TW200412948A - Therapeutic compounds - Google Patents

Abstract

Compounds of formula (I) are found to antagonise N-type calcium channels, wherein R1 to R4 are organic residues.

Description

200412948 Rose, description of the invention: [the technical field to which the invention belongs] The present invention relates to specific pyrazolidone, oxazolidinone, and imidazolidone derivatives' which can be used as inhibitors of N-type calcium channels. [Prior art] Fu Li ion channels have gradually been fully characterized and this is especially true for calcium channels. Voltage-controlled calcium channels are important components of the nervous system's function and they can emit pain signals. Today, seven sub-, (L, N, τ, 〇, p, Q, and R) 1 of these channels have been identified by borrowing neurons and non-neuronal cells_ expressed in various combinations (Perez_Reyes, E;. Schneider , Τ., Review of Drug Development II, 1994, 33, 295 · 318). These channels are now recognized as effective targets for pain treatment and can be used as neuroprotective agents (cox, B; Denyer, j c. Professional opinion on therapeutic patents, 1998, 8, 1237_125 ()). WO 99/6289 1 discloses unremarkable ketones and partial pitutanone compounds as potassium channel inhibitors. The neuropathic inhibitor is expected to be used in the treatment of cardiac arrhythmias, cell proliferative diseases, auditory system diseases, central nervous system modulation, motor dysfunction of the ganglia, lungs, blood, blood, blood, blood, blood, and pulse Thousands muscle contractility — disease. '[Summary of Content], the following has been found ---, a sense calcium channel pan-inhibitor. Accordingly, the present invention provides a compound of formula (I), or a ready-to-drug acceptable salt, for use in the manufacture of a medicine that can be used to treat or prevent a type 1 disease, a disease, or condition: 〇 R2 ^ 运 ’

Rly A 0), Y-R3 87682 200412948 where: Z is -S-, -S (0)-, -S〇2-, or _NR_, where R is fluorene, CrG alkyl, or -CCKCVCe alkyl); R is gas or Ci_c6 alkyl; R2 is hydrogen, fluorine or cvc6 alkyl; Y is-(CRy2n (CRy 丄, _ (cRu w2) m or-(CRy2) mA- (CRy2VX3- (cRy2) m, where: -p, m, and η are each independently an integer of 0 to 4; -A is an aryl group, a heteroaryl group, a carbocyclic group or a heterocyclic group; -χ3 is -0_, S_, -NR, or -S (0) _, _S02-, _0-C0_, -S-C0-, -NR -CO-, -CO-O-, -CD or CONR, where R is hydrogen, Ci-CVfe group, c2-c6 Diluted or c2_c6 alkynyl; _X4 is '-s ·, -nr'-, -s (0)-or -S02-, where R' is hydrogen, Cr c6 alkyl, c2-c6 alkenyl or c2-c6 Alkynyl; each is the same or different and is hydrogen, CVC6 alkyl, c2-c6 alkenyl, c2-C6 alkynyl, aryl or heteroaryl; R3 represents aryl, heteroaryl, heterocyclyl or Carbocyclyl; and R4 are:-Ci is a chemical bond, Cl_c ^ alkyl, c2_c6 alkynyl, or (^-(^ alkynyl);-when d is a chemical bond, Xi is a chemical bond and when Ci * Cl-c6 is When alkyl, C2-C6 alkynyl or C2_C0 alkynyl, Xi represents a chemical bond or -〇-, -S-, -NR'-, _s〇_, -S02-, _CO_, -C〇_S-, _C0_0 ·, _CO-NR, _, _S-C〇_, _〇_CO_, _NR, -CO_, _C0-〇-R ,, -C0-0_, _CO-87682 200412948 NR'm〇 ... -co O Rn co NRI, _c〇sine, r "c〇nr, 〇_CO-NR'- Or -NR'-CO-O-, where each R 'is the same or different and represents a gas, phenyl, Ci-C: 6 alkyl, (VC6fluorenyl or c2-C6 alkynyl and each R "is the same or Is different and represents Cl_c0 alkylene, (: arylene, or C2-C6 alkynyl; _Arl is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl * _Ra_, hetero, aryl_ Ra_ or carbocyclic ring * _Ra_, in which the alkylene group, the allenyl group or the C2_C6 block group;. The alkylene group, c: 2-C6 fluorenyl group or [2-(: 6 alkynyl group; -X2 is a chemical bond Or -0_, _s-, -NR,-, -SO-, -S02-, -CO-, -CO-S-, -C0.〇_, _c〇-NR1, jC〇 ... 〇c〇 ... (3), -c〇-〇m〇_, _co „c〇〇mR, _c〇_ NR,, -CO-NR, mNR,-, · N1 ^ 0; or 〇c〇NR, where each R is the same Or different and represents hydrogen, phenyl, Ci_C6fluorenyl, C2_C6fluorenyl or C2 _ (: 6alkynyl and each R "is the same or Is different and represents Ci_c6 alkylene, CrC6 alkylene or 02- (6 alkylene); and -C3 is CVC6 alkylene, c2_cdtfluorenyl or c2_c6 alkylene. As used herein (CVC6fe group or group is a straight or branched alkyl group containing fluorene to 6 carbon atoms +, such as Cl-C4 fluorenyl group or group. Examples of Ci_C4 alkyl group are methyl / ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, and tertiary butyl. The alkyl or group can be unsubstituted or substituted at any position. It is typically 'unsubstituted or carries i, 2 or 3 Substituents. For example, it may be substituted. Suitable substituents include aryl groups such as phenyl, aryl, Ci_6 alkyloxy, CVCA alkyl, _2, _Nh (Ci_C6 alkyl- which {6 烧 87682 200412948 Group) 2, halogen, cyano, nitro, -NHCCKCVCe alkyl), -c0-nh- (CVC6 alkyl), -feO-CKCrC ^ alkyl), and -0-CO- (CrC6 alkyl). Preferred substituents are aryl, halogen, CVC2methoxy, _nh2, _NH (Ci-yl) and aryl) 2 ', especially fluorine and meridian. The substituents on the alkyl group are typically themselves unsubstituted. As used herein, Ci-C6 alkynyl is linear or branched (31- (36 alkynyl). Typically it is (^ -0: 4 alkynyl such as methyl, ethyl, propyl, Isopropyl or n-butyl. The alkylene may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. For example, it may be unsubstituted. Suitable substituents include aryl groups such as phenyl, light group, Cl-C6 alkyloxy, Ci-C6 alkylthio, -NH2, _NH (Cl_C6 alkyl), _N (CVC6 alkyl) 2, sulphonate, cyanide Group, nitro, _nhco- (c "c6 alkyl), · 〇0-ΝΗ _ ((: v0: 6 alkyl), -CO-CKCVC6 alkyl) & _〇_CO- (Cl-C6 alkyl The preferred substituents are hydroxy, halogen, Cl-C2 alkoxy, -NH2, and (Ci_c2 alkyl) and -NCCrC2 alkyl) 2 ', especially fluorine and hydroxyl, most preferably fluorine. Alkyl The substituents above are typically unsubstituted by themselves. As used herein, a C2-C6 alkenyl or group is a straight or branched fluorenyl group containing 2 to 6 carbon atoms, such as a C2-C4 alkenyl or group. C2_c4 Examples of alkenyl groups are ethylene / n-propenyl and n-T allyl. There are _ double bonds. This double bond is typically in the α-position of the alkenyl group. It is branched and substituted. Typical groups. For example, it may be unsubstituted, hydroxyl, cvc6 alkoxyalkenyl, or the group may be unsubstituted. Or at any position j, it is unsubstituted or substituted with 1, 2 or 3 substituents. Suitable substituents include aryl groups such as phenyl, "87682 200412948, cvc6 alkylthio, _NH2,- ΝΗ (ίνί: 6 alkyl), -NCCVC ^ alkyl) 2, halogen, cyano, nitro, -NHCO- (CrC6 alkyl),-(: 0 .; «-((^-daggeryl) , -CO-CKCrC ^ alkyl) and -O-CCMCVCgalkyl). Preferred substituents are hydroxy, halogen, oxy, -NH2, -NH (CV C2fluorenyl), and -NCCrC: 2 alkylh, Especially fluorine and hydroxyl, the most preferred is fluorine. The substituent on the fluorenyl group is typically unsubstituted by itself. The CrC6 alkenyl group used herein is a linear or branched (: 2-(: 6 alkenyl group. Typical The above is a CrC4 alkynyl group such as acetylene, phenylene, or butylene. Typical alkenyl groups have only one double bond. This double bond is typically in the α-position of phenylene. Shen Yanji can be Wei Substituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. Preferably it is unsubstituted. Suitable substituents include aryl groups such as phenyl, hydroxyl, Cl_C6 alkoxy , Ci_C6 alkylthio, -NH2, _NH (CVC6 alkyl), -N (CVC6 alkyl) 2, halogen, cyano, nitro, -NHCO-dC ^ alkyl), -CO-NH ^ CVC ^ Alkyl), -CO-CKCi-Ce alkyl), and -O-CCKCi-Cs alkyl). Preferred substituents are hydroxy, oxon, Ci-C ^ alkoxy, _NH2, -Nl ^ CrC alkyl) and -N (Cl-C2 alkylh, especially fluorine and hydroxyl, most preferably fluorine. The substituent on the alkenyl group is typically itself unsubstituted. As used herein, a C2_C0 alkynyl or group is a straight or branched alkynyl group containing 2 to 6 carbon atoms, such as a CrC4 alkynyl or group. CVC: 4 Examples of alkynyl are ethynyl, propynyl, and n-butynyl. Typically alkynyl has only one reference bond. This reference bond is typically in the-position of the block. The fluorenyl or group may be unsubstituted Or substituted at any position. Typical 87682 -10-200412948 'It is unsubstituted or carries 1, 2 or 3 substituents. It is preferably unsubstituted. Suitable fluorenyl groups include aryl groups such as phenyl , Hydroxyl, Cl-c6 ^ oxy,

Ci_C6 alkylthio, _Nh2, alkyl), -N (0 ^ ί: 6 alkyl) 2, halogen, cyano, nitro, -NHCO- (CVC6 alkyl), -CO-NHJCVC ^^), -CO-O_ (Cl-C6 alkyl) and -0_CCKCl_C6 alkyl). The preferred substituents are hydroxy, glucone, C2C2alkoxy, _NH2, _nh (cvc2 alkyl), and N (C ^ C2k group) 2 ', especially fluorine and benzyl, and most preferably fluorine. The above substituents are typically themselves unsubstituted. As used herein, C ^ C: 6alkynyl is a linear or branched c: 2-C6alkynyl. In typical terms, it is a CyC4decynyl group such as ethylidene. Base, propylene block or butyl block. Typical upper block has only one parameter bond. This bond is typically in the α-position of the block. The block group can be unsubstituted or in any position. Substituted. Typically it is unsubstituted or has 1 or 2 substituents. It is preferably unsubstituted. Suitable substituents include aryl groups such as phenyl, hydroxyl, alkoxy, Ci-C ^ sulfur

