Substituted spirocyclic cgrp receptor antagonists

sensory cells of the trigeminal ganglion that contain several neuropeptides, including CGRP. Stimulation of the trigemine ganglion in cats results in increased levels of CGRP, and in men activation of the trigemine system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al. , Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the dura in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP (837), a peptide CGRP antagonist (Williamson et al. Cephalgia, 1997, 17, 525-531). Stimulation of the trigeminal ganglion increased facial blood flow in rats, which was inhibited by CGRP (8-37) (Escott et al. Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmosets produced increased facial blood flow which could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. L Pharmacol., 2000, 129, 420- 423). Thus the vascular effects of CGRP can be attenuated, prevented or reversed by an antagonist of CGRP.

CGRP-induced vasodilation of the rat middle meningeal artery has been shown to sensitize neurons of the lower meninge nucleus (Williamson et al. The CGRP Family: Calcitonin Gene-Related Peptid (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Likewise, distension of dural blood vessels during migraine headache could sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extracranial pain and facial allodynia, could be the result of sensitized trigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as antagonists of CGRP makes them useful pharmacological agents for disorders which involve CGRP in humans and animals, but particularly humans. Such disorders include migraine and periodic vascular headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 12611268; Edvinsson et al. Cephalalgia, 1994, 14, 320-327); chronic tension headache (Ashina et al .. Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al .. Pain, 2000, 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988, 24, 739-768; Delay-Goyet et al .. Acta Physiol. Scanda. 1992, 146, 537-538; Salmon et al .. Nature Neurosci., 2001, 4 (4), 357-358); eye pain (May et al. Cephalalgia, 2002, 22, -195-196), dental pain (Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin-dependent diabetes (Molina et al. Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al. Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404,; Schini et al. . Am. I. Physiol., 1994, 267, Η2483-Η2490; Zheng et al., J. Virol, 1993, 67, 57865791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794-1798); syndrome

<img file="MA30558B1_D0001.tif" />

opioid withdrawal (Salmon et al .. Nature Neurosci., 2001, 4 (4), 357-358); morphine tolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143);

psoriasis; encephalitis, brain trauma, ischemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al .. Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Gepp etti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic skin redness, skin pinkness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189 (3), 225); inflammatory bowel disease, irritable bowel syndrome (Hoffman et al. Scandinavian Journal of Gastroenterology, 2002, 37 (4) 414422) and cystitis. Acute or prophylactic treatment of headache, including migraine and periodic vascular headache is particularly important.

The present invention relates to compounds which are useful as ligands for CGRB receptors, in particular to antagonists for CGRP receptors, to processes for their preparation, to their use in therapy, to pharmaceutical compositions comprising the same and to methods of therapy. using those.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

<img file="MA30558B1_D0002.tif" />

دب حم α²--α⁴ (I) (in which the variables A ', A², AT³, AT⁴, m, n, J, Q, R⁴, E^at, E^b, E^vs, R⁶, R? ١ R ؟, R٢, rPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of those diseases in which CGRP is involved.

-3 DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula I:

AT2.٨4

4٥١ t

<img file="MA30558B1_D0003.tif" />

in which :

Al is chosen from:

(1) -O-, (2) -S (O) y-, (3) _SÎ (OR^at) -C14alkyl-, where the alkyl is unsubstituted or substituted with 1 to 5 halo, (4) -Si (Calkyl) 2, where each alkyl is independently unsubstituted or substituted by 1 to 5 halo-, (5) -CRR- , (6) -N (R؟) _, (7) - (CO) -, (8) -CRR) -, (9) -C (NR٥) -SO2R٥) R) -, (10) -C ( N (R٥) (CO) R^at) (R^at) -, (11) -C (N (R^b) (C = O) OR^at) (R^at) -, (12) -CR٠٥R٠٠-, and (13) -N (R))) - ؛

AT² is chosen from:

(1) -CRR-, (2) -CR٥ ؛ R '؛ -, and (3) - (C = O) -;

AT³ is chosen from:

<td> (1)</td><td>-CR٥R? -١</td>

<td> (2)</td><td>-NR) -,</td>

<td> (3)</td><td>-CRR) '-, and</td>

<img file="MA30558B1_D0004.tif" />

TITLE OF THE INVENTION 0 009? ؛! لال ا

Spirocyclic substituted antagonists of CGRP receptors

BACKGROUND OF THE INVENTION

CGRP (calcitonin gene-related peptide) is a naturally occurring 37 amino acid peptide that is generated by tissue-specific alternative processing of calcitonin messenger RNA and is widely distributed throughout the central and peripheral nervous system. . CGRP is predominantly localized in central and afferent sensory neurons and regulates several biological actions, including vasodilation. The

CGRP is expressed in alpha and beta forms which vary from one and three amino acids in rats and humans, respectively. CGRP-alpha and CGRP-beta show similar biological properties. When released from the cell, CGRP elicits its biological responses by binding to specific cell surface receptors which are predominantly coupled to adenylyl cyclase activation. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of cerebral, cardiovascular, endothelial, and smooth muscle origin.

On the basis of pharmacological properties, these receptors are divided into at least two subtypes, denoted CGRPi and CGRP ؛. A fragment of CGRP lacking seven N-terminal amino acid residues, human α-CGRP- (8-37), is a selective antagonist of. CGRP], while the linear analogue of CGRP, diacetoamidomethyl cysteine ​​CGRP ([Cys (ACM) 2,7] CGRP), is a selective agonist of CGRP ؛. CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and periodic vascular headache. In clinical studies, elevated levels of CGRP in the jugular vein have been observed during migraine attacks (Goadsby et al., Ann.

Neurol., 1990, 28, 183-187), salivary levels of CGRP are elevated in subjects suffering from migraines between attacks (Bellamy et al. Headache, 2006, 46, 24-33), and it has been demonstrated that CGRP itself triggered migraine headaches (Lassen et al., Cephalagia, 2002, 22, 54-61). In clinical trials, the CGRP antagonist BI13N4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al., New Eng. J. Med.; 2004,

350, 1104-1110) and was able to prevent the headache induced by CGRP Infusion in a control group (Petersen et al. Clin. Pharmacol. Ther., 2005, 77, 202-213).

CGRP-regulated activation of the trigeminovascular system may play an essential role in the pathogenesis of migraine. In addition, CGRP activates receptors on smooth muscle of intracranial vessels, resulting in increased vasodilation, which is believed to contribute to the disease. of head during migraine attacks (Lance, Headache Pathogenesis: -Monoamines, Neuropeptides, Purines and Nitri: Oxide, Lippincott-Raven Publishers, 1997. 3-9). The middle meningeal artery, the princhde artery in the dura, is innervated by fibers

إرتج (1) hydrogen, (2) -c ؛ alkyl, which is unsubstituted or substituted by 1 to 6 halo, (3) halo, (4) -ORet (5) -CN;

R⁶ and R? are each independently selected from:

(1) hydrogen, (2) -Ci-kle, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

(a) halo, (b) -OR (c) -C3cycloalkyl, (d) phenyl or heterocycle, in which said heterocycle is selected from:

pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl, indolyl, indazolyl, benzimidazolyl, and oxazolyl, which each phenyl or heterocycle is unsubstituted or substituted by 1 to 5 substituents independently:

(i) halo, (ii) -C alkyl, which is unsubstituted or substituted by 1 to 5 halo, (iii) -OR٥, (iv) RR, (V) -CN, and (vi) 0X0 ؛ (e) -C (R, (f) -C (= O) NRR, (g) -S (O) vR٩ (h) -CN, (i) RR, (j) -N (R^b) C (= 0) R٥, (k) -NR) SO2R٥, (l) -CF3, (m) -O-CO2R٥, (n) -O- (C = O) -NR^bRC, (o) -NR^b- (CO) -NR^bR٥, and (P) -C (= O) R٥, (3) -C3.scycloalkyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

أكع

<img file="MA30558B1_D0005.tif" />

<td></td><td>(at)</td><td>halo.</td>

<td></td><td>(b)</td><td>-CN,</td>

<td></td><td>(ء)</td><td>-Calkyl, which is not substituted or substituted by 1 to 3 halo, and</td>

<td></td><td>(d)</td><td>-GOLD</td>

<td> 5</td><td colspan="2">(4) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl.</td>

pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidine, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl OR heterocycle is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

<td> 10</td><td></td><td>(at)</td><td>halo.</td>

<td></td><td></td><td>(b)</td><td>-GOLD^at,</td>

<td></td><td></td><td>(vs)</td><td>-C3-6cycloalkyl,</td>

<td></td><td></td><td>(d)</td><td>phenyl, which is unsubstituted or substituted with 1 to 5 substituents each</td>

<td></td><td></td><td></td><td>independently selected from:</td>

<td> 15</td><td></td><td></td><td>(i) halo.</td>

<td></td><td></td><td></td><td>(ii) -c alkyl, which is unsubstituted or substituted by 1 to 6 halo, and</td>

<td></td><td></td><td></td><td>(iii) -OR^at,</td>

<td></td><td></td><td>(e)</td><td>-C0₂R^at,</td>

<td></td><td></td><td>(f)</td><td>-CONRR,</td>

<td> 20</td><td></td><td>(g)</td><td>-S (O) R,</td>

<td></td><td></td><td>(h)</td><td>-CN,</td>

<td></td><td></td><td>(i)</td><td>-NRR,</td>

<td></td><td></td><td>(j)</td><td>-N (RC (O) R^at,</td>

<td></td><td></td><td>(k)</td><td>-N (R^b) SO₂R٥,</td>

<td> 25</td><td></td><td> (1)</td><td>-O-CCR,</td>

<td></td><td></td><td>(m)</td><td>-O- (CO RR,</td>

<td></td><td></td><td>(not)</td><td>-NR^b- (C = O) -NR٥R٠,</td>

<td></td><td></td><td>(o)</td><td>-HORN^at,</td>

<td></td><td></td><td>(P)</td><td>-Ci-6alkyl, which is unsubstituted or substituted by 1 to 6 halo, and</td>

<td> 30</td><td></td><td>(g)</td><td>oxo;</td>

<td></td><td> (5)</td><td>halo.</td><td></td>

<td></td><td> (6)</td><td>-GOLD</td><td></td>

<td></td><td> (7)</td><td>-CN,</td><td></td>

<td></td><td> (8)</td><td colspan="2">-GOLD</td>

<td> 35</td><td> (9)</td><td colspan="2">-N (R^b) C (= O) R^at,</td>

<td></td><td> (10)</td><td>-NRR</td><td>vs</td>

<td></td><td> (11)</td><td colspan="2">-C (= O) NR R, and</td>

<td></td><td> (12)</td><td>-O (C =</td><td>0) R^at;</td>

- ٦158 or R⁶ and R⁷ and the atom or carbon atoms to which they are attached assemble to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxanyl, dioxanyl , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofiiranyl, tetrahydropyranyl, tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

(a) (b)

(ء)

-Calkyl, which is unsubstituted or substituted with 1 to 3 substituents each independently selected from:

<td>(i)</td><td>halo.</td>

<td>(ii)</td><td>-OR٥,</td>

<td>(iii)</td><td>-C3.٥cycloalkyl,</td>

<td>(iv)</td><td>-C0₂R^at,</td>

<td>(V)</td><td>-NR^bRC,</td>

<td>(vi)</td><td>-S (O) R,</td>

<td>(vii)</td><td>-C (= 0) RR, and</td>

<td>(viii)</td><td>phenyl.</td>

-C3.6cycloalkyl, wherein the C3.6cycloalkyl group is optionally fused to the ring, and which C3.6 cycloalkyl group is unsubstituted or substituted with 1 to 3 substituents each independently selected from:

<td>(i)</td><td>halo.</td>

<td>(ii)</td><td>-GOLD^at,</td>

<td>(iii)</td><td>-C3.6Cycloalkyl,</td>

<td>(iv)</td><td>-CCR,</td>

<td>(V)</td><td>-NR^bR٥,</td>

<td>(vi)</td><td>-S (O) R,</td>

<td>(vii)</td><td>-C (= O) NR R, and</td>

<td>(viii)</td><td>phenyl.</td>

phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, imidazolyl, furanyl, tetrahydrofiranyl, thiazolyl and oxazolyl, in which the heterocycle is or optionally fused with heterocycle with or optionally fused with the heterocycle, piperazinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, imidazolyl, furanyl, tetrahydrofiranyl, thiazolyl and oxazolyl! the nucleus, and which phenyl

-83Ό§58

OR heterocycle is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

<td></td><td></td><td>(i) halo.</td>

<td></td><td></td><td>(ii) -Calkyl, which is unsubstituted or substituted by 1 to 5 halo.</td>

<td> 5</td><td></td><td>(iii) -OR “,</td>

<td></td><td></td><td>(iv) -CCR *,</td>

<td>ا</td><td></td><td>(V) -O (C = O) R^at,</td>

<td></td><td></td><td>(vi) -CN,</td>

<td></td><td></td><td>(vii) -NR٥R٠,</td>

<td> 10</td><td></td><td>(viii) oxo.</td>

<td></td><td></td><td>(ix) -C (0) RR,</td>

<td></td><td></td><td>(x) -N (R٥) C (= O) R٥,</td>

<td></td><td></td><td>(xi) -N (R٥) CÛ2R٥,</td>

<td></td><td></td><td>(xii) -0 (C0) NRR, and</td>

<td> 15</td><td></td><td>(xiii) -S (OR,</td>

<td></td><td>(d)</td><td>-GOLD",</td>

<td></td><td>(e)</td><td>-CO₂R١</td>

<td></td><td>(f)</td><td>-C (= O) NRR,</td>

<td></td><td>(g)</td><td>-S (OR٥,</td>

<td> 20</td><td>(h)</td><td>-CN,</td>

<td></td><td>(i)</td><td>halo.</td>

<td></td><td>G)</td><td>-NRR,</td>

<td></td><td>(k)</td><td>-N (R^b)HORN^at,</td>

<td></td><td> (1)</td><td>-N (R^b) S٠2R٥,</td>

<td> 25</td><td>(m)</td><td>-O-COR,</td>

<td></td><td>(not)</td><td>-O- (C = O) -NRR,</td>

<td></td><td> (0)</td><td>-NR^b- (C = O) -NRR,</td>

<td></td><td>(P)</td><td>-COR, and</td>

<td></td><td>(q)</td><td>oxo;</td>

<td colspan="2">30 R⁸ is independently selected from</td>

<td> (1)</td><td>hydrogen.</td>

<td> (2)</td><td>-C (= O) R^at,</td>

<td> (3)</td><td> -0“,</td>

<td> (4)</td><td>-S (= O) R٥,</td>

<td> 35 (5)</td><td>-SO₂R٥,</td>

<td> (6)</td><td>-C (= O) NRR,</td>

-9Calkyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

<td></td><td>(at)</td><td>halo.</td>

<td></td><td>(b)</td><td>-GOLD^at,</td>

<td> 5</td><td>(vs)</td><td>-Ccycloalkyl,</td>

<td></td><td>(d)</td><td>phenyl or heterocycle, in which said heterocycle is chosen from:</td>

<td></td><td></td><td>pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl.</td>

<td></td><td></td><td>piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and</td>

<td></td><td></td><td>oxazolyl, which phenyl or heterocycle is not substituted or substituted by</td>

<td> 10</td><td></td><td>1 to 5 substitutes each independently chosen from:</td>

<td></td><td></td><td>(i) halo.</td>

<td></td><td></td><td>(ii) -Calkyl, which is unsubstituted or substituted by 1 to 5 halo, and</td>

<td></td><td></td><td>(iii) -OR^at,</td>

<td></td><td></td><td>(iv) -NRR,</td>

<td> 15</td><td></td><td>(v) -C (= O) R٥,</td>

<td></td><td></td><td>(vi) -ORa and</td>

<td></td><td></td><td>(vii) oxo.</td>

<td></td><td>(e)</td><td>-C0₂R^at,</td>

<td></td><td>(f)</td><td>-C (= O) NRR,</td>

<td> 20</td><td>(g)</td><td>-S (O) R,</td>

<td></td><td>(h)</td><td>-CN,</td>

<td></td><td>(i)</td><td>-RR,</td>

<td></td><td> 0)</td><td>-N (R٥) C (= O) R٥,</td>

<td></td><td>(k)</td><td>-N (R٥) SO₂R٥,</td>

<td> 25</td><td> (1)</td><td>-CF3,</td>

<td></td><td>(m)</td><td>-O-COR,</td>

<td></td><td>(not)</td><td>-O- (C = O) -NRR,</td>

<td></td><td>(O)</td><td>-NR٥- (C = O) -NRR, and</td>

<td></td><td>(p)</td><td>-C (= O) R3,</td>

<td> 30</td><td colspan="2">(8) -Ccycloalkyl, which is unsubstituted or substituted with 1 to 6 substituents each</td>

<td></td><td colspan="2">independently selected from:</td>

<td></td><td>(at)</td><td>halo.</td>

<td></td><td>(b)</td><td>-CN,</td>

<td></td><td>(ء)</td><td>-OR and</td>

(d)

Cjalkyl, which is unsubstituted or substituted by 1 to 6 halo;

or R⁷ and R⁸ and the atoms to which they are attached join together to form a 4, 5, 6 or 7 membered alkyl or heteroalkyl ring optionally containing a heteroatom

Additional -10158 selected from N, O, and s, wherein the sulfur is optionally oxidized to sulfone or sulfoxide, which ring is unsubstituted or substituted with 1 to 4 substituents each independently selected from:

<td></td><td>(at)</td><td>halo.</td>

<td> 5</td><td>(b)</td><td>phenyl, which is unsubstituted or substituted with 1 to 3 substituents each</td>

<td></td><td></td><td>independently selected from: halo, OR٥, CN, and -C (= O) OR٥,</td>

<td>ا</td><td>(vs)</td><td>-OR٥, and</td>

<td></td><td>'(d)</td><td>-Cl 6alkyl, which is unsubstituted or substituted with 1 to 6 halo;</td>

R is independently selected from:

(1) hydrogen.

(2) -C alkyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

(a) halo, (b) -OR (c) -CN, (d) phenyl, and (e) Ccycloalkyl, which is unsubstituted or substituted with 1 to 6 halo.

(3) -Ccycloalkyl, which is unsubstituted or substituted with 1 to 6 halo;

R is independently selected from the group comprising:

phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofiranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzoxyrazol benzothiazol, benzazothiazol, benzazothiazol benzazothyl, benzazothiazol benzazothyl, benzazothiazol benzazothyl, benzaziazol benzazothyl, benzazothiazol chromanyl, cinnolinyl, dibenzofiranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthiazolyl, oxadiazolyl, 2-0X0X0azepinyl, 4-oxonaphthyridinyl, 2-oxonaphthyridinyl, 2-oxipyroxylidopolidoxylinyl, 4-oxonaphthyrididoxylinyl, 2-oxonaphthyridinyl, 2-oxonaphthyridinyl, 2-oxopolidoxinolidoxyl oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuanyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulphoxide, thiamorpholinyl sulphone, thiazolyl, thiazolinyl, thienothoxiaziirazenyl, thienothoxiazenylhydryl, thienothoxiaziirazenyl, thienothoxiazenazenyl, thienoxiaziirazenyl, thienoxiaziirazenyl

ء رأي

36558 tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, where R '' is unsubstituted or substituted with 1 to 5 substituents each independently selected from R¹², R '², R¹⁴, R٠5a and R'5٥;

R '², R '², R '⁴, R'5a and R5 ؛ b are each independently selected from:

(1) -C 1-6alkyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

<td></td><td>(at)</td><td>halo.</td>

<td></td><td>(b)</td><td>-OR®,</td>

<td> 10</td><td>(vs)</td><td>C-ecycloalkyl,</td>

<td></td><td>(d)</td><td>phenyl or heterocycle, in which said heterocycle is chosen from:</td>

<td></td><td></td><td>pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl.</td>

<td></td><td></td><td>piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and</td>

<td></td><td></td><td>oxazolyl, which phenyl or heterocycle is unsubstituted or substituted by</td>

<td> 15</td><td></td><td>1 to 5 chacin substituents independently selected from:</td>

<td></td><td></td><td>(i) halo.</td>

<td></td><td></td><td>(ii) -Ci.6alkyl, which is unsubstituted or substituted with 1 to 5 halo, and</td>

<td></td><td></td><td>(iii) -OR®,</td>

<td></td><td>(e)</td><td>-CR®,</td>

<td> 20</td><td>(f)</td><td>-C (= O) NRR,</td>

<td></td><td>(g)</td><td>-S (O) R٥,</td>

<td></td><td>(h)</td><td>-CN,</td>

<td></td><td>(i)</td><td>-RR٥,</td>

<td></td><td> 0)</td><td>-NR) C (= O) R®,</td>

<td> 25</td><td>(k)</td><td>-N (R^b) S0₂R^d,</td>

<td></td><td> (1)</td><td>-CF3,</td>

<td></td><td>(m)</td><td>-O-CO2R٥,</td>

<td></td><td>(not)</td><td>-O- (C = O) -NRR,</td>

<td></td><td> (٥)</td><td>-R- (C = O) -NRR, and</td>

<td> 30</td><td>(P)</td><td>-C (= O) R®,</td>

<td></td><td>(2) -Cl-</td><td>scycloalkyl, which is unsubstituted or substituted with 1 to 5 substituents each</td>

<td></td><td colspan="2">independently selected from:</td>

<td></td><td>(at)</td><td>halo.</td>

<td></td><td>(b)</td><td>-CN,</td>

<td> ٦5</td><td>(vs)</td><td>-Ci.6alkyl, which is unsubstituted or substituted with 1 to 5 halo.</td>

<td></td><td>(d)</td><td>-OR®, and</td>

إكز

-12158

<td></td><td></td><td>(e)</td><td>phenyl, which is unsubstituted or substituted by 1 to 5 substituents where the</td>

<td></td><td></td><td colspan="2">substituents are each independently selected from:</td>

<td></td><td></td><td></td><td>(i) -OR®,</td>

<td></td><td></td><td></td><td>(ii) halo.</td>

<td> 5</td><td></td><td></td><td>(iii) -CN, and</td>

<td></td><td></td><td></td><td>(iv) -C alkyl, which is not substituted or substituted by 1 to 5</td>

<td>I</td><td></td><td></td><td>halo.</td>

<td></td><td>زل)</td><td colspan="2">phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl.</td>

<td></td><td></td><td colspan="2">pyrimidinyl, pyrazinyl, pyridazinyl, pipérdinyl, piperazinyl, pyrrolidinyl.</td>

<td> 10</td><td></td><td colspan="2">thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is</td>

<td></td><td></td><td colspan="2">not substituted or substituted with 1 to 5 substituents each independently selected</td>

<td></td><td></td><td>among</td><td> ٠</td>

<td></td><td></td><td>(at)</td><td>halo.</td>

<td></td><td></td><td>(b)</td><td>-OR®,</td>

<td> 15</td><td></td><td>(vs)</td><td>-C3.6cycloalkyl,</td>

<td></td><td></td><td>(d)</td><td>phenyl, which is unsubstituted or substituted with 1 to 5 substituents each</td>

<td></td><td></td><td></td><td>independently selected from:</td>

<td></td><td></td><td></td><td>(i) halo.</td>

<td></td><td></td><td></td><td>(ii) -c alkyl, which is unsubstituted or substituted by 1 to 6 halo, and</td>

<td> 20</td><td></td><td></td><td>(iii) -OR®,</td>

<td></td><td></td><td>(e)</td><td>-OR®,</td>

<td></td><td></td><td> ٠)</td><td>-C (= O) NRR,</td>

<td></td><td></td><td>(g)</td><td>-S (O) R,</td>

<td></td><td></td><td>(h)</td><td>-CN,</td>

<td>5 إ</td><td></td><td>(i)</td><td>-NRR,</td>

<td></td><td></td><td>G)</td><td>-N (R٥) C (= O) R®,</td>

<td></td><td></td><td>(k)</td><td>-NR) S0R,</td>

<td></td><td></td><td>(I)</td><td> -</td>

<td></td><td></td><td>(m)</td><td>-O- (C = O) -NRR,</td>

<td> 30</td><td></td><td>(not)</td><td>-NR٥- (C = O) -NRR,</td>

<td></td><td></td><td> (٥)</td><td>-C (= O) R®, and</td>

<td></td><td></td><td>(P)</td><td>-c alkyl, which is not substituted or substituted by 1 to 6 halo.</td>

<td></td><td> (4)</td><td>halo.</td><td></td>

<td></td><td> (5)</td><td>oxo.</td><td></td>

<td> 35</td><td> (6)</td><td>-GOLD^at,</td><td></td>

<td></td><td> (7)</td><td>-CN,</td><td></td>

<td></td><td> (8)</td><td>-GOLD</td><td></td>

<td> (9)</td><td>-C (= O) R®,</td>

<td> (10)</td><td>-NRR,</td>

<td> (11)</td><td>-S (O) R,</td>

<td> (12)</td><td>٠C (= O) NR^bRC,</td>

<td> (13)</td><td>-O-COR,</td>

<td> (14)</td><td>-N (R^b) CO2R٥,</td>

<td> (15)</td><td>-o- (c = o) -rR,</td>

<td> (16)</td><td>-N- (O) -NRR,</td>

<td> (17)</td><td>-SOzNRR,</td>

<td> (18)</td><td>-N (Rb) SO2R٥,</td>

<td>or R٠5®</td><td>and R ؛ and the atom or:</td>

atoms to which they are attached assemble to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl, or optionally the sulfur oxide sulfoxide, which nucleus is unsubstituted or substituted by 1 to 5 substituents each independently selected from:

(a) Calkyle, which is not substituted or substituted by 1 to 3 substituents each independently selected from:

<td>(i)</td><td>halo.</td>

<td>(he)</td><td>-OR®,</td>

<td>(iii)</td><td>-C3-6cycloalkyl,</td>

<td>(iv)</td><td>-CO2R®,</td>

<td>(V)</td><td>-NRbRC,</td>

<td>(vi)</td><td>-S (O) R,</td>

<td>(٧ü)</td><td>-C (= O) RR and</td>

<td>(viii)</td><td>phenyl.</td>

(b)

(ء) (d) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is not substituted or substituted by 1 to 5 substituents each independently selected from:

(i) (ii) (iii)

-OR®, halo.

halo,

-c alkyl, which is not substituted or substituted by 1 to 5 halo, and -OR,

'كح

3 ، Θ558

<td>(e)</td><td>-GOLD*,</td>

<td>(f)</td><td>-C (= O) NRR,</td>

<td>(g)</td><td>-s (O) R,</td>

<td>(h)</td><td>-CN,</td>

<td>(i)</td><td>-NRR,</td>

<td>G)</td><td>-N (R٥) CO) R٥,</td>

<td>(k)</td><td>-NR) SO2R٥,</td>

<td> (1)</td><td>-0-C0₂R^d,</td>

<td>(m)</td><td>-O- (C = O) NRR,</td>

<td>(not)</td><td>-NR٥- (C = O) -NR R, and</td>

<td> (٠)</td><td>-C (= O) R٥;</td>

R is independently selected from: (1) hydrogen.

(2) -Calkyl which is not substituted or substituted by 1 to 5 halo, (3) -COR (4) (5) (6)

-CHO-CHCHSiCHs,

-CHOP (= O) (OR٥) 2,

- (CH) k-phenyl, which is unsubstituted or substituted by 1 to 3 substituents each independently selected from:

halo,

-OR١

-CN, and

-Cl-6 alkyl, which is unsubstituted or substituted by 1 to 6 halo;

(a) (b) (c) (d) ل is independently selected from:

(1) C (R'٥٥) -, (2) -CR R؟ -, (3) -c (o) -, and (4) -NR) -;

Y is independently selected from:

<td> (1)</td><td>= C (R^I٥b) -,</td>

<td> (2)</td><td>-CRR.</td>

<td> (3)</td><td>-CO)-,</td>

<td> (4)</td><td>N, and</td>

<td> (5)</td><td>-N (R'٥٥) -;</td>

R¹⁷ and R¹⁸ are each independently selected from:

(1) hydrogen, (2) halo.

-15158 (3) (4) (a) (b)

(ء)

-OR®,

-Calkyl, which is unsubstituted or substitutes for 1 to 4 substituents each independently selected from:

halo,

-OR®,

-CN, (d) phenyl or heterocycle, in which said heterocycle is chosen from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofiiranyl, tetrahydropyranyl and non-pyrazinyle or hetero-substituted or heterocycle, which substituted with 1 to 5 substituents each independently selected from:

(i) (ii) (iii)

(٤٧) (a) (b) (c) (d) (e)

-OR halo,

-CN,

-Cialkyl which is not substituted or substitutes for 1 to 6 halo, phenyl or heterocycle in which heterocycle is chosen from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofiirazinyl, and tetrahanyyl, tetrahydrofiirydropyl, and tetrahanyyl or heterocycle is un-substituted or substitutes for 1 to 5 substituents each independently selected from:

halo,

-CN, -OR, nitro, -Ci.6alkyl which is unsubstituted or substitutes for 1 to 6 halo;

or r! 7 and r! 8 and the atom to which they are attached join together to form a 4, 5, or 6 membered ring optionally contained a heteroatom selected from N, O, and s, in which the sulfur is optionally oxide to sulfone or sulfoxide, which ring is unsubstituted or substituted by 1 to 4 substituents each independently selected from:

(a) halo, (b) '-OR®, (c) -C alkyl, which is unsubstituted or substituted by 1 to 6 halo, and (d) phenyl;

R'٥® and Rieb are each independently selected from:

(1) hydrogen.

-16٠58 (2) -Calkyl, which is unsubstituted or substitutes for 1 to 5 substituents each independently selected from:

(a) halo,. (b) -OR (c) -C3٠6cycloalkyl, (d) phenyl or heterocycle, in which said heterocycle is chosen pami: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted by 1 to 3 substituents each independently selected from:

(i) halo, (ii) -OR٥, (iii) -CN, and (iv) Calkyl, which is not substituted or substitutes for 1 to 6 halo, (3) phenyl or heterocycle, in which the heterocycle is chosen as a : imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrofuyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which one phenyl or 3 substituted heterocycle is each not independently selected from one substituted phenyl or 3 substituted by 1 unsubstituted one per 1 unsubstituted one per 1 unsubstituted one per 1 unsubstituted phenyl :

(a) halo, (b) -OR^at, (c) -C3.6cycloa! ky! e, (d) -Calkyl which is unsubstituted or substituted with 1 to 6 halo, and (e) phenyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected among:

(i) halo, (ii) -Calkyl, which is unsubstituted or substituted by 1 to 6 halo, and (iii) -OR *,

<td> (4)</td><td>halo.</td>

<td> (5)</td><td>-OR٥,</td>

<td> (6)</td><td>-CN,</td>

<td> ٢٦١</td><td>-GOLD*,</td>

<td> (8)</td><td>RR, and</td>

<td> (9)</td><td>-C (= O) NR^bR٠;</td>

-173 © 558 or Ri6a and Ri٥b and the atom (s) to which they are attached assemble to form a ring chosen from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, dihydrofur anyle, dihydropyranyl, thiazolyle, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

(a) -Cialkyl, which is unsubstituted or substituted with 1 to 3 substituents each independently selected from:

(i) halo, (ii) -OR (iii) -C3- ، cycloalkyl, (iv) phenyl or heterocycle, in which heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl , which phenyl or heterocycle is unsubstituted or substituted with 1 to 5 substituents each independently selected from:

(I) -OR “, (II) halo, (III) -CN, and (IV) -Cjalkyl which is not substituted or substituted by 1 to 6 halo, (v) -OR *, (vi) -RR, ( vii) -S (OR, (viii) -C (= O) NRR, (ix) -NR) (OR *, and (x) -N (R٥) SOzR٥, (b) phenyl or heterocycle, wherein said heterocycle is chosen from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted by 1 to 5 substituents each independently selected from:

(i) halo, (ii) -OR *, (iii) -CN, and (iv) -Calkyl which is unsubstituted or substituted by 1 to 6 halo, (c) halo,

-18’4/

3Φ558

<td></td><td>(d)</td><td>-S (O) ٧R٥,</td>

<td></td><td>(e)</td><td>-GOLD^at,</td>

<td></td><td>(f)</td><td>-CN,</td>

<td></td><td>(g)</td><td>-C (O) R٥,</td>

<td> 5</td><td>(h)</td><td>-NRR,</td>

<td></td><td>(i)</td><td>-C (= O) NRR,</td>

<td>ا</td><td>G)</td><td>-HORN,</td>

<td></td><td>(k)</td><td>- (NRCCRa,</td>

<td></td><td> (1)</td><td>-O- (CO) -NRR,</td>

<td> 10</td><td>(m)</td><td>- (NR٥) - (C = O) -NRR,</td>

<td></td><td>(not)</td><td>oxido.</td>

<td></td><td>(o)</td><td>oxo, and</td>

<td></td><td>(P)</td><td>- | b)_SO₂Rd;</td>

R^at is independently selected from:

(1) hydrogen, (2) c alkyl, which is unsubstituted or substituted with 1 to 7 substituents each independently selected from:

(a) halo, (b) -O-C1.6alkyl, which is unsubstituted or substituted by 1 to 6 halo, ..

