(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`( 43) International Publication Date
`28 October 2004 (28.10.2004)
`
`PCT
`
`(10) International Publication Number
`WO 2004/092166 A2
`
`(51) International Patent Classification7:
`
`C07D 471/00
`
`(74) Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(21) International Application Number:
`PCT /US2004/0 10851
`
`(22) International Filing Date:
`
`9 April2004 (09.04.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/463,089
`60/510,352
`
`15 April 2003 (15.04.2003) US
`10 October 2003 (10.10.2003) US
`
`(71) Applicant (for all designated States except US): MERCK
`& CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BURGEY, Christo(cid:173)
`pher, S. [US/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US). DENG, Zhengwu, J. [CN/US];
`126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`NGUYEN, Diem, N. [US/US]; 126 East Lincoln Av(cid:173)
`enue, Rahway, NJ 07065-0907 (US). PAONE, Daniel,
`V. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065-0907 (US). SHAW, Anthony, W. [US/US]; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`WILLIAMS, Theresa, M. [US/US]; 126 East Lincoln
`Avenue, Rahway, NJ 07065-0907 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro(cid:173)
`pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR,
`GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI, SK,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: CGRP RECEPTOR ANTAGONISTS
`
`(57) Abstract: The present invention is directed
`to compounds of Formula (I) and Formula (II)
`(where variables R1, R2, R3, R4, A, B, G, J, Q,
`T, U, V, W, X and Y are as defined herein) useful
`as antagonists of CGRP receptors and useful in
`the treatment or prevention of diseases in which the
`CGRP is involved, such as headache, migraine and
`cluster headache. The invention is also directed
`to pharmaceutical compositions comprising these
`compounds and the use of these compounds and
`compositions in the prevention or treatment of such
`diseases in which CGRP is involved.
`
`(Ill
`
`iiiiiiii
`iiiiiiii
`!!!!!!!!
`
`-iiiiiiii
`iiiiiiii -
`--
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`1
`
`EX2071
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01427
`
`

