TW200813019A - CGRP receptor antagonists - Google Patents

Abstract

The present invention relates to CGRP receptor antagonists, pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions.

Description

200813019 IX. Description of the Invention: [Technical Field] The present invention relates to a CGRP receptor antagonist, a pharmaceutical composition thereof, and a method thereof for treating a CGRP receptor-mediated disease and condition. [Prior Art] CGRP (calcultonin gene-related peptide) is a naturally occurring 37 amino acid peptide which is produced by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous systems. CGRP is primarily involved in sensory transmission into neurons and central neurons and mediates several biological functions, including vasodilation. CGRP is expressed in the alpha-form and the beta-form, which differ in the presence of one or three amino acids in rats and humans, respectively. CGRP-a and CGRP-β exhibit similar biological properties. CGRP, when released from a cell, initiates its biological response by binding to a specific cell surface receptor that is primarily coupled to activate adenylate cyclase. CGRP receptors (including CGRP receptors from brain, cardiovascular, endothelial, and smooth muscle sources) in several tissues and cells have been identified and pharmacologically assessed. I, CGRP is an effective vasodilator associated with the pathology of cerebrovascular disorders such as migraine and cluster headaches. In clinical studies, high levels of CGRP were found in the jugular vein during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on intracranial vascular smooth muscle, leading to increased vasodilation, which is the primary source of headache during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery (the aorta of the dura mater 121775.doc 200813019) is innervated by sensory fibers from a trigeminal ganglion containing several neuropeptides, including CGRP. Trigeminal ganglion stimulation in cats leads to an increase in CGRP content, and activation of the trigeminal nervous system in humans leads to increased flushing of the face 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 of rats increases the diameter of the middle meningeal artery and enhances the effect of blocking by CGRP (8-37) (peptide CGRP antagonist) previously administered (Williamson et al, Cephalalgia, 1997, 17, 525- 53 1). Trigeminal ganglion stimulation increases blood flow to the face of the body that is inhibited by CGRP (8-37) (Escott et al., Brain Res 1995, 669, 93-99). Electrostimulation of the trigeminal ganglion of the sputum produces increased blood flow to the face blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al, Br J. Pharmacol, 2000, 129, 420-423), thus CGRP The antagonist attenuates, prevents or counteracts the vascular effects of CGRP. In a recently reported clinical trial, the CGRP receptor antagonist BIBN 4096 BS has been reported to be effective in the treatment of acute exacerbations of migraine (Olesen et al, N. Engl. J. Med. 2004, 350: 1104-1110). CGRP-mediated vasodilation of the rat middle meningeal artery indicates sensitization of neurons in the trigeminal nerve nucleus (Williamson et al, The CGRP Family: Calcitonin Gene-Related Peptide (CGRP)? Amylin and Adrenomedullin, Landes Bioscience, 2000 , 245-247) o Similarly, dilatation of the dura mater during migraine can sensitize trigeminal neurons. Some related symptoms of migraine (including extracranial pain and facial touch pain) may be the result of sensitization of trigeminal neurons (Burstein et al., 8111. Neurol. 2000, 47, 614-624). CGRP antagonists may be beneficial in attenuating, 121775.doc 200813019 to prevent or counteract the effects of neuronal sensitization. The ability of the compounds of the invention to act as CGRP antagonists makes them suitable agents for CGRP related disorders in humans and animals, but especially humans. These conditions include: migraine and cluster headaches (Doods, Curr Opin·Inves· Drugs, 2001, 2 (9), 1261-1268; 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) Toothache (Awawdeh et al, Int Endocirin. 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. Virol, 1993, 67, 5786 · 5791); shock, sepsis (Beer et al, Crit. Care Med., 2002, 3 0 (8) , 1794-1798); holly 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 for men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. 121775.doc 200813019

Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis, brain trauma, ischemia, stroke, epilepsy and nerves Degenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); Dermatological diseases (Geppetti and Holzer, Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogenic skin redness, skin Rose and red therapy; tinnitus (Herzog et al, J. Membrane Biology, 2002, 189 (3), 225); inflammatory bowel disease, colorectal dysentery (Hoffman et al, Scandinavian Journal of Gastroenterology, 2002, 37 (4) ) 414-422) and cystitis. Acute or prophylactic treatment of headaches, including migraine and cluster headaches, is especially important. The present invention relates to a compound which is useful as a ligand for a CGRP receptor, the anti-C GRP receptor antagonist, its medical composition and use thereof. SUMMARY OF THE INVENTION The present invention provides a compound of formula I:

Or a pharmaceutically acceptable salt thereof. These compounds are useful as antagonists of CGRP receptors and are therefore useful in the treatment of CGRP mediated conditions. The present invention also provides pharmaceutical compositions thereof and uses thereof. 0 121775.doc 200813019 [Embodiment] 4 Hydrates and Definitions: The compounds of the present invention include the compounds described generally above and are disclosed herein. Further description of the species, subclass and substance. The following definitions apply as used herein unless otherwise stated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition). In addition, the general principles of organic chemistry are described in 'Organic Chemistry'', Thomas Sorrell, University Science Books, Sausalito: 1999 and, March's Advanced Organic Chemistry, 5th edition, Smith, MB and March, J. ed., John Wiley & Sons, New York: 2001, the entire contents of which is hereby incorporated by reference herein. Substituted by a particular class, subclass, and substance of the invention. It should be understood that the phrase π as appropriate substituted "may be used interchangeably with the phrase ''substituted or unsubstituted π. In general, the term "substituted π, whether or not referred to by the term", as the case π, refers to the replacement of a hydrogen group in a given structure with a particular substituent. Unless otherwise indicated, optionally substituted groups may have substituents at each substitutable position of the group, and may have more than one position selected from a particular group in any given structure. When substituted, the substituents at each position may be the same or different. The combination of substituents contemplated by the present invention is preferably a combination of substituents which form a stable compound or a chemically feasible compound. As used herein, the term 121775.doc -10- 200813019 π stable '' means substantially unchanged when subjected to conditions that permit its preparation, detection, and preferably its recovery, purification, and for use in the disclosure herein. A compound of one or more purposes. In some embodiments, the stabilizing compound or chemically feasible compound is a compound that does not substantially change when held at a temperature of 4 〇 t: 44 (v rc or less, in the absence of moisture, or under other chemically reactive conditions for at least one week). As used herein, the term "aliphatic" or "aliphatic" means a substituted or unsubstituted straight chain (ie, unbranched) of one or more unsaturated units. Or a branched hydrocarbon chain; or fully saturated or containing one or more unsaturated but non-aromatic units (also referred to herein as "carbocyclic rings," cycloaliphatic " or "cycloalkylindoles, and molecules The remainder of the remainder has a single point of attachment of a monocyclic hydrocarbon or a biguanide. Unless otherwise stated, the aliphatic group contains 1-2 million aliphatic carbon atoms. In some embodiments, the aliphatic group contains one Aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 8 aliphatic carbon atoms. In other embodiments, the aliphatic group contains six aliphatic carbonogens +, and in other embodiments, The aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, the cyclolipid Family " (or "carbocyclic" or "cycloalkyl") means a monocyclic q-C8 hydrocarbon which is fully saturated or contains one or more unsaturated but non-aromatic units, has a single point of attachment to the rest of the molecule or Bicyclic or tricyclic C8_Ci4 hydrocarbons wherein any individual ring in the bicyclic system has 3-7 members. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, Alkynyl and its group: such as (i-alkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (for example, ten Hydronaphthalene), bridged bicycloalkyl (such as norbornyl or [2·2·2]bicyclooctyl) or bridged tricycloalkane 121775.doc 200813019 (such as adamantyl). As used herein, The term "heteroaliphatic" means an aliphatic group in which one or two carbon atoms are independently substituted with one or more of oxygen, sulfur, nitrogen, squam or sphagnum. The group may be substituted or Unsubstituted branched or unbranched cyclic or acyclic groups and including ''heterocyclic ring', noisy for gan ""^ ^ % miscellaneous? Base, heterocycloaliphatic, or "heterocyclyl, group. As used herein, the term "heterocycle,,,"heterocyclyl", "heterocycloaliphatic" A non-aromatic f-ring, bicyclic or bicyclic ring system in which the ring group 1 is - or a plurality of ring atoms are independently selected heteroatoms. In some embodiments, "heterocycle,, "heterocyclic group" , a heterocycloaliphatic, or "heterocyclyl" has three to fourteen ring members, wherein - or more of the ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen or scale; and in the system Each ring contains from 3 to 7 ring members. The term "heteroatom" means oxygen, sulfur or nitrogen (including any oxidized form thereof, such as S = 0, S 〇 2, etc.; any form of nitrogen in the form of nitrogen; or The ring may be substituted for one or more of the nitrogen's such as n (e.g., in the 3,4-m base), nh (as in the base group) or NR+ (e.g., in the N-substituted pyrrolidinyl group). The term "haloaliphatic" and "dentate alkoxy" means an aliphatic or alkoxy group optionally substituted with one or more halogen atoms. The term "豳素" or "卣The base " is responsible for F, C1, ^ or 1. Examples of aliphatics include -CHF2, Ming-CF3, _CF2- or full-alkyl, such as _CF2CF" used alone or as part of a larger part ( For example, the term "aryl" used in "aryl" and "quot; aryloxy" or "aryloxy" is used to mean that there are five to fourteen rings in her mound. Monocyclic, bicyclic, and tricyclic systems of members wherein at least the ring is aromatic and wherein each ring in the system contains 3 to 7 rings. 121775.doc -12-200813019. The term "aryl," It can be used interchangeably with "aryl ring," and the term "aryl" also refers to a heteroaryl ring system as defined below. The term "heteroaryl" used alone or as part of a larger part (as in "heteroaralkyl" or "heteroarylalkoxy") means having a total of five to fourteen ring members. Monocyclic, bicyclic, and tricyclic systems wherein at least one ring of the system is aromatic, at least one ring of the system containing one or more heteroatoms, and wherein each ring in the system contains from 3 to 7 ring members. Heteroaryl, interchangeably with the term 'heteroaryl ring' or the term "heteroaromatic". An aryl group (including an aralkyl group, an aralkyloxy group, an aryloxyalkyl group, and the like) or a heteroaryl group (including a heteroarylalkyl group and a heteroarylalkoxy group and the like) may contain one Or multiple substituents. Suitable substituents on the unsaturated carbon atom of the aryl or heteroaryl group are selected from halo; -R. ; -OR. ; -SR. 1,2-decyloxy; 1,2-ethanedioxy; R as appropriate. Substituted phenyl (Ph); optionally substituted by R° -O(Ph); R as appropriate. Substituting -(CHJbKPh); _CH=CH(Ph); -N02 ; -CN ; -N(R°) 2 ; _NRC(0)R° ; -NRC(0)N( R0)2; -NRC02R° ; -NR°NRC(0)R° ; -NR°NRC(0)N(R°)2 ; -NR0NRC02R0 ; -C(0)C(0)R. ; -C(0)CH2C(0)R° ; -C02R° ; -C(0)R. ; -c(o)n(ro)2 ; -0C(0)N(R0)2 ; -s(o)2ro ; -so2n(ro)2 ; -S(0)R0 ; ·ΝΙ10802Ν(Ι10)2 ; -NR0S02R0 ; -C(=S)N(R0)2 ; -C(=NH)-N(R°)2 ; or -(CH2)0_2NHC(O)R. , wherein each independently occurring R° is selected from the group consisting of hydrogen, optionally substituted Ci-6 aliphatic, unsubstituted 5-6 membered heteroaryl or heterocycle, phenyl, -O(Ph) or- CH2(Ph), or although defined above, two independently of the same substituent or different substituents, 121775.doc • 13-200813019, V and R. The atoms to which the group is bonded together form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 〇_3 heteroatoms independently selected from nitrogen, oxygen or sulfur. R. The optional substituent on the aliphatic group is selected from the group consisting of NHCCm aliphatic group, n (Ck4 aliphatic group) 2, halogen group 'Cw aliphatic group, 0H, oxime (c" aliphatic group), N〇 2. CN, c〇2H, c〇2 (cw aliphatic group), anthracene (halogenated C!·4 aliphatic group) or halogenated Ci4 aliphatic group, wherein R. Each of the above. ! • 4 aliphatic groups are unsubstituted. The aliphatic or heteroaliphatic or non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic or non-aromatic heterocyclic ring are selected from the substituents listed above for the unsaturated carbon of the aryl or heteroaryl group and additionally include the following groups: =0, =S, =NNHR*, =NN(R*)2, —NNHC(0)R,=Li HC〇2 (burning base), =nnhso2 (burning base) or Ben-NR 'where each R* Independently selected from hydrogen or optionally substituted ci 6 aliphatic groups. The optional substituent on the aliphatic group of R is selected from the group consisting of NH2, hydrazine ((^_4 aliphatic group), N (CN4 aliphatic group) 2, halogen group, Cl_4 aliphatic group, oh, CKCm aliphatic group) , N02, CN, C02H, CCMCu aliphatic group), hydrazine (dentate Cw aliphatic group) or halogenated (Cw aliphatic group), wherein each of the above Cl_4 aliphatic groups of R* is unsubstituted. The optional substituent on the nitrogen of the η υ non-aromatic heterocyclic ring is selected from the group consisting of _R+, _N(R+)2, -C(0)R+, _C02R+, -C(0)C(0)R+, ·< :(〇)(:Η2(:(0)ΙΙ+, -S02R+, -S02N(R+)2, _c(=s)N(R+)2, -C(=NH)-N(R+)2 or - NR+S〇2R+; wherein R+ is hydrogen, optionally substituted Cl_6 aliphatic group, optionally substituted phenyl group, optionally substituted _0(ph), optionally substituted -CH2(Ph) Substituted - (CHObKPh), optionally 121775.doc -14- 200813019 substituted -CH=CH(Ph) or unsubstituted with one to four heteroatoms independently selected from oxygen and nitrogen bitumen 5-6 membered heteroaryl or heterocyclic ring, or although defined above, the two independently occurring substituents or different substituents on the different substituents together with the atoms to which the respective R groups are bonded form a 〇_3 independent selection a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring of a heteroatom of nitrogen, oxygen or sulfur. The aliphatic or R to an optional substituent on the phenyl ring is selected from the group consisting of νη2. Νη〇^·4 aliphatic group), N (Cl_4 aliphatic group) 2, halogen group, Ci4 aliphatic group, OH, 〇 ((^·4 aliphatic group), n〇2, CN, C02H, COyc!4 aliphatic group), 0 (halogenated Cw aliphatic group) or _ (<:1. 4 aliphatic group), wherein each of the above C 1 _ 4 aliphatic groups of R+ is unsubstituted. "System" refers to a moiety comprising two or more rings, wherein at least one ring has two points of attachment to another ring via a common carbon ring atom. In some embodiments, as described above in detail, two R independently occur. (or R, or any other variable group similarly defined herein), together with the atoms to which the variable groups are bonded, form 3-8 having 〇-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. a cycloalkyl, heterocyclyl, aryl or heteroaryl ring. Two independently occurring R. (or R+, or any other variable group similarly defined herein) is combined with each variable group. Exemplary rings formed by atoms include, but are not limited to, the following: a) two independently occurring Rs that bind to the same atom and form a ring with the other atom (or R+, or any other variable similarly defined herein). a group, such as N(R.) 2, in which two r are present. Together with the nitrogen atom, piperidin-1-yl, piperidine is formed. - 丨-yl or morpholine _4_ group; and ... independently appearing two R atoms (or R+, or any other variable similarly defined herein) that binds to different atoms and forms a ring with them. a group), for example, 121775.doc -15-200813019, OR 〇 〇 〇 〇 〇 〇 取代 取代 取代 取代 取代 取代 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Ring: It should be understood that when two R(R+) (or R+, or any other variable group similarly defined herein) appearing independently, together with the atoms to which each variable group is bonded, other various rings may be formed, and The examples detailed are not intended to be limiting. "Structures shown herein are also intended to include all isomeric forms of the structure (eg, enantiomeric, diastereomeric, and geometric (or conformational) forms; eg, the conformation of each asymmetric center and its s, unless otherwise stated. Configuration; (z) and (8) double bond isomers and (Z) and (8) configuration isomers. Due to &, individual stereochemical isomers and enantiomers, diastereomers and geometry of illegal compounds (or a conformational) mixture is within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures not herein It is also intended to include compounds which differ only by the presence of one or more atoms which are isotopically enriched. For example, they have a structure such as ruthenium (except hydrogen is replaced by helium or gas, or carbon is replaced by 13c concentrated carbon or % concentrated). Compounds other than carbon are within the scope of the invention. These compounds are useful in biological assays as, for example, analytical tools or probes. The term 丨f aryl·C1-C6 aliphatic beauty is another sweet, a, Earth and, similar terms mean aryl The linker is linked to the core molecule. For example, the term "aromatic-C2-alkyl-," means _CH2CH2ph linkage. Soil solid and benzyl group and core molecule in one embodiment 'present invention Provided a compound of formula I: 121775.doc -16 - 200813019

Wherein: X is S, SO or so2; Z is a bond or NR7, ο, s, ch2, c(0), NR7C(0)NR7, wherein R is hydrogen, Cl-C4 aliphatic or C(0) a C1-C4 aliphatic group; Z7 is a bond, ο, CH20 or c(〇); the soil A is a phenyl group or a 4-7 membered heterocyclic or heteroaryl ring or a 10-14 membered bicyclic heteroaryl ring or a heterocyclic ring. Wherein the heterocyclic or heteroaryl ring has 1 to 4 heteroatoms selected from the group consisting of hydrazine, N or S; wherein ring A is optionally substituted with up to 5 Ri substituents; wherein: Z2 is a bond, z1 is a bond, NR7, 〇, S, CH2, C(O), nr7c(o)nr7; or wherein: z1, Z2 and R6 are absent, ring A is not aromatic and ring A and ring B form a spiro ring system; Is hydrogen or a C1-C4 aliphatic group; m is 1-3; η is 1-3, the limiting condition is m+ny; RY is aryl, heteroaryl, cycloaliphatic, C1-C6 aliphatic , aryl-C1-C6 aliphatic-, heteroaryl-C1_C6 aliphatic group...heterocyclic group_C1_C6 lipid 121775.doc -17- 200813019 valeryl- or lenyl-C1-C6 aliphatic group · wherein Ry is optionally substituted with up to 5 R2 substituents; R is fluorene, aryl, heteroaryl, C1-C6 aliphatic, aryl_ci_C6 aliphatic-, heteroaryl-C1-C6 - wherein Rx is optionally substituted with up to 5 R3 substituents; or two Rx together with the carbon atom to which they are attached form a 3-9 membered monocyclic ring, a 9-14 membered bicyclic ring or a 12-14 membered tricyclic aryl group, a heteroaryl group a heterocyclic or heterocyclic ring system wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from the group consisting of hydrazine, S and N; wherein the ring system formed by two Rx is optionally substituted with up to 5 R4 substituents; Z > R is absent, is a mouse, CN, C1-C6 aliphatic group, halo-C1-C6 aliphatic soil Cl C6 month, 〇 ( ((halo _ci_C6 aliphatic), halo, aromatic a base-C1-C6 aliphatic or heteroaryl-C1_C6 aliphatic group; = is a single bond or a double bond; the restriction is that when it is a double bond, then rZ and one are absent; each foot is not present, Independently hydrogen, halogen, pendant oxy, C1_C6 aliphatic, halo-C1-C6 aliphatic, _〇_C1_C6 aliphatic, _〇_(halo-C1_C6月曰知基), An aryl group, an aryl-C1-C6 aliphatic group-, a C3-C7 cycloaliphatic group; or two R groups together form an optionally substituted C3-C7 cycloaliphatic group or heteropoly wherein the heterocyclic ring has up to 3 a hetero atom selected from the group consisting of ruthenium, S and N; The ring is formed by substitution of up to 5 R5 substituents; wherein each of Ri, R2, r3, 4 and 5 is independently q_rM; wherein Q is a bond or a C1_C6 aliphatic chain, wherein q Up to two phases 121775.doc 200813019 The ortho-indenylene unit is optionally replaced by CO, co2, coco, CONR, OCONR, NRNR, NRNRCO, NRCO, NRC〇2, NRCONR, SO, S02, NRS02, S02NR , NRS02NR, O, S or NR; wherein each occurrence of RM is independently selected from R', halogen, N02, CN, OR', SRf, N(Rf)2, NRlC(0)R, NR'C(0 N(R,)2, NR, C02R, C(〇)Rf, C02R, OC(0)R, C(0)N(R,)2, 〇C(0)N(R,) 2. SOR', S02R, S02N(Rf)2, NR'SC^R1, NRfS02N(R')2, C(0)C(〇)R' or C(0)CH2C(0)R'; Each occurrence of R is independently selected from hydrogen or, as the case may be, 0-5 RK substituted C! 6 aliphatic groups; and each occurrence of RK is independently selected from -Rv, halogen, -N02, -CN, - ORv, -SRV, -N(RV)2, -NRvCORv, -NRvCON(Rv)2, -nrvco2rv, -CORv, -C02Rv, -OCORv, -CON(Rv)2, -C(=N-CN), -OCON(Rv)2, -S ORv, -S02Rv, -S02N(Rv)2, -NRvS02Rv, -NRvS02N(Rv)2, -COCORv, -COCH2CORv, -op(o)(orv)2, -p(o)(orv)2, -op (o) 2〇rv, -P(0)2ORv, -PO(Rv)2 or -OPO(Rv)2, wherein Rv is hydrogen or an unsubstituted CN6 aliphatic group; and each of them exhibits R' independence The ground is hydrogen, as the case may occur, 0-5 RM1 substituted C!_6 aliphatic groups; and each occurrence of RM1 is independently selected from -RT, halogen, -N02, -CN, -ORT, -SRT, - N(RT)2, -NRTCORT, -NRTCON(RT)2, -NRTC02RT, -CORT, -C02RT, -OCORT, -CON(RT)2, -C(=N-CN), -OCON(RT)2 , -SORT, -S02RT, -S02N(RT)2, ·NRTSOsRT, -NRTS02N(RT)2, -COCORT, -coch2cort, -op(o)(ort)2, 121775.doc -19- 200813019 -Pt( o) (ort)2, _〇P(〇)2〇rT, _P0(rT)2 or _〇p〇(RT)2, where f is hydrogen or an unsubstituted C1.6 aliphatic group; Is a 3_membered saturated, partially unsaturated or fully unsaturated single bad with G_3 independent helium, oxygen or sulfur heteroatoms, or 8-12 saturated with 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur a partially unsaturated or fully unsaturated double ring system, wherein the single ring or The cyclical appearance occurs after the occurrence of 〇5 Ru substitutions; and each occurrence of rU is independently selected from the 〇3 氺 which is optionally present (^ is substituted and has 〇_3 independently selected from nitrogen, oxygen or sulfur A 3'8-membered saturated, partially unsaturated or monounsaturated monocyclic ring of an atom, or -RQ, halogen, = 0, =NRQ, -N02, -CN, -〇RQ, SRQ, -N(RQ)2, -NRQCORQ , -NRQCON(RQ)2, -NRQC02RQ, -C0RQ, _c〇2rQ, -〇c〇rq ...c〇n(rQ)2, -C(=N-CN), -0C0N(RQ)2, -sorQ , -S02rQ, -S02N(rQ)2, -NRQS02RQ, -NRQS02N(RQ)2, -COCORQ, -COCH2CORQ, -0P(0)(0Rq)2 > -P(〇)(〇rQ)2 . - OP(〇)2〇rQ . -P(〇)2〇rQ . -P0(RQ)2 or -OPO(rQ)2, wherein RQ and RQ1 are hydrogen or unsubstituted Cl6 aliphatic group; or R and R1 (the two Rs present or the two Rs present), together with the atoms to which they are bound, form a 3-12 member saturated, partially unsaturated or fully zero with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. An unsaturated monocyclic or bicyclic ring wherein the monocyclic or bicyclic ring is optionally substituted with 0-5 RT1; and each occurrence of iRT1 is independently selected from -Rs, halogen, =0, =NRS, -N〇2, - CN, O Rs, -SRs, -N(RS)2, -NRsCORs, -NRsCON(Rs)2, -NRsC02Rs, -CORs, -C02Rs, -OCORs, -CON(Rs)2, -C(=N-CN), ·0(:0Ν(Ι13)2, -SORs, -S02Rs, sense S02N(Rs)2, -NRsS02Rs, -NRsS02N(Rs)2, -COCORs, -COCH2CORs, 121775.doc -20- 200813019 -op(o (ors)2, -P(0)(orS)2, _〇p(9)2〇RS, _p(9)2〇RS, PO(R)2 or OP〇(R)2 '丨Rs is hydrogen or unsubstituted Ci .6 aliphatic group. In one embodiment of Formula I, 'z2 is a bond, R6 is hydrogen and 21 is a bond. In another embodiment of Formula I, Z2 is a bond, R6 is hydrogen and " is ^^7, Ο, S, CH2, c(0) or NR7C(0)NR7. In one embodiment of Formula I, Z, R6 are not 氲 and 21 is a bond. In one embodiment of Formula I, Z2-R6 is not hydrogen XZ^NR7, 〇, s, CH2, c(0) or NR7C(〇)NR7. In one embodiment of formula i, = is a single bond. In one embodiment of Formula I, two are single bonds and both Rw are hydrogen. In one embodiment of formula I, Rz, if present, is C1_C6 alkyl, halo-C1-C6 alkyl- or-0-C1-C6 alkyl. In one embodiment of formula I, RZ, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or 〇Et. In one embodiment of Formula I, at least an alkyl group, a halo group, a C6 alkyl group or a -〇-ci-C6 alkyl group. In one embodiment of formula I, at least one is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. In one embodiment of formula I, one Rw is hydrogen and the other is alkyl, halo-C1-C6 alkyl- or-0-C1-C6 alkyl. In one embodiment of formula I, one Rw is hydrogen and the other Rw is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. In one embodiment of Formula I, RY is optionally halogenated, 〇H, _c, C4, 121,775.doc -21 - 200813019 alkoxy, -C1-C4 alkoxycarbonyl or bis(C1-C4 alkyl) Amino-substituted one or more C1-C6 aliphatic groups. In one embodiment of Formula I, RY is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3 dimethyl-butyl, 3-methyl-butyl , 2·methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxycarbonyl)_3_methyl-butyl 'hydroxymethyl)_3_methyl- Butyl, allyl, ethynyl, 2-(-ethylamino)ethyl, 1-methyl-2-indolyl-ethyl, 3-yl-2-(2-dimethyl-propyl) 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl or 2,2,3,3,3-pentafluoro-propyl. In one embodiment of Formula I, Ry is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-mercapto-butyl Or 2·methyl-propyl. In one embodiment of Formula I, 1 is (3_(::8 cycloaliphatic or C1-C6 aliphatic) substituted with a C3-C8 cycloaliphatic group. In one embodiment of Formula I , 1^ is (: 3-(::6 cycloalkyl or C1-C6 alkyl-substituted by C3-C6 cycloalkyl. In one embodiment of formula I, ry is cyclopropyl, cyclohexyl, Cyclohexylmethyl-, cyclopropylmethyl- or cyclohexylethyl-. In one embodiment of formula I, Ry is pyridyl (C1-C6)alkyl-, tetrahydrofuranyl (C1-C6 alkyl) -, or N_(ci_cg phenyl pyrrolidinyl). In one embodiment of formula I, tetrahydrofuran-2-yl-methyl-, pyridine-3-yl-methyl-, pyridin-4-yl · Ethyl, pyridin-2-yl-ethyl-, pyridine-4-yl-methyl-, 1-indole _5-yl or 2-(indolyl-pyridin-2-yl-B In one embodiment of formula I, RY is phenyl or phenyl substituted C1-C6 aliphatic-, which is optionally substituted with up to 5 R2 substituents, The R2 substituent is independently selected from halo or a 5-6 membered heterocyclic ring having 1-3 heteroatoms selected from ruthenium, osmium or S. In one embodiment of formula I, RY is phenyl, 2,6-difluoro Phenyl, Benzyl, 4-fluorophenylmethyl-, 4-morpholinium phenyl-, 2-piperidinylphenyl- or phenylethyl-hydrazine In one embodiment of formula I, one Rx is hydrogen and Another; rX is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents, the R3 substituents being independently selected from C1-C6 aliphatic, phenyl, halogen, C3-C6 cycloaliphatic Or a 4-7 membered heterocyclic ring wherein the heterocyclic ring is optionally substituted with up to 3 Ru substituents wherein the heteroaryl or heterocyclic ring has up to three heteroatoms selected from N, hydrazine or S. In one embodiment, one Rx is hydrogen and the other px is a phenyl or u-pyridyl group having up to two R3 substituents, and the r3 substituent is independently selected from a halogen or a 4-7 membered heterocyclic ring, wherein the heterocyclic ring is optionally Up to 2 Ru substituents substituted wherein the heterocycle has up to three heteroatoms selected from N, fluorene or S. In one embodiment of Formula I, one Rx is hydrogen and the other Rx is at 2 positions via 4_ a phenyl group substituted with a heterocyclic ring and substituted with a halogen at the 3-position. In one embodiment of formula I, one Rx is hydrogen and the other Rx is phenyl or phenyl substituted with the following group: piperazinyl, 4-methyl-piperazin-1-yl, 4-ethyl-peri —I group, 'propyl-piperazin-1-yl, 4-butyl-piperazin-1-yl, 4-isopropyl-limizazine-1-yl, 4-tert-butylpiperazine-1 -Based, 4-cyclopropylpiperazine-;[_土四弟一丁气基基·旅召-1-yl, 4-yl-based-Brigade σ-based, 4-ethoxy-based-biting-1 · 、, morpholin-4-yl, ϋpyrazole·1-yl, imidazolium-fluorenyl, 121775.doc -23- 200813019 0 piroxidin-1-yl, 3-diamine-° Biloxi-1-yl, 4-(唆唆-1-yl), anthracene, pyridyl (1-mercaptopiperidin-4-yl)piperazin-1-yl or 1-(2,2, 2-Trifluoroethyl) 嘻-1-yl. In one embodiment of Formula I, a pyridyl group wherein Rx is hydrogen and the other Rx is acridinyl or substituted with: piperazinyl, 4-methyl-piperazin-1-yl, 4-ethyl - piperazin-1-yl, 4-propyl-piperazin-1-yl, 4-butyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-third 5-piperazin-1-yl, 4-cyclopropylpiperidinyl-l-yl-1-yl, 4-tert-butoxy-yl-cyclohexyl-l-yl, 4-yl-radical-based, 4-ethoxylated Carbonyl-piperidin-1-yl, morpholin-4-yl, l-good-pyrazole-1-yl, imidazolium-i-yl, σ piroxicam-1-yl, 3-dimethylamine唆_ι_基, 4-(旅咬_1_基) piperidine, pyridyl (1-methylpiperidine-4-yl) piperazin-1-yl or 1-(2,2,2-trifluoro Ethyl) traceazine-1-yl. In one embodiment of Formula I, one Rx is hydrogen and the other Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of: C1-C6 aliphatic, Cyano, halo, halo-C1_C6 aliphatic...aryl_C1-C6 aliphatic-, heteroaryl-C1_C6 aliphatic-, aralkyloxy, bis(Cl_C6 aliphatic) amine ·, _0_C1-C6 aliphatic group, -s(〇)_cl_C6 aliphatic group or -S(0)2-C1-C6 aliphatic group. In one embodiment of Formula I, one Rx is hydrogen and the other Rx is a C3-C7 cycloaliphatic substituted with up to five R3 substituents as appropriate and having up to three heteroatoms selected from oxime, ^^ or 8. A cyclyl or heterocycloaliphatic ring wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. In one embodiment of Formula I, the Rx is selected from the group consisting of cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2 ugly-piperidyl, tetrahydro-2H-thiopyranyl, 121775 .doc •24- 200813019 9H-苐-9_ base or slightly sigma. In one embodiment of Formula I, two Rx, together with the carbon atom to which they are attached, form a 3-9 membered monocyclic, 9-14 membered bicyclic or 12·14 membered tricyclic aryl, heteroaryl or heterocyclic system, Wherein each heteroaryl or heterocyclic ring has up to 3 heteroatoms selected from the group consisting of ruthenium, § and N; the ring formed by the two Rx is substituted by up to 5 R4 substituents; In one embodiment, the ring system is selected from the group consisting of 9Η_^_9_yl, tetrahydro-2-indole-pyran-4-yl, tetrahydro-2-indole-thiopyran-4-yl, cyclobutyl, cyclopentyl, ring Hexyl, cycloheptyl, cyclohexenyl, piperidinyl or benzyl-piperidine. In another embodiment of Formula I, the compound has the formula ΙβΑ : 〇

