2g FH ₄₅ N ₄ O ₅ S ₂ )

Calculated: C, 47.08; H, 5.85; N, 6.95

Found: C, 47.09; H, 5.86; N, 7.04

1.8 TFA

TLC: R _f 0.4 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit time 3.50 min, purity 99%

FAB MS: m / z 601 (M + H) @ +

136

EXAMPLE 85 ((7,7-Dimethyl-2-endo- (2s-ethylamino-4- (methylsulfonyl) butiramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) 4- (2-methylphenyl) -piperazine

peratural reduced

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine (206 mg, 0.371 mmol) and DMF (30 mL) were added with iodetane (0.015 mL; 0.19 mmol) and DIEA (0.097 mmol; 0.56 mmol). The reaction mixture was stirred at room temperature for 48 hours. The solvent is removed under pressure, the residue is dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (3 x 50 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 98: 2: 0.2 CH ₂ Cl ₂ : MeOH: NH ₄ OH as eluent. The resulting oil is dissolved in a mixture of CH ₃ CN and water containing 0.1% TFA to give the TFA salt of the title compound (white powder, 40% yield).

Analysis: (C _2g H ₄₆ N ₄ O ₅ 3 ₂ )

FW = 682,451

Calculated: C, 52.57; H, 6.96; N, 8.21

137

Found: C, 52.30; H, 6.92; N, 8.19

0.15 H ₂ O, 0.85 TFA

TLC: R _f = 0.46 (96: 4: 0.4 CH ₂ Cl ₂ : MeOH: NH ₄ OH)

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

EXAMPLE 86

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

SO ₂ CH ₃

A solution of N-Boc-N-methyl-L-methionine broth (0.899 g; 3.04 mmol) and BOP (1.35 g; 3.0 mmol) and DMF (50 mL) was stirred for 10 min. A solution of 1 - ((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.80 g) is added dropwise. 2.77 mmol) and DMF (15 mL), then DIEA (5.2 mL; 3.0 mmol) was added to the reaction mixture to bring the reaction mixture to pH 8 (by drop on E. Merck pH paper strip). After 16 hours, DMF is removed under reduced pressure and the residue is dissolved in ethyl acetate (100 mL), washed with 5% (w / w) aqueous citric acid solution (100 mL) and saturated aqueous sodium bicarbonate solution (2 x 100 mL). The organic phase is dried (MgSO 4), filtered and the solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 40:60 hexane: EtOAc as eluent. The title compound is obtained (white amorphous material, 90% yield).

Analysis: (C ₃₂ H ₅₂ N ₄ O ₇ S ₂ )

FW = 690.95

Calculated: C, 57.36; H, 7.88; N, 8.11

Found: C, 57.68; H, 7.84; N, 8.13

0.25 EtOAc

TLC: R _f = 0.27 (40:60 Hexane: EtOAc)

HPLC (method A): exit time 11.21 min, purity 99 +% FAB MS: m / z 669 (M + H ⁺ )

EXAMPLE 87

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

CH

HN

H

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S- (t-butyloxycarbonyl) methylamino-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) -heptan-1-yl) ) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (1.0 g, 1.5 mmol) and

139

DCM (25 mL), TFA (25 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (4 x 50 mL). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed under reduced pressure. The title compound is obtained (amorphous material, 95% yield).

Analysis: (C ₂₇ H ₄₄ N ₄ O ₅ S ₂ )

FW = 612.15

Calculated: C, 56.11; H, 7.92; N, 8.15 Found: C, 56.14; H, 7.78; N, 9.16 0.40 EtOAc, 0.45 H ₂ O

TLC: R _f = 0.16 (97: 3 DCM: MeOH)

HPLC (method A): exit time 8.23 min, purity 99 +% FAB MS: m / z 569 (M + H ⁺ )

EXAMPLE 88

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

NH

0 '

140

The title compound is synthesized from N-Boc-Ntrideuteromethyl-L-methionine sulfone and 1 - ((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine according to the procedures in Examples 86 and 87. Evaporation under reduced pressure from EtOAc and hexane gave the title compound (white amorphous material).

Analysis: (C _{2 7} D ₃ H ₄₃ N ₄ O ₅ S ₂ )

FW = 606.22

Calculated: C, 56.26; H, 7.28; N, 9.24

Found: C, 55.93; H, 7.67; N, 9.18

0.35 EtOAc, 0.20 H ₂ O

TLC: R _f = 0.16 (97: 3 DCM: MeOH)

HPLC (method A): exit time 8.23 min, purity 99 +% FAB MS: m / z 572 (M + H ⁺ )

EXAMPLE 89

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

141

A stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine (0.433 g, 0.781 mmol) and DIEA (0.203 mL; 1.17 mmol) and DMF (10 mL) were cooled to 0 ° C. Iodomethane-d ₃ (0.50 mL, 0.786 mmol) was added via syringe. The reaction mixture was gradually warmed to room temperature and then stirred for 16 hours. The reaction mixture was then cooled to 0 ° C and another 0.5 eq. Of CD ₃ I and DIEA was added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL). The EtOAC solution was washed with a saturated aqueous sodium bicarbonate solution (2 x 25 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. HPLC analysis of the crude product contains unreacted L-368, 899, mono-, bis- and trialkylated products. The desired bis-alkylated product is isolated by flash chromatography on a silica gel column using 98: 2 CH ₂ Cl ₂ : MeOH as the eluent. The fractions containing the pure product were combined and the solvent removed under reduced pressure. An oil is obtained which is lyophilized from a 1: 2 mixture of acetonitrile and water containing 0.1% TFA to give the title compound as a TFA salt (white powder).

Analysis: (C ₂ gDgH ₄ gN ₄ O ₅ S ₂ )

0.80 TFA, 2.45 H ₂ O

FW = 724.256

Calculated: C, 49.08; H, 6.36; N, 7.74

Found: C, 49.12; H, 6.55; N, 7.43

TLC: R _f = 0.43 (95: 5: 0.5 DCM: MeOH: NH ₄ OH)

HPLC (method Ά7: exit, time 8.33 min, purity 99 +% FAB MS: m / z 589 (M + H ⁺

142

EXAMPLE 90

1 - ((7,7-Dimethyl-2-endo- (2s-tris (trideuteromethyl) amino4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- ( 2-methylphenyl) -piperazine

CH

A stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine (426 mg, 0.768 mmol), DIEA (0.40 mL, 2.3 mmol) and DMF (20 mL) were cooled to 0 ° C. Iodomethane-d ₃ (0.16 mL, 2.5 mmol) was added via syringe. The reaction mixture was slowly cooled to room temperature and stirred for 48 hours. The solvent is removed under reduced pressure. The residue was purified by preparative HPLC reverse phase using a gradient of acetonitrile to water with 0.1% TFA. Lyophilization gives the title compound (white powder, 50% yield).