(c) hydroxyl, (d) -CN, and (e) phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, firanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofhranyl, tetrahyl and tetrah pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted by 1 to 3 substituents each independently selected from:

(i) halo, (ii) -O-Calkyl, which is unsubstituted or substituted by 1 to 6 halo, (iii) -CN, (iv) nitro, (v) hydroxyl, and (vi) -Cl. 6alkyl, which is not substituted or substituted by 1 to 6 halo, (3) phenyl or heterocycle in which said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, firanyl.

piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofirranyl, tetrahydropyranyl

-191 '(a) (b) (c) (d) (e) (f) (4) (1) (2) (a) (b) (c) (d) (e) and pyrazinyl, which phenyl OR heterocycle is unsubstituted or substituted with 1 to 3 substituents each independently selected from:

halo,

-CN,

-0-C) ٥alkyl, which is unsubstituted or substituted by 1 to 6 halo, nitro, hydroxyl, and

-Calkyl, which is not substituted or substituted by 1 to 6 halo, and

C-ôcycloalkyl, which is unsubstituted or substituted by 1 to 6 halo;

R^b and RC are independently selected from:

hydrogen.

C1-6alkyl, which is unsubstituted or substituted with 1 to 7 substituents each independently selected from:

halo,

-GOLD¹,

-CN,

-GOLD¹, phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which is substituted by phenyl or heterocycle 1, unsubstituted or heterocycle 1 with 3 substituents each independently selected from:

halo,

-GOLD¹,

-C alkyl, which is unsubstituted or substituted by 1 to 6 halo, and nitro, phenyl or heterocycle, in which said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl , tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents each independently selected from:

halo,

-GOLD¹,

-c١.6alkyl١ which is unsubstituted or substituted by 1 to 6 halo, -C3-6cycloalkyl, which is unsubstituted or substituted by'1 to 6 halo, -CN, and (i) (ii) (iii) (iv) (a) (b)

(٠) (d) (e)

٠58 (f) -COR, (4) -C3-6cycloalkyl, which is unsubstituted or substitutes for 1 to 6 halo;

or R^b and RC and the nitrogen to which they are attached join together to form a 4, 5, or 6 member ring optionally containing an additional heteroatom selected from N, O, and s, wherein the sulfur is optionally oxidized to a sulfone or sulfoxide , which ring is unsubstituted or substituted by 1 to 4 substituents each independently selected from:

(a) halo, (b) -OR®, and (c) -C alkyl, which is unsubstituted or substituted by 1 to 6 halo, and (d) phenyl;

R٥ is independently selected from:

(1) Calkyl, which is unsubstituted or substituted by 1 to 4 substituents each independently selected by pami: ٠ (a) halo, (b) -OR^at, (c) -ORa, (d) -CN, and (e) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofurofuryl , tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 to 3 substituents each independently chosen:

(i) halo, (ii) -OR®, (iii) -Cl ٥alkyl, which is unsubstituted or substituted by 1 to 6 halo, and (iv) nitro, (2) phenyl or heterocycle, whereby said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted each independently from 1 to 3 substituents:

(a) halo, (b) -OR®, (c) -Calkyl, which is not substituted or substituted by 1 to 6 halo.

(d) -C3.6cycloalkyl, which is unsubstituted or substituted by 1 to 6 halo (e) -CN, and (f) -Oet (3) -C3-6cycloalkyl, which is unsubstituted or substituted by 1 to 6 halo ;

R^e and R^f are independently selected from:

(1) hydrogen, (2) -Calkyl, which is unsubstituted or substituted by 1 to 6 halo, (3) phenyl, and (4) benzyl;

or when R^e and Rf and the atom to which they are attached join together to form a 3, 4, 5 or 6 membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to a sulfone or sulfoxide , which ring is unsubstituted or substituted with 1 to 4 substituents each independently selected from:

(a) halo, (b) -OR (c) -c alkyl, which is unsubstituted or substituted by 1 to 6 halo, and (d) phenyl;

m is 1,2, or 3;

nestl, 2, or 3;

vesto, l, or2;

kesto, 1, or 2;

and the pharmaceutically acceptable salts thereof and the individual enantiomers and diastereomers thereof.

One embodiment of the invention comprises compounds of formula Ia:

<img file="MA30558B1_D0006.tif" />

where A ', A², AT³, J, Y, E^at, E^b, E^vs, R⁶, and R⁷ are defined here;

and the pharmaceutically acceptable salts thereof and the individual enantiomers and diastereomers thereof.

؛ Y

Another embodiment of the invention comprises compounds of formula

Ib:

<img file="MA30558B1_D0007.tif" />

<img file="MA30558B1_D0008.tif" />

Ib in which AA², AT³, E, E^b, E٥, R^b , R⁶, and R⁷ are defined here;

and the pharmaceutically acceptable salts thereof and the individual enantiomers and diastereomers thereof.

Another embodiment of the invention comprises compounds of formula Ic:

<img file="MA30558B1_D0009.tif" />

A 'A

<img file="MA30558B1_D0010.tif" />

in which A ', A², AT³, E^at, E^b, E^vs, R٥ and R⁷ are defined here;

and the pharmaceutically acceptable salts thereof and the individual enantiomers and diastereomers thereof.

In one embodiment of the present invention a! is independently selected from:

<td> (1)</td><td> -0-,</td>

<td> (2)</td><td>-S (O) v-,</td>

<td> (3)</td><td>-CRR-,</td>

<td> (4)</td><td>-NR) -,</td>

<td> (5)</td><td>-C (N (R^b) (C = O) OR^at) R) -,</td>

<td> (6)</td><td>- (CO) -, and</td>

<td> (7)</td><td>-NR ا) -, in which V, R⁶, R⁷, R⁸, R^at, R^b, R^vs and r! ) are defined here.</td>

In one embodiment of the present invention ٨1 is -Ο-.

In one embodiment of the present invention A ؛ is S (O) v-, in which

V is defined here.

-23'//1

In one embodiment of the present invention is -CRR-, in which R⁶ and R⁷ are defined here.

In an embodiment of the present invention A ؛ is CH.

In an embodiment of the present invention ٨1 is -N (R⁸) -, where R⁸ is defined here.

In one embodiment of the present invention ٨1 is -ΝΗ-.

In one embodiment of the present invention a! is -C (OR٥) H-, where R^at is defined here.

In one embodiment of the present invention a! is -C (= o) -.

In one embodiment of the present invention A ؛ is -C (NR R) H-, where R^b and RC are defined here.

In one embodiment of the present invention a! is C (N (R^b) (C = O) OR٥) H-, in which R^atetR^b are defined here.

In one embodiment of the present invention a2 is independently selected from:

(1) -CRR-, (2) -CR'٥R٠ ؛ -, and (3) - (CO) -, where R⁶, R⁷, Rio and R are defined here.

In one embodiment of the present invention a2 is -CRR-, wherein R⁶ and R⁷ are defined here.

In one embodiment of the present invention a2 is -CH-.

In one embodiment of the present invention a2 is CO) -.

In one embodiment of the present invention a3 is independently selected from:

(1) -CRR-, (2) -CR) ٥R) '-, and (3) -NR)') -, where R٥, R⁷, R'٥ and R '٠ are defined here.

In one embodiment of the present invention A³ is -CRR⁷-, where R⁶ and R⁷ are defined here.

In one embodiment of the present invention A³ is -CR) ٥R ؛) -, in which R١٥ and R ؛؛ are defined here.

In one embodiment of the present invention a4 is independently selected from:

(1) -CRR-,

313558

<td></td><td> (2)</td><td>, - ؛ 'CR٠٥R-</td>

<td></td><td> (3)</td><td>-N (R) ') -,</td>

<td></td><td> (4)</td><td>and, - (؟ N (R-</td>

<td></td><td> (4)</td><td>a link between A² and A³, where R٥, R⁷, R⁸, R'٥ and R '' are defined here.</td>

<td> 5</td><td></td><td>In one embodiment of the present invention a4 is CH.</td>

<td></td><td></td><td>In one embodiment of the present invention a4 is a bond between A²</td>

<td>l</td><td></td><td>and A³.</td>

<td></td><td></td><td>In one embodiment of the present invention E^at is -C (R ؛^at) =, where</td>

R ؛^at is defined here.

In one embodiment of the present invention E^at is -C (H) =.

In one embodiment of the present invention E^at is -N =.

In one embodiment of the present invention E٥ is -C (R^5b) =, where R^5b is defined here.

In one embodiment of the present invention E٥ is -C (H) =.

In one embodiment of the present invention E٥ is -N =.

In one embodiment of the present invention EC is -CR٥) =, where r5٥ is defined herein.

In one embodiment of the present invention EC is -C (H) =.

In one embodiment of the present invention EC is -N =.

In one embodiment of the present invention Q is CO) -.

In one embodiment of the present invention R⁴ is chosen from:

hydrogen and Calkyl, which is unsubstituted or substituted with 1 to 5 fluoro.

In one embodiment of the present invention R⁴ is hydrogen.

In one embodiment of the present invention R^5a, R^5b and r5c are independently selected from hydrogen and halo.

In one embodiment of the present invention R^5a, R^5b and R^5c are hydrogen.

In one embodiment of the present invention R⁶ and R? are independently selected from:

(1) hydrogen, (2) -Calkyl, which is unsubstituted or substituted with 1 to 5 substituents where the substituents are each independently selected from: halo, phenyl, and -OR^at, (3) Ccycloalkyl, which is un-substituted or substituted by 1 to 5 fluoro, (4) phenyl or heterocycle, which is un-substituted or substituted by 1 to 5 halo, wherein heterocycle is defined herein, (5) halo, ( 6) -OR٥, (7) -NR R, and (8) -O (C = O) R^at, where R^at, R^b and RC are defined here.

In one embodiment of the present invention R٥ and R⁷ are independently selected from hydrogen, OH and -Cialkyl, which is unsubstituted or substituted with 1 to 5 fluoro.

In one embodiment of the present invention R⁶ and R⁷ are independently selected from hydrogen, -NRR and -Cialkyl, which is unsubstituted or substituted with 1 to 5 fluoro, where R^b and RC are defined here.

In one embodiment of the present invention R⁶ and R⁷ are independently selected from hydrogen and -c alkyl, which is unsubstituted or substituted with 1 to 5 fluoro.

In one embodiment of the present invention R⁶ and R⁷ are ethyl, which are unsubstituted or substituted with 1 to 5. fluoro.

In one embodiment of the present invention R⁶ and R⁷ are methyl, which are unsubstituted or substituted with 1 to 3 fluoro.

In one embodiment of the present invention R⁶ and R⁷ and the carbon atom or atoms to which they are attached assemble to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, dioxolanyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, which ring is unsubstituted or substituted with 1 to 6 substituents each independently selected from:

(1) -c alkyl, which is unsubstituted or substituted with 1 to 3 substituents where the substituents are each independently selected from: halo, and -OR^at, (2) phenyl or pyridyl, wherein the phenyl or pyridyl is optionally fused with the ring, and which phenyl or pyridyl is unsubstituted or substituted with 1 to 3 substituents each independently selected from: halo, OR^at, and -Calkyl, which is unsubstituted or substituted with 1 to 5 fluoro, (3) halo, and (4) - where R^at is defined here.

إلا

<img file="MA30558B1_D0011.tif" />

In one embodiment of the present invention R⁸ is selected from: hydrogen, -C (= O) R٥, -CCR, -SO2R٥, and -c alkyl, which is not substituted or substituted by 1 to 5 fluoro, in which R^at and R^d are defined here.

In one embodiment of the present invention R⁸ is chosen from:

hydrogen, and -Calkyl, which is unsubstituted or substituted with 1 to 5 fluoro.

In one embodiment of the present invention R⁸ is hydrogen.

In one embodiment of the present invention R⁸ is methyl

In one embodiment of the present invention R⁸ and R⁷ and the atoms to which they are attached join together to form a 4, 5, 6, or 7 membered alkyl or heteroalkyl ring optionally containing an additional heteroatom selected from N, O, and s, wherein the sulfur is optionally oxidized to a sulfone or sulfoxide, which ring is unsubstituted or substituted by 1 to 4 substituents each independently selected from:

(1) halo.

(2) phenyl, which is unsubstituted or substituted with 1 to 3 substituents each independently selected from: halo, OR^at, CN, and-C (= O) OR^at, (3) -OR^at, and (4) -Cl kyl, which is unsubstituted or substituted by 1 to 6 halo, in which R^at is. defined here.

In one embodiment of the present invention R¹⁰ is selected from: hydrogen, and -C] -6alkyl١ which is unsubstituted or substituted by fluoro.

In one embodiment of the present invention R'٥ is hydrogen.

In one embodiment of the present invention R is independently selected from the group comprising:

phenyl, furanyl, pyrazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, tetrazolyl, thienyl, triazolyl, and isoxazolyl, where R is unsubstituted or substituted with 1 to 5 substituents each independently selected from r! 2, R13, R'4, R^15a and Ri5b, where R٠2, R '³, R'4, R and Ri5b are defined here.

In one embodiment of the present invention R is phenyl, which is unsubstituted or substituted with 1 to 5 substituents each independently selected from R2 ؛, r13, r'4, R³؛؛ and R'5b, in which R'2, R¹³, R١4, R5 ؛ a and R^15b are defined here.

In one embodiment of the present invention R^PG is selected from: hydrogen and -c alkyl, which is unsubstituted or substituted with 1 to 3 halo.

In one embodiment of the present invention rP٥ is methyl.

In one embodiment of the present invention rP٥ is hydrogen.

-٦٦-

;/AT

<img file="MA30558B1_D0012.tif" />

In one embodiment of the present invention ل is = C (R^I6a)-_; -CR٠7r) 8 or Ν ') -, in which Rie ،, R'7, R'؟ and R^b are defined here.

In one embodiment of the present invention ل est = C (R'٥^at) -, in which 5 R'٥^at is defined here.

In one embodiment of the present invention ل is -CR٠7r'8-, wherein r! 7 and R) 8 are defined herein.

In one embodiment of the present invention ل is -CH.

In one embodiment of the present invention ل is -N (R^b) _, where R^b10 is defined here.

In one embodiment of the present invention ل is -NCI) ​​-,

In one embodiment of the present invention Y is = C (R'٥^b) -, -CR٠7r) 8 or -C (= o) -, in which R^16b, r! 7 and R'8 are defined here.

In one embodiment of the present invention Y is = C (R'٥^b)-, in which

R٠٥^b is defined here.

In one embodiment of the present invention Y is -C (= O) -.

In one embodiment of the present invention R '^b٥ and R'٥^b are independently selected from:

(1) hydrogen, (2) -C alkyl, which is unsubstituted or substituted with 1 to 3 fluoro, and (3) phenyl or heterocycle, in which heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, triazolyl , isoxazolyl and morpholinyl.

In one embodiment of the present invention R^]6a and R'٥^b and! the atom or atoms to which they are attached join together to form a ring selected from phenyl, pyridyl, and pyrimidinyl, which ring is unsubstituted or substituted with 1 to 3 substituents each independently selected from: halo, OR^at and -Calkyl, which is unsubstituted or substituted with 1 to 3 fluoro, in which R^at is defined here.

In one embodiment of the present invention R^{) 6a} and R'٥^b and the atom or atoms to which they are attached assemble to form a ring selected from pyridyl, and pyrimidinyl.

In one embodiment of the present invention mestl ..

In one embodiment of the present invention nestl.

-28058

In one embodiment of the present invention n is 2.

It should be understood that when one or more of the structures or substructures enumerated above enumerates multiple substituents having the same designation each of these variables may be the same as or different from each variable designated in the same way. For example, if R is listed more than once in an embodiment of formula I, each case of R⁸ in formula I may independently be any one of the substructures defined according to R⁸. The invention is not limited to the structures and sub-structures in which each R⁸ must be the same for a given structure. It is the same compared to any variable appearing several times in a structure or substructure.

The compounds of the present invention may contain one or more asymmetric centers and thus may appear as racemates and racemic mixtures, single enantiomers, mixtures of diastereomers and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the different substituents on the molecule. Each of these asymmetric centers will independently produce two optical isomers and it is intended that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are within the scope of the invention. The present invention is intended to include all isomeric forms of compounds of formula I.

Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are believed to include both the E and Z geometric isomers.

The present invention includes compounds of formula I in which one or more hydrogen atoms can be replaced by deuterium.

The tautomers of the compounds defined in Formula I are also included within the scope of the present invention. For example, compounds comprising carbonyl-CHCO) - groups (keto forms) can undergo tautomerism to form hydroxyl groups -CHC (OH) - (enol forms). Both keto and enol forms are included within the scope of the present invention.

As will be understood by those skilled in the art, not all of the R⁶ and R⁷ are capable of forming a nucleus structure. In addition, even those substituents capable of forming rings may or may not form a ring structure.

As will also be understood by those skilled in the art, halo or halogen as used herein are intended to include chlorine, fluorine, bromine and iodine.

As used herein, "alkyl" is intended to mean linear, branched, and cyclic structures having no carbon-to-carbon double or triple bonds. Thus C1-6 alkyl is defined to identify a group having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement. "Cycloalkyl" is an alkyl, some or all of which forms

-29Λ 'a ring of three or more atoms. Co or Co alkyl is defined to identify the presence of a direct covalent bond.

The term "alkenyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-α-carbon double bond, in which the hydrogen may be replaced by one. additional carbon-α-carbon double bond.

The term "alkynyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-α-carbon triple bond.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring having up to 7 elements in each ring, in which at least one ring is aromatic.

The term "heterocycle" or "heterocyclic", as used herein unless otherwise specified, represents a stable monocyclic ring system having 4 to 8 members or stable bicyclic heterocyclic having 8 to 12 members which is either saturated or unsaturated, and which comprises carbon atoms and from six to six heteroatoms selected from the group consisting of N, O, s, P and Si, and wherein the nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and comprising any bicyclic group in which any of the heterocyclic rings defined above is fused with a benzene ring. The heterocyclic ring can be attached to any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidine, chromane, dihydrofirrane, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazolidinone, imidazoline, imidazolinone, indoline, isochromanazoline, isoindoxolidoline, isothiazazine, isoindoxolidine, isothiazazine, isoindoxolidine, isothiazazine morpholine, morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane, 2-oxohexahydroazepine, 2-0X0piperazine, 2oxopiperidine, 2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofiran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine and N-oxides thereof.

The term "heteroaryl," as used herein unless otherwise specified, represents a stable monocyclic ring system having 5 to 7 members or stable bicyclic heterocyclic having 9 to 10 members which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which comprises carbon atoms and from one to six heteroatoms chosen from the group comprising N, O, s, P and Si, and wherein the nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and comprising any bicyclic group in which any of the heterocyclic rings

158 defined above is made with a benzene ring. The heterocyclic ring can be attached to any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzioxazole, benzofiirane, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, fine, firrazane, imidazole, indazole, indothiazin, isolizine, is , isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, 'purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.

The term "alkoxy", as in C1-C6 alkoxy, is intended to include alkoxy groups having 1 to 6 carbon atoms of linear, branched and cyclic configuration.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are within sound medical judgment, suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable benefit / risk ratio.

As used herein, "pharmacologically acceptable salts" refers to derivatives in which the initial compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the initial compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfirric, sulfamic, phosphoric, nitric acid and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fiimaric, toluenesulfonic, methanesulfonic, disulfonic ethane, oxalic, isethionic, and the like.

When the compound of the present invention is basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic.

-313 (0558 sulfuric, tartaric, p-toluenesulfonic, and the like. According to one aspect of the invention the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, like is used herein, references to compounds of formula I are intended to include also pharmaceutically acceptable salts.

The illustration of the invention is the use of the compounds described in

Examples and here. The specific compounds according to the present invention comprise a compound which is selected from the group consisting of the compounds described in the following Examples and the pharmaceutically acceptable salts thereof and the individual diastereoisomers thereof.

The compounds of the invention are useful in a method of antagonizing CGRP receptors in a patient such as a mammal in need of such antagonism comprising administering an effective amount of the compound. The present invention relates to the use of the compounds described herein as CGRP receptor antagonists. In addition to primates, particularly humans, a variety of other mammals can be treated according to the method of the present invention.

Another embodiment of the present invention relates to a method for treating, controlling, ameliorating, or reducing the risk of a disease or condition in which the CGRP receptor is involved in a patient which comprises administering to the patient a therapeutically effective amount of a compound which is a CGRP receptor antagonist.

The present invention further relates to a process for the manufacture of a medicament for antagonism of CGRP receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, eg, a human, male or female, in which antagonism of CGRP receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound which will elicit the biological or medical response of a tissue, system, animal or human which is desired by the researcher, veterinarian, doctor of medicine or other clinician. As used herein, the term "treatment" refers to both the treatment and the prevention or prophylactic therapy of the ailments mentioned, particularly in a patient who is predisposed to such disease or condition.

The term "composition" as used herein is intended to include a product comprising the ingredients specified in quan. specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. Such a term with respect to a pharmaceutical composition, is intended to include a product comprising the active ingredient (s), and the inert ingredient (s) which constitute the carrier, as well as any product which results, directly or indirectly, from the

نمد

158 combination, complexation or aggregation of two or more of the ingredients, or the dissociation of one or more of the ingredients, or any other type of reaction or interaction of one or more of the ingredients. Therefore, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is understood that the carrier, diluent or excipient must be ¹ compatible with the other ingredients of the composition and not be deleterious for the recipient thereof.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo to provide the required compound. Thus, in the treatment methods of this. invention, the terms "administering" or "administering a" compound will include the treatment of various conditions described with the compound specifically described or with a compound which may not be specifically described, but which is converted to give the specified compound in vivo. after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. II. Bundgaard, Elsevier, 1985. The metabolites of these compounds include active species produced upon introduction of the compounds of this invention into the biological medium.

The utility of the compounds of the present invention as antagonists of CGRP receptor activity can be demonstrated by methodology known in the art. Inhibition of the binding of!²⁵Ι-CGRP at receptors and functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEIVER BINDING ASSAY: binding of '²⁵Ι-CGRP at receptors in membranes of SK-NMC cells was performed essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 µg) were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgC and 0.2% bovine serum albumin (BSA)) containing 10 pM of ؛ I-CGRP and antagonist. After incubation at room temperature for 3 h, the assay was terminated by filtration through GFB glass fiber filter plates (PerkinElmer) which were blocked with 0.5% polyethyleneimine for 3 h. Filters were washed three times with ice assay buffer (10mM HEPES, pH 7.4 and 5mM MgCl), then the plates were air dried. Scintillation fluid (50 µL) was added and the radioactivity was measured on a Topcount (Packard Instrument). Data analysis was performed using Prism and the K {value was determined using the Cheng-Prusoff equation (Cheng &amp; Prusoff (1973) Biochem. Pharmacol.

2,3099-3108).

RECOMBINANT RECEIVER: the human CL receptor (Genbank accession number L7638O) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3'PmeI fragment. Human RAMP1 (Genbank accession number AJOO1014) was subcloned into the expression vector pIRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 3'NotI fragment. HEK 293 cells (human embryonic kidney cells; ATTC &amp; CRL-1573) were cultured in DMEM with 4.5 g / L glucose, 1 mM sodium pyruvate and 2 mM glutamine to which was added 10% fetal bovine serum (FBS), 100 units / mL penicillin and 100 Pg / mL streptomycin, and maintained at 37 ° C and 95% humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Generation of a stable cell line was achieved by cotransfecting 10 µg of DNA with 30 µg of Lipofectamine 2000 (Invitrogen) in 75 cm2 flasks. The CL receptor and RAMP1 expression constructs were cotransfected in equal amounts. Twenty-four hours after transfection the cells were diluted and selective medium (growth medium + 300 µg / mL hygromycin and 1 µg / mL puromycin) was added the next day. A clonal cell line was generated by deposition of single cells using FACS Vantage SE (Becton Dickinson). The growth medium was adjusted up to 150 pg / mL hygromycin and 0.5 pg / mL puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing the recombinant human CL / RAMP1 receptor were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA, and Complete protease inhibitors (Roche ). The cell suspension was disturbed with a laboratory homogenizer and centrifuged at 48,000g to isolate the membranes. The pellets were resuspended in harvest buffer with 250 mM sucrose and stored at 70 c. For binding assays, 20 µg of membranes were incubated in 1 ml of binding buffer (10 mM HEPES, pH 7.4, 5.mM MgCl, and 0.2% BSA) for 3 hours at room temperature containing 10 pM 25 ؛ j-hCGRP (GE Healthcare) and the antagonist. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (PerkinElmer) which were blocked with 0.05% polyethyleneimine. Filters were washed 3 times with ice cold assay buffer (10mM HEPES, pH 7.4 and 5mM MgCl). Scintillation fluid was added and the plates were read on a Topcount (Packard). Non-specific binding was determined and data analysis was performed with the apparent dissociation constant (Ki) determined using a linear least squares fit of the CPM bound radioactivity data against the equation below :

Yobs = + ((Medicine] / Ki (l + (radioactive marker] / Kd) لر

-34 Where Y is the observed bound CPM radioactivity, Ymax represents total bound counts, Ymin represents non-specific bound counts, (Ymax - Ymin) represents specific bound counts,% Imax represents maximum inhibition in percentage,% Imin is minimal inhibition as a percentage, the radioactive label is the probe, and Kd is the apparent dissociation constant for the radioactive ligand for the receptor as determined by hot saturation experiments,

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in complete growth medium at 85,000 cells / well in 96 well polyD-lysine coated plates (Corning) and grown for approximately 19 h prior to assay. The cells were washed with PBS and then incubated with the inhibitor for 30 min at 37 ٥c and 95% humidity in complete Cellgro serum free / low protein medium (Mediatech, Inc.) with L-glutamine and 1 g / L of BSA. Isobutyl-methylxanthine was added to the cells at a concentration of 300 μΜ and they were incubated for 30 min at 37 ٥c. Human orCGRP was added to the cells at a concentration of 0.3 nM and they were allowed to incubate at 37 ٥c for 5 min. After stimulation of Ι'α-CGRP the cells were washed with PBS and processed for cAMP determination using a two-step assay procedure according to the manufacturer's recommended protocol (screening assay system direct from cAMP SPA; RPA 559; GE Healthcare). Dose-response curves were plotted and IC values ​​determined from a 4-parameter logistic fit as defined by the equation y = ((ad) / (l + (x / c) b) td, where y = response, X = dose, a = max response, d = min response, c = inflection point and b = tilt.

In particular, the compounds of the following examples have an activity conrme antagonists of the CGRP receptor in the above-mentioned assays, generally with a K \ or CI value of less than about 50 μΜ. Such a result is indicative of the intrinsic activity of the compounds when they are used as antagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly humans.

The compounds of the present invention are useful in the treatment, prevention, amelioration, control or risk reduction of one or more of the following conditions or diseases: headache; migraines; periodic vascular headaches; chronic tension headaches; pain; Chronic Pain ; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; dental pain; diabetes; diabetes

-35-58 non-insulin dependent; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opioid withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases;

neurogenic skin redness, pinkness of the skin and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions which could be treated or prevented by antagonism of CGRP receptors. Acute or prophylactic treatment of headache, including migraine and periodic vascular headache is particularly important.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of the risk of the diseases, disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of the risk of the aforementioned diseases, disorders and conditions in combination with other agents.

The compounds of the present invention can be used in combination with one or more other medicaments in the treatment, prevention, control, amelioration or reduction of the risk of the diseases or conditions for which the compounds of formula I or the other medicaments are useful, where combining the drugs together is safer or more effective than either drug alone. Such other drug (s) may be administered, by a route and in an amount commonly used for them, simultaneously or sequentially with a compound of formula I. When a compound of formula I is used simultaneously with one or more other drugs, a pharmaceutical composition in the form of unit doses containing these other drugs and the compound of formula I is preferred. However, the combination therapy can also include therapies in which the compound of formula I and one or more other drugs ؛ are administered according to different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when they are each used alone. Therefore, pharmaceutical compositions of the present invention include those which contain one or more other active ingredients, in addition to a compound of formula I. Such combinations include combinations of a compound of the present invention not only with another active compound, but also with two or more other active compounds. Likewise, the compounds of the present invention can be used in combination with other medicaments which are used in the prevention, treatment, control, amelioration, or reduction of the risk of the diseases or conditions for which the compounds. of the present invention are useful. Such other drugs may

-36058 be administered, by a route and in an amount commonly used for these, simultaneously or sequentially, with a compound of the present invention. When a compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing these other drugs in addition to the compound of the present invention is preferred. Therefore, pharmaceutical compositions of the present invention include those which also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention and the other active ingredient (s) can be varied and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention and the other agent will generally be in the range of about 1000: 1 to about 1: 1000. , or from about 200: 1 to about 1: 200. The combinations of a compound of the present invention and the other active ingredients will generally also be within the aforementioned range, but in each case an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and the other active ingredients can be administered separately or together. In addition, administration of a component may be before, during or after administration of the other agent (s), and by the same or different routes of administration.

The compounds of the present invention can be administered by the oral, parenteral (eg, intramuscular, intraperitoneal, intravenous, ICV, intracistemal, subcutaneous injection, or implant injection or infusion), inhalation spray or infusion routes. , nasal, vaginal, rectal, sublingual or topical and may be presented, singly or together, in appropriate unit dose presentations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of. the invention are effective for use in humans.

Pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, etc. hard or soft capsules, or syrups or elixirs.

-٦ لآ-

اد

أكدا

The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are commonly applied in the treatment of the aforementioned pathological conditions.

In the treatment, prevention, control, amelioration, or reduction in risk of conditions which require antagonism of CGRP receptor activity an appropriate dose level will generally be about 0.01 to 500 mg per kg of the patient's body weight per day which can be administered in single or multiple doses. A suitable dose level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dose may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing from 1.0 to 1000 milligrams of active ingredient, in particular 1.0, 5.0, 10.0, 15.0 20, 0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient for symptomatic dose adjustment relative to the patient to be treated. The compounds can be administered on a 1-4 times per day regimen, or can be administered once or twice per day.

In the treatment, prevention, control, amelioration, or reduction of the risk of headache, migraine, chronic periodic headache, or other diseases for which the compounds of the present invention are indicated, generally satisfactory results. are obtained when the compounds of the present invention are administered at a daily dose of from about 0.1 milligram to about 100 milligrams per kilogram of body weight of the animal, given as a single daily dose or in divided doses two to six times a day, or in an extended-release form. For most large mammals, the total daily dose is about 1.0 milligrams to about 1000 milligrams, or about 1 milligram to about 50 milligrams. In the case of a 70 kg adult male, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response.

Several processes for the preparation of the compounds of this invention are illustrated in the following Examples. Starting materials are made according to procedures known in the art or as illustrated herein.

Compounds of the present invention can be readily prepared according to Scheme 1 and the specific examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. In these reactions, it is also possible to use variants which are themselves known to those skilled in the art but are not mentioned here in more detail.