Wherein: the cyclic oxime is a 4-7 membered heterocyclic ring which forms a spiro ring system with the brigant ring via a carbon atom, wherein ring A is optionally substituted with a substituent or a substituted phenyl or heteroaryl group. The ring is fused; wherein the ring A has up to two ring heteroatoms selected from the group consisting of ruthenium in addition to the nitrogen ring atom; wherein the ring oxime is substituted with at most a "substituent" in addition to the side oxy group; ^, 尺^一和乂 as defined herein. In one embodiment of the formula Ι-A, = is a single bond, and if rZ is present, it is 121775.doc -25- 200813019 hydrogen. In the formula I-Α In one embodiment, = is a single bond and ^ is ^-alkyl, halo-C1-C6 alkyl- or -0-C1-C6 alkyl. In one embodiment of formula Ι-A, Rz is If present, it is fluorine, methyl, ethyl, n-propyl, CF3, CHF2, OMe or 〇Et. In one embodiment of formula Ι-A, at least an alkyl group, a halo group - a C1-C6 alkyl group - or - 0-C1-C6alkyl. In one embodiment of Formula I-Α, at least one rW is fluoro, decyl, ethyl, n-propyl, CF3, CHF2, OMe, or OEt. Medium, two are single bonds, one rW is hydrogen and the other rW is C1-C6 alkyl _ base-(: 1-〇6 alkyl or -0-C1-C6 alkyl. In one embodiment of formula Ι-A, one rW is hydrogen and the other rW is fluoro, fluorenyl, ethyl, N-propyl, CF3, CHF2, OMe or OEt. In one embodiment of formula Ι-A, two are single bonds and each Rw is hydrogen. In one embodiment of formula Ι-A, Ry is halo as appropriate a C1-C6 aliphatic group substituted with one or more of a group, hydrazine H, a C1-C4 alkoxy group, a C1-C4 alkoxycarbonyl group or a bis-(C1-C4 alkyl)amino group. In one embodiment, ry is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-mercapto-butyl, 2- Methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, i-(methoxycarbonyl)-3-methyl-butyl, hydroxymethyl)-3-methyl-butyl, Allyl, ethynyl, ethylamino)ethyl, i-methyl-2-methoxy-ethyl, 3-carbyl-2,2-dimethyl-propyl, 2,2,2 -Trifluoroethyl, 3,3,3-trifluoro-propyl or 2,2,3,3,3-pentafluoro-propyl. 121775.doc -26- 200813019 In one embodiment of Formula IA, RY is decyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl 3-methyl-butyl or 2-mercapto-propyl. In one embodiment of formula Ι-A, RY is a C3-C8 cycloaliphatic group or a C3-C8 substituted by a C3-C8 cycloaliphatic group. 6 aliphatic group - In one embodiment of formula Ι-A, RY is a C3-C6 cycloalkyl group or a C1-C6 alkyl- group substituted with a C3-C6 cycloalkyl group. In one embodiment of formula Ι-A, RY is cyclopropyl, cyclohexyl, cyclohexyldecyl-, cyclopropylmethyl- or cyclohexylethyl-. In one embodiment of the formula Ι-A, RY is pyridyl (C1_C6)alkyl-, tetrahydrofuranyl(C1-C6 alkyl)-, N-(C1-C4 alkyl)-pyrrolidinyl-(C1- C6 alkyl)-. In one embodiment of formula I_A, RY is tetrahydrofuran-2-yl-indenyl-, pyridin-3-yl-methyl-,. Ratio of 17 to 4-yl-ethyl-, ® ratio bit-2-yl-ethyl-, π-pyridin-4-yl-methyl-, 1-oxazol-5-yl or 2-(Ν- Methyl)-pyrrolidin-2-yl-ethyl-. In one embodiment of the formula Ι-A, RY is phenyl or phenyl substituted C1-C6 aliphatic-, which is optionally substituted with up to 5 R 2 substituents independently selected from halogen or A 5-6 membered heterocyclic ring having 1-3 hetero atoms selected from the group consisting of ruthenium, osmium or S. In one embodiment of the formula Ι-A, RY is phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl-, 4-morphinylphenyl-, 2-tour Phenyl- or stupidyl-ethyl. In one embodiment of the formula Ι-A, "is a single bond, one Rx is hydrogen and the other Rx 121775.doc -27- 200813019 is an aryl or heteroaryl ring optionally substituted with up to 5 R3 substituents. , the R3 substituent is independently selected from a C1-C6 aliphatic group, a phenyl group, a halogen group, a spear, a cycloaliphatic group or a 4-7 membered heterocyclic ring having up to 3 Ru substituents, wherein the heteroaryl or hetero The ring has up to three heteroatoms selected from N, oxime or S. In one embodiment of Formula Ι-A, one Rx is hydrogen and the other Rx is phenyl or acridinyl having up to two R5 substituents, the R5 substituents are independently selected from _ or have up to 2 Ru substitutions A 4-7 membered heterocyclic ring wherein the heterocyclic ring has up to two heteroatoms selected from N, oxime or S. In one embodiment of formula Ι-A, one Rx is hydrogen and the other Rx is phenyl substituted at the 2 position with a 4-7 membered heterocyclic ring and substituted at the 3 position with a halogen. In one embodiment of the formula Ι-A, a phenyl group wherein Rx is hydrogen and the other Rx is phenyl or substituted by the following group: piperazinyl, 4-indolyl-piperazine-indenyl, 4 _ethyl-pyridin-1-yl, 4-propyl-bistazine-1-yl, 4-butylheptazine-丨-yl, 4-isopropyl-pyridin-1-yl, 4- Tributyl 嗓-1 -yl, 4-cyclopropylpyrazine-1-yl, 4-tert-butoxycarbonyl-piperazine _; [-based, 4-hydroxy-piperidinyl, 4-ethoxy Carbonyl-piperidine-1-yl, morpholin-4-yl, 1-/7-pyrazole·indolyl, oxazole-; μ group, pyrrolidin-1-yl, 3-dimethylamino-pyrrole Acridine _ 丨 _ base, 4 _ (piperidinyl) base bite, ° ratio. Stationary (1-methyl brigade bite) ♦ ♦ _; [· base or ι_ (2, 2, 2-trifluoroethyl) σ-endazine-1-based. In one embodiment of the formula Ι-A, a pyridyl group wherein Rx is hydrogen and the other Rx is a pyridyl group or substituted with the following group: piperazinyl, methyl-piperidin-; 1-yl, 4- Ethyl-azinozinyl, 4-propyl-benzin-1-yl, 4-butyl, _ 嗓-1-yl, 4-isopropyl-piperazine-indolyl, tert-butyl Azinyl, cyclopropyl-Benqin-1-yl, 4-tert-butoxy-based _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _基-旅°定-1-yl, morphin-4-yl, specific ol-1-yl, sulphate-1-yl, σ ratio 17 each 11 -1-yl, 3-dimethylamino-吼11 each bite_1_base, 4-(Brigade σ定-1 -base) sigma, ° ratio ϋ定基(1 -Methyl Niang 定定_ 4 -基) 旅唤-1 -基或1 _ (2,2,2-Trifluoroethyl)piperazine-1 -yl. In one embodiment of Formula Ι-A, one Rx is hydrogen and the other Rx is phenyl or heteroaryl C1-C6 aliphatic optionally substituted with one or more substituents independently selected from the group consisting of , chaotic, halo, halo-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aryl-alkoxy, di(C1 -C6 aliphatic)amino-,-0-C1-C6 aliphatic, -S(0)-C1-C6 aliphatic or -S(0)2-C1-C6 aliphatic. In one embodiment of Formula Ι-A, at least one Rx is hydrogen and the other Rx is a C3-C7 cycloaliphatic substituted with up to five R3 substituents as appropriate and having up to three heteroatoms selected from hydrazines, s A cyclyl or heterocycloaliphatic ring wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. In one embodiment of formula Ι-A, the Rx is selected from the group consisting of cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2-indoleyl, tetrahydro-2H-thiopyranyl, 9H-苐-9-yl or piperidinyl. In one embodiment of the formula Ι-A, = is a single bond, and two RXs together with the carbon atom to which they are attached form a 3-9 membered monocyclic ring, a 9-14 membered bicyclic ring or a 12-14 membered tricyclic aryl group, a heteroaryl group. Or each heteroaryl or heterocycle in the heterocycle m has up to 3 heteroatoms selected from 0, SD; wherein the ring system formed by two rX is optionally substituted with up to 5 R4 substituents; In an embodiment, the ring system is selected from the group consisting of 9n_"-yl, tetra-n-decyl, tetrahydro, cyclobutyl, cyclopentane 121775.doc -29-200813019, cyclohexyl, cycloheptyl, cyclo Hexenyl, piperidinyl or fluorenyl-piperidinyl 4-yl. In one embodiment of formula I or IA, ring A is selected from the group consisting of: XX vv

>wA)rc\. s

CwB)〇

r-NT X 乂 A-i

A-iv or wherein: p is 0 - 2, q is 0-2; the constraint is p + q$2 ; 1 and WB are each independently selected from NR1, 〇, S, SO, S02, (^(R1) )] or ^CR1 (when P or q is 2); W is -〇(Ε^)2, =〇(Κ^)-, =N- or -Ν(Κ^)-; WF does not exist or is It is selected from _c(ri)2, =c(Ri)·, =N_4_N(Rl; its constraint condition is \\^ and WFf are both =N- or -NCR1)·; Ring B1 is up to 5 depending on the situation. a phenyl substituted with a R1 substituent or a 5-6 membered heteroaryl ring; and R1 is as defined herein. In another embodiment of formula I or Ι-A, ring a has the formula Ai. 121775.doc -30· 200813019 In Formula I or I-Α, in Formula I or Ι·Α· In Formula I or I-Α· In Formula I or I-Α· In Formula I or I-Α- In Formula I or I-Α的· In the formula I or I-Α - in the formula I or I-Α in the formula I or I-Α - in the formula I or Ι _ - - in the formula I or I-Α - in the formula I or I-Α - in the formula I or I-Α - in the formula I or I-Α - in the formula I or I-Α - in the formula I or Ι Α - in the formula I or I-Α Or -CRkCR1 - 〇 is in the formula I or I-Α or -CRkCR1-. In the case of the formula I or I-Α, the ring A has the formula A-ii. In the case of & only, the ring A has the formula A -iii. In the case of Ring A has the formula A-iv. In the example, both WE and WF are =c(Rl). In the example, WE is and WF is =N-. In the embodiment, p is. In the embodiment, Ρ In the embodiment, P is OJLq is 2. In the embodiment, WA is NNi. In the embodiment, WA is 〇. In the embodiment, WA is c(R1) 2. In the embodiment, wA is c (Ri) 2aRi is hydrogen. In the embodiment, WB is NR1. In the embodiment, \\^ is 〇. In the embodiment, Wb is c(ri) 2. In the embodiment, wb is c(Rl)2&Rl In the embodiment, ? is 2 and 1 8 is c(r1)2_c(r1) - in the embodiment, q is 2 and the ore is c(r1)2_c(r1). In the embodiment, ring A is selected From: 121775.doc • 31 - 200813019

Α·Η A-i-k or A-i-1 wherein the ring is optionally substituted with up to 4 Ri substituents. In one embodiment of Formula I or I-A, Ring a is selected from:

A-i-e A-i-f or A_i_g · wherein the ring is optionally substituted with up to 4 R1 substituents. In one embodiment of Formula I or I-A, Ring A is selected from the group consisting of:

Wherein the ring system is optionally substituted with up to 4 R1 substituents. In one embodiment of Formula I or I-A, Ring A is selected from the group consisting of: 121775.doc -32- 200813019

ζχΝχ

Η A-ii-g

〇 A-ii-h

It is replaced by up to four R1 substituents in the case of Ί j jsa, 、, μ 糸. In another embodiment of Formula 1 or 8, the compound has the formula Ι-Β 〇

Wherein the cyclic oxime is a 4-7 membered heterocyclic ring fused to a phenyl or heteroaryl ring substituted with up to five R1 substituents, as the case may be; wherein the ring oxime also contains up to two rings in addition to the nitrogen ring atom. From 〇, 1<[or an additional ring heteroatom of s; wherein ring A is optionally substituted with up to 5 R1 substituents in addition to the pendant oxy group; Ri, Rx, RY and X are as defined herein. In one embodiment of formula IB, ry is optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxycarbonyl or bis(ci-C4 alkyl)amine. A C1-C6 aliphatic group. In one embodiment of Formula IB, ry is methyl, ethyl, propyl, isopropyl 121775.doc-33-200813019, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(nonoxycarboyl)-3-methyl-butyl , 1-(methyl)-3-indenyl-butyl, allyl, ethynyl, 2-(diethylamino)ethyl, 1-methyl-2-indolyl-ethyl, 3 -transyl-2,2-dimethyl-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl or 2,2,3,3,3-pentafluoro -propyl. In one embodiment of Formula IB, RY is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimercapto-butyl, 3-methyl-butyl Or 2_ thiol-propyl. In one embodiment of Formula I-B, 1^ is a €3-€8 cycloaliphatic group or a C3-C8 cycloaliphatic group substituted CM-C6 aliphatic group-. In one embodiment of formula I-B, RY is C3-C6 cycloalkyl or C1-C6 alkyl- substituted by C3-C6 cycloalkyl. In one embodiment of Formula I-B, RY is cyclopropyl, cyclohexyl, cyclohexyldecyl-, cyclopropylmethyl- or cyclohexylethyl-. In one embodiment of Formula IB, RY is pyridyl (C1-C6)alkyl-, tetrahydrofuranyl (C1-C6 alkyl)., N-(C1-C4 alkyl)-pyrrolidinyl-(C1- C6 alkyl)-. In one embodiment of Formula IB, ry is tetrahydrofuran-2-yl-indenyl, pyridyl-3-yl-methyl-, aceto-4-yl-ethyl-, π-bit _2-based -ethyl-, orpyridin-4-yl-methyl-, 1H-indazol-5-yl or 2-(N-methyl)-pyrrolidin-2-yl-ethyl-. In one embodiment of Formula IB, ry is phenyl or phenyl substituted iC1_C6 aliphatic-, which is optionally substituted with up to 5 R2 substituents, R2 substituents 121775.doc-34-200813019 independently selected From a halogen or a 5-6 membered heterocyclic ring having 丨3 of a hetero atom selected from N, oxime or 8 In one embodiment of Formula 1-B, RY is phenyl, 2,6-difluorophenyl, gang Base, 4-fluorophenylmethyl-, 4-morphine phenyl... 2_Bentyl phenyl or phenylethyl-. In one embodiment of Formula IB, Rx is an aryl or heteroaryl ring optionally substituted with up to 5 & 3 substituents, the R3 substituents being independently selected from the group consisting of C1_C6 aliphatic base groups, halogens, cycloaliphatic groups a 4-7 membered heterocyclic ring having up to 3 Ru substituents, wherein the heteroaryl or heterocyclic ring has up to three heteroatoms selected from n, 0 or S. In one embodiment of Formula IB, Rx is phenyl or acridinyl having up to two 113 substituents, and the R3 substituents are independently selected from halo or 4-7 heterocyclic, wherein up to 2 Substituted with a Ru substituent wherein the heterocyclic ring has up to three heteroatoms selected from the group consisting of ruthenium, osmium or S. In one embodiment of Formula I-B, Rx is phenyl substituted with a 4-7 membered heterocyclic ring at the 2 position and substituted with a _ element at the 3 position. In one embodiment of Formula IB, Rx is acridinyl, phenyl or phenyl substituted with the following groups: a sulfhydryl group, a 4-methyl-Becken-1-yl group, a 4-ethyl hydrazine _ 1 Base, 4-propyl-Phenyl 0-methyl-yl, 4-butyl-bron-1-yl, 4-isopropylpyrazine-1-yl, 4-tert-butylpiperazine·ι_yl , 4-cyclopropylpiperazinyl, 'second butoxycarbonyl-bistazin-1-yl, 4-hydroxy-tripridinyl, 4-ethoxyl group_Brigade bite 1"" base, holly- 4-Base, 1 ΰ 嗤-1-yl, miso-1-yl, ton oxime 1-yl, 3-dimethylamino-pyrrolidine-fluorenyl, 4-(piperidine-hydrazine) Piperidine, this bite group (1-methylpyrazine-4-yl) bridging Qin-1-yl or 1-(2,2,2-trifluoroethyl) abbreviated _ 121775.doc - 35- 200813019 1 -Base 0 In one embodiment of Formula I-Β, Rx is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 aliphatic , cyano, dentate, halo-C1-C6 aliphatic _, aryl _(^1_匸6 aliphatic-, heteroaryl-C1-C6 aliphatic-, aralkyloxy, Bis(C1_C6 aliphatic) Amino, -0-C1-C6 aliphatic, -S(0)-C1-C6 aliphatic or -S(0)2-C1-C6 aliphatic In one embodiment of Formula IB, Rx is C3-C7 cycloaliphatic or heterocycloaliphatic substituted with up to five R3 substituents as appropriate and having up to three heteroatoms selected from the group consisting of hydrazine, N or S. a ring wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. In one embodiment of formula IB, the fused ring is selected from the group consisting of cyclopentyl, cyclohexyl, cyclohexenyl, and ring. Heptyl, tetrahydro-2/7-branyl, tetrahydropyranyl, 9H_-9-yl or tether base. In one embodiment of formula IB, ring A is selected from:

Where: is, C(O) or sCR1-; r is 〇_ 2 ; W^N or =C-; 1£ is, =(:(111). ' =N_ or ^(R1)·; 121775.doc -36- 200813019 WF does not exist or is selected from -c(ri)2, =c(Rl)_, =N or _N(Rl)_ ; the constraint is \\^ is not equal to WF=1^ _ or _N(Ri)_ ; Y is c(0), s(0) or s(0)2; Ring B1 is optionally up to 5 phenyl substituted with 1 substituent or 5-6 member Ring, and = is a single bond or a double bond, R1 is as defined herein. In one embodiment of Formula IB, wc^_c(Rl)2. In another embodiment of Formula IB, wC^=cr1_ In one embodiment of the formula 1-:8, Wc is c(〇). In one embodiment of the formula IB, ^ is 〇. In one embodiment of the formula IB, 1 < is 1. In the formula IB In one embodiment, in one embodiment of Equation IB, wD is n. In one embodiment of Equation 1-B, wd is = c_. In one embodiment of Formula IB, ¥ is (:( In one embodiment of Formula IB, ¥ is s(〇). In one embodiment of Formula IB, γ is s(〇) 2. In one embodiment of Formula IB, Ring a is selected from :

121775.doc •37· 200813019

A-v-e

>

A-y-h

Wherein the ring is optionally substituted with up to 4 r i substituents. In one embodiment of Formula I-B, Ring a is selected from:

A-vi-a

A-vi-b

A-vi-d A-vi-c

Assume. A-vi-h

H or A-vi-I \ wherein the ring is optionally substituted with up to 4 R1 substituents. In one embodiment of Formula IB, Ring A is optionally substituted with up to 5 substituents selected from the group consisting of C1-C6 aliphatic, C1-C6 aliphatic oxy, C1-C6 halogenated lipid a group, a CN, a halogen group, a pendant oxy group, an optionally substituted C3-C7 cycloaliphatic group, or an optionally substituted group of the following groups. 121775.doc -38- 200813019 Cyclol, π-l- yl, valenyl, indole, miso, mitolinyl, pyridinyl, pyrazolyl, pyrazolinyl, pyrazolyl, pyridyl, Bittersyl, benzylidene, piperazinyl or morpholinyl. In one embodiment of the formula ,-Β, q in Ri is a bond. In one embodiment of the formula, q_rm in Ri is q_r. In one embodiment of the formula, Q is present and R is hydrogen. In one embodiment of the formula ,-Β, q is present and r is a ci-C6 aliphatic group. In one embodiment of the formula ,-Β, r is fluorenyl, ethyl, propyl or butyl. In one embodiment of the formula ,-Β, r is hydrogen. In one embodiment of the formula ,-Β, R, is a C1-C8 aliphatic group substituted with up to three substituents selected from the group consisting of halo, CN, CF3, CHF2, OCF3 or OCHF2, Wherein at most two methylene units of the C1-C8 aliphatic group are optionally substituted with -CO·, -CONH(C1_C4 alkyl)_, -C〇2-, -OCO-, _N(C1-C4 alkyl C〇2-, -Ο-, -N(C1-C4 alkyl)CON(Cl_C4 alkyl)-, -0C0N(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S_, -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02- or -N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. In one embodiment of Formula IB, R is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally the case Substituting up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, 〇CHF2 or C1-C6 alkyl, wherein up to two methylene units in the C1-C6 alkyl group are optionally substituted with - CO-, -C0NH(C1-C4 alkyl)-, -C02-, -OCO-, -N(Cn-C4 alkyl)C02_, -〇-, -N(C1-C4 alkyl)C0N(C1_C4 alkane Base)-, 121775.doc -39- 200813019 -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)·,- S02N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02- or -N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. In one embodiment of Formula IB, R' is an 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having a heteroatom independently selected from nitrogen, oxygen, or sulfur, wherein R, optionally up to 3 Substituted with a substituent selected from a halogen group, CN, CF3, CHF2, OCF3, OCHF2 or C1-C6 alkyl group, wherein up to two indenylene units in the C1-C6 alkyl group are optionally substituted with -CO-, - C0NH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -0_, -N(C1-C4 alkyl)CON(Cl-C4 alkyl) -, -OCON(Cl-C4 alkyl)-, -N(Cn-C4 alkyl)CO-, -S., -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)- , N(C1-C4 alkyl)S02- or -N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. In one embodiment of Formula IB, the two appearing together with the atoms to which they are bound form a heteroatom having 0-4 independently selected from nitrogen, oxygen, or sulfur, optionally replaced by 3, 12 members, partially not a saturated or fully unsaturated monocyclic or bicyclic ring wherein R, as the case may be substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, 〇CF3, 〇CHF2 or C1-C6 alkyl groups, wherein the C1- Up to two methylene units in the C6 alkyl group are optionally substituted with -co-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C〇2 -, -Ο-, -N(C1-C4 alkyl)C0N(C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N((n-C4 alkyl)CO-,- S·, -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02- or -N(C1-C4 alkyl)S02N(C1-C4 Alkyl)-. 121775.doc -40- 200813019 In one embodiment, the compounds of the invention include the compounds of Table 1 and Table 1A. In another embodiment, the compounds of the invention include those in Table 1. These compounds. In another embodiment, the compounds of the invention include those compounds of Table 1 。. In the examples, the compounds of the present invention include those in Table i and Table 1, with the exception of compounds Nos. 85, 97 and 105. In another embodiment, the compounds of the present invention include those in Table 1. Compounds, with the exception of compounds Nos. 85, 97 and 105. In one embodiment, the invention provides formula j, a compound:

Wherein: X is S, so or so2; z is present or absent; wherein: when Z is present, ring A is linked to ring B via a single bond; ring A is a 4-7 membered heterocyclic or heteroaryl ring or ^ When Z is absent, ring A and ring B together form a 10-14 membered bicyclic heterocycle of the spiro ring system, wherein N or S heteroatoms; more than 5 R1 substituents are substituted; ring A has 丨-4 choices From 〇, N or S, which ring A depends on the situation, up to 5 1^1 121775.doc -41 - 200813019 m is 1-3; n is 1-3; the constraint is m+n$4 ·, RY Is aryl, heteroaryl, cycloaliphatic, C1-C6 aliphatic, aryl-aliphatic or cycloaliphatic-aliphatic; wherein ry is optionally substituted with up to 5 R2 substituents;

Rx is hydrogen, halo, aryl, heteroaryl, C1-C6 aliphatic, aryl-C1-C6 aliphatic, heteroaryl_C1_C6 aliphatic, wherein Rx is optionally substituted by up to 5 R3 Substituent; or two RX together with the carbon atom to which they are attached form a 3-9 membered cycloaliphatic or heterocyclic ring wherein the heterocyclic ring has up to 3 heteroatoms selected from the group consisting of ruthenium, 8 and > Cyclic conditions are substituted by up to 3 R3 substituents; wherein the ring formed by two Rx is optionally substituted with up to 5 4 substituents; Z _ R is absent, is hydrogen, CN, C1-C6 aliphatic, halogen -C1-C6 aliphatic group, 0-C1-C6 aliphatic group, 〇-(halo-C1-C6 aliphatic group), halogen group, aryl-C1-C6 aliphatic group or heteroaryl group_C1_C6 An aliphatic group; = is a single bond or a double bond; the restriction is that when it is a double bond, then "and a Rw does not exist;

Rw is independently hydrogen, halo, pendant oxy, C1_C6 aliphatic, halo-C1-C6 aliphatic, 0-C1-C6 aliphatic, _ci-C6 aliphatic, aryl, An aryl-C1-C6 aliphatic group, a C3_C7 cycloaliphatic group; or two RWs together form an optionally substituted C3-C7 cycloaliphatic or heterocyclic group, wherein the heterocyclic ring has up to 3 selected from the group consisting of hydrazine, a hetero atom of S&N; wherein the ring formed by the two 11~ is optionally substituted with up to 5 5 substituents; 121775.doc -42- 200813019 wherein each occurrence of R1, R2, R3, R4 and R5 independently Is Q-RM; wherein Q is a bond or a CrCs aliphatic chain, wherein at most two non-adjacent subunits in Q are replaced by CO, C02, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRC02 , NRCONR, SO, S02, NRS02, S02NR, NRS02NR, O, S or NR; wherein each occurrence of RM is independently selected from R', halogen, N02, CN, OR1, SRf, N(R,)2, NR , C(0)R', NR, C(0)N(R,)2, NR丨C02R, C(0)R, C02Rf, 0C(0)R, C(0)N(R, 2, 0C(0)N(R,)2, SORf > S02R? - S〇2N(Rf)2 ^ NR,S02R, ^ ΝΕ^02Ν(ΙΙ')2 C(0)C(0)R' or C(0)CH2C(0)R', wherein each occurrence of R is independently selected from hydrogen or an optionally substituted Cw aliphatic group; Optionally selected from hydrogen or an optionally substituted group selected from a Cw aliphatic group, a C6_1G aryl group, a heteroaryl ring having 5 to 10 ring atoms or having 3 to 10 ring atoms. a heterocyclic ring, or a ring in which R and R' together with or with the atom to which they are bonded or together with the atom to which they are bonded, form 5-8 having 〇_3 heteroatoms independently selected from nitrogen, oxygen or sulfur. A cycloalkyl, heterocyclyl, aryl or heteroaryl ring. In one embodiment, it is a double bond and Rz and a Rw are absent; in another embodiment, = is a single bond. In another embodiment, one Rw is hydrogen and the other Rw is not hydrogen. In another embodiment, both Rw are hydrogen. In an embodiment, m is 1 and η is 1. In another embodiment, m is 1 and η is 2. Or, m is 2 and η is 1. Or, m is 2 and η is 2. In another embodiment, 1 is (: 1-〇6 alkyl or halo-C1-C6 alkyl. 121775.doc -43- 200813019 or 'RZS-0-Cl-C6 alkyl. Illustrative Rz Including fluorine, methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc. In another embodiment, alkyl or halo-C1_C6 alkyl. Or, Rw is -〇_C1_C6 alkyl. Illustratively includes, for example, fluorine, methyl, ethyl, n-propyl, CF3, CHF2, OMe, OEt, etc. In another embodiment, two rWs together with the carbon atom to which they are attached form an optionally substituted C3 -C9 cycloalkyl or 3-9 membered heterocyclic ring. Exemplary such rings include cyclopropyl, cyclopentyl or cyclohexyl.

In one embodiment, RY is a c1-C6 aliphatic group optionally substituted with one or more halo, OH, ci-C4 alkoxy, C1_C4 alkoxycarbonyl or bis-(C1_C4 alkyl)amine groups. . Illustrative examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl- Propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxycarbonyl)-3-indenyl-butyl, 1-(hydroxyindenyl)-3-methyl·butyl Base, allyl, ethynyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl-propyl, 2 , 2,2-trifluoroethyl, 3,3,3-tris-propyl or 2,2,3,3,3-penta-propyl. In another embodiment, RY is a C3-C8 cycloaliphatic group or a Cn-C6 aliphatic group substituted with a C3-C8 cycloaliphatic group. In one embodiment, RY is a C3-C6 cycloalkyl group or a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. Illustrative examples include cyclopropyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl or cyclohexylethyl. In another embodiment, RY is acridinyl (C1-C6) alkyl, tetrahydrofuranyl (C1-C6 alkyl), N-(C1-C4 alkyl)-cyclinoside-(C1-C6 alkane base). 121775.doc -44- 200813019 Illustrative examples include tetrahydrofuran-2-ylmethyl, pyridin-3-yl-indenyl, acridin-4-yl-ethyl, pyridin-2-yl-ethyl, pyridine 4-yl-fluorenyl, 1H_indol-5-yl or 2-(N-fluorenylpyrazine-ethyl. In another embodiment, RY is optionally substituted phenyl or via ( A C1_C6 aliphatic group substituted with a substituted phenyl group. Exemplary embodiments include phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenylmethyl or phenylethyl. In one embodiment, both Rx are hydrogen. In one embodiment, Rx is phenyl or heteroaryl, such as 吼σ, wherein the phenyl or heteroaryl optionally has up to three selected from 〇, s Or a hetero atom of hydrazine is optionally substituted with a substituted 3-7 membered heterocyclic or heteroaryl ring. Exemplary Rx includes phenyl, acridine or phenyl substituted with the following groups: piperazinyl, 4 - mercapto-piperazin-1-yl, 4_t-butoxycarbonyl-piperazine-indenyl, 'hydroxy-piperidinyl, 4-ethoxycarbonyl-piperidinyl, morpholine_4_ Base, ugly, pyridinium-1-yl, miso _ 1 _ base or π ratio bite. In another embodiment, Rx a phenyl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of C1_C6 aliphatic, cyano, hydrazino, aryl-C1-C6 aliphatic, aryl- C1-C6 aliphatic, heteroaryl-C1-C6 aliphatic, aralkyloxy, bis(C1_C6 aliphatic) amine, 〇_C1-C6 aliphatic, S(0)_C1_C6 aliphatic 4S(〇)2_cl_C6 aliphatic group. In another embodiment, Rx is an optionally substituted C3_C7 cycloaliphatic or heterocycloaliphatic ring having up to three heteroatoms selected from the group consisting of fluorene and N4S, wherein The ring is optionally fused to one or more phenyl or heteroaryl rings. Exemplary rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2-phenanthranyl, tetrahydro- 2 thiopyranyl, 9H-indoleyl, piperidinyl, etc. 121775.doc -45- 200813019 In another embodiment, two RXs together with the carbon atom to which they are attached form 3-9, as appropriate A cycloaliphatic or heterocyclic monocyclic, bicyclic or tricyclic ring. Exemplary embodiments include 9Η·苐_9_yl, tetrahydro-2-indole-cardyl, tetrahydro-2-open-thiopyran- 4-yl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring The alkenyl group, piperidinyl or piperidinyl _4_ section yl group _ In another embodiment, the present invention provides a compound of formula A: square

Wherein: Ring A is a 4-7 membered heterocyclic ring which forms a spiro ring system with the piperidine ring via a carbon atom CA, wherein the heterocyclic ring is optionally fused to a optionally substituted phenyl or heteroaryl ring; wherein the ring A In addition to the nitrogen ring atom, it also contains up to two other ring heteroatoms selected from fluorene, lanthanum or $; wherein ring A is substituted with up to 5 R1 substituents, in addition to the pendant oxy group; R, Rx, RY, Rz , Rw and χ are as defined above. In one embodiment, = is a double bond and Rz and a Rw are absent; in another embodiment, = is a single bond. In another embodiment, 1 is C1-C6 alkyl or halo-C1-C6 alkyl. Or ' RZa_〇-Cl-C6 alkyl. Exemplary Rz includes methyl, ethyl, n-propyl, CF3, CHF2, OMe, oxime Et, and the like. In another embodiment, rw is C1-C6 alkyl or halo-C1_C6 alkyl. 121775.doc -46- 200813019 Ethyl, which forms the ring together or Rw is -0-C1-C6 alkyl. Illustrative! ^ includes methyl, propyl, CF3, CHF2, OMe, OEt, and the like. In another embodiment, the two Rw and the carbon atom to which they are attached are optionally substituted C3-C9 cycloalkyl or 3-9 membered heterocycle. Examples of spears include cyclopropyl, cyclopentyl or cyclohexyl. In one embodiment, Ring A is selected from the group consisting of: f

X %

I R1

A-i

P is 0-2; q is 0-2; the constraint is p + q$2; WA and WB are each independently selected from dish 1, 〇, S, SO, S02, C^R1) or ^CR1 (when When p or q is 2);

We^-C(R1)2 > =C(R1)- >=N-^-N(R1)-; WF does not exist or is selected from -C(ri)2, =c(Ri)_, =1^_ or _N(Ri)·; the restriction condition is simultaneous ==N- or -N^1)-; 121775.doc -47- 200813019 Β1 is a substituted phenyl or 5_6 member An aryl ring; R1 is as defined above. In another embodiment, Ring A or 'A' has the formula A-iv. In an embodiment, the ring has the formula A-i. Has the formula A-ii. Or, Ring A has the formula A-iii. In another embodiment, in an embodiment, \\^ and WF are both =c(Rl), W^=C(R!)-, and WF is =N-. In an embodiment, p is Oic^O. In another embodiment, ... and q is zero. In another embodiment, P is 0 and q is 1. In yet another embodiment, both P and q are one. Or, p is 〇 and 1 is 2. or,? It is 2 and. In the embodiment - WA is NR丨. In another embodiment, 〇. Or, wA is c(Rl)2. In an embodiment, R1 is hydrogen. In an embodiment, Wb is NR1. In another embodiment, _ is 〇. Or, wB is C(R1)2. In an embodiment, R1 is hydrogen. In another embodiment, P is 2 and WA is c(r1)2_c(r1)2 -crLcr1 ... In another embodiment -CRkCR1 ... 'q is 2 and wB is or in an embodiment, the ring Series A is selected from:

A-1-c

X 乂 X K gn A-i-d A-i-h 121775.doc 200813019 X 乂 X K Κ X Κ ΓΧ rT rT rt Οτ^Λο hvnh γΝΗ HNy° A-i-i A-i-j A-i-k A-i-1 wherein the ring is optionally substituted with up to four R1 substituents. In another embodiment, Ring A is selected from the group consisting of:

A-i_e A-i-f A-i-g

Wherein the ring is optionally substituted with up to 4 R1 substituents. In another embodiment, Ring A is selected from the group consisting of: X % X % X %

A-ii-a A-ii-b wherein the ring system is optionally substituted with up to 4 R1 substituents. In another embodiment, ring A is selected from:

A-ii-h 121775.doc -49- 200813019

Wherein the ring system is substituted with up to 4 R1 substituents as appropriate.

In the examples, the compound of the present invention has the formula Γ-Β f

Wherein ring A also contains up to two additional ring heteroatoms in addition to the nitrogen ring atom; 〇, N or s up to 5 R1 substituents are substituted, and ring A is removed from the side oxy group by R, R, RY and X are as defined above. In the tenth embodiment, the ring A is selected from the group consisting of

among them:

Wc is -(^(R1)], C(O) or ^CR1-; r is 0-2; wd4n or =c·; w^-C(r1)2, =c(r1)_, =N| N(r1)·,·121775.doc -50- 200813019 WFf exists or is selected from -(:(1^)2,, =N- or -N^1)-; the constraint is that WE is different from WF Is =N- or -Ν^1)-; Υ is C(O), S(O) or s(o)2; Ring B 1 is optionally substituted phenyl or heteroaryl ring; = is a single Key or double bond; R1 is as defined above. In an embodiment, Wc is -CnR1). Or, Wc is ^CR1-. Or, WC is C(O). In an embodiment, r is zero. Or, r is 1. Or, r is 2. In another embodiment, the drop is 1^. Or, WD is =C-. In an embodiment, Y is C(O). Or, Y is S(O). Or, Y is s(0)2. In one embodiment, Ring A is selected from the group consisting of:

A-v-a A-v-b A-y-c A-v-d

A-v-e A_v-f A-v-g A-v-h

121775.doc -51 - 200813019 wherein the ring condition is substituted with up to 4 R1 substituents. In an embodiment, the ring A is selected from the group consisting of

Wherein the ring is optionally substituted with up to 4 R1 substituents. In one embodiment, Ring A is optionally substituted with up to 5 substituents selected from the group consisting of C1-C6 aliphatic, C1-C6 aliphatic-oxy, C1_C6^ aliphatic, CN, a halo group, a pendant oxy group, an optionally substituted c3_C7 cycloaliphatic group, or an optionally substituted ring selected from the group consisting of phenyl, tert-butyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, Imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl or morpholinyl. In an embodiment, Q does not exist. In other embodiments, q_rm is R'. In an embodiment, R is hydrogen. Or, the ruler is ^- with an aliphatic group. Exemplary R includes a C1-C6 alkyl group such as methyl, ethyl, propyl or butyl. 121775.doc -52- 200813019 In one embodiment, R' is hydrogen. In one embodiment, R' is a C1-C8 aliphatic group substituted with up to three substituents selected from the group consisting of halo, CN, CF3, CHF2, OCF3 or OCHF2, wherein the C1-C8 Up to two methylene units in the aliphatic group are optionally substituted with -CO-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -〇-, -N (C1-C4) based CON(Cn-C4 alkyl)-, -0C0N(C1-C4 alkyl)_, -N(cn-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1_C4 alkyl)S02- or -N(C1-C4 alkyl)S02N (C1-C4 alkyl group ° in one In the examples, R is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R, optionally up to 3 selected from halo Substituent substitution of a group of CN, CF3, CHh, OCF3, OCHF2 or C1-C6 alkyl group wherein at most two methylene units of the C1-C6 alkyl group are optionally substituted with -co-, -CONH (C C4 alkyl)-, -CO2-, -N(C1-C4 alkyl) C〇2-, -〇-, -N(C1-C4 alkyl) CON(C-C4 alkyl), -OCON( Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2- or -N(C1-C4 alkyl)S02N(C1- C4 alkyl)-. In one embodiment, R is an 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic system having 5 hetero atoms independently selected from nitrogen, oxygen or sulfur, wherein R Substituting up to three substituents selected from halo, CN, CF3, CHF2, OCF3, 〇CHF2 or CH-C6 alkyl as appropriate, wherein up to two methylene units in the C1-C6 alkyl group are optionally The substitution is 121775.doc -53- 200813019 -C0NH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -O-, -N(C1- C4 alkyl)C0N(C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO_, _S-, -N(C1-C4 alkyl), - S02N(C1-C4 alkyl)_, N(C1-C4 alkyl)S02- or _N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. In one embodiment, two are present R', together with the atom to which it is bonded, forms an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein R Substituting up to three substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2 or C1-C6 alkyl, wherein up to two subunit units in the C1-C6 alkyl group are optionally substituted -CO-, -C0NH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -Ο-, -N(C1-C4 alkyl)C0N ( C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S02N(C1 -C4 alkyl)-, N(C1-C4 alkyl)S02- or _N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. Exemplary compounds of the invention are shown in Tables 1 and 1A below. Table 1: 121775.doc -54- 200813019

121775.doc -55- 200813019

121775.doc 56- 200813019

121775.doc -57- 200813019

121775.doc -58- 200813019

121775.doc -59- 200813019

121775.doc 60- 200813019

121775.doc -61 - 200813019

121775.doc 62- 200813019 17 _ Γ\ \ ο^η〇0 Γ%〇ύ^ ' W 0 fV ιΤ 雠101 ...................... .............................—涵——w— ΊΛί Η ι t .JI ▲ ·典〇λ·Α^Ι ^Ο ^Ys ......一” ' .13⁄43⁄4 HP; 1通< V^VS Factory 0❹▲利,! ▲(4) 〇〇C^° HQ 〇Νό 1D8 107 --,...—m.... ................................ _ Γ^Νν^ (Ογ^ Factory g 〇°<i 0 0Q= ° 121775.doc •63- 200813019

121775.doc 64- 200813019

121775.doc -65- 200813019

121775.doc 66- 200813019 145 146 147 η gas / . . Η %. ό r^O 〇 TO S=:o 0 rv 148 149 150 Η y/Ά / 0 o^n^s f?n-a U. 0 f N household G g° 0 f~nr° 151 152 153 〇ro tt3 0 f >° C^〇 154 155 156 Q:X° ΟΛη Ό K Vo 0 f%〇 〇人 67- 121775.doc 200813019

121775.doc 68- 200813019

121775.doc 69- 200813019

121775.doc 70- 200813019

121775.doc -71 - 200813019 205 208 207 03⁄4 f" H v〇0 r%〇Ho jesO ...... 〇rv 208 209 210 〇人校人^ yru}X factory..丄.'. H :' ft <5" 211 212 213 H>〇0人H人214 215 216 .^ο t 0 rV Ho >: 〇. : . 0 f%〇\ ～τΓ^ι Ο义H丄-72 - 121775.doc 200813019

121775.doc 73- 200813019

121775.doc -74- 200813019

121775.doc 75- 200813019

121775.doc -76- 200813019

121775.doc 77- 200813019

Performance: 121775.doc -78- 200813019

121775.doc 79- 200813019

121775.doc -80 - 200813019

121775.doc -81 - 200813019

121775.doc -82- 200813019

121775.doc -83 - 200813019

121775.doc 84- 200813019

121775.doc -85- 200813019

121775.doc -86 _ 200813019

121775.doc -87 - 200813019

121775.doc -88 - 200813019

121775.doc •89- 200813019

121775.doc 90- 200813019

121775.doc -91 - 200813019

121775.doc -92- 200813019

121775.doc -93 - 200813019

The compounds of the invention are readily prepared by methods well known in the art. For purposes of illustration, the synthetic schemes used to prepare the compounds of the invention are shown below. Scheme 1: Preparation of a compound of formula I: 121775.doc -94- 200813019

ΝΗ

Rw pw thiazolidinone core Θ amine core 甴 丨 丨 ' ^ a) HATU, D 〖PEA, DMF, RT, 16 hours of formula I compound as shown in the above Scheme 1 ^ Table, which will contain The core of the guanidine and the core of the thiazolidinone are combined in a suitable form. Compound. Scheme 1 : Preparation of a compound of formula I:

HCT (I)

Process 2: Preparation of thiazolidinone core acid (acid-I)··

a) DMF or toluene or benzene, 4 Α molecular sieve, 80 ° C, 1_2 hours b) Weiduccinic acid, 80 ° C, 16 hours of process 3 ° preparation of the oxazolidinone core acid (acid ΙΙ): 121775.doc -95- 200813019

^Rx :N, rY

rRX : N, rY (acid-II) a) Et0H/H2S04, 80 ° C, 24 hours b) LiHMDS, THF, 15 minutes, then RW-LG, 0 ° C to room temperature, 16 hours