Analysis: (C ₃ | H ₄ DgF ₃ QN ₄ O ₂ S ₂ )

0.6 TFA

FW = 788.284

Calculated: C, 49.06; H, 6.34; N, 7.11

Found: C, 49.13; H, 6.61; N, 6.96

143

TLC: R _f = 0.11 (90: 10: 0.5 DCM: MeOH: NH ₄ OH)

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

EXAMPLE 91

1 - ((7,7-Dimethyl-2-endo- (2s-n, n-dimethylformamidinyl-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-Methylphenyl) -piperazine

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (100 mg; 0.18 mmol) and DMF (2 mL) were added dimethylformamide dimethyl acetal (xx mL; 0.54 mmol). After 24 hours, the solvent is removed under reduced pressure. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with water (2 x 25 mL). The organic phase is dried (MgSO ₄ ), filtered and the solvent is removed under reduced pressure. The title compound is obtained ((white amorphous material, evaporated on ^; reduced pressure from chloroform, 90% yield).

Analysis (C ₂₉ H, _n N ₅ O ₅ S,)

144

Calculated: C, 53.70; H, 7.27; N, 10.65

Found: C, 53.87; H, 7.27; N, 10.66

0.4 CHCl ₃

TLC: R _f 0.35 (95: 5: 0.5 DCM: MeOH: NH ₄ OH)

HPLC (method A): exit time 8.34 min, purity 99 +% FAB MS: m / z 610 (M + H ⁺ )

EXAMPLE 92

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

H

HN

To a stirred solution of 1 - ((7,7-dimethyl-2-endo (2S-amino-4- (methylsulfonyl) -butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) - 4- (2-Methylphenyl) -piperazine (100 mg, 0.18 mmol) and DMF (4 mL) were added with methyl acetate (100 mg; 0.91 mmol) and sodium carbonate (150 mg; 1.5 mmol). After 48 hours, the mixture was filtered through celite and the solvent removed under reduced pressure. The resulting dark oil was purified by flash column chromatography over silica gel using a gradient elution of 95: 5: 0.5 CHCl 3: MeOH: NH ₄ OH to 85: 15: 0.75 CHCl ₃ : MeOH: NH ₄ OH. LioLT 3592 B

Filtration from a 1: 3 mixture of CH ₃ CN and water containing 0.1% TFA gives the TFA salt of the title compound (white powder, 25% yield).

Analysis: (C ₂₈ H ₄₅ N ₅ O ₅ S ₂ )

Calculated: C, 48.90; H, 6.70; N, 9.50 Found: C, 48.71; H, 6.45; N, 9.62 1.0 TFA, 1.5 H ₂ O

TLC: R _f 0.29 (85: 15: 0.75 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 9.05 min, purity 97.9%

FAB MS m / z 596 (M + H &lt; + & gt ^; ).

EXAMPLE 93

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

a stirred solution of (2S-amino-4- (methylsulfonyl) -butyric- (7,7-dimethyl-2-endonico) -bicyclic-C.2.i) - heptan-1-i

- me t a n - s u j. f o n i: -methyl.fen;

.p-pips

146 N (200 mg; 0.36 mmol) and MeOH containing 1% by volume acetic acid (4 mL) were added 4-5 molecular sieves (3A), t-butyloxycarbonyl-4-piperidinone (78 mg; 0.39 mmol) and sodium cyanoborohydride. (20 mg, 0.36 mmol). After 5 hours, quench the reaction with aqueous sodium bicarbonate solution (0.5 mL) and remove the solvent under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 95: 5 CHCl ₃ : MeOH as eluent. The resulting oil is lyophilized from a mixture of H ₂ O and CH ₃ CN containing 0.1% TFA. TFA salt of the title compound is obtained (white powder, 85% yield).

Analysis: (C ₃ gH ₃₉ N ₃ O ₇ S ₂ )

Calculated: C, 47.75; H, 6.10; N, 6.79

Found: C, 47.76; H, 6.07; N, 7.12

2.5 TFA, 0.45 H ₂ O

TLC: R _f 0.27 (95: 5 CHCl ₃ : MeOH)

HPLC (method A): exit 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 1 - ((7,7-dimethyl-2-endo (2S- (4- (1-t-butyloxycarbonyl) piperidinyl) amino-4- {methylsulfonyl) butyramide) -bicyclo- (2.2 .1) -heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) -piperazine (100 mg; 0.14 mmol) and dichloromethane (20 mL), TFA (15 mL) was added. After 1 hour, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (4 x 25 mL), brine (25 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from dichloromethane under reduced pressure afforded the title compound (white amorphous material, 90% yield).

Analysis: (C ₃₁ H ₅₁ N ₅ O ₅ S ₂ )

Calculated: C, 55.13; H, 7.70; N, 9.79

Found: C, 55.09; H, 7.64; N, 10.07

0.6 CH ₂ Cl ₂

TLC: Rf0.ll (90: 10: 1 CKCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.13 min, purity 99 +%. FAB MS: m / z 638 (M + H &lt; + & gt ^; ).

148

EXAMPLE 95

1 - ((7,7-Dimethyl-2-endo- (2s-amino-4-hydroxybutyramido) bicyclo (2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylyl) - piperazine

CH ·

HN ₂ N stirred solution of 1 - ((7,7-dimethyl-2-endoamino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine (2.0) g; 5.1 mmol) and DMF (20 mL), N-Boc-L-homoserine, O-benzyl ether (1.73 g, 5.61 mmol), hydroxybenzotriazole hydrate (0.87 g, 5.7 mmol), DIEA (2.6 mL, 11.6 mmol) were added. ) and EDC (1.09 g; 5.7 mmol). After 24 hours, the solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (100 mL), washed with 5% aqueous citric acid (2 x 25 mL), water (25 mL), and saturated aqueous sodium bicarbonate solution (2 x 50 mL), dried (MgSO _4). ) and filtered. The solvent is removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 1: 1 hexane: EtOAc as eluent. 1 - ((7,7-Dimethyl-2-endo- (2S-t-butyloxycarbonylamino-4- (benzyloxy) be ramido) bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) -4 ( 2-methylphenyl) -piperazine (white amorphous material, 90% yield). The nitrogen protecting group is removed by dissolving in dichloromethane (15 mL) and adding TFA (10 mL). After 1 hour, the solvent is removed under reduced pressure

149 gui. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution (4 x 50 mL), dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give 1 ^- ((7,7-dimethyl-2-endo- (2S-amino-4- (benzyloxy) -butyramide) bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl ) -4- (2-methylphenyl) -piperazine (white amorphous material, 95% yield). The oxygen protecting group is removed by dissolving in methanol containing 5% by volume acetic acid (50 mL) and stirring with palladium black (150 mg) under hydrogen pressure at normal pressure. After 24 hours, the reaction mixture was purged with argon, the catalyst removed by filtration through celite, and the solvent removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using 90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH as eluent. The title compound is obtained (white amorphous material, evaporated under reduced pressure from a mixture of chloroform and ether, 90% yield).