DIAGRAM 1

-3810

3Ô§58

<img file="MA30558B1_D0013.tif" />

<img file="MA30558B1_D0014.tif" />

Scheme 1 illustrates the general strategy for the preparation of the compounds of the present invention by coupling a carboxylic acid intermediate (A) to an amine (B) to give the desired product the amide c. Various carboxylic acid intermediates, such as those described herein (see below), can be coupled to a variety of amines to provide the compounds of the present invention. There are many known strategies for performing such coupling chemistry, including the use of coupling reagents, such as EDC with HOBT, PyBOP, HAUT, CDI and the like. Alternatively, carboxylic acid A can be activated as an acid chloride or anhydride, for example, to facilitate reaction with the amine of interest. Activation of amine B, for example, as the corresponding aluminum amide which can be reacted with a carboxylic acid ester derivative A, can also be a useful strategy in cases where the amine is relatively unreactive. In some instances, different protecting group strategies well known to those skilled in the art of organic synthesis may be employed to enable the preparation of a particular compound of the present invention.

It is understood that alternative methodology may also be employed in the synthesis of these major intermediates. For example, racemic reaction sequences can be used, followed by chiral separations in the appropriate steps to provide compounds of the present invention. The exact choice of reagents, solvents, temperatures, and other reaction conditions will depend on the nature of the product desired. In some cases, appropriate protecting group strategies can be used.

In some cases the final product can be further modified, for example, by manipulation of substituents. These manipulations can include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are well known to those skilled in the art.

In some cases, the order of carrying out the above reaction schemes can be varied to facilitate the reaction or to avoid unwanted reaction products. In addition, different protecting group strategies can be employed to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for a better understanding of the invention. These examples are for illustration only and should not be construed as limiting the invention in any way.

-39 INTERMEDIATE!

<img file="MA30558B1_D0015.tif" />

^ 65 ^ -6- (3,5-Diflu0r0phénvD-3,3-diinethylpiperidin-2-0ne

Step A. Dimethyl 2,2-dimethylpentanedioate

To a solution of 3,3-dimethyldihydro-277-pyran-2,6 (377) -dione (20.0 g, 141 mmol) in MeOH (140 mL), at room temperature and under a constant stream of nitrogen , TMSCl (7.64 g, 70.3 mmol) was added. The reaction mixture was then heated to 60 ° C for 3.25 h, before being cooled to room temperature. The reaction mixture was then concentrated in vacuo before being diluted with diethyl ether (200 mL) and water (100 mL). The organics were then washed with 100 mL, individually, of each of the following aqueous solutions: 1 M NaOH, 1 M HCl, water, semi-saturated brine and saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated, in vacuo, to give the title compound, which was used without further purification. MS: mtz = 189 15 (Μ + 1).

Step B. Methoxv 5-methoxv-4.4-dimethvl-5-oxopentanoïaue acid

A solution of dimethyl 2,2-dimethylpentanedioate from Step A (25.4 g, 135 mol) in MeOH (150 mL), THF (100 mL) and water (100 mL) was obtained added potassium carbonate (36.2 g, 262 mmol). The two-phase solution was allowed to stir for 68 h, at room temperature, after which the reaction was complete at about 50 ٥/٥. The extracts were carefully extracted under vacuum so that the starting materials did not vaporize. The aqueous layer was diluted with water (266 mL) and then extracted with diethyl ether until no additional MD was detected in the aqueous layer. The aqueous layer was made acidic by adding 6M HCl (95 mL), and then saturated with NaCl. This aqueous layer was extracted once with diethyl ether (250 mL). This ethereal layer was washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. MS: mlz = 175 (Mtl).

Step c. Methyl 5-lmeth0xv (methvBamin01-2.2-dimethvl-5-0X0Pentan0ate

To a solution of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid from Step'B (7.00 g, 40.2 mmol), in DCM was added DMF (0.1 mL), followed by the slow addition of chloride

-40318 of oxalyl (5.00 g, 39.4 mmol) over 33 minutes, during which the reaction flask was kept under a constant stream of dry nitrogen. Stirring was continued under a light jet of dry nitrogen for an additional hour, during which time the rate of evolution of carbon dioxide decreased. This freshly formed acid chloride was then transferred using a cannula into a 500 mL round-bottom flask, cooled to 0 ° C, which contained Nmethoxymethanamine hydrochloride (5.76 g, 59 , 1 mmol) and triethylamine (15.9 g, 158 mmol). Fifteen minutes after the complete addition of the acid chloride, the ice bath was removed and the reaction was allowed to warm to room temperature. After 1 h at room temperature, diethyl ether (100 mL) was added to precipitate part of the triethylamine hydrochloride, which was filtered and washed with additional diethyl ether. The combined organics were then washed with 1 M HCl (100 mL X 2), 1 M NaOH (100 mL), water (100 mL), semi-saturated brine (100 mL) and saturated brine (100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound which was used without further purification. MS: mlz = 218 (Μ + 1).

Step D, Methyl 5- (3,5-difluorophenyl) -2,2-dimethyl-5-oxopentanoate

To a solution of methyl 5- [methoxy (methyl) amino) -2,2-cfimethyl-5 oxopentanoate! de) 'Step c (4.68 g, 21.6 mmol) in THF (46.8 mL), cooled to 0 ٠c, 3,5-difluorophenyl magnesium bropure (65 mL, 0.5 M in THF, 32.3 mmol) over 30 minutes. The reaction was allowed to stir at room temperature for 2 h, after which no further reaction progress was observed. Additional 3,5-difluorOphenyl magnesium bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added over 30 minutes. After 3 h at 0 ° C, the reaction was quenched by the rapid addition of a cold (0 ° C) solution of EtOH (71 mL) and conc. HCl. (5.0 mL). The reaction was then diluted with water (200 mL) and diethyl ether (400 mL). The organics were washed with water (200 mL X 3) and brine (100 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by chromatography on silica gel, eluting with a gradient of CHClhexanes - 50:50 to 100: 0, to give the title compound. MS: mlz = 239 (M 31 (MeO ')).

Step E. Methyl (553-5-ir (53-tërt-butvlsulfinvllaminoL5- (3.5-difluorophénvl١-2.2diméthvlpentanoate

To a solution of methyl 5- (3,5-difluorophenyl) -2,2-dimethyl-5-oxopentanoate from Step D (500. mg, 1.85 mmol) and (53-2-methylpropane-2- sulfinamide (336 mg, 2.78 mmol) in THF (6.5 mL), titanium tetraethylate (616 mg, 2.52 mmol) was added. The reaction vessel was quickly capped and placed in a bath. at 60 ° C for 3 hours. After cooling

-41.

to room temperature a septum and nitrogen inlet were attached before cooling to 0 ° C. Sodium borohydride (191 mg, 5.05 mmol) was then added, and a complete reaction was observed after 15 minutes. Methyl alcohol was then added slowly until the gas evolution stopped. The reaction mixture was then diluted with saturated brine (6.5 mL) with rapid stirring. The resulting slurry was filtered through Celite, washing with EtOAc as necessary. The combined organics were then washed with brine, sedated over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by chromatography on silica gel, eluting with an EtOAcHexanes gradient - 10:90 to 70:30, to give the title compound containing about 12% of the corresponding ethyl ester. MS: mlz = 376 (M +

Step F. (6_l3,5) -6 - (؟ - Difluorophénvl) -3,3-dimethylpiperidin-2-one

A solution of methyl (55) -5 - (((5) - lutylsulfinyl] amino} -5- (3,5-difluorophenyl) -2,2dimethylpenta oate from Step E (300. mg, 0.800 mmol) in MeOH (16 mL) was cooled to 0 ° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 30 seconds, after which the reaction vessel was stoppered and left. standing in the ice bath for 15 minutes. Dry nitrogen was bubbled through the solution for 30 minutes, before the solvent was removed in vacuo. Additional MeOH (~ 50 mL) was added, and then extracted in vacuo. After dissolving in a third volume of MeOH (16 mL), triethylamine (323 mg, 3.2 mmol) was introduced and the mixture was heated to 65 ٥c for 16 hours. After cooling to room temperature, the solvent was extracted in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: mlz = 240 (Μ + 1).

-4258 ج 0&gt; 3

INTERMEDIATE 2

<img file="MA30558B1_D0016.tif" />

(5R) -5- (3,5-DifluorophényD-2,2-dimethylthiomorpholin-3-one

Step A. 2- {r2- (3,5-Difluorophenyl) -2-oxoethyl-10I-2-methylpropano'ic acid

To a solution of 3.5 difluorophenacyl bromide (845 mg, 3.60 mmol) in THF (12 mL) and water (12 mL) was added sodium bicarbonate (317 mg, 3.78 mmol). ) and 2mercaptoisobutyric acid (432 mg, 3.60 mmol). The reaction mixture was allowed to stir at room temperature for 1.0 h under a stream of nitrogen. The reaction mixture was diluted with diethyl ether (50 mL) and 1Μ HCl (15 mL). The organic layer was then washed with 20 mL of saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used without further purification. MS: w / z 229 (M - CO2II).

Step B, Methyl 2-٢r2- (3_٦5-difluorophenyl) -2-oxoethyl٦thio | -2-methylpropanoate

To a solution of 2 - {[2- (3,5-difluorophenyl) -2-oxoethylthio} -2-methylpropano'ic acid from Step A (400 mg, 1.46 mmol) in MeOH (3 mL), trimethylsilyldiazomethane (2M in hexanes) was added until the yellow color persisted. The reaction mixture was stirred for an additional twenty minutes. The reaction mixture was diluted with ether (30 mL) and water (10 mL). The organics were washed with 5% sodium bicarbonate and then with saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by chromatography on silica gel, eluting with a gradient of CHClHexanes - 40:60 to 90:10, to give the title compound. MS: m / z = 229 (M - CO 2Me).

Step c. Ethyl 2- {r (27?) - 2-r (Zgrt-butylsulfinvl) amino٦-2- (3,5-difluorophenyl) ethyI٦thio) -2methylpropanoate

To methyl 2 - {[2- (3,5-difluorophenyl) -2-oxoethyljthio} -2-methylpropanoate from Step B (500. mg, 1.74 mmol) was added (7?) - (t ) -2-methyl-2propanesulfinamide (254 mg, 2.09 mmol) under a constant stream of nitrogen. The reagents were dissolved in THF (17 mL), and to the above mixture was added titanium ethoxide (796 mg, 3.49 mmol). The reaction was stoppered and stirred at 60٥c for 15 hours. The reaction was complete as determined by analysis.

-43A /

558 ج 3

LCMS and transesterification was observed. The reaction was gradually cooled to 0 ° C under nitrogen. To the reaction mixture was added sodium borohydride (132 mg, 3.49 mmol). The reaction was complete after fifteen minutes as indicated by LCMS analysis. The reaction was quenched after a further twenty minutes of stirring with methanol until gas evolution had stopped. Saturated brine (30 mL) was added with vigorous stirring and the resulting slurry was filtered through Celite and washed with aliquots of ethyl acetate. The organic layer was then washed with brine and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with an EtOAcHexanes gradient 20:80 to 75:25, to give the title compound (containing 10% of the diastereomer unwanted).

MS: ot / z = 408 (M٠1).

Step D. (57?) - 5- (3,5-Difluorophenyl) -2,2-dimethylthiomorpholin-3-one

To a solution of methyl 2 - {[(2-ft) -2 - [(fôrhutylsulfinyl) amino] -2- (3,5-difluorophenyl) ethylj thio} -2-methylpropanoate from Step c (428 mg, 1.09 mmol) in MeOH (20 mL), cooled to 0 ° C, anhydrous HCl gas was added for 1 minute. The reaction was stoppered and allowed to stand at 0 ° C for fifteen minutes, after which nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional McOII (30 mL) was added and it was further concentrated in vacuo. This was repeated with further addition of MeOH and triethylamine (440. mg, 4.35 mmol). To the resulting residue were added toluene (10 mL) and triethylamine (440 mg, 4.35 mmol). A reflux condenser was attached and the mixture stirred at 115 ° C. After one week of stirring, the reaction was judged 90% complete by LCMS. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (50 mL) and washed individually with 20 mL of each of the following aqueous solutions: 1 M HCl (twice), water, and saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of MeOHCHCl -1: 99 to 5:95, to give the title compound. MS: mlz = 258 (M ٠ 1).

-443ΘΙ58

INTERMEDIATE 3

<img file="MA30558B1_D0017.tif" />

Me

Benzyl 5- {rOS۴) -feN-butvlsulfinvl1iminol-2,2-dimethvlDentanoate

Step A. Benzyl 2,2-dimethylpent-4-enoate

Has a mixture of K2CO3 (1.58 g, 11.5 mmol), 2,2-dimethylpent-4-enoic acid (1.30 g, 10.1 mmol) and DMF (8.1 mL ) Benzyl bromide (1.40 g, 8.19 mmol) was added slowly over 15 minutes. After 4 hours the mixture was diluted with a mixture of water (80 mL) and diethyl ether (80 mL). The organic layer was separated and washed successively with 80 mL of 5% aqueous sodium bicarbonate, saturated copper sulfate, slightly acidic water, semi-saturated brine, and then saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used without further purification. MS: m / z = 219 (M 1 ؛).

Step B. Benzyl 5-hydroxy-2,2-dimethylpentanoate

To a solution of benzyl 2,2-dimethylpent-4-enoate (5.74 g, 26.3 mmol, prepared according to Step A) in THF (100 mL) was added a solution of 9-ΒΒΝ (63 , 1 mL, 31.6 mmol, 0.5 M in THF) over 20 minutes, under nitrogen. The reaction was allowed to stir at low temperature for 17 hours. An aqueous solution of sodium acetate (7.3 g, 89 mmol, in 18 mL of water) was then added, which was followed by the slow addition of aqueous hydrogen peroxide (18 mL, solution to 30% by weight) with occasional cooling in a bath at 0 ° C. This mixture was allowed to stir at room temperature for 1.5 hours, before being extracted with ethyl acetate. The combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of MeOHDCM -1: 99 to 10:90, to give the title compound. MS: mlz = 237 (M + 1).

Step c. Benzyl 2.2-dimethvl-5-0X0Pentan0ate

To a solution of oxalyl chloride at -78 ° C (4.80 g, 37.8 mmol) in DCM (200 mL) was added DMSO (5.91 g, 75.6 mmol) dropwise. over 10 minutes. After 25 minutes of additional stirring, a -78 ٥c solution of benzyl 5-hydroxy-2,2-dimethylpentanoate (4.06 g, 17.2 mmol. Step B) in DCM (200 mL) was added to using a cannula over 75 minutes. After stirring for an additional 30 minutes, triethylamine (13.9 g, 137 mmol) was added slowly over 25 minutes. The cooling bath was allowed to warm up, while the reaction was stirred for an additional 18 hours. The reaction solvent was then extracted in vacuo, and the residue was dissolved in a mixture of diethyl ether and water (containing enough HCl to remain acidic). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.67 g), which was used without further purification.

Step D. Benzyl d-IiOSTte rt-butvlsulfinvlliminol-2.2-dimethvlpentanoate

To a mixture of benzyl 2,2-dimethyl-5-0X0pentan0ate (1.06 g, 4.54 mmol. Step C) and

Anhydrous CuSO 4 (1.59 g, 9.98 mmol) in DCM (10 mL) was added (5) -2-methylpropane2-sulfinamide (0.550 g, 4.54 mmol). This mixture was stirred for 22 hours, before being filtered through a pad of Celite. Additional DCM was used to wash the Celite.

The combined organics were concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of MeOHDCM 0.5: 99.5 to 1.5: 98.5, to give the title compound, MS; m / z = 338 (M + 1).

INTERMEDIATE 4

<img file="MA30558B1_D0018.tif" />

(major sulfoxide isomer)

٢ (37?) - 3- (3,5-Difluorophenyl) -l-oxvdo-5-oxothiomorpholin-4-yl٦acetic acid (major sulfoxide isomer ')

Step A. Benzyl r (3J?) - 3-f3,5-difluorophenyl) -5-oxothiomorpholin-4-yl٦acetate

To a 0 ٥c solution of (57?) - 5- (3,5-difluorophenyl) thiomorpholin-3-one (247 mg, 1.08 mmol, prepared by analogy to intermediate 2) in THF (8, 0 mL) Sodium hydride (38 mg, 1.5 mmol, 95% by weight) was added. After 5 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature. After stopping the evolution of hydrogen gas, as evaluated by an oil bubbler, the reaction mixture was cooled to 0 ° C, before the introduction of benzyl acetate (272 mg, 1. 19 mmol). After 5

نملأ minutes, the ice bath was removed and the reaction was stirred for 15 hours. The bulk of the THF was extracted under reduced pressure. The residue was then diluted with water and ether. The aqueous layer was extracted once with ether and the combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of MeOHDCM - 0.5: 99.5 to 5:95, to give the title compound. MS: m / z = 378 (M + 1).

Step B. Benzyl 1 (, - 3 /?١-3-t3.5-difluoronhénvl -1 -oxvdo-5-oxothiomornholin-4-vllacetate A a solution of benzyl [(37?) - 3- (3,5- difluorophenyl) -5-oxothiomorpholin-4-yl] acetate (151 mg, 0.399 mmol, from Step A.) in MeOH (10 mL) aqueous hydrogen peroxide (30 drops, ~ 0.8 mL, 30% by weight), and aqueous HCl (5 drops, 3M HCl.) This mixture was then heated to 40 ٥c for 2.5 hours. After cooling to room temperature, the bulk of the MeOH was removed in vacuo, and the residue was partitioned between 50 mL of water and 100 mL of diethyl ether. The organics were washed with saturated brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel eluting with a gradient Hexanes: Et Ac - 1: 1 to 100% EtOAc, to give 24.5 mg of the minor sulfoxide isomer and 93.6 mg of the major sulfoxide isomer. MS: mlz = 394 (M) 1),

Step c. R (3j?) - 3- (3.5-difluorophénvl) -l-oxvdo-5-oxothiomomholin-4-vllacetic acid (major sulfoxide isomer)

A solution of benzyl [(37?) - 3- (3,5-difluorophenyl) -l-oxydo-5-oxothiomorpholin-4-yl] acetate (93.6 mg, 0.238 mmol, majority isomer, of Step B ) in MeOH (5 mL) was purged with nitrogen. The septum plugging the reaction vessel was briefly removed to allow introduction of Pd / C (-18 mg, 10% Pd / C). The vessel was then purged with hydrogen from a balloon, before a fresh hydrogen balloon was attached. After LCMS analysis indicated that the reaction had stopped at 60% conversion, the hydrogen atmosphere was replaced with nitrogen. The mixture was then filtered through a pad of Celite, washing with MeOH as needed. The filtrate was concentrated in vacuo to give a residue which was diluted with aqueous sodium bicarbonate (2%) and ether. The aqueous layer was extracted with ether (4 times) to extract unreacted starting material. The aqueous layer was then made acidic by the addition of 3M HCl, and then was saturated with NaCl. This acidic aqueous layer was then extracted three times with DCM and three times with EtOAc. Both organics were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. MS: m / z = 304 (Mil).

<img file="MA30558B1_D0019.tif" />

INTERMEDIARIES

<img file="MA30558B1_D0020.tif" />

F (minority sulfoxide isomer)

Ί (3 /?) - 3- (3.5-difluorophénvl) -l-oxvdo-5-oxothiomoroholin-4-vllacétiaue acid (minority sulfoxide isomer)

A solution of benzyl [(3Æ) -3- (3,5-difluorophenyl) -l-oxydo-5-oxothiomorpholin-4-yl] acetate (24.5 mg, 0.062 mmol, minor isomer, of the preparation of Intermediate 4, Step B) in MeOH (2 mL) was purged with nitrogen. The septum plugging the reaction vessel was briefly removed to allow introduction of Pd / C (~ 6 mg, 10% Pd / C). The vessel was then purged with hydrogen from a balloon, before a fresh hydrogen balloon was attached.

After LCMS analysis indicated that the reaction was proceeding slowly, a 10% Pd / C suspension was introduced using a syringe. After 2.25 hours the hydrogen atmosphere was replaced by nitrogen. Then the mixture was filtered through a pad of Cel te, washing with MeOII as necessary. The filtrate was concentrated in vacuo to provide the title compound, which was used without further purification. MS: m / z = 304 (Mtl).

INTERMEDIATE 6

<img file="MA30558B1_D0021.tif" />

R (3À) -3- (3,5-difluorophénvl) -l, l-dioxvdo-5-oxothiomorpholin-4-yl٦acetic acid

Step A. Benzyl l (3)?) - 3- (3,5-difluoronhénvl) -ll-dioxvdo-5-oxothiomornholin-4-vllacetate

To a solution of benzyl [(3 /?) - 3- (3,5-difluorophenyl) -5-oxothiomorpholin-4-yl] acetate (65.9 mg, 0.175 mmol, of the preparation of Intermediate 4, Step A) In DCM (3 mL) was added m-CPBA (86.0 mg, 0.350 mmol, 70% by weight). After 17 hours of stirring at room temperature, the reaction mixture was applied in a column of silica gel to be purified, eluting with a gradient of Hexanes: EtOAc - 95: 5 to 50:50, to give the

إكدا

<img file="MA30558B1_D0022.tif" />

The title compound, which was 83% pure (the remainder being m-CPBA), and was used without further purification.

Step B. ٢ (3.Æ) -3- (3,5-difluorophénvl) -ll-dioxvdo-5-oxothiomorpholin-4-vllacetic acid

A solution of benzyl [(3Æ) -3- (3,5-difluorophenyl) -l, 1-dioxydo-5-oxothiomorpholin-4yljacetate (71.7 mg, 0.145 mmol, 83%, from Step A) in MeOH (3 mL) was purged with ا of nitrogen. The septum plugging the reaction vessel was briefly removed to allow introduction of Pd / C (14 mg, 10% Pd / C). The vessel was then purged with hydrogen from a balloon, before a solid balloon of hydrogen was attached. After 30 minutes the atmosphere of hydrogen was replaced by nitrogen. Then the mixture was filtered through a pad of Celite, washing with MeOH as needed. The filtrate was concentrated in vacuo to provide the title compound. MS: m / z = 320 (M11).

INTERMEDIATE 7

<img file="MA30558B1_D0023.tif" />

l- {٢2- (Trimethvlsilvl) ethoxy٦methylI-1,3-dihydro-2.H-pyrrolo٢2,3-blpyridin-2-one

Step A. l-U2-TiméthvlsilvBéthoxvlméthvlL177-Dvrrolof2.3-blnvridine

Sodium hydride (dispersion at 60 ⁰/ in mineral oil; 16.2 g, 0.404 mol) was added portionwise over 25 min to a solution of 7-azaindole (39.8 g, 0.337 mol) in DMF (200 mL) at 0 ٠c and the mixture was stirred for 1 h. 2- (Trimethylsilyl) ethoxymethyl chloride (71.8 mL, 0.404 mol) was then added slowly over 15 min, keeping the temperature of the reaction mixture below 10 ٥c. After 1 h the reaction was quenched with water (500 mL) and the mixture was extracted with CH2Cl2 (5 X 300 mL). The combined organic layers were washed with saturated brine, dried over MgS0₄, filtered, concentrated and dried under high vacuum to give the title compound. MS: m / z = 249 (M + 1).

Step B. 3,3-Dibromo-lf ٢2- (triméthvlsilvl) ethoxvlméthvlI-1.3-dihvdro-277-pyrrolor2,3-b٦ pyridin-2-one

A solution of 1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrtolo [2,3-b) pj ^ ridine from Step A (43.1 g, 0.1735 mol) in dioxane ( 300 mL) was added dropwise over 3.0 min to a suspension of pyridine hydrobromide perbromide (277 g, 0.8677 mol) in dioxane (300

-أ ر ٦

-4958 ج © 3 mL). The reaction was stirred at room temperature using a mechanical overhead stirrer to produce two layers. After 60 min the reaction was quenched with water (300 mL) and extracted with EtOAc (500 mL). The aqueous layer was further extracted with EtOAc (2 X 300 mL) and the combined organic layers were washed with HO (4 X 300 mL; the final wash was pH 5-6) followed by brine (300 mL), dried over MgS0₄, filtered and concentrated in vacuo. The crude product was immediately dissolved in CHCl and the solution filtered through a pad of silica, eluting with CHCl until the dark red color was completely eluted from the pad. The filtrate was washed with saturated aqueous NaHO (400 mL), then brine (400 mL), dried over MgS0₄, filter, and concentrated in vacuo to give the title compound. MS: mlz = 423 (M ٠ 1).

Step Cl- (٢2- (Trimethvlsilyl) ethoxvlmethvl} -L3-dihvdro-27 / -pyrrolor2,3-b٦pyridin-2-one

Zinc (100g, 1.54 mol) was added to a solution of 3,3-dibromo-1 - {[2- (trimethylsilyl) ethoxyjmethyl} -l, 3-dihydro-2H-pyrro! O [2,3 -bjpyridin-2-one (65 g, 0.154 mol) in THF (880 mL) and NH₄C1 aqueous salute (220 mL). After 3 h, the reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between EtOAc and HO which resulted in the formation of a white precipitate. The two layers were filtered through a Celite pad and the layers were separated. The aqueous layer was washed with EtOAc (2 X 500 mL) and the combined organic layers were washed with HO, dried over MgS0₄, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with CHClEtOAc - 90:10, to give the title compound. MS: mlz = 265 (M t

INTERMEDIARIES

Ο2Ν

<img file="MA30558B1_D0024.tif" />

1.2--1¾ (bromomethyl-4-nitrobenzene

Step A. (4-Nito-1.2-phenvlenedimethanol

A solution of 4-nitrophthalic acid (40 g, 189.5 mmol) in THF (500 mL) was added dropwise over 1.5 h to a solution of a borane-THF complex (1 M, 490 mL, 490 mmol), maintaining the reaction temperature between 0 ° C and 5؟ c. After the addition, the reaction mixture was allowed to warm slowly to room temperature and stirred for 18

<img file="MA30558B1_D0025.tif" />

h. MeOH (100 mL) was added carefully and the solid precipitated dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0٥c, and 10N NaOH was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3 X 600 mL) and the combined organic layers were washed with brine, dried over N2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m / z = 207 (M - OH ا CHN).

Step B.! .2-, 5A (bromomethyD-4-nitrobenzene

Phosphorus tribromide (20.1 mL, 212 mmol) in Et2٠ (250 mL) was added dropwise over 1.5 h to a solution of (4-nitr0-1,2-phenylene) dimethanol. from Step A (35.3 g,

193 mmol) in Et20 (750 mL). After 18h the reaction mixture was cooled to 0 0c and quenched with HO (100 mL). The layers were separated and the organic layer was washed with HO (2 X 200 mL), then aqueous saturated NaHO, dried over Na.₂SO4, filtered, and concentrated in vacuo to give the title compound. MS: m / z = 309 (Μ + 1).

INTERMEDIATE 9

<img file="MA30558B1_D0026.tif" />

tf) -5-Amino-1. 3-dihvdrosniroIndèn-2.3'-nvrrolor2.3-blpvridinl-2 '(T77) -on

Step A. (±) -5-Nitro-l'-i٢2- (trimethylsilvl) ethoxvlmethvl) -l, 3-dihydr0spir0rindene-2,3'Pvrr01or2,3-b٦pyridinl-2'ÎHone

To a solution of l, 2-٥٥ (bromomethyl) -4-nitrobenzene (40.9 g, 132 mmol, described in intermediate 8) and l-2] ؛-( trimethylsilyl) ethoxyJmethyl} -l, 3- dihydro-277-pyrrolo [2,3hjpyridin-2-one (31.5 g, 119 mmol, described in intermediate 7) in DMF (2 L) cesium carbonate (129 g, 397 mmol) was added , in portions, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and HO (1 L) ). The organic layer was washed with HO (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 0: 100, to give the title compound. MS: m'z = 412 (Mtl).

؛ لا

<img file="MA30558B1_D0027.tif" />

Step B. (±) -5-Amino-l'-ir2- (trimethylsilvl) ethoxv٦methyl} -L3-dihvdrospirorindene-2,3'pyrrolo٢2,3-à٦pyridin٦-2ïl'7: f) -one

A mixture of Pd / C at 10 3) يحبا g) and (±) -5-nitro-l '- ([2- (trimethylsiIyl) ethoxy] methyl} -l, 3dihydrospiro [indene-2,3'-pyrrolo [2,3-è] pyridin] -2 '(l'77) -one from Step A (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL) under a nitrogen atmosphere (about 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing thoroughly with MeOH, and the filtrate was concentrated in vacuo to give the title compound MS: mlz = 382 (Mtl).

Step c. tert-Butyl (7?) - (2'-oxo-l '- {i2- (trimethvlsilvl) ethoxy] methvll-Ll'.2^,, 3-tetrahydrospiro lindene-2.3'-pvrrolof2.3-blpyridinl-5-vl carbamate

A solution of (±) -5-amino-l '- {[2- (trimethylsilyl) ethoxyjmethyl} -l, 3-dihydrospiro [indene-2,3'pyrrolo [2,3-b] pyridinj-2' (l '77) -one from Step B (104 g, 273 mmol) and di-butyl dicarbonate (71.5 g, 328 mmol) in CHCl (1 L) was heated at reflux for 17 h. The refioid mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with hexane: EtOAc - 100: 0 to 50:50, to give the racemic product. The enantiomers were resolved by HPLC, using a ChiralPak AD column and eluting with EtOH. The first major peak to elute was tert-butyl (5j- (2'-oxo-l '- {P (trimethylsilyl) ethoxyjmethyl} -l, T, 2', 3-tetrahydrospirofindene-2,3'-pyrolo [2 , 3-٥] pyridin] -520 yl) carbamate, and the second major peak to elute was iert-butyl (7?) - (2'-οχο-1 '- {[2٠ (trimethylsilyl) ethoxy] methyl} - 1,1 ', 2', 3-tetrahydrospiro [indene-2,3'-pyrrolo [2,3-bjpyridin) -5yl) carbamate, the title compound. MS: mlz = 482 (M 1 ا).

StepD. (7?) - 5-Amino-l, 3-dihydrospiroèneindene-2,3'-pyrrolo٢2,3-blpyridinl-2 '(l'77) -one

A solution of tert-butyl (7?) - (2'-oxo-l '- {[2- (trimethylsilyl) ethoxyjmethyl} -l, l', 2 ', 3tetrahydrospiro [indene-2,3'-pyrrolo [2 Step c, 3-bJpyridinj-5-yl) carbamate (13.4 g, 27.8 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was again saturated with HCl (g) every 30 min until starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (1.9 mL, 27.8 mmol) and 10 N sodium hydroxide (6 mL, 60 mmol) to adjust the mixture. to pH 10. After 30 min the mixture was diluted with HO (400 mL) and extracted with CHCl3 (1 L). The organic layer was dried over Na2SO،, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (35 mL) to give the title compound. MS: mlz = 252 (M + 1).

INTERMEDIATE 10

؛/٦

<img file="MA30558B1_D0028.tif" />

R (57?) - 5- (3,5-difluorophenyD-2,2-dimethyl-3-oxomorpholin-4-yllacetic acid

Step A. N-ï (Ss, l ^) - 2- {rtert-Butyl (dimethyl) silylloxy} -1- (3,5-difluorophenyl) ethyl٦-2methylpronane-2-sulfinamide

To a stirred solution of (, Ss) -A - ((lE) -2- {l] l, utyl (dimethyl) silyi;] oxy} ethylidene) -2methylpropane-2-sulfinamide (5.00 g, 17.9 mmol) [Tang et al. (2001) ر. Org. Chem., 66, 87728778] in THF (75 mL) at -78 ٥c was added 3,5-difluorophenylmagnesium bromide (71.6 mL of a 0.5 M solution in THF, 35.8 mmol ) drip. The reaction mixture was stirred at -78 ° C for 5 h, then allowed to warm slowly to room temperature and the stirring continued for 18 h. The mixture was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3 X 75 mL). The combined organic layers were dried over Na2 ،؟ O4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHClEtOAc - 100: 0 to 80:20, to give the title compound. MS: mlz = 392 (Mil).

Step B. f27?) - 2-Amino-2-i3,5-difluorophenyl) ethanol

To a solution of N - [(Ss, 1A) -2 - {[ferr-butyl (dimethyl) silyl] oxy} -1- (3,5-difluorophenyl) ethyl] -2methylpropane-2-sulfinamide from Step A (1.50 g, 3.81 mmol) in MeOH (40 mL) at 0 ٥c HCl (9.5 mL of a 2 M solution in Et2O, 19 mmol) was added. After 20 min the reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in HO (25 mL) and the mixture was extracted with EtOAc (2 X 50 mL) and these organic extracts were discarded. The aqueous phase was adjusted to pH 10 by the addition of 1N NaOH and extracted with EtOAc (2 X 50 mL). These organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: mlz = 174 (Μ1 ؛).