NaOH (aqueous solution), Me 〇 H; wherein LG is a suitable leaving group. Scheme 4: Preparation of thiazolidinone core acid (acid-III)··

(acid-III) a) BOP, DZPEA, THF, 6 hours, followed by NaBH4, room temperature b) LiCb LiHMDS, RZ-LG, -78 ° C to -4 ° ° C; where LG is a suitable leaving group c) Jones oxidation, 〇°c Scheme 5: Preparation of 嗟嗤π-butanone core acid (acid-IV) · 121775.doc • 96- 200813019

a) THF/trimethoxy orthoformate, thioacetic acid, 80 ° C, 16 hours or DMF, 2 hours, 80 ° C; followed by thioacetic acid, 80 ° C, 16 hours.

b) LDA, -78 ° C to room temperature; then ethyl glyoxylate, room temperature, 16 hours c) NaOII (aqueous solution); MeOII. Scheme 6: Preparation of thiazolidinone core acid (acid V):

a) mCPBA, CHC13, 0 ° C to room temperature, 16 hours. Process 7 · Preparation of amine core (C_A_i-d):

i. (A-i-d) & (A-i-h)

a) 4-methoxybenzyl gas, TEA, 〇MF b) bis(2-chloroethyl) carbamic acid -

1 hexyl butyl ester, LDA, THF

c) TFA/DCM The amine core CAie in which ring A is Aie (see ordering & see above) can be prepared by the method of Process 121775.doc-97. 200813019 7. Scheme 8: Amine Core CA-ii- Preparation of c: 〇

ν' Bz

Ν, Ό Η (C-A-ii-c)

a) Polyphosphoric acid, 100 ° C; followed by phenylurea, 150 ° C b) MeOH, HC b Pd / C, H 2 Scheme 9: Preparation of the amine core C_A-ii-d:

b

a) LiHMDS

b) TFA/DCM

Scheme 10: Preparation of the amine core C_A-ii-e:

a) NaHMS

b) H2, Pd/C 121775.doc -98 - 200813019 c) HC1 Scheme 11: Preparation of the amine core C-A_v-e:

Boc I

a) NaBH4CN b) CDI or S0C12 or 1,1'-sulfonyldiimidazole

c) TFA/DCM The amine cores C-A-v-a, C-A-v_c and C-A-v-f containing Ring A Examples A-v-a, A_v_c and A-v-f, respectively, can be readily prepared using the procedure of Scheme 11. Scheme 12: Alternative Preparation of Amine Core C-A-v-e Boc Boc Rno

a) C0C12 b) Aminoacetaldehyde dimethyl acetal

c) TFA/DCM Scheme 13: Preparation of the amine core C-A-vi-a:

a) TEA, DCM, room temperature, 16 hours 121775.doc -99- 200813019 b) CDI, THF/DCM, 16 hours.

c) TFA/DCM Scheme 14: Preparation of the amine core C_A-vi-c:

Nh2 (C-A-vi-c) a) TEA, DCM, room temperature, 16 hours

b) 1, hydrazine-sulfonyl diimidazole, THF/DCM /

c) TFA/DCM Scheme 15: Preparation of the amine core C_A-vi-f:

Boc I M

(C-A-vi-f) N~\ N—Boc

a) PPh3, CBr4, DCM, 0 ° C to room temperature, overnight

b) NaN3, H20, CH3CN c) 1) PPh3, toluene, room temperature, 16 hours; 2) 48% HBr in acetic acid/acetic acid, 100 ° C, 1 hour

d) 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester, NaBH(OAc)3, AcOH, DMF 121775.doc -100- 200813019

e) CDI, THF

f) TFA/DCM Process 16: Preparation of Amine Core A-v_e··

a) DCM, D'PEA b) NaOCN, AcOH,

c) TFA/DCM Scheme 17: Preparation of the amine core A-v-f:

a) H2, Pd/C, MeOH Scheme 18: Preparation of the amine core A-v_g:

a) H2NNHBoc, EtOH b) Pt02, AcOH, H2

c) TFA 121775.doc 101 - 200813019

d) D, PEA, THF e) Et2NH, THF Scheme 19: Preparation of the amine core A-vi-h: ?oc

(A-vi-h)

a) NaBH(OAc)3, DCE

b) CDI, CH3CN c) HCM, Et20 Scheme 20: Preparation of the amine core A-vi-i:

(A-vi-i)

a) 2,4-dimethoxybenzamide, DMA, TEA

b) LiAlH3, THF

NaBH(OAc)3,

c) 4-terminated oxypiperidine-1-carboxylic acid tert-butyl ester AcOH, DCE

d) CDI, DMF 121775.doc -102- 200813019

e) TFA/DCM Process 21: Preparation of Amine Core A-ii_h:

a) NaH, SEM-C Bu DMF b) Pyridine hydrobromide high bromide, dioxane

c) Zn, AcOH

d) cis-1,4-dichlorobut-2-ene, Cs2C03, DMF

e) TFA/DCM

f) 0S04, Me3N-0, DCM g) NaI04, EtOH, H20

h) NH4OH, H2, Pd/C Scheme 22: Preparation of the amine core A-ii-i:

a) NaHMDS, B0C20, THF

b) nBuLi, TMEDA, 4-sided oxypiperidine-1-carboxylic acid benzyl ester, THF

c) H2, Pd/C 121775.doc -103 - 200813019

d) EtOH Process 23 · Preparation of Amine Core A-i-h:

Early 〇c

A-i-h

a) KHMDS, 3-bromopropene, THF

b) 03, MeOH, DCM, then Me2S

c) 'BuSONH2, CuS04, DCE d) PhLi, Et20

e) HC1, MeOH Scheme 24: Preparation of the amine core A-ii-j: % 〇 〇

A-ii-j 121775.doc -104- 200813019 a) (2-Methoxy-2-sided oxyethyl)(triphenyl) chlorinated scale, benzene

b) DBU, DMF

c) 3·bromo-2-aminopyridine, AlMe3, DCE

d) NaH, SEM-C Bu THF e) PdfBwh, dicyclohexylmethylamine, dioxane

f) TFA

g) H2, Pd/C Scheme 25: Preparation of the amine core A-i-i:

Boc, 'U-

Boc,

BoCv

N C〇〇H NHCbz NHCIdzH2 nh2 NH2 c

d

Nl c Bo

a) EDC, HOBt, NH3, TEA, DMF

b) H2, Pd/C, EtOH c) 1 ((trimethoxymethyl) benzene, toluene

d) TFA/DCM Scheme 26: Preparation of the amine core A-i-j: 121775.doc -105- 200813019

A-H

a) 2,4-dimethoxybenzylamine, TMSCN b) H2, Rh/alumina

c) CDI

d) TFA/DCM

e) H2, Pd/C Scheme 27: Preparation of the amine core A-i-k:

121775.doc -106 200813019

a) 2,4-dimethoxybenzamine, TMSCN b) H2S04

c) 1) KOH

2) H2S04, KOH d) LiAlH4

e) CDI

f) 1) TFA/DCM 2) H2, Pd/C Scheme 28: Preparation of the amine core A-i-1:

a) TMSCN b) LiAlH4 c) COCl2

d) 1) TFA/DCM 2) H2, Pd/C Amine core A-i-a can be prepared according to the method disclosed in WO2005097795. The amine core A_ii-a can be prepared according to the method disclosed in US2006293281 by the method disclosed in WO 775. doc 107-200813019 ... 6-membered ring-based amine core 200701-7. The amine core A v h is prepared according to the party (4) disclosed by 0. The amine core Α· _ is prepared according to the method disclosed by the doctor (4). Prepared by the method disclosed in hydrochloric acid: 1 -I „ ττ r ^ nucleus ~A - V i - 2GG5G5655G. (4) Heart A_ v can be based on CW PWW. domain, 34 (5), i9〇7 i9 / # ( The method disclosed in the method can be prepared. The amine core A_vi_e can be commercially available. The amine core Avh can be prepared according to the method disclosed in w〇2〇〇7〇16〇87. It is not described in the scheme, experiment or reference. Other amine cores; prepared by methods known to those skilled in the art. It will also be appreciated that certain compounds of the invention may exist as free forms for disposal or, if appropriate, as pharmaceutically acceptable derivatives thereof. Exist, according to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other administration of a patient in need thereof, either directly or An adduct or derivative that indirectly forms a compound, or a metabolite or residue thereof, as described herein. As used herein, the term "pharmaceutically acceptable salt" refers to a suitable medical judgment. Organizations with humans and lower animals A salt which is used without any abnormal toxicity, irritation, allergic reaction and the like and which corresponds to a reasonable benefit/risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt of the compound of the present invention or the present invention A salt of a compound which, upon administration to a recipient, is capable of forming, directly or indirectly, a compound of the invention or an active metabolite or residue thereof. As used herein, the term "active metabolite or residue" means a metabolite thereof. Or the residue is also an antagonist of CGRP. 121775.doc -108- 200813019 A pharmaceutically acceptable salt is well known in the art. For example, SM huge専k in J·Pharmace Sciences, 19ηη, 66, X The pharmaceutically acceptable salts are described in detail in the above, which are incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of the scientifically acceptable non-toxic acid addition salts are amine and inorganic acids (such as hydrochloric acid, hydrobromic acid, acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, cisplatin). a salt formed by diacid, tartaric acid, citric acid, succinic acid or malonic acid or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, Alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane Alkane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate 'fumarate, gluconate, glycerol phosphate, gluconate, hemisulfate , heptanoate, hexanoate, iodate, 2-hydroxy-ethanesulfonate 'lactate, lactate, laurate, lauryl sulfate, malate, maleate, Malonate, methanesulfonate, 2-naphthoate, nicotinic acid, nitrate, oleate, oxalate, palmitate, pamoate' pectinate, persulfate Salt, 3-phenylpropionate, citrate, picrate, pivalate, propionate, stearate, succinate, sulphate, sulphur Acid, thiocyanate, p-toluenesulfonate salts horizontal, undecanoic acid burn, valerate salts, and the like salts. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and NlQ-4 alkyl) salts. The invention also encompasses any quaternization of a basic nitrogen-containing group of the compounds disclosed herein. Water 121775.doc -109- 200813019 A soluble or oil soluble or dispersible product can be obtained by this quarterly reaction. Typical metal or soil metal salts include sodium, clock, salt, salt, magnesium and the like. If appropriate, other pharmaceutically acceptable salts include the use of counterions (such as ions, oxy-oxygen, formate, sulfate, acid sulphate, nitrate, low-carbon sulphonate and aryl acid) Non-toxic ammonium, quaternary ammonium and amine cations formed. As stated above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, as used herein, C which comprises a solvent suitable for the particular dosage form, dilution And any other or all of a liquid or other liquid vehicle, dispersion or suspension aid, surfactant, isotonic agent, thickener or emulsifier, humectant, solid binder, slip agent and the like. Remington, s Pharmaceutical, 16th edition, £ w

Martin (Mack Publishing c〇, East〇n, i98〇) discloses various carriers for the formulation of pharmaceutically acceptable compositions and their known preparation techniques. Unless any conventional carrier medium is incompatible with a compound of the invention, such as any other component of a pharmaceutically acceptable composition that produces any undesirable biological effect or interaction in a detrimental manner, its use encompasses the present invention. Within the scope. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers; alumina; aluminum stearate, Neem, and serum proteins such as human serum albumin; Buffering substance, such as phosphate, glycine, sorbic acid or potassium sorbate, a mixture of glycerol and vinegar of saturated plant fatty acids; water, salt or electrolyte, such as protamine sulfate, dihydrogen hydride, hydrogen phosphate Gasification, salt, colloidal cerium oxide, Sanshixi acid town, · Polyethylene sulphate remaining; polyglycolate; butterfly; Polyethylene 121775.doc > 110- 200813019 稀-聚氡化丙妇-嵌Segment polymer; lanolin; sugars, such as lactose, glucose and sucrose; powders such as corn starch and horsehair powder; cellulose.: such as sodium carboxymethyl cellulose, ethyl cellulose sodium and acetate Sodium, scutellaria powder; malt; sulphate; talcum powder; excipients, such as cocoa glutinous rice and suppository wax;; from, such as peanut oil, cottonseed oil, safflower oil, sesame oil, eucalyptus oil, x ^ _, rice oil and soybean oil; glycols such as propylene glycol or polyethylene : alcohol, ester, such as ethyl oleate and dodecanoic acid B; agar; buffer

Such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution (Ringer, ss〇luti〇n); ethanol and phosphate buffer solution, and other non-toxic compatible lubrication Agents, such as sodium and stearic acid, as well as coloring agents, mold release agents, centering flavors and fragrances, preservatives and antioxidants, may also be present in the compositions at the discretion of the formulator. The pharmaceutically acceptable composition of the present invention may be orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, or topically (e.g., by powder, ointment, depending on the severity of the infection to be treated). Or drops (d), buccal (eg, oral or nasal spray) or similar to humans and other animals. In certain embodiments, the compounds of the present invention can be administered orally or parentally, at a dose of from about 1 mg to about 50 rng per kilogram of body weight per day, preferably from about 1 mg to about 25 mg. One or more times to achieve the desired therapeutic effect. Liquid dosage forms suitable for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents (such as water or other solvents), solubilizers and emulsifiers commonly used in the art, such as ethanol, iso 121775.doc -111 - 200813019 propanol, ethyl carbonate , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oil (in detail, cottonseed oil, peanut oil, corn oil, seed oil, olive oil, Castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents. Injectable preparations, e.g., sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dissolving or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenteral diluent or solvent, for example, a solution of hydrazine, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any mild fixed oil may be used, including synthetic glycerol mono- or glycerol diacetate. Further, an injectable preparation can be prepared using a fatty acid such as oleic acid. The injectable formulations may be sterilized by, for example, filtration through a filter of retained bacteria, or by combining a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile 2 or its injectable medium prior to use. Extinction, main: to extend the effect of the compounds of the invention, it is usually necessary to slow the absorption of subcutaneous or intramuscular/shot compounds. This can be accomplished by using a liquid suspension of a crystalline material having poor water solubility. Subsequent to the rate of dissolution of the compound, depending on the crystal size and crystalline form, or by hunting or suspending the compound in an oil vehicle, the delay in the form of the compound administered by the enteral administration is achieved. absorb. A biodegradable polymer (such as a poly-acetic acid vinegar form straw which is opened from a microcapsule matrix to form a compound for a human parent day) to form a compound: a capsule matrix (4) a compound release rate depending on the ratio and used The specific polymer properties f μ can be added to two: the example of the degradable polymer of the article includes " eight other biological h examples include sour vinegar) and poly (acid Xuan). Storage rods :: Injections: The preparations are also prepared by trapping the compounds in a body that is compatible with body tissues: your liposome or microemulsion. Preferably, the composition suitable for administration via the rectal tract is (iv), and the suppository can be obtained by combining the compound of the present invention with a suitable non-irritating excipient or carrier (such as; Mixing _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The liquid and thus melts in the rectum or vaginal cavity releases the active compound. Solid dosage forms suitable for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or phosphoric acid and/or a) filler or extender, Such as temple powder, lactose, sucrose, glucose, mannitol and citric acid; b) binders, such as slow methyl cellulose, alginate, gelatin, polyethylene alpha ketone, vegetable sugar and gum arabic c) a humectant such as glycerol; d) a disintegrant such as agar-agar, strontium carbonate, potato starch or tapioca starch, alginic acid, certain oxalates and sodium carbonate; e) a dissolution retarder such as stone f; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc , calcium stearate, magnesium stearate, solid polyethylene glycol, dodecyl 121775.doc -113- 200813019 sodium sulfate and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like. The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. It may optionally contain opacifying agents and may also have a composition which will, if appropriate, release the active ingredient in a delayed manner only in certain portions of the intestinal tract. Examples of the encapsulating composition that can be used include polymers and butterflies. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like. The active compound can also be in the form of a microcapsule encapsulated using one or more excipients as described above. The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the art. In such solid dosage forms, the active compound can be combined with at least one inert diluent such as sucrose, lactose or powder. Conventionally, these dosage forms may also contain other materials than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, lozenges and pills, such dosage forms may also contain buffering agents. It may optionally contain opacifying agents and may also have a composition such that it will, if appropriate, preferentially release the active ingredient in a certain portion of the intestinal tract in a delayed manner. Examples of the encapsulating composition that can be used include polymers and waxes. 121775.doc -114- 200813019 Formulations suitable for topical or transdermal administration of a compound of the invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is sterile and pharmaceutically acceptable

The carrier and any desired preservatives or buffers are mixed as desired. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. Moreover, the present invention encompasses the use of transdermal patches' with the added advantage of allowing compound transfer to the body. These dosage forms are prepared by dissolving or dispersing the compound in a medium. Absorption enhancers can also be used to increase the passage of the compound across the skin. The rate of absorption can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. It will also be appreciated that the compounds of the present invention and pharmaceutically acceptable compositions can be used in combination therapy, i.e., such compounds and pharmaceutically acceptable compositions can be/or other one or more desired therapeutic agents or medical procedures simultaneously or Apply before or after it. The combination of therapeutic (therapeutic agents or procedures) in the poetic combination regimen should take into account the compatibility of the desired therapeutic agent and/or procedure and the desired therapeutic effect to be obtained. It will also be appreciated that the therapy may achieve the desired effect on the same condition: for example, the compound of the invention may be administered concurrently with another agent for treating the same condition, or it may achieve different effects (eg, control = side effects) h. As used herein, the other therapeutic agents that are used to treat or prevent a disease or condition are referred to, and are specific to the disease or condition being treated, and exemplary other therapeutic agents include ( But not limited to): non-opioid-like painkillers (吲哚, such as Etodolac, Ind〇methacin, sulindac, Tomi: Ding (10) Na () Such as 'nabumet_'; oxicam, 121775.doc -115 - 200813019 such as piroxicam; P-aminophenol derivatives, such as acetaminophen (Acetaminophen); Propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates, such as Aspen Asprin, choline magnesium salicylate, Diflunisal; fenamate, such as meclofenamic acid, mefenamic acid; and mouth ratio Sputum, such as Phenylbutazone; or sputum-like substances (narcotics) agonists (such as Codeine, Fentanyl, Hydromorphone), Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine (Buprenorphine), Butorphanol, Dezocine, Nalbuphine, and Pentazocine. In addition, non-drug analgesic methods can be combined with one or more of the present invention. Compounds can be used in combination with drugs. For example, anesthesiology (intraspinal infusion, nerve block), neurosurgery (neurolysis of CNS channels), nerve stimulation (transcutaneous electrical nerve stimulation, spinal stimulation) can also be used. Physical therapy (physical therapy) Orthotic devices, diathermy), or psychologic (cognitive methods - hypnosis, biofeedback, or behavioral methods) method. Other appropriate therapeutic agents or methods are generally described in The Merck Manual, 17th edition, edited by Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration (Food and Drug 121775.doc -116-200813019).

The Administration website www fda g〇v, the entire contents of which are hereby incorporated by reference. The additional therapeutic agent is present in the compositions of the present invention in an amount not exceeding the amount normally administered as a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of the other therapeutic agent in the compositions disclosed herein is in the range of from about 50% to about 1% of the amount of the agent normally present in the composition comprising the agent as the only therapeutically active agent. /0. The compounds of the invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions suitable for coating implantable medical devices, implantable medical devices such as prostheses, prosthetic valves, vascular grafts, endovascular stents And catheter. Thus, in another aspect, the invention includes a composition suitable for coating an implantable device, the composition comprising the compounds of the invention as generally described above and various classes and subclasses herein, and suitable for coating The carrier of the implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as generally described above and various classes and subclasses herein, and suitable for coating the same The carrier of the implanted device. Suitable methods of coating and coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026 and 5,304,121. The coatings are typically biocompatible polymeric materials such as hydrogel polymers, polymethyl acetonide, polyhexanoic acid vinegar, polyethylene glycol, polylactic acid, and B-wine vinegar And mixtures thereof. Such coatings may optionally be further covered by a suitable fluorinated polyoxo, polythoracic, polyethylene glycol, fat-filled or combinations thereof to provide controlled release characteristics of the compositions. The compounds of the invention are useful in methods of antagonizing CGRP receptors in those in need of such antagonism, such as 121775.doc • 117-200813019 mammals, which comprise administering an effective amount of a compound. The invention relates to the use of a compound disclosed herein as an antagonist of a CGRP receptor. In addition to primates (especially humans), a variety of other mammals can be treated in accordance with the methods of the present invention. Another embodiment of the present invention relates to a method of treating, controlling, ameliorating or reducing the risk of a CGRP streak-related disease or condition in a bipolar, the method comprising administering a therapeutically effective amount of a compound which is an antagonist of a CGRp receptor ) to the patient.