`

`wo 2004/092166
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`PCT /US2004/01 0851
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`TITLE OF THE INVENTION
`CGRP RECEPTOR ANTAGONISTS
`
`5
`
`BACKGROUND OF THE INVENTION
`CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid
`peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and
`is widely distributed in the central and peripheral nervous system. CGRP is localized
`predominantly in sensory afferent and central neurons and mediates several biological actions,
`including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three
`amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar
`biological properties. When released from the cell, CGRP initiates its biological responses by
`binding to specific cell surface receptors that are predominantly coupled to the activation of
`adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in
`several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth
`15 muscle origin.
`
`10
`
`20
`
`25
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`30
`
`CGRP is a potent vasodilator that has been implicated in the pathology of
`cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated
`levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al.,
`Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on the smooth muscle of
`intracranial vessels, leading to increased vasodilation, which is thought to be the major source of
`headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines,
`Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle
`meningeal artery, the principle artery in the dura mater, is innervated by sensory fibers from the
`trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion
`stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the
`trigeminal 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 mater
`in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior
`administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia,
`1997, 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which
`was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation
`of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be
`blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,
`2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or
`
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`
`reversed by a CORP antagonist. In recently reported clinical trials, the CORP receptor antagonist
`BIBN 4096 BS was reported to be effective in treating acute attacks of migraine (Olesen et al.,
`N. Engl. J. Med. 2004, 350:1104-1110).
`CORP-mediated vasodilation of rat middle meningeal artery was shown to
`sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CORP Family:
`Calcitonin Gene-Related Peptide (CORP), Amylin, and Adrenomedullin, Landes Bioscience,
`2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may
`sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extra(cid:173)
`cranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et
`al., Ann. Neurol. 2000,47, 614-624). A CORP 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 CORP antagonists
`makes them useful pharmacological agents for disorders that involve CORP in humans and
`animals, but particularly in humans. Such disorders include migraine and cluster headache
`(Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,
`320-327); chronic tension type 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
`20 Neurosci., 2001, 4(4), 357-358); eye pain (May et al. Cephalalgia, 2002, 22, 195-196), tooth pain
`(Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus
`(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. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J.
`25 Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794-
`1798); opiate withdrawal syndrome (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, ischaemia, stroke, epilepsy, and neurodegenerative diseases
`(Rohrenbeck et al., Neurobiol. of Disease 1999,6, 15-34); skin diseases (Geppetti and Holzer,
`Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous
`redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002,
`189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al.
`
`30
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`wo 2004/092166
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`PCT /US2004/01 0851
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`Scandinavian Journal of Gastroenterology, 2002, 37(4) 414-422) and cystitis. Of particular
`importance is the acute or prophylactic treatment of headache, including migraine and cluster
`headache.
`
`5
`
`The present invention relates to compounds that are useful as ligands for CGRP
`receptors, in particular antagonists for CGRP receptors, processes for their preparation, their use
`in therapy, pharmaceutical compositions comprising them and methods of therapy using them.
`
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`1
`
`The present invention is directed to compounds of Formula 1:
`a'lT'u
`
`~2 \-fo
`)'fs),_9 /y~
`R _y
`)\-w-x-JI\_G NH
`II ~ I(
`R2~ --B R4
`y
`0
`R2 A
`
`and Formula II:
`
`I
`
`II
`
`(where variables R1, R2, R3, R4, A, B, G, J, Q, T, U, V, W, X andY are as defined herein)
`useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in
`20 which the CGRP is involved, such as headache, migraine and cluster headache. The invention is
`also directed to pharmaceutical compositions comprising these compounds and the use of these
`compounds and compositions in the prevention or treatment of such diseases in which CGRP is
`involved.
`
`25
`
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`
`DET All...ED DESCRIPTION OF THE INVENTION
`
`The present invention is directed to CGRP antagonists which include compounds of Formula 1:
`a'lT'u
`
`1
`
`;r),_g ~Ay~
`~2 R~--l
`R _y
`)\w-x-JI\_G NH
`II ~ I(
`R2~ --B R4
`0
`y
`R2A.
`
`wherein:
`
`A is a bond, C(R2)2, 0, S(O)m or NR 2;
`
`I
`
`I
`R is selected from:
`
`5
`
`10
`
`15
`
`1)
`
`H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, and heterocycle,
`
`unsubstituted or substituted with one or more substituents independently selected
`from:
`
`20
`
`25
`
`30
`
`a)
`b)
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`h)
`i)
`
`Cl-6 alkyl,
`C3-6 cycloalkyl,
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`(F)pC 1-3 alkyl,
`
`halogen,
`OR4.
`O(CH2)s OR4,
`
`-4-
`
`5
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`

`wo 2004/092166
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`PCT/US2004/010851
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`5
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`10
`
`j)
`
`k)
`I)
`m)
`n)
`o)
`p)
`
`q)
`r)
`
`s)
`t)
`u)
`
`v)
`
`C02R4.
`(CO)NR10Rll,
`O(CO)NR10Rll.
`N(R4)(CO)NR lOR 11.
`N(R 10)(CO)R 11,
`N(R 10)(CO)OR 11,
`S02NR10Rll.
`N(R10) so2Rll.
`S(O)mRlO,
`
`CN,
`NRlORll
`'
`N(R10)(CO)NR4Rll, and,
`O(CO)R4;
`
`15
`
`2)
`
`aryl or heteroaryl, unsubstituted or substituted with one or more
`substituents independently selected from:
`a)
`C 1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`20
`
`25
`
`30
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`h)
`i)
`
`j)
`
`k)
`I)
`m)
`n)
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`
`(F)pC1-3 alkyl,
`
`halogen,
`OR4.
`0(CH2)sOR4.
`C02R4.
`(CO)NR10Rll.
`O(CO )NR lOR 11,
`N(R4)(CO)NR lOR 11.
`N(R lO)(CO)R 11,
`
`- 5 -
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`