Analysis: (C ₂₅ H ₄₀ N ₄ O ₄ S)

Calculated: C, 59.28; H, 8.05; N, 10.74

Found: C, 59.42; H, 8.02; N, 10.72

0.15 CHCl ₃ , 0.15 ether

TLC: R _f 0.18 (90: 10: 0.75 (CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.31 min, purity 99 +% FAB MS: m / z 493 (M + H ⁺ )

EXAMPLE 96

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

150

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2S-amino-4-hydroxybutyramido) -bicyclo- (2.2.1) -heptan-1-yl) methanesulfonyl) - 4- (2-methylphenyl) -piperazine with 1-t-butyloxycarbonyl-4-piperidinone followed by removal of the nitrogen protecting group by treatment with TFA as described in Examples 93 and 94. The crude product was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water. , with 0.1% TFA. Lyophilization yields the TFA salt of the title compound (white powder, 50% yield).

Analysis: (C ₃₀ H ₄₉ N ₅ O ₄ S)

Calculated: C, 43.60; H, 5.34; N, 6.73

Found: C, 43.61; H, 4.95; N, 7.12

3.9 TFA, 1.15 H ₂ O

TLC: R _f 0.10 (90: 10: 1) CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 7.85 min, purity 99 +% FAB MS: m / z 576 (M + H ⁺ )

EXAMPLE 97

1 - ((7,7-Dimethyl-2-endo- (2s- (4-tetrahydropyranyl) amino4-hydroxy-butyramido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4 - (2-Methylphenyl) -piperazine

151

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2S-amino-4-hydroxybutyramidc) -bicyclo- (2.2.1) -heptan-1-yl) methanesulfonyl) - 4- (2-methylphenyl) -piperazine with 4-tetrahydropyranone as described in Example 68. The crude product was purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from a mixture of chloroform and methanol under reduced pressure affords the title compound (white amorphous substance).

Analysis: (C ₃₀ H ₄₈ N ₄ O ₅ S)

Calculated: C, 60.02; H, 8.16; N, 9.18

Found: C, 60.04; H, 8.09; N, 9.14

0.2 CHCl 3, 0.3 CH 3 OH

TLC: R _f 0.35 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.82 min, 96% purity FAB MS: m / z 577 (M + H ⁺ )

EXAMPLE 98

1 - ((7,7-Dimethyl-2-endo- (2s- (1,1-dioxo-4-tetrahydrothiopyranyl) amino-4-hydroxybutyramido) -bicyclo- (2.2.1) hepta n-1-yl) -mersulfonyl) -4- (2-methylphenyl) -piperazinine

152

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-4-hydroxybutyramido) -bicyclo- (2.2.1) -heptan-1-yl) methanesulfonyl) -4- (2 -methylphenyl) -piperazine with 4-tetrahydrothiopyranone and the sulfone formed by oxidation according to the procedures described in Examples 73 and 74. The crude product is purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from chloroform under reduced pressure affords the title compound (white amorphous substance).

Analysis: (C ₃ oH ₄ gN ₄ OGS ₂₎

Calculated: C, 54.13; H, 7.26; N, 8.31

Found: C, 54.15; H, 6.91; N, 8.15

0.4 CHCl ₃ , 0.1 H ₂ O

TLC: R _f 0.30 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.79 min, purity 97% FAB MS: m / z 625 (M + H ⁺ )

EXAMPLE 99

1 - ((7,7-Dimethyl-2-endo- (2s-amino-3-hydroxypropionamido) -bicyclo- (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-methylsulfonyl) piperazine

153

The title compound is obtained from 1 - ((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine and Boc The crude product was purified by flash chromatography on a silica gel column using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as the eluent to purify the nitrogen protecting group by TFA using TFA. Evaporation from chloroform under reduced pressure affords the title compound (white amorphous material, 90% yield).

Analysis: (C ₂₄ H ₃₈ N ₄ O ₄ S)

Calculated: C, 56.19; H, 7.43; N, 10.77

Found: C, 56.24; H, 7.50; N, 10.86

0.35 CHCl ₃

TLC: R _f 0 ..32 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit 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-hydroxypropionamide.) -Bicyclo-2.2.1) heptan-1-yl) -metharsulfonyl ) -4- (2-Methylferlyl ·) -piperazine. ·. ·,

154

HN • N

H

OH

The title compound is obtained by alkylation under reductive conditions of 1 - ((7,7-dimethyl-2-endo- (2Samino-3-hydroxypropionamido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl ) -4- (2-methylphenyl) -piperazine with 1-t-butyloxycarbonyl-4-piperidinone followed by deprotection of the nitrogen with TFA according to the procedures described in Examples 93 and 94. The crude product is purified by preparative HPLC reverse phase using acetonitrile. and water gradient, with 0.1%

TFA. Lyophilization yields the TFA salt of the title compound (white powder, 80% yield).

Analysis: (C ₂₉ H ₄₇ N ₅ O ₄ S)

Calculated: C, 44.20; H, 5.14; N, 7.89

Found: C, 44.63; H, 4.62; N, 7.88

TFA, 0.9 CH ₃ CN

TLC: R _f 0.05 (90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 7.99 min, purity 99 +%

FAB MS: m / z 562 (M + H &lt; + & gt ^; ).

EXAMPLE 101

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

155

The title compound is obtained by alkylation under reducing conditions with i - ((7,7-dimethyl-2-endo- (2Samino-3-hydroxypropionamido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4- ( 2-methylphenyl) -piperazine with 4-tetrahydropyranone according to the procedures described in Example 68. The crude product is purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from ethyl acetate under reduced pressure afforded the title compound (white amorphous material, 90% yield).