Group, -nh2, _νη (< ^-(: 6 alkyl), alkyl) 2, _ prime, cyano, nitro, -NHCOJCrC ^ alkyl), -CO-NHJCVC ^ alkyl), -co -ckcvcv) and _0-C0_ (Cl_C6). The preferred substituents are per-radical, i-prime, (VC2alkoxy, -NH2, -NHCCi-Calkyl), and -N (C1-C2fluorenyl) 2, especially fluorine and hydroxyl, most preferably fluorine. The substituent on the alkenyl group is typically itself unsubstituted. As used herein, an aryl group is typically a CO_C1G aryl group such as phenyl or fluorenyl. Phenyl is preferred. Aryl may be unsubstituted or substituted at any position. It typically has 0, 1, 2, 3 or 4 substituents. Suitable substituents include functional elements, 87682 -11-200412948 CVC6 alkyl, CVC6 alkoxy, CVCVJ ^ thio, c3-c6 carbocyclyl, c3-C6 epoxybreaking oxygen, O3-C6 carbosulfanyl, C2 -C6 fluorenyl, C2-C6 fluorenyloxy, C2-C6 alkenylthio, C2-C6: l ^ yl, C2-C6 alkoxy, C2-C6 thio, hydroxy, -NH2, -NHCCi-C ^ Alkyl), -NCCVCs alkyl) 2, -SiCCi-CV ^) 3, cyano, nitro, -NH-CO-CCi-Cs alkyl), -CO-NHJCVC ^ alkyl), -CO -CKCVC ^ alkyl) and -0-C0- (CVC6alkyl). Examples of suitable substituents include halogen, CrCs alkyl, Ci-Cs alkoxy, cardio-dkanylthio, c3-c6 carbocyclyl, c3-c6 carboepoxy, c3-c6 carbosulfanyl, CVC6 Group, c2-c6: #oxy, c2-c6 sulfanyl, c2-c6 alkynyl, c2-c6 alkynyloxy, C2_c6 alkynylthio, hydroxyl, -NH2, -NHCCi-Ce alkyl), -NCCr C6 alkyl) 2, cyano, nitro, -NH-CCKCVC ^ alkyl), -CO_NH-((VC6 alkyl), -CO-CKCVC6 alkyl), and -O-CO-CCrCs alkyl). Preferred substituents include CrG alkyl, CrC * alkoxy, CrC * alkylthio, C5-C6 carbon epoxy, C2-C4 carbonyl, C2-C4 fluorenyl, halogen (such as fluorine), hydroxyl _NH2, -NH (CVC2alkyl), _N (CVC2alkyl) 2, -NH-CCHCVC2alkyl), cyano and -SiCCVC ^ alkyl) 3. Examples of preferred substituents include CVC4 alkyl, CVC4 alkoxy, alkylthio, c5-c6 carboepoxy, C2_C: 4 methoxy, 1¾ (such as fluorine), light group, _NH2 '-NHCCVC alkane Group), -N (CVC2 alkyl) 2 and _NH_c〇_ (Ci-c2 alkyl). The substituent on the aryl group is typically unsubstituted or substituted with 1, 2 or 3 other substituents selected from the group consisting of halogen, hydroxyl, oxy, Ci_C6 alkylthio, _NH2, -NHA-Cs alkyl ), _N (Ci_c6 alkyl) 2, -NH_c0_ (CVC6 alkyl), -co-nh- (cvc6 alkyl), _cn (Ci_c6 alkyl), and -O-CCMC ^ C6 alkyl). These other substitutions are essentially unsubstituted. It is better than 87682-12-200412948. The CrC6 alkyl group present on the other substituent is Cl-c2 alkyl group. Substituted tombs in Wanji are unsubstituted or substituted with 1, 2 or 3 as a southern or other substituent, preferably a _ group substituent. The relevant aryl groups used include those in which an aryl group is fused to a heterocyclic group or a heteroaryl f t fused ~ system, system 'is typically fused to a monocyclic heterocyclic or heteroaryl group. This thick mouth system is a phenyl ring fused to a pyridyl group to form an isoquinolinyl group and a 5 or 6-membered heterocyclic ring that is fused to ^ to 2 or ◦ and S. Phenyl, such as fused to 丨, 4-dioxocyclohexyl ring to form 1,4-benzene: benzodioxo-cyclohexyl phenyl ring, fused to 丨, 3-dioxopentyl group A phenyl ring of 3-benzodioxycyclopentyl and a phenyl ring fused to a tetrahydrofuranyl ring to form a 2,3-dihydrobenzofuranyl group. As used herein, a heteroaryl group is typically a 5- to 10-membered aromatic ring containing at least one heteroatom, such as 1, 2, or 3 heteroatoms selected from 0, S & N, such as a 5- or bifurcated ring. . The examples include pyridyl, pyridyl, pyrimidinyl, daphnyl, furanyl, phenphenyl, imidyl, η-synthetic group, late rocky, cylinyl, isopropyl group, p-base A η sitting base, far spit base and E Junji. TT is preferred over yttrium, succinyl, thienyl, imidazolyl, and pyrrolyl. Heteroaryl may be unsubstituted or substituted at any position. It typically carries 0, 1, 2 or 3 substituents. Preferably, it is unsubstituted. Suitable substituents include halogen, (VC6 alkyl, CVCV ^ oxy, CVC6 alkylthio, C3-C6 %% group, C3-C6 carboepoxy, C3-C6 carboepthio, C2-C6 alkenyl, C2- C_oxy, c2-C6 alkenylthio, c2-c6 alkynyl, c2-c6 alkynyloxy, C2-c6 alkynylthio, hydroxyl, -NH2, -NHCCrCs alkyl), alkyl) 2, cyano , Nitro,-> ^ _ (: 〇_ (0: 1-(: 6 alkyl),-(: 〇-: ^ 11-((: 1-(: 6 87682 -13- 200412948 alkyl)) , -CO-〇- (C "c6 alkyl) and _〇_c〇jCi_c6 alkyl). Preferred substituents include Ci-C4fe ~, alkoxy, C1-C4 thio, C5-C6 carbon Epoxy group, C2-C4 alkoxy group, _ element (such as fluorine), hydroxyl group, -NH2, _NH (c "c2 alkyl), _N (CVC2 alkyl) alkyl). Particularly preferred substituents include < ^ -(: 4 alkyl and halogen atoms. Substituents on heteroaryl groups are typically unsubstituted or substituted with 1, 2 or 3 other substituents selected from the group consisting of: halogen, hydroxy, 〇1_〇6 Oxygen, Ci_c6 thiol, _NH2, _NH (CVC6 thiol), -NA-Ce thiol, 2, _Jan-CCKCVC6 thiol), _C0_nh (Ci C6 thiol), _c〇〇_ (Ci_C6 thiol) ) And -〇-CO- (cvC6 alkyl). These other substituents are typically unsubstituted by themselves. Preferably, the Ci_c6 alkyl group present on the other substituent is a ^ _02 alkyl group. More preferably, the substituent on the heteroaryl group It is unsubstituted or substituted with one, two, or three other substituents which are halo substituents, preferably the substituent on the heteroaryl group is unsubstituted. As used herein, the related heteroaryl group includes a heteroaryl group which is thick A fused ring system bonded to the aryl, other heteroaryl or heterocyclic group is typically fused to a monocyclic aryl, other heteroaryl 4 heterocycle I. An example of this fused heteroaryl is fused to Benzene%, especially peryl, includes benzimidazolyl, benzofuranyl, quinolinyl, and isoquinolyl. The gray ring group used herein is a non-aromatic saturated or unsaturated hydrocarbon ring, typically having 3 to 6 branches Atoms. For example, it may be a saturated hydrocarbon% (ie,% k group) containing 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl or it may have 1 or 2 Hydrocarbon ring, preferably 丨 double bonds. An example is cyclohexyl. A preferred carbocyclyl is cyclopentyl. 87682 -14- 200412948 Carbocyclyl may be Substituted or substituted at any position. Typically it carries 0, 1, 2, 3 or 4 substituents. Suitable substituents include halogen, Cp C6 alkyl, Ci_C6: feoxy, Ci-C6 sulfur Group, C3-C6 cyclohexyl group, C3-C6 carboepoxy group, C3-C6 carbosulfanyl group, C2-C6 fluorenyl group, C2-C6 fluorenyl group, C2-c6 fluorenylthio group, C2-C6 block group , C2-C6 block oxy, C2-C6 fast thio, aryl, C, C4 alkylene dioxy, -NH2, -NHCCrC ^ alkyl), _N (CVC6 alkyl) 2, cyano, nitro , -NH-CCKCVC ^ alkyl), -CO-NH_ (CV c6 alkyl), -CO-CKCrC ^ alkyl) alkyl). Preferred substituents include CVC4 alkyl, CrCU alkoxy, Cl_cv ^ thio, c5-c6 < epoxy, CVC4 晞 oxy, dentin (such as fluorine), hydroxyl, · Nη2, -Nl ^ Ci-C ^ Alkyl), -NCCrCaalkyl) alkyl). Preferably the carbocyclyl is unsubstituted. The substituents on the carbocyclyl are typically unsubstituted or substituted with 1, 2, or 3 other substituents selected from the group consisting of: _ prime, hydroxyl, c "c6 alkoxy 'Ci_C6 thiothio, _NH2,- NHCCVC6 alkyl), -na-Cg alkyl) 2, -NH-CCKCVC6 alkyl), _co_nh_ (Ci-C6 alkyl), _c〇〇 (Ci_C6 alkyl), and -O-CC ^ Ci-C6 alkyl ). These other substituents are typically unsubstituted by themselves. Preferably, the C6 alkyl group present on the other substituents is an alkyl group. More preferably, the substituents on the carbocyclic group are unsubstituted. The heterocyclic group used is typically a non-aromatic, saturated or unsaturated C5_C1G carbocyclic ring in which one or more, for example, one, two, or three fluorene atoms, are replaced by a heteroatom selected from N, O, and S. Saturated hetero A cyclic group is preferred. Examples of suitable heterocyclic groups include piperidinyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolyl, 1, oxodicyclohexyl, and i, 3 • dioxopentyl Tetrahydrofuran 87682 • 15- 200412948 group, pyrrolidinyl, 1,4-dioxocyclohexyl and 1,3-dioxocyclopentyl, especially tetrahydrofuranyl, i, 4-dioxocyclohexyl And dioxoyl, preferably $ 14. Dioxoyl. Heterocyclyl can be unsubstituted or substituted at any position. Typically T has 0, 1, 2, 3 or 4 substitutions Suitable substituents include halogen, C-C6 alkyl, Cl_c ^ oxy, Cl_cv ^ thio, 0 < 6 carbocyclyl, stone transepoxy, CrC6 carbosulfanyl, CrC6 alkenyl, c2- c6 alkenyloxy, c2_ C6 alkenylthio, c2_c6 alkynyl, c2_c6 alkynyloxy, C2_C6 alkynylthio, fluorenyl, α _ (: 4 elongation dioxy, · νη2, _nh (Ci_c6 alkenyl), 氺% % Alkyl) 2, cyano, nitro, _NH-CO_ (Cl-C6 alkyl), -CO_NH_ (cv C6 alkyl), _CO_〇_ (Cl-C6 alkyl), and -〇_co_ (CVC6 Alkyl). Preferred substituents include cvcu alkyl, CVC4 alkoxy, (: ^ alkylthio, c5_c ^ alkoxy, c2-c4 alkoxy, _ prime (such as fluorine), hydroxyl, _NH2 , -NHCCi-C ^ alkyl), -NCCVC] alkyl preferably heterocyclic group is unsubstituted.