The invention further relates to a method of preparing a drug capable of elevating < CGRP receptor activity in humans and animals' which comprises combining a medium of the invention with a pharmaceutical carrier or diluent. Subjects treated by such methods are typically male or female mammals, such as humans, that are required to combat cGRp receptor activity. The term "therapeutically effective amount" means that the substance being sought by a researcher, veterinarian, physician or other clinician can induce a biological, or medical, amount of tissue, system, animal or human. "Therapeutic" as used herein refers to a prophylactic treatment of a treatment and prevention, and a condition or a condition as mentioned, especially for a patient susceptible to the disease or condition. The ability of the inventive compound to act as a CGRp antagonist makes it an agent for coffee-related disorders in humans and animals, but especially humans. The next I " can be used to treat, prevent, improve, control or reduce the risk of silk or disease: headache; migraine; tension headache; pain; chronic pain; neurogenic inflammation and pain; Pain; eye pain; toothache; diabetes" non-姨岛121775.doc -118- 200813019 Dependent Diabetes · ' #十_ ^ 丙' gold &illness;inflammation;arthritis; bronchial reaction over-extension, snoring ·Technology · 'External ·' sepsis; sputum tablet withdrawal syndrome; morphine resistance, hot flashes for men and women; atopic dermatitis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic skin Redness, skin rosy and rash, tinnitus; inflammatory bowel disease, colonic irritability, cystitis; and other conditions that can be treated or prevented by antagonizing CGRP receptors. It is especially important for the treatment of headaches (including migraine and cluster headaches). The compounds of Benqiming are additionally suitable for the prevention, treatment, control, improvement or reduction of the diseases, disorders and conditions described in this article. The method of risk is further suitable for use in combination with other agents for preventing, treating, controlling, or ameliorating the risk of the above-mentioned diseases, disorders, and conditions. The compounds of the present invention may be combined with one or more other drugs. A medicament for treating, preventing, managing, ameliorating or ameliorating the risk of a disease or condition wherein the compound or other drug has utility for the disease or condition, wherein the combination of drugs is generally safer or more effective than the drug alone. (Other) other drugs may be administered by means of a drug delivery route, in a usual amount, in combination with Formula I (IV) or sequentially. When a compound of Formula I is used together with - or a plurality of other drugs, the other drug and formula are included. A pharmaceutical composition in unit dosage form is preferred. However, combination therapy may also include administering a compound of formula J and one or more other drugs in accordance with a non-overlapping process. The invention also encompasses that when used in combination with - or a plurality of other active ingredients, the compounds of the invention and the other active ingredients may be used at a lower dosage than that used when each is used alone. Thus, 121775.doc 119-200813019 is used. The pharmaceutical compositions of the present invention comprise such compositions which, in addition to a compound of formula i, also contain one or more additional active ingredients. For example, the compounds of the invention may be formulated for use with an anti-inflammatory or analgesic or anti-migraine agent, Such as ergotamine or 5-HT.sub.l agonist, especially 5-HT.sub.lB/lD agonist, such as sumatriptan, naratriptan, Zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan and rizatriptan; Oxygenase inhibitors, such as selective cyclooxygenase-2 inhibitors, such as rofecoxib, etoricoxib, celecoxib, valdecoxib or parecoxib (paracoxib); non-steroidal anti-inflammatory agent Or a cytokine inhibitory anti-inflammatory agent, for example, in combination with the following compounds, such as aspirin, ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam ( Meloxicam), piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, aceamic acid, formazan, flufenamic acid (flufenamic acid), tolfenamic acid, diclofenac, sigma-gamma, apazone, nimesulide, nabumetone, Tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, Olsalazine or sulfasalazine 121775.doc -120-200813019 (sulfasalazine) and its analogs; or steroid analgesics. Similarly, the compounds of the invention may be administered in combination with analgesics such as acetaminophen, phenacetin, codeine, fentanyl, sufentanil, methadone , acetyl methadol, buprenorphine or π π. Furthermore, the compounds of the present invention can be used in combination with the following agents: interleukin inhibitors, such as interleukin-1 inhibitors; ΝΚ-1 receptor antagonists, such as aprepitant; NMDA antagonists; NR2B Antagonist; bradykinin-1 receptor antagonist; adenosine A1 receptor agonist; sodium channel blocker, such as lamotrigine; tablet agonist, such as levomethadyl (levomethadyl) Acetate) or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, such as indomin; Agent; vanilloid receptor antagonist; mGluR5 agonist, antagonist or potentiator; GABA A receptor modulator, such as acetamprosate calcium; smectin antagonist or agonist , including smoke tests; scorpion venoms or antagonists; selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, sertraline, duloxetine ( Duloxetine), escitalopram or citalopram Tricyclic antidepressants, such as amitriptyline, doxepin, protriptyline, desipramine, trimipramine or mipa Imipramine; a leukotriene antagonist, such as montelukast or zafirlukast; 121775.doc -121-200813019 An inhibitor of nitric oxide or an inhibitor of nitric oxide synthesis. The compounds of the present invention can also be used in combination with ergot alkaloids such as ergotamine, ergonovine, ergot new test, methylergonovine, and ergo horn (metergoline), ergoloid mesylate, dihydroergotamine, dihydroergocornine, dihydroergocristine, dihydroergo Dihydro ergo cry p tine, dihydro-I-ergocryptine, dihydro-.theta·-ergocryptine, ergot poison (ergotoxine), ergocornine, ergocristine, ergocryptine, I-ergocryptine, Θ-麦角隐亭 (• Theta.-ergocryptine), ergosine, ergostane, bromocriptine or methysergide 〇 In addition, the compounds of the present invention can be used in combination with the following agents : β-adrenergic antagonists, such as ° timolol, propranolol Propanolol, atenolol or nadolol and the like; MAO inhibitors, such as phenelzine; about ion channel blockers, such as flunarizine ), nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin; neuroleptics, such as Olanzapine and quetiapine; anticonvulsant 121775.doc -122- 200813019 drugs, such as topiramate, zonisamide, tonabersat, Carabersat or dival proex sodium; angiotensin II antagonists, such as losartan and candesartan cilexetil; angiotensin Invertase inhibitors, such as lisinopril; or botulinum toxin type A. The compounds of the invention may be used in combination with a potentiating agent such as caffeine, H2-antagonist, simethicone, hydrazine or barium hydroxide; decongestants such as phenyl adrenal gland Phenylphrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, adrenaline, naphazoline, xylometazoline, cycloheximide Propyl propylamine or levo-desoxy_ephedrine; antitussives such as codeine, hydrocodone, caramiphen, carbetapentane or dexame Dextromethorphan; diuretic; prokinetic agent, such as nietoclopramide or domperidone; and sedative or non-sedating antihistamine. In a particularly preferred embodiment, the compounds of the invention are used in combination with an anti-migraine agent such as ergotamine; a 5-HT.sub.l agonist, especially a 5-HT.sub.lB/lD agonist , in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, danitriptan and rizatriptan; and cyclooxygenase Inhibitors, such as selective cyclooxygenase-2 inhibitors, in particular, rofecoxib, etoricoxib, celecoxib, 121775.doc -123 - 200813019 meloxicam, valdecoxib or parec Xi. The human, and σ include not only the group of the compound of the present invention and another active compound but also a combination of two or more other active compounds. The 5 sample ix compound can be used in combination with other drugs for preventing, treating, controlling, ameliorating or reducing the risk of the disease or condition to which the compound of the present invention is applied. These other drugs can be administered simultaneously or sequentially by a usual route and in a usual amount, with the present hairy mouth. When the compound of the present invention is used together with one or more of the drugs, a pharmaceutical composition containing the other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention comprise compositions which, in addition to a compound of the invention, also contain one or more additional active ingredients. 1 The weight ratio of the compound of the 'X compound to the other active ingredient is variable and depends on the effective agent of the knife. Generally, an effective agent for each active ingredient should be used. Therefore, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to other agents is usually about from about 1 to about 2 or about 200:1 to about 20,000. Within the scope. Combinations of the compounds of the present invention with other active ingredients are also generally within the above ranges, but in each case an effective amount of each active ingredient should be employed. In the combination of materials, the compound of the invention may be separated from or otherwise in addition to other active agents. Furthermore, one component can be administered prior to, concurrently with, or after administration of the other agent and via the same or different routes of administration. The compound of the present invention can be administered orally, in the north, or in the intestine (for example, intramuscularly, intraperitoneally, intravenously, intracerebroventricularly or infused, subcutaneously or implanted). Nasal, vaginal, rectal, sublingual or topical routes of administration 121735.doc -124- 200813019 Le and can be formulated individually or together to form a non-toxic carrier, adjuvant, which is acceptable for the pharmaceuticals suitable for the (4) route of administration. And a suitable unit dose of the vehicle, δ weekly formulation. In addition to the treatment of warm-blooded animals, the compounds of the invention are also effective for human use. The following examples are set forth to provide a better understanding of the invention as described herein. It is to be understood that the examples are for illustrative purposes only and should not be construed as being in any way. / Example General LC/MS method LC/MS data was obtained using the following: pESciex αρι_15 (ΚΕΧ LC/MS, Shimadzn LC-8A pump, Gilson 215 autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 10 -99% CH3CN (0.035% TFA)/H20 (0.05% TFA) gradient, Phenomenex Luna 5u C18 column (5〇χ4·60 mm), Shimadzu SPD-10A UV/Vis debt detector, Cedex 75 ELSD predator. Mass spectrometry method for separation of diastereomeric mixtures: ' Purification of various diastereomeric mixtures of the invention using a Gilson 322 pump, Gilson 215 liquid handler, Gilson 819 injection module using semi-preparative Gilson HPLC. Gilson 156 UV/ Vis detector monitoring, using a gradient of 20-70% CH3CN (0.1% TFA)/H20 (0.1% TFA) on an Agilent Zorbax, SB-C18 column (21.2x100 mm, 5 #111) at a flow rate of 15·0 mL/min 第三4-(l,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester 121775.doc -125- 200813019

^Boc Synthesis of 4-(1,2-dihydro-2-oxo-5-phenylimidazolium-3-yl)piperidine as described in J. Med. Med. Chem., 2005, 48, 5 921 - 丨 - tert-butyl formate. A solution of 2-bromo-1-acetophenone (5 g, 25 mmol) in DCM (10 mL) was added dropwise to a solution of 4-aminopiperidine-1 -carboxylic acid tert-butyl ester (6 g). , 30 mmol) and a stirred solution of DZPEA (9.84 ml, 57.5 ml) in DCM (50 ml). Sodium cyanate (3.41 g, 52.5 mmol) was added, then the reaction mixture was cooled to EtOAc <RTI ID=0.0>> Stir at room temperature for 16 hours. The reaction mixture was poured into water and extracted with DCM (3×). The organics were combined, washed with water (3 times), brine, dried (MgSO4) and evaporated. The residue was triturated with EtOAc (EtOAc)EtOAc. LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 344; 5-phenyl-3-(piperidin-4-yl)-1Η-imidazole-2 (3H> ketone

Wide NH Adding TFA (4 ml) to 4-(1,2-dihydro-2-oxo-5-phenylimidazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (4 g) In a solution of DCM (20 ml), and the mixture was stirred at room temperature for 4 hr. Evaporation gave the TFA salt (quant.) of the desired product. LC/MS (10% to 99%): M/Z (M+H) + (observed) = 244; iR = 1.06 〇121775.doc -126- 200813019 4_(2_nitrobenzylamino)per Pyridin-1-carboxylic acid tert-butyl ester

A solution of 1-(bromomethyl)-2-nitrobenzene (13.2 g, 61 mmol) in DCM (60 mL) was added dropwise to 4-amine-bromo- s- 14·6 g, 73 mmol) and a solution of TEA (13.4 m, EtOAc, EtOAc) The reaction mixture was then poured into water and the layers were separated. The aqueous layer was then extracted with DCM (2 times). The organic layers were combined, washed with water (2 times), brine, dried (MgSO4) and evaporated. The residue was dissolved in EtOAc and filtered thru EtOAc. The cerium oxide was washed with EtOAc until TLC analysis showed no other material to dissolve. Evaporation gave the product as an orange oil (24 g, 74%). LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 336; T-butyl 4-(2-aminobenzylamino)piperidinecarboxylate

A solution of 4-(2-nitrobenzylamino)piperidine q-carboxylic acid tert-butyl ester (24 g, 71.6 mmol) in MeOH (150 mL) The reaction mixture was filtered and evaporated to give a crude amine which can be used without further purification. 4-(1,2-dihydro-2-oxoquinazolin-3(411)-yl)piperidine-1-decanoic acid tert-butyl ester 121775.doc •127- 200813019

A solution of CDI (7.7 g, 47.5 mmol) in 1:1 DCM: THF (100 ml) was added dropwise to the 4-(2- succinylamino) A solution of the ester (13.2 g, 43.2 mmol) in THF (400 ml). The reaction mixture was evaporated to give an oil which was crystallised from EtOAc. The precipitate was washed with cold EtOAc and dried to dry LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 332; iR = 3.01. 3,4-Dihydro-3-(piperidin-4-yl)quinazoline-2(1H)-one

Add TFA (15 ml) to 4-(1,2-dihydro-2-oxoquinoxaline 3(4Η)-yl)piperidine-1-carboxylic acid tert-butyl ester (3·5 g, 10.6 mmol) in DCM (20 mL) EtOAc. The reaction mixture was evaporated, followed by co-evaporation (2 times) with EtOH to give the desired product of &lt LC/MS (10% to 99%): M/Z (M+H) + (observed J value) = 232 ; tR = 0.38 〇 1-(2-bromoethyl)· 2-nitrobenzene

Add CBr4 (49.5 g, 150 mmol) to 1·(2·B 121775.doc -128-200813019 base)-2-nitrobenzene (21 ml, 150 mmol) and triphenylphosphine at 0C (39.2 g, 150 mmol) in DCM (400 mL). The reaction mixture was quenched with EtOAc (EtOAc m. The residue was taken up in EtOAc and the precipitated Ph30 was filtered and solvent was removed. Repeat this twice more. Column chromatography (〇% to 10% EtOAc in Hx) was purified to afford oil. 2-(2-nitrophenyl)ethylamine

A solution of NaN3 (6 g, 91.6 mmol) in water (20 ml) was added to a solution of 1-(2-bromoethyl)-2-nitrobenzene (6.96 g, 30.5 mmol) in CH3CN. The reaction mixture was refluxed for 20 hours. The solution was cooled and extracted with DCM (3 times). The organics were combined, washed with brine, dried (MgSO4) and evaporated. The residue was dissolved in toluene (160 ml), and EtOAc (EtOAc, EtOAc) The solvent was evaporated to dryness <RTI ID=0.0></RTI> and the residue was taken from &lt;RTI ID=0.0&gt;&gt; The reaction mixture was cooled, concentrated and extracted with DCM. The aqueous solution was brought to pH about 10 with NaOH (aq) and extracted with EtOAc (3 times). The organics were combined, washed with brine, dried (MgSO4) and evaporated. T-butyl 4-(2-nitrophenylethylamino)piperidine-1-carboxylate 121775.doc -129- 200813019 ?oc

2-(2-Nitrophenyl)ethylamine (4 g, 24 mmol) and 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester (4.8 g, 24 mmol) in MeOH. The pH of the stirred solution in (48 ml) was 5. NaBH3CN (2.3 g, 36 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated and the residue was crystallisjjjjjjjjj The fractions /W 'knife-away' of the organic layer of salt water washed with 5 dry (Na2S〇4) and evaporated to dryness. Purification by column chromatography (0% to 7 ° / MeOH in DCM) afforded desired. LC/MS (10% to 99%)·· M/Z (M+H)+ (observed value) = 350, &quot;λ = 2·22. 4-(2-aminophenylethylamino)piperidine-1-carboxylic acid tert-butyl ester

zBoc Add 10% Pd/C (1.05 g) to a solution of 4-(2-nitrophenylethylamino)piperidine-1-carboxylic acid tert-butyl ester (10.5 g) in EtOH (180 ml). The reaction mixture was stirred overnight at room temperature under H2. The reaction mixture was filtered and evaporated to dryness crystals LC/MS (10% to 99%): M/Z (M+H) + (observed) = 320; 4-(1,2,4,5-tetrahydro-2-oxooxybenzoquinone [d][l,3]diazepin-3-yl)piperidine·1-carboxylic acid tert-butyl ester 121775.doc -130- 200813019

CDI (4.86 g, 30 mmol) was added portionwise to 4-(2-aminophenylethylamino)piperidine-1-carboxylic acid tert-butyl ester (6.9 g, 30 mm 〇l) in DMF (110 ml) The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organics were combined, washed with water, brine and evaporated to give the desired product. LC/MS (10% to 99%): M/Z (M+H) + (observed) = 346 &quot; and = 3.24. 4,5-Dihydro-3-(piperidin-4yl)-1Η-benzoquinone [d][l,3]diazepine-2(3H)-one

Add TFA (5 ml) to 4-(1,2,4,5-tetrahydro-2-p-oxybenzoquinone [d][l,3]diazol-3-yl)piperidin-1- A solution of the butyl citrate (10 g, 2.89 mmol) in DCM (5 mL). The reaction mixture was evaporated, followed by co-evaporation (2 times) with EtOH to give the desired product as a TFA salt. LC/MS (10% to ί 99%): M/Z (M+H) + ( observed) = 246; tR = 1.75. 4-(2-Aminopyridin-3-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Add 4-tert-oxyl brittle 1-carboxylic acid tert-butyl ester (5.75 g, 28.8 mmol) to 2,3-diamine oxime (3.0 g, 27.5 mmol) in DCE (45 ml) 121775.doc -131· 200813019 In solution, and the reaction mixture was stirred at room temperature for 5 minutes, then NaBH(OAc)3 (8.7 g, 41.7 mmol) was added portionwise, and stirring was continued at room temperature until LCMS It is judged that the reaction is completed. The reaction was carried out at 5 Torr. Na〇H is stopped. The layers are separated and the organic layer is dried via Na2S〇4. Evaporation gave the desired product (4.96 g). LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 293; 4-(2,3-dihydro-2-indolyl imidazolium [4,5-b]pyridine-1_yl)piperidine-1-carboxylic acid tert-butyl ester

Add CDI (4.2 g, 25.7 mmol) to 4-(2-amino) in portions at room temperature

Pyridin-3-ylamino)piperidine-i-carboxylic acid tert-butyl ester (3〇g, mm〇1) in K CKbCN (206 ml), and the reaction mixture was stirred at room temperature for 16 hours. . The reaction mixture was evaporated to dryness and the residue was dissolved in dcm and water. The layers were separated and the organic layer was washed with brine, dried (Na.sub.2) and evaporated. Purification by column chromatography ( EtOAc / EtOAc (EtOAc) LC/MS (10% to 99%): M/Z (M+H) + (observed) = 319; q = 31. 1-(Brigade-4-yl)-1Η_imidazole幷[4,5-b]. Bipyridine-2(3H)-one 121775.doc -132- 200813019

P price. 4-(2,3-Dihydro-2-oxo-imidazolium [4,5-b]pyridin-1-yl)piperidine _;[_ decyl citrate (3.39 g, 1 〇· A solution of 7 mmol) in 2 N HCl in Et.sub.2 (20 mL) was stirred for 2 hr. The solvent was evaporated and the residue was triturated with EtOAc (EtOAc)EtOAc. LC/MS (10% to 99%): M/Z (M+H)+ (observed) = 219; ίπ = 0·36 〇 2_(2,4-dioxybenzylaminol nitrile

I 2,4-Dimethoxybenzaldehyde (52 ml, 34.6 mmol) and TEA (4.8 ml, 34.6 mmol) were added to 2_chloro-3-cyanobite (4.0 g, 28.9 mmol) in DMA (58 ml) The solution in the solution was at 8 Torr. Stir under the arm for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organics were combined, dried (Na2SO4) and evaporated. Column chromatography (〇·5 〇 /. to 5% EtOAc (with 0.1% TEA) in DCM) LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 270; g = 3.05. N-(2,4-dimethoxybenzyl)·3_(aminomethyl)pyridine-2-amine

121775.doc -133- 200813019 2-(2,4-Dimethoxybenzylamino)pyridine-3-carbonitrile (〇·55 g, 2·04 mmol) with LiAlH4 (2.2 ml, 1 Ν, The solution of 4·4 mmol) was stirred at room temperature until the completion of the reaction was judged by LCMS. The reaction was quenched with saturated aqueous Na2CO3 and the layers were separated. The organic layer was dried (Na2SO4) LC/MS (10% to 99%): M/Z (M+H) + (observed) = 274; tR = 0 · 2 8 〇4-((2-(2,4-dimethoxybenzyl) Aminobutyl)pyridin-3-yl)methylamino)piperidine-1_carboxylic acid tert-butyl ester

Add NaBH(OAc)3 (0.43 g, 2.04 mmol) to N-(2,4-dimethoxybenzyl)-3-(aminomethyl)acridin-2-amine (2.04 mmol) and 4- The side of the oxy-hydroxyl-bate-1_carboxylic acid tert-butylate (0.41 g, 2·04 mmol) in a mixed solution of DCE (8 ml) and AcOH (115 pL, 2·04 mmol), and The reaction was stirred at room temperature until the reaction was judged to be completed by LCMS. The reaction mixture was diluted with aq. EtOAc (EtOAc m. Purification by column chromatography (MeOH/EtOAc) LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 457; G = 2.19. 4-(1-(2,4-dimethoxybenzyl)_1,2-dihydro-2-oxoacridinium[2,3-d]pyrimidin-3-(4H)-yl)piperidine 1-butylic acid tert-butyl ester 121775.doc -134- 200813019

CDI (1.23 g, 7.6 mmol) was added portionwise to 4_((2-(2,4-dimethoxy)-amino)-pyridin-3-yl)methylamino)piperidine-decanoic acid Butyl ester (2_89 g ' 6.33 mmol) in DMF (42 ml) and the reaction mixture was stirred at 120 C for 2 hours. Add another portion (〇 82 g) and the reaction mixture at 13 ° ° The mixture was stirred for 6 hours, then stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with DCM. The organics were combined, dried (Na2S04) and evaporated to dryness by column chromatography (1 () to 8 〇0 Purification of / EtOAc in EtOAc (EtOAc) (EtOAc:EtOAc:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj _Dihydro·3·(piperidinyl-4-yl)pyridinium[2,3-d]pyrimidine-2(1H)-one

Ο 2_(4_Phenoxy-2-phenyl-3-((pyridyl-4-yl)methyl)thiazolidin-5-yl)acetic acid

A solution of benzofural (0.75 mmol, 79.6 mg) with 2-molecular sieves and 2-(pyridin-4-yl)ethylamine (97.3 mg, 0.9 mmol) in DMF (0.5 ml). 200813019 at 80. Heat underarm for 2 hours. A solution of decyl succinic acid (1.13 mmol, 168 mg) in DMF (0.2 ml) was added and the mixture was then warmed at &lt The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N EtOAc, EtOAc (EtOAc)EtOAc. LC/MS (10% to 99%): M/Z (M+H) + ( sbs) = 329; 1-(2-(2·(4-Phenyloxy-2-phenyl-3-((inthrol-4-yl)methyl)thiazolidin-5-yl)ethinyl)piperidin-4) )-1Η-benzoquinone [d]imidazole-2(3Η)-one (compound #45)

3-((吼口定-4-yl)methyl) 嗤 嗤-5-yl)acetic acid (0.15 mmol, 49 mg), 1-(piperidin-4-yl)-1Η-benzoquinone [d] Imidazole-2(3H)-one (0.15 mmol, 3 3 mg) and DJPEA (0.375 mmol, 65·3 μΐ) in 4:1 CH3CN:DMF (0.5 ml) and the reaction mixture at room temperature Stir for 16 hours. The title compound was obtained by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA) /H20 (0 〇 5% TFA). </ RTI> <RTIgt; , J=6.3 Ηζ, 2Η), 7.40-7.38 (m, 2Η), 7.33-7.29 (m, 5Η), 121775.doc -136- 200813019 7.06-6.92 (m, 4H), 5.55-5.53 (m, 1Η) ), 4·55 (d, J=4.4 Hz, 2H), 4.45 -4.42 (m, 3H), 4.07 (d, m, 2H), 3·42·3·41 (m, 1H), 3.20-3.15 (m,1H),3·(Η-2.90 (m,1H), 2.66 (m,2H), 1.88 (m,2H) ppm 〇2-(3-methyl-4-oxophenylthiazole Acetate

A solution of 4 A molecularist's clumsy (〇·75, 79.6 mg) and T amine hydrochloride (60·8 mg, 0.9 mmol) in DMF (0.5 ml) was heated at 80 ° C for 2 hours. . A solution of decyl succinic acid (113 mm 〇 1,168 mg) in DMF (0.2 ml) was added and the reaction was heated under ribs for an additional 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N EtOAc, water and evaporated to dryness to give the desired product which can be used without further purification. 3,4-Dihydro-3-(1-(2-(3•methyl-4-oxo-2-phenylthiazolidin-5-yl)ethionyl)piperidin-4-yl)quina Oxazoline_2 (ih)-ketone (compound #273)

Add HATU (〇·1 8 mmol, 68 mg) to 2-(3-indolyl-4-oxo-2-phenylindole-5-yl)acetic acid (〇_2 mmol, 50 mg , 3,4-dihydro-3-(mouth 唆-4-yl) 喧 琳 -2-2(1H)-one TFA salt (0.15 mmol, 49 mg) and D&gt;EA (0·375 mmol, 65.3) The solution was stirred at room temperature for 16 hours at 4:1 CH3CN:DMF (0.5 ml). The title compound was obtained by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA) /H20 (0.05% TFA). LC/MS (10% to 99%): M/Z (M+H) + (observed) = 465.5; ίR = 2·18. 1HNMR (400 MHz, CDC13) δ 7.34-7.22 (m, 5H), 7.12 (t, J=7_5 Hz, 1H), 7.00 (d, J=7.5 Hz, 2H), 6.95-6.89 (m, 2H), 6.61 (d, J=7.8 Hz, 2H), 5.46-5.41 (m ,1H), 4.70 (m,1H)5 4.56 (m,1H), 4.26 (m, 3H), 3.86 (m,1H), 3.50 (m,1H), 3.32 (m,1H),3.12-3.08 ( m, 1H), 2.89 - 2.73 (m, 1H), 1.69 (m, 3H) ppm. 2-(3-isopropyl-4-oxo-2,phenylthiazolidin-5-yl)acetic acid

A solution of benzaldehyde (〇 75 mmol, 79.6 mg) with 4A molecular sieves and isopropylamine (53.1 mg, 0.9 mmol) in DMF (0.5 ml) was heated at 80 ° C for 2 hours. Add a solution of succinic acid (1.13 mmol, 168 mg) in DMF (0.2 mL). The layers were washed with 1 N EtOAc, EtOAc (EtOAc EtOAc). Benzyl-2 phenylthiazolidine·5-yl)ethenyl)bistidine-4_yl)quinazoline-2(1Η)-one (compound #255) 121775.doc -138- 200813019

&amp; Add HATU (0.18 mmol, 68 mg) to 2-(3-isopropyl-4-oxo-2-phenylindole _5_yl)acetic acid (〇·2 mmol' 56 mg) , 1-(旅.定-4 -基)_ 1H-benzoquinone [d] miso-2(3H)-ketone (0·1 5 mmol, 33 mg) and DJPEA (0.375 mmo, 65·3 μΐ) The solution in 4:1 CH3CN:DMF (0.5 ml) was stirred at room temperature for 16 h. The title compound was obtained by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA) /H20 ( 〇·〇 5% TFA). LC/MS (10% to 99%): Μ/Ζ (Μ+Η)+(observed)=493.5; h = 3.1. 4 NMR (400 MHz, CDC13) δ 7.31-7.25 (m,5H), 7.14 -7.10 (m, 1H), 7.05 (s, 1H), 7.00 (m, 1H), 6.93-6.89 (m, 1H), 6.62 (d, J = 7.8 Hz, lH), 5.56 (m, lH), 4.72 (m, lH), 4.47-4.41 (m, 2H), 4.27-4.19 (m, 2H), 4.02-3.96 (m, 1H), 3.87 (m, 1H), 3, 36-3.29 (m, 1H) ), 3.13-3.10 (m, 1H), 2.70 (m, 2H), 1.70-1.60 (m, 3H), 1.20 (dd, J = 2.0, 6·9 Hz, 3H), 0.94 (m, 3H). Isoamyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid

Phenylfurfural (5.06 ml, 50 mmol) with isoamylamine (5.82 ml, 50 121775.doc -139- 200813019

(7.51 g' 50 mmol) and stirred for a further 16 h at EtOAc. The mixture was taken from EtOAc (EtOAc). The desired product was obtained as a yellow oil (11.3 g). ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazole-5-yl)acetate

2-(3-Isopentyl-4-o-oxo-2-phenylindole-5-yl)acetic acid (2 2 g, 7.2 mmol) in EtOH (20 ml) &amp; H2S04 (1 ml) The solution was refluxed for 16 hours. The solution was evaporated to dryness and the residue was dissolved in Et EtOAc and sat.