Analysis: (C ₂₉ H _{4 S} N ₄ O ₅ S)

Calculated: C, 61.40; H, 8.30; N, 9.30

Found: C, 61.03; H, 8.13; N, 9.54

0.45 ethyl acetate

TLC: R _f 0.30 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A):. exit time 8.76 min, 98% purity FAB MS: m / z 563 (M + H ⁺ )

Analysis: (C ₂₄ H ₃₈ N ₄ O ₄ S)

Calculated: C, 56.19; H, 7.43; N, 10.77

Found: C, 56.24; H, 7.50; N, 10.86

0.35 CKCl ₃

TLC: R 0.32 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

156

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

EXAMPLE 102

1 - ((7,7-Dimethyl-2-endo (2s- (1,1-dioxo-4-tetrahydrothiopyranyl) amino-3-hydroxypropionamido) -bicyclo (2.2.1) -heptan-1-yl) - methanesulfonyl) -4- (2-methylphenyl) piperazine _ __

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-3-hydroxypropionamido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4- (2- methylphenyl) -piperazine with 4-tetrahydrothiopyranone and the sulfone formed by oxidation according to the procedures described in Examples 73 and 74. The crude product is purified by flash column chromatography on silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from chloroform under reduced pressure affords the title compound (white amorphous substance).

Analysis: (C ₂₉ H ₄₆ N ₄ O ₆ S ₂ )

Calculated: C, 54.99; H, 7.72; N, 8.85 Pasta: C, 55.01; H, 7.99; N, 8.76

157

1.25 H ₂ O

TLC: R _f 0.35 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit 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-1-yl) -methanesulfonyl) -4- (2-methylphenyl) -piperazine

The title compound is obtained from 1 - ((7,7-dimethyl-2-endo-amino-bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) -4- (2-methyl-phenyl) -piperazine and Boc-L The threonine was subsequently deprotected under nitrogen using TFA according to the procedures described in Examples 35 and 36. The crude product was purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Lyophilization from a mixture of CH ₃ CN and water containing 0.1% v / v TFA gives the TFA salt (white powder) of the title compound.

Analysis: (C ₂₅ H ₄₀ N ₄ O ₄ S)

Calculated: C, 4 9.32; H, 6.09; N, 8.07

158

Found: C, 49.35; H, 6.01; N, 7.93

1.75 TFA

TLC: R _f 0.15 (95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.51 min, purity 99 +% FAB MS: m / z 4 93 (M + H ⁺ )

EXAMPLE 104

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

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-3s-hydroxybutyramido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4- ( 2-methylphenyl) -piperazine with 1-t-butyloxycarbonyl-4-piperidinone, followed by removal of the nitrogen protecting group by treatment with TFA as described in Examples 93 and 94. The crude product was purified by preparative HPLC reverse phase using a gradient of acetonitrile and water. % TFA. Lyophilization gives the TFA salt of the title compound (white powder, 30% yield).

Analysis: (C ₃₀ H ₄₉ N ₅ O ₄ S)

159

Calculated: C, 46.87; H, 6.24; N, 7.81

Found: C, 46.88; H, 6.01; N, 8.00

2.5 TFA, 0.2 H ₂ O

TLC: R _f 0.09 (90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.10 min, purity 99 +% FAB MS: m / z 576 (M + H ⁺ )

EXAMPLE 105

1 - ((7,7-Dimethyl-2-endo- (2s- (4-tetrahydropyranyl) amino-3s-hydroxy-butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4- ( 2-methylphenyl) -piperazine

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-3s-hydroxybutyramido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4- ( 2-methylphenyl) -piperazine with 4-tetrahydropyranone as described in Example 68. The crude product is purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from chloroform under reduced pressure affords the title compound (white amorphous material, 90% yield).

Analysis: (C ₃₀ K _{4 S} N _d O ₅ S)

Calculated: C, -58.92;

9.0 6

H, 7.88; N,

160

Found: C, 5 9.07, - H, 7.87; N, 9.13 Ο. 35 CHCl ₃ TLC: R _f 0.44 {95 : 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH) HPLC (method A): exit time 8.96 min, purity 99% FAB MS: m / z 577 (M + H ⁺ ) EXAMPLE 106

1 - ((7,7-Dimethyl-2-endo- (2s- (4-ethoxycarbonyl) cyclohexylamino-4- (methylsulfonyl) -butyramido) -bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) piperazine

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-4- (methylsulfonyl) butyramido) -bicyclo (2.2.1) -heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine with 4-tetrahydropyranone as described in Example 68. The crude product is purified by flash column chromatography on silica gel using 2: 1 ethyl acetate-hexane as eluent. Two isomers of the title compound are obtained which differ in the ethoxycarbonyl substituent configuration (white amorphous compounds).

Isomer no. 1

159

Calculated: C, 46.87; H, 6.24; N, 7.81 Found: C, 46.88; H, 6.01; N, 8.00

2.5 TFA, 0.2 H ₂ O

TLC: R _f 0.09 (90: 10: 1 CHCl ₃ : MeOH: NH ₄ OH)

HPLC (method A): exit time 8.10 min, purity 99 +%

FAB MS: m / z 576 (M + H &lt; + & gt ^; ).

EXAMPLE 105

1 - ((7,7-Dimethyl-2-endo- (2s- (4-tetrahydropyranyl) amino-3,5-hydroxy-butyramido) -bicyclo- (2.2.1) heptan-1-yl) methanesulfonyl) -4 - (2-Methylphenyl) -piperazine

The title compound is obtained by alkylation under reductive conditions of 1 - ((7,7-dimethyl-2-endo- (2Samino-3s-hydroxybutyramido) -bicyclo- (2.2.1) -heptan-yl) -methanesulfonyl) -4- (2-Methylphenyl) -piperazine with 4-tetrahydropyranone as described in Example 68. The crude product was purified by flash column chromatography over silica gel using 95: 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH as eluent. Evaporation from chloroform under reduced pressure affords the title compound (white amorphous material, 90% yield).