The substituents on the heterocyclyl are typically unsubstituted or substituted with one, two, or three other substituents selected from: halogen, hydroxyl, Ci_C6 alkoxy, Ci_C6 alkylthio, _nh2, _NH (CVC6 Alkyl), _n (Ci-c6 alkyl), _nh_ CCKCVC6 alkyl), _C0-NH_ (CVC6 alkyl), -CO-CKCVCA group) and -O-COjCi-C6 alkyl group). These other substituents are typically themselves unsubstituted. Preferably, the C1-C6 alkyl group present on the other substituent is a ^ _02 alkyl group. More preferably, the substituent on the heterocyclyl is unsubstituted. As used herein, related heterocyclyls include fused ring systems in which the heterocyclyl is fused to the aryl, the heteroaryl, or other heterocyclyl, and is typically fused to a single ring 87682 -16-200412948 aryl, hetero Aryl or other heterocyclyl. Preferably, the fused ring system is a heterocyclic group fused to a benzene ring. — An example of this fused heterocyclyl is 1,4.benzodioxocyclohexyl. The nanin used in the production of this text is typically chlorine, 1, bromine or kiln and preferably chlorine or fluorine. As used herein, a fluorenyl, alkenyl, alkynyl, or carboepoxy group is typically the alkyl, alkenyl, fluorenyl, or carbocyclyl group attached to an oxygen atom. Alkylthio, alkenylthio, alkynylthio, or carbosulfanyl groups are typically the alkyl, fluorenyl, bulk, or carbocyclyl groups attached to a sulfur atom. When 2 is _ dish-, it is typically -COCH3 or _co_ch2_c; h3. Typically, Z is -S-, -so-, or -0. For example, z may be -s_ or _〇_. Better 2 is _8_. Typically, I is hydrogen or unsubstituted C1-C4 alkyl. Preferably, R1 is hydrogen or • CH3. Better R! For hydrogen. Typically, R2 is hydrogen or unsubstituted Ci_C6 alkyl. Preferably, r2 is hydrogen or unsubstituted CpC: 4 alkyl. More preferably, r2 is hydrogen. Typically, each Ry is the same or different and is hydrogen, CrQ alkyl, aryl, or heteroaryl. It is preferred that each Ry is the same or different and is hydrogen, 0 <4 alkyl or phenyl. Preferably each 1 ^ is the same or different and is hydrogen, _CH3, -CH2_CH3 or an unsubstituted phenyl group. Typically, when two or more Ry groups are present, no more than two, preferably no more than one, the Ry group is an aryl or heteroaryl group. Typically, each Ry is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: "C4 alkyl, CrC4 alkoxy, halogen, hydroxyl, nh2, NH (Ci-C2fe group) or N (Ci-C2 alkyl group h. Preferably, the substituent on Ry is selected from the group consisting of CKC2 alkyl, CirC2 alkoxy, halogen, and hydroxyl. Typically, the substitution on R / is essentially unsubstituted. Better Ry is unsubstituted. A is typically a square group such as a winter group, or a heteroaryl group such as p-pyridyl, sulfanyl 87682 -17- 200412948, far-phenyl, imidazolyl or pyrrolyl, especially pyridyl, , Sedenyl or pyrrolyl. Preferably A is phenyl, pyridyl, thienyl or pyrrolyl, for example a is phenyl, pyridyl or pyrrolyl. Preferably A is heteroaryl, especially pyrenyl or Pyridyl. Pyridyl is preferred. The A group is typically unsubstituted or substituted with 1, 2, or 3 substituents. The A is preferably unsubstituted. The substituent on a is typically selected from Ci -C4 alkyl, C "C4 alkoxy, halogen, hydroxyl, nh2, NK ^ CrC2 ^) or N (Ci-C2alkyl) 2. Preferably, the substituent on a is selected from Ci-C2alkyl Base, CrC2 alkoxy, halogen and In the X3 group, R 'is typically hydrogen or an unsubstituted Cl_c6 alkyl group, preferably dihydro or -ch3, and most preferably Hydrogen. Typically, 乂 3 is -0_, -S-, -s〇_, _s〇2_, -O-CO-, -co-o-, -NH-CO-, or -CO-NH-. Better x3 is -S-, -SO-, -S02 ·, or -NH-CO-, more preferably -0-, _s〇2-, or -NH-CO ·. Typically, p is 0 or 1, and more preferably 〇. Typical ㈤ is 0 or i. Typically 11 is i or 2, preferably 1. In the X4 group, R is typically hydrogen or unsubstituted Cl_c6 alkyl group, preferably ~ hydrogen or -CH3 , Preferably hydrogen. Typically, 4 is _〇_, _8_, or _ dish, ·, where R 'is as defined above. Preferably, 4 is _〇- or _8 ... more preferably 1 is _ 〇_. Among them, Ry, A, x3, 1.1 and 11 are as defined above. More preferably γ is formula A. R3 is typically an aryl group, a heteroaryl group or a carbocyclic group. Preferably, when R3 is an aryl group 'It is a phenyl group or a phenyl group fused to a heteroaryl group or a heterocyclic group. An example of this fused ring system is fused to a group of 5 to 6 having 1 or 2 heteroatoms selected from 0, s and N -Membered heterocyclic phenyl. This fused ring system A preferred example is 丨, 3_benzobis, 87682 -18- 200412948 oxypentyl 2,3-hydrobenzofuran, and when substituted for aryl i, it is phenyl, 13_benzo Di-hexyl. Compared with -air depletion i £ d earth bucket, winter, a lactocyclopentyl, 2 3: lice benzofuran or M_benzodioxycyclohexyl, preferably benzyl or 13Ϊ When it is a heterologous group, it is preferably a tonyl group, a phenol group, a sulphone group, or an external group; or each of the groups, or a heteroaromatic group of s 4 77 -4 @ m β A basic ring such as quinolyl, quinolinyl, or benzo. Main, such as when tR3 is heteroaryl, its m furanyl, pyrrolyl, or fused to a phenyl group with a heterocyclyl per example , Isojunlinyl or benzodiazepine. Good, when R3 is heteroaryl, 'it may be pyridyl' sedenyl, furyl, fenyl, or benzoanyl such as sulfanyl, ranyl, such as linyl or benzoan When R3 is a heteroaryl group, it is preferably an edendyl group or a thiophene group. When R3 is a carbocyclic group, it is preferably a cyclopentyl group or a cyclohexyl group, and most preferably a cyclopentyl group. More preferably, R3 is a phenyl K group, a 4 phenyl group, a sulfanyl group, a quinuclyl group, a benzocranyl group, a cyclopentyl group, and a benzo: oxycyclohexyl group, a M benzodioxy group Cyclopentyl or 2,3-dihydrobenzofuranyl. For example, R3 may be phenyl, fluorenyl, furanyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzodioxycyclohexyl, 1,3-benzodioxycyclopentyl, or 2,3_dihydrobenzofuranyl. Preferably R3 is phenyl, 1,3-benzodioxycyclopentyl, pyridyl or pyrenyl. 'R3 is typically a group other than a thio group. 'R3 is typically unsubstituted or substituted with 1, 2 or 3 substituents. This substituent is typically selected from halogens such as fluorine, chlorine or bromine, mesityl, cyano, Ci-C6 alkyl, CVC6 alkyl, Cl-c6 alkylthio, c2-c6 alkenyl, C2-C6 alkenyl Oxy group, c2-c6 sulfanyl group, c2_c6 alkynyl group, c2_c6 alkynyl group, C2-C6 alkynyl group 87682 -19- 200412948 group, CrC6 carbocyclyl group, C3-C6 post-epoxy group, C3-C6 carbosulfide group Group, -NH-C〇_ (Ci-C6 alkyl), -C0_NH- (Ci_c6 alkyl), -NR, R "(wherein R, and R" are each independently hydrogen or Cl-C: 6 alkyl) And _Si (Rf, ') 3 (wherein each R "is independently Cl-C4 alkyl). For example, the substituent may be selected from halogen such as fluorine, chlorine or bromine, hydroxyl, alkyl, Ci_c6, ^ oxy, Ci_c6 ^ thio, C2_C6fluorenyl, C2-cv ethoxy, C2_C ^ thio, c2_C6 alkynyl, € 2_6alkynyloxy, c2-c6 block thio, (: 3_〇6 carbocyclyl , C3_c6 carboepoxy, c3_c6 carbosulfanyl, -NH-C0- (Cl-C6 alkyl) ... c0-nh- (Ci-C6fluorenyl) and -NR'R "(wherein R, and R "are each independently fluorene or Ci_C6 alkyl). Preferred substituents on R3 are halogen, hydroxyl, Ci_C4 alkyl, Crq alkoxy, CVC4 alkylthio, C2_C4 fluorenyl, _NR, R ,, (where & Amp, and Rn are each independently hydrogen or eve: 4 alkyl) and -Si (R ",) 3 (where each R &quot; is independently alkyl). Examples of preferred substituents on R3 are halogen, Ci_C4 alkyl Group, Ci_C4 alkoxy group, CVC4 alkylthio group, c2-c4 alkenyl group, 〇2_〇4 alkenyl group, C3_C6 carbocyclyl group, C3-C6 cycloepoxy group, _nh_C0_ (Ci_c2 alkyl group), and _N ( Ci_c2 alkyl) 2. Examples of better substituents on R are halogen, cyano, Ci_C4 alkyl, cvc4 alkoxy, Cl-C ^ thio, C2-C4 alkenyl, C2_C4 alkoxy, ^ C6 carbon Roxy, -NH_CO-Me, -N (CH3) 2, and Si (R &quot;) 3, where each R, &quot; is independently a CrC4 alkyl group. An example of a better substituent on R3 is halogen ,. (Vc4alkyloxy, Cl_C4 ^ thio, C2-C4oxy, CrC6 carboepoxy, _NH-CO-Me &amp; _N (CH3) 2. Typically, the substitution on R3 is essentially unsubstituted Or it is substituted with other substituents selected from the group consisting of i element, especially fluorine and hydroxyl. Typically, Cl is a chemical bond or a q-C6 alkylene group, preferably a * Ci_C4 alkylene 87682 • 20- 200412948 group. . Better (^ is a chemical bond or unsubstituted CrC4 alkylene, such as Replace it with ^-^^ 烧 基. Preferably, C! Is a chemical bond, -CH2_,-(ch2) 2-,-(CH2) 3-, or-(ch2) 4-. For example, c ^ -CH2-, _ (CH2) 2_4_ (ch2) 3-. For the avoidance of doubt, the orientation of the X1 base is from the left-hand side of the base to the heart and the right-hand side of the base to Ari. Therefore, when X ^ -S-CO-, -CV XrAi ^ -Ci-S-CO-Ar !. Each R | in the 'Xi group is typically the same or different and is hydrogen or an unsubstituted phenyl SCVC6 alkyl group, preferably hydrogen, -CH3 or -CH2-CH3 :. More preferably, each R 'in the Xi group is hydrogen. Typically, each R "in the 1 group is an unsubstituted Cl-c6 alkylene group, preferably _CH2_4_CH2_CH2-. More preferably, each R '· is _CH2-. Typically, Xi is a chemical bond or _〇_, -S_, -NR'_, -S-C0_, -0-C0-, -C0_0_, _CO-S_,-丨 丨 -⑶- or _C〇_NRf_, where r is as defined above. Better X! Is a chemical bond or -0-, -S-, -S-CO-, -O-co-, or -NH-CO-. More preferably, Xi is a chemical bond or -〇-, -S-, -S_CO_, -O- CO-. Preferably, Xi is a chemical bond or _0- or _8-. Typically, Ari is heteroaryl, heterocyclyl, aryl, carbocyclic, heteroaryl- (CVCe alkyl)-, Heterocyclyl- (Cl-C6 alkyl)-, aryl-((^-fluorenyl)-or s-transyl-(-((1; 1- (1; 6-alkyl))-. When Ari is Heteroaryl_ (Ci_C6alkyl)-, ♦-(Ci-C6: fe group)-, heterocyclyl group)-or carbon edge group-([1-.6 pit group, the alkyl part is typical It is unsubstituted methyl or ethyl. Preferred Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl- (Ci-C2 alkyl)-or aryl- ( Ci-q alkyl). More preferably, Ari is heteroaryl, heterocyclyl, aryl, ashyl or heteroaryl- (c 1-C 2 )-, Such as heteroaryl, heterocyclyl, square or heterosquare- (C1-C2 alkyl). When Ari is heteroaryl 'it's better 87682 -21 · 200412948 di =, phenyl or benzene It is preferably a phenyl group. When _ is a 1 1C2 alkyl group), it is preferably pyrenyl-methyl-, pyridyl-methyl-methyl-methyl- ', more preferably furanyl- Methyl-. Known as heterocyclic two; :: Why. F, Paiji "Chenyi group or one group or fused" &quot; Maipu soil Chengyi 5 · or 6_ Bayer heterocyclic group 'for example 1,4-benzodioxocyclohexyl or oxo-, oxocyclopentyl. More preferably, when '&amp; 14 heterocyclyl, it is preferably tauronyl, or' It is bisdioxocyclohexyl. The present invention —Specific Example T, when it is known as a miscellaneous material, it is not a heterocyclic ring containing Cl bonded by nitrogen atom. When Afl is aryl ', it is preferably phenyl or fused to 5_ or 6_ A membered heterocyclic phenyl group such as 1,3-benzodioxycyclopentyl or M benzodioxycyclohexyl. More preferably, when Ar is an aryl group, it is phenyl or benzodioxycyclopentyl When ^ is transmethyl, it is typically an unsaturated or saturated hydrocarbon ring containing 3 to 8 carbon atoms, such as 3 to 6 carbon atoms. When Ari is a carbocyclic ring , Which is preferably c3_c8 ',' preferably C3_C6J fluorenyl or cyclohexyl. Typically, when c1 &amp; x1 each represents a chemical bond, Ari is a heteroaryl, heterocyclyl, or carbocyclyl, wherein the hetero Aryl, heterocyclyl, and carbocyclyl typically have the aforementioned definitions of Aq groups. Typically, ATi * is unsubstituted or carries one or more, e.g., 1, 2, or 3 substituents on a cyclic group. The substituent is typically selected from the group of elements such as fluorine or chlorine, CiAfe, meridian, CVC4oxy, -NR, R, and _NH-C0-R, where R 'and Rn are the same or different And is selected from hydrogen and unsubstituted Ci_c4 environment group. Fortunately, the substituents of the father are fluorine, benzyl, methoxy, dimethylamino and CO-CH3. The substitution on the 'Ar 1 base is typically unsubstituted. More preferably, An is unsubstituted pyridyl, pyrrolidinyl, benzo-benzodioxy 87682-22-200412948, cyclopentyl or cyclohexenyl, unsubstituted C3-C6 cycloalkyl, or unsubstituted Or phenyl substituted by 1, 2 or 3 substituents selected from halogen, Cl_c4 alkyl, C2-C4 alkenyl, CrC4 alkoxy, Ci-CU alkylthio and _N (CH3) 2 substituents, The substitution on 8 1 ^ is basically unsubstituted. Typically, alkylene is preferably (^-(: 4 alkylene). C2 is typically unsubstituted or substituted with one or two substituents selected from hydroxyl and fluorine, especially fluorinated. For example C2 is unsubstituted. For the avoidance of doubt, the orientation of the X2 group is the left-hand side of the indicated base is bound to (^ and the right-hand side of the base is not bonded to C3. Therefore, for example, when &amp; is _N_c (&gt; 〇_, then the group C2-X2_c3 is -c2-N-C0-0_c3-. Each R in the X2 group on octa is the same or different and is argon or unsubstituted Ci (: 6 alkyl or phenyl, Preferably, it is hydrogen, _CH3 or · CH2CH3. More preferably, each R 'in the group is hydrogen. Typically, each R &quot; in the x2 group is unsubstituted Ci_c6 alkylene group, preferably _ (:: 112_ or _ (: ^ 2 (: 112. More preferably, each R &quot; is. On eight soils, the χ2 series of chemical bonds may be _〇_, _s_, S-, -C0-0_, _co_NR, _, _S_C0_, _〇_c〇 ... _NR | _c〇_, _〇_ co-nr, ... nr, _Cq_◦ ... s_⑺ or ⑶_s, where R is as defined above. Preferably, X2 is a chemical bond or _〇_, _S_, _c〇〇, 〇c〇 , Each ⑺ ... C0 each or _NH_C0_0_. Preferably, χ2 is a chemical bond or 〇_, -m〇_ or _NH_C0_0_, For example, X2 is a chemical bond or _〇_, each, -CO-0- or -NH-CO-O-. Its: r C3 is a fluorenyl or M fluorenyl group. Preferably. 3 is a sulfonyl or alkynyl group , Such as Cl_C4 @ group. The μ type is unsubstituted or one or more such as 丨, 2 or 3 selected from hydroxyl, _NHp entertainment 87682 -23-200412948 group), -N (Ci-C2 alkyl) 2 And halogen substituents, preferably light and halogen. C3 is unsubstituted or on the primary carbon (that is, the carbon atom at the end of the chain) with (a)-a radical or (b ) 1, 2, or 3 substituents, which are preferably fluorine substituents. The substituents on C3 are typically unsubstituted by themselves. In a specific example of the present invention, X2 is a group other than -NRf-. Therefore χ2 Typically a chemical bond or -0, -8 ,,-(1; 0-,-(110-8-,-(11〇-〇_,-(30 ^ 11,-, -S-CO-, _〇 -CO_, -NRf-CO_, -0-C0_NR, _NR, _CO-〇-, -S-C0-, or -CO-S-, where R 'is as defined above. In this specific example, a C3 With substituents NR, R ", where R, and R" are each independently hydrogen or Cl-C6 alkyl. Therefore, C3 is typically (: "0: 6 alkyl or c2-c6 alkenyl, each of which is take Or substituted by one or more substituents such as 1, 2 or 3 selected from the group consisting of hydroxy and ¾. Preferred compounds of formula (I) and their prodrugs and their pharmaceutically acceptable salts are: Z is -S- , -SO-or -0-for example or -0;