`wo 2004/092166
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`PCT/US2004/010851
`
`5
`
`o)
`p)
`
`q)
`
`r)
`
`s)
`t)
`u)
`
`v)
`
`N(R lO)(CO)OR 11,
`S02NR10R11,
`
`N(RlO) S02Rll,
`S(O)mRlO,
`
`CN,
`NR10Rll
`'
`N(RlO)(CO)NR4Rll, and
`
`O(CO)R4~
`
`2
`10 R is independently selected from:
`
`1)
`
`H, Co-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl and heterocycle,
`
`15
`
`20
`
`25
`
`30
`
`unsubstituted or substituted with one or more substituents independently selected
`from:
`a)
`b)
`c)
`
`C1-6 alkyl,
`C3-6 cycloalkyl,
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`
`d)
`
`e)
`
`f)
`
`g)
`h)
`i)
`j) .
`
`k)
`1)
`m)
`n)
`o)
`p)
`
`(F)pC1-3 alkyl,
`
`halogen,
`OR4.
`O(CH2)sOR4,
`C02R4,
`
`(CO)NR1DR11.
`O(CO)NR lOR 11.
`N(R4)(CO)NR 10R11,
`N(R lO)(CO)R 11,
`N(R lO)(CO)OR 11,
`S02NR lOR 11.
`
`- 6-
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`

`wo 2004/092166
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`PCT/US2004/010851
`
`q)
`
`r)
`
`s)
`t)
`u)
`
`v)
`
`N(RlO) S02Rll.
`
`S(O)mRlO,
`
`CN,
`NRlORll ,
`N(RlD)(CO)NR4Rll, and,
`O(CO)R4;
`
`2)
`
`aryl or heteroaryl, unsubstituted or substituted with one or more substituents
`independently selected from:
`a)
`Cl-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`d)
`
`e)
`
`t)
`
`g)
`h)
`i)
`j)
`
`k)
`1)
`m)
`n)
`
`o)
`p)
`
`q)
`
`r)
`
`s)
`t)
`u)
`v)
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`(F)pC 1-3 alkyl,
`
`halogen,
`OR4.
`O(CH2)sOR4,
`C02R4.
`
`(CO)NR lOR 11.
`O(CO)NRlDRll.
`N(R4)(CO)NR lOR 11,
`N(R lD)(CO)R 11,
`N(RlO)(CO)ORll.
`S02NR lOR 11.
`N(R 10) S02R 11.
`S(O)mRlO,
`
`CN,
`NRlDRll ,
`N(R 1D)(CO)NR4Rll, and
`O(CO)R4,
`
`- 7-
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`