Analysis: (C ₃₀ H ₄₈ N ₄ O ₅ S)

Calculated: C, 58.92; H, 7.83; N, 9.06

160

Found: C, 59. 07; H, 7.87; N, 9.13 0.35 CHCl ₃ TLC: R _f 0.44 (95 : 5: 0.5 CHCl ₃ : MeOH: NH ₄ OH) HPLC (Method A): exit time 8.96 min, purity 99% FAB MS: m / z 577 (M + H ⁺ )

EXAMPLE 106

1 - ((7,7-Dimethyl-2-endo- (2s- (4-ethoxycarbonyl) cyclohexylamino-4- (methylsulfonyl) -butyramido) -bicyclo (2.2.1) heptan-1-yl) -methanesulfonyl) -4- (2-Methylphenyl) piperazine

The title compound is obtained by alkylation under reducing conditions 1 - ((7,7-dimethyl-2-endo- (2Samino-4- (methylsulfonyl) butyramido) -bicyclo- (2.2.1) -heptan-1-yl) -methanesulfonyl) - 4- (2-methylphenyl) -piperazine with 4-tetrahydropyranone as described in Example 68. The crude product is purified by flash column chromatography on silica gel using 2: 1 ethyl acetate-hexane as eluent. Two isomers of the title compound are obtained which differ in the ethoxycarbonyl substituent configuration (white amorphous compounds).

Isomer no. 1

163

The title compound is obtained by hydrolysis of the higher R _f isomer from Example 106. 1 - ((7,7-Dimethyl2-endo- (2s- (4-ethoxycarbonyl) cyclohexylamino-4- (methylsulfonyl) butyramide) -bicyclo- ( 2.2.1) heptan-1-yl) methanesulfonyl) -4- (2-methylphenyl) piperazine (50 mg;

0.071 mmol) was dissolved in THF (2 mL) containing 2 N NaOH (1 mL). The reaction mixture is stirred at room temperature for 2 days, citric acid is added to pH 3 and the product is extracted with ethyl acetate. The solvent is removed under reduced pressure to give the title compound (amorphous material).

Analysis: (C ₃₃ H ₅₂ N ₄ O ₇ S ₂ )

Calculated: C, 53.60; H, 7.27; N, 6.84

Found: C, 53.64; H, 7.15; N, 6.85

0.65 ethyl acetate, 0.95 CHCl ₃

TLC: R _f 0.44 (90: 10: 0.5 CHCl ₃ : MeOH: HOAc)

HPLC (method A): exit time 9.39 min, purity 99% FAB MS: m / z 781 (M + H ⁺ )

TABLE

In addition to the compounds exemplified, the compounds of the present invention are listed in the table below. These compounds have been synthesized using the synthesis procedures and techniques set forth above in the Schemes and Examples and their variations, which are well known to those skilled in the art and do not require too many additional experiments. All variable substituents are listed in the tables below in relation to the following general structural formula:

164

R ²

In this general structural formula, all values of V are for the substituted carbon atom at position 2 of the camphor ring, so that only two bonds are shown for the carbon atom mentioned in the table below, and the other two belong to the camphor ring. When only one bond is shown for this carbon atom, it should be understood that there is a double bond between the 2 and 3 positions on the camphor ring.

165

TABLE OF REPLACEMENTS, INDICATIONS V

C _n , OH

OH

ch ₃

166

TABLE (Continued)

O

167

TABLE (Continued)

168

TABLE (Continued)

O

169

TABLE (Continued)

O

170

TABLE (Continued) _< ch ₃ o

0 = /

OH

171

TABLE (Continued)

O

CH ₃

172

TABLE (Continued)

O

o o

ch ₃ h

173

TABLE (Continued)

NO '

OH

174

TABLE (Continued)

OH

O

175

The present invention also includes, but is not limited to, the following additional compounds:

176

177

EXAMPLE 109

RADIOLIGANDE CONNECTION TEST

High affinity [ ³ H] Oxytocin (OT) ([tyrosyl, 3.5 [ ³ H] OT; 30-60 Ci / mmol; New England Nuclear. Boston, MA) binds to uterine OT receptors based on assay (Fuchs, AR; F; Soloff, MS 1985 J. Clin. Endocrinol. Age 60:37) using an untreated uterine membrane preparation derived from rats treated with (0.3 mg / kg, ip; 18-24) diethylstilbestrol dipropionate (DES). . Performed analysis under competitive conditions (60 minutes; 22 ° C) using 1 nM i d-ίΙ OT

178 in assay buffer containing 50 mM Tris-HCl, 5 mM MgCl ₂ and 0.1% BSA, pH 7.4. Non-specific binding (10% of total binding) was assessed using lmM unlabeled OT and the binding reaction was stopped by filtration through a glass fiber filter using a cell harvester (Model 7019, Skatron, Ine., Sterling VA). The IC ₅₀ (concentration of test compound that inhibits OT by 50%) is given unless otherwise stated.

Binding of [ ³ H] Vasopressin (AVP) ([Phenylalanyl-3, 4, 5- ³ H] AVP; 8090 Ci / mmol; New England Nuclear) to Crude Membrane Preparation Derived from Male Rat Liver (AVP-V ₁ Links) ) or renal medulla (AVP-V ₂ links) were measured according to Butlen and at room temperature. (Butlen, D; Guillon, G; Rajerison, RM; Jard S; Sawyer, W. H; Manning, M. 1978 Mol. Pharmacol. 14: 1006).

The competitive assay was performed under equilibrium conditions (30 min at 30 ° C) using lnM [ ³ H] AVP (liver) or 2nM [ ³ H] AVP (kidney) in the following assay buffer: 100 mM Tris-HCl, 5 mM MgCl ₂ , 0.1% BSA, 50 mM phenylmethylsulfonyl fluoride and 50 mg / ml bacitracin, pH 8.0. Non-specific binding (5-10% of total binding) was evaluated using 10 mM unlabeled AVP and the binding reaction was stopped by filtration as described above for the [ ³ HJOT assay.

Κ ₃ values for each compound were determined from 3-6 IC ₅₀ measurements (Κ _± = IC ₅₀ / l + c / K _d ) (Cheng, YC; Prosoff, WH; 1973 Biochem Pharmacol 22: 3099) using the K _d values obtained. from binding to saturation test: [ ³ H] OT (uterus), 0.7 nM; [ ³ H] AVP (liver), 0.4 nM; [ ³ H] AVP (kidney), 1.4 nM.