Ri is hydrogen or unsubstituted Ci-C # alkyl; R2 is hydrogen or unsubstituted alkyl; Y is-(CRy2) m-X4- (CRy2) n •,-(CRy2) mA- (CRy2) m- or _ (CRy2) m-A_ (CRy2) p_X3- (CRy2) m, where-each 1 ^ is the same or different and is hydrogen or unsubstituted alkyl or phenyl; A is aryl or hetero Aryl is unsubstituted or substituted with 1, 2 or 3 selected from unsubstituted CVC4 alkyl, CVC4 alkoxy, halogen, hydroxyl, NH2, 87682-24-200412948 NHCCVC2 alkyl) and N (〇ν (: 2 alkyl) 2 substituent substitution; -X3 is -0-, -S-, -SO-, -S02-, -0-C0-, -CO-0-, -NH-CO- or- CO-NH-; -X4 is -O-, _s- or -NR'- where R is hydrogen or -Ch3; -ρ is 0 or 1; m is 0 or 1 and η is 1 or 2; R3 is aromatic Group, heteroaryl or ring-forming group, which are unsubstituted or substituted with 1, 2 or 3 members selected from halogen, hydroxy, cyano, CVC6 alkyl, CVC6 alkoxy, CV C6sulfanyl, C2-C6 Androyl, C2-C6 alkoxy, C2_C6 alkenylthio, C2, C6 bulk, C2-C6 alkynyloxy, c2-C6 alkynylthio, C3_C6 carbocyclyl, C3-C6 carboepoxy, C3-C6 Carbosulfanyl, _NH-CO_ (CVC6 alkyl), _CO_NH- (CVC6 alkyl), -NR'R "( Wherein R and R "are each independently hydrogen or Cl_c6 alkyl) and -Si (R" ') 3 (wherein each R ", independent alkyl) are substituted with substituents, and the substitution on r3 is essentially unsubstituted or And substituted by 1, 2 or 3 other substituents selected from the group consisting of hydrogen and hydroxy; R4 is where: -Cl is a chemical bond or unsubstituted (^ -0: 4 alkylene; -tC! Is a chemical bond) Is a chemical bond and when Ci is an unsubstituted Ci_c4 ak group, 'Xi is a chemical bond or _〇_, -S-, _nR,-, _S-CO-, -0-CO_ ... CO-O-, _co_s— _NR _C0 or _C0, where r is hydrogen or unsubstituted phenyl or Cl_C6 alkyl;-^ is heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl_ (c "C2 alkynyl is unsubstituted or has 1, 2 or 3 cyclic groups selected from the group consisting of halide, CVC4 alkyl, hydroxyl, Cl-c4 alkoxy, _NR, R, or _NH_C0- R (where R, &amp; Rn is the same or different and is selected from the group consisting of hydrogen and CpCU alkyl group) 87682 -25- 200412948 group substitution;-^ 'CrC4 alkylene group, which is unsubstituted or one or two selected Substituted from hydroxy and fluorine substituents; -X2 is a chemical bond or -O-, I, _NR, ..._ c ..._ cc) _s, ⑶4, -CO-NR,-, -S-CO-, -ο-co ... tear, _c〇〇〇〇NR, -NR'-CO-O-, -S-CO- or- CO-S ... where R is chlorine ~ CH4-Ch2-ch3; and _ (: 3 is CVC4 alkyl or CyC4 alkenyl, each of which is unsubstituted or via iv 2 or 3 selected from hydroxyl, -NH2, _Nh (Ci_c2 alkyl), _N (Ci_c2 alkyl) 2 and halogen substituents. Still more preferred compounds of formula (I) and their pharmaceutically acceptable salts are: Z is -S- or; R 1 is gas or unsubstituted C 1 -C 4 alkyl; R 2 is hydrogen or unsubstituted Base;-(CRy2) mA- (CRy2) m- or Y is-(CRy2) m-X4_ (CRy2) n-,-(CRy2) mA- (CRy2) p-X3- (CRy2) m, where- Each Ry is the same or different and is fluorene or unsubstituted C "C4 alkyl or phenyl; -A is aryl or heteroaryl which is unsubstituted or i, 2 or 3 selected from unsubstituted Ci-cu alkyl, eve: 4 alkoxy, halogen, hydroxy, NH2, NH (CVC2 alkyl) and N (Cl_C2 alkyl h substituents; -x3 is -0-, -S-,- so ...- S〇2 ... do c〇 -... C0-0 _NH-CO- or -CO-NH-; 87682 -26- 200412948-X4 is -0 ·, _S- or -NR '· where R' is hydrogen Or _ch3; _p is 0 or 1; m is 0 or 1 and η is 1 or 2; R3 is aryl, heteroaryl or carbocyclyl, which is unsubstituted or selected from i, 2 or 3 Halogen, hydroxyl, q-C6 alkyl, cvc6 alkoxy, Cl_C6 alkylthio, c2-c6 fluorenyl, C2-C6 fluorenyl, C2-C6 thiothio, C2-C6 ^: radical, C2-C6 Alkynyloxy, c2-c6 alkynylthio, (33-(: 6 carbocyclyl, c3-C6 carboepoxy, c3 -c6 carbosulfanyl, -NH-CC ^ CrC ^ alkyl), -CO-NHJCVC ^ alkyl) and -NR'R "(wherein R 'and R" are each independently hydrogen or Cl_c6 alkyl) Substituent substitution, the substitution on R3 is essentially unsubstituted or substituted with 1, 2 or 3 other substituents selected from halogen and via substituents; R4 is -CVX ^ AnS-CrXrCs, where: is unsubstituted Alkylene; -Xι is a chemical bond or -0-, _S-, _NR,-, -S-CO-, -o-co-, -CO, 〇-, -C0-S_, -NR'-CO- Or -CO-NR'-, where R is hydrogen or an unsubstituted winter group or Ci_C6 alkyl; -Ari is heteroaryl, heterocyclyl, aryl, or heteroaryl-(Ci-C) -), Which is unsubstituted or carries 1, 2 or 3 on a cyclic group selected from the group consisting of autogen, CpC4 alkyl, hydroxyl, CrCU alkoxy, -NR, Rn or -NH-CO-R (Wherein R and Rn are the same or different and are selected from hydrogen and alkynyl); -C2 is an unsubstituted Ci-Czl · fluorene group; -X2 is a chemical bond or -0, -s -, -NR,-, -CO-, -CO-S-, -CO-0,, -CO-NR1-, _S_CO_, _〇-CO_, _NRf-CO_, _〇-CO-NR,, -NR ^ CO-O-, -S-CO- or -CO-S-, where R 'is hydrogen -CH3 or -CH2, CH3; and 87682 27- 200412948 -C3 is a CrCU straight group, which is unsubstituted or selected from 1, 2 or 3 light groups, _NH2, -NH (Cr-CV ^ group) ... N (Cl_c2 alkyl) 2 and _ prime are substituted. Preferred compounds of formula (I) are compounds of formula (IA), their prodrugs and their pharmaceutically acceptable salts:

Where: Y is a radical of the formula-(CH2) m〇 (CH2)-, -A- or -A-X3- (CH2) m, where A is phenyl, pyridyl or pyrrolyl, which is unsubstituted or Substituted by 1, 2 or 3 substituents selected from -CH3, -CH2-CH3, -〇CH3, -OCH2-CH3, halogen and hydroxyl, X3 is -〇-, -S〇2_ or -NH-C 〇-, and m is 0 or 1; R3 is phenyl, fluorenyl, sulfanyl, p-quinuclyl, benzopyranyl, cyclopentyl, 1,4-benzodioxycyclohexyl, 1 , 3-Benzene-lactamyl-pentamyl or 2,3-dihydrobenzofuranyl, which is unsubstituted or has 1, 2 or 3 selected from halogen, hydroxyl, Ci-C6 ^ yl, Ci-Ce Fluorenyloxy, Ci-C6 sulfanyl, C2-C6 alkenyl, Ci-C6 alkenyloxy,: C2-C6, fluorenylthio, C2-C6 alkynyl, 〇2- (: 6-block oxy, C2 -c6 alkynylthio, c3-c6 carbocyclyl, C3-C6 carboepoxy., C3-C6 carbosulfanyl, -NH-CO- (Cr_C6 alkylp alkyl) and -NR'R "( Where R, and R "are each independently hydrogen or Ci-C6 alkyl) substituents. Instead, the substitution on R3 is essentially unsubstituted or 1, 2, or 3 others selected from halogen and hydroxyl Substituent substitution; 1 and R4 are _〇1-11_ 八 1 * 1 or-(: 2_ 又 2 &lt; 3, Among them, -〇1 is-(〇: 112) · »,-(CH2) 2- or-(CH2) 3-; 87682 • 28-200412948-X is a chemical bond or _〇_ ,, -S-CO- Or -〇_c〇_--Ar is epitope, p-pyridyl, p-sedenyl, benzobismethyl, sulfan-based, 1,3-benzodioxycyclopentyl, or 14-benzene And dioxocyclamyl, methyl earth octadecyl is unsubstituted or has 丨, 2 or 3 groups selected from fluorine, several groups, _ ^-N (CH3) 2 &amp; -NH-CO_CH3 Substitution; • C2 is a straight-chain unsubstituted Cl-C4 alkylene; -X2 is a chemical bond or -0-, -C0-0- or -NH-CO-O-; and-^ is a heart ^ 4 Alkyl, which is unsubstituted or substituted on the primary carbon with &amp;) one hydroxy or (b) 1, 2, or 3 functional group substituents. Preferably, in the compound of formula (IA), &amp; is phenyl , Fluorenyl, furanyl, quinolinyl, | benzofuranyl, cyclopentyl, L4-benzodioxocyclohexyl, 3, benzobenzodioxopentyl, or 2,3-dihydrobenzo Furanyl, which is unsubstituted or substituted by 1, 2 or 3, selected from _ prime, Cl_C4 alkyl, C2_C4 alkenyl, Ci_C4 alkoxy, CVC4 alkylthio tomb, C2-C4 alkoxy, (: 3- (: 6 carbocyclyl, c3-C6 ring completion Oxygen ... NH-CCKCVC2 alkyl) and _N (Cl_C0 alkyl) 2 are substituted by the substituents of 'R3. The substitution on R3 is basically unsubstituted or by 1, 2 or 3: selected from the group consisting of Other substituents. Take the compound of formula (I) as a compound of formula (IA,), its prodrug and its pharmaceutically acceptable salts: 0,