Step C..2-Chloroir (17 (') - l- (3,5-difluorophénvl) -2-hvdroxyéthvl٦acetamide

Has a solution of (2 ^?) - 2-amino-2- (3,5-difluorophenyl) ethanol from Step B (630 mg, 3.64 mmol) and triethylamine (0.51 mL, 3.64 mmol) in CH2Cl2 (40 mL) at 0 ٥c chloroacetyl chloride (0.29 mL, 3.64 mmol) was added. After 20 min the reaction mixture was quenched with saturated aqueous NaHO (15 mL) and extracted with CH2Cl2 (2 X 25 mL). The

رر

0558 Combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SC&gt; 4, filtered, and concentrated in vacuo to give the title compound. MS: m / z = 250 (Μ + 1).

Step D. (57?) - 5- (3.5-Difluorophénvl) morpholin-3-one

To a solution of 2-chloro-A - [(1Æ) -1- (3,5-difluorophenyl) -2-hydroxyethyljacetamide from Step c (840 mg, 3.37 mmol) in THF (75 mL) at 0 ° C NaH (291 mg of a 60% dispersion in oil, 7.28 mmol) was added and the mixture was stirred at room temperature for 1 h. Saturated aqueous NHCl (10 mL) was added and the mixture was extracted with EtOAc (2 X 20 mL). The combined organic layers were dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 75:25 to 25:75 gradient, to give the title compound. MS: mlz = 214 (M + 1).

Step E. CtButvl 37? ١-3- (3.5-difluorophénvl١-5-oxomorpholine-4-carboxvlate

A solution of (57?) - 5- (3,5-difluorophenyl) morpholin-3-one from Step D (570 mg, 2.67 mmol), dieri-butyl dicarbonate (584 mg, 2.67 mmol), and 4-dimethylaminopyridine (327 mg, 2.67 mmol) in ClICl (30 mL) was stirred at room temperature for 1 h. The solvent was extracted under reduced pressure and the residue was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 90:10 to 50:50 gradient, to give the title compound. MS: w / z = 377 (MtNat CHCN).

Step F. tetButvl i57D-5- &lt;3.5-difluorophénvl١-2.2-dimethvl-3-oxomorpholine-4-carboxvlate A a 1 M solution of sodium ٥A (tri methylsilyl) amide in THF (1.60 mL, 1.60 mmol) at -78 ° C a solution of tert-butyl (3Æ) -3- (3,5-difluorophenyl) -5oxomorpholine-4-carboxylate from Step E (500 mg, 1.60 mmol) in DME (15 mL) at 78 ° C. The resulting mixture was stirred at -78 ° C for 10 min then iodomethane (0.099 mL, 1.60 mmol) was added. After stirring at -78 ° C for an additional 1 h, the reaction mixture was slowly decanted using a cannula into a 1 M solution of sodium ٥A (trimethylsilyl) amide in THF (1.60 mL, 1 , 60 mmol) at -78 ° C. The resulting mixture was stirred at -78 ° C for 10 min then a second equivalent of iodomethane (0.099 mL, 1.60 mmol) was added. After stirring at -78 ° C for an additional 1 h, the reaction mixture was quenched with saturated aqueous NHCl (10 mL) and extracted with EtOAc (2 X 25 mL). The combined organic layers were dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexaneEtOAc -90: 10 to 60:40 gradient, to give the title compound. MS: 286 = ص (M - C4H7).

X /

<img file="MA30558B1_D0029.tif" />

Step G. (57?) - 5- (3,5-Difluorophénvl) -2,2-dimethylmorpholin-3-one

To a solution of ZerZ-butyl (5Æ) -5- (3,5-difluorophenyl) -2,2-dimethyl-3-oxomorpholine-4carboxylate from Step F (225 mg, 0.66 mmol) in CH2Cl2 ( 3 mL) at room temperature was added TFA (0.49 mL, 6.6 mmol). After stirring for 1 h, the reaction mixture was concentrated in vacuo to give the title compound. MS: mlz = 242 (M + 1).

Step H, Ethyl r (5R) -5- (3,5-difluorophényD-2,2-dimethyl-3-oxomorpholin-4-yl '| acetate

To a stirred solution of (5R) -5- (3,5-difluorophenyl) -2,2-dimethylmorpholin-3-one from Step G (150 mg, 0.62 mmol) in DMF (2 mL) at 0 ٥c was added NaH (27 mg of a% dispersion in oil, 0.68 mmol). After 10 min, ethyl bromoacetate (104 mg, 0.62 mmol) was added and the mixture was stirred at 0 ٥c for 30 min. Saturated aqueous NaHCO3 (5 mL) was added and the mixture was extracted with EtOAc (2 X 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 95: 5 gradient to 70:30, to give the title compound. MS: mlz = 328 (M 11).

Step I. ٢ (5jR) -5- (3,5-difluorophenyl) -2,2-dimethyl-3-oxomorpholin-4-vl1acetic acid

To a solution of ethyl [(5R) -5- (3,5-difluorophenyl) -2,2-dimethyl-3-oxomorpholin-4-yl] acetate from Step H (150 mg, 0.46 mmol ) in THF (3 mL) and Η2Ο (3 mL) 1N aqueous LiOH (0.55 mL, 0.55 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was purified directly by HPLC using a reverse phase C18 column and eluting with a gradient of H20: CHCN: CF3CO2H 90: 10: 0.1 to 5: 95: 0.1. Hydrophilization gave the title compound. MS: mlz = 300 (Mil).

INTERMEDIATE 13

<img file="MA30558B1_D0030.tif" />

<img file="MA30558B1_D0031.tif" />

Lithium lt67?) - 4-fie ^ -butoxvcarbonvl) -6-t3.5-difluorophénvI) -3.3-diméthvl-2-oxoninerezin-lvllacétate

٠؛ 2/

Step A. Methyl 2-ir2-i3,5-difluorophénvl) -2-oxoéthvHamino&gt; -2-meth \ lr) ropanoate

A mixture of methyl a-aminoisobutyrate hydrochloride (10.3 g, 67.0 mmol), 3,5-difluorophenacyl bromide (15.0 g, 63.8 mmol), and K2CO3 (17.6 g, 128 mmol ) in DMF (100 mL) was stirred at room temperature for 3 h. Saturated aqueous NallO (400 mL) was added and the mixture was extracted with EtOAc (1 L). The organic layer was washed with brine, dried over Na2S٠4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 0: 100, to give the title compound. MS: m / z = 272 (M + 1).

Step B, (±) -ethyl r6- (3,5-difluorophénvl) -3,3-dimethyl-2-oxopiperazin-1-vllacetate

A mixture of methyl 2 - {[2- (3,5-difluorophenyl) -2-oxoethyl] amino) -2-methylpropanoate from Step A (8.60 g, 31.7 mmol), ester hydrochloride Ethyl glycine (44.3 g, 317 mmol), and AcOH (5.71 mL, 95 mmol) in MeOH (300 mL) was stirred at room temperature for 10 min. NaCNBH (2.39g, 38.0mmol) was added and the pH of the mixture was checked and adjusted to pH ~ 5 as needed. The reaction mixture was heated to 50 ° C for 18 h. Additional AcOH (4 mL) was added and the reaction mixture was heated to 60 ٥c for 6 h then allowed to cool and concentrate in vacuo to a volume of about 150 mL. The resulting mixture was carefully quenched with saturated aqueous NaHO (300 mL) and then extracted with CllCl (1 'L). The organic extract was washed with brine, dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with: EtOAc - 100: 0 to 0: 100, to give the title compound. MS: m / z = 327 (M 11).

Step c. teU-Butyl (5A) -5- (3,5-difluorophenyl) -4- (2-ethoxy-2-oxoethyl) -2,2-dimethyl-3oxoninerezine-1 -carboxylate

A solution of ethyl [8- (3,5-difluorophenyl) -10-oxo-6,9-diazaspiro [4.5] dec-9-yl) acetate from Step B (2.27 g, 6.96 mmol ), MTAdiisopropylethylamine (0.607 mL, 3.48 mmol), and di-rrbutyl dicarbonate (15.2 g, 69.6 mmol) in acetonitrile (30 mL) was stirred at 60 ٥c for 18 h, then refioid and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a hexane.EtOAc - 100: 0 to 0: 100 gradient, to give the racemic product. The enantiomers were separated by SFC, using a Chiralcel OD column eluting with CO2: MeOH - 80:20. The first major peak to elute was terbutyl (55) -5- (3,5-difluorophenyl) -4- (2-ethoxy-2-oxoethyl) -2,2-dimethyl-3oxopiperazine-1 -carboxylate and the second peak majority to elute was tert-butyl (5 ^) - 5- (3,5difluor0phenyl) -4- (2-eth0xy-2-0X0ethyl) -2,2-dimethyl-3-0Xopiperazine-1-carboxylate, the title compound . MS: w / z = 371 (M - C4H7).

-5630558

StepD. Lithium ^ 6 ^ ١-4- ^ e ^ -butoxycai-bonvl) -6 - ('3.5-difluoroDhénvl) -3.3-dimethvI-2oxopiperazin-l-yllacetate

To a solution of terLbutyl (5R) -5- (3,5-difluorophenyl) -4- (2-ethoxy-2-oxoethyl) -2,2-dimethyl3-oxopiperazine-1 -carboxylate from Step c (1, 18 g, 2.77 mmol) in THF (18 mL) and HO (2 mL) 1N aqueous LiOH (3.04 mL, 3.04 mmol) was added and the resulting mixture was stirred at room temperature for 5 h. The mixture was adjusted to pH 6 by the addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m / z = 343 (M CH).

INTERMEDIATE 14

<img file="MA30558B1_D0032.tif" />

(Ô ') - r6- (3-fluoro-4-methylphenyl) -3٩3-dimethyl-2-oxopiperidin-1-yl٦acetic acid

Step A٠G3) -6 - (؟ - Fluoro-4-méthvlphenyl) -3.3-dimethylpiperidin-2-one

To a stirred solution of benzyl (5s) -5 - [(ter h tylsulfinyl) iminoj-2,2-dimethylpentanoate (1.00 g, 2.96 mmol, described in Intermediate 3) in toluene (28 mL) at - 78 ٥c 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 M solution in THF, 5.93 mmol) was added. The reaction mixture was warmed to room temperature for 2 h, and then heated to reflux for 2 h. The solvent was extracted in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of HOCHCNCFsCCH - 90: 10: 0.1 to 5: 95: 0.1. Lyophilization provided the title compound. MS: mlz = 236 (M 1 ؛).

Step B. 6STÎ6 - ('3-Fluoro-4-méthvhénvl') - 3.3-dimethvl-2-oxopiperidin-1-vl acetic acid

To a stirred solution of (5) -6- (3-fluoro-4-methylphenyl) -3,3-dimethylpiperidin-2-one from Step A (80 mg, 0.340 mmol) in DMF (3 mL) at At room temperature NaH (19 mg of a 60% dispersion in oil, 0.476 mmol) was added. After 15 min, methyl bromoacetate (0.051 mL, 0.544 mmol) was added and the mixture was stirred for 16 h. Sodium hydroxide (0.061 mL of a 10 M solution, 0.612 mmol) was added and the mixture was mixed.

٠s٦158 stirred for 2 h. The crude product was purified directly by HPLC using a reverse phase C18 colomer and eluting with a H2O: CH gradient.₃CN: CF₃CO2H - 90: 10: 0.1 to 5: 95: 0.1. The compound was further purified by SFC, using a ChiralPak AD column eluting with CC&gt; 2: MeOH -91: 9, to give the title compound. MS: m / z = 294 (Mil).

<img file="MA30558B1_D0033.tif" />

Lithium D-3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl٦acetate

Step A. Methyl (2f?) - 2-٢ (2-oxo-2-phenylethyl) aminolpropanoate, TFA salt A mixture of (Æ) -anine methyl ester hydrochloride (1.00 g, 7.16 mmol), of 2bromoacetophenonc (2.85 g, 14.3 mmol), and Na! ΙΟ (1.20 g, 14.3 mmol) in DMF (20 mL) was stirred at room temperature for 6 h. The reaction mixture was quenched with 1N aqueous HCl (25 mL) and the mixture was extracted with EtOAc (2 X 35 mL) and the organic layer was discarded. The aqueous phase was adjusted to pH 10 with Na₂Aqueous CO3 saturates and then extracted with EtOAc (3 X 75 mL). The combined organic extracts were dried over Na₂SO4, filters, and vacuum concentrates. The crude product was purified by HPLC using a reverse phase c 18 column and eluting with a gradient of O'.CHCNUFjCCH - 90: 10: 0.1 to 5: 95: 0.1. Concentration of the fractions containing the product in vacuo gave the title compound. MS: mlz = 222 (M + 1).

Step B. Methyl r (37?) - 3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl٦acetate

To a stirred mixture of methyl (2f?) - 2 - [(2-oxo-2-phenylethyl) amino) propanoate, TFA salt, from Step A (152 mg, 0.452 mmol) and methyl ester hydrochloride of glycine (85 mg, 0.678 mmol) in MeOH (1 mL) was added AjA-diisopropylethylamine (0.197 mL, 1.13 mmol), followed by AcOH (0.155 mL, 2.71 mmol). The resulting mixture was stirred at room temperature for 10 min, then NaCNBH (34 mg, 0.54 mmol) was added. The reaction mixture was heated to 50 c for 18 h then allowed to cool. Formaldehyde (0.067 mL of a 37% aqueous solution, 0.90 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with

زب اط

<img file="MA30558B1_D0034.tif" />

1N aqueous HCl (5 mL) and the mixture was extracted with EtOAc (2x10 mL) and the organic layer was discarded. The aqueous phase was adjusted to pH 10 with saturated aqueous Ν٤2θ and then extracted with EtOAc (3 X 15 mL). The combined organic extracts were dried over iaSO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of

H2O: CH3CN: CF3CO2H - 90: 10: 0.1 to 5: 95: 0.1. Fractions containing the product were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO،, filtered, and concentrated in vacuo to provide the title compound. MS: mlz = 277 (M 1 ؛).

Step c. Lithium r (37?) - 3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl٦acetate

A solution of methyl [(3Æ) -3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yljacetate from Step B (50 mg, 0.18 mmol) in THF (1 mL) has 1N aqueous LiOH (0.20 mL, 0.20 mmol) was added and the resulting mixture was stirred at room temperature for 4 h. The mixture was adjusted to pH 6 by the addition of 1N HCl and concentrated to dryness in vacuo to give the title compound. MS: mlz = 263 (M + 1).

INTERMEDIATE 20

<img file="MA30558B1_D0035.tif" />

R (57?) - 2,2-diethyl-3-oxo-5-phenylmorpholin-4-yl٦acetic acid

Step A. 2-Chloro-.V-fil- ^ 1-2-hvdroxv-1 -phénvléthvllbutanamide

Has a solution of (Æ) -2-phenylglycino! (2.00 g, 14.6 mmol) and triethylamine (2.03 mL, 14.6 mmol) in CH2Cl2 (100 mL) at 0 ٥c 2-chlorobutyryl chloride 25 (1.66 mL, 14.6 mmol). After 30 min the reaction mixture was quenched with saturated aqueous NaHO (30 mL) and extracted with CH2Cl2 (2 X 75 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SCL, filters, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 70:30 to 0: 100 gradient, to give the title compound. MS: mlz = 30,242 (Mil).

نملا

3058

Step Β٠ (27?, 57?) - 2-ethvl-5-phenvlmorpholin-3-one

To a solution of 2-chl0r0-N - [(lÆ) -2-hydr0xy-1-phenylethyl] butanamide from Step A (2.75 g, 11.4 mmol) in THF (200 mL) at 0 ٥c NaH (983 mg of a 60% dispersion in oil, 24.6 mmol) was added and the mixture was stirred at room temperature for 18 h. Of

Saturated aqueous NaHO (20 mL) was added and the mixture was extracted with EtOAc (3 X 40 mL). The combined organic layers were dried over N2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 75:25 to 0: 100 gradient, to give the title compound. MS: m / z = 206 (M 1 ا).

Step C tert-Butyl (27?, 57?) - 2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate

A solution of (27?, 57?) - 2-ethyl-5-phenylmorpholin-3-one from Step B (900 mg, 4.41 mmol), of di- ؛ dicarbonate ert-butyl (962 mg, 4.41 mmol), and 4-dimethylaminopyridine (538 mg, 4.41 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 4 h. The mixture was washed with 10% citric acid (35 mL), then dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc-95: 5 to 60:40 gradient, to give the title compound. MS: m / z = 250 (M -C4H7).

Step D. Zcrt-Butyl (57?) - 2,2-diethyl-3-oxo-5-phenylmorpholine-4-carboxylate

To a 1 M solution of sodium ٥A (trimethylsilyl) amide in THF (1.64 mL, 1.64 mmol) at -78 ٥c was added dropwise a solution of tert-butyl (27?, 5T?) - 2-ethyl-3-oxo-5phenylmorpholine-4-carboxylate from Step c (500 mg, 1.64 mmol) in DME (25 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 10 min then iodoethane (0.131 mL, 1.64 mmol) was added. After stirring at -78 ° C for 30 min, then at -30 ° C for 30 min, the reaction mixture was cooled to -78 ° C and quenched with saturated aqueous NH4Cl (20 mL) then extracted with EtOAc (2 X 40 mL). The combined organic layers were dried over Na2§04, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of hexane: EtOAc - 95: 5 to 70:30, to give the title compound. MS: m / z = 278 (M - C4H7).

Step E. ft57? L-2.2-diéthvl-3-oxo-5-phenvlmornhoIin-4-vllacétiaue acid

Essentially following the procedures described for Intermediate 10, but using tert-butyl (57?) - 2,2-diethyl-3-oxo-5-phenylmorpholine-4-carboxylate in place of tert-butyl (57 ?) - 5- (3,5-difluorophenyl) -2,2-dimethyl-3-oxomorpholine-4-carboxylate, the title compound was prepared. MS: wU = 292 (M 11).

INTERMEDIATE 21

-603Θ558

<img file="MA30558B1_D0036.tif" />

Acid iï4&gt; S ', 6_lS ') - 6-f3,5-difluorophenyl) -4-hydroxy-3,3-dimethvl-2-oxopiperidin-1-yl' | acetic

Step A. 6- (3,5-Difluorophénvl ') - 3..3-dimethvloiperidine-2.4-dione

Has a solution of 3,3-dimethylpyridine-2,4 (177.3E7) -dione (978 mg, 7.03 mmol) [US Patent

525 231] in benzene (10 mL) 3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THE, 25 mmol) was added and the resulting mixture was heated. until reflux for 1.5 h. The mixture was cooled, quenched with 1N aqueous HCl (10 mL), made basic with saturated NaHO solution (100 mL) and extracted with EtOAc (2 X 150 mL). The combined organic layers were washed with HO (50 mL), then brine (50 mL), and dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc 100: 0 to 60:40 gradient, to give the title compound. MS: m / z = 254 (Mtl).

Step B. £ ^ -6- (3.5-Diflu0r0phénvfl-4-hvdr0XV-3.3-dimethvIpiperidin-2-0ne

To a solution of 6- (3,5-difluorophenyl) -3,3-dimethylpiperidine-2,4-dione from Step A (20.18 g, 80 mmol) in THF (600 mL) and CHOH ( 25 mL) at 0 ٥c NaBH (4.57 g, 121 mmol) was added. After 2.5 h, the reaction mixture was quenched with HO (200 mL) and concentrated in vacuo. The residue was partitioned between HO (600 mL), saturated aqueous NaHO (200 mL) and EtOAc (1 L). The organic layer was separated and the aqueous layer was extracted with FEtOAc (600 mL). The combined organic layers were dried over NazSCf1, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCICHOH - 100: 0 to 88:12, to give the title compound, which contained approximately 20 ٥/٥ of the corresponding trans isomer. MS: m / z = 256 (Mtl).

Step c. Ethyl r (4₁S٦6_&gt;6 - (؟ - f3.5-difluorophénvl) -4-hvdroxv-3.3-dimethvl-2-oxoniperidin-lyllacetate

To a solution of cz^٠5-6- (3,5-difluorophenyl) -4-hydroxy-3,3-dimethylpiperidin-2٦one from Step B (17.1 g, 67.0 mmol) in THF (400 mL) at 0 ° C NaH (60% dispersion

<img file="MA30558B1_D0037.tif" />

in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate (8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NHCl (100 mL), diluted with HO (700 mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organic extract was dried over Na2S٠4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 0: 100, to give the alcohol as a mixture of four isomers. Further purification was achieved by HPLC, using a ChiralPak AD column and eluting with EtOH: Et2NH - 90: 10: 0.1. The first major peak to elute was a mixture of ethyl [(45,65) -6- (3,5-difluorophényI) -4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl] acetate and ethyl [(45,6Æ) -6- (3,5-difluorophenyl) -4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yi; iacetate (about 5: 1). The second major peak to be eluted was a mixture of ethyl [(47?, 67?) - 6- (3,5diflu0r0phenyl) -4-hydr0xy-3,3-dimethyl-2-0X0piperidin-1-yl] acetate and ethyl [(4 ^, 65) -6- (3,5diflu0r0r0phenyl) -4-hydr0xy-3,3-dimethyl-2-0X0X0piperidin-1-yl] acetate (about 3: 1). Further purification of the second major peak was obtained by SFC, using a ChiralPack AD column eluting with CC »2: MeOH: Et2NH - 90: 10: 0.1, to give ethyl [(47?, 67? ) -6- (3,5-difluorophenyl) -4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yljacetate, which eluted first, and ethyl [(47?, 65) -6 - (3,5-difluorophenyl) -4-hydroxy-3,3-dimethyl-2oxopiperidin-1 -yl! Acetate, which eluted second. Further purification of the first major peak was obtained by SFC, using a ChiralPack AD column eluting with

CO2: MeOH: Et2NH - 90: 10: 0.1, to give ethyl [(45.67?) - 6- (3,5-difluorophenyl) -4-hydroxy3,3-dimethyl-2-0X0piperidin-1 -yl] acetate, which eluted first, and ethyl [(45.60) -6- (3,5diflu0r0phenyl) -4-hydroxy-3,3-dimethyl-2-0X0piperidin-1-yl] acetate , who was elected second, composes the title. MS: mlz = 342 (M t 1).

Step D. [(45,65) -6- (3,5-difluorophénvl) -4-hydroxv-3,3-dimethvl-2-oxopiperidin-lvllacetic acid

To a solution of ethyl [(45 ', 65) -6- (3,5-difiuorophenyl) -4-hydroxy-3,3-dimethyl-2-oxopiperidinl-yljacetate from Step c (64 mg, 187 mmol ) in THF (1 mL) and HO (0.5 mL) LiOH monohydrate (14 mg, 334 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 1N HCl (0.40 mL, 400 mmol), concentrated in vacuo and dried to give the title compound. MS: mlz = 314 (Mt

INTERMEDIATE 22

-6230558

<img file="MA30558B1_D0038.tif" />

R (6.S) -6-f3.5-difluorophénvl) -3.3-dimethvl-2,4-dioxo٠iperidin-l-yl٦acetic acid

Step A. Ethyl ٢ (65٦-6- (3_١5-difluorophénvl١-3.3-dimethYl-2,4-dioxopiDeridin-1-yllacetate

To a solution of ethyl [(45,66) -6- (3,5-diflu0r0phenyl) -4-hydr0xy-3,3-dimethyl-2-0xopiperidinl-yljacetate (470 mg, 1.377 mmol, described in intermediate 21) in acetone (24 mL) at 0 ° C was added a solution of chromium (VI) trioxide (174 mg, 1.740 mmol) in HO (0.5 mL) and H2SO4 (0.147 mL, 2, 75 mmol), in three portions over 5 min and the mixture was stirred at 0 ٥c for 30 min. Most of the acetone was removed by concentration in vacuo, and the residue was basified with saturated aqueous NaHO (75 mL) and extracted with EtOAc (2X.

100 mL). The combined organic layers were washed with brine (40 mL) and dried over Na2S () 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCICHOH - 100: 0 to 92: 8, to give the title compound. MS: m / z = 340 (M t 1).

Step B, Ri-6- (3.5-difluorophénvl) -3,3-dimethvl-2,4-dioxopiperidin-l-vllacetic acid

To a solution of ethyl [(6iS) -6- (3,5-difluorophenyl) -3,3-diméhl-2,4-dioxopiperidin-1-yl] acetate from Step A (170 mg, 0.501 mmol) in THF (2 mL) and Η2Ο (1 mL) LiOH monohydrate (36 mg, 0.858 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1 N HCl (1 mL, 1 mmol), concentrated in vacuo and dried to give the title compound. MS: m / z = 312 (Mi 1).

INTERMEDIATE 25

<img file="MA30558B1_D0039.tif" />

Lithium r (8A) -8- (3,5-difluorophénvl) -10-oxo-6,9-diazaspiror4.51dec-9-yl1acetate

Step A. Methyl l-aminocvclopentanecarboxvlate hydrochloride

A solution of 1-aminocyclopentanecarboxylic acid (2.00 g, 15.5 mmol) in MeOH (30 mL) was saturated with HCl (g). The resulting mixture was aged at room temperature for 2 h and concentrated in vacuo to provide the title compound. MS: m / z = 144 (M + 1).

Step B. Methyl 1- (12- (3,5-difluorophenyl) -2-oxoéthvllamino١cvclopenanecarboxvlate

A mixture of methyl l-aminocyclopentanecarboxylate hydrochloride from Step A (1.50 g, 10.5 mmol), 3,5-difluorophenacyl bromide (3.20 g, 13.6 mmol), bhiHCC ( 1.32 g, 15.7 mmol) in DMF (30 mL) was stirred at room temperature for 6 h. Aq 1N HCl (50 mL) was added and the mixture was extracted with EtOAc (75 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 10 by the addition of saturated aqueous Na2O (150 mL) and the mixture was extracted with EtOAc (3 X 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of HCCIICNCCCH - 90: 10: 0.1 to 5: 95: 0.1. The fractions containing the product were combined and concentrated to provide the title compound as the TFA salt. MS: m / z = 298 (M 11).

Step c. Ethyl r (87?) - 8- (3,5-difluorophenyl) -10-oxo-6,9-diazaspiro٢4.5٦dec-9-yl٦acetate

To a stirred mixture of methyl l - {[2- (3,5-difluorophenyl) -2-oxoethyl) amino} cyclopentanecarboxylate, TFA salt, from Step B (1.10 g, 2.67 mmol) and Glycine ethyl ester hydrochloride (560 mg, 4.01 mmol) in MeOH (7.5 mL) ALV-diisopropylethylamine (1.17 mL, 6.69 mmol) was added, followed by AcOH (0.77 mL, 13.4 mmol). The resulting mixture was stirred at room temperature for 10 min, then NaCNBH (252 mg, 4.01 mmol) was added. The reaction mixture was heated to 60 ° C for 72 h then allowed to cool . The reaction mixture was quenched with NaHC

<img file="MA30558B1_D0040.tif" />

aqueous saturated and then extracted with EtOAc (3 X 50 mL). The combined organic extracts were dried over baSOi, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of H2٥: CH3CN: CF3CO2H - 90: 10: 0.1 to 5: 95: 0.1. Fractions containing the product were combined, basified with saturated aqueous NaHC, and extracted with EtOAc. The organic extract was dried over Na2S٠4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by SFC, using a ChiralPack AD column eluting with Ο: ΜεΟΗ - 90:10. The first major peak to elute was ethyl [(85) -8- (3,5difluorophenyl) -10-oxo-6,9-diazaspiro [4.5] dec-9-yl] acetate, and the second major peak to elute was ethyl [(8 ^) - 8- (3,5-difluorophenyl) -10-oxo-6,9-diazaspiro [4.5jdec-9-yl] acetate, the title compound. MS: / ζ = 353 (M11).

Step D. Lithium 1 (82 () - 8- (3. 5-difluorophénvl) -10-oxo-6.9-diazaspirof4.51dec-9-vllacetate

To a solution of ethyl [(8 ^) - 8- (3,5-difluorophenyl) -10-oxo-6,9-diazaspiro [4.5jdec-9-yl) acetate from Step c (90 mg, 0, 26 mmol) in THF (3 mL) and HO (1 mL) 1N aqueous LiOH (0.31 mL, 0.31 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 6 by the addition of 1N HCl and concentrated to dryness under ١'idep ،) to give the title compound. MS: w / z ~ 325 (M 1 آ).

INTERMEDIATE 26

<img file="MA30558B1_D0041.tif" />

٢ (65) -6- (3,5-difluorophénvl) -3,3-diethyl-2-oxopiperidin-1-yllacetic acid

Step A. Ethyl (55) -5 - l (5) -të rt-butvlsulfinvllaminoL5- (3.5-difluorophénvl) pentanoate

Has an ethy solution! 5- (3,5-difluorophenyl) -5-oxovalerate (5.00 g, 19.5 mmol) and (5) -2methylpropane-2-sulfinamide (2.88 g, 23.8 mmol) in THF ( 123 mL) titanium tetraethylate (8.18 mL, 39.0 mmol) was added. The reaction vessel was quickly capped and placed in a 60 ° C bath for 16 h. After cooling to room temperature a septum and nitrogen inlet were attached before cooling to 0 ° C. Sodium borohydride (1.48 g, 39.0 mmol) was then added, and a complete reaction was observed after 1 h. Methyl alcohol was then slowly added until stopping.

58 سة! 'Gaseous evolution. The reaction mixture was then diluted with brine (60 mL) with rapid stirring. The resulting slurry was filtered through (elite, washing with EtOAc as needed. The combined organics were then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. give an oil. This oil was purified by chromatography on silica gel, eluting with an EtOAcHexanes - 10:90 to 50:50 gradient, to give the title compound. MS: m / z = 362 (M ٠ 1).

Step B. (6, S3-6- (3.5-Difluoronhénvloiperidin-2-one

A solution of ethyl (5S) -5 - {[(6j-fort-butylsulfinyl] amino} -5- (3,5-difluorophenyl) pentanoate from Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was refioidized to 0 c. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 1 minute, after which the reaction vessel was sealed and left to cool. sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, before removing the solvent in vacuo. Additional MeOH (-50 mL) was added, and then extracted in vacuo. After dissolving in a third volume of MeOH (100 mL), ethylamine (6.78 mL, 48.9 mmol) was introduced and the mixture was heated to 65 ° C for 3 hours. After cooling to room temperature, the solvent was extracted in vacuo and the residue was partitioned between diethyl ether (100 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: mlz = 212 (M 11).

Step c. iert-Butyl (263-2- (3.5-difluorophenyf) -6-oxopiperidine-l-carboxvlate

A solution of (65) -6- (3,5-difluorophenyl) -piperidin-2-one from Step B (2.08 g, 9.85 mmol), di-ttvtbutyl dicarbonate (4.30 g, 19.7 mmol), and 4-dimethylaminopyridine (1.20 g, 9.15 mmol) in CHCl (50 mL) was stirred at room temperature for 20 h. An additional portion of di-rrbutyl dicarbonate (1.25 g, 5.73 mmol) was added and the solution stirred for a further 16h. The solvent was extracted under reduced pressure and the residue was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient 100: 0 to 0: 100, to give the title compound. MS: mlz = 256 (M - C4H7).

Stage D. Zert-Butvl (6_t3.5) -6 - (؟ - difluorophénvl) -3,3-diéthvlpiperidin-2-one-l-carboxvlate A solution of crbutyl (2, S) -2- (3,5-difluorophenyl) -6-oxopiperidin-l -Step c carboxylate (1.53 g, 4.91 mmol) and iodoethane (0.993 mL, 12.3 mmol) in THF (15 mL) at -78 ٥c 1 M solution was added sodium ٥fr (trimethylsilyl) amide in THF (10.8 mL, 10.8 mmol) dropwise over 15 min. The resulting mixture was stirred at -78 ٥c for

<img file="MA30558B1_D0042.tif" />

min and at 0 ° C for 2 h, then quench with saturated aqueous NHCl (50 mL) and extract with EtOAc (3 X 50 mL). The combined organic layers were dried over Eato, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 100: 0 to 50:50 gradient, to give the title compound.