Aqueous Na2C 3 (3 times), brine was washed and evaporated to give the desired product. 2-(3-isopentyl-4-oxo-2-phenylindole) propionic acid

Add LiHMDS (0.28 ml, 1 N, 0.28 mmol) dropwise to ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetate at 〇 °C (84 mg, 0.25 mmol) in a stirred solution in THF and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 1 N EtOAc (EtOAc) The organics were combined, dried (MgS04) and steamed 121775.doc-140-200813019 dry. Purification by preparative TLC (7:1; Hx:EtOAc) 2-(3-Isoamyl-4-oxo-2-phenylindole-9-yl)propionic acid

2-(3-Isoamyl-4-o-oxo-2-phenyl-β-purine-5-yl)propionic acid (12 mg, 〇·〇 34 mmol) with aqueous NaOH (0.068 ml, 1 N) , a solution of 0.068 mmol in MeOH (0.2 mL), EtOAc (EtOAc) 3-(1-(2-(3-isopentyl-4-yloxy-2-phenylindole _5-yl)propyl idyl)piperidin-4-yl)-3,4_ Dihydroquinazoline-2(1H)-one (compound #156)

HATU (17 mg, 0.044 mmol) was added to 2-(3-isopentyl·4_s-lactyl-2-n-yl sigma-5-yl)propionic acid (11 mg, 0.034 mmol), 3, 4_Dihydro-3-(piperidin-4-yl)quinazoline·2( 1H)-one TFA (17 mg, 0.051 mmol) and Ε^ΡΕΑ (24 μΐ, 0.14 mmol) in DMF (0·2 ml) In the solution, the reaction mixture was stirred at room temperature for 16 hours. By using 10%-99. Preparation of CH3CN (0.035% TFA) / H20 (0.05% TFA). 121775.doc -141- 200813019 3-Isoamyl-2-phenylthiazolidin-4-one

A solution of isoamylamine (0.58 ml, 5 mmol), benzaldehyde (1 ml, 1 〇mm〇i) and thioglycolic acid (1·〇5 ml, 15 mmol) in THF (7 ml) at 75° Stir for 16 hours at C. The rm was poured into water and extracted with EtOAc (3 times). The organics were combined, washed with 1 N EtOAc (2×), brine, dried (M.sub.ss.sssssssssssssssssssssss . 2-(3-I-amyl-4-oxo-2-phenylindolide-5-yl)ethyl acetate

Add LDA (1.1 m to about 1 μ in THF; freshly prepared from nBuLi and diisopropylamine) to 3-isoamyl-2-phenylindole-4-one (0.25) at -78 °C g, 1 mmol) in a stirred solution in THF and the reaction mixture was warmed to warm. Ethyl acetate (24 ml, about 50% w/v in toluene, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1N EtOAc (EtOAc) The organics were combined, washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography (5 to 15% EtOAc in EtOAc) 2-(3-Isoamyl_4_ oxo-2-phenyl-arreazolbita-5-yl)acetic acid 121775.doc -142- 200813019

Ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidine-5-yl)acetate

(0.031 g, 〇.1 mm 〇l) and a solution of NaOH aqueous solution (3 ml, 1 N) in MeOH were stirred at 40 ° C for 2 hr. Add HCl (0.5 ml, 1 N) and evaporate MeOH. Water and Et0Ac were added and the layers were separated. Using 玢〇8 (: extracting the aqueous layer (2 times), all the organic layers were combined, dried (MgS 〇 4) and evaporated to give the desired product (11 mg, 36%). -3_(1-(2-(3-isopentyl-oxo-phenylphenylthiazolidin-5-yl)ethenyl)n-indol-4-yl)indolyl 2(1 H)-one

Oxy-2, Benthoquinone, acetic acid (π mg, 0.03 6 mmol), 3,4-dioxin-3-(piperidin-4yl)quinazoline-2 (1 Η)- A solution of the ketone TFA (18 mg, 0.054 mmol) and DZPEA (22 <RTI ID=0.0></RTI> </RTI> <RTIgt; The title compound was obtained by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA) /H2O (0.05% TFA). Preparation A: Synthesis of 1 Ή-spiro [Biridine-4,4,·quinoline]_2, (3Ή)-ketone 121775.doc -143 - 200813019

3-Sideoxy-2,3-dihydrospiro[茚-1,4,-piperidine]-1,-carboxylic acid terpene vinegar f (20 g, 06.4 mm oi) with MeOH/HCi (2.5 moi/ The mixture of L, i00 mL) was stirred overnight. After evaporation, the residue was washed with EtOAc (EtOAc)EtOAc. Cbz-Cl (4.66 g, 27.33 mmol) was added dropwise to snail [茚-1,4,piperidin]-3(2H)-one hydrochloride (5.0 g, 24.84 mmol) and Et3N at 〇 °C. (7.54 g, 74.53 mol) in CH2C12 (50 mL). The reaction was allowed to warm to room temperature and stirred overnight. The precipitate was filtered, washed with 玢2 且 and dried to give 3-t-oxy-2-,2-dihydrospiro[p-l,4,-piperidine]-1,- carboxylic acid benzyl ester (6.1 g. Rate 99%). 3-Phenoxy-2,3-dihydrospiro[茚-1,4,-piperidine]_1, benzyl formate (3 g, 10.3 mmol) in NH2OH.HCl (1·43 g, A solution of 20·6 mmol) and NaOAc (1·52 g, 18.53 mmol) in EtOH (30 mL) The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried over Na 2 SO 4 and then taken to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&& Benzyl ester (3.14 g, yield 99%) which was used directly in the next step. 2,4,6-Trichloro-[1,3,5]-triterpene (1.32 g, 7.16 mmol) was added to DMF (9·6 mL) while maintaining at 25 °C. The reaction was monitored by TLC until the TCT was exhausted. Then add 3-(hydroxyimino)-2,3-dihydrospiro[茚_1,4'-piperidine]-1,-formic acid benzyl ester (1.6 g, 4.77 mmol) in DMF (17 mL) . After the addition, the mixture was stirred overnight at room temperature. Add water. The mixture was extracted with EtOAc. The combined organic layers were washed with aq. EtOAc (EtOAc m. The residue was purified by preparative HPLC to give 2'-s-oxy-2,3,-dihydro-1,H-spiro[唆-4,4'·喧琳]-1 -carboxylic acid benzyl g (260 mg, yield 6%). 2'-Sideoxy-2',3'-Dihydro-1Ή-spiro[piperidin-4,4'-quinoline]-1-carboxylic acid benzyl ester (1.2 g, 3.4 mmol) and Pd/C ( A mixture of 200 mg of MeOH (20 mL) was hydrogenated at room temperature for 3 h under atmospheric pressure. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified twice by preparative HPLC to give 1 s-s-[piperidine-4,4f-quinoline]-2'(3Ή)-one as a TFA salt (11 mg, 11%) 〇4 NMR (CDC13) δ 7.65 (d, J=7_5 Ηζ, 1 Η), 7·29-7·45 (m, 3 H), 3.45 (d, /=12.3 Hz, 2 H), 3.20 (t, «7 = 12.3 Hz, 2 H), 2.96 (s, 2 H), 2.10-2.21 (m, 2 H), 1.70 (d, 7 = 14.1 Hz, 2 H). MS (ESI) m/z 217.06 [M+H]+. Preparation of B··spiro[4H-3,1-benzoxazine--4,4,-piperidine]-2(1//)-one

121775.doc -145 200813019 N_Boc-aniline (16.12 g, 83.4 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to _7 〇 °C. To this solution was added dropwise a solution of 1 77 of butyllithium in pentane (11 mL, 187 mmol) at -7 (TC) under nitrogen atmosphere. 30 min at _70 ° C After that, the solution was warmed to -20 ° C and maintained at the temperature for 2 hours. The solution was cooled to -70 ° C and N-Boc-4 piperidone (15.98 g, 80.2 mmol) in anhydrous tetrahydrofuran. The solution in (5 〇 mL) was treated dropwise. The solution was slowly warmed to room temperature, treated with potassium tributoxide (25 mg) and stirred overnight at room temperature under nitrogen. Diluted in 300 mL), cooled in an ice water bath and adjusted to pH 7 with 1 · 〇 # HC1 (aqueous). The layers were separated and the aqueous layer was extracted once with diethyl ether (1 mL). After washing with saturated brine, it was dried over Na~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purified to give 2-ytoxy-i,2-dihydrospiro[benzoquinone[d][l,3]oxazine-4,4,piperidine]-1,-carboxylic acid as a pale yellow solid Butyl ester (8.687 g, 34% yield) LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-Ci8j 10-99% CH3CN/0.05% TFA); ^-NMR (400 MHz? CDC13) δ 9·06 (br s, 1H), 7.28 (m, 1H), 7·12 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 4.12 (br d, J = 9.9 Hz, 2H), 3.36 (br t , J=12.4 Hz, 2H)? 2.13 (br d? J=13A Hz3 2H)5 1.98 (m, 2H), 1_51 (s, 9H). The pendant oxy-1,2·dihydrospiro[phenylhydrazine [d][l,3]oxazin-4,4,-piperidine]_1, _ 曱酉夂 酉曰 (6·71 g, 21.1 mm〇i) is dissolved in di-methane (50 mL) Treated with di-glycolic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, and then dissolved in acetonitrile and concentrated under reduced pressure. The salt was cooled in an ice-water bath, dissolved in ice cold saturated brine (2 mL) and HW (50 mL) and basified with ice cold 35% NaOH (aq). The obtained) was added to the aqueous layer to initiate crystallization. The resulting suspension was cooled in an ice water bath, filtered, rinsed with ice cold and dried to give 3·071 g of white crystalline solid snail [benzoquinone [(1][1 3] ° oxazin-4,4' given trip α] -2 (lH) -g with a free inspection. An additional 800 mg of free base (total yield = 84%) was obtained by extracting the mother liquor with ethyl acetate (10 x 50 mL) and then triturating the crude free base with acetonitrile. LC/MS m/z 219.2 [M+H]+, retention time 0·58 min (RP-C18, 10-99% CH3CN/0.05% TFA); W-NMR (400 MHz, DMSO-d6) δ 10.17 ( Br s,1H), 7.23 (m, 2H), 7.02 (m,1H), 6.87 (dd,&gt;8.2,1·2 Hz,1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H). 1-section base gas 啥琳-3-yl) brigade bite 4-fermentation

A solution of 2-chloroquinoline (1.0 g, 6.11 mmol) in THF (10 ml) was added dropwise to LD (3.4 ml, 2 EtOAc in hexane/THF) in THF (5 ml) In the solution, and the reaction mixture was stirred at 78 ° C (3 stirring for 1 hour, followed by dropwise addition of 1-benzylpiperidin-4-one (1·22 g, 6.22 mmol) in THF (2 ml The reaction mixture was stirred at -78 ° C to room temperature for two hours, cooled to -20 ° C, quenched with water and extracted with EtOAc. The organics were combined, dried (Na2SO4) and evaporated. Column chromatography (1 to 15% 121775.doc -147- 200813019

Purification of MeOH in DCM afforded the desired product. lC/MS (10% to 99%): M/Z (M+H) + (observed) = 353; iR = 2.24. 3-(1-benzyl-1,2,3,6-tetrahydroindole|biter-4_yl)quinoline-2(111)-one

/ a solution of 1-benzyl-4-(2-chloroquinolin-3-yl) 唆-4-ol (1 g, 2.84 mmol) in 6 N HCl (9 mL). The reaction mixture was cooled, water was added and the precipitated product was filtered and dried (0,27 g). LC/MS (10 〇/〇 to 99%): M/Z (M+H)+ (observed) = 317; iR=2.18. 3-(piperidin-4-yl)quinolin-2(1H)·one

3-(1-pyramid-1,2,3,6-tetrahydropyridin-4-yl)phosphonium-2(1 H)-one (〇·25 g, 0.29 mmol) at 40 C The solution was stirred for 6 hours with 1% Pd/c (130 mg) in MeOH (20 mL). The catalyst is filtered and the solvent is evaporated to give the desired product. LC/MS (10% to 99%): M/Z (M+H) + ( observed) = 229; Analytical data for certain compounds of the invention are shown in Table 2 below. Table 2 121775.doc -148- 200813019 Compound # LC/MS IVI+1 LC/RT min 1 533.5 3.36 2 633. 1.45 3 603.5 3.35 4 551.5 3.22 5 599.5 3.07 6 549.5 1.98 7 632.7 2.34 8 549.5 3.63 9 507.5 3.24 10 620.5 1.89 11 563.5 3.77 12 521. 3.31 13 621.5 3.77 14 595.5 3.8 15 559.3 3.72 16 597.5 3.62 17 633. 1.47 18 569.5 3.37 19 593.5 3.17 20 615.5 3.23 21 577.7 3.94 22 619.7 1.39 23 621.5 3.8 24 507.3 3.25 25 571.5 3.72 26 567.5 3.72 27 562.4 3.28 28 615.7 1.41 29 506.4 2.96 30 509.7 2.91 31 545.7 3.64 32 527.3 1.98 33 555.3 3.55 34 647. 1.46 35 529.3 3.12 36 583.3 1.86 37 541.7 3.8 38 507.5 3.25 39 626.7 1.53 40 633.5 1.42 41 535.5 3.54 42 704.7 2.23 43 536.3 2.24 44 571.3 3.57 Compound # LC/MS M+1 LC/RT min 45 542.5 2.13 46 542.5 2.39 47 620.5 1.27 48 585.3 3.82 49 634.5 1.74 50 632.7 1.49 51 563.7 2.08 52 661.7 1.47 53 568.5 2.22 54 585.3 3.84 55 619.5 3.68 56 612.5 1.52 57 555.5 2.13 58 555.3 3.37 59 606.4 2.39 60 601.5 1.37 61 563.5 3.34 62 5 73.4 3.06 63 546.5 3.27 64 563.5 3.36 65 641.3 3.89 66 573.4 3.05 67 539.5 3.45 68 667.5 1.42 69 508.6 3.1 70 634.5 1.93 71 543.5 2.31 72 690.5 2.16 73 563.5 3.82 74 557.5 4.15 75 501.5 3.5 76 589.5 1.98 77 562.5 2.41 78 535.5 3.51 79 587.3 3.79 80 551.5 3.47 81 665.7 1.46 82 550.5 2.42 83 549.5 3.12 84 531. 1.78 85 517.5 1.21 86 513.3 3.53 87 525.5 3.5 88 615.5 1.88 -149- 121775.doc 200813019 Compound # LC/MS M+1 1: Li _ 1 min 89 603.5 3.77 90 551.5 3.22 91 541.5 2.05 92 583.5 3.6 93 535.5 3.51 94 574.5 2. 95 527.3 1.96 96 505.3 3.2 97 487.5 1.41 98 549.7 3.63 99 733.7 2.26 100 553.5 2.08 101 549.5 1.89 102 619.5 2.58 103 579.5 3.64 104 507 3.22 105 487.5 1.37 106 604.7 2.21 107 507.5 3.27 108 528.1 2.28 109 533.3 3.11 110 533. 3.28 111 492.5 3.43 112 567.5 3.53 113 535.5 2.95 114 587.5 1.32 115 601.5 1.84 116 489.5 3. 117 551.5 3.12 118 537.4 2.95 119 633. 120 634.5 1.74 121 564.7 1.84 122 553.6 3.16 123 563.7 3.79 124 564.7 2.91 125 621.5 3.22 126 565.5 3.55 127 569.5 3.44 128 556.5 2.39 129 651.5 1.39 130 588.5 2.13 131 588.4 3.22 132 479.3 3.02 Compound # LC/MS M+1 LC/RT min 133 551.5 3.22 134 549.5 1.98 135 597.5 3.65 136 607.3 1.96 137 583.5 3.58 138 519.5 3.28 139 551.5 3.44 140 626.5 1.58 141 493.1 3.76 142 681.7 1.47 143 538.7 3.52 144 620.7 1.68 145 601.5 3.15 146 469.5 2.56 147 561.5 3.7 148 522. 1.52 149 553.5 3.57 150 648.7 1.79 151 515.7 1.96 152 578.5 1.89 153 612.5 1.46 154 541.7 2.06 155 571.5 3.6 156 535. 3.52 157 534.4 2.77 158 555.3 3.6 159 537.5 3.06 160 620.5 1.89 161 619.7 1.38 162 619.7 1.36 163 633.5 1.37 164 579.5 3.62 165 571.5 3.75 166 573.5 1.91 167 477.3 4.08 168 574.5 2.05 169 605.5 3.61 170 539.5 3.38 171 549.5 3.62 172 535.5 3.45 173 618.7 1.41 174 531.5 3.37 175 586.5 3.47 176 522. 1.52 -150- 121775.doc 200813019 Compound LC/MS M+1 LC/RT min 177 479.5 3. 178 579.5 3.39 179 589.5 3.3 180 563.7 3.67 181 567.5 3. 95 182 522.5 2.54 183 601.7 1.83 184 606.5 1.83 185 556.5 2.48 186 521.6 2.67 187 527.3 3.19 188 513.5 3.52 189 559.3 3.13 190 547.3 3.15 191 547.5 1.74 192 487.5 1.82 193 719.7 2.21 194 621.5 3.79 195 525.5 3.41 196 515.7 3.07 197 577.7 3.84 198 。 。 。 。 。 。 。 。 。 215 618.7 2.28 216 589.5 3.57 217 585.3 3.77 218 471.3 2.79 219 607.5 1.99 220 537.5 3. Compound # LC/MS M+1 LC/RT min 221 587.5 3.7 222 549.5 1.98 223 508.2 2.53 224 587.5 1.78 225 593.5 3.53 226 513.3 3.29 227 546.5 3.28 228 581.3 3.27 229 647.7 1.42 230 491.3 2.97 231 569.5 3.5 232 592.5 3.38 233 597.3 1.91 234 571.5 3.77 235 618.7 2.28 236 556.5 2.2 237 569.5 3.43 238 551.5 3.13 239 543.5 3.3 240 637.4 3.61 241 539.5 3.57 242 601.3 3 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 259 519. 3.07 260 601.5 1.34 261 446.5 3.03 262 563.7 3.75 263 592.7 1.98 264 547.5 3.57 -151 - 121775.doc 200813019 Compound # LC/MS M+1 LC/RT min 265 572.7 3.4 266 522.5 2.96 267 553.5 1.91 268 601.3 3.61 269 493.3 3.13 270 506.4 2.77 271 505.5 3.14 272 551.5 3.41 273 465.5 2.88 274 620.7 1.24 275 485.5 3.31 276 515.7 1.98 277 588.7 2.05 278 542.5 2.35 279 597.5 3.65 280 561.5 1.78 2δι 499.1 3.98 282 575.5 3.05 283 569.5 3.45 284 493.5 3.13 285 607.5 1.54 286 563.5 3.32 287 567.5 2.85 288 570.5 1.33 289 573.5 1.27 290 606.5 1.62 291 573.5 1.73 292 590.7 2.16 293 550.5 1.79 294 592.7 1.79 295 587.5 1.34 296 620.7 1.71 297 587.5 1.79 298 604.5 2.23 299 564.5 1.88 300 606.5 1.86 301 620.7 1 .78 302 619 1.42 303 630 1.49 304 606.5 1.71 305 525.5 1.24 306 525.5 1.25 307 649.7 1.41 308 589.5 2.13 Compound # LC/MS M+1 LC/RT min 309 609.5 2.18 310 623.7 2.23 311 595.5 2.12 312 549.7 2 313 539.5 1.32 314 539.6 1.31 315 575.7 2.08 316 561.5 2.02 317 561.5 2.04 318 575.5 2.09 319 620.4 1.61 320 634.4 1.68 321 633.7 1.47 322 633.7 1.5 323 651.5 1.42 324 665.5 1.48 325 663.7 1.42 326 663.7 1.45 327 620.5 1.32 328 634.7 1.41 329 620.5 1.3 330 634.5 1.35 331 605.5 1.48 332 619.7 1.56 333 647.7 1.41 334 647.7 1.49 335 633.5 1.45 336 633.5 1.47 337 638.5 1.26 338 637.5 1.39 339 679.7 1.49 340 693.7 1.52 341 666.5 1.34 342 691.5 1.51 343 665.7 1.41 344 665.5 1.42 345 679.7 1.46 346 677.7 1.44 347 。 。 。 。 。 。 。 。 。 。 。 。 1.29 358 679.7 1.46 359 653.7 1.41 360 651.5 1.45 361 665.5 1.5 362 638.5 1.29 363 663.7 1.44 364 675.7 1.56 365 689.5 1.63 366 662.5 1.38 367 695.7 2.02 368 709 2.01 369 647.7 1.52 370 661.7 1.55 371 663.7 1.45 372 677.7 1.5 373 633 1.42 374 633 1.42 375 661.6 1.53 376 707 1.56 377 661.6 1.61 378 634.6 1.26 379 730.9 1.31 380 634.6 1.37 381 703.9 1.16 382 636.7 1.33 383 649.7 1.48 384 715.7 1.61 385 663.7 1.54 386 622.7 1.28 387 688.7 1.43 388 647.7 1.43 389 691.7 1.53 390 664.7 1.32 391 651.7 1.47 392 733.7 2.07 393 706.7 1.82 394 638.5 0.95 395 693.6 1.63 396 693.6 1.7 Compound # LC/MS M+1 LC/RT min 397 638.5 1.24 398 651.7 1.47 399 651.7 1.47 400 707.7 1.58 401 707.7 1.53 402 710.9 1.5 403 737.7 1.68 404 634.5 1.32 405 66 。 。 。 。 。 。 。 。 。 。 。 。 。 421 632.4 1.88 422 634.6 1.44 423 620.6 1.83 424 520.4 1.65 425 605.4 1.52 426 607.4 1.12 427 593.4 1.52 428 591.6 1.7 429 707.4 1.77 430 707.4 1.91 431 707.4 1.77 432 707.4 1.87 433 709 1.49 434 709 1.49 435 623 1.21 436 680 1.29 437 680 1.29 438 682 1.3 439 733.6 1.68 440 733.6 1.7 153- 121775.doc 200813019 Compound # LC/MS Μ +1 LC/RT min 441 706.6 1.45 442 706.4 1.5 443 649.7 1.21 444 676.5 1.44 445 680 1.48 446 680 1.33 447 645.5 1.98 448 672.6 2.42 449 669.5 3.2 450 693.6 2.75 451 664.5 2.98 452 694.7 3.12 453 657 3.05 454 657.5 3.1 455 652.5 1.98 456 652.5 1.98 457 717.1 2.88 458 638.5 1.94 459 638.5 2 LC/MS Μ +1 LC/RT min 460 695.2 2.3 461 681.3 2.45 462 625.4 2.87 463 652.4 3.31 464 637.3 3.29 465 624.5 1.91 466 651.2 2.13 467 637.5 1.97 468 625.4 2.94 469 638.5 3.2 470 624.5 1.98 471 651.2 2.21 472 637.2 2.13 473 652.5 1.94 474 679.5 2.13 475 652.5 1.98 476 r^^frs # - U/ Ό.Ο B.ΙΌ 477 605 1.36 Using SK-N-MC-BLA (4 C10) Measurement of CGRP functional antagonism: The characteristics of CGRP functional antagonism were identified by cell-based transcription assay using recombinant SK-N-MC cell lines. To introduce the transcription reporter system, SK-N-MC cell lines were transduced with a retroviral vector containing the β-endoprotinase gene located downstream of the cAMP-responsive promoter. The expression of β-endoprostase is initiated by cAMP enhancement as a downstream event of endogenous CGRP receptor activation. Single pure lines were isolated using fluorescence activated cell sorting (FACS), based on CGRP-induced β-endoprostase activity. The β-inactamase activity was measured using a fluorescent energy transfer (FRET) dye CCF4. CCF4 is a substrate for β-endoprolinase (Zlokarnik G et al., Science, 279 (5347): 84-88, 1998) and is cleaved into a product in which the fluorescent signal is different from the parent. Using the previously published values, 4C10 pure lines suitable for dose-dependent β-endoprostase expression were selected for different concentrations of CGRP and consistent pharmacology. To evaluate the functional antagonist activity of the compound in the SK-N-MC (4C10) cell line of -154-121775.doc 200813019, the inhibition of β-endoprostase expression by the compound in the presence of CGRP was evaluated. SK-N-MC (4C10) supplemented with 1 mM non-essential amino acid solution (Invitrogen), 100 units/ml penicillin-streptomycin (Invitrogen), 1 mM sodium acrylate (Invitrogen) and 10% fetal The bovine serum was cultured in minimal essential medium (MEM) (Invitrogen). For the beta-endosaminol assay, low concentrations of serum (1% FBS in MEM) were used. On the day before the assay, 30,000 cells were plated in each well of a 384-well plate (Becton Dickinson) coated with poly-amino acid. SK-N-MC (4C10) was pre-incubated with the compound for 30 minutes before the addition of 200 pM CGRP. The assay was incubated at 37 ° C for 3 hours to allow β-endoprolinase to be expressed. CCF4 dye was added and incubated for 2 hours at room temperature. The fluorescent signal of the product was read at 400 nm excitation wavelength and 460 nm emission wavelength using a fluorescence plate reader (topological complementary plate reader (tcPR)) and the parental fluorescence signal was read at 535 nm. The ratio of values at 460 to 535 nm was used to calculate the percent activation. Perform curve fitting and IC5G calculations using MOD3. I125-CGRP combined with displacement assay to calculate the Ki of the compound