Y‘R3 R4—N ζ (ΙΑ ’)

Wherein: Z is or -SO- group; Y is a group of formula -A- 'where A is unsubstituted pyridyl or unsubstituted fluorenyl group of 87682 -29- 200412948; / is phenyl group, 4 phenyl group Group, pyridinyl group or i, 3-benzodioxycyclopentyl group, which is unsubstituted or substituted with 1, 2 or 3 selected from the group consisting of nanin, hydroxyl, Ci_C4 alkyl 'Ci_, ethoxy, Ci- C4fethio, c2-c4fluorenyl, _NR, R ,, (where R, and Rn are hydrogen or Ci-C6 alkyl) and Si (R ",) 3 (where R", are independently Ci_c4 alkanes Substituent substitution, the substitution on R3 is essentially unsubstituted or substituted by 1, 2 or 3 other substituents selected from the group consisting of hydrogen and hydroxy; R4 is where:; -Cl is a chemical bond or unsubstituted (^-(: 4-alkylene; Xi is a chemical bond when C1 is a chemical bond and when q is an unsubstituted c "c4-alkylene group, X! Is a chemical bond or _〇_ or _8_; Unsubstituted pyridyl, pyrrolidinyl, L3-benzodioxopentyl or cyclohexenyl, unsubstituted CyC: 6 cycloalkyl or unsubstituted or selected from 1, 2 or 3 Of functional elements, Cl_c4 alkyl, c2_C4 alkenyl, Ci_C4 alkoxy, CVC4sulfanyl, and -N (CH3) 2 Substituent substitution, the substitution on Ari is essentially unsubstituted; alkylene, which is unsubstituted or substituted with one or two substituents selected from hydroxyl and fluorine; -X2 is a chemical bond or -0-, -S -Or-CO_〇-; and a pit group or a C2_C4 fluorenyl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen and halogen. In a specific example of the present invention, the formula ( I) '_YR3 in the compound is not a substituted or unsubstituted phenoxydongyl group, a phenoxyP sephenyl group, a decyloxyphenyl group, a decylthiophenyl group, or a sulfanylphenyl group. Typically, _YRS is not a substituted or unsubstituted fluorenyl, phenoxyphenyl, phenoxythienyl, fluorenyl, benzylthiophenyl, or arylphenyl or carbazole group. More typically, Y in formula 不 is not a chemical bond or a phenoxy, fluorenyl, sulfanyl, or furyl group. Furthermore, 'R4 is typically not (a) _Y-NR3R4, where Y is an alkylene And & is the same as or different from R4 and is selected from the group consisting of hydrazone, or an aryl group, or an alkyl group to form an alkylene group containing 4 to 5 carbon atoms and optionally inserted through nitrogen or oxygen, ^) pyridylalkyl And (c) pipe -4-yl-alkyl, optionally substituted by alkyl, aryl, or aralkyl. In this specific example, & is not -NR, _, and Cs is unsubstituted or substituted on a primary carbon atom. (A) a ci C4 alkyl group substituted with one hydroxyl group or (b) 1, 2 or 3 substituents, and Aq is not pyridyl or piperidinyl, preferably not 6-membered heteroaryl or heterocyclic Preferred compounds of formula (I) include: 1.2- [4- (4-bromo-phenyl) -pyridine_3_yl] _3_ (3,5_difluoro_benzyl) _pyrazolidine- 4-keto 2. 2- [4_ (4-bromo_benzyl) -pyridine_3_yl] -3_ (2,3,4_trifluoro_benzyl) _orazolidine-4-one 3. 2- [4- (4-Bromo-phenyl) -pyridine_3_yl] _3_ (2,5_difluoro-benzyl) _pyrazolidin-4-one 4. 3 (2-dongo [1 , 3] monooxycyclopenta-5-yl_ethyl) -2- [4- (4-bromo-phenyl) _ koubidian-3 -yl] -psaijundian-4 -reward5.3 -Isobutyl_2_ (4_phenyl4-Hydroxy-3-yl) -pyrimazole bite-4_one 6. 2- (4-benzo [1,3] dioxocyclo-5-yl-pyridine _3-yl) isobutyl ketazolidine-4-one 7. 3-isobutyl-2- (4-pyrimin-2-yl-pyridin-3-yl) -oxazolidine_82_ketone 87682 -31-• 2- [4- (4-Ci-phenylpyridine-3 -yl] -3- (2 • cyclohex-1-enyl-ethyl)-vocal -4-Ketone • 2-[4,41] bi-p ratio_ 3 -yl · 3 -isobutyl-p-septamidine-4 -fluorene with 2- [4- (4-chloro-phenyl) ratio Yodo-3 -yl] -3-isobutyl-p-septate Yodoyodo-4 -Iso- "2- [4- (4-fluoro-phenyl) -pyridin-3-yl] -3_isobutyl -Pyrimazin-4-one 2. 2- [4- (3_ &lt; Ostyl-Winter-based) -p ratio lake-3_yl] -3-isobutyl- ^ plug β sitting lake 4.13. 3-isobutyl-2- [4- (4-dimethoxymethoxy-phenyl-phenyl) -ρbito-3-yl]-隹 Bite-4 -one,-· 14 · 3-isobutyl 2- (4-p-tolyl-pyridin-3-yl) -pyrazolidin-4-one 15.3-isobutyl-2 · [4- (4-trifluorosilyl-phenyl ) -Pyridin-3-yl] -pyrazolidin-4-one 16.Isobutyl-2- [4- (4-methylthio-phenyl) -pyridin-3-yl] -thiazolidine-4 -Keto l7 · 2- [4- (4-ethyl-phenyl) -pyridin-3-yl] -3-isobutyl-pyrazolidin-4-one 18 · 4- (3-isobutyl- 4-oxo-thiazolidine-2-yl) -3- (4-methoxy-phenyl) -metapyridine; chloride 19.3_ (4-chloro-phenyl) -4- (3-isobutyl 4-oxo-thiazolidine-2-yl) -pyridine &amp;; chloride 20 · 3- (4-fluoro-phenyl) -4- (3-isobutyl-4-oxo-pyrazolidine -2-yl) -pyridine hydrazone; chloride 21 · 4- (3-isobutyl-4 -oxoplug Yodo-2 -yl) -3-p-tolyl-p ratio Yodomonone; chloride 22.2 (4-bromo-phenyl) -3 · (3-isobutyl-4-oxo-pyrimazole Pyridin-2-yl) -pyridazine; chloride 87682 -32- 200412948 23 · (3 · Xingbutyl-4-oxo_thiazolidine_2 · yl) _2_ (cardiomethoxy_phenyl) &gt; Pyridinium plant chloride 24.2 (4-chlorophenyl) -3- (3-isobutyl_4_oxo-pyrazolidine-2_yl) _pyridinium chloride; chloride 25 · 2- (4 · Fluorophenyl) -3_ (3_isobutyl-4_oxo · Dazolidin_2_ylbibidinium hydrazone; Chloride, 6.3 (3-Isobutyloxetazosin_2 _Yl) _2_p-tolyl_pyridine · pyridine; chloride group 2 [4 (4_difluoromethyl-phenyl) _lippyridin j · yl] -Yintudian_Lu 4-one— = ♦ Isobutyl I oxodistitutyl)-Outer Dyke-Heart-based] Jonitrile 29 · Isobutyl-2-Bu (4_methoxy_phenyl) "pyridolyl]-far Oxazolide_ 4-keto 30 · 3 · isobutyl-2_ [4- (4-ethylfluorenyl-phenyl) ”is more than 4-ketone 4-ketone ~ / holeylphenyl) _4_ (3_isobutyl Base_4_oxo "stopper seat_2 · yl) _pyridine tweezers; chloride 32'3_isobutyl_4_oxo4㈣_2m ♦ ethenyl-phenyl) Chloride 2 2 2 •-(3-isobutyl-4-oxo "sedetidine_2_yl) _2_ (4_trifluoromethyl-phenyl &gt; pyridine hydrazone; chloride, (cyano-phenyl)- 3- (3-isobutyl-4-oxo_pyrazolidine_2-yl> &gt; pyridine tweezers; chloride 3 5 (3xobutyl-4-oxo_thiazolidine_2_yl) _2_ (4_vinyl_phenyl) _ 87682 -33-200412948 pyridine hydrazone; chloride 36 · 2- [4- (4-Cyso-fluorenyl) -ρ than orapod-3-yl] -3- (3 -Methyl-butyl) -p plug. Zyodo-4-fluorene is the same as 37.2- [4_ (4-, / odor-phenyl)-^? Bisodo-3-yl] -3- (2,2,3,3,3-penta-propyl ) -Yuantudian-4 -Yuan38 · 2- [4- (4- &gt; Scent-phenyl) -pbiyodo-3-yl] -3-ethyl-Farguchi TU Dian-4 -Yun;-40. 2- [4- (4- &gt; Scent-phenyl) -ρ biyodo-3-yl] -3-pentyl-ρ plug 11 41. 2- [4- (4-'/ Oxyl-phenyl) -p biyodo-3-yl] -3-phosphonomethyl-rhodoxy- 4-ketone 42.2- [4- ( 4-bromo-phenyl) -pyridin-3-yl] -3- (3-isopropoxy-propyl) -orallydine-4-one 43 · 3-dilute propyl-2- [4- (4-Brexyl-phenyl) -p-bito-3-yl] -p-setitu 4-44-4 3-isobutyl-2- (4-m-tolyl-pyridin-3-yl) -Pyrazolidin-4-one

45. 2- [4- (2,4-Dimethyl-phenyl) -p ratio lake-3-yl] -3-isobutyl-xetulol-4-one 46. 3-isobutyl 2- (4-o-tolyl-pyridine-3_yl) -pyrazolidin-4-one 47.4 (4-bromo-phenyl) -3- (3-isobutyl-1,4 -Dioxo-1 λ * 4 * -pyrimazolium-2 -yl) -ρ bidian; chloride 48.2 2- [4- (4-> odor-phenyl) -ρ bidian-3- Phenyl] -3 -di-dibutyl-π plug and bite -4-酉 49. 2- [4- (4- &gt; odor-phenyl) -ρ biyodo-3-yl] -3- Hexyl-mouth plug mouth sitting lake 4- 淀 and 50_ 2- (3 -benzo [1,3] dioxopentyl-5-yl-ρ biyodo-4-yl) -3-amylpentyl-mouth Saiyan Lake-4-酉 same 87682 -34- 200412948 51. 4- [4- (3 -ί Curtain amyl-4-oxo-p Saijundian-2-yl) -p ratio lake-3-yl ] Wax 52. 3-cyclopentyl-2- [3- (4-dimethylamino-phenyl) -pyridin-4-yl] -oxazolidin-4-one 5 3. 3-cyclopentyl- 2- [3- (4-trifluoromethyl-phenyl) -pyridine-4-yl] -pyrazolidin-4-one 54. 3-cyclopentyl-2- [3- (4-methoxy -Phenyl) -pyridin-4-yl] -pyrazolidine-4 -one 55. 3-Mulpentyl-2- 2- [3- (4-methylthio-phenyl) -p-Hydro-4 -Radical;]-ρ plug 1: 7 azedo-4-one 5 6.3-per pentyl-2- [3- (4-ethyl-fluorenyl) -π ratio lake -4 -yl] -p Setu Dian-4-酉 Dong 57 · 2- [3- (4-&gt; Smelt-Winter-Based) -pbidian-4_base] _3_? Mupentyl-ρ Setu Dian-4- 酉 Dong 58 CID-005 5699 3-Cyclopentyl-2- [3- (3,4-dimethyl-phenyl) -pyridine-4-yl] -sulturol-4-pyridine with 59.3-isobutyl 2--2- [3- (4-Ethyl-phenyl) -pyridin-4-yl] -pyrazolidin-4-one