MS: m / z = 312 (M - CH).

Step E. (£ 6) -6- (3,5-Difluorophénvl) -3,3-diethvlpiperidin-2-one

To a solution of ZerLbutyl (65) -6- (3,5-difluorophenyl) -3,3-diethylpiperidm-2-one-lcarboxylate from Step D (1.22 g, 3.32 mmol) in CIICl ( 7 mL) at room temperature was added TFA (3 mL). After stirring for 1.5 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between CICI (30 mL) and saturated NaHO (30 mL). The layers were separated and the aqueous layer was further extracted with CHCl (2 X 30 mL). The combined organics were dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: mlz = 268 (M 1 -ا).

Step F. E6, S3-6 - ('3.5-difluorophénvl١-3.3-diethvl-2-oxopiperidin-l-vllacetic acid

To a stirred solution of (65 ') - 6- (3,5-difluorophenyl) -3,3-diethylpiperidin-2-onc from Step E (850 mg, 3.18 mmol) in THF (15 mL) at room temperature NaH (178 mg of a 60% dispersion in oil, 4.45 mmol) was added. After 15 min, methyl bromoacetate (0.469 mL, 5.09 mmol) was added and the mixture was stirred for 1 h. Sodium hydroxide (9.54 mL of a 1 M solution, 9.54 mmol) was added and the mixture stirred for an additional 16 h at 50 ٥c. The reaction mixture was poured onto 1 M HCl (30 mL) and extracted with EtOAc (3 X 30 mL). The combined organic layers were dried over Na2S٥4, filtered, and concentrated in vacuo to provide the title compound, which could be used without further purification. MS: mlz = 326 (M + 1).

<img file="MA30558B1_D0043.tif" />

1/8 ^ 1-10-oxo-8-phenvl-6.9-diazaspiroi4.5dec-9-vl | acetic acid hydrochloride

-6ΊStep A. Methyl lr (2-oxo-2-phenylethyl) aminolcvclopentanecarboxvlate

A mixture of methyl l-aminocyclopentanecarboxylate hydrochloride (2.00 g, 11.1 mmol, described in Intermediate 25), 2-bromoacetophenone (2.44 g, 12.2 mmol), and NaHO (2.34 g , 27.9 mmol) in DMF (20 mL) was stirred at room temperature for 5 h. ؛ 'HO (25 mL) was added and the mixture was extracted with EtOAc (2 X 75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of IpOCHCN.'CFsOH - 90: 10: 0.1 to 5: 95: 0.1. Fractions containing the product were combined, adjusted to pH 10 by the addition of saturated aqueous FaO and extracted with EtOAc (2 X 75 mL). The combined organic layers were dried over N12SO4, filtered, and concentrated in vacuo to provide the title compound. MS: miz = 262 (M + 1).

Step B. Ethyl ٢ (8 ./?)- 10-oxo-8-phenvl-6,9-diazaspiror4.51dec-9-vl1acetate

To a stirred mixture of methyl l - [(2-oxo-2-phenylethyl) amino cyclopentanecarboxylate from Step A (1.10 g, 2.67 mmol) and glycine ethyl ester hydrochloride (881 mg, 6, 31 mmol) in EtOH (10 mL) AcOH (0.72 mL, 12.6 mmol) was added. The resulting mixture was stirred at room temperature for 5 min, then NaCNBH (397 mg, 6.31 mmol) was added. The reaction mixture was heated to 70 ٥c for 3 h then allowed to cool. The reaction mixture was quenched with saturated aqueous NaHO and then extracted with EtOAc (3 X 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and running with a H2O: CH3CN: CF gradient.₃CO2H - 90: 10: 0.1 to 5: 95: 0.1. The fiactions containing the product were combined, basified with saturated aqueous NaHCCh, and extracted with EtOAc. The organic extracts were dried over Na2SC&gt; 4, filters, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with hexane: EtOH 60:40. The first major peak to elute was ethyl [(8 &lt;S) -10-oxo-8-phenyl-6,9diazaspiro [4.5jdec-9-yljacetate and the second major peak to elute was f (8Æ) ethyl -10-oxo8-phenyl-6,9-diazaspiro [4.5] dec-9-yl] acetate, the title compound. MS: = 317 (M1).

Step c. R (87?) - 10-oxo-8-phenyl-6,9-diazasniro٢4.51dec-9-vl1acetic acid hydrochloride To a solution of ethyl [(87?) - 10-oxo-8-phenyl-6 Step B, 9-diazaspiro [4.5] dec-9-yl] acetate (407 mg, 1.29 mmol) in THF (8 mL) and HO (2 mL) was added 1 N aqueous LiOH ( 1.54 mL, 1.54 mmol) and the resulting mixture was stirred at room temperature for 4 h.

The mixture was adjusted to pH 4 by the addition of 1N HCl and concentrated to dryness in vacuo to give the title compound. MS: m! Z = 289 (M t 1).

<img file="MA30558B1_D0044.tif" />

Ii67? L-6-i3.5-difluorophénvB-3.3-diethvl-2-oxopinerazin-l-vIlacétiaue acid hydrochloride

Step A. Methyl 2-amin0-2-ethvlbutan0ate hydrochloride

A solution of 2-amino-O-2-ethylbutano-acid (3.00 g, 22.9 mmol) in MeOH (200 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 24 h, during which time it was allowed to cool to room temperature and was again saturated with HCl (g) twice. After 24 h at reflux, the cooled mixture was concentrated in vacuo to provide the title compound. MS: m / z = 146 (M I1).

Step B. Methyl 2- (12- (3.5-difluorophénvl-2-oxoéthvllaminol-2-éthvlbutanoate

A mixture of methyl 2-amino-2-ethylbutanOate hydrochloride from Step A (2.10 g, 11.6 mmol), 3,5-difluorophenacyl bromide (2.99 g, 12.7 mmol), and NaHO (2.43 g, 28.9 mmol) in DMF (20 mL) was stirred at 45 ٠c for 1 h, and at room temperature for 2 h.

Aq 1N HCl (50 mL) was added and the mixture was extracted with EtOAc (75 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 10 by the addition of saturated aqueous Na2C٥3 (150 mL) and the mixture was extracted with EtOAc (3 X 75 mL). The combined organic layers were treated with CF3CO2H (1.5 mL), dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of 90: 10: 0.1 15: 95: 0.1 HCCHCNCFjCCH. The fractions containing the product were combined, basified with

Saturated aqueous NaHO, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m / z = 300 (M ا 1).

'30 Step c. Methyl rf67? ١-6- (3.5-difIuorophenyl) -3,3-diethyl-2-oxopiperazin-1-yl٦acetate

To a stirred mixture of methyl 2 - {[2- (3,5-difluorophenyl) -2-oxoethyl] amino} -2-ethylbutanoate from Step B (475 mg, 1.59 mmol) and ester hydrochloride ethyl glycine (332 mg, 2.38 mmol) in MeOH (5 mL) were added titanium (IV) isopropoxide (1.16mL, 3.97mmol) and AcOH (0.273 mL, 4, 76 mmol). The resulting mixture was stirred at room temperature for 15 min, then NaCNBH (150 mg, 2.38 mmol) was added. The stirred reaction mixture was heated at 50 ° C for 18 h, then at 70 ° C for 24 h, and allowed to cool. The mixture was quenched with saturated aqueous NaHO and then extracted with EtOAc (2 X 30 mL). The combined organic extracts were dried over baSOi, filters, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a H2O: CHCN: CF3CO2H gradient - 90: 10: 0.1 to 5: 95: 0.1. Fractions containing the product were combined, basified with saturated aqueous NaHO, and extracted with EtOAc. The organic extracts were dried over Na2SC&gt; 4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with: EtOH - 60:40. The first major peak to elute was methyl [(65) -6- (3,5-dîfluorophenyl) -3,3-diethyl-2-oxopiperazin-lyljacetate and the second major peak to elute was methyl [(65) - 6- (3,5-difluorophenyl) -3,3diethyl-2-oxopiperazin-1-yljacetate, the title compound. MS: mlz = 341 (M t 1).

Step D. [(6 ^) - 6- (3,5-difluoronhénvl) -3.3-diethvl-2-oxonir) erazin-lvllacetic acid hydrochloride

To a solution of methyl [(65) -6- (3,5-difluorophenyl) -3,3-ethyl-2-oxopiperazin-1-yl] acetate from Step c (43 mg, 0.126 mmol) in THF (0.75 mL) and HO (0.25 mL) 1N aqueous LiOH (0.139 mL, 0.139 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 4 by the addition of 1N HCl and concentrated to dryness in vacuo to give the title compound. MS: mlz = 327 (M 1 ؛).

INTERMEDIATE 32

<img file="MA30558B1_D0045.tif" />

Lithium K85) -6- (erbutoxvcarbonvl) -8- (3.5-difluoroohénvl) -10-oxo-6.9-diazasniro [4.51dec-9vllacetate

<img file="MA30558B1_D0046.tif" />

Step A. Methyl l- {٢2- (3,5-difluorophenyl) -2-oxoethyl ~ | amino} cyclopentanecarboxylate A mixture of methyl l-aminocyclopentanecarboxylate hydrochloride (10.0 g, 55.7 mmol, described in intermediate 25), 3,5-difluorophenacyl bromide (14.4 g, 61.2 mmol), and baPCL (22.8 g, 139 mmol) in DMF (100 mL) was stirred at room temperature for 3 , 5 h. The reaction mixture was acidified with 1N aqueous HCl and the mixture was extracted with EtOAc (200 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 8-9 by the addition of saturated aqueous NaHO and the mixture was extracted with EtOAc (3 X 250 mL). The combined organic layers were washed with brine, dried over LaSCL, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of hexane: EtOAc-90: 10 to 50:50, to give the title compound. MS: m / z = 298 (M + 1).

Step B. Ethyl [8- (3.5-difluoronhénvl ') - 10-oxo-6.9-diazaspiroi4.51dec-9-vllacetate

A mixture of methyl 1 - {[2- (3,5-difluorophenyl) -2-oxoethyl} amino} cyclopentane carboxylate 'from Step A (10.0 g, 33.6 mmol), ethyl ester hydrochloride glycine (46.9 g, 336 mmol), and AcOH (5.78 mL, 101 mmol) in MeOH (300 mL) was stirred at room temperature for 10 min. NaCNBlb (2.54g, 40.4mmol) was added and the pH of the mixture was checked and adjusted to pH ~ 5 as needed by the addition of AcOH. The reactional angel was heated to 50 c for 18h then allowed to cool. The reaction mixture was carefully quenched with saturated aqueous NaHO (250 mL) and then extracted with CHCl (3 X 200 mL). The combined organic extracts were dried over baSCL, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with EtOAc - 100: 0 to 0: 100, to give the title compound. MS: m / z = '353 (M f 25 1).

Step c. ZerZ-Butyl (8Â) -8- (3,5-difluorophenyl) -9- (2-ethoxy-2-oxoethyl) -10-oxo-6,9diazaspirof4.51decane-6-carboxvlate

A solution of ethyl [8- (3,5-difluorophenyl) -10-oxo-6,9-diazaspiro [4.5] dec-9-yl] acetate from Step B (3.00 g, 8.51 mmol ), AAdiisopropylethylamine (0.743 mL, 4.26 mmol), and di-Zert-butyl dicarbonate (9.29 g, 42.6 mmol) in acetonitrile (25 mL) was stirred at 60 ٠c for 6 h, then cooled and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 95: 5 to 50:50 gradient, to give the racemic product. The enantiomers were separated by HPLC, using an OD Chiralcel column and eluting with: z-PrOH: Et₂NH - 60: 40: 0.1. The first major peak to elute was tert-butyl (8 ^) - 8- (3,5-difluorophenyl) -9- (2-ethoxy ^ 2-oxoethyl) -10oxo-6,9-diazaspiro [4.5] decane- 6-carboxylate and the second major peak to elute was tert-71 butyl (87?) - 8- (3,5-difluorophenyl) -9- (2-ethoxy-2-oxoethyl) -10-oxo-6.9 -diazaspiro [4.5] decane-6carboxylate, the title compound. MS: mlz = 397 (M - CH).

Step D. Lithium ٢ (87?) - 6- (rerr-butoxycarbonyl) -8- (3,5-difluorophenyl) -10-oxo-6,9diazaspirof4.5ldec-9-vllacetate

Has a solution of rert-butyl (8Æ) -8- (3,5-difluorophenyl) -9- (2-ethoxy-2-oxoethyl) -10-oxo-6,9diazaspiro [4.5] decane-6-carboxylate of the 'Step c (50 mg, 0.11 mmol) in THF (0.75 mL) and IIO (0.25 mL) 1N aqueous LiOH (0.12 mL, 0.12 mmol) was added and the The resulting mixture was stirred at room temperature for 6 h. The mixture was adjusted to pH 7 by the addition of 1N HCl and concentrated to dryness in vacuo to give the title compound. MS: mlz = 369 (M-CH).

<img file="MA30558B1_D0047.tif" />

Lithiumr (37?) - l- (tert-butoxvcarbonyI) -3- (3,5-difluoroph.enyl) -3-methyl-5-oxo-L4-diazaspiro ٢5.5٦undéc-4-yl٦acetate

Step A. Di-tër hutyl, 1- (3.5-difluorophdnvlehvl | imidodicarbonatc

To a solution of [1- (3,5-difluorophenyl) ethyljamine (10.0 g, 63.6 mmol) in CH c (200 mL) at 0 ° C was added di-tert-butyl dicarbonate ( 13.9 g, 63.6 mmol) and the resulting mixture was stirred at room temperature for 18 h. The solvent was extracted under reduced pressure. To the residue were added di-rerhtyl dicarbonate (20.8 g, 95.4 mmol) and DMAP (7.78 g, 63.6 mmol) and the reaction mixture was heated at 80 ° C for 2 h. The mixture was allowed to cool and di-tet-butyl dicarbonate (69.4 g, 3.18 mmol) was added. The reaction mixture was heated at 80 ° C for 2 h, allowed to cool, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of hexane: EtOAc - 98: 2 to 90:10, to give the title compound. MS: mlz = 421 (M + NatCHCN).

-٦٦-

<img file="MA30558B1_D0048.tif" />

Step Β٠ tert-Butyl 2-r (ter / -butoxycarbonyl) aminol-2- (3,5-difluorophenyl) propanoate To a stirred suspension of potassium ert-butylate in THF (300 mL) at -78 ٥c we have add a solution of di-tert-butyl [1- (3,5-difluorophenyl) ethyl imidodicarbonate from Step A (22.0 g, 61.6 mmol) in THF (200 mL), dropwise over 45 min. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3 h. The reaction mixture was cooled to -78 ٥c and quenched with 1N aqueous HCl (300 'mL), warmed to 0 ^vsC, and poured into Et2O (300 mL). The organic layer was extracted and the aqueous layer was further extracted with Et2O (300 mL). The combined organic extracts were dried over Na2S٥4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with: EtOAc - 95: 5 to 80:20, to give the title compound. MS: mlz = 421 (M t Na + CHCN).

Step c, fôr / L-Bütyl ri- (3,5-difluorophenyl) -l-methyl-2-oxoethylcarbamate

To a stirred solution of tert-butyl 2 - [(tert-butoxycarbonyl) amin0j-2- (3,5-diflu0r0phenyl) propanoate from Step B (2.00 g, 5.60 mmol) in THF (20 mL ) at -78 ° C was added LiAlH (5.60 mL of a 1 M solution in THF, 5.60 mmol), dropwise. The reaction mixture was stirred at -78 ° C for 6 h, then quenched with EtOAc (5.6 mL), then HO (15.6 mL), then 1 N aqueous NaOH (5.6 mL), then EtOAc (17 ml.). The reaction mixture was warmed to room temperature, stirred for 1 h, filtered, and extracted with EtOAc (2 X

40 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound of sufficient purity to be used in the next step. MS: mlz: 186 (M-CO2C4H7).

Step D. Methvl hydrochloride Laminocvclohexanecarboxylate

By essentially following the procedures described in Intermediate 25 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: mlz = 158 (M1 · 1).

Step E, Methvl l- {٢2 - [(tert-butoxycarb0nvl) amin0٦-2- (3,5-diflu0r0phénvl) pr٠pyllamin0} cvclohexanecarboxvlate

A mixture of terhutyl [1- (3,5-difluorophenyl) -1-methyl! -2-oxoethyl carbamate from Erape c (500 mg, 1.75 mmol), methyl 1-aminocyclohexanecarboxylate hydrochloride from Step D ( 1.38 g, 8.76 mmol), and AcOH (0.301 mL, 5.26 mmol) in MeOH (15 mL) was stirred at room temperature for 30 min. NaCNBH (165 mg, 2.63 mmol) was added and the pH of the mixture was checked and adjusted to pH ~ 5 as needed by the addition of AcOH.

The reaction mixture was stirred at room temperature for 1 h, then quenched with

-٦٦-

<img file="MA30558B1_D0049.tif" />

Saturated aqueous NaHO (10 mL) and extracted with CHCl (2 X 50 mL). The combined organic extracts were dried over Na.₂SO₄, filters, and vacuum concentrates. The crude product was purified by chromatography on silica gel, eluting with EtOAc - 100: 0 to 80:20, to give the title compound. MS: m / z = 427 (M ٠ 1).

Step F. Methyl 1- (r2-amino-2- (3,5-difluorophenyl) propvl1amino) cyclohexanecarboxyIate A solution of methyl l - ([2 - [(ie٢t-butoxycarbonyl) amino) -2- (3,5-difluorophenyl ) propyl) aminojcyclohexanecarboxylate from Step E (280 mg, 0.657 mmol) in EtOAc (5 mL) at 0 ° C was saturated with HCl (g). The reaction mixture was aged at 0٥c for 30 min, then carefully poured into saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (2 X 15 mL). The combined organic extracts were dried over Na₂S04, filters, and concentrates under vacuum to give the title compound. MS: m / z = 327 (M + 1).

Step G. (37?) - 3- (3,5-Difluorophénvl) -3-methyl-1,4-diazaspiror5.5٦undecan-5-one

A solution of methyl 1 - {[2-amino-2- (3,5-difluorophenyl) propyi;] amino} cyclohexanecarboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80 ° C for 3 h, allowed to cool, then poured into saturated aqueous NaHCO 3 (5 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over Na₂SO4, filters, and concentrates under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a gradient of EtOAcMeOH - 100: 0 to 92: 8, to give the racemic product. The enantiomers were separated by HP LC, using a ChiralPack AD column and eluting with hexane: EtOHENH - 40: 60: 0.1. The first major peak to elute was (3 ^) - 3- (3,525 difluor0phenyl) -3-methyl-1,4-diazaspiro [5.5] undecan-5-one, the title compound, and the second major peak to elute. was (35) -3- (3,5-difluorophenyl) -3-methyl-1,4-diazaspiro [5.5] undecari-5one. MS: m / z = 295 (M 11).

Step H. erButyl (371-3- (3,5-difluorophenyl ') - 3-methvl-5-oxo-1.4-diazaspirof5.51undecane-130 carboxylate

A solution of (37?) - 3- (3,5-difluorophenyl) -3-methyl-1,4-diazaspiro [5.5] undecan-5-one from Step G (90 mg, 0.306 mmol), ALMdiisopropylcthylamine (0.027 mL, 0.153 mmol), and dï- / er ؛ -butyl dicarbonate (667 mg, 3.06 mmol) in acetonitrile (2 mL) was stirred at 60 ٥c for 8 h, then cooled and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 95: 5 to 50:50 gradient, to give the title compound. MS: m / z = 339 (M - C4H7).

-٦٩-

؛ U

3Θ558

Step I. / eri-Butvl (3. ^) - 3 - (- 3,5-difluorophénvl) -4 - (- 2-ethoxv-2-oxoéthvD-3-méthvl-5-oxo-1.4diazasoiro [5.51undecane- l-carboxvlate

To a stirred solution of tert-butyl (3Æ) -3- (3,5-difluorophenyl) -3-methyl-5-oxo-1,4diazaspiro [5.5Jundecan-1-carboxylate from Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0 ٥c NaH (12 mg of a 60% dispersion in oil, 0.30 mmol) was added. After 5 min ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowed to warm to room temperature and stirring continued for 1 h. Saturated aqueous NaHO (2 mL) was added and the mixture was extracted with EtOAc (2x5 mL). The combined organic layers were dried over Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 95: 5 to 60:40 gradient, to give the title compound. MS: m / z = 425 (M CH).

Step J. Lithium r (3j?) - l- (tër tutoxvcarbonvl) -3- (3.5-difluorophénvl) -3-méthvl-5-oxo-l.415 diazasnirof5.51undec-4-vllacetate

To a solution of (arhutyl (3 (?) - 3- (3,5-difluorophenyl) -4- (2-ethoxy-2-oxoethyl) -3-methyl-5oxo-1,4-diazaspiro [5.5] undecane- Step I 1-carboxylate (65 mg, 0.135 mmol) in THF (1.5 mL) and HO (0.5 mL) was added 1 N aqueous LiOH (0.14 mL, 0.14 mmol) ) and the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 7 by the addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. m / z = 397 (M - C4H7).

<img file="MA30558B1_D0050.tif" />

Acid | - (5.R) -l '- (terlu) xvcarbonvl) -4.6-difluoro-3'-oxo-2.3-dihvdro-4'Hdispir0Î'cvcl0pentane-1.2'-pinerzine-5'.l-indenl-4 '-vllacétiaue

Step A.4'.6'-Difluoro-2 ', 3'-dihvdro-2 # .5F (-soiro (imidazolidine-4.1'-indènel-2.5-dione

A mixture of 4,6-difluoroindan-lone [Musso et al. (2003) J. Med. Chem., 46, 399-408) (14.5 '30 g, 86 mmol), NaCN (12.9 g, 262 mmol), and (IHCCL (16.8 g, 175 mmol) in HO (150

-753 &lt;© 558 mL) and EtOH (150 mL) was heated at 70 ° C for 3 h. From (NH₄)₂CO₃ Additional (16.8 g, 175 mmol) was added and heating at 70 ° C continued for 4 h. The mixture was concentrated to dryness under reduced pressure. To the residue was added HO (200 mL) and the precipitate was isolated by filtration, washed with HO, and dried to give the title compound. MS: m / z = 280 (M 5 t1CHCN).

Step B. l-Amino-4.6-difluoroindane-l-carboxylic acid hydrochloride

A mixture of 4 ', 6'-difluoro-2', 3'-dihydro-277,577-spiro [imidazolidine-4, 1'-indene-2,5-dione from Step A (16.7 g, 70, 1 mmol) and HCl conc. (90 mL) in a high pressure reactor was heated at 180 ٥c for 5 h. The mixture was cooled to 0 ° C, ventilated well, and concentrated to dryness in vacuo to give the title compound. MS: m / z = 214 (M 11).

Step c. Methyl l-amino-4.6-difluoroindane-l-carboxvlate hydrochloride

A solution of 1-amino-4,6-difluoroindan-1-carboxylic acid hydrochloride (2.00 g, 15.5 mmol) in MeOH (100 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 20 h and concentrated in vacuo to provide the title compound. MS: m / z = 228 (Mil).

Step D. Methyl lf (terCbutoxvcarbonvBaminol-4.6-difluoroindane-l-carboxylate

A solution of methyl Lamino-4,6-difluoroindan-1-carboxylate hydrochloride from Step c (3.82 g, 14.5 mmol), AUdiisopropylethylamine (5.62 g, 43.5 mmol), and Di-tetbutyl dicarbonate (15.8 g, 72.5 mmol) in acetonitrile (40 mL) was stirred at 60 ° C for 3 h, then cooled and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 40:60, to give the title compound. MS: m / z = 228 (M-CO2C4H7).

Step E. te -Butvl 14.6-difluoro-1 - livdroxvmétl-2.3-dihvd ro-1 / Linden-1 -vl Icarbamate

To a stirred solution of methyl l - [(teH-butoxycarbonyl) aminoj-4,6-difluoroindan-lcarboxylate from Step D (2.80 g, 8.55 mmol) in THF (30 mL) at -78 ° LiAlH (18.0 mL of a 1 M solution in THF, 18.0 mmol) was added dropwise over 30 min. The reaction mixture was stirred at -78 ° C for 2 h, then quenched with HO (1 mL) followed by aqueous 1 N NaOH (2 mL). then HO (2 mL), followed by EtOAc '(2 mL). The reaction mixture was warmed to room temperature, saturated aqueous NaHO (150 mL) was added, and the mixture was extracted with EtOAc (200 mL). The organic extract was dried over Na2SO.₄, filtered, and concentrated in vacuo. The bnrt product was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 100: 0 to 50:50 gradient, to give the title compound. MS: m / z = 244 (M - C4H7).

اد)

058

Step F. erf-Butvl (4.6-difluoro-1 -formvl-2.3 -dihvdro-1 LLindén-1 -vl carbamate

To a stirred solution of oxalyl chloride (0.91 mL, 10.4 mmol) in CHCl (40 mL) at -78 ° C was added DMSO (1.48 mL, 20.9 mmol), drop by drop, over 5 min. The reaction mixture was stirred for 30 min, during which time it was heated to -60 ٥c, followed by a solution of etbutyl [4,6-difluoro-1 - (hydroxymethyl) -2,3-dihyd O-1 LLinden -] -yljcarbamate from Step E (2.08 g, 6.95 mmol) in CHCl (22 mL) was added dropwise over 30 min. During the addition, the reaction temperature rose to -45 c and it was stirred at this temperature for an additional 15 min. To the resulting mixture was added A, A-diisopropylethylamine (7.28 mL, 41.7 mmol), dropwise over 2 min. The mixture was allowed to warm to 0 ٠c, stirred for 15 min then poured into ice (60 mL) and 1N aqueous HCl (30 mL). The resulting mixture was extracted with CH2Cl2 (2 X 100 mL). The combined organic extracts were washed with HO (30 mL), then brine (50 mL), then dried over EaSCL, filtered, and concentrated in vacuo to give the title compound. MS: mtz = 224 (M - OC4H9).

Step G. Methyl l-٢ (il - [(/ erZ-butoxycarbonvI) aminol-4.6-difluoro-2.3-dihvdro-l /; - indén-lyllméthvDaminolcvclonentanecarboxvlate

A mixture of tert-butyl (4,6-difluoro-1 -formyl-2,3-dihydro-177-inden-1 -yljcarbamate. From Step F (890 mg, 2.99 mmol), methyl Laminocyclopentanecarboxylate ( 4.25 g, 29.7 mmol, described in Intermediate 25), and AcOH (2.10 mL, 36.7 mmol) in MeOH (32 mL) was stirred at room temperature for 20 min. NaCNBH (405 mg, 6.44 mmol) was added and the pH of the mixture was checked and adjusted to pH ~ 5 as needed by the addition of AcOH. The reaction mixture was stirred at room temperature for 23 h, then quenched with saturated aqueous NaHCCh (80 mL) and extracted with EtOAc (200 mL). The organic extract was washed with HO (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with hexane: EtOAc 100: 0 to 30:70, to give the title compound. MS: m / z = 425 (M + 1).

Step H. Methyl l-ff hydrochloride (l-amino-4.6-difluoro-2.3-dihvdro-l # -indén-l-vl ~) methyllaminolcvclonentanecarboxylate

A solution of methyl l - [({1 - [(/ 'erUbutoxycarbonyl) amino] -4,6-difluoro-2,3-dihydro-lL / -indénLyl} methyl) amino] cyclopentanecarboxylate from Step G (753 mg , 1.77 mmol) in EtOAc (40 mL) at 0 ٥c was saturated with HCl (g). The reaction mixture was aged at 0 ° C for 45 min then concentrated in vacuo to give the title compound. MS: mlz = 325 (M

-٦٦-

<img file="MA30558B1_D0051.tif" />

Step L4.6-Difluoro-2.3-dihydro-377-dispirorcvclopentane-l, 2'-pinerazine-5 ', l-indcn | -3'one

A solution of methyl l - {[(l-amino-4,6-difluoro-2,3-dihydro-l # -inden-lyl) methyljamino} cyclopentanecarboxylate hydrochloride from Step H (741 mg, 2.05 mmol ), and AcOH (5.0 mL, 6.28 mmol) in xylenes (50 mL) was heated at 150 ٥c for 24 h, allowed to cool, and concentrated to dryness under reduced pressure. The residue was partitioned between saturated aqueous NaHO (80 mL) and EtOAc (100 mL). The organic extract was washed with HO (60 mL), dried over dubaSO ،, filtered, and concentrated under reduced pressure to give the title compound. MS: m / z = 293 (Mil).

Step J. fert-Butvl ('5j? ~) -4,6-difluoro-3'-oxo-2.3-dihvdro-l'7disnirocvcloDentane-1.2'pÎperazine-5'. 1 -indene-1 '-carboxylate

A solution of 4,6-difluoro-2,3-dihydro-3'H-dispiro [cyclopentane-1,2'-piperazine-5 ', linden] -3'-one from Step I (453 mg, 1 , 55 mmol), ALAdiisopropylethylamine (0.135 mL, 0.78 mmol), and di-tert-butyl dicarbonate (3.45 g, 15.8 mmol) in acetonitrile (6 mL) was stirred at 50 ° C for 18 h. The reaction mixture was partitioned between saturated aqueous NaHO (40 mL) and EtOAc (60 mL). The organic extract was dried over baSOi (, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 100: 0 to 50: gradient: 50, to give the racemic product The enantiomers were separated by HPLC, using a ChiralPack AD column and eluting with hexane: EtOH: Et2NH - 40: 60: 0.1. The first major peak to elute was ehutyl (5Æ) -4,6-difluoro-3'-oxo-2,3-dihydro-l'7dispiro [cyclopentane-1,2'-piperazine5 ', l-indene] -l '-carboxylate, the title compound, and the second major peak to elute was tertbutyl (55) -4,6-difluoro-3'-oxo-2,3-dihydro-ELdispiro [cyclopentane-1,2'- piperazine-5 ', 125 indenej-1'-carboxylate. MS: m / z = 337 (M - CH).

Step K.rerZ-Butyl (57?) - 4 '- (2-ethoxy-2-oxoethyl) -4,6-difluoro-3'-oxo-2,3-dihydro-l'7 / dispirolcvclooentane-l .2 '-ninerezine-5', l -indènel-1 '-carboxylate

To a stirred solution of tert-butyl (5 ^) - 4,6-difluoro-3'-oxo-2,3-dihydro-l'77-dispiro

[cyclopentane-1,2'-piperazin-5 ', l-Indene] -l'-carboxylate from Step 217) ل mg, 0.553 mmol) in THF (4 mL) at room temperature NaH ( 44 mg of a dispersion at 60 ° 0 ا؟ in 1 oil. 1.11 mmol). After Olin, ethyl bromoacelate (185 mg, 1.11 mmol) was added and the mixture was allowed to warm to room temperature and stirring continued for 3 h. Saturated aqueous NaHO (25 mL) was added and the mixture was extracted with EtOAc (2 X 30 mL). The combined organic layers were washed with brine, dried over N2SO4, filtered, and concentrated in vacuo. The product

;؛ ' رك '

Crude 3Θ558 was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient

- 100: 0 to 50:50, to give the title composition. MS: m / z = 479 (Μ + 1).

Step L. Acid r (57? ١-l '- (tert-butoxvcarbonvl١-4,6-difluoro-3'-oxo-2^l', 3-dihvdro-4'Hdispirorcyclopentane-l, 2'-piperazine-5', l-inden٦-4'-yllacetic

To a solution of tert-butyl (57?) - 4 '- (2-ethoxy-2-oxoethyl) -4,6-difluoro-3'-oxo-2,3-dihydrol'77-dispiro [cyclopentane-1, Step K 2'-piperazin-5 ', l' '- indene] -l'-carboxylate (258 mg, 0.539 mmol) in THF (3 mL) was added 1 N aqueous LiOH (0.65 mL, 0.65 mmol) and the resulting mixture was stirred at room temperature for 20 h. To the reaction mixture were added THF (3 mL), EtOH (0.2 mL), and 1N aqueous LiOH (0.20 mL, 0.20 mmol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was acidified by the addition of 1N aqueous HCl (0.9 mL, 0.9 mmol) and concentrated to dryness in vacuo to give the title compound. MS: m / z = 451 (M 1 ا).