The purified SK-N-MC membrane was purchased from Perkin Elmer. The membrane was quickly thawed and placed on ice. The compound was diluted with a CGRP binding solution (25111), 148-HC1, pH 7.4, 5 mM MgCl2, 0.1% BSA and 0.05% Tween. The membrane was diluted 1:20 with the binding solution and homogenized for 3 sec using a Tissue Matster-50 homogenizer (Omni International). A homogenized film is added to the compound in the binding solution. After incubation for 10 minutes at room temperature, a final concentration of 46 pM of I125-iodotyrosylmercapto-calcitonin-gene related peptide (GE 121775.doc -155 - 200813019 healthcare) was added to the membrane and compound. After incubation for 2 hours at room temperature, the reaction was stopped by rapid filtration through a 0.5% PEI-treated GF/C filter plate (Perkin Elmer), and the filter plate was ice-cold washed with a cell harvester (Tomtec) (50 mM). Tris HC1, pH 7.4, 5 mM MgCl2 and 0.1% BSA) Wash. The radioactivity of the filter and plate was read on a Topcount (Packard). Non-specific binding was determined by a control reaction in which 1 μΜ of unlabeled CGRP was pre-incubated with a membrane prior to the addition of I125-CGRP. Total binding was determined by a control reaction of the membrane with I125-CGRP in the absence of the compound. The I125-CGRP substitution was calculated as a percentage of the compound using a non-specific control reaction and a complete binding control reaction. Perform curve fitting using MOD3. The Ki of the compound was calculated by the Cheng and Prusoff equation (Cheng Y.5 Prusoff WH? Biochem. Pharmacol. 22: 3099-3 108, 1973) using the Kd of the CGRP for the membrane and the amount of I125-CGRP for the assay. . The exemplary compounds of the present invention of Table 1 were found to be CGRP antagonists in the above I125-CGRP binding assay and in the CGRP functional antagonist assay. The IC5 and Ki data for the selected compounds of the invention are shown in Table 3 below. In Table 3, the symbols of the IC5G line and the Ki line have the following meanings: &quot;A" means &lt;1 μΜ; ΠΒΠ means between 1 μΜ and 5 μΜ; “Cn means &gt; 5 μΜ and ' 'ND' means no data. Table 3 121775.doc -156- 200813019

Compound # IC50 Ki 1 AA 2 AA 3 AA 4 A ND 5 巳ND 6 A ND 7 A ND 8 AA 9 AA 10 AA 11 A ND 12 AA 13 A ND 14 AA 15 AA 16 AA 17 ND A 18 B ND 19 CC 20 AA 21 A ND 22 B ND 23 A ND 24 B ND 25 A ND 26 A ND 27 C ND 28 AA 29 C ND 30 BA 31 A ND 32 A ND 33 AA 34 A ND 35 B ND 36 A ND 37 AA 38 A ND 39 ND ND

Compound # ICSO Ki 40 ND ND 41 AA 42 ND ND 43 BA 44 AA 45 C ND 46 B ND 47 A ND 48 AA 49 AA 50 ND ND 51 A ND 52 ND ND 53 CC 54 AA 55 B ND 56 ND ND 57 A ND 58 AA 59 A ND 60 AA 61 BC 62 AA 63 AA 64 BA 65 A ND 66 AA 67 AA 68 ND ND 69 A ND 70 AA 71 C ND 72 ND ND 73 A ND 74 B ND 75 B ND 76 AA 77 C ND 78 AA

Compound # 1C50 ΚΪ 79 AA 80 AA 81 ND ND 82 B ND 83 A ND 84 AA 85 C ND 86 B ND 87 BB 88 AA 89 A ND 90 B ND 91 A ND 92 A ND 93 AA 94 C ND 95 A ND 96 B ND 97 C ND 98 B ND 99 ND ND 100 A ND 101 C ND 102 AA 103 C ND 104 CC 105 CC 106 AA 107 AA 108 C ND 109 BA 110 CC 111 C ND 112 C ND 113 AA 114 AA 115 AA 116 BA 117 B ND 121775.doc 157- 200813019

Compound # 1C50 Ki 118 BA 119 ND A 120 AA 121 A ND 122 CA 123 A ND 124 B ND 125 A ND 126 A ND 127 BC 128 BA 129 ND ND 130 B ND 131 C ND 132 B ND 133 C ND 134 A ND 135 A ND 136 A ND 137 A ND 138 A ND 139 B ND 140 ND ND 141 C ND 142 ND ND 143 C ND 144 AA 145 AA 146 C ND 147 AA 148 BA 149 AA 150 AA 151 A ND 152 A ND 153 ND ND 154 A ND 155 A ND 156 A ND 157 C ND 158 B ND 159 AA 160 AA 161 A ND 162 ND ND 163 ND ND 164 B ND 165 A ND 166 A ND 167 C ND 168 B ND 169 BA

Compound # IC50 ill 170 AA 171 AA 172 AA 173 ND ND 174 AA 175 AA 176 BA 177 B ND 178 B ND 179 A ND 180 B ND 181 A ND 182 AA 183 AA 184 AA 185 A ND 186 C ND 187 BA 188 AA 189 C ND 190 CB 191 A ND 192 A ND 193 ND ND 194 AA 195 BC 196 B ND 197 C ND 198 AA 199 ND ND 200 C ND 201 B ND 202 AA 203 BA 204 BB 205 B ND 206 A ND 207 A ND 208 AA 209 A ND 210 A ND 211 BA 212 AA 213 B ND 214 B ND 215 A ND 216 ND ND 217 A ND 218 C ND 219 B ND 220 ND ND 221 A ND

Compound # ii· ill 222 A ND 223 C ND 224 AA 225 AA 226 BA 227 AA 228 B ND 229 ND ND 230 CB 231 A ND 232 B ND 233 A ND 234 A ND 235 B ND 236 BA 237 AC 238 B ND 239 A ND 240 BA 241 B ND 242 B ND 243 B ND 244 AA 245 C ND 246 A ND 247 B ND 248 AC 249 A ND 250 C ND 251 CB 252 A ND 253 B ND 254 B ND 255 BA 256 AA 257 A ND 258 B ND 259 AA 260 AA 261 C ND 262 B ND 263 AA 264 AA 265 AA 266 AA 267 A ND 268 AA 269 B ND 270 C ND 271 AA 272 B ND 273 B ND 121775.doc -158- 200813019

杂 # IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC IC 292 B ND 293 A ND 294 A ND 295 AA 296 AA 297 AA 298 A ND 299 AA 300 A ND 301 AA 302 AA 303 AA 304 ND A 305 B ND 306 CC 307 AA 308 A ND 309 B ND 310 A ND 311 B ND 312 A ND 313 A ND 314 C ND 315 AA 316 C ND 317 BA 318 A ND 319 A ND 320 A ND 321 A ND 322 B ND 323 A ND 324 AA 325 A ND

Compound # IC50 Ki 326 ND ND 327 ND ND 328 AA 329 ND ND 330 BA 331 AA 332 C ND 333 B ND 334 A ND 335 AA 336 AA 337 ND ND 338 A ND 339 ND ND 340 CC 341 AA 342 B ND 343 ND ND 344 A ND 345 AA 346 A ND 347 AA 348 BC 349 AA 350 AA 351 BA 352 A ND 353 AA 354 AA 355 ND ND 356 A ND 357 AA 358 C ND 359 ND ND 360 A ND 361 B ND 362 B ND 363 AA 364 C ND 365 AA 366 A ND 367 AA 368 ND ND 369 B ND 370 A ND 371 AA 372 C ND 373 B ND 374 BB 375 AA 376 A ND 377 B ND

Compound # 1C50 ill· 378 A ND 379 A ND 380 AA 381 C ND 382 A ND 383 B ND 384 C ND 385 B ND 386 ND ND 387 A ND 388 C ND 389 AA 390 C ND 391 CC 392 C ND 393 A ND 394 AA 395 C ND 396 B ND 397 CC 398 C ND 399 C ND 400 AA 401 AA 402 AA 403 BA 404 B ND 405 BA 406 ND A 407 AA 408 A ND 409 CA 410 A ND 411 B ND 412 A ND 413 A ND 414 BC 415 BA 416 ND ND 417 B ND 418 C ND 419 B ND 420 C ND 421 A ND 422 A ND 423 A ND 424 A ND 425 A ND 426 B ND 427 ND ND 428 C ND 429 ND ND 121775.doc 159. 200813019

Compound # IC50 Ki 430 c ND 431 A A 432 A A 433 C ND 434 A A 435 B A 436 A A 437 A A 438 A ND 439 A ND 440 ND ND 441 A ND 442 A ND 443 A ND 444 C ND 445 B ND

IC50 Ki 446 A A 447 A A 448 A ND 449 ND ND 450 ND ND 451 B ND 452 A ND 453 A ND 454 C ND 455 B ND 456 B A 457 A A 458 A A 459 A A 460 ND ND 461 A A

Compound # ill· Ki 462 AA 463 BA 464 B ND 465 B ND 466 A ND 467 B ND 468 A ND 469 AA 470 AA 471 AA 472 A ND 473 C ND 474 BA 475 AA 476 C ND 477 CA 121775.doc -160 -

Claims (1)