60 · 3-phosphorimyl-2- [3- (4-ethylenyl-phenyl) -p biyodo-4-yl] -mouth plug -2- [3- (4-ethylenyl-fluorenyl) -p-bito-4-yl] -p-sedulate_ 4-one 62 · 3-isopropyl-2- [3- (4- Ethyl-winteryl) -p than Yodo-4-yl] -ρ plug 1 ^ zolide * 4-one 63 · 3-second butyl_2- [3- (4-ethyl fine-phenyl) _p than Yodo · 4-based] -ρ plug. Zydidine-4- 酉 is the same as 64. 3- (1_ethyl-propyl) -2- [3- (4-vinyl-phenyl) -exo (: Yodo-4-yl) -distant 87682- 35- 200412948 Mouth-sweet-4-酉 with 65 · 3-isobutyl-2- [3- (4-ethylfluorenyl-phenyl) -pyrimyl_2_yl] -oxazolide_ 4 -remuneration 66.3-Isobutyl-2_ [4_ (4-Ethyl-phenyl) -diphen-3-yl] -Soul? · 67 · 2- {4- [4- (1,2_dihydroxy- Ethyl) -phenylpyridinylb% isobutyl-pyrazolidine_4-one 68.2 2- {4- [4- (2- (Rosyl-ethyl) -phenyl] ratio lake-3_ } _3_Isobutyl <^ Southinozo-4-one69 · 2- {4- [4_ (1-Cyclo-ethyl) -phenyl] -pyridin-3-ylbu 3-isobutyl -Pyridine-4-one 70. 2- {4- [4- (2,2-monofluoro-ethylenyl) _phenyl] -ubiyodo_3_kib 3_isobutyl_ ρ Sejun bite-4 -one 71.3 3-isobutyl-2- [4- (4-trifluoroethylfluorenyl_phenyl) _pyridine_3_yl] -pyrazole bite-4 -Pay 72 · 2- {4- [4- (1-fluoro-ethylfluorenyl) -phenyl] _pyridine-3_ylb 3-isobutyl-pyrimidine-4-one 73 · 3-isobutyl-2 -[3- (4-Vinyl-phenylpyridin-2-yl] · pyrazolidine_cardiolun; and its prodrugs and pharmaceutically acceptable salts. Particularly preferred compounds of formula (I) and formula (I) are as N_type dance channel inhibitor : Two: Tongji inhibitor is a more active compound (ie, it is a selective pan-equivalent agent = Daobao resistance agent). Typically this compound has an anti-channel inhibitory effect compared to ™ 32 cells in the same 剌 87682 -36 -200412948 shows lower L-type material channel suppressive effect. Therefore, it has fewer side effects than non-selective N-type dance channel A resistance. The pharmaceutically acceptable salts used in this article are compatible with medicine. Acceptable acids or tested salts. Pharmaceutically acceptable acids also include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, monophosphoric acid, argon bromide or nitric acid, and organic acids such as citric acid, butanil, cisbutan: , _ Fruit acid, ascorbic acid, butyric acid, tartaric acid, ·: formic acid H medicinal acid, acetic acid, benzoic acid, or p-toluene.. Commercial medicine can be connected to the alkaline base containing alkali metals (such as sodium Or potassium) and alkaline earth metals (such as about or thorium) hydroxides and rich domain amines, pure amines or miscellaneous duties, months *. The present invention especially includes pharmaceutically acceptable salts where γ is of the formula _A_ -2A is pyridoxyl, and the pyridyl group on γ has a positive charge on the nitrogen atom. The formula used herein I) A prodrug of a compound is a compound that can react in vivo to form a formula (chemical). An example. A prodrug of a compound of formula ⑴ is an example in which a compound of formula ⑴: 1, 2-: hydroxyethyl or a group exists as an epoxy ring. In particular, the epoxy 5 coat may be present as a substituent on the R3 group. An example of a suitable prodrug is a compound, 31-butyl-2- [4- (4-epoxyethyl_phenyl) 4 than yododonyl] 4. -The compounds of the invention contain one or more palmar centers. For the avoidance of doubt, the chemical structure not included herein is intended to include all stereoisomers of the compounds shown. Contains racemic and non-racemic mixtures and pure enantiomers and / or diastereomers. . • The preferred compounds of Benmomine are optically pure isomers. Thus, for example, preferred compounds of formula (I) with only one palm center each contain R in a substantially pure state "87682 -37- 200412948 Enantiomers, S Enantiomers in a substantially pure state And mixtures of enantiomers containing excess R-enantiomer or excess S-enantiomer. The present invention also provides a pharmaceutical composition comprising a compound of formula (II) or a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. ’

Where Z, γ, Rl, R3 and as defined above, but with the condition that when z is S 'R1 is hydrogen and R4 is 2- (4-methoxyphenethyl), Y_R3 is not 4-methoxyphenyl Or 4-pyrrolidinyl phenyl; (b) when Z4S and Ri are hydrogen, Y-R3 is not _phenyl-OA ^ R, where A? Is CVC5 alkynyl and R1 is 1-pyrrolidinyl , Piperidinyl, 4 · morpholinyl,: U-Pyridyl, or 4-pyridyl; and 0) When: R is hydrogen and r4 is -cvi-c: 3 where C2 is unsubstituted In the case of c2_c3 alkylene, X2 is and C: 3 is an unsubstituted Cl_C2 alkyl group, and _Y_R3 is not a phenoxyphenyl group, a fluorenyloxy group, or a phenylhydrosulfide group. 4-chlorophenoxyphenyl or 4-nitrophenoxyphenyl. The pharmaceutical composition typically contains up to 85% by weight of a compound of the invention. More typically it contains up to 50% by weight of a compound of the invention. Preferred pharmaceutical compositions are those which are sterile and non-pyrogenic. Furthermore, the pharmaceutical composition provided by the present invention typically contains a substantially pure optical isomer of the compound of the present invention. For the avoidance of doubt, this pharmaceutically acceptable carrier or diluent is non-existent. Qian Ming also provides the compounds of the formula („) as defined above, their prodrugs and pharmaceutically acceptable salts for use in the treatment of human or animal bodies. —, Certain compounds of the present invention ... are believed to be new. The present invention Therefore, this 87682 -38- 200412948 compound is provided. Therefore, the present invention provides a compound of formula (Γ), a prodrug thereof, and a medical agent thereof.

R

(Γ) Pharmaceutically acceptable salts, where R1, R3, and R4 are as defined in the foregoing formula (1), (18), or (18), and Z is -0- or -SO-, and Υ is formula_ Wherein A is a heteroaryl group, provided that when Z is S 'R is 氲' Y is unsubstituted p-pyridyl and r3 is molyl phenyl, and R4 is a C "Xi-Ar ^ group where ΑιΆ3 to 6-membered carbocyclyl: Typically, in the compound of formula (I '), A is an ethenyl group, a sulfanyl group, a phenanyl group, an imidino group, or a p-pyrrolyl group. For example, A may be pyridyl or pyrhalyl, preferably pyridyl. The group A is typically unsubstituted or substituted with 1, 2 or 3 substituents. Preferably, the group A is unsubstituted. The substituents on A are typically selected from those defined by the above formulas (I), (IA), and (IA,). Typically, compounds of formula (Γ) R3 is as defined in the foregoing formulae (I), (IA), and (IA ". Among them, R3 is substituted, and the substituent is typically not a bromine, and the atom is not an atom. Therefore, the substituent is typically The upper system is selected from fluorine or chlorine, hydroxyl, cyano, cvc6 alkyl, CVC6 alkoxy , CV-C6 alkylthio, C2-C6 alkenyl, c2_c6 alkoxy, C2-C6 alkenylthio, (: 2-0: 6alkynyl ', (^-(^ alkynyloxy, C2-C6 ^ : Sulfur, C3-C6 carbocyclyl., C3-C6 carbocyclyl, C3-C6 carbosulfanyl, -NH-CO-CCi-C ^ alkyl), -CO-NH-CCVCg alkyl) , -NR'Rn (where R, and R "are each independently hydrogen or K6 alkyl) and Si (R", :) 3 (where each R1 &quot; is independently CVC4 alkyl). The preferred substituents on R3 are Fluorine, chlorine, hydroxyl, cyano, CrG alkyl, 87682 -39- 200412948 1oxy, Ci-C4feithio, C2-C4fluorenyl,-] sjR, RT '(wherein r and R are each independently hydrogen Or CrC: 4 alkyl groups) and Si (R ",) 3 (wherein each R", is independently a c alkyl group). The more preferred substituents on R3 are fluorine, chlorine, cyano, Ci_C4 alkyl, Cl C4 ^ Oxygen, Ci-C ^ thio, c2_c4fluorenyl, c2-C4fluorenyloxy, c C6 carbon epoxy, -NH-CO-Me, -N (CH3) 2, and Si (R ,,,) 3 (Wherein each R ,, is independently C ^ C: 4 alkyl). Still more preferred substituents on R3 are Ci_C4 alkyl, Ci_C4 alkyloxy, CVC4 alkylthio, and C2-C4 fluorenyl.

Typically, the substitution on R is essentially unsubstituted or substituted with one, two, or another substituent selected from the group consisting of fluorine, especially fluorine and hydroxyl.

Preferably, in the compound of the formula (I,), Y is a group of formula, wherein eight is unsubstituted pyridyl or pyrenyl, and R3 is aryl, heteroaryl, heterocyclic or carbonyl. 'It is unsubstituted or substituted by 1, 2 or 3 selected from fluorine, chlorine, alkyl, Crc6 alkyl, Cl_c6 ^ oxy, Ci_c ^ thio, C2-C6 alkenyl' q_C6 alkenyloxy, c2- c6 sulfanyl, c2-c6 alkynyl, c2-c ^ oxy, c2_ca: fe thio, C3-C6 carbocyclyl, c3-c6 carboepoxy, c3-c6 carbosulfanyl, -NH- CO- (CVC6 alkyl), -CO-NH-CCVCg alkyl), -NR, R ,, (where R 'and R "are each independently hydrogen or Cl-C6 alkyl) and Si (R, M) 3 (Wherein each R ,, is independently Ci CUk group) is substituted with a substituent, and the substitution on R3 is basically unsubstituted or substituted with 1, 2 or 3 other substituents selected from the group consisting of autogen and cycline. More preferably Y is a radical of the formula -A-, where A is unsubstituted pyridyl or thienyl 'and R is aryl, heteroaryl, heterocyclyl or carbocyclyl, which is unsubstituted or , 2 or 3 are selected from hydroxyl, CVC6 alkyl, Ci_C6 alkoxy, CV C6 alkylthio, c2_c6 alkenyl, c2_c6 alkenyloxy, c2-C6 alkenylthio, c2-C6 Bulk, C2-C &amp; oxy, c2-C &amp; thio, c3-C6 carbocyclyl, C3_C6 carbon 87682 -40- 200412948 epoxy, C3_C6 carbosulfanyl, -NH-CO- (Ci-C6 Alkyl), -CO-NH- (C "C6 alkyl"): Nr'r "(wherein R 'and R" are each independently hydrogen or (^ -〇: 6 alkyl) and Si (R ",) 3 (where each r "is independently a Cl-c4 fluorenyl group), and the substitution on R3 is essentially unsubstituted or substituted with 1, 2 or 3 other substituents selected from halogen and hydroxyl. More preferably, the compound of formula (Γ) is a compound of formula (IA &quot;), a prodrug thereof, and a pharmaceutically acceptable salt thereof:,