<img file="MA30558B1_D0052.tif" />

(A) -f4 '- (7ert-butoxvcarbonvlL4.6-difluoro-5'.5'-dimethvl-6'-oxo-2,3-dihvdro-l'77-sDiro [indene1,2'-piperazin٦-1' -yllacetic acid

By essentially following the procedures described in Intermediate 34, but using methyl α-aminoisobutyrate in place of methyl 1 -aminocyclopentanecarboxylate, the title compound was obtained. MS: m / z = 425 (M -t-1).

INTERMEDIATE 36

<img file="MA30558B1_D0053.tif" />

O Me Me

<img file="MA30558B1_D0054.tif" />

14-ite lutoxvcarb0nvl١-3.3-dimethvl-2-0X0-1.4-diazasDir0r5.6ld0déc-l-vllacétiaue acid

Essentially following the procedures described in Intermediate 34, but using methyl a-aminoisobutyrate in place of methyl l-aminocyclopentanecarboxylate, and using methyl l-aminocycloheptanecarboxylate hydrochloride in place of methyl l-amino hydrochloride- 4,6-difluoroindan-1-carboxylate, the title compound was obtained. MS: mlz = 369 (M ب

INTERMEDIATE 37

<img file="MA30558B1_D0055.tif" />

Acid٢Ç3&gt; S^,) -3-f3,5-diiluorophenyl١-l-oxo-9-oxa-2-azaspiro٢5.51undec-2-yllacetic

Essentially following the procedures described in Intermediate 26, but using 2-iodoethyl ether in place of iodoethane, the title compound was obtained. MS: mA = '340 (Mil).

INTERMEDIATE 38

<img file="MA30558B1_D0056.tif" />

Methyl l -! D (3M-3-amiiio-3-Dhéiivlni-QD٧ !! amino cvclonentane carboxylate

؛ / X

3Θ558

Step A. Ethyl (35) -3-ritgrf-but0xycarb0nyl) amin01-3-phenylpr0pan0ate

To a solution of (5 [) - 3-amino-3-phenylpropanol, ethyl ester hydrochloride (2.50 g, 10.9 mmol) and Boc-anhydride (2.38 g, 10, 9 mmol) in CECI (16.3 mL) was slowly added triethylamine (3.03 mL, 21.8 mmol). After 4.5 hours the reaction mixture was applied to the top of a silica gel column, and after elution with an EtOAchexanes gradient - 5:95 to 40:60 the title compound was obtained. MS: m / z = 294 (M + 1).

Step B. tert-Butyl [(| 3-oxo-1-phenylpropyllcarbamate

To a dry, cooled (-78 ٥C) solution of ethyl! (3L3 - (؟ - [(ter ؛ -butoxycarbonyl) amino] -3phenylpropanoate from Step A (1.00 g, 3.41 mmol) a solution of DiBA1-H (6.82 mL, 6, 82 mmol, 1 M in CHCl) slowly over 30 min After an additional 30 min of stirring at -78 ° C, the reaction was quenched by the rapid addition of saturated aqueous La Rochelle salt (32 mL). The cooling bath was then removed and the reaction was allowed to stir rapidly until a remarkable reduction in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 X 30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by gel chromatography on silica, eluting with an EtOAchexanes 5:95 to 40:60 gradient, to give the title compound. MS: m / z = 20,150 (M - CO2C4H7).

Step c. Methvl 1 - (((3.91-3-1 (grt-butoxvcarbonvllaminol-3-phenvloropyllaminol cvclopentanecarboxvlate

Has a solution of tert-butyl [(1 3 - (؟ - οχο-1 -phenylpropyljcarbamate from Step B (0.820 g, 3.29 mmol) and methyl 1 -aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) ) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol) After stirring at room temperature for 20 min, NaHB (0Ac) 3 (1.74 g, 8.22 mmol) was added as a solid. After the reaction was complete, saturated aqueous NaHO (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHO (3 mL) were then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were 'dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by chromatography on silica gel, eluting with a gradient of MeOH: DCM 1:99 to 6:94, to give the title compound. MS: m / z = 377 (Μ i 1).

Step D. Methvl l-fi (3 &lt;S3-3-amino-3-phenvlpropvllaminolcvclopentanecarboxvlate bishydrochloride

إرلأ

To a cooled (0 C) solution of methyl 1 - ({(3٠5) -3 - [(ί t&gt; utoxycarbonyl) aminoJ-3phenylpropyl} amino) cyclopentanecarboxylate from Step c (0.920 g, 2.44 mmol) in MeOH (49 mL) Excess anhydrous hydrogen chloride gas was added. After 30 min the solution was purged with dry nitrogen for about 40 min. The solvent was then removed in vacuo to provide a solid / oil mixture. Additional MeOH (50 mL) was then added and subsequently extracted in vacuo to provide the title compound. MS: m / z = 277 (Mil).

INTERMEDIATE 41

<img file="MA30558B1_D0057.tif" />

3-Amin0-5.7-dihvdrospirofcvclonentai Dvridine-6.3'-r&gt; vrro! Ol2.3Alr&gt; vridinl-2'il'7Aone.

isomer A

Step A. (±) -r - {[2- (TriméÎhvlsilyl) ethoxvlmethylI-377-spiforcvclopentane-r, 3'-pvrroIor2,3blpyridine٦-2 ', 3 (l ^,H) -dione

To a solution of 1- {[2- (trimethylsilyl) ethoxy] methyl} -1, 3-dihydro-2T7-pyrroIo [2,3-٥] pyridin-2one (2.50 g, 9.46 mmol, described in intermediate 7) and cesium carbonate (6.78 g, 20.8 mmol) in DMF (45 mL) was added dropwise a solution of 1,4-dibromobutn-2_ one [Meijere et al. (2001) Eur. J. Org. Chem. 20, 3789-3795] (1.59 g, 12.3 mmol) in DMF (45 mL). After 68 h, the mixture was partitioned between Et٩o (200 mL) and HO (200 mL). The organic layer was separated and the aqueous layer was further extracted with Et2O (2 X 100 mL). The combined organic layers were dried over Na2S٥4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 75:25, to give the title compound. MS: m / z = 333 (Mtl).

Step B. ('± l-3-Nitro-l'-H2-firiméthvlsilvlléthoxvlméthvD-5.7-dihvdrospirolcvclopental٥l pvridine-6.3'-pvrrolof2.3-٥lpyridinl-2٢l'771-one

A mixture of (±) -l '- {[2- (trimethylsilyl) ethoxy] methyl} -377-spiro [cyclopentane-1,3'-pyrrolo

[2,3-٥] pyridine] -2 ', 3 (1'77) -dione from Step A (230 mg, 0.692 mmol) and 1-methyl-3,5dinitropyridin-2 (1 ^ -one [ Tohda et al. (1990) Tiw. Chem. Soc. Japan 63, 2820-2827] (173 mg.

0.869 mmol) in 2 M ammonia in MeOH (3.5 mL) was heated to reflux for 18 h. The mixture was concentrated in vacuo and purified by gel chromatography.

<img file="MA30558B1_D0058.tif" />

silica, eluting with a hexaneEtOAc - 100: 0 to 50:50 gradient, to give the title compound. MS: mlz = 413 (M + 1).

Step c. (± l-3-Amino-l'T f2 - ('triméthvlsilvl') ethoxvlméthvll - 5.7-dihvdrosniro [cvclopenta f۵lpvridine-6.3'-Dvrrolof2.3-٥lpvridinl-2 '(l'fi3-one

A mixture of 10% Pd / C (20 mg) and (±) -3-nitro-l '- {[2- (trimethylsilyl) ethoxy] methyl} _ 5,7-dihydrospiro [cyclopenta [٥) pyridine- 6,3'-pyrrolo [2,3-٥; | pyridin] -2 '(l '19) -one from Step B (117 mg, 0.284 mmol) was stirred vigorously in MeOH (5 mL) under a hydrogen atmosphere (about 1 atm). After 4.5 h the mixture was filtered through a pad of Celite, washing thoroughly with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: mA = 383 (Mt 1).

StepD. 3-Amino-5.7-dihvdrosnirolcvclonetai۵] nvridine-6,3'-pvrrolol2.3-٥lnvridin] -2 '(7Aone ,, isomer A

A solution of (±) -3-amino-l '- {[2- (trimethylsilyl) ethoxyjmethyl} -5,7-dihydrospiro [cyclopenta [۵] pyridine-6,3'-pyrrolo [2,3-٥ ] pyridin] -2 '(E0-one from Step 0 (117 mg, 0.306 mmol) in MeOH (5 mL) was saturated with HCl (g) The mixture was stirred for 30 min and then concentrated in vacuo The residue was dissolved in MeOH (3 mL) and treated with ethylenediamine (0.020 mL, 0.306 mmol) and ION sodium hydroxide to adjust the mixture to pH 10. After 1 hr, the reaction mixture was purified directly by HPLC using an 018 reverse phase column and eluting with a gradient of H0: CH3CN: CF3CO2H-90: 10: 0.1 to 5: 95: 0.1. Lyophilization provided the racemic title compound such as the TFA salt. The enantiomers were resolved by HPLC, using a ChiralPak AD column and eluting with EtOH. The first major peak to elute was 325 amino-5,7-dihydrospiro [cyclopenta [èjpyridine-6,3'-pyrrolo [2,3-٥] pyridin] -2 '(1'77) -one, isomer A, the title compound, and the second major peak to elute was 3-amino-5,7dihydrospiro [cyclopenta [to] pyridine-6,3'-pyrrolo [2,3-Z&gt;] pyridin] -2 '(the L /) - one, isomer B. MS: mlz = 253 (Mil).

INTERMEDIATE 42

<img file="MA30558B1_D0059.tif" />

3-Amino-5₁7-dihvdrospirorcvclopentarc٦pvridine-6١3'-Dvrr٠lor2_١3-Z? 1pyridirÎl-2 '(l' // ١-one٦ isomer A

Step A. 4.5--5 ^ hydroxymethylpyridine ^ -carbonitrile

To a solution of dimethyl 6-cyanopyridine-3,4-dicarboxylate Hashimoto et al. (1997) Heterocycles 46, 581] (2.00 g, 9.08 mmol) in EtOH (50 mL) was added lithium borohydride (4.54 mL of a 2 M solution in THF, 9.08 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h, and then cooled to 0 ° C. Saturated aqueous NaHCO3 (20 mL) was added slowly and the quench mixture was extracted with EtOAc (9 X 100 mL). The combined organic extracts were dried over Na2SC&gt; 4, filters, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH - 100: 0 to 85:15, to give the title compound. MS: Wz = 165 (Mil).

Step B. 4.5-'gA (bromomethyl) nvridine-2-carbonitrile

To a solution of 4.5-6A (hydroxymethyl) pyridin-2-carbonitrile from Step A (750 mg, 4.57 mmol) in THF (15 mL) was added phosphorus tribromide (1.61 g , 5.94 mmol) in THF (5 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h, and then cooled to 0 ٥c. Saturated aqueous NaHO (5 mL) was added slowly and the quenched mixture was extracted with CHCl (2 X 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 100: 0 to 25:75 gradient, to give the title compound. MS: m / z = 291 (Mil).

Step c. ί ±) -2'-Οχο-1'.2 ', 5.7-tetrahvdrospiroicvclooentaiclpvridine-6.3'-pyrroIol2.3-61 pyridinel-3-carbonitrile

To a solution of 4.5-6E (bromethyl) pyridin-2-carbonitrile from Step B (2.56 g, 8.83 mmol) and 1,3-dihydro-2H-pyrrolo [2,3-6 ] pyridin-2-one [Marfat &amp; Carta (1987) Tétrahedron Lett. 28,

4027] (1.18 g, 8.83 mmol) in THF (120 mL) and HO (60 mL) was added lithium hydroxide monohydrate (1.11 g, 26.5 mmol). After 20 min the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 X 100 mL). Organic extracts

The combined were dried over Na2S٠4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH: ΝΗ4ΟΗ - 100: 0: 0 to 95: 5: 1, to give the title compound. MS: mlz = 263 (M + 1).

Step D. (±) -Sodium 2'-oxo-l ', 2', 5,7-tetrahydrospirorcyclopenta٢clpyridine-6,3^,-pyrrolo٢2,3blpyridinel-3-carboxylate

To a solution of (±) -2'-oxo-l ', 2', 5,7-tetrahydrospirotcyclopenta [ç] pyridine-6,3'-pyrrolo [; 2,3-pyridine-3-carbonitrile from Step c ( 1.53 g, 5.83 mmol) in EtOH (20 mL) to 5 M aqueous NaOH (3.50 mL) was added. The mixture was refluxed for 72 h, with additional 5 M aqueous NaOH (2.00 mL) added after 6 h. The reaction mixture was allowed to reflow and was concentrated to dryness in vacuo to give the title compound of sufficient purity to be used in the following steps. MS: mlz = 282 (M + 1).

Step E. (±} -teri-Butyl (2'-oxo-r, 2'.5.7-tetrahydrospirorcyclopenta٢٥٩٠vridme-6.3'-r&gt; ynOlo ٢2,315 &amp; lnyridinl-3-vllcarbamate

To a suspension of (±) -sodium 2'-oxo-l ', 2', 5,7-tetrahydrospiro [cyclopenta [c] pyridine-6,3'pyrr010 [2,3-٥jpyridine] -3-carboxylate! 'Step D (1.64 g, 5.83 mmol) and triethylamine (1.62 mL, 11.7 mmol) in ietbutanol (50 mL) was added diphenylphosphoryl azide (1.89 mL, 8.75 mmol) and the mixture was heated at reflux for 72 h. Additional diphenylphosphoryl azide (1.89 mL, 8.75 mmol) was added after 24 hrs and 56 hrs. The reaction mixture was concentrated in vacuo and then partitioned between IClCl (75 mL) and saturated NaHO (100 mL). The organic layer was separated and the aqueous layer was further extracted with CHC (2 X 50 mL). The combined organic layers were dried over

Na2SC&gt; 4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH: ΝΗ4ΟΗ - 100: 0: 0 to 95: 5: 1, to give the title compound. MS: mlz = 353 (M + 1).

Step F. 3-Amino-5.7-dihvdrospirolcvclonentafclpyridine-6.3'-nvrrolo (2.3-٥lnvridinl-2 '(' 1 '# 1one, isomer A

A solution of (±) -er-butyl (2'-οχο-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [c] pyridîne-6,3'pyrro! O [2,3-۵] pyridin] -3-yl) carbamate from Step E (1.39 g, 3.94 mmol) was stirred in CHCl (10 mL) and TFA (3 mL) for 18 h and then concentrated in vacuo to provide the racemic title compound such as the TFA salt. The enantiomers were resolved by HPLC, using a ChiralPak AD column eluting with MeOH. The first major peak to elute was 3-amino-5,7-dihydrospiro [cyclopenta [c] pyridine-6,3'-pyrrolo [2,3-٥] pyridin] -2 '(177) -0ne, isomer A, the title compound, and the second major peak to elute was 3-amino-5,7-

نمم

-85dihydrospiro [cyclopenta [c] pyridine-6,3'-pyrcolo [2,3-٥] pyridin] -2 '(177) -one, isomer B. MS: m / z = 253 (Mil).

INTERMEDIATE 43

<img file="MA30558B1_D0060.tif" />

(±) -2-Amino-5٩7-dihydrospirorcyclopenta٦? / ٢pvridine-6٩3'-pyrrolor2,3-àlpyridinl-2ïl'7j٦-one

Step A. Dimethyl 6-cvanopyridine-2.3-dicarboxvlate

To a solution of dimethyl pyridine-2,3-dicarboxylate 1-oxide [Niiyami et al. (2002) Bioorg. Med. Chem. Lett. 12, 3041] (15.3 g, 72.5 mmol) and trimethylsilyl cyanide (15.7 mL, 117 mmol) in DME (161 mL) was added dimethylcarbamoyl chloride (10.5 mL, 114 mmol). The reaction mixture was heated at reflux for 72 h, and then cooled to 0 ° C. Saturated aqueous NaHO (800 mL) was added slowly and the quench mixture was extracted with EtOAc (2 X 1 L). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient - 100: 0 to 50:50, to give the title compound. MS: m / z = 221 (Mi 1).

Step B. 5.6-7 ?؛ hvdroxvmethvf) nvridine-2-carbonitrile

To a solution of dimethyl 6-cyanopyridin-2,3-dicarboxylate from Step A (13.0 g, 59.0 mmol) in EtOH (295 mL) was added lithium borohydride (29.5 mL of a 2 M solution in THF, 59.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h, and then cooled to 0 ٥c. Saturated aqueous NaHC (200 mL) was added slowly and the quenched mixture was extracted with EtOAc (9 X 100 mL). The combined organic extracts were dried over Na2S٥4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH - 100: 0 to 85:15 ,. to give the title compound, fyis: mtz = 165 (Ml).

Step c. 5,6-7? A (br0m0methvf) pvridine-2-carbonitrile

To a solution of 5,6-è۵ (hydroxymethyl) pyridin-2-carbonitrile from Step B (2.50 g, 15.2 mmol) in THF (76 mL) was added phosphorus tribromide (5, 36 g, 19.8 mmol) in

<img file="MA30558B1_D0061.tif" />

THF (20 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h, and then cooled to 0 ° C. Saturated aqueous NaHO (20 mL) was added slowly and the quenched mixture was extracted with CHCl (2 X 200 mL). The combined organic extracts were dried over baSOi, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 100: 0 to 30:70 gradient, to give the title compound. MS: mlz = 291 (M 1 ب).

Step D. (±) -2'-Oxo-l '- {r2- (triméthvlsilvl) ethoxv٦méthvB-r, 2', 5,7-tetrahvdrospîro [cyclopenta (blpyridine-6.3'-nvrrolol2.3-blpvridinel-2-carbonitrile

To a solution of 5.6-6A (bromomethyl) pyridin-2-carbonitrile from Step c (1.80 g, 6.21 mmol) and 1- {[2- (trimethylsilyl) ethoxy] methyl} -l , 3-dihydro-277-pyrrolo [2,3-٥] pyridin-2-one (1.64 g, 6.21 mmol, described in intermediate 7) in DMF (207 mL) carbonate was added cesium (6.07 g, 18.6 mmol), in portions, over 5 min. After 18h, the mixture was partitioned between CHCl (100 mL), saturated aqueous NaHO (100 mL) and brine (200 mL). The organic layer was extracted and the aqueous layer was further extracted with CHC (2X

100 mL). The combined organic extracts were dried over baSCfi, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 100: 0 gradient to 10:90, to give the title compound. MS: ml 393 (M r 1).

Step E.EA-2'-oxo-l'.2'.5.7-tetrahvdrospiro [cvclopentan&gt; lpvridine-6.3'-nyrrolof2.3-61pvridinel2-carboxylic acid

To a solution of (±) -2'-oxo-l '- {[2- (trimethylsilyl) ethoxy] methyl} -l', 2 ', 5,7-tetrahydrospiro [cyclopenta [è] pyridine-6,3' -pyrr010 [2,3-6] pyridin-2-carbonitrile from Step D (690 mg, 1.76 mmol) in THF (5 mL) 3N aqueous HCl (36 mL) was added. The mixture was heated at reflux for 18 h, allowed to cool and concentrated to dryness in vacuo. The reaction mixture was dissolved in water (12 mL) and purified directly by HPLC using a reverse phase C18 column and eluting with a IIO.'CIICN.'CFjCCH - 95: 5: 0.1 gradient to 5: 95: 0.1. Lyophilization of the fractions containing the product gave the title compound. MS: mlz = 282 (M i

Step F. (±) -tert-Butyl (2'-oxo-r, 2^l.5,7-tetrahvdrospiro٢cvclopenta٢61pvridine-6,3'-pyrrolo ٢2,3frlpyridinlfl-vllarbamate

To a suspension of (±) -2'-oxo-l ', 2', 5,7-tetrahydrospiro [cyclopenta [٥] pyridine-6,3'-pyrrolo [2,3hjpyridinej-2-carboxylic acid from Step E (224 mg, 0.796 mmol) and triethylamine (0.333 mL, 2.39 mmol) in tetbutanol (5 mL) was added diphenylphosphoryl azide (0.258 mL, 1.20 mmol) and the mixture was added heated to reflux for 1 hour. The reaction mixture was concentrated in vacuo and then partitioned between CHC (20 mL) and saturated NaHCO3 (20

إكد

0558 ا 3 mL). The organic layer was separated and the aqueous layer was further extracted with CHCl (2 X 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH: NHH - 100: 0: 0 to 95: 5: 1, to give the title compound. MS: m / z = 353 (M + 1).

Step G. (T) -2-Amino-5.7-dihvdrospirorcvclonentalblnvridine-6.3'-pvrrolol2.3-hlr&gt; vridin] 2 '(l-one

A solution of (±) -tert-butyl (2'-oxo-l ', 2', 5,7-tetrahydrospiro [cyclopenta [h] pyridine-6,3'pyrrolo [2,3-h] pyrîdîn] -2 -yl) carbamate from Step F (147 mg, 0.417 mmol) was stirred in CHC (6 mL) and TFA (1 mL) for 3 h and then concentrated in vacuo to provide the title compound as the salt of TFA. MS: m / z = 253 (Μ 1 1).

INTERMEDIATE 44

<img file="MA30558B1_D0062.tif" />

I ('5 ^ .8S3-Li (benzvloxv) carbonvl] -8-3.5-difluorophénvl) -6-oxo-L7-diazaspirol4.51 dec-7yllacetic acid

Step A.! -Benzyl 2-methvl i2Rl-2- (3-0X0nr0pyl ') pvrr01idin-1.2-dicarb0xvlate

To a solution of DMSO (5.11 mL, 72.1 mmol) in CHC (25 mL) at -78 ° C was added a solution of oxalyl chloride (3.15 mL, 36.0 mmol) in CHCl (25 mL) dropwise. After 10 min of additional stirring, a solution of 1-benzyl 2-methyl (2 ^) - 2- (3hydroxypropyl) pyrrolidine-l, 2-dicarboxylate [Cox and Lectka (1998) J. Am. Chem. ، S'oç. 120, 10660-10668] (7.72 g, 24.0 mmol) in CH2Cl2 (50 mL) at -78 ٥c was added dropwise. After stirring for an additional 1 h, triethylamine (16.7 mL, 120 mmol) was added slowly. The reaction mixture was stirred for 1 h at -78 ° C and 2.5 h at room temperature. Water (100 mL) was added slowly and the quenched mixture was extracted with EtOAc (3 X 100 mL). The combined organic extracts were washed with 10 ٥/٠ HCl (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexane: EtOAc gradient -90: 10 to 0: 100, to give the title compound. MS: mlz = 320 (Mtl).

158

Step B. l-Benzvl 2-methvl ί2 #) - 2-Τ3Μ-34 E.S'tert-butvlsulfinvlliminolnropvB pyrrolidine l, 2-dicarboxylate

To a mixture of 1-benzyl 2-methyl (2Æ) -2- (3-0X0pr0pyl) pyrr01idin-1,2-dicarboxylate from Step A (1.69 g, 5.29 mmol) and anhydrous CuSO ، ( 2.36 g, 10.6 mmol) in CH2Cl2 (10 mL) was added (S ') - 2-methylpropane-2-sulfinamide (0.641 g, 5.29 mmol). This mixture was stirred for 25 h before being filtered through a pad of Celite. Additional CH2Cl2 was used to wash the Celite. The combined organics were concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a hexane: EtOAc - 95: 5 to 0: 100 gradient, to give the title compound. MS: m / z = 423 (M 1 ؛).

Step c. l-Benzvl 2-methvl 12 ^ 1-2-11363-3 ICfttert-butvIsulfinvlIamino 1 -3-13.5difluorophénvl) propvllpyrrolidine-l .2-dicarboxvlate

To a stirred solution of 1-benzyl 2-methyl (2Æ) -2 - ((3 £) -3 - {[(6 ') - tert-butylsulfinyl) imino} propyl) pyrrolidine-1,2-dicarboxylate Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at -78 ° C was added 3,5-difluorophenylmagnesium bromide (14.8 mL of a solution

0.5 M in THF, 7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at -78 ٥C, 3.5 h at -10 ٥C, and then at room temperature for 1.5 h. The mixture was quenched with saturated aqueous NHCl (50 mL) and extracted with EtOAc (3 X 30 mL). -The combined organic layers were washed with brine (30 mL), dried over NajSCL, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a hexaneEtOAc - 95: 5 to 0: 100 gradient, to give the title compound. MS: m / z = 537 (M t 1).

Step D. Benzvl t57? .863-8-t3.5-difluorophénvl) -6-oxo-1.7-diazasniroi4.5ldecane-1-carboxvlate HCl (g) was bubbled through a solution of 1-benzyl 2- methyl (27?) - 2 - [(36) -3 {[(6 ') - ؛ ert-butylsulfinyl] amino} -3- (3,5-difluorophenyl) propyl] pyrrolidine-1,2-dicarboxylate Step c (1.02 g, 1.90 mmol) in MeOH (25 mL) at 0٥C for 1 min. After 1 hour of stirring, the reaction mixture was concentrated to dryness in vacuo. To the crude product suspended in toluene (25 mL) was added triethylamine (2.12 mL, 15.2 mmol), and the reaction mixture was heated to reflux for 66 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH: ΝΗ4ΟΗ - 100: 0: 0 to 95: 5: 1, to give the title compound. MS: m / z = 401 (M1).

Step E. Acid E57? .8y) -l-Ebenzvloxv١carbonvll-8-t3.5-difluorophénvD-6-oxo-1.7 diazaspirof4.5ldec-7-vllacétique

<img file="MA30558B1_D0063.tif" />

To a stirred solution of benzyl (5Æ, 8 ^ -8- (3,5-difluorophenyl) -6-oxo-1,7-diazaspiro [4.5] decane-1 -carboxylate from Step D (541 mg, 1, 35 mmol) in THF (3 mL) at room temperature was added NaH (81 mg of a 60% dispersion in oil, 2.03 mmol). After 30 min, ethyl bromoacetate ( 0.1 96 mL, 1.76 mmol) was added and the mixture was stirred for 30 min. Sodium hydroxide (8.11 mL of a 1 M solution, 8.11 mmol) was added. and the mixture stirred for 16 h. The reaction mixture was poured onto 1 M HCl (20 mL) and extracted with CHCl (3 X 20 mL). The combined organic layers were dried over baiO, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reverse phase C18 column and eluting with a gradient of

HCCHCNClCtH-90: 10: 0.1 to 5: 95: 0.1 to give the title compound. MS: w / z = 459 (M

INTERMEDIATE 45

<img file="MA30558B1_D0064.tif" />

Acid r (3₁S^f) -9-٢ (benzyloxy) carbonvl٦-3- (3١5-difluorophénvl) -l-oxo-2١9-diazaspiro٢5.5٦undéc-2vllacétiaue

Step A. Methvl 4-allvlpiperidine-4-carboxvlate

HCl (g) was bubbled through a solution of 4-allyl-1- (tutoxycarbonyl) piperidine-4-carboxylic acid [Jiang et al. (2004) Bioorg. Med. Chem. Lett. 14, 3675-3678] (6.50 g,

24.1 mmol) in McOH (200 mL). The solution was heated at reflux for 16 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: mlz = 184 (M1).

Step B. 1-Benzyl 4-methvl 4-allylpiperidine-L4-dicarboxvlate

A mixture of methyl 4-allylpiperidine-4-carboxylate from Step A (5.30 g, 24.2 mmol), N (benzyloxycarbonyloxy) succinimide (7.25 g, 29.1 mmol), and NMdiisopropylethylamine ( 12.7 mL, 72.7 mmol) in CHCN (61 mL) was stirred for 16 h. The solvent was extracted in vacuo and the residue was partitioned between EtOAc (100 mL) and saturated NaHCCL (100 mL). The

ذكن

558 The organic layer was separated and the aqueous layer was further extracted with EtOAc (2 X 100 ml The combined organic extracts were concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of hexane: EtOAc - 100: 0 to 40:60, to give the title compound MS: mlz = 318 (M fl).

Step c. 1-Benzvl 4-methvl 4-i2-oxoethvl piperidine-] .4-dicarboxvlate

To a solution of ؛ 'Step B 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (4.45 g, 14.0 mmol) in THF (70 mL) at 0 ° C was added a methyl borane sulfire complex (28.0 mL of a 2 M solution in THF, 56.1 mmol). The reaction mixture was warmed slowly to room temperature and stirred for 16 h, then quenched with water and concentrated in vacuo. The residue was dissolved in CHCl (140 mL) and a solution of PCC (6.65 g. 30.8 mmol) and 4Â molecular sieves (6.65 g) in CHCl (50 mL) at 0 ٥c. The reaction mixture was warmed to room temperature and stirred for 16 h, then diluted with ether (200 mL) and filtered through a pad of Celite. Additional ether was used to wash the Celite. The combined organics were concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient: from CHCl 3OH - 100: 0 to 95: 5, to give the title compound. MS: mlz = 356 (M f Na).

٢ (35) -9-r (benzyloxy) carbonyll-3- (3,5-difluorophénvl) -l-oxo-2,9-diazaspiro٢5.51undec-2yllacetic acid

Essentially following the procedures described for Intermediate 44, but using 1-Benzyl 4-methyl 4- (2-0X0ethyl) piperidine-1,4-dicarboxylate in place of 1-Benzyl 2-methyl (27?) -2- (3-oxopropyl) pyrrolidine-1,2-dicarboxylate, the title compound was prepared. MS: mlz = 473 (Mfl).

EXAMPLE 1

<img file="MA30558B1_D0065.tif" />

M-E4Xl-3-Methvl-2.5-dioxo-l'.3'-dihvdrosnirofimidazolidine-4.2'-indenl-5'-vll-2- (76 ±) -2-oxo-6 phenylpiperidin-! -vllacetamide

Step A. (±) - (2-oxo-6-phenylpiperidin-1-yl) acetic acid

-91058

To a stirred solution of (±) -6-phenylpiperidin-2-one (155 mg, 0.885 mmol) in THF (10 mL), cooled to 0 ° C, was added NaH (30.0 mg, 1.24 mmol). The ice bath was removed and the reaction was allowed to warm to room temperature. After 1 h at room temperature, the reaction was cooled down to 0 ٥c before the introduction of methyl bromoacetate (149 mg, 0.973 mmol). After 40 min the ice bath was removed and the reaction stirred under nitrogen for 12 h. Additional amounts of NaH and methyl bromoacetate were then added in portions to consume almost all of the lactam, as judged by LCMS analysis. Once enough lactam was consumed, 1 M aqueous sodium hydroxide was added (1 mL, 1 mmol). Once a majority of the methyl ester was saponified (~ 3h), the reaction was quenched with 1M hydrochloric acid (5 mL), and EtOAc (50 mL). The organics were washed with saturated brine (twice), dried over sodium sulfate, filtered and concentrated in vacuo, to produce a residue which was used without further purification. MS: m / z - 234 (Mil).

Step B. ^ -fr4N) -3-Methvl-2.5-dioxo-l'.3'-dihvdrosniro! Imidazolidine-4.2'-indénl-5'-vll-2-t16Α) 2-0X0-6-phenvlnineridin-l- vl acetamide

To a solution of (±) - (2-oxo-6-phenylpiperdin-1-yl) etic acid of Step A (100, mg, 0.429 mmol), HOAt (29.0 mg, 0.214 mmol) and (4S) -5'-amino-3-methyl-T, 3'-dihydro-2H, 5Æspiro [imidazolidine-4,2'-indene] -2,5-dione (109 mg, 0.472 mmol, prepared according to Bell, IM, and AI, Dem. Int. PCT, wo 2004082605 Α2) in DMF (5.0 mL) EDCI (115 mg, 0.600 mmol) was added. This solution was stirred at room temperature for 15 h. Then the reaction was quenched by the addition of 1 M HCl (10 mL) and EtOAc (50 mL). The organics were further washed with an additional aliquot of 1Μ HCl (10 mL), then saturated brine (20 mL X 2), which was followed by drying over sodium sulfate. The organics were then filtered, concentrated in vacuo, and applied to a silica gel column to be purified, eluting with a gradient of CHCIMeOH - 99.5: 0.5 to 95: 5. Fractions containing clean product were pooled and concentrated in vacuo to give the title compound. MS: mlz = 447 (M + 1). HRMS: m / z = 447.2013; calculated m / z = 447.2027 for C25HN4O4.