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`
`5
`
`or, any two independent R2 on the same or adjacent atoms may be joined together to form
`a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl,
`phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl,
`imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl,
`morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide,
`azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
`tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl~
`
`10
`
`RIO and Rll are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl,
`aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy,
`
`where R10 and R11 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl,
`piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5
`substituents where the substituents are independently selected from R4 ;
`
`15
`
`20
`
`25
`
`30
`
`R4 is independently selected from: H, C 1-6 alkyl, (F)pC 1-6 alkyl, C3-6 cycloalkyl, aryl,
`heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy;
`
`X is Cor S;
`
`Y is 0, (R4)2, NCN, NS02CH3, NCONH2, or Y is 02 when X is S;
`
`R6 is independently selected from Hand:
`a)
`C 1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`d)
`
`e)
`
`f)
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`(F)pC1-3 alkyl,
`
`- 8 -
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`g)
`h)
`i)
`
`j)
`
`k)
`l)
`m)
`n)
`o)
`p)
`q)
`r)
`
`s)
`t)
`u)
`v)
`
`halogen,
`OR4.
`O(CH2)sOR4
`C02R4.
`
`,
`
`(CO)NRlORll.
`O(CO)NR lOR 11.
`N(R4)(CO)NR lOR 11,
`N(RlO)(CO)R11.
`N(RlO)(CO)ORll.
`S02NR lOR 11.
`N(RlO) S02R11.
`S(O)mRlO,
`
`CN,
`NRlORll,
`N(R 10)(CO)NR4R 11, and
`O(CO)R4;
`
`G-J is selected from: N, N-C(R5)2, C=C(RS), C=N; C(RS), C(R5)-C(R5)2, C(R5)-C(R5)2-
`C(R5)2, C=C(R5)-C(R5)2, C(R5)-C(R5)=C(R5), C(R5)-C(R5)2-N(R5), C=C(R5)-N(R5),
`C(R5)-C(R5)=N, C(R5)-N(R5)-C(R5)2, C=N-C(R5)2, C(R5)-N=C(R5), C(R5)-N(R5)-N(R5),
`C=N-N(R5), N-C(R5)2-C(R5)2, N-C(R5)=C(R5), N-C(R5)2-N(R5), N-C(RS)=N, N-N(R5)(cid:173)
`C(R5)2 and N-N=C(R5);
`
`Q, T, U and V are each independently a carbon atom or a nitrogen atom wherein at least one but
`no more than three of Q, T, U and V are nitrogen atoms, of which one may be optionally an N(cid:173)
`oxide, and wherein when any of Q, T, U, or Vis a carbon atom it is unsubstituted or substituted
`where the substituents are independently selected from R 6;
`
`5
`
`10
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`15
`
`20
`
`25
`
`R5 is independently selected from H, substituted or unsubstituted C 1-C3 alkyl, CN, OR4,
`30 N(R4)2 and C02R4;
`
`R3 is independently selected from H, substituted or unsubstituted Ct-C3 alkyl, F, CN and
`C02R4;
`
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`p Is
`m Is
`n IS
`sis
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`5
`
`0 to 2q+ 1, for a substituent with q carbons;
`0, 1 or 2;
`0 or 1;
`1, 2 or 3;
`
`and pharmaceutically acceptable salts and individual diastereomers thereof.
`
`Further embodiments of the invention are CGRP antagonists of Formula I which
`include compounds of the Formula Ia:
`
`10
`
`wherein:
`A is a bond, C(R2)2, 0, S(O)m or NR2;
`B is (C(R2)2)n;
`
`Y is 0 or NCN; and
`n is 0 or 1; and
`R1, R2, R4, W, Y, R3, G-1, Q, T, U, V and mare as defined in Formula I;
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`Still further embodiments of the invention are CGRP antagonists of Formula I
`which include compounds of the Formula Ib:
`
`15
`
`20
`
`25
`
`11
`
`

`

`wo 2004/092166
`
`PCT /US2004/01 0851
`
`Ib
`
`wherein:
`A is a bond, C(R2)2, 0, S(O)m or NR2;
`5 B is (C(R2)2)n;
`
`n is 0 or 1; and
`R1, R2, R4, W, R3, G-1, Q, T, U, V and m are as defined in Formula I;
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`10
`
`Additional embodiments of the invention are CORP antagonists of Formula I
`which include compounds of the FormulaIc:
`
`a'lT'u
`R1
`~ ji-
`)r>,-• { T' v
`~~N o
`wy NC)---G "').(" NH
`2 R4
`R
`
`0
`
`II
`0
`
`R
`
`R2
`
`15
`
`wherein:
`R1, R2, R4, W, R3, G-1, Q, T, U, V and mare as defined in Formula I;
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`Ic
`
`Additional embodiments of the invention are CORP antagonists of Formula I
`which also include compounds of the Formula Id:
`R1
`·
`2 R2 I
`
`a'lT'u
`3 ~ /]I_
`
`20
`
`JR )1-9
`RtNyo
`{ T-v
`~WYN~G"').("NH
`
`2
`R
`
`R2A R4
`
`0
`
`ld
`
`II
`0
`
`wherein:
`A is C(R2)2, 0, S(O)m or NR2;
`
`R1, R2, R4, W, R3,G-J, Q, T, U, V and mare as defined in Formula I;
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`25
`
`- 11 -
`
`12
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`Additional embodiments of the invention are CORP antagonists of Formula I
`which include compounds of the Formula Ie:
`a-::::J., U
`R 1
`R2 ~-<0
`(Rs),_9 J)y~
`~~t A~y~GI(NH
`
`0
`
`R2 A
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`le
`
`wherein:
`A is C(R2)2, 0, S(O)m or NR 2;
`
`R1, R2, R4, W, R3, G-J, Q, T, U, V and mare defined in Formula I;
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`Further embodiments of the invention are CGRP antagonists of Formulae Ia -le,
`
`wherein:
`
`R1 is selected from:
`
`1)
`
`H, C 1-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted
`
`with one or more substituents independently selected from:
`a)
`C 1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`h)
`i)
`
`j)
`
`aryl, unsubstituted or substituted with 1-5 substituents where
`the substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`(F)pC1-3 alkyl,
`
`halogen,
`OR4.
`O(CH2)sOR4.
`C02R4.
`
`- 12-
`
`13
`
`