Wherein: Z is or -SO-; Y is a group of formula, wherein A is unsubstituted pyridyl or unsubstituted pyridyl; R3 is phenyl, phenyl, pyridyl or ^ -benzodi Oxycyclopentyl is unsubstituted or substituted with 1, 2 or 3 selected from fluorine, chlorine, hydroxyl, cyano, Ci_C4 alkyl, cvq alkoxy, Cl_C4 alkylthio, c2_C4 alkenyl, _NRfR (wherein R 'and R "are each independently hydrogen or Ci_C4 alkyl) and substituted with ㊉ ,,,) 〆 where each R, &quot; is independently q-C4 alkyl) is substituted, and the substitution on R3 is basically Substitute or another, two or two or three other substituents selected from the group consisting of 129 and light groups;-匸 丨 is a chemical bond or unsubstituted Ci_C4 alkylene; Tian ^ is a chemical bond X1 is a chemical bond and when Cl is an unsubstituted alkylene group, Xl is a chemical bond or _〇_ or _s_; 87682 -41-200412948-ΑΓι is an unsubstituted p-pyridyl group, said Luodian group, 1,3-benzobis Oxycyclopentyl or cyclohexenyl, unsubstituted CrC6 cycloalkyl or unsubstituted or selected from 1, 2 or 3 halogen, CrC4 alkyl, C2-C4 fluorenyl, Ci_C4 alkyloxy, Ci-C4 alkylthio and -N (CH3) 2 substitution Substituted phenyl group, the substitution on Ari is essentially unsubstituted; _C2 is Ci-C4 '; it is unsubstituted or substituted with one or two substituents selected from the group consisting of fluorine and fluoro; -X2 is also A bond or -〇-, -S- or _CO-0-; and-匸 3 is a CrC4 alkyl or C2_C4 晞 group, which is an unsubstituted or i, 2 or 3 group selected from hydroxyl and halogen To replace. ’Preferred novel compounds are compounds of formula (IB) and pharmaceutically acceptable salts thereof,

R3, Y, and z are as defined in the foregoing formula (Γ); are, or _c2_X2i_c3, or Ci-C6 fluorenyl or C2_C6 fluorenyl, wherein Cl, χι, C2, and C3 are as defined in the aforementioned Wu (I,); -Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl_Ra_ or heterofluorenyl RR is C1-C6 alkynyl, CVC6 fluorenyl or C2_C6 alkynyl, medium g An is unsubstituted phenyl or is substituted by one or two substituents selected from methyl, ethyl, methoxy, ethoxy, phenoxy, t, bromine and nitro. C1 &amp; x1 are both chemical bonds or q is a methyl group and χι is 〇-S-, -ΝΚΛ, _s〇 ... advise 2 ·, s NR,-, -S-C0 ·, 4C〇 ... · c. ... c〇〇r &quot; _c〇Specific 87682 -42- 200412948, -C0-NR'R ,, -C0-0-, -CO-OKO-NR1-, -CO-NR, R, CO-NR'_ , _〇-CO-NR'- or -NR'-CO-O-, where each R is the same or different and represents hydrogen, phenyl, Ci_C6: fe group, C2-C6 dilute group or C2-C6 alkyne: And each Rn is the same or different and represents Ci-C6 alkynyl, C2-C6 fluorenyl or C2-C6 alkynyl; and X 2 'is -〇-, -S-,-NR'-,- S Ο,-S Ο 2-,-C Ο-, -C Ο-S-, -CO-0-, -CO-NRf-, -S-CO-, -O-CO-, -NRf-CO-, -C0-0-R, -CO-Ο- , -CO-NR, R ', -CO-0-, -C0-0_R ,, -C0-NR 丨-, -C〇-NR'R' '-CO-NRf-, -NRf-C0-0- Or -O-CO-NR'-, wherein each R 'is the same or different and represents chloro, phenyl, Ci-Csfe, C2-C6 alkyl, or C2-C6 alkynyl; and each R "is the same or Different and represents CrCs alkylene, (: 2-(: 6alkenyl or C2-C6alkynyl. In the compound of formula (IB), R1, R2, R3, Y, Z, C2 &amp; C3 are preferably as described above) Definition of formula (I) or formula (IA). Typically, in compounds of formula (IB), R4 is -CVXi-Arr or -C2-X2, -C3 or &lt; ^-(: 4 alkyl group. Typically, formula ( IB) In the compound (^ and again), as defined in the foregoing formula (I) or formula (IA), provided that Arr is unsubstituted phenyl or is selected from methyl, ethyl, When methoxy-, ethoxy-, phenoxy-, chloro-, bromo-, and nitro-substituted phenyl groups, both C1 &amp; X1 are chemical bonds or (^ is a methyl group and X is -0-,- S-, -NRf ·, -SO-, -S〇2-, -CO-S-, -C0-0-, -C0_NRf-, -S-C0-, -0-C0-, -NR, -C0 -, -C0-0-R ,, -C0-0-, -C0-NR'Rn-C0-0-, -C0-0-R ', -CO-NR, ·, -CO-NR, R, , -CO-NR'-, -0_C0-NR'-, or -NR'-C〇-〇-, where each R, and R, 'as mentioned above has 87682 -43- 200412948 formula (I) or formula (ΙΑ ). Preferably or any substituted phenyl group when ArΓ is unsubstituted and does not have at least one substituent selected from the group consisting of fluorine, -NCCrCs alkyl) 2, -NH-CO ^ Ci, e oxyl) and several groups When Ci and Xi are both chemical bonds or Ci is methyl and Xi is -〇-, -S-, -NRf-,,; S〇, -S Ο 2-, C 〇 _S,-C Ο-Ο-- C Ο-NR 丨-, -S-C Ο-,-〇 ~ cq -NR, -CO-, -CO-0-R ,, -CO-0-, -C0-NR, R ,, _C0-0-, .C〇〇R '' _ CO-NR'-, -CO-NR'R, '-CO_NR,-, _〇-CO-NR,-or .Nr, CO-O-, Wherein each of r, and R "is as defined above. Better, when Ari .; is unsubstituted or substituted phenyl, both Ci and Xi are chemical bonds or c! Is methyl and meaning 1 -Ο-, -S-, -NRL, -SO-, -S02-, -CO-S-, .Γπ Ο-, _CO-NR'-, _S_CO_, _〇-CO_, _NRf_CO_, _CO_〇-r "_ CO-O-, _CO-NR'R ', CO-0-, _C0-0-R &quot; _C0-NR 丨-, NR'R &quot; -CO-NR'-, -〇-C〇_NR, Or _NR'_c〇〇_, wherein each R, and r are as defined above. Typically, Ari in the above formula (IB) is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl- (Cl_c6alkyl) _ or heterocyclyl_ (cvc6alkyl). When — is heteroaryl- (Cl_C6fluorenyl) _ or heterocyclic l (ci_c6alkyl), this alkyl group is unsubstituted methyl or ethyl. Preferably, fine, is heteroaryl: pushyl, carbocyclyl, or heteroarylalkyl)-, such as heterosquaryl, heterocyclyl, 1¾: its +, bu or heteroaryl-(CrQ alkyl)-. Preferably, when Arr is; ^ ', it is a phenyl group with a thick 2 $ mouth- or heterocyclic ring, such as 1,3-benzodioxocyclopentyl or 1,4 · dibenzodioxo. Jiji. More preferably, when Arr is phenyl, it is I, 3 -dongodioxo and its soil. When An is a heteroaryl group, a heterocyclic group, a carbocyclyl group or a heterosquaryl group, -Earthine-', it preferably has the same meaning as the above-mentioned corresponding group of 87682 -44- 200412948. More preferably, Arr is unsubstituted pyridyl, pyrrolidinyl, 1,3-benzodioxycyclopentyl or cyclohexenyl, or unsubstituted cycloalkyl. Typically, Aq in the formula (IB) is an unsubstituted or cyclic group with one or more, for example, 1, 2, or 3 substituents. The substituent is typically selected from the group consisting of fluorine or gas, Ci-C4 alkyl, hydroxyl, Cl-c4 alkoxy, -NR, R, and -NH-CO-R, where R 'and R " It is selected from fluorene and unsubstituted ci_C4 alkyl. Preferred substituents are fluorine, benzyl, methoxy, dimethylamino and _N only_CO-CH3. More preferred substituents are thorium and boryl. , _N (cH3) 2, and CH3. Typically, the substitution of An on the base is essentially unsubstituted. Typically, X2 in the above formula (IB), each R in the group, is the same or different and is hydrogen or unsubstituted. Substituted phenyl or ci-C 6 alkyl is preferably hydrogen, _ c H 3 or -CH 2 CH 3. More preferably, each R ′ in the X 2 group is hydrogen. Typically, each R n in the χ 2 · group is unsubstituted. The substituted C1-C6 elongation group is preferably _CH2- or -CH2-CH2-. More preferably, each Rn is -CHr. Typically, X2 in the above formula (IB) is -0-, -S ... -NR,-, S-, _C0_0_, -CO-NR 丨 ... S-CO_, _〇-CO_, -NR, -C〇_, -〇-CO-NR'-, -NRf-C0-0-, -S-CO- or -CO-S · », where R 'is as defined above for formula (I) or formula (IA). Preferably, x2. Is _〇_, -S_, _c〇_〇 ·, -O-CO-, -S-CO-, -CO-S- or -NH-CO-O .. Best, χ 2, is, -S-, -CO-O- or -NH-CO-O- 0 When R4 in the above formula (IB) represents a Ci-Gfe group or a C2_C6 alkenyl group, it is typically a CyC: 6 alkyl group Or C ^ C: 6 alkenyl. In addition, the alkyl or fluorenyl group may be straight or branched, unsubstituted or substituted. For example, R4 may represent unsubstituted branch 87682 • 45- 200412948

CrC4alkenyl 'is especially second butyl. Typically, Ci-c6 alkyl or c2-c6 alkenyl is unsubstituted or substituted with 1, 2, or 3 substituents. Suitable substituents are those listed above as examples of suitable substituents on the alkyl or fluorenyl groups. Preferred substituents include commercial elements', especially fluorine. Typically, the substitution on a C-C6 alkyl or c2-c6 dilute base is essentially unsubstituted. More preferred examples of the novel compounds of the present invention are the above-mentioned compound numbers 1 to 73 and other medicines and pharmaceutically acceptable salts thereof. Compounds of formula VII can be prepared by conventional routes, such as those illustrated in the following reaction schemes A to e.

Reaction n A

The hydrazone or ketone of formula (II) in the reaction scheme (A) is reacted with the amine of formula R4_NH2 in the presence of HSCHR2-C02H. The reaction is typically carried out in a solvent such as benzene or toluene at elevated temperature, for example, 80 to 100 rpm. It is thus possible to prepare compounds of formula IX where 2 is §. The inverse 'shown in Reaction Scheme A should be carried out in a "single tank" reaction or stepwise, so the compound of formula (II): reacts with an amine of formula RfNH2, and the obtained imine intermediate is then reacted with HSCHR2_CO2H. In blood type, when A, r / /, soil * stepwise reaction, both reaction steps are carried out in a solvent such as benzene or toluene at a temperature of 80 ° C to 100 ° C. 'I |

Reaction diagram B

87682 -46- 200412948 ο R3y

(NH4) 2C03 HSC Qiu 2C02H --- P-

R4-L R〆

F Another method for preparing pyrazolidinone is shown in Reaction Scheme B, and thus the compound of formula (III) is obtained by introducing an amine using ammonium carbonate. Compounds of formula (I) where Z is S can be prepared from the intermediates of formula (III) obtained by standard methods. For example, a compound of formula (IIIM) and a compound of formula, R4-L (wherein L is a leaving group such as a chlorine atom) can be prepared in a solvent such as THF at room temperature in the presence of a base such as NaH; or the like.

Reaction diagram C λ-At

R4-NH2

Αγ-L

H3CjHR2C02H

In order to prepare a pyrazolidinone of the formula (I) having a substituted pyridyl group or a substituted thienyl group at the 2-position of the pyrazolidinone ring, it can be made that Arl has a leaving group X such as bromine or trifluoro The methane sulfonate group and (ii) a methyl or keto group of pyridine or pyrimidine of the formula (V), a pyridine or pyrimine of the formula (V) is condensed with an amine of the formula R4-NH2 in the presence of HSCHR2-co2h to obtain formula (VI) The compounds are shown in Reaction Scheme C. An aromatic ring can then be coupled to the pyridine or pyrimidine ring. This coupling can be used under Still conditions using catalysts such as Pd (PPh3) 4 and trialkylstannyl (hetero) aryl compounds 87682 -47- 200412948, preferably tributyltin alkyl (hetero) aryl compounds. Next. This coupling can also be performed under Suzuki conditions, so aryl halides and arylboronic acids are in the presence of a catalyst such as Pd (PPh3) 4 and a base such as K2C03 or Na2C03 in a solvent such as tetrahydrofuran at elevated temperature. For example, condensation is performed at 80 to 120 ° C.