179

IC ₅₀

1,000 nM

150 nM

180 nM nM

100 nM nM nM nM nM nM

48% inhibition at 100 nM 54 nM 23rd % inhibition at 100 nM 1 , 100 nM 44 % inhibition at 1,000 nM 64 % inhibition at 1,000 nM 36 % inhibition at 100 nM 75 % inhibition at 1,000 nM 31st % inhibition at 1,000 nM 72 % inhibition at 1,000 nM 38 % inhibition at 1,000 nM 78 % inhibition at 1,000 nM

0 nM

60 nM

34 % inhibition at 100 nM 3 5 n M n • -ί O < % inhibition at 100 nM

180

35 % inhibition at 100 nM 78 % inhibition at 1,000 nM 16th % inhibition at 10.00 nM

% inhibition at 10.00 nM

% inhibition at 1,000 nM 460 nM inhibition at 100 nM 7.7 nM 1.2 nM 5.4 nM % inhibition at 1,000 nM % inhibition at 1,000 nM 6.3 nM 9.2 nM 110 nM 26th nM 12th nM 20th nM 15th nM 30th nM ^25th nM % inhibition at 100 nM 38 nM % inhibition at 100 nM 28th nM 14th nM

nM

181

54 nM

66% inhibition at 100 nM

5 to 6 nM

While the invention has been described and illustrated by reference to certain more suitable examples, those skilled in the art will appreciate that various changes, modifications, and modifications may be made without departing from the spirit and scope of the invention. For example, due to differences in mammalian susceptibility to the compounds, other effective doses than those indicated above may be used to prevent preterm delivery or for other indications above. The specific pharmacological response may also vary with and depending on the active compound chosen, the presence of the pharmaceutical carrier, and the type of formulation or administration. Such expected variations or different results are considered to be consistent with the subject matter and practice of the present invention. It is desirable that the scope of the invention be limited to the claims of the invention as set forth below, and that these claims be interpreted as broadly as may be justified.

Claims (15)