`

`wo 2004/092166
`
`PCT /US2004/01 0851
`
`k)
`1)
`m)
`
`CN,
`NRlORll and
`'
`O(CO)R4; and
`
`5
`
`2)
`
`aryl or heteroaryl, unsubstituted or substituted with one or more substituents
`independently selected from:
`a)
`C 1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`c)
`(F)pC1-3 alkyl,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`d)
`e)
`f)
`
`g)
`h)
`
`i)
`j)
`
`k)
`1)
`m)
`
`halogen,
`OR4.
`C02R4.
`
`(CO)NR lOR 11,
`so2NR10R11,
`N(RlO) S02Rll.
`
`S(O)mR4,
`
`CN,
`NRlDRll and
`'
`'
`O(CO)R4;
`
`R2 is selected from:
`
`1)
`
`H, Co-C6 alkyl, C2-C6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or
`
`substituted with one or more substituents independently selected from:
`a)
`C1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`
`aryl, unsubstituted or substituted with 1-5 sustituents where the
`substituents are independently selected from R4,
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from R4,
`(F)pC1-3 alkyl,
`halogen,
`
`- 13-
`
`14
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`h)
`i)
`
`j)
`
`k)
`
`I)
`m)
`n)
`
`OR4,
`O(CH2)sOR4,
`C02R4,
`S(O)mR4,
`
`CN,
`NR lOR 11, and
`O(CO)R4; and
`
`2)
`
`aryl or heteroaryl, unsubstituted or substituted with one more substituents
`independently selected from:
`Ct-6 alkyl,
`a)
`C3-6 cycloalkyl,
`b)
`(F)pCl-3 alkyl,
`c)
`
`d)
`e)
`f)
`
`g)
`h)
`
`i)
`j)
`
`k)
`I)
`m)
`
`halogen,
`OR4,
`C02R4,
`(CO)NRlORll,
`so2NR10Rll,
`N(R10) S02Rll,
`S(O)mR4,
`
`CN,
`NRlDRll, and
`O(CO)R4,
`
`or, any two independent R2 on the same or adjacent atoms may be joined together to form
`a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl,
`phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl,
`imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl,
`morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide,
`azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
`tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl;
`
`RlO and Rll are independently selected from: H, C1-6 alkyl, (F)pCl-6 alkyl, C3-6 cycloalkyl,
`aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or Ct-C6 alkoxy,
`
`- 14-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`15
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`where RlO and Rll may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl,
`piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5
`substituents where the substituents are independently selected from R4
`
`5 R4is independently selected from: H, Cl-6 alkyl, (F)pCl-6 alkyl, C3-6 cycloalkyl, aryl,
`heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy;
`
`10 G-J is selected from:
`
`N, such that when G-J is so defined the following structure forms:
`
`15
`
`20
`
`N-C(R 5)2, such that when G-J is so defined the following structure
`
`forms:
`
`C=C(R5), such that when G-J is so defined the following structure forms:
`
`- 15-
`
`16
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`a-:::::.T'u ¢ 11
`
`V
`
`H
`
`R5
`
`-~
`
`0
`
`C=N, such that when G-J is so defined the following structure forms:
`
`C=C(R5)-C(R5)2, such that when G-J is so defined the following structure forms:
`
`C(R5)-C(R5)=C(R5), such that when G-J is so defined the following structure forms:
`a-:::::-T'u
`Rs ~~
`
`Rs~~H
`~R5 0
`
`10
`
`15
`
`- 16-
`
`17
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`N-C(R5)2-C(R5)2 , such that when G-J is so defined the following structure forms:
`
`, and
`
`5 N-C(R5)=C(R5), such that when G-J is so defined the following structure forms:
`
`10 Q, T, U and V are each independently a carbon atom or a nitrogen atom wherein at least one but
`no more than three of Q, T, U and V are nitrogen atoms, of which one may be optionally an N(cid:173)
`oxide, and wherein when any of Q, T, U, or Vis a carbon atom it is unsubstituted or substituted
`where the substituents are independently selected from R6;
`
`15
`
`20
`
`25
`
`R6 is independently selected from Hand:
`a)
`Ct-6 alkyl,
`C3-6 cycloalkyl,
`b)
`c)
`(F)pC 1-3 alkyl,
`
`d)
`e)
`f)
`
`g)
`h)
`i)
`j)
`
`halogen,
`OR4.
`C02R4.
`
`(CO)NR lOR 11,
`S02NR lOR 11,
`N(R10) S02Rll.
`S(O)mR4,
`
`- 17-
`
`18
`
`