200813019 X. Patent application scope: 1. A compound of formula I: Wherein: X is s, so or S〇2; z is a bond or NR7, 0, S, ch2, c(o), nr7c(o)nr7, wherein R7 is hydrogen, CH-C4 aliphatic or c ( 〇) C1-C4 aliphatic group; Z2 is a bond, 0, ch2〇 or c(0); 裱8 is phenyl or 4-7 membered heterocyclic or heteroaryl ring or 1〇_14 member bicyclic An aryl or heterocyclic ring wherein the heterocyclic or heteroaryl ring has a hetero atom selected from the group consisting of hydrazine, N or S; wherein ring A is optionally substituted with up to 5 sizing substituents; wherein: Z2 is a bond , Z! is a bond, nr7, 〇, s, CH2, c(〇), nr7c(o)nr7; or wherein: Z and R are absent, ring A is not aromatic and ring A is associated with ring B Forming a spiro ring system; R6 is hydrogen or a C1-C4 aliphatic group; γπ is 1 - 3 ; n is 1-3; the limiting condition is m+i^4; 121775.doc 200813019 RY is an aryl group, a heteroaryl group , cycloaliphatic, C1-C6 aliphatic, aryl_C1-C6 aliphatic-, heteroaryl-C1-C6 aliphatic-, heterocyclyl-C1-C6 aliphatic- or cycloaliphatic a aryl-C1-C6 aliphatic group; wherein ry is optionally substituted with up to 5 R2 substituents; Rx is hydrogen, aryl, heteroaryl, C1-C6 aliphatic, aryl-C1_C6 aliphatic- ,miscellaneous a base-C1-C6 aliphatic group-, wherein Rx is optionally substituted with up to 5 R3 substituents; or two Rx together with the carbon atom to which they are attached form a 3-9 membered single ring, 9-14 membered double ring or 12-14 member 3 a cycloaryl, heteroaryl or heterocyclic ring system wherein each heteroaryl or heterocycle has up to 3 heteroatoms selected from the group consisting of ruthenium, S and n; wherein the ring system formed by two Rx is optionally up to 5 Substituted by R4 substituent; Rz is absent, is hydrogen, CN, C1_C6 aliphatic group, halo-C1-C6 aliphatic group, 0-C1-C6 aliphatic group, 〇·(halo-C1_C6 aliphatic group) , halo, aryl-C1-C6 aliphatic or heteroaryl-^ is an aliphatic group; = is a single bond or a double bond; the restriction is that when it is a double bond, then rZ and a Rw are not Existence; each is absent or independently hydrogen, halo, pendant oxy, aryl group, halo-CH-C6 aliphatic group, _〇_cl_C6 aliphatic group, _〇 (halogen group) a C1-C6 aliphatic group, an aryl group, an arylaliphatic group, or a C3_C7 cycloaliphatic group; or two Rw groups to form an optionally substituted C3-C7 cycloaliphatic group or a heteroquinone, wherein a heterocyclic ring having up to 3 heteroatoms selected from the group consisting of hydrazine and S&amp;N; The ring formed by two Rw is optionally subjected to up to 5 R5 substituents. 121775.doc 200813019 generation; wherein each occurrence of R1, R2, R3, R4 and R5 is independently Q-RM; wherein Q is a bond or Cl-C6 aliphatic chain in which up to two non-adjacent methylene units in Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRC02, NRCONR, SO, S02 , NRS02, S02NR, NRS02NR, O, S or NR; wherein each occurrence of RM is independently selected from R', halogen, N02, CN, ORf, SR', N(R,)2, NR^CO)^, NR , C(0)N(R,)2, NR'C02R, C(0)R, C02R, 0C(0)R, C(0)N(R,)2, 0C(0)N (Rf)2, SOR, S02R, S02N(R,)2, NR, S02R, NR, S02N(R,)2, C(0)C(0)R' or C(0)CH2C(0 R, wherein each occurrence of R is independently selected from hydrogen or, as the case may be, 0-5 RK substituted Cu aliphatic groups; and each occurrence of RK is independently selected from the group consisting of Rv, halogen, -N02, -CN , -ORv, -SRV, -N(RV)2, -NRvCORv, -NRvCON(Rv)2, -NRvC02Rv, -CORv, -C02Rv, -OCORv, -CON(Rv)2, -C(=N-CN ), -OCON(Rv)2, -SO Rv, -S02Rv, -S02N(Rv)2, -NRvS02Rv, -nrvso2n(rv)2, -COCORv, -COCH2CORv, -0P(0)(0Rv)2, -P(0)(0Rv)2, -0P (0) 20Rv, -P(0)20Rv, -PO(Rv)2 or _〇P〇(Rv)2, wherein Rv is hydrogen or an unsubstituted CN6 aliphatic group; and each of them exhibits R' independence The ground is hydrogen, as the case may occur, 0-5 RM1 substituted Cu aliphatic groups; and each occurrence of RM1 is independently selected from -RT, halogen, -N02, -CN, -ORT, -SRT, -N ( RT)2, 121775.doc 200813019 _NRTCORT, -NRTCON(RT)2, -NRTC02RT, -CORT, -C02RT, _OCORT, -CON(RT)2, -C(=N-CN), -OCON(RT)2 -SORT, -S02RT, -S02N(RT)2, -NRTS02RT, -NRTS02N(RT)2, -COCORT, -COCH2CORT, -0P(0)(0RT)2, -P(〇)(〇RT)2 , -0P(0)20RT, -P(0)20RT, -PO(RT)2 or -〇P〇(RT)2, wherein RT is hydrogen or an unsubstituted Ci-6 aliphatic group; or R' a 3-8 member saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or having 0-5 independently selected from nitrogen, oxygen or sulfur A saturated, partially unsaturated or fully unsaturated bicyclic system of 8-12 members of an atom, The monocyclic or bicyclic ring is optionally substituted with 0-5 Ru; and each occurrence of the ruler 11 is independently selected from the 0-3-RQ1 substitutions as the case may occur and has 0-3 independently selected from nitrogen, a 3-8 member saturated, partially unsaturated or fully unsaturated monocyclic ring of a hetero atom of oxygen or sulfur, or Ru is -RQ, halogen, =0, =NRQ, -N02, -CN, -ORQ, -SRQ, - N(RQ)2, -NRQCORQ, -NRQCON(RQ)2, -NRQC02RQ, -CORQ, -C02RQ, -OCORQ, -CON(RQ)2, -C(=N-CN), -OCON(RQ)2 -sorq, -so2rq, -so2n(rq)2, -nrqso2rq, -nrqso2n(rq)2, -cocorq, -coch2corq, -op(o)(orq)2, -p(o)(orq)2 -op(o)2orq, -p(o)2orq, -PO(RQ)2 or -OPO(RQ)2, wherein RQ&amp;RQ1 is hydrogen or an unsubstituted cle6 aliphatic group; or R and R', The two Rs or the two R's appearing together with the atoms to which they are bound form a 3-12 member saturated, partially unsaturated or fully unsaturated single having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. a ring or a bicyclic ring in which the monocyclic or bicyclic ring is optionally substituted with 〇-5^71; and each occurrence of RT1 is independent 121775.doc 200813019 is selected from -Rs, halogen, = , =NRS, -N02, -CN, -ORs, -SRs, -N(RS)2, -NRsCORs, -NRsCON(Rs)2, -NRsC02Rs, -CORs, _C02Rs, -OCORs, -CON(Rs)2 , ·0: (=Ν_αΝ〇, -OCON(Rs)2, -SORs, -S02Rs, -S02N(Rs)2, -NRsS02Rs, -nrsso2n(rs)2, -COCORs, -COCH2CORs, -op(o) (ors) 2, -P(0)(0Rs)2, -0P(0)20Rs, -P(0)2ORs, ·ΡΟ(ν)2 or _OPO(Rs)2, where Rs is hydrogen or not Substituted Ci.6 aliphatic group. 2. The compound of claim 1, wherein Z2 is a bond, R6 is hydrogen and Z1 is a bond. 3. The compound of claim 1, wherein Z2 is a bond, R6 is hydrogen and Z1 is NR7, 0, S, CH2, C(0) or NR7C(0)NR7. 4. The compound of claim 1, wherein Z2-R6 is not hydrogen and Z1 is a bond. 5. The compound of claim 1, wherein Z2-R6 is not hydrogen and Z1 is NR7, 0, S, ch2, c(o) or nr7c(o)nr7. 6. The compound of claim 1, wherein = is a single bond. 7. The compound of claim 1, wherein = is a single bond and both Rw are hydrogen. The compound of any one of claims 1-7, wherein Rz, if present, is C1-C6 alkyl, halo-C1-C6 alkyl- or-0-C1-C6 alkyl. 9. The compound of claim 8, wherein Rz, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. The compound according to any one of claims 1 to 6, wherein at least one Rw is a C1-C6 alkyl group, a halo-C1-C6 alkyl group or a-0-(M-C6 alkyl group. The compound of claim 10, wherein at least one Rw is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe, or OEt. One Rw is hydrogen and the other RW is C1-C6 alkyl, halo-C1-C6 alkyl- or -0-C1-C6 alkyl. 13. The compound of claim 12, wherein one Rw is hydrogen and the other A rW is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. 14. A compound according to any one of the preceding claims, wherein ry is one or more of the following groups, as appropriate a C1-C6 aliphatic group substituted with a group: halo, hydrazine H, -C1-C4 alkoxy, -C1-C4 alkoxycarbonyl or bis-(C1-C4 alkyl)amino-. a compound of 14 wherein ry is decyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, methyl- Propyl, 2-methoxy-ethyl, 3-ethoxypropyl, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(hydroxymethyl)-3 -Methyl-butyl, allyl, ethynyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, hydroxy·2,2-dimethyl-prop Base, 2,2,2-trifluoroethyl, 3,3,3-trifluoro*-propyl or 2,2,3,3,3-pentafluoro-propyl. 16. The compound of claim 15 Wherein RY is decyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3·dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl The compound of any one of the preceding claims, wherein ry is a C3-C8 cycloaliphatic group or a C1-C6 aliphatic group substituted by a C3-C8 cycloaliphatic group. a compound wherein RYgC3_C6 cycloalkyl or C1-C6 alkyl-substituted by C3-C6 cycloalkyl. 19. The compound of claim 18, wherein ry is cyclopropyl, cyclohexyl, cyclohexylmethyl-, Cyclopropyl decyl- or cyclohexylethyl-. 20. A compound according to any one of the preceding claims, wherein is a pyridyl group (C1_121775.doc 200813019 C6)alkyl-, tetrahydrofuranyl (C1_C6 alkane) And / or N_(C1-C4 alkyl)-pyrrolidinyl-(C1-C6 alkyl)-. 21. The compound of claim 2, wherein tetrahydrofuran-2-yl-曱Base-, pyridyl-3-yl-methyl-, pyridyl-ethyl-, pyridin-2-yl-ethyl-, pyridine-4-yl-methyl-, 1H-indazole-5-yl or A compound of any one of the preceding claims, wherein RY is phenyl or substituted by (phenyl) C1-C6 aliphatic A group-, optionally substituted with up to 5 R2 substituents, wherein the 'R2 substituent is independently selected from halo or a 5-6 membered heterocyclic ring having 1 to 3 heteroatoms selected from N, hydrazine or S. The compound of claim 22, wherein ry is phenyl, 2,6-difluorophenyl, benzyl, fluorophenylmethyl... 4-morpholinium phenyl...2-piperidinylphenyl- Or phenylethyl-. A C3-C6 cycloaliphatic or 4-7 heterocyclic ring wherein the heterocyclic ring is optionally substituted with up to 3 Ru substituents wherein the heteroaryl or hetero is selected from N, 0 or S heteroatoms. The compound of any one of clauses 1 to 23, wherein _rX is hydrogen and the other: x is an aryl or heteroaryl ring 'R3 substituent substituted with up to 5 substituents as appropriate. Independently selected from the group consisting of C1_C6 aliphatic phenyl, dentate, 25. The compound of claim 24, which is hydrogen and which is hydrazine and has at most a phenyl group, the R3 substituent is independently selected from A dentate or a 4-7 membered heterocyclic ring wherein the heterocyclic ring is optionally substituted with up to 2 substituents, wherein the heterocyclic ring has up to three heteroatoms selected from N, oxime or S. 0 121775.doc 200813019 26· The compound of claim 25, wherein one Rx is hydrogen and the other rx is phenyl substituted at the 2 position with a 4-7 membered heterocyclic ring and substituted at the 3 position with a halogen. 27. The compound of claim 24, wherein one Rx is deuterium and the other Rx is phenyl or a phenyl group substituted by the group: sigma-methyl, 4-methyl-α 辰 _1 _, 4 -ethyl-Bistazin-1-yl, 4-propyl-rhodium-1-yl, 4-butyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4- Third butyl piperazine-1-yl, 4-cyclopropylbenzarazine-1-yl, 4-tert-butoxycarbonyl-piperazine _; [-yl, 4-hydroxylpiperidinyl, 4-ethyl Oxycarbonyl-Bigidine_1_yl, 琳琳-4_基,卜好_pyrazolyl, sorrel-1 _ yl, 洛洛 bite 1 _ base, 3-dimethylamino group · ϋ比洛唆_ 1 · Base, 4- (Brigade bite-1-base) π bottom bite. Than the base (丨-methyl-branched _4_yl) 嗓 _ 1· base or 1-(2,2,2-trifluoroethyl) piperazin-1-yl. 28. The compound of claim 24, wherein one Rx is hydrogen and the other Rx is pyridinyl substituted with pyridine or substituted with: piperazinyl, 4-methyl-piperazine-j-yl, 4 -ethyl-piperazine-丨-yl, each propyl-piperazine-丨-yl, 4-butyl-piperidin-1, 4-isopropyl-piperazin-1-yl, 4-third Butyl piperazin-1-yl, 4-cyclopropylpyrazine-1·yl, 4-tert-butoxycarbonyl-piperazine-:μ group, 4-hydroxyl group, 4 ethoxycarbonyl- Piperidin-1-yl, morpholin-4-yl, 1-dan-pyridin-1-yl, imidazol-1-yl, pyridyl-4-yl, 3-dimethylaminopyrrolidin-1. , 4-(piperidinyl-indoleyl)piperidine, pyridyl (indole-methylpiperidin-4-yl)piperazin-1-yl or 1-(2,2,2-trifluoroethyl)per Pyrazin-1-yl. The compound of any one of the above claims, wherein -rX is hydrogen and the other R is a phenyl or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of: C1-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, heteroaryl-C1_C6 aliphatic 121775.doc 200813019 base-, aromatic Alkoxy, bis(C1-C6 aliphatic)amino..._0_C1_C6 aliphatic, _S(〇)-Cl-C6 aliphatic or -S(0)2_C1-C6 aliphatic. The compound of any one of clause 1 to 23, wherein one Rx is hydrogen and the other RX is optionally substituted with up to five R3 substituents and has up to three heteroatoms selected from ruthenium, N or S. A C3-C7 cycloaliphatic or heterocycloaliphatic ring wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. 31. The compound of claim 30, wherein the compound is selected from the group consisting of cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, tetrahydro-2iy-piperidyl, tetrahydro-2-indothanyl, 9H_ ^-9-Base or pie bite. 32. The compound of any one of clauses -23, wherein two of them together with the carbon atom to which they are attached form a 3-9 membered monocyclic ring, a 9-14 membered bicyclic ring or a 12-14 membered aryl group, a heteroaryl group or a heterocyclic ring system. Wherein each heteroaryl or heterocycle has up to 3 heteroatoms selected from the group consisting of hydrazine, S&amp;N; wherein the ring system formed by two rX is optionally substituted with up to 5 R4 substituents. 33. The compound of claim 32, wherein the ring system is selected from the group consisting of 9沁#__, , tetrahydro 4-pyran-4-yl, tetrahydro-2 ugly-thiopyranyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, piperidinyl or fluorenyl-p-piperidin-4. The compound of claim 1, wherein the compound has the formula ΙβΑ : 〇 121775.doc 200813019 wherein: two is 4, a heterocyclic ring which forms a snail with the brigant ring via a carbon atom cA, wherein ring A is optionally fused with a substituent or a heteroaryl ring substituted as appropriate by the substituent (4). Wherein ring A has, in addition to the nitrogen ring atom, up to two other ring heteroatoms selected from the group consisting of hydrazine and domain S; and wherein % A is substituted with up to 5 R1 substituents, in addition to the pendant oxy group. 3 5 · The compound of claim 4 4 is composed of ^ ^ mouth substance where = is an early bond and if 2 is present, it is hydrogen. 3 6 · The compound of claim 3 4, 1 by ^ οσ &quot; where = is an early bond and Rzg C1-C6 alkyl yl group &lt; 1-C6 alkyl- or _〇_c 1-C6 base. 37. The compound of claim 36, wherein RZ, if present, is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. The compound according to any one of claims 34 to 37, wherein at least one of them is (3) C6 alkyl, _s_cl_C6 alkyl or _〇_cl_C6 alkyl. 3. The compound of claim 38, wherein at least one rW is fluorine, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. The compound of Claim 37, wherein = is a single bond, one rW is hydrogen and the other RW is C1-C6 alkyl, halo-C1-C6 alkyl or _0_C1, C6 alkyl. 41. The compound of claim 40, wherein one Rw is hydrogen and the other rW is fluoro, methyl, ethyl, n-propyl, CF3, CHF2, OMe or OEt. 42. The compound of claim 37, wherein = is a single bond and each Rw is hydrogen. 43. The compound of any one of claims 34 to 42, wherein RY is a C1_C6 aliphatic group substituted by one or more of the following groups: 121775.doc -10- 200813019: halo, hydrazine H, C1-C4 An oxy group, a C1-C4 oxocarbonyl group or a bis-(c-C4 alkyl) group. 44. The compound of claim 43, wherein rY is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-mercapto-butyl Base, 2-methyl-propyl, 2-decyloxy-ethyl, 3-ethoxypropyl, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(hydroxymethyl)_3 Methyl-butyl, allyl, ethynyl, 2-(diethylamino)ethyl, 1-methyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl -propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl or 2,2,3,3,3-pentafluoro-propyl. 45. The compound of claim 44, wherein RY is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-didecyl-butyl, 3-mercapto-butyl Base or 2-methyl-propyl. The compound according to any one of claims 34 to 42, wherein RY is a C3-C8 cycloaliphatic group or a C1-C6 aliphatic group-substituted by a C3-C8 cycloaliphatic group. 47. The compound of claim 46, wherein RY is C3-C6 cycloalkyl or C1-C6 alkyl- substituted by C3-C6 cycloalkyl. 48. The compound of claim 47, wherein 0 is cyclopropyl, cyclohexyl, cyclohexylmethyl-, cyclopropylmethyl- or cyclohexylethyl-. 49. The compound of any one of claims 34-42, wherein ry is pyridyl (C1_C6)alkyl-, tetrahydrofuranyl (C1_C6 alkyl)^N_(C1_C4 alkyl)-pyrrolidinyl-(C1- C6 alkyl)-. 50. The compound of claim 49, wherein RY is tetrahydrofuran-2-yl-methyl, pyridin-3-yl-indenyl, pyridyl-4-yl-ethyl-, pyridin-2-yl-ethyl _, Pyridin-4_yl-fluorenyl-, 1Η·carbazole·5-yl or 2-(small methyl)-pyrrolidine·2-121775.doc -11 - 200813019 yl-ethyl-. The compound of any one of claims 34 to 42, wherein rY is phenyl or (phenyl) substituted C1-C6 aliphatic-, which is optionally substituted with up to 5 ft 2 substituents, R 2 substituent Independently selected from the group consisting of _- or a 5-6 membered heterocyclic ring having a hetero atom selected from n, oxime or S. 52. The compound of claim 51, wherein RY is phenyl, 2,6-difluorophenyl, decyl, 4-fluorophenylmethyl-, 4-morpholinium phenyl...2-piperidinylbenzene Base - or stupid ethyl-. The compound of any one of clauses 4 to 5, wherein _ is a single bond, one RX is hydrogen and the other RX is optionally an aryl or heteroaryl ring substituted with up to 5 substituents, R3 The substituent is independently selected from a C1_C6 aliphatic, phenyl, i, C3-C6 cycloaliphatic or 4-7 membered heterocyclic ring wherein the heterocyclic ring is optionally substituted with up to 3 RU substituents, wherein the heteroaryl The base or heterocycle has up to three heteroatoms selected from N, oxime or S. 54. The compound of claim 53, wherein - RX is hydrogen and the other is phenyl or acridinyl having up to two R5 substituents, the R5 substituents being independently selected from halo or having up to 2 substituents A 4-7 membered heterocyclic ring wherein the heterocyclic ring has up to three heteroatoms selected from N, oxime or 8. Clothing 55. As requested. The compound of 54' wherein one rX is hydrogen and the other rX is a phenyl group substituted at the 2-position, 'a 4-7 membered heterocyclic ring, and substituted at the 3-position with a _ _ _. 56. The compound of claim 54, wherein -rX is hydrogen and the other -rX is phenyl or, '7&lt;, the lower group substituted styryl: piperazinyl, 4-methyl-piperazine-yl, ^ Chen Qin 1-based, 4-propyl-piperazine _ 1 _ group, 4 butyl _ piperazine _ "based, 'isopropyl-piperazine small group, 4 - tert-butyl piperazinyl, hydrazine Cyclopropyl 121775.doc -12- 200813019 piperazine-1-yl, 't-butoxycarbonyl-piperazinyl, 4-hydroxy-piperidinyl, ethoxycarbonyl-piperidin-1-yl, morpholine- 4-yl, Bu//_pyrazol-1-ylmidin-1-yl, 吼p each bite _ 1 -yl, 3-dimethylamino _ σ ratio slightly _ 1 · yl, piperidine 丨_ yl) piperidine, pyridyl (hydrazine-methyl piperidin-4-yl) piperazine _ h or 1-(2,2,2-trifluoroethyl) piperazinyl. 57. a compound wherein _RX is hydrogen and another ruthenium is pyridyl or substituted with the following group: piperidinyl, 4-methyl-piperazine-buyl, 4-ethyl-piperazine -丨_yl, 4-propyl-piperazinyl, 4-butyl-piperidinyl, 4-isopropyl-pyrazine-based, 't-butylpiperazinyl, 4-cyclopropylpiperazine -1 - group, 4-tert-butoxycarbonyl-piperazin-1-yl, 4_ Base-Brigade sigma, 4_ethoxycarbonyl-piperidin-1-yl, morpholin-4-yl, 1-7/-pyrazol-1-yl, imidazolyl, pyrrolidine-fluorenyl, 3_ Diammonium-pyrrolidinyl-1-yl, 4-(piperidinyl)piperidine, pyridyl (indole-methylpiperidin-4-yl)piperazin-1-yl, 1-(2 The compound of any one of claims 34-52, wherein one is hydrogen and the other Rx is optionally selected from one or more independently. a phenyl or heteroaryl group substituted with a substituent of the following group: C1-C6 aliphatic, cyano, halo, _yl-C1-C6 aliphatic-, aryl-C1-C6 aliphatic-, Heteroaryl-C1_C6 aliphatic group...aralkyloxy group, di(C1-C6 aliphatic)amino group,-0-C1-C6 aliphatic group, _S(0)-C1-C6 aliphatic group or -S (0) A compound of any one of claims 34-52, wherein at least one rX is hydrogen and the other Rx is optionally substituted with up to five R3 substituents and has at most two a C3-C7 cycloaliphatic or heterocycloaliphatic ring selected from the group consisting of a hetero atom of hydrazine, N or S, wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. 121775.doc -13- 200813019 合ο The compound of Item 59, wherein the Rx is selected from the group consisting of cyclopentyl, cyclohexene &amp; alkenyl, 5 hexyl, tetrahydro-2 pentanyl, tetrahydro-2 sinyl 9H _葙-9-based or σ辰π-based. 62. The compound of claim 61, wherein the ring system is selected from the group consisting of: -9-yl, tetrahydro-2i7-piperazin-4-yl, tetrahydro-2-indolyl-4-yl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloglycan, J is ρ, knee lean hexenyl, piperidinyl or 1-benzyl-piperidin-4-yl. The compound of any one of the items 34-52, wherein the bond, the two carbon atoms to which they are attached, form a 3_9 Μ single ring, a singer or a 12-14 member dinuclear aryl group, a hetero aryl group. Or a heterocyclic ring system wherein each heteroaryl or X heterocyclic ring has up to 3 heteroatoms selected from the group consisting of; wherein the ring system formed by two Rx is optionally substituted with up to 5 4 substituents. The compound of any one of claims 34 to 62, wherein the ring is selected from the group consisting of A-iii Where: 121775.doc -14- 200813019 P is 0 - 2 ; q is 0 · 2; the constraint is p + qs2; W and ~ are each independently selected from NR1, Ο, S, SO, S02, C (Rl ) 2 or = CRl (when P or q is 2); WE is -C(R1)2, =c(Rl)...=N_*_N(Rl)_ ; does not exist or is selected from, = ice or - N^1)-; The limiting condition is that WE and WF* are simultaneously =N- or -NCR1)-; % B 1 is a phenyl substituted with up to 5 R1 substituents or 5-6 members 0 heteroaryl as appropriate Base ring; and R1 is as defined in claim 34. 64. The compound of claim 63, wherein ring A has the formula a. "65. The compound of claim 63, wherein ring A has the formula A-ii. 66. The compound of claim 63, wherein the ring VIII has the formula A compound of claim 63, wherein the compound of claim 64 has the formula A_iv. 68. The compound of claim 64 or 66, wherein all are =c(r1). 69. The compound of claim 64 or 66, wherein wE is =c(Rl)_ and ^ is =N-. 70. A compound according to any one of claims 63, wherein 1) is 〇 and (1 is 〇. 71) as claimed in claim 63-69 A compound of any of the preceding claims, wherein 卩 is 丨 and 9 is 〇. 72. The compound of any one of claims 63-69, wherein {) is 〇 and 4 is 2. 73. as in any one of claims 63-72 The compound of any one of claims 63-72, wherein wa is 〇. 75. The compound of any one of claims 63-72, wherein 膂8 is 〇(]11)2. The compound of any one of claims 63-72, wherein the arm is (:(]^1)2 and]11 121775.doc -15-200813019 is hydrogen. 77. Any one of claims 63-72 Compound 78. as requested The compound of any one of claims 63-72, wherein the compound of any one of claims 63-72 is hydrogen, wherein WB is NR1, wherein WB is hydrazine. Where WB is ¢:(1^)2, where WB is (:$1)2 and is 1 81. The compound of any one of 63_72, 〇, where P is 2 and WA is C(R) A compound of any one of the preceding claims, wherein -CRkCR1 - 83. The compound of claim 63, wherein the ring VIII is selected from the group consisting of 2 and wB is Ο (X ΝΗ, 〇 Ν Η Ο N Η Ο A-i-a A-i-b A-1-c ^ κ &gt;: κ Vnh ο丫' ο ο A-i-j A-i-k or A_i_l wherein the ring is optionally substituted with up to 4 R1 substituents. 84. The compound of claim 63, wherein ring a is selected from the group consisting of: ~N Η ΗΝ, A-i-i, ΝΗ A-i-d A_i_h ΗΝ 〇 τ Ο 121775.doc -16- 200813019 Wherein the ring is optionally substituted with up to 4 R1 substituents. 85. The compound of claim 63, wherein the ring a is selected from the group consisting of: Wherein the ring system is optionally substituted with up to 4 R1 substituents. 86. The compound of claim 63, wherein the ring a is selected from the group consisting of: aS A-ii-f A-ii-g wherein the ring system is optionally substituted with up to 4 R1 substituents. 87. A compound as claimed in claim 1, wherein the compound has the formula: 121775.doc •17· 200813019 Ο - a 4-7 membered heterocyclic ring fused to a phenyl hydrazine or a heteroaryl ring optionally substituted with up to 5 R1 substituents, optionally containing up to two rings in addition to the nitrogen ring atom Other ring heteroatoms from S, S; and wherein ring A is substituted with up to 5 R1 substituents, as appropriate, in addition to the pendant oxy group. 88. The compound according to claim 87, wherein ry is a C1-C6 aliphatic group substituted by one or more of the following groups: halo, hydrazine H, C1-C4 alkoxy, C1_C4 alkoxycarbonyl or Di-(C1-C4 alkyl)amino group. 89. The compound of claim 88, wherein ry is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl , 2-mercapto-propyl, 2-methoxy-ethyl, 3-ethoxypropyl, ι_(methoxycarbonyl)-3-methyl-butyl, 1-(hydroxymethyl)- 3. Methyl-butyl, allyl 'ethynyl, 2-(diethylamino)ethyl, 1-indenyl-2-methoxy-ethyl, 3-hydroxy-2,2-dimethyl Base-propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-propyl or 2,2,3,3,3·pentafluoro-propyl. 90. The compound of claim 89, wherein RY is methyl, ethyl, propyl 'isopropyl, butyl, tert-butyl, 3,3-dimethyl-butyl, 3-methyl-butyl Base or 2-methyl-propyl. The compound of claim 87, wherein RY is a C3-C8 cycloaliphatic group or a ci-C6 aliphatic group-substituted by a C3-C8 cycloaliphatic group. 92. The compound of claim 87, wherein RY is C3-C6 cycloalkyl or C1-C6 alkyl-substituted by C3-C6 cycloalkyl. 93. The compound of claim 92, wherein the ring is a cyclopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a cyclopropylmethyl group or a cyclohexylethyl group. 94. The compound of claim 87, wherein RY is pyridyl (C1-C6)alkyl, tetrahydrofuranyl (C1-C6 alkyl)- or N-(C1-C4 alkyl)-pyrrolidinyl-(C1 -C6 burning base)_. 95. The compound of claim 94, wherein rY is tetrahydrofuran-2-yl-methyl-, hydrazide-lat-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridin-2-yl -ethyl-' &quot; than biting _4_yl-methyl-, 1 Η-carbazole _5. group or 2-(Ν-methyl)-pyrrolidin-2-yl-ethyl-. 96. The compound of claim 87, wherein rY is phenyl or a (phenyl) substituted C1_C6 wax group, optionally substituted with up to 5 112 substituents, the R2 substituents being independently selected from the group consisting of or having 1-3 heterocyclic rings of 5-6 members selected from heteroatoms of N, hydrazine or S. 97. The compound of claim 96, wherein is phenyl, 2,6-difluorophenyl, benzyl, 'fluorophenylmethyl-, 4-morpholinium phenyl, 2-piperidinylbenzene Base _ or benzylethyl-. 98. The compound mX according to any one of the items 87 to 97, which is an aryl or heteroaryl ring optionally substituted with 5 R3 substituents, the R3 substituents being independently selected from the group consisting of C1 - C6 aliphatic groups, stupid a H, a C3-C6 cycloaliphatic group or a 4·7-shelled heterocyclic ring wherein the heterocyclic ring is optionally subjected to up to 3 RU substituents. 121775.doc -19-200813019 0 or S generation 'where the heteroaryl group or The heterocyclic ring has up to three selected from N heteroatoms. Such as! The compound of claim 98, wherein Rx is a substituent having up to 2 R3 substituents or a σ fluorenyl group, and the substituents of R3 are independently selected from halogen or oxime auxiliaries wherein the heterocyclic ring is optionally substituted with up to 2 Ru A base substitution wherein the heterocyclic ring has up to three heteroatoms selected from the group consisting of ruthenium, osmium or S. 〇 100. The compound of claim 99, wherein RX is phenyl substituted at the 2 position by a 4-7 heterocyclic ring and substituted at the 3 position by a valence. 1〇1·The compound of the claim &quot;, RX in the oxime is a guanidine group, a phenyl group or a phenyl piperazine group substituted by the following group, 4-methyl-piperazine 丨 丨 基, 4 _Ethyl_Chen Qin_1-yl, 4-propyl-piperazine-丨-yl, 4-butyl-piperazine-丨-yl, 4-isopropyl-piperazine-1-yl, 4_ Third butyl piperazine-1-yl, 4-cyclopropylpiperazine _ 4 一-butoxy benzyl decyl-1-yl, 4-cyano-pyridyl, 4-ethoxycarbonyl-peri Acridine_丨_yl, morpholine·'base, Buhao·pyrazole-oxime-based, amide-based 1, pyrrolidine-1-yl, 3-dimethylamino-pyrrolidin-yl-yl, 4_( Piperidine, pyridyl (1-methylpiperidin-4-yl) piperazin-1-yl or 1-(2,2,2-di-rhenyl)pyrene-yl. The compound of any one of the items 87-97, wherein rX is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of CKC6 aliphatic, cyanide , halo, halo-C1-C6 aliphatic, aryl-C1-C6 aliphatic-, heteroaryl-ci-C6 aliphatic-, aralkyloxy, di-(C1-C6) Aminyl-, -〇_ci-C6 aliphatic, -S(O)-C1-C6 aliphatic or aliphatic. 103. The compound of any one of claims 87-97, wherein rX is C3 substituted by up to five R3 substituents as appropriate, and has up to three heteroatoms selected from the group consisting of ruthenium and N4S. a C7 cycloaliphatic or heterocycloaliphatic ring wherein the ring is optionally fused to one or more phenyl or heteroaryl rings. The compound of claim 103, wherein the Rx is selected from the group consisting of cyclopentyl, cyclohexylcyclohexenyl, cycloheptyl, tetrahydro-2fn-n-butyl, tetrahydro-2H-perylthio, 9H-oxime Winter base or piperidinyl. The compound of claim 87, wherein the ring A is selected from the group consisting of: Wc^-C(R1)2 . C(0)ic=CR1.; r is 0-2; wherein: WD is N or =C-; , =N- or -NCR1)-; W does not exist or is selected from -C(ri)2, =c(Ri)·, =N• or _n(r1)_ ; the constraint is ^^ and ...17 are not equal to =N- or -N^1)-; Y is C(O), s(0) or s(0)2; and ring B1 is a phenyl or 5-6 membered acyl ring substituted by up to 5 111 substituents as appropriate; and === is a single bond or double key. 106. A compound according to claim 1 , wherein wc^_c(r1)2. The compound of claim 105, wherein wc is 121775.doc -21 - 200813019 1〇8. The compound of claim 105, wherein Wc is C(O). The compound of any one of claims 105-108, wherein r is hydrazine. The compound of any one of claims 1 to 5 to 8 wherein r is 1. 1H. A compound according to any one of claims 1 to 5-1, wherein r is 2. 112. The compound of any of claims i〇5_ul, wherein wd is N. The compound of any one of the preceding claims, wherein 0 is = (: _. 114. The compound of any one of claims 105-113, wherein γ is C(〇). The compound of any one of clauses 105 to 113, wherein ¥ is %〇). The compound of any one of claims 105-113, wherein 丫 is 8(0)2. 117. The compound of claim 1 , wherein the ring a is selected from the group consisting of: * 八-V a j Λ _ν_Κ; wherein the ring is optionally substituted with up to 4 R1 substituents. Π 8. The compound of claim 105, wherein ring a is selected from the group consisting of: 121775.doc 22- 200813019 Ο A_vi-a Α - vi-b A-vi-c A-vi-d Wherein the ring is optionally substituted with up to 4 R1 substituents. 119. The compound of claim 1 , wherein ring A is optionally substituted with up to 5 substituents selected from the group consisting of C1-C6 aliphatic, C1-C6 aliphatic-oxy, C1-C6 Halogenated aliphatic, CN, halo, pendant oxy, optionally substituted C3-C7 cycloaliphatic, or optionally substituted as follows: phenyl, oxamethane, σ, 洛洛洛, σ, pirinyl, σ, 嘻, imidazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, oxazolidinyl, pyridyl, pyrimidinyl, piperidine Base, piperazinyl or hydrazino. The compound of any one of claims 105-119, wherein Q in Ri is a bond. The compound of any one of claims 1 to 5, wherein Q1 is Q-R'. The compound of any one of claims 1 to 5, wherein q is present and the size is hydrogen. The compound of any one of claims 105-119, wherein Q is present and is converted to a C1-C6 aliphatic group. 124. The compound of claim 123, wherein R is decyl, ethyl, propyl or butyl. 125. The compound of claim 121, wherein W is hydrogen. 126. The compound of claim 121, wherein R is a C1-C8 aliphatic group substituted with up to three substituents selected from the group consisting of halo, CN, CF3, CHF2, OCF3 or OCHF2, wherein The C1-C8 aliphatic group to () more than two methylene units are optionally substituted with -CO-, -CONH(C1-C4 alkyl)-, -C〇2-, -oco-, -N ( C1-C4 alkyl)C〇2-,-0-, -N(C1-C4 alkyl)C0N(C1-C4 alkyl)-, -〇CON(Cl-C4 alkyl)-, -N(C1 -C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)_, N(C1-C4 alkyl)S〇2- or _N( C1-C4 alkyl)S02N(C1-C4 alkyl)-. 127. The compound of claim 121, wherein R is a 3-8 member having 3 hetero atoms independently selected from nitrogen, oxygen or sulfur. Saturated, partially unsaturated or not completely I# saturated monocyclic, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2 or ChC6 alkyl, wherein the C1- Up to two indenylene units in the C6 alkyl group are optionally substituted with -CO-, -C0NH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)C0N ( C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, _N(C1_C4 alkyl)CO-, -S-, -N(C1_C4 alkyl)-, -S02N(C1-C4 alkyl) -, N(C1_C4 alkyl)S02- or -N(C1-C4 alkyl)S02N(C1-C4 alkyl)-. 121775.doc -24- 200813019 128. The compound of claim 121, wherein R is An 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 〇-5 independently selected from nitrogen, oxygen or sulfur, wherein R' is optionally selected from the group consisting of halo, CN, CF3 Substituted with a substituent of CHF2, 〇CF3, OCHF2 or a C1-C6 alkyl group, wherein up to two methylene units in the C1-C6 alkyl group are optionally substituted with _CO_, _CONH (Cl-C4 alkyl)-, _C〇2-, -0C0-, -N(C1-C4 alkyl)C(V, -〇-, ·Ν(€η-[4 alkyl)C0N(C1-C4 alkyl)-, -OCON( Cl-C4 alkyl)_, -N(C1-C4 alkyl)CO-, -S-, f&quot; -N(C1-C4 alkyl)-, -S02N(C1-C4 alkyl)-, N( C1-C4 alkyl)S02- or -N(C1-C4 alkyl)S02N (C1-C4 alkyl ° 129. The compound of claim 121, wherein two of the R's are formed together with the atom to which they are bonded 0-4 independent choices a 3-12 member-saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring, optionally substituted with a hetero atom of oxygen or sulfur, wherein R1 is optionally selected from the group consisting of a dentate group, CN, CF3, CHF2 Substituting a substituent of hydrazine CF3, OCHF2 or ChC6 alkyl, wherein up to two methylene units in the Cl-C6 alkyl group are optionally substituted as _CO_, alkyl)-, _C02-, _OCO_, - N(C1-C4 alkyl)C02-, -〇-, -N(C1-C4 alkyl)CON(Cl-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(CM- C4 alkyl)CO-, -S-, -N(C1_C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1-C4 alkyl)S02• or _N(C1-C4 alkyl ) S02N (C1-C4 alkyl)-. 130. A compound selected from Table 1 or Table 1A. A pharmaceutical composition comprising a compound according to any one of claims 1-130 and a pharmaceutically acceptable carrier, adjuvant or vehicle. 121775.doc -25- 200813019 further comprising additional treatment 132. The pharmaceutical composition of claim 131, the agent 'dosing, preventing, improving, controlling or alleviating the words of the subject, dying, licking, 1. "or headache; migraine; clustering k-type pain, neurogenic inflammation, eye pain; toothache; diabetes; a variety of symptoms or diseases; headache; chronic tension headache; pain and inflammatory pain; Sexual pain :: Island-dependent diabetes; vascular disease; inflammatory hyperglycemia, asthma; shock; sepsis; sputum withdrawal syndrome y, Ma Fei Naiwen; hot flashes of men and women; allergic dermatitis; encephalitis; Trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic skin redness, skin rosy and red therapy; tinnitus; inflammatory bowel disease, large intestine &amp; or cystitis 'This method involves the examination of the need A compound that is administered, or a pharmaceutically acceptable composition comprising the compound. 134. The method of claim 133, wherein the method is for acute or prophylactic treatment of headaches, including migraine and cluster headaches. 135. The method of claim 133 or 134, further comprising additional agents. 136·If you ask for an item! The method of 3, wherein the additional agent is selected from the group consisting of an anti-inflammatory agent, an analgesic or an anti-migraine agent. The method of claim 136, wherein the additional agent is selected from the group consisting of an interleukin inhibitor, an NK-1 receptor antagonist, an NMDA antagonist, an NR2B antagonist, a bradykinin-1 receptor antagonist, and adenosine A1 receptor agonist; sodium channel blocker, opioid agonist, lipoxygenase inhibitor, alpha receptor antagonist, alpha receptor agonist, vanilloid receptor antagonist, mGluR5 efficacies 121775 .doc -26- 200813019 Agents, antagonists or potentiators, GAB AA receptor modulators, smoke antagonists or agonists, muscarinic agonists or antagonists, selective serotonin reuptake inhibitors, Tricyclic antidepressants, leukotriene antagonists, nitric oxide inhibitors or inhibitors of nitric oxide synthesis. 138. The method of claim 135, wherein the additional agent is selected from the group consisting of ergot biopsies. 139. The method of claim 135, wherein the additional agent is selected from the group consisting of a p-adrenergic* antagonist, a MAO inhibitor, a calcium channel blocker, an anticonvulsant, an angiotensin 11 antagonist, angiotensin Invertase inhibitor or botulinum toxin type 8. 140. The method of claim 135, wherein the additional agent is selected from the group consisting of: a potentiator such as a coffee test; a Η2 antagonist; a decongestant; a cough suppressant; a diuretic; a prokinetic agent; or a sedative or non-sedative Sexual antihistamines. 121775.doc -27- 200813019 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the representative figure is simple: 8. If the case has a chemical formula, please reveal the best display. Chemical formula of the inventive feature: 121775.doc