EXAMPLE 2

أكد

-92158

<img file="MA30558B1_D0066.tif" />

j 2-٢ (5ff) -5- (3,5-Difluorophenyl) -2,2-dimethyl-3-oxo-4-thiomorpholinyl٦-A7'-ri4&gt; $ ') - 3-methyl-2,5di0xg-l ', 3'-dihydr0spir0iimidaz01idin-4.2'-inden] -5'-vllacetamide

Starting from (5Æ) -5- (3,5-difluorophenyl) -2,2-dimethylthiomorpholin-3-one (Intermediate 2), the compound in Example 2 was prepared by following procedures analogous to that for preparation of Example 1, to provide the title compound. MS: m / z = 551 (M ا Na). HRMS: m / z = 529.1734; calculate m / z = 529.1716 for C26HF2NO4S.

<img file="MA30558B1_D0067.tif" />

2-i (5ff) -5- (3.5-Difluorophénvll-2.2-dimethvl-1-oxvdo-3-oxo-4-thiomorpholinvl- | -AM (4.Sl-3methyl-2,5-di0X0-l'.3 '-dihydr0spirorimidaz01idin-4,2'-indenl-5'-yllacetamide

Step A. (52D-5- (3.5-DifluoronhénvD-2.2-diméthvlthiomorpholin-3-one

Has a solution of 2 - [(5R) -5- (3,5-difluorophenyl) -2,2-dimethyl-3-oxo-4-thiomorpholinyl] -A [(4٠9) -3-methyl-2,5- dioxo-l ', 3'-dihydrospiro [imidazolidine-4,2'-indenJ-5'-yi; | acetamide (Example 2) in 1.5 mL of 0 ٥c chloroform, 3- acid was added chloroperoxybenzoic acid (21 mg with 77% purity, 0.121 mmol). LCMS analysis of the reaction mixture after two hours revealed that all starting material was consumed. Calcium hydroxide (14 mg, 0.185 mmol) was added to the reaction and stirred for forty minutes. The mixture was vacuum filtered through filter paper and the solid was washed with chloroform (3 x 10 mL). The filtrate was concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of MeOHCHCl -1: 99 to 5:95, to give the title compound. MS: m / z = 545 (M t H). HRMS: m / z = 545,1653; calculated m / z = 545.1665 for C26HF2N4O5S.

EXAMPLE 4

٠ اد

<img file="MA30558B1_D0068.tif" />

2-1 (25) -2- (3,5-Difluorophenyl) -2,5,5-trimethyl-6-oxo-1-piperidinyl٦-٨Z-r (45^,) -3-methyl-2,5dioxo-1 '3'-dihvdrospiro | imidaz01idin-4.2'-mden | -5'-ν1 acetamide

Step A. Methyl (5E) -5 - [(/ ez * / '- butvlsulfmvl) imino | -5- (3.5-diiluorophénvl) -2.2diméthvlpentanoate

To a solution of methyl 5- (3,5-difluorophenyl) -2,2-dimethyl-5-oxopentanoate from Intermediate 1, Step D (500 mg 85% purity, 1.85 mmol) and (5) -2-Methylpropane-2sulfinamide (336 mg, 2.78 mmol) in THF (9.5 mL), titanium tetraethoxide (904 mg, 3.70 mmol) was added. The reaction vessel was quickly capped and placed in a bath at 60^vsC for 2 hours. After cooling to room temperature the reaction mixture was then diluted with saturated brine (9.5 mL) with rapid stirring. The resulting slurry was titrated on Celite, washing with EtOAc, as needed. The combined organics were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by chromatography on silica gel, eluting with a gradient of MeOHCHCl - 0.5: 99.5 to 3:97, to give the title compound. MS: mfz = 374 (M t 1).

Step B. Methyl (55 ') - 5-rtZerZ-but١-'lsulfinvl) aminol-5- (3,5-difIuorophenyl) -2.2dimethylhexanoate

To a solution of methyl (5E) -5 - [(tezT-butylsulfinyl) imino] -5- (3,5-difluorophenyl) -2,2dimethylpentanoate (342 mg, 0.920 mmol) in CHCl (6 mL) at 0 ° C, methylmagnesium bromide was added dropwise over five minutes as a 3M solution in

Diethyl ether (0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to be complete by LCMS analysis. The reaction was quenched by the dropwise addition of 1 M HCl (5 mL), followed by 5 mL of water. The aqueous layer was extracted once with CHCl3 (10 mL) and the organics were combined and washed once with brine (15 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of EtOAcHexanes - 10:90 to 55:45, to give composes it title. MS: m / z = 390 (M 1 ا).

Step C. (6S) -6- (3,5-Difluorophenyl) -3,3,6-trimethylpiperidin-2-one

نميح

<img file="MA30558B1_D0069.tif" />

To a solution of methyl (5S) -5 - [(ter 7butylsulfinyl) amino] -5- (3,5-difluorophenyl) -2,2dimethylhexanoate (1.14 g, 2.93 mmol) in MeOH (60 mL) , cooled to 0 ٥c, anhydrous HCl gas was added for 1 minute. The reaction was stoppered and allowed to stand at 0 ° C for fifteen minutes at which time the reaction was complete by LCMS analysis. Nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (50 mL) was added and it was further concentrated in vacuo. This was repeated with further addition of MeOH and triethylamine (1.18 g, 11.7 mmol). To the resulting residue were added toluene (50 mL) and triethylamine (1.18 g, 11.7 mmol). A reflux condenser was attached and the mixture stirred at 110 ° C. After five days of stirring at reflux, the reaction was judged complete by LCMS.

The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (75 mL) and washed individually with 30 mL of each of the following aqueous solutions: 1 M HCl (twice), water, saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with a gradient of

MeOHCHCl - 1:99 to 5.5: 94.5, to give the title compound. MS: mlz = 254 (M + 1).

Step D, Methyl r (2₁y) -2- (3,5-difluorophenyl) -2,5,5-trimethvl-6-oxopiperidin-l-yl1acetate To a solution of (6S) -6- (3,5-difluorophenyl) -3,3, 6-trimethylpiperidin-2-one (540. mg, 2.13 mmol) in THF (20 mL), refioid to 0 ° C potassium hydride (approximately 86 mg, 2.13 mmol) was added , such as a 30% suspension in oil) under a constant stream of nitrogen. The reaction was allowed to stir for 30 minutes at which time methyl bromoacetate (391 mg, 2.56 mmol) was added at 0 ° C. LCMS analysis after 1 hour indicated that the reaction was incomplete, then additional potassium hydride was added (approximately 43 mg, 1.06 mmol, as a 30% suspension in oil) at 0 ° vs. The reaction was stoppered well and was stirred for an additional 16 hours, during which time the bath temperature warmed to room temperature. The reaction was judged to be 46% complete by LCMS analysis. The reaction was cooled to 0 ° C and saturated aqueous ammonium chloride (5 mL) was added to quench the potassium hydride. To the reaction was added 1 M aqueous HCl (5 mL) and the reaction was diluted with ethyl acetate. The organic layer was washed once with brine and then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with an EtOAcHexanes - 10 gradient. : 90 to 75:25, to give the title compound. MS: mlz = 326 (M 1 ؛).

Step E. Potassium rf2_&gt;2 - (؟ - f3.5-difluorophénvl) -2,5.5-trimethvl-6-oxopiperidin-l-yl1acetate

اد

3QS58

To a solution of methyl [(25) -2- (3,5-difluorophenyl) -2,5,5-trimethyl-6-oxopiperidin-lyljacetate from Step D (298 mg, 0.916 mmol) in THF (9 mL) at room temperature was added potassium trimethylsilanolate (147 mg, 1.14 mmol). The reaction was stirred for 24 hours and was found to be incomplete by LCMS analysis. Additional amounts of potassium trimethylsilanolate were added as needed. The reaction was concentrated in vacuo to give a residue which did not require further purification. MS: m / z = 312 (Mil for parent acid).

Step F, 2 - [(25) -2- (3,5-Difluorophenyl) -2,5,5-trimethvl-6-oxo-1-piperidinvl٦-.7٧-r (4S) -3-méthvl10 2.5-di0X0 -l ', 3'-dihvdr0spir0fimidaz01idin-4.2'-indenl-5'-vllacetamide

Starting from potassium [(25) -2- (3,5-difluorophenyl) -2,5,5-trimethyl-6-oxopiperidin-lyljacetate (182 mg, 0.522 mmol), Example 4 was prepared by following a procedure analogous to that for the preparation of Example 1, Step B, to provide the title compound. MS: m / z = 525 (Mtl). HRMS: m / z = 525.2326; calculate m / z = 525.2308 for C28H30F2N4O4.

EXAMPLE 6

<img file="MA30558B1_D0070.tif" />

<img file="MA30558B1_D0071.tif" />

2-f ('45 .65) -6- (3.5-Difluorophénvl) -4-hvdroxv-3.3-dimethvl-2-oxopiperidin-l-vll-A / -l ('2Rl-2'-oxol.l'.2' .3-tetrahvdrospirolindene-2.3'-pvrrolo, 2.3-blpvridinl-5-vllacetamide

A mixture of [(45,65) -6- (3,5-difluorophenyl) -4-hydroxy-3,3-dimethyl-2-oxopiperidÎn-lyljacetic acid (130 mg, 0.415 mmol, described in Intermediate 21), de (7?) - 5-amino-1,3dihydrospiro [indene-2,3'-pyrrolo [2,3-6] pyridin] -2 '(l'F /) - one (140 mg, 0.557 mmol, described in intermediate 9), HOBT (82 mg, 0.535 mmol), and EDC (95 mg, 0.498 mmol) in DMF (2 mL) was stirred at room temperature for 6 h. The reaction mixture was partitioned between HO (50 mL), saturated aqueous NaHCO3 (30 mL) and EtOAc (100 mL). The organic layer was dried over Na2S٠4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCMCHOH 100: 0 to 90:10, to give the title compound. MS: m / z = 547 (M t 1.). HRMS: m / z = 547.2169; calculated m / z = 547.2151 for C30H29F2N4O4.

-96 EXAMPLE 7

<img file="MA30558B1_D0072.tif" />

<img file="MA30558B1_D0073.tif" />

<img file="MA30558B1_D0074.tif" />

2- [i65'l-6- (3 5-Difluorophénvl١-3.3-dimethvl-2.4-dioxopiperidin-l-vl | -.A - [(2.R) -2'-oxo-l.l ', 2' .3tetrahydr٠spir0٢indene-2,3'-pvn010r2,3-b1pvridinl-5-yl1acetamide

A mixture of [(65) -6- (3,5-difluorophenyl) -3,3-dimethyl-2,4-dioxopiperidin -! - yl] acetic acid (156 mg, 0.501 mmol, described in Intermediate 22 ), de (7ü) -5-amino-1,3-dihydrospiro [indene

2,3'-pyrrolo [2,3-5] pyridin [] - 2 '(70-one (145 mg, 0.577 mmol, described in intermediate 9), from HOBT (95 mg, 0.620 inmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between HO (60 mL) and EtOAc (100 mL). The organic layer was dried over Na2S٥4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCCHOH - 100: 0 to 90:10, to give the title compound. MS: m / z = '545 (M + 1). HRMS: m / z = 545.2025; calculated m / z = 545.1995 for C30H27F2N4O4.

EXAMPLE 8

<img file="MA30558B1_D0075.tif" />

<img file="MA30558B1_D0076.tif" />

<img file="MA30558B1_D0077.tif" />

2-1 (45.650-4-Amino-6 - ('3.5-difluorophénvl') - 3.3-dimethvl-2-oxopiperidin-1-vll-A - [(2j? ١-2'-oxo1.1 '.2' .3-tetrahvdrosnirolindene-2.3'-pvrrolo [2.3-٥lpyridinl-5-vllacetamide

A mixture of 2 - [(65) -6- (3,5-difluorophenyl) -3,3-dimethyl-2,4-dioxopiperidin-1-yl] -. A - [(2Æ) -2'ΟΧΟ-1 , 1 ', 2', 3-tetrahydrospiro [indene-2,3'-pyrrolo [2,3-b] pyridin] -5-yl] acetamide (380 mg, 0.698 mmol, described in Example 7) and NHOAc (571 mg, 7.41 mmol) in CHOH (2 mL) was stirred at room temperature for 20 min. NaCNBH (498 mg, 7.92 mmol) was

ر 4.

added and stirring was continued at room temperature for 12 h. The reaction mixture was diluted with HO (40 mL) and aqueous NaHO (70 mL) and extracted with EtOAc (2 X 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with a gradient of CHCICHOH - 100: 0 to 80:20, to give 2 - [(47?, 65) _ 4-amino-6- ( 3,5-difluorophenyl) -3,3-dimethyl-2-oxopiperidin-l-yI] -A - [(27?) - 2'-oxo-l, l ', 2', 3tetrahydrospiro [indene-2,3 '-pyrrolo [2,3-٥) pyridin] -5-yl] acetamide, which eluted first, and 2 - [(4S ', 6S) -4-amino-6- (3,5-difluorophéyl) -3,3-diméhl-2-oxopiperidin-1-yl] -N - [(2.R) - 2'-oxo1,1 ', 2', 3-tetrahydrospiro [indene-2,3'-pyrrolo [2,3-٥] pyridin] -5-yl] acetamide, which eluted second, the title compound. MS: m / z = 546 (M 11). HRMS: mlz = 546.2287; calculated m / z = 546.2311 for C30H30F2N5O3.

EXAMPLE 10

<img file="MA30558B1_D0078.tif" />

<img file="MA30558B1_D0079.tif" />

2-l (6 ^) - 6- (3.5-Difluoronhénvl) -3.3-diéthvl-2-oxoninerezin-l-vll-Al (22 - (؛ '- oxo-Ll'.2'.3tetrahvdrosniro | indene-23' -Dvrrolol2.3-Plnvridinl-5-vllacetamide

A mixture of [(6 ^) - 6- (3,5-difluorophenyl) -3,3-diethyl-2-oxopiperazin-1_ yljacetic acid hydrochloride (43 mg, 0.119 mmol, described in Intermediate 29), ( Æ) -5-amino-1,3dihydrospiro [indene-2,3'-pyrrolo [2,3-٥] pyridin) -2 '(70-one (30 mg, 0.119 mmol, described in Intermediate 9 ), HOBT (27 mg, 0.179 mmol), and EDC (34 mg, 0.179 mmol) in DMF (0.5 mL) was stirred at room temperature for 18 h. The reaction mixture was purified directly by HPLC using a reverse phase C18 column and eluting with a gradient of H20: CHCN: CF3CO2H - 90: 10: 0.1 to 5: 95: 0.1. Fractions containing pure product were combined, basified with saturated aqueous NaHO, and extracted with EtOAc. The organic extracts were dried over NSO ،, filtered, and concentrated in vacuo to give the title compound. MS: m / z = 560 (M 1 ب). HRMS: mlz = 560,2469; calculated m / z = 560.2468 for C31H32F2N5O3.

EXAMPLE 12

<img file="MA30558B1_D0080.tif" />

<img file="MA30558B1_D0081.tif" />

<img file="MA30558B1_D0082.tif" />

2 - [(4U? ') - 8 - (, 3.5-difluorophénvl) -10-oxo-6,9-diazaspiro | -4.5 | dec-9-vl | -AM0LR') - 2 'oxo-l hydrochloride. 2'.3-tetrahvdrosDîrofindene-2.3'-pvrrolol2.3-٥lDyridinl-5ÿl | acetamide

A mixture of lithium [(87?) - 6- (ter / -butoxycarbonyl) -8- (3,5-difluorophenyl) -10-oxo-6,9dÎazaspiro [4.5) dec-9-yl] acetate (30 mg, 0.070 mmol, described in intermediate 32), of (Æ) -5amino-l, 3-dihydrospiro [indene-2,3'-pyrrolo [2,3-è] pyridin] -2 '(l'77) - one (20 mg, 0.079 mmol.

described in Intermediate 9), HOBT (14 mg, 0.092 mmol), and EDC (18 mg, 0.092 mmol) in DMF (0.5 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (5 mL) and washed successively with 10% citric acid (2 mL), HO (2 mL), saturated aqueous NaHCO 3 (2 mL), and brine (2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with CHClEtOAc - 100: 0 to 0: 100, to give the product protected with Boc. The product protected with Boc was dissolved in EtOAc (3 mL), the solution was cooled to 0 ° C, and HCl (g) was boiled for 1 min. The mixture was aged at 0٥c for 15 min and the title compound was isolated by filtration. MS: mlz = 558 (M + 1). HRMS: m / z = 558.2300; calculated = 558.2311 for C31H30F2N5O3.

EXAMPLE 13

<img file="MA30558B1_D0083.tif" />

2-i167?) - 6- (3,5-difluorophenyl) -3.3-dimethvl-2-oxopiperazin-1-yl1ir (27?) - 2'oxo-Ll ', 2'.3-tetrahvdrospirofindene-2.3' hydrochloride -pvrrolof2.3-٥lpvridinl-5-vl] acetamide

Has a mixture of lithium [(67?) - 4- (tert-butoxycarbonyl) -6- (3,5-difluorophenyl) -3; 3-diméÎhyl-2oxopipérazinlyljacetate (1.12 g, 2.77 mmol, described in! 'Intermediate 13), of (Æ) -5-amino

-99l, 3-dihydrospiro [indene-2,3'-pyrrolo [2,3-6jpyridin] -2 '(l' //) - one (835 mg, 3.32 mmol, described in intermediate 9), and HATU (1.26 g, 3.32 mmol) in DMF (12 mL) N-methylmorpholine (0.61 mL, 5.54 mmol) was added and the resulting mixture was stirred at temperature. room temperature for 90 min. The reaction mixture was diluted with EtOAc (500 mL) and washed successively with 10% citric acid (100 mL), HO (100 mL), saturated aqueous NaHO (100 mL), and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with CHCl'MeOH - 100: 0 to 90:10, to give the product protected with Boc. The Boc-protected product was dissolved in EtOAc (75 mL), the solution was cooled to 0 ° C, and HCl (g) was bubbled for 2 min. After 15 min, additional HCl (g) was boiled for 1 min. The mixture was aged at 0٥C for 30 min and concentrated in vacuo to provide the title compound. MS: m / z = 532 (M 1-ا). HRMS: m / z = 532.2172; calculate m / z = 532.2155 for C29H28F2N5O3.

EXAMPLE 15

<img file="MA30558B1_D0084.tif" />

2-٢ (9 S) -11 -Oxo-9-phenyl-6,1O-diazaspiroH.ôIundec- 10-ylHr (27?) - 2'-oxo-1,1 ', 2', 3 tetrahvdr0snir01indene-2.3 ' -nvrr010Î2.3-٥lpvridinl-5-vllacetamide

Step A. Methyl l- (fi'3&gt; y) -3 -! ('2-oxO2-lf (2 / i?) - 2'-oxo-l.l'.2'.3-tetrahvdrospirofindene-2.3' pvrrolol2.3-àlpvridinl-5-vllamino) ethvl١aminol-3-nhénvlpronvHamino١cvclo pentanecarboxylate

To a cooled (0 ° C) solution of (2 /?) - 5-amino-1,3-dihydrospiro [indene-2,3'-pyrrolo [2,3z?] Pyridin] -2 '(l' // ) -one (0.100 g, 0.398 mmol. Intermediate 9) and triethylamine (100. pL, 0.716 mmol) in THF (8 mL) was added bromoacetyl bromide (46.0 pL, 0.523 mmol). After allowing the reaction to warm to room temperature, triethylamine (0.230 mL, 1.67 mmol) and methyl l - {[(35) -3-amino-3-phenylpropyl] amino} cyclopentanecarboxylate bis- hydrochloride (0.139 g, 0.398 mmol. Intermediate 38) was added, before warming the reaction to 50 ° C for 17 h. After cooling to room temperature, the reaction mixture was diluted with chloroform and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with

-100 additional chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by chromatography on silica gel, eluting with a gradient of CHCl 3 MeOHNHOH 99: 1: 0.1 to 92: 8: 0.8, to give the title compound. MS: m / z = 568 (M + 1).

Step B. Potassium l - (؛ f3_&gt;y) -3-r ('2-oxo-2-i٢ (2Àl-2'-oxo-l, l^,, 2 ', 3-tetrahvdrospirorindene-2,3' pvrrolo | 23-hlnvridinl-5-vllaminolethvBaminol-3-phenvlpropvllaminolcvclo pentanecarboxylate

To a stirred solution of methyl l - ({(3S) -3 - [(2-oxo-2 - {[(2Æ) -2'-oxo-l, T, 2 ', 3-tetrahydrospiro ndene-2,3 '-pyrroloP, 3-۵] pyridin] -5-yl] amino} ethyl) amino] -3-phenylpropyl} amino) cyclopentanecarboxylate from Step A (0.141 g, 0.249 mmol) in dry THF (5 mL) on added KOTMS (64.0 mg, 0.498 mmol) and the reaction mixture was heated to 40 ٠c, at which point the desired product began to precipitate. Two more amounts of KOTMS (~ 60 mg X 2) were added over the next 2 h resulting in complete consumption of the starting material. The mixture was then allowed to cool to room temperature. The THF, which contained only traces of product, was then removed from the precipitated product by decantation. This solid was then washed with two more amounts of anhydrous THF (5 mL X 2), to provide the title compound. MS: m / z = 554 (Mil).

Step c. 2-1 (960-11 -Oxo-9-phenvl-6.10-diazasnirol4.61undéc-lΟ-νΙΙ-Α-Ι ^ Ι-Σ'-οχο-1.1 '.2'.3 tetrahvdr0spir0 [indene-2.3'-Pvrr01012 .3-٥lpvridinl-5-vllacetamide

To a stirred solution of potassium l - ({(3 ^ -3 - [(2-oxo-2- {2 - (^ 2) ؛ '- oxo-l, l', 2 ', 3-tetrahydrospiro

Step B [indene-2,3'-pyrrolo [2,3-٥] pyridinj-5-yl] amino} ethyl) amino (3-phenylpropyl} amino) cyclopentanecarboxylate (0.147 g, 0.249 mmol) in DMF (8.3 mL) EDCI (0.0720 g, 0.374 mmol) and HOAt (0.0340 g, 0.249 mmol) were added. The reaction mixture was then heated to 40 ٠c. After 1 h, additional EDCI (0.0350 mg) was added and the reaction temperature was increased to 50 ° C, for 15 h. The reaction was allowed to cool to room temperature before being diluted with 5% aqueous sodium bicarbonate (100 mL) and chloroform (100 mL). The organics were washed successively with water (100 mL) and saturated brine (100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by chromatography on silica gel, eluting with a gradient of CHCIMeOH - 99: 1 to 91: 9, to give the title compound. MS: m / z = 536 (Mtl). HRMS: m / z = 536.2694; calculated m / z = 536.2656 for C3H34N5O3.

EXAMPLE 19

-10130558

<img file="MA30558B1_D0085.tif" />

2-r (8S) -8- (3,5-Difluorophénvl) -6-oxo-7-azaspiro٢4.51dec-7-yll-7٧ '- (2'-oxo-l', 2 ', 5,7 tetrahydrospirorcyclopentarô1pyridine -6,3'-pynOlor2,3-àlpyridin1-2-vI) acetamide

A mixture of [(85 ') - 8- (3,5-difluorophenyl) -6-oxo-7-azaspiro [4.5] dec-7-yi acid; acetic (21 mg, 0.067 mmol, described in intermediate 86), of (±) -2-nrÎno-5,7-dihydrospiro [cj / clopenta

[6] pyridine-6,3'-pyrrolo [2,3-٥] pyridin] -2 '(l'77) -one (17 mg, 0.067 mmol, described in intermediate 43), PyClu (28 mg , 0.080 mmol), and N, N Mdiisopropylethylamine (0.058 mL, 0.33 mmol) in THF (1 mL) was stirred at room temperature for 16 h. The reaction mixture was purified directly by HPLC using a reverse phase C18 column and eluting with a gradient of HOCHCNCFsCCH - 90: 10: 0.1 to 5: 95: 0.1. Lyophilization provided the title compound as the TFA salt. MS: m / z = 558 (M + 1). HRMS: mlz = 558.2313; calculated m / z = 558.2311 for C31H30F2N5O3.

EXAMPLE 20

<img file="MA30558B1_D0086.tif" />

2-1 (85) -8- (3,5-Difluorophénvl١-6-oxo-7-azaspiro٢4.51dec-7-yll-٨٢- (2'-oxo-r, 2 ', 5,7 tetrahvdrospirolcvclopentar٥lpvridine-6.3' -pvrroIof2.3-61pvridinl-3-vllacetamide. isomer A

A mixture of [(85) -8- (3,5-difluorophenyl) -6-oxo-7-azaspiro [4.5] dec-7-yl] acetic acid (50 mg, 0.16 mmol, described in intermediate 86), of 3-amino-5,7-dihydrospiro [cyclopenta [6) pyridine-6,3'-pyrrolo [2,3-to] pyridin] -2 '(l'7 /) - one, isomer A (39 mg, 0.16 mmol, described in Intermediate 41), HATU (88 mg, 0.23 mmol), and AAMdiisopropylethylamine (0.135 mL, 0.77 mmol) in DMF (1 mL) was stirred at room temperature for 16 h. Of

NHOH (10 drops) was added and the reaction mixture was purified directly by HPLC in

-102 using a reverse phase Cl8 column and eluting with a gradient of HCCHCNCFsOH-90: 10: 0.1 to 5: 95: 0.1. Lyophilization provided the title compound such as the TFA salt. MS: mlz = 558 (Μ + 1). HRMS: m / z = 558.2301; calculate mlz = 558.2311 for C31H30F2N5O3.

EXAMPLE 21

<img file="MA30558B1_D0087.tif" />

2-1 (859-8-3,5-Difluoronhénvl ') - 6-oxo-7-azasoirol4.5ldec-7-vll-A- (2'-oxo-l'.2'.5.7tetrahvdrospiro (cvcloDentalclnvridine-6.3 '-Dvrrolo (2.3-٥ | pyridinl-3-vllacetamide. Isomer A

A mixture of [(85) -8- (3,5-difluorophenyl) -6-oxo-7-azaspiro [4.5] dec-7-yl] acetic acid (128 mg, 0.395 mmol, described in intermediate 86 ), 3-amino-5,7-dihydrosp ؛ ro [cyclopenta [c] pyridine-6,3'-pyrrolo [2,3-b] pyridin] -2 '(l' / i) -one, isomer A (66.5 mg, 0.264 mmol, described in Intermediate 42), HATU (160 mg, 0.422 mmol), and Nmethylmorpholine (0.087 mL, 0.791 mmol) in DMF (1 mL) was stirred at room temperature for 18 h. The reaction mixture was purified directly by HPLC using a reverse phase C18 column and eluting with a gradient of 90: 10: 0.1 to 5: 95: 0.1 HCFCHCNCFjCCH. Lyophilization provided the title compound as the TFA salt. MS: mlz = 558 (Mil). HRMS: m / z = 558.2334; calculate mlz = 558.2311 for C3H30F2N5O3.

The examples appearing in the following tables were prepared by analogy to the examples and intermediates above, as is described or prepared following similar transformations with modifications known to those skilled in the art. The necessary starting materials and intermediates have been described herein (see above), are commercially available, known in the literature, or readily synthesized by those skilled in the art. In some cases, additional synthetic transformations well known to those skilled in the art have been used after the main amide coupling to provide other valuable products. Simple protective group strategies have been applied in some mechanisms. Some of the examples described in the tables have been synthesized as

-10330,558 mixtures of stereoisomers and subsequently purified to give individual isomers. In some cases, the applicable experimental procedures are shown in the tables.