`

`WO 2004/092166
`
`PCT/US2004/010851
`
`k)
`I)
`m)
`
`CN,
`NRlORll and
`O(CO)R4; and
`
`5
`
`R5 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, CN, OR4,
`
`N(R4)2 and C02R4;
`
`R3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and
`C02R4;
`
`0 to 2q+1, for a substituent with q carbons
`pIS
`m is
`0 to 2;
`1 to 3;
`sis
`and pharmaceutically acceptable salts and individual stereoisomers thereof.
`
`Still further embodiments of the invention are CORP antagonists of Formulae Ia-
`
`10
`
`15
`
`Ie, wherein:
`
`I
`R is selected from:
`
`20
`
`1)
`
`H, C 1-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted
`
`with one or more substituents independently selected from:
`a)
`C1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`R4
`'
`
`d)
`
`phenyl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from
`
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from
`
`and where heteroaryl is selected from:
`imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,
`pyrimidine, and thiazole;
`
`25
`
`30
`
`- 18-
`
`19
`
`

`

`WO 2004/092166
`
`PCT/US2004/010851
`
`e)
`
`f)
`
`g)
`h)
`i)
`j)
`
`k)
`I)
`m)
`
`heterocycle, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from
`R4, and where heterocycle is selected from:
`azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine,
`pyrrolidine, tetrahydrofuran, and tetrahydropyran;
`(F)pC 1-3 alkyl,
`
`halogen,
`OR4,
`O(CH2)sOR4,
`C02R4,
`
`CN,
`NRlDRll
`'
`O(CO)R4;
`
`aryl or heteroaryl, selected from:
`phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,
`pyrimidine, and thiazole,
`unsubstituted or substituted with one or more substituents independently selected
`from:
`a)
`b)
`c)
`
`C1-6 alkyl,
`C3-6 cycloalkyl,
`(F)pC1-3 alkyl,
`
`d)
`e)
`f)
`
`g)
`h)
`i)
`j)
`
`k)
`I)
`m)
`
`halogen,
`OR4,
`C02R4,
`
`(CO)NRlORll,
`S02NR10R11,
`N(R 10) S02R 11,
`S(O)mR4,
`
`CN,
`NR1DR11 and
`'
`O(CO)R4;
`
`5
`
`10
`
`15
`
`2)
`
`20
`
`25
`
`30
`
`R2 is selected from:
`
`- 19-
`
`20
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`1)
`
`H, Co-C6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or
`
`more substituents independently selected from:
`a)
`C 1-6 alkyl,
`b)
`C3-6 cycloalkyl,
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`h)
`i)
`j)
`
`k)
`1)
`m)
`
`phenyl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from
`R4
`'
`heteroaryl, unsubstituted or substituted with 1-5 substituents
`where the substituents are independently selected from
`R4
`'
`and where heteroaryl is selected from: benzimidazole, benzothiophene,
`furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole,
`pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole;
`heterocycle, unsubstituted or substituted with 1-5 substituents where the
`substituents are independently selected from R4, and where heterocycle is
`selected from: azetidine, imidazolidine, imidazoline, isoxazoline,
`isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine,
`pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and
`thiazolidine;
`(F)pC 1-3 alkyl,
`
`halogen,
`OR4.
`
`O(CHz)sOR4.
`C02R4.
`
`CN,
`NR lOR 11, and
`O(CO)R4; and
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2)
`
`aryl or heteroaryl, selected from:
`phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole,
`oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole,
`thiophene, and triazole;
`
`-20-
`
`21
`
`