DEFINITION OF INVENTION A compound of the formula R ² F R ¹¹ -Z or pharmaceutically acceptable salts thereof, wherein X is (1) C or (2) N; Y is (1) carbonyl or (2) sulfonyl; Z is a substituent which may or may not be present; when present, it is unsubstituted alkyl or alkyl substituted by carboxyl; R * is (1) hydrogen, (2) alkyl, or (3) NH; 183 R is hydrogen; R ¹ and R ² together form an alkyl bridge of three or four methylenes; R ³ and R ^{4 are} independently selected from one or more groups, including: (1) hydrogen, (2) halogen, (3) alkylsulfonyl, (4) alkoxy, (5) unsubstituted alkyl or alkyl substituted by hydroxy, alkoxy, alkylsulfonyl, amine, alkylamine or dialkylamine; R ⁵ and R ^{6 are} independently selected from one or more groups, including: (1) hydrogen, (2) alkyl, (3) alkyl substituted with an amine, hydroxy, alkoxy, alkylsulfonyl, arylsulfonyl, alkylamine or dialkylamine; (4) phenylalkyl or (5) oxo; R and R are independently selected from one or more groups, including: (1) hydrogen, (2) alkyl, 184 (3) combined to form an unchanged cycloalkyl substituted with hydroxyls alkyl; cycloalkyl; or or hydroxy R ⁹ and R ¹⁰ taken together form epoxy Z R ⁹ and R ¹⁰ independently of one another are made up of one or more groups, including: (i) hydrogen, (2) hydroxyl, (3) halogen, (4) oximino group, (5) methyl, (6) carboxyl, (7) oxo group, (8) alkoxycarbonyl, (9) alkylcarbonyloxy, (10) alkoxycarbonylalkoxy, (11) trihalogenalkylsulfonyloxy, (12) an unsubstituted amine or an amine substituted with one or several radicals, including alkyl, carboxy kilo or alkoxycarbonylalkyl; "11 R is (D hydrogen, (2) -N (R ¹² ) -CO-R ¹³ or (3) -CO-N (R ¹⁴ ) -R ¹⁵ ; _π 12 (1) hydrogen, 185 (2) alkoxy, (3) unsubstituted alkyl or alkyl substituted with one or more substituents including carboxyl, hydroxy, aloxy, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, (4) alkoxycarbonyl or (5) alkoxycarbonylamine; R is (1) hydrogen, (2) alkoxy, (3) arylalkoxy, (4) carboxyl, (5) alkoxycarbonyl, (6) alkoxycarbonylamine, (7) unsubstituted cycloalkyl or cycloalkyl substituted by carboxyl, (8) unsubstituted phenyl or phenyl , substituted with one or more substituents including carboxyl, carboxyalkyl or SO ₃ H, (9) an unsubstituted amine or an amine substituted with one or more substituents, including carboxyl, alkylsulfonyl or unsubstituted five-membered heterocyclic ring 1 or 2 heteroatoms, where the heteroatom is N, (10) heterocyclic rings optionally selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings containing 5, 6, 7 or 6 members in total and i, 2, 3 or 4 nitrogen heteroatoms; having a total of 5 or 6 members 186 and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent wherein said heterocyclic ring contains one or more radicals, including alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyanoalkyl, cyanoalkyl, cyano substituted amine wherein said substituent is one or more radicals including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; or (11) unsubstituted or substituted alkyl wherein said substituent is one or more radicals including hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl , alkylphenyl, carboxyalkylphenyl, cyano radical, sulfate, alkyl sulfonyl, acetamidine, formamidine, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkoxycarbonyl, halogen, thio, alkylthio radical, alkoxycarbonyl, alkoxycarbonylalkyl, Het or an unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahydropyranyl, tetratiapyranyl, tetratiapyranyl S-oxide, tetratiapyranyl S-dioxide, tetrahydrothia, , cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, sulfate, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted; 187 cyclic ring containing 1 or 2 heteroatoms and when said heteroatoms are N, Cyc is substituted or unsubstituted cycloalkyl, said substituent being selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het being heterocyclic rings selected from a group consisting of: unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 members in total and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings is one or more radicals including alkyl, amine, carboxyl, carboxyalkyl, arylalkyl, carboxyarylalkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aroxyalkyl, aroxy an oxo group, SO ₃ H, or an unsubstituted or substituted amine, said substituent being alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; ¹ 4 15 R * and R independently of one another are (1) hydrogen, (2) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydrogen, carboxyl, amine, aminoalkylamine, aminocarbonyl, hydroxyl, alkoxy, alkylthio, thioalkyl , alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl, or unsubstituted penLT 3592 B 188 cyano-saturated heterocyclic rings containing 1 or 2 heteroatoms, wherein said heteroatom is N is or (3) the heterocyclic rings are selected from the group consisting of unsubstituted or substituted saturated or substituted saturated or unsaturated rings having a total of 5, 6, 7 or 8 members and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms selected from the group consisting of N, O, S and said substituent being one or more radicals including alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; m and n are integers from 0 to 1. 2. A compound having the following general formula: R ² R ¹¹ -Z or pharmaceutically acceptable salts thereof, wherein X is (1) C or (2) N; 189 Y is (1) carbonyl, or (2) sulfonyl; Z is a substituent which may or may not be present; when present, it is unsubstituted alkyl or alkyl substituted by carboxyl; R is (1) hydrogen, (2) alkyl or (3) NH; R ² is hydrogen; R ¹ 2 and R together form an alkylene bridge of three or four methylenes; 3 4 R and R independently one or more groups, one from between them: of another is consisting of (1) hydrogen, (2) halogen, (3) alkylsulfonyl, (4) an alkoxy group, (5) unchanged or changed alkyl, when mentioned the substituent is amine, alkylamine or dialkyl- amine; R ⁵ and R ° independently one from of another is consisting of one or more groups, between them: 190 (1) hydrogen, (2) alkyl, (3) alkyl substituted with amino, alkylsulfonyl, arylsulfonyl, alkylamine or dialkylamine; (4) phenylalkyl or (5) oxo; R ⁷ and R ^{8 are} independently selected from one or more groups, including: (1) hydrogen, (2) alkyl, (3) taken together to form an unsubstituted cycloalkyl or cycloalkyl substituted with hydroxyl or hydroxy- alkyl; R ⁹ and R ¹⁰ taken together to form a cyclic epoxy; R ⁹ and R ^{10 are} independently selected from one or more groups, including: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) oximino, (5) methyl; (6) carboxyl, (7) oxo, (8) alkoxycarbonyl, (9) alkylcarbonyloxy, (10) alkoxycarbonylalkoxy, (11) sulfonyloxy; (12) trihalogenalkylsulfonyloxy, 191 (13) unsubstituted amine or amine substituted by alkoxycarbonyl kilo; R ^U is 5 (D hydrogen, (2) -N (R ^{9 * * 12} ) -CO-R ¹³ or (3) -CO-N (R ¹⁴ ) -R ¹⁵ ; _, 12 R is 10th (D hydrogen, (2) alkoxycarbonylamine, (3) alkyl or (4) alkylsulfonylalkyl; 15th R ¹³ is (D hydrogen, (2) alkoxy group, (3) arylalkoxy, (5) alkoxycarbonyl, 20th (6) alkoxycarbonylamine, (7) unmodified or modified i mas the substituent is carboxyl, (8) unchanged or modified Substituent 25 is one or more radicals including carboxyl, carboxyalkyl or SO ₃ H, (9) an unsubstituted or substituted amine when said substituent is unsubstituted or substituted alkyl, wherein the substituent ¹ is one or more radicals, including carboxyl, alkylsulfonyl or an unsubstituted five-membered heterocyclic ring containing 1 or 2 heteroatoms, said heteroatom being N, 192 (10) heterocyclic rings optionally selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having a total of 5, 6, 7 or 8 members and 1, 2, 3 or 4 N heteroatoms; having 5 or 6 members in total and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings is one or more radicals including alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, arylalkyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyano-sulfonyl, cyano-sulfonyl, wherein said substituent is one or more radicals, including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (11) unsubstituted or substituted alkyl, wherein said substituent is one or more radicals including hydroxyl, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyalkyl , cyano radical, sulfate, alkylsulfonyl, acetamidine, formamidine, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkoxycarbonyl, halogen, thio, alkylthio radical, alkoxycarbonyl, alkoxycarbonylalkyl, Het or unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahydropyranyl, tetratiapyranyl, tetratiapyranyl S-oxide, tetratiapyranyl S-dioxide, tetrahydrothiapyranyl, , hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, sulfate, carboxyl, alkylsulfonyl, karLT 3592 B 193 boxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenylalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a 5-membered heterocyclic ring substituted with 1 or 2 heteroatoms and substituted with 1 or 2 heteroatoms; when said substituent is selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolinyl, Het is a heterocyclic ring selected from the group consisting of: unsubstituted or substituted saturated or unsaturated rings having 5, 6, 7 or 8 members and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms from the group consisting of N, O, S; wherein said substituent on any of said heterocyclic rings is one or more radicals including alkyl, amine, carboxyl, carboxyalkyl, arylalkyl, carboxyarylalkyl, alkoxycarbonyl, substituted haloalkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aroxyalkyl, aryloxyalkyl, an oxo group, SO ₃ H, or an unsubstituted or substituted amine, said substituent being alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; 14 15 R and R independently of one another are (1) hydrogen, (2) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydrogen, carboxyl, amine, aminoalkylamine, amine 3592 B 194 nocarbonyl, hydroxyl, alkoxy, alkylthio, thioalkyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenylalkyl, hydroxyphenalkyl, or unsubstituted five-membered saturated heterocyclic rings containing 1 or 2 heteroatoms, heteroatoms, a group containing unsubstituted or substituted rings having 5, 6, 7 or 8 members in total and 1, 2, 3 or 4 N heteroatoms; having a total of 5 or 6 members and 1 or 2 O heteroatoms; having a total of 5 or 6 members and a 1 S heteroatom; or having a total of 6 members and two different heteroatoms selected from the group consisting of N, O, S and said substituent being one or more radicals including alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; and m and n are integers from 0 to 1. A compound having the formula CH h ₃ g ...... SO 195 or a pharmaceutically acceptable salt thereof, wherein R ¹ is (1) hydrogen, (2) alkoxycarbonyl, (3) alkyl; _π 2 R is (1) hydrogen, (2) alkoxyl, (3) arylalkoxyl, (4) alkoxycarbonyl, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl, said substituent being carboxyl, (7) unsubstituted or substituted phenyl, substituent or multiple substituents on the group, carboxyl, carboxyalkyl, or SO ₃ H, wherein said substituent is (8) unsubstituted or substituted, wherein said substituent is unsubstituted or substituted alkyl, including carboxyl, alkylsulfonyl or unsubstituted pentane a heterocyclic ring containing 1 or 2 heteroatoms when the heteroatom is N, (9) unsubstituted or substituted rings having the formula 196 wherein said substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo, or an unsubstituted or substituted substituent, wherein the substituent is one or more alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkoxyl, arylalkoxy, , Het or an unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, amin carbonylalkyl, alkylaminocarbonyl, phenylalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a five-membered heterocyclic ring containing 1 or 2 heteroatoms and wherein said heteroatoms are N, Cyc is substituted or unsubstituted cycloalkyl, said substituent being selected from the group consisting of carboxylcarbonyl; , hydroxyl, oxo or spiro-dioxo 3592 B 197 solinyl, Het are unsubstituted or substituted rings of the formulas below when the substituent is one or more radicals including alkyl, amine, carboxyl, carboxyalkyl, carboxyarylalkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkyl, , alkoxycarbonyl, oxo, SO3H, or an unsubstituted or substituted amine, said substituent being one or more radicals including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. A compound of the formula 198 or a pharmaceutically acceptable salt thereof R ¹ is present (D hydrogen, (2) alkoxycarbonyl, (3) alkyl; R ² is present (D hydrogen, (2) alkoxyl, (3) arubaxyl, (4) alkoxycarbonyl, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl when the substituent is carboxyl, (7) unsubstituted or substituted phenyl, a substituent or several substituents being from the group, carboxyl, carboxyalkyl or SO ₃ H, when mentioned which contains (8) unchanged or substituted amine is unchanged or substituted when mentioning pa- alkyl in which is one or more substituents including carboxyl, alkylsulfonyl or an unsubstituted five-membered heterocyclic ring containing 1 or 2 heteroatoms when the heteroatom is N, (9) unsubstituted or substituted rings of the formula Dec. 199 Q.S. O < ς * ° when said substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo or mono-substituted or unsubstituted amine, among them alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unsubstituted or substituted alkyl, said substituent being one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, , alkoxycarbonylalkyl, Het or an unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, amino arbonylalkyl, alkylaminocarbonyl, phenylalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a five-membered heterocyclic ring containing 1 or 2 heteroatoms and said heteroatoms being N, Het being unsubstituted or substituted rings of the formula wherein said substituent is one or more radicals including alkyl, amino, carboxyl, carboxyalkyl, karboksiarilalkilas, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoksialkoksialkoksialkilas, arilalkilakarbonilas, arylalkoxyalkyl, aralkoxycarbonyl, oxo, SO ₃ H or an unsubstituted or substituted amino as mentioned in the substituent is composed of one or several radicals, including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. A compound of the formula or a pharmaceutically acceptable salt thereof, wherein 201 R ¹ is present (1) hydrogen, (2) alkoxycarbonyl, (3) alkyl; R ² : is (D hydrogen, (2) alkoxyl, (3) arylalkoxyl, (4) alkoxycarbonyl, (5) alkoxycarbonylamine (6) unsubstituted or substituted cycloalkyl when said substituent is carboxyl, (7) unsubstituted or substituted phenyl where said substituent or substituents are from the group consisting of carboxyl, carboxyalkyl or SO ₃ H, (8) unsubstituted or substituted amine, wherein said substituent is unsubstituted or substituted alkyl containing one or more substituents, including carboxyl, alkylsulfonyl or unsubstituted five-membered heterocyclic ring containing 1 or 2 heteroatoms, where the heteroatom is N, (9) unsubstituted or substituted rings of formula O s. 202 when said substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted one or more of the substituents substituted alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl, or (10) unsubstituted or substituted alkyl wherein said substituent is composed of one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, , Het or an unsubstituted or substituted amine wherein said substituent is one or more radicals including alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminocarb bonylalkyl, alkylaminocarbonyl, phenylalkyl, or unsubstituted or substituted alkylcarbonyl, said substituent being a five-membered heterocyclic ring containing 1 or 2 heteroatoms and said heteroatoms being N, Het being unsubstituted or substituted rings of the formula wherein said substituent is one or more radicals , including alkyl, amine, carboxyl, carboxyalkyl, 203 carboxyarylalkyl, alkoxycarbonyl, halogen-substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, arylalkylacarbonyl, arylalkoxyalkyl, arylalkoxycarbonyl, oxo, SO ₃ H or unsubstituted or substituted aromatic, or alkoxycarbonylalkyl. A compound of the formula or a pharmaceutically acceptable salt thereof, wherein R ¹ is (1) hydrogen, (2) alkoxycarbonyl, (3) unsubstituted or substituted alkyl, said substituent being hydroxyl, alkoxyl, carboxyl, carboxyalkyl, alkylsulfonyl or alkoxycarbonyl; R is (1) hydrogen, (2) alkoxyl, (3) arylalkoxyl, 204 (4) alkoxycarbonyl, (5) alkoxycarbonylamine, (6) unsubstituted or substituted cycloalkyl, said substituent being carboxyl, ( 7) unsubstituted or substituted phenyl, said substituent or substituents being from the group consisting of carboxyl, carboxyalkyl or SO ₃ H, (8) unsubstituted or substituted amine, said substituent being unsubstituted or substituted alkyl containing one or more substituents , including carboxyl, alkylsulfonyl or an unsubstituted five-membered heterocyclic ring containing 1 or 2 heteroatoms when the heteroatom is N, (9) unsubstituted or substituted rings of the formula wherein said substituents are one or more radicals including alkyl, carboxyl, carboxyalkyl, carboxyarylalkyl, arylalkylcarbonyl, arylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted amine, said substituent being one or more radicals including alkyl, carboxyalkyl, alkoxycarbonyl or alkoxy 205 (10) alkyl, unsubstituted or substituted, said substituent being one or more radicals including hydroxyl, carboxyl, carboxyalkylphenyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, arylalkyl, arylalkoxycarbonyl, halo, alkoxycarbonyl, alkoxycarbonylalkyl, substituted or unsubstituted alkyl; wherein said substituent is one or more radicals, including alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, Cyc, alkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenylalkyl, or an unsubstituted or substituted alkylcyclo ring, 2 heteroatoms, and when said heteroatoms are N, Cyc is substituted or unsubstituted cycloalkyl, said substituent selected from the group consisting of alkoxycarbonyl, carboxyl, hydroxyl, oxo or spirodioxolinyl, Het being unsubstituted or substituted Ieda having the formula shown below with a mention of the substituent is one or more radicals such as alkyl, amino, carboxyl, carboxyalkyl, karboksiarilalkilas, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoksialkoksialkoksialkilas, heterocyclylalkyl, arylalkoxyalkyl ¹ arilalkokLT 3592 B 206 sikarbonilas, oxo, SO ₃ H or an unsubstituted or substituted amino where the substituent is mentioned consists of one or more radicals such as alkyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. or a pharmaceutically acceptable salt thereof. A compound of the formula or a pharmaceutically acceptable salt thereof. The sulfate salt of the compound of claim 8. 207 The tartrate salt of the compound of claim 8. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, characterized in that 5 comprising a compound according to claim 1. Use of a compound according to claim 1 for the manufacture of a medicament for antagonizing oxytocin binding to its receptor binding sites in mammalian biological systems. Use of a compound according to claim 1 for the manufacture of a medicament for the prevention of preterm labor. Use of a compound according to claim 1 for the manufacture of a medicament for stopping delivery before cesarean section. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of dysmenorrhea.