TABLE 12

<img file="MA30558B1_D0088.tif" />

<td>Example</td><td>R⁶</td><td>R⁷</td><td>Rio</td><td>R11</td><td> *</td><td> ٥/٥</td><td>ICMS (Μ + 1)</td>

<td> 22</td><td>H</td><td>H</td><td>H</td><td>phenyle</td><td> ±</td><td>s</td><td> 447</td>

<td> 23</td><td>Me</td><td>Me</td><td>H</td><td></td><td> ±</td><td>s</td><td> 511</td>

<td> 24</td><td>Me</td><td>W \ e</td><td>H</td><td></td><td>s</td><td>s</td><td> 511</td>

<td> 25</td><td>Me</td><td>WA</td><td>H</td><td>3,4-difluorophenyl</td><td>R</td><td>s</td><td> 511</td>

<td> 26</td><td>WA</td><td>Me</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td>s</td><td> 511</td>

<td> 27</td><td>Me</td><td>Me</td><td>H</td><td>3-methyl-2-thienyl</td><td>R</td><td>s</td><td> 495</td>

<td> 28</td><td>Me</td><td>Me</td><td>H</td><td>3-methyl-2-thienyl</td><td>S</td><td>s</td><td> 495</td>

<td> 29</td><td>Me</td><td>Me</td><td>Me</td><td>3,5-difluorophenyl</td><td>S</td><td>s</td><td> 525</td>

<td> 30</td><td>AT</td><td>Ph</td><td>H</td><td>H</td><td> ±</td><td>s</td><td> 447</td>

<td> 31</td><td>H</td><td>Ph</td><td>H</td><td>H</td><td> ±</td><td>R</td><td> 447</td>

<td> 32</td><td>And</td><td>And</td><td>H</td><td>3,5-diflu٠r٥phenyl</td><td>s</td><td>s</td><td> 539</td>

TABLE 13

<img file="MA30558B1_D0089.tif" />

<td>Example</td><td>R⁶</td><td>R⁷</td><td>R⁸</td><td>R⁹</td><td>A1</td><td>R ”</td><td> *</td><td>ICMS (Μ + 1)</td>

<td> 33</td><td>Me</td><td>Me</td><td>H</td><td>AT</td><td> 0</td><td>phenyle</td><td></td><td> 477</td>

<td> 34</td><td>H</td><td>H</td><td>H</td><td>H</td><td>S</td><td>3,5-difluorophenyl '</td><td></td><td> 501</td>

<td> 35</td><td>H</td><td>H</td><td>H</td><td>AT</td><td>SO2</td><td>3,5-difluorophenyl</td><td></td><td> 533</td>

'at

-104158

<td> 36</td><td>H</td><td>H</td><td>Me</td><td>Me</td><td>s</td><td>phenyl</td><td></td><td> 493</td>

<td> 37</td><td>H</td><td>H</td><td>AT</td><td>H</td><td>SO</td><td>3,5-d ؛ flu٥rophenyl</td><td>minority</td><td> 517</td>

<td> 38</td><td>H</td><td>H</td><td>AT</td><td>H</td><td>SO</td><td>3,5-difluorophenyl</td><td>majority</td><td> 517</td>

<td> 39</td><td>Me</td><td>Me</td><td>H</td><td>AT</td><td>SO</td><td></td><td>minority</td><td> 545</td>

<td> 40</td><td>And</td><td>And</td><td>H</td><td>AT</td><td> 0</td><td>3,5-difluorophenyl</td><td></td><td> 541</td>

TABLE 14

<img file="MA30558B1_D0090.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>R١1</td><td> *</td><td> ٥/٥</td><td>ICMS (M٠1)</td>

<td> 41</td><td>H</td><td>H</td><td>phenyl</td><td> ±</td><td>S</td><td> 447</td>

<td> 42</td><td>H</td><td>H</td><td>phenyle</td><td> ±</td><td>R</td><td> 447</td>

<td> 43</td><td>Cl</td><td>Cl</td><td>phenyle</td><td> ±</td><td>S</td><td> 515</td>

<td> 44</td><td>Cl</td><td>Cl</td><td>phenyle</td><td> ±</td><td>R</td><td> 515</td>

TABLE 15

<img file="MA30558B1_D0091.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>R</td><td>R ”</td><td> *</td><td> ٥/٠</td><td>ICMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 45</td><td> 1</td><td>Me</td><td>OH</td><td>3,5-difluorophenyl</td><td>s</td><td>s</td><td> 527</td><td>Ex. 6</td>

TABLE 16

<img file="MA30558B1_D0092.tif" />

.15

-105-

<img file="MA30558B1_D0093.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>Rio</td><td>R ”</td><td> *</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 46</td><td>Me</td><td>Me</td><td>H</td><td>3,4-diflu٥r٥phenyl</td><td> ±</td><td> 531</td><td>Ex. 10</td>

<td> 47</td><td>Me</td><td>Me</td><td>H</td><td>3,4-difluorophenyl</td><td>R</td><td> 531</td><td>Ex. 46</td>

<td> 48</td><td>Me</td><td>Me</td><td>H</td><td>3,4-difluor٥phen٧le</td><td>S</td><td> 531</td><td>Ex. 46</td>

<td> 49</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 531</td><td>Ex. 10</td>

<td> 50</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 547</td><td>Ex. ٩٢١</td>

<td> 51</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 527</td><td>Ex. 10</td>

<td> 52</td><td>Me</td><td>Me</td><td> ١٢١</td><td>5-fluor٥-2-methylphenyl</td><td>S</td><td> 527</td><td>Ex. 10</td>

<td> 53</td><td> 1</td><td>Me</td><td>U</td><td>4-fluor٥-2-methylphenyl</td><td>S</td><td> 527</td><td>Ex. 10</td>

<td> 54</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 527</td><td>Ex. 10</td>

<td> 55</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 543</td><td>Ex. 10</td>

<td> 56</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 513</td><td>Ex. 10</td>

<td> 57</td><td>Me</td><td>Me</td><td>H</td><td></td><td>S</td><td> 547</td><td>Ex. 10</td>

<td> 58</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 527</td><td>Ex. 10</td>

<td> 59</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 525</td><td>Ex. 10</td>

<td> 60</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 525</td><td>Ex. 10</td>

<td> 61</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 525</td><td>Ex. 10</td>

<td> 62</td><td>Me</td><td>Me</td><td>Me</td><td></td><td>s</td><td> 545</td><td>Ex. 10</td>

<td> 63</td><td></td><td>Me</td><td>H</td><td>3,5-dichlo٢٥phenyl</td><td>s</td><td> 563</td><td>Ex. 10</td>

<td> 64</td><td>Me</td><td>Me</td><td>H</td><td>3-thien٧le</td><td>s</td><td> 501</td><td>Ex. 10</td>

<td> 65</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 501</td><td>Ex. 10</td>

<td> 66</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 535</td><td>Ex. 1.0</td>

<td> 67</td><td>Me</td><td>Me</td><td>H</td><td>1,3-ben2٥dioxol-5-yl</td><td>s</td><td> 539</td><td>Ex. 10 '</td>

<td> 68</td><td>Me</td><td>Me</td><td>H</td><td>3-fluor٥-4-'methoxyphenyl</td><td>s</td><td> 543</td><td>Ex. 10</td>

<td> 69</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 547</td><td>Ex. 10</td>

<td> 70</td><td>Me</td><td>Me</td><td>H</td><td>phenyle</td><td>s</td><td> 495</td><td>Ex. 10</td>

<td> 7٩</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 563</td><td>Ex. 10</td>

<td> 72</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 513</td><td>Ex. 10</td>

<td> 73</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 541</td><td>Ex. 10</td>

<td> 74</td><td>Me</td><td>Me</td><td>H</td><td>cyclohexyl</td><td>s</td><td> 501</td><td>Ex. 10</td>

<td> 75</td><td>Me</td><td>Me</td><td>H</td><td>cyclop٢opyle</td><td>s</td><td> 459</td><td>Ex. ١Q</td>

<td> 76</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 529</td><td>Ex. 10</td>

<td> 77</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s.</td><td> 563</td><td>Ex. 10</td>

<td> 78</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 509</td><td>Ex. 10</td>

<td> 79</td><td>Me</td><td>Me</td><td>H</td><td>4-methylpheny! E</td><td>s</td><td> 509</td><td>Ex. 10</td>

'٠٨

-1063Θ558

<td> 80</td><td>Me</td><td>Me</td><td>H</td><td>4- (methylth0 ؛) phenyl</td><td>S</td><td> 541</td><td>Ex. 10</td>

<td> 81</td><td>Hey</td><td>Me</td><td>H</td><td>4-chloro-2-methyl! Phenyl</td><td>S</td><td> 543</td><td>Ex. 10</td>

<td> 82</td><td>Me</td><td>Hey</td><td>H</td><td>benzyl</td><td>S</td><td> 509</td><td>Ex. 10</td>

<td> 83</td><td>Me</td><td>Me</td><td>H</td><td>4-chlorophenyl</td><td>s</td><td> 529</td><td>Ex. 10</td>

<td> 84</td><td>Me</td><td>Me</td><td>H</td><td>isopropyl</td><td>s</td><td> 461</td><td>Ex. 10</td>

<td> 85</td><td>Hey</td><td>Me</td><td>H</td><td></td><td></td><td> 563</td><td>Ex. 10</td>

<td> 86</td><td>Me</td><td>Hey</td><td>H</td><td>2- (methylsulfonyl) phenyl</td><td>s</td><td> 573</td><td>Ex. 73</td>

<td> 87</td><td>Me</td><td>Me</td><td>H</td><td>4- (methylsulfonyl) phenyl</td><td>s</td><td> 573</td><td>Ex. 80</td>

<td> 88</td><td>Hey</td><td>Hey</td><td>H</td><td></td><td> ±</td><td> 563</td><td>Ex. 10</td>

<td> 89</td><td>Hey</td><td>Me</td><td>H</td><td></td><td></td><td> 627</td><td>Ex. 10</td>

<td> 90</td><td>Me</td><td>Me</td><td>H</td><td></td><td>s</td><td> 509</td><td>Ex. 10</td>

<td> 91</td><td>Me</td><td>Hey</td><td>H</td><td></td><td></td><td> 54'9</td><td>'Ex. '10</td>

<td> 92</td><td>Me</td><td>Me</td><td>H</td><td></td><td></td><td> 565</td><td>Ex. 10</td>

<td> 93</td><td>Me</td><td>H</td><td>H</td><td></td><td>s</td><td> 517</td><td>Ex. 10</td>

<td> 94</td><td>And</td><td>And</td><td>H</td><td>3,5-difluorophenyl</td><td>s</td><td> 559</td><td>Ex. 10</td>

TABLE 17

<img file="MA30558B1_D0094.tif" />

<img file="MA30558B1_D0095.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>A١</td><td>Rio</td><td>R11</td><td> *</td><td>ICMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 95</td><td>Me</td><td>Me</td><td> 0</td><td>H</td><td>phenyle</td><td>R</td><td> 497</td><td>Ex. 6</td>

<td> 96</td><td>Me</td><td>H</td><td> 0</td><td>AT</td><td>phenyle</td><td>R</td><td> 483</td><td>Ex. 6</td>

<td> 97</td><td>H</td><td>H</td><td>O</td><td>AT</td><td>phenyle</td><td>R</td><td> 469</td><td>Ex. 6</td>

<td> 98</td><td>Me</td><td>Me</td><td> 0</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 533</td><td>Ex. 6</td>

<td> 99</td><td>And</td><td>And</td><td> 0</td><td>AT</td><td>phenyle -</td><td>R</td><td> 525</td><td>Ex. 6</td>

<td> 100</td><td>AT</td><td>Me</td><td> 0</td><td>H</td><td>.phenyl</td><td>R</td><td> 483</td><td>Ex. 6</td>

<td> 101</td><td>Hey</td><td>Me</td><td> 0</td><td>AT</td><td></td><td>S</td><td> 533</td><td>Ex. 6</td>

<td> 102</td><td>Hey</td><td>Me</td><td>S</td><td>H</td><td></td><td>R</td><td> 549</td><td>Ex. 2</td>

<td> 103</td><td>AT</td><td>And</td><td> 0</td><td>H</td><td></td><td>R</td><td> 497</td><td>Ex. 6</td>

<td> 104</td><td>And</td><td>And</td><td> 0</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 561</td><td>Ex. 6</td>

-107-

<img file="MA30558B1_D0096.tif" />

<td> 105</td><td>Hey</td><td>Hey</td><td>cf₂</td><td>H</td><td></td><td>S</td><td> 567</td><td>أة</td>

<td> 106</td><td>Me</td><td>Me</td><td>1,3-dioxolan-2-yl</td><td>H</td><td>3,5-difluo٢٥plienyl</td><td>S</td><td> 589</td><td>Ex. 7</td>

TABLE 18

<img file="MA30558B1_D0097.tif" />

<img file="MA30558B1_D0098.tif" />

<td>Example</td><td>R</td><td> ٩٦</td><td>R</td><td> *</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 107</td><td>Me</td><td>Hey</td><td>3,5-difluorophenyl</td><td>R</td><td> 545</td><td>Ex. 7</td>

<td> 108</td><td>And</td><td>And</td><td>3,5-difluorophenyl</td><td>S</td><td> 573</td><td>Ex. 7</td>

<td> 109</td><td>And</td><td>And</td><td>3,5-dif! Uo٢ophenyl</td><td>R</td><td> 573</td><td>Ex.٦</td>

TABLE 19

<img file="MA30558B1_D0099.tif" />

<img file="MA30558B1_D0100.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>R</td><td> *</td><td>R ”</td><td> ٥/٠</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 110</td><td>Me</td><td>Me</td><td>GOES</td><td>R</td><td>3,5-difluoopheny! E</td><td>R</td><td> 547</td><td>ذبم.لات ١</td>

<td> 111</td><td>Me</td><td>Me</td><td>H</td><td>R</td><td>3,5-diflU0r0phenyl</td><td>S</td><td> 547</td><td>Ex. 6</td>

<td> 112</td><td>Me</td><td>Me</td><td>H</td><td>S</td><td>3,5-difluorophenyl</td><td>R</td><td> 547</td><td>Ex. 6</td>

<td> 113</td><td>Me</td><td>Me</td><td>Hey</td><td>S</td><td> -</td><td>S</td><td> 561</td><td>Ex. 6</td>

<td> 114</td><td>And</td><td>And</td><td>H</td><td>'S</td><td> -</td><td>S</td><td> 575</td><td>Ex. 6</td>

<td> 115</td><td>And</td><td>And</td><td>H</td><td>R</td><td></td><td>R</td><td> 575</td><td>Ex. 6</td>

<td> 116</td><td>And</td><td>And</td><td>GOES</td><td>R</td><td>3,5-dif! Uo٢ophenyl</td><td>S</td><td> 575</td><td>Ex. 8</td>

<td> 117</td><td>Hey</td><td>Me</td><td>Me</td><td>R</td><td>3,5-difluorophenyl </td><td>R</td><td> 561 -</td><td>Ex. 6</td>

حم

-108 TABLE 20

<img file="MA30558B1_D0101.tif" />

<img file="MA30558B1_D0102.tif" />

<td>Example</td><td>R®</td><td>R?</td><td>R</td><td> *</td><td>HR</td><td> ٥/٠</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 118</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td> ±</td><td>3,5-diflU0r0phenyl</td><td>S</td><td> 646</td><td>Ex. 8</td>

<td> 119</td><td>Me</td><td>Me</td><td>H</td><td>ب</td><td>3,5-difluo rophenyl</td><td>S '</td><td> 546</td><td>Ex. 8</td>

<td> 120</td><td>Me</td><td>Me</td><td>Me</td><td>s</td><td>3,5-dif! Uo٢ophenyl</td><td>S</td><td> 560</td><td>Ex. 8</td>

<td> 121</td><td>Me</td><td>Me</td><td>H</td><td>s</td><td>3,5-difluorophenyl</td><td>s</td><td> 546</td><td>Ex. 8</td>

<td> 122</td><td>Me</td><td>Me</td><td>H</td><td>R</td><td>3,5-diflu0r0phenyl</td><td>s</td><td> 546</td><td>Ex. 8</td>

<td> 123</td><td>And</td><td>And</td><td>H</td><td>S</td><td>3,5-difluo٢ophény! E</td><td>s</td><td> 574</td><td>Ex. 8</td>

<td> 124</td><td>And</td><td>And</td><td>H</td><td>R</td><td>3,5-difluorophenyl</td><td>s</td><td> 574</td><td>Ex. 8</td>

TABLE 21

<img file="MA30558B1_D0103.tif" />

<img file="MA30558B1_D0104.tif" />

<td>Example</td><td>R®</td><td>R⁷</td><td>Ri</td><td>R ”</td><td> *</td><td>ICMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 125</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td>phenyl</td><td> ٤</td><td> 596</td><td>Ex. 12</td>

<td> 126</td><td>Me</td><td>Me</td><td>H</td><td></td><td> ±</td><td> 496</td><td>Ex. 12</td>

<td> 127</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td>phenyl</td><td>s</td><td> 596</td><td>Ex. 12</td>

<td> 128</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td>phenyl</td><td>R</td><td> 596</td><td>Ex. 12</td>

<td> 129</td><td>Me</td><td>Me</td><td>H</td><td>phenyl</td><td>R</td><td> 496</td><td>Ex. 12</td>

<td> 130</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td></td><td>S</td><td> 632</td><td>Ex. 13</td>

<td> 131</td><td>Me</td><td>Me</td><td>tert-butoxycarbonyl</td><td></td><td>R</td><td> 632</td><td>Ex. 13</td>

<td> 132</td><td>Me</td><td>Me</td><td>Me</td><td>3,5-difluorophenyl</td><td>R</td><td> 546</td><td>Ex. 13</td>

-109-

<img file="MA30558B1_D0105.tif" />

<td> 133</td><td>Me</td><td>Me</td><td>acetyl</td><td>3,5-difluorophenyl</td><td>R</td><td> 574</td><td>Ex. 13</td>

<td> 134</td><td>Me</td><td>Me</td><td>methylsulfonyl</td><td>3,5-diflu٥r٥phenyl</td><td>R</td><td> 610</td><td>Ex. 13</td>

<td> 135</td><td>H</td><td>Me</td><td>Me</td><td>phenyle</td><td> +</td><td> 496</td><td>Ex. 10</td>

<td> 136</td><td>Me</td><td>H</td><td>Me</td><td>phenyle</td><td> ±</td><td> 496</td><td>Ex. 10</td>

<td> 137</td><td>H</td><td>Bn</td><td>Me</td><td>phenyle</td><td>S</td><td> 572</td><td>Ex. 10</td>

<td> 138</td><td>AT</td><td>Bn</td><td>Me</td><td>phenyle</td><td>R</td><td> 572</td><td>Ex. 10</td>

<td> 139</td><td>And</td><td>And</td><td>Me</td><td>phenyle</td><td> ±</td><td> 524</td><td>Ex. 10</td>

<td> 140</td><td>And</td><td>And</td><td>H</td><td>phenyle</td><td> ±</td><td> 538</td><td>Ex. 10</td>

<td> 141</td><td>And</td><td>And</td><td>H</td><td>3,5-diflu0٢0phenyl</td><td>s</td><td> 560</td><td>Ex. 10</td>

<td> 142</td><td>H</td><td>Ph</td><td>Me</td><td>phenyle</td><td>s</td><td> 558</td><td>Ex. 10</td>

<td> 143</td><td>H</td><td>Ph</td><td>Me</td><td>phenyle</td><td>R</td><td> 558</td><td>Ex. 10</td>

<td> 144</td><td>H</td><td>/ '- Pr</td><td>Me</td><td>phenyle</td><td>S</td><td> 524</td><td>Ex. 10</td>

<td> 145</td><td>H</td><td>/ '- Pr</td><td>Me</td><td>phenyle</td><td>R</td><td> 524</td><td>Ex. 10</td>

<td> 146</td><td>H</td><td>/-Drank</td><td>Me</td><td>phenyle</td><td>S</td><td> 538</td><td>Ex. 10</td>

<td> 147</td><td>H</td><td>/-Drank</td><td>Me</td><td>phenyle</td><td>R</td><td> 538</td><td>Ex. 10</td>

<td> 148</td><td>/-Drank</td><td>H</td><td>Me</td><td>phenyle</td><td>S</td><td> 538</td><td>Ex. 10</td>

<td> 149</td><td>^ -Bu</td><td>H</td><td>Me</td><td>phenyle</td><td>R</td><td> 538</td><td>Ex. 10</td>

<td> 150</td><td>CH2CF3</td><td>H</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 586</td><td>Ex. 10</td>

<td> 151</td><td>CH2CF3</td><td>H</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td> 586</td><td>Ex. 10</td>

<td> 152</td><td>H</td><td>CH2CF3</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 586</td><td>Ex. 10</td>

<td> 153</td><td>Me</td><td>Me</td><td>PhCHz</td><td>3,5-difluorophenyl</td><td>R</td><td> 622</td><td>Ex. 13</td>

<td> 154</td><td>Me</td><td>Me</td><td>CF3CH2</td><td>3,5-difluorophenyl</td><td>R</td><td> 614</td><td>Ex. 13</td>

<td> 155</td><td>Me</td><td>Me</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td> 532</td><td>Ex. 13</td>

TABLE 22

<img file="MA30558B1_D0106.tif" />

<img file="MA30558B1_D0107.tif" />

<td>Example</td><td>Ri</td><td>not</td><td>Rio</td><td>R</td><td> *</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 156</td><td>H</td><td> 3</td><td>H</td><td>phenyle</td><td>R</td><td> 522</td><td>Ex. 10</td>

<td> 157</td><td>H</td><td> 3</td><td>H</td><td>phenyle</td><td>S</td><td> 522</td><td>Ex. 10</td>

-110-

٠ رم ٠

<img file="MA30558B1_D0108.tif" />

<td> 158</td><td>Me</td><td> 1</td><td>H</td><td></td><td>i</td><td> 508</td><td>Ex. 10</td>

<td> 159</td><td>Me</td><td> 2</td><td>H</td><td>phenyl</td><td> ±</td><td> 522</td><td>Ex. 10</td>

<td> 160</td><td>؛ Erf-butoxycarbonyl</td><td> 3</td><td>AT</td><td>3,5-difluorophenyl</td><td>R</td><td> 658</td><td>Ex. 12</td>

<td> 161</td><td>H</td><td> 3</td><td>H</td><td>3,5-diflu٥rophény! E</td><td>S</td><td> 558</td><td>Ex. 12</td>

<td> 162</td><td>H</td><td> 4</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 572</td><td>Ex. 12</td>

<td> 163</td><td>AT</td><td> 4</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td> 572</td><td>Ex. 12</td>

<td> 164</td><td>H</td><td> 3</td><td>H</td><td>2-bromo-3,5-difluorophenyl</td><td>R</td><td> 636</td><td>Ex. 10</td>

<td> 165</td><td>AT</td><td> 3</td><td>H</td><td>4-bromo-3 | 5-difluo٢ophenyl</td><td>R</td><td> 636</td><td>Ex. 10</td>

<td> 166</td><td>H</td><td> 4</td><td>Me</td><td>3,5-difluorophenyl</td><td>R</td><td> 586</td><td>Ex. 13</td>

<td> 167</td><td>H</td><td> 4</td><td>Me</td><td>3,5-difluorophenyl</td><td>S</td><td> 586</td><td>Ex. 13</td>

<td> 168</td><td>H</td><td> 5</td><td> ١٠</td><td>3,5-difluorophenyl</td><td>R</td><td> 600</td><td>Ex. 13</td>

<td> 169</td><td>H</td><td> 5</td><td>Me</td><td>3,5-difluorophenyl</td><td>S</td><td> 600</td><td>Ex. 13</td>

<td> 170</td><td>ert-butoxycarbonyl</td><td> 3</td><td>Me</td><td>3,5-difluorophenyl</td><td>R</td><td> 72&lt;؟</td><td>Ex. 12</td>

<td> 171</td><td>؛ Ert-butoxycarbonyl</td><td> 3</td><td> 1</td><td>3,5-difluorophenyl</td><td>S</td><td> 672</td><td>Ex. 12</td>

<td> 172</td><td>H</td><td> 3</td><td>Me</td><td>3,5-difluorophenyl</td><td>R</td><td> 572</td><td>Ex. 12</td>

<td> 173</td><td>H</td><td> 3</td><td>Me</td><td>3,5-difluorophenyl</td><td>S</td><td> 572</td><td>Ex. 12</td>

<td> 174</td><td>fert-butoxycarbonyl</td><td> 3</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td> 658</td><td>Ex. 12</td>

TABLE 23

<img file="MA30558B1_D0109.tif" />

<td>Example</td><td>R®</td><td> *</td><td>R ”</td><td> *</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 175</td><td>H</td><td>S</td><td>phenyl</td><td>R</td><td> 508</td><td>Ex. 10</td>

<td> 176</td><td>H</td><td>S</td><td>phenyl -</td><td>S</td><td> 508</td><td>Ex. 10</td>

<td> 177</td><td>H</td><td>R</td><td></td><td>R</td><td> 508</td><td>Ex. 10</td>

<td> 178</td><td>H</td><td>R</td><td> -</td><td>'S</td><td> 508</td><td>Ex. 10</td>

<td> 179</td><td>Me</td><td>S</td><td>ئ</td><td>R</td><td> 522</td><td>Ex. 10</td>

<td> 180</td><td>Me</td><td>S</td><td>phenyl</td><td>S</td><td> 522</td><td>Ex. 10</td>

<td> 181</td><td>Me</td><td>S</td><td></td><td>R</td><td> 558</td><td>Ex. 10</td>

<td> 182</td><td> ٠</td><td>S</td><td>3,5-difluorophenyl</td><td>S</td><td> 558</td><td>Ex. 10</td>

دس

3Θ558

TABLE 24

<img file="MA30558B1_D0110.tif" />

<img file="MA30558B1_D0111.tif" />

<td>Example</td><td>RS</td><td>R⁷</td><td>R¹</td><td>R²</td><td> *</td><td>R</td><td> *</td><td>LCMS (M٠1)</td><td>Applicable experimental procedures</td>

<td> 183</td><td>Me</td><td>Me</td><td>AT</td><td>Me</td><td>R</td><td>phene</td><td>R</td><td> 510</td><td>Ex. 10</td>

<td> 184</td><td>Hey</td><td>Me</td><td>H</td><td>Me</td><td>s</td><td>phenyl -</td><td>s</td><td> 510</td><td>Ex. 10</td>

<td> 185</td><td>Me</td><td>Me</td><td>H</td><td>Me</td><td>R</td><td></td><td>R</td><td> 546</td><td>Ex. 10</td>

<td> 186</td><td>Me</td><td>Me</td><td>AT</td><td>Me</td><td>s</td><td>3,5-difluorophenyl</td><td>s</td><td> 546</td><td>Ex. 10</td>

TABLE 25

<img file="MA30558B1_D0112.tif" />

<img file="MA30558B1_D0113.tif" />

<td>Example</td><td>r1</td><td>X</td><td>Rio</td><td>R ”</td><td> *</td><td>LCMS (Mtl)</td><td>Applicable experimental procedures</td>

<td> 187</td><td>H</td><td> 0</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> 574</td><td>Ex. 10</td>

<td> 188</td><td>H</td><td> 0</td><td>H</td><td>3,5-difluorophenyl</td><td>s</td><td> 574</td><td>Ex. 10</td>

-112558 ج 3

TABLE 26

<img file="MA30558B1_D0114.tif" />

<img file="MA30558B1_D0115.tif" />

<td>Example</td><td>Ri</td><td>not</td><td>X</td><td> *</td><td>ICMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 189</td><td>fert-butoxycarbonyl</td><td> 3</td><td>F</td><td>R</td><td> 684</td><td>Ex. 13</td>

<td> 190</td><td>fert-butoxycarbonyl</td><td> 3</td><td>F</td><td>S</td><td> 684</td><td>Ex. 13</td>

<td> 191</td><td>H</td><td> 3</td><td> ٢</td><td>R</td><td> 584</td><td>Ex. 13</td>

<td> 192</td><td>AT</td><td> 3</td><td>F</td><td>S</td><td> 584</td><td>Ex. 13</td>

<td> 193</td><td>؛ Ert-butoxycarbonyl</td><td> 3</td><td>H</td><td> ±</td><td> 648</td><td>Ex. 13</td>

<td> 194</td><td>H</td><td> 3</td><td>H</td><td>i</td><td> 548</td><td>Ex. 13</td>

TABLE 27

<img file="MA30558B1_D0116.tif" />

<img file="MA30558B1_D0117.tif" />

<td>Example</td><td>Ri</td><td>not</td><td>X</td><td> *</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 195</td><td>rert-butoxycarbonyl</td><td> 3</td><td>V</td><td> ٤</td><td> 658</td><td>Ex. 13</td>

<td> 196</td><td>H</td><td> 3</td><td>F</td><td> ٤</td><td> 558</td><td>Ex. 13</td>

-11358 جج &lt;3

TABLE 28

<img file="MA30558B1_D0118.tif" />

<img file="MA30558B1_D0119.tif" />

<td>Example</td><td>R¹</td><td>LCMS (Mtl)</td><td>Applicable experimental procedures</td>

<td> 197</td><td>terf-butoxycarbonyl</td><td> 602</td><td>Ex. 13</td>

<td> 198</td><td>H</td><td> 502</td><td>Ex. 13</td>

TABLE 29

<img file="MA30558B1_D0120.tif" />

<td>Example</td><td>X</td><td>Y</td><td>Z</td><td>not</td><td>R</td><td> *</td><td> ٥/٥</td><td>LCMS (Μ + 1)</td><td>Applicable experimental procedures</td>

<td> 199</td><td>؛ CH</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-fluorophenyl</td><td>s</td><td></td><td> 537</td><td>Ex. 10</td>

<td> 200</td><td>CH</td><td>CH</td><td> 0</td><td> 2</td><td>3,5-difluorophenyl</td><td>s</td><td></td><td> 553</td><td>Ex. 10</td>

<td> 201</td><td>CH</td><td>CH</td><td>CH</td><td> 2</td><td>3,5-difluorophenyl</td><td>s</td><td></td><td> 551</td><td>Ex. 10</td>

<td> 202</td><td>Net</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-difluorophenyl</td><td>s</td><td>R</td><td> 566</td><td>Ex. 10</td>

<td> 203</td><td>NH</td><td>ch₂</td><td>CH</td><td> 1</td><td>3,5-difluorophenyl</td><td>s</td><td>R</td><td> 538</td><td>Ex. 10</td>

-114-

&lt;كع

<img file="MA30558B1_D0121.tif" />

TABLE 30

<img file="MA30558B1_D0122.tif" />

<td>Example</td><td>X</td><td>Y</td><td>z</td><td>not</td><td>R11</td><td> *</td><td> ٥/٥</td><td>LCMS (M٠1)</td><td>Applicable experimental procedures</td>

<td> 204</td><td>CH</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-diflu0r0phenyl</td><td>s</td><td></td><td> 557</td><td>Ex. 10</td>

<td> 205</td><td>CH</td><td>ch₂</td><td>NH</td><td> 2</td><td>3,5-difluorophenyl</td><td>s</td><td></td><td> 572</td><td>Ex. 10</td>

<td> 206</td><td>CH</td><td>CH,</td><td>NMe</td><td> 2</td><td>3,5-diflu0r0phenyl</td><td>s</td><td></td><td> 586</td><td>Ex. 10</td>

<td> 207</td><td>CH</td><td>bond</td><td>bond</td><td> 1</td><td>phenyle</td><td> ±</td><td></td><td> 493</td><td>Ex. 10</td>

<td> 208</td><td>CH</td><td>CH</td><td> 0</td><td> 2</td><td>3,5-difluorophenyl</td><td>s</td><td></td><td> 573</td><td>Ex. 10</td>

<td> 209</td><td>NH</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-difluorophenyl</td><td>s</td><td>R</td><td> 558</td><td>Ex. 10</td>

<td> 210</td><td>NCOCHPh</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-difluorophenyl</td><td>s</td><td>R</td><td> 692</td><td>Ex. 10</td>

<td> 211</td><td>NMe</td><td>CH</td><td>CH</td><td> 1</td><td>3,5-difluorophenyl</td><td>s</td><td>R</td><td> 572</td><td>.. Ex. 10</td>

<td> 212</td><td>NCHCFs</td><td>CH</td><td> -</td><td> 1</td><td>3,5-difluo٢٥phenyl</td><td>s</td><td>R</td><td> 640</td><td>Ex. 10</td>

<td> 213</td><td>CH</td><td>CH</td><td>NCOCHPh</td><td> 2</td><td>3,5-difluorophenyl</td><td>s</td><td></td><td> 706</td><td>Ex. 10</td>

TABLE 31

<img file="MA30558B1_D0123.tif" />

<td>Example</td><td>X</td><td>Y</td><td>Z</td><td>A١</td><td>not</td><td>Rio</td><td>R ”</td><td> *</td><td> ٥/٥</td><td>LCMS (MH)</td><td>Applicable experimental procedures</td>

<td> 214</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>s</td><td> ±</td><td> 558</td><td>Ex. 20</td>

<td> 215</td><td>CH</td><td>CH</td><td>ch₂</td><td>CH₂</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>s</td><td>Isomer B</td><td> 558</td><td>Ex. 20</td>

<td> 216</td><td>CH</td><td>CH</td><td>ch₂</td><td>NH</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td>Isomer A -</td><td> ٠ 559</td><td>Ex. 20</td>

<td> 217</td><td>CH</td><td>CH</td><td> 0</td><td>ch₂</td><td> 2</td><td>H</td><td>3,5-difluorophenyl</td><td>S</td><td>Isomer A</td><td> 574</td><td>Ex. 20</td>

36558

<td> 218</td><td>CH</td><td>ch₂</td><td>CH</td><td>NH</td><td> 1</td><td>Me</td><td>3,5-dif! U٥rophenyl</td><td>R</td><td>Isomer A</td><td> 573</td><td>Ex. 20</td>

TABLE 32

<img file="MA30558B1_D0124.tif" />

<img file="MA30558B1_D0125.tif" />

<td>Example</td><td>X</td><td>Y</td><td>Z</td><td>AT¹</td><td>not</td><td>Rio</td><td>R ”</td><td> *</td><td> ٥/٥</td><td>ICMS (M-tl)</td><td>Applicable experimental procedures</td>

<td> 219</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td> 1</td><td>H</td><td>3,5-diflu0r0phenyl</td><td>s</td><td>Isomer B</td><td> 558</td><td></td>

<td> 220</td><td>CH</td><td>CH</td><td>CH</td><td>NH</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td>Isomer A</td><td> 559</td><td>Ex. 21</td>

<td> 221</td><td>CH</td><td>CH</td><td>CH</td><td>NH</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td>Isomer B</td><td> 559</td><td>Ex. 21</td>

<td> 222</td><td>CH</td><td>CH</td><td>CH</td><td>NH</td><td> 1</td><td>H</td><td>3,5-difluorophenyl</td><td>R</td><td> ±</td><td> 559</td><td>Ex. 21</td>

<td> 223</td><td>CH</td><td>CH</td><td>Q</td><td>CH</td><td> 2</td><td>H</td><td>3,5-diflu0٢0phenyl</td><td>S</td><td>Isomer A</td><td> 574</td><td>ù.2.٩</td>

<td> 224</td><td>CH</td><td>ch₂</td><td>CH</td><td>NH</td><td>'the</td><td>Me</td><td>3,5-difluorophenyl</td><td>R</td><td>Isomer A</td><td> 573</td><td>Ex. 21</td>

Although specific enantiomers and diastereomers appear in the Examples and Intermediates above, it will of course be understood by those skilled in the art that modifications to reaction conditions and reagents (e.g., but not Limited: use of opposite chirality for starting materials, different catalysts, use of opposite chirality for reactants; use of a different enantiomer or diastereoisomer following chiral resolution) will provide variant enantiomers and diastereomers, all of which are within the spirit and scope of the invention. It is understood that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is intended to include all and such isomeric forms of these compounds.

Although the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will understand that several adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may. be carried out without departing from the spirit and the field of the invention. For example, effective doses other than the particular doses as set forth herein may apply as a result of variations in the reactivity of the mammal being treated for one.

-116-

<img file="MA30558B1_D0126.tif" />

any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary depending on and depending on the particular active compounds chosen, the presence or absence of pharmaceutical carriers, as well as the type of presentation and mode of administration employed, and such variations or differences. expected in the results are contemplated in accordance with the objects and practices of the present invention. It is therefore contemplated that the invention will be defined by the scope of the following claims and that these claims be interpreted as broadly as possible.