`

`wo 2004/092166
`
`PCT /US2004/01 0851
`
`unsubstituted or substituted with one or more substituents independently selected
`from:
`a)
`b)
`c)
`
`Ci-6 alkyl,
`C3-6 cycloalkyl,
`(F)pC 1-3 alkyl,
`
`d)
`e)
`f)
`
`g)
`h)
`i)
`j)
`
`halogen,
`OR4,
`C02R4,
`
`(CO)NR lOR 11,
`S02NR lOR 11,
`N(R 10) S02R 11,
`
`S(O)mR4,
`
`CN,
`k)
`NR10R11 and
`I)
`'
`m) O(CO)R4,
`
`or, any two independent R2 on the same or adjacent atoms may be joined together to form
`a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl,
`phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl,
`imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl,
`morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide,
`azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
`tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`R 10 and R 11 are independently selected from: H, C 1-6 alkyl, (F)pC 1-6 alkyl, C3-6 cycloalkyl,
`aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or Ci-C6 alkoxy,
`
`where R10 and Rll may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl,
`piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5
`substituents where the substituents are independently selected from R4;
`
`30
`
`R4is independently selected from: H, C1-6 alkyl, (F)pCl-6 alkyl, C3-6 cycloalkyl, aryl,
`heteroaryl and phenyl, unsubstituted or substituted with hydroxy or C 1-C6 alkoxy;
`
`- 21 -
`
`22
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`5 G-J and Q-T-U-V are as follows:
`
`G-J is Nand Q-T-U-V is N=C(R6)-C(R6)=C(R6), such that when G-J and Q-T-U-V are so
`defined the following structure forms:
`
`~ R'
`:p_•
`Rs
`
`::--
`
`.\NYNH
`0
`
`10
`
`15
`
`G-J is Nand Q-T-U-V is C(R6)=N-C(R6)=C(R6), such that when G-J and Q-T-U-V are so
`defined the following structure forms:
`
`G-J is Nand Q-T-U-V is C(R6)=C(R6)-N=C(R6), such that when G-J and Q-T-U-V are so
`defined the following structure forms:
`
`-22-
`
`23
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`G-J is Nand Q-T-U-V is C(R6)=C(R6)-C(R6)=N, such that when G-J and Q-T-U-V are so
`defined the following structure forms:
`
`G-J is Nand Q-T-U-V is C(R6)=C(R6)-N=N, such that when G-J and Q-T-U-V are so defined
`the following structure forms:
`
`10
`
`15
`
`G-J is Nand Q-T-U-V is C(R6)=N-C(R6)=N, such that when G-J and Q-T-U-V are so defined
`the following structure forms:
`
`G-J is Nand Q-T-U-V is N=C(R6)-C(R6)=N, such that when G-J and Q-T-U-V are so defined
`the following structure forms:
`
`- 23-
`
`24
`
`

`

`wo 2004/092166
`
`PCT/US2004/010851
`
`5 G-J is N-C(R5)2 and Q-T-U-V is C(R6)=C(R6)-C(R6)=N, such that when G-J and Q-T-U-V are
`
`so defined the following structure forms:
`
`NH
`
`-~-N
`y
`0
`
`10 G-J is N-C(R5)2 and Q-T-U-V is C(R6)= N-C(R6)=C(R6), such that when G-J and Q-T-U-V
`
`are so defined the following structure forms:
`
`15
`
`G-J is C=C(R5) and Q-T-U-V is C(R6)=C(R6)-C(R6)=N, such that when G-J and Q-T-U-V are
`so defined the following structure forms:
`
`- 24-
`
`25
`
`

`

`wo 2004/092166
`
`PCT /US2004/01 0851
`
`5
`
`10
`
`15
`
`0
`
`G-J is C=C(R5) and Q-T-U-V is C(R6)=N-C(R6)=C(R6), such that when G-J and Q-T-U-V are
`so defined the following structure forms:
`
`0
`
`G-J is C=N and Q-T-U-V is C(R6)=C(R6)-C(R6)=N, such that when G-J and Q-T-U-V are so
`defined the following structure forms:
`
`G-