Reaction diagram D

Reaction Scheme'D provides a method for preparing a compound of formula (I) where Z is 0. In this reaction diagram, a compound of formula (II) can be reacted with a compound of formula (VII) under standard reaction conditions, as described by Giraud et al., Journal of Organic Chemistry, 1998, 63, 9162-9163. Compounds of formula (VII) can also be compounded by compounds of formula R4-NH2 and compounds L-CO-CH (R2) OH (wherein L is a leaving group such as OH) by standard amidine coupling reactions using coupling agents such as EDCI / HOBT, HATU Or HBTU (which is known to those skilled in the art). Compounds of formula (II) can also react with H2N-CO-CH (R2) OH under standard conditions, as described by Giraud et al. To obtain compounds of formula (VIII). Compounds of formula (I) where 1 is 0 can then be prepared from the intermediates of formula (VIII) obtained by standard methods. For example, it enables a compound of formula (VIII) and a compound of formula R4-L (wherein L is a leaving group such as a chlorine atom) in the presence of a base such as NaH in a solvent such as THF at 87682 -48- 200412948

Prepared by reaction at room temperature. Reaction diagram E

Reaction Scheme E provides &lt; a method for preparing a compound of the present invention wherein Z is -NH-. The reaction conditions of the steps described in the reaction of FIG. 4 can be found in, for example, Frutos et al., Tet. Assymmetry, 2001, 12, 101-104. In reaction diagram E, wherein P represents an amine-protecting compound of the formula (IX) and the formula « The amine of R4-NH2 is typically reacted in a solvent such as THF or DMF in the presence of a coupling agent such as EDCI / HOBT at about 0 to 40 ° C. Typically, P is a Boc protecting group or a Z (benzyloxycarbonyl) protecting group. The resulting compound of formula (X) is then deprotected using standard techniques. When P is Boc, the deprotection reaction is typically performed by reaction with trifluoroacetic acid (TFA) in dichloromethane 87682 -49- 200412948. When P is Z, the deprotection reaction is typically carried out in the presence of a catalyst such as 5% palladium / carbon. The resulting compound of formula (XI) can then be reacted with a compound of formula (II) as defined above under standard conditions as described by Frutos et al. This reaction is typically carried out in a solvent such as CH2C12. The cyclization reaction of the obtained compound of the formula (XII) can be performed, for example, in the presence of AcA1 and MeOH to obtain a compound of the formula (I) in which Z is -NH-. The compound of formula (I) in which Z is -NR- can of course be obtained by using the corresponding compound in which Z is -NH- and the group LR (where L is a leaving group such as a halogen atom) in the presence of the coupling agent 洳 EDCI / HOBT in about Prepared by reaction at 0 to 40 ° C. Further synthetic operations of the compound of formula (I), such as bromination, nitration, and deuteration, can be performed in a conventional manner to reach other compounds of formula (I). For example, a compound of formula (I) in which fluorine is present can be prepared from a corresponding compound in which R2 is hydrogen and Et3N.3HF in CH3CN. The compound of formula (I) thus obtained can be salified by appropriate acid or base treatment. Racemic mixtures obtained by any of the methods described above can be resolved by standard techniques such as dissolution on a palm chromatography column. Compounds of formula (II), (III), (VII), (IX), hschr2-co2h, C1-CO-CH (R2) Bi ·, L-CO-CH (R2) OH and N2N_CO-CH (R2) OH And amines of formula R4-NH2 are known compounds or can be prepared by analogous known methods. The compounds of the present invention are found to be inhibitors of N-type calcium channels. Furthermore, many of the preferred compounds of the present invention exhibit selectivity for L-type calcium channels. The compounds of the invention are therefore therapeutically useful. The compounds of the invention can be administered in a variety of dosage forms. Therefore, it can be administered orally, for example, as a bonding agent, a sugar hinge, a tablet bond, an aqueous or oily suspension, a dispersible powder 87682 -50- 200412948, or a granule. * &amp; _ ▲ The preferred pharmaceutical composition of the month is a composition of suitable formulations such as lozenges and capsules suitable for oral administration. The compounds of the present invention can also be administered by non-hunting and non-heart-hunting drugs, and can be administered subcutaneously, intravenously, intramuscularly, intrasternally, nipple, didermal or hunting injection technology. The compound can also be administered as a suppository. -The preferred route of administration is inhalation. Compared to inhaling through many oral routes-inhalation (General Medicine King has the advantage that it is directly delivered to the area rich in blood supply. Therefore, its absorption of glandular cells has several surface repairs and is rich in blood supply and bypassed Metabolism for the first time. The preferred pharmaceutical composition of the present invention therefore contains a person suitable for inhalation. The present invention also provides an inhalation device containing the pharmaceutical composition. The device is typically a metered dose inhaler (MDI), And each ancient comparison _) &amp; has a medically acceptable chemical propellant to push medicine out of the inhaler. Typically, the propellant is a fluorine barrier. Other preferred inhalation devices include a nebulizer. Mouth nebulizer is a device that can deliver a fine liquid mist medicine through the "mask" of the nose and mouth. It is often used to treat asthma patients who cannot use an inhaler ▲ _ dagger. % Children, young children, and severe patients of all ages. The inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, which can deliver the compound of the present invention without the need for a propellant. Typically, the inhalation device contains a spacer. Intermediate substances can be individually inhaled. Larger quantities of medicine are directly entered into the lower respiratory tract, rather than into the throat. Many spacers are placed on the end of the inhaler, and in some cases, a canister is inserted into the device. It has a retention chamber and a one-way, flat n-spacer with spacers to prevent the drug from escaping to the air. Many patients, especially young children, have a difficulty in coordinating their inhalation by adjusting the actions required for the swelling portion of the inhaler by 87682 -51- 200412948. For these patients, a spacer is particularly recommended. Another preferred route of administration is nasal administration. The nasal cavity is highly permeable, and the drug is very easy to be incinerated and absorbed quickly and efficiently, more so than the lozenge drug. Intranasal drug delivery is less painful and non-invasive than injection, and produces less anxiety in the patient. Drugs can be delivered nasally in smaller doses than tablets. In this way, the absorption is extremely fast and bypasses the first metabolism, thus reducing inter-patient variability. The nasal delivery device enables the drug to be administered at a precisely metered dose. Therefore, the pharmaceutical composition of the present invention is typically suitable for intranasal administration. Furthermore, the present invention also provides an intranasal administration device containing the pharmaceutical composition. Another preferred route of administration is percutaneous administration. The present invention therefore provides a transdermal patch containing a compound of the present invention or a pharmaceutically acceptable salt thereof. Sublingual administration is also preferred. The invention therefore also provides sublingual lozenges comprising a compound of the invention or a pharmaceutically acceptable salt thereof. The compounds of the invention are typically formulated for administration in a pharmaceutically acceptable carrier or diluent. For example, solid oral dosage forms may contain active compounds, diluents such as lactose, glucose, sucrose, cellulose, corn starch, or potato starch; lubricants such as silicone, talc, stearic acid, magnesium stearate, or calcium stearate, and / Or polyethylene glycol; binders such as starch, acacia, gelatin, methyl cellulose & methyl cellulose or polyvinylpyrrolidone; disintegrants such as starch, brown bath acid, brown bath salt or Sodium starch glycolate; foaming mixtures; dyes; sweeteners; humectants such as lecithin, polysorbate, lauryl sulfate; and non-toxic and physiologically inert substances commonly used in pharmaceutical formulations. The 87682 -52-200412948 pharmaceutical composition can be, known in the form of tablets, right-hand seventh, 4 such as fine blending, granulation, G enamel making or coating process. 、 Private 1 I oral administration of liquid dispersion can be brand pulp can be ancient / 丨, seven water, emulsion and suspension. Today's Hammer 3 has, for example, sucrose or glycerin and / or mannose in sucrose as a carrier. °% and / or sorbitol heart suspension and emulsion may contain, for example, natural gum, gum, methylcellulose, carboxymethyl carbamidine—exhaustive sodium alginate, intramuscular injection of the second, t, polyethylene glycol As a vehicle. Myocardial / Wang She foot suspension liquid or solution can contain 1 »sexual load such as helmet seedlings and medicine; medicine can be used in conjunction with warfare such as black water, olive oil, ethyl oleate-and suitable if needed The amount of Lido + + is known as two glycols and llclocine hydrochloride. &gt; The solution for king shot or infusion may contain, for example, &gt; », &amp; 1 is a carrier or preferably a solution of tritium, water, isotonic salt. The compounds of the present invention are therapeutically useful in the treatment or prevention of conditions regulated by N-type dance channels. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical for treating or preventing a condition regulated by an N-type calcium channel. Also provided is a method of treating a patient suffering from or susceptible to a condition regulated by each channel of M, the method comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. These compounds can be used as calcium channel antagonists and thus can suppress the individual's disease. The condition can be relieved by reducing the influx of cells that cause the disease to sink. 0 N-type calcium channels are known to be closely related to the regulation of pain conduction. Typically, the compounds of the invention are therefore useful as analgesics. N-type | Bow channels have been identified as particularly important in pain signal transmission in the chordae (Chaplan S.R. PQgI * el j w 87682 -53- 200412948

Yaksh T.L. J. Pharm. Exp. Then 1994, 269, 1117-1123, Diaz, A., Dickenson, A. Pain, 1997, 69, 93-100). Indeed, a series of recent clinical studies have confirmed the important role of N-type calcium channels in pain transmission (Mathur, V.S .; McGuire, D .; Bowersox, S.S .;

Miljanich, G.P .; Luther, R.R. Pharmaceutical News, 1998, 5, 2 5-29). The compounds of the present invention are therefore particularly effective in relieving pain. Therefore, this medicine is typically used to relieve pain and the patient is suffering from or susceptible to the pain. The compounds of the present invention are effective in relieving slowness and acute pain. Acute pain is generally understood as the discomfort, prediction of feelings and emotional experiences associated with some sort of autonomic (reflex) response, and the dissatisfaction, feelings and emotional experiences of mental and behavioral reactions caused by injury or disease. A discussion of acute pain can be found in Halpern (1984) Advanced Pain Research and Treatment, Volume 7, page 147. Tissue injury induction-a series of nerve stimulations which are transmitted to the spinal cord by the damage receptors and transmitted to the spinal cords and transmitted to the upper part of the central system. Examples of sexual pain that can be relieved by the compounds of the present invention include musculoskeletal pain such as joint pain, lower back pain and boil pain, teeth, post-operative pain, labor pain such as childbirth pain, acute headache pain, myalgia, and visceral pain. It is understood that for people who continue to exceed the acute disease, and have sustained injury to recovery, the discussion of halal pain, chronic pain, or chronic pain can be found in * pen 4 test and dedication. Chronic pain is sometimes caused by damage to the receptor and force. Can be borrowed from the examples of the present invention, including the second, 7th, a, birth, milk, love, &lt; k sex pain 蹋 ° ~ _, ,, dysentery, post-herpetic neuralgia (because of the damage in the skin # 分 右Festering herpes zoster disease, anti- ^ ^ associated with skin changes in the knife cloth, urinary neurodegenerative disease, burning pain ($ 4 pain state) ,; burning pain fantasy limb "pain, due to osteoarthritis ^ 87682- 54- 200412948 Pain, rheumatism Guan Yijie, such as ,,,, and other causes &lt; Pain, cancer-induced pain, HIV-related pain, extensive rain, migraine, and other conditions related to chronic head pain: severe and Mild hyperalgesia, inflammatory pain, injury receptor pain, spinal cord therapy, spinal cord injury pain, spinal cord pain, central pain, pain after central sore, pain after soaking, non-cardiac chest pain, irritating bowel syndrome, f long ~% Of the diseases are related to pain and indigestion. Some of the chronic pains mentioned above, such as triple neuralgia, diabetic neurodegenerative disease: burning pain, fantasy limb pain, and pain after central stroke have been classified as nerves :::: one of menstrual pain Non-limiting definition is lack of due to trauma or illness p and D0 pain caused by peripheral or central nervous system insufficiency under stimulation. Of course, the compounds of the present invention can be used to soothe or reduce the occurrence of neuropathic pain. Blocking N-type calcium channels can inhibit the release of excitatory amino acids Therefore, its characteristics can be used to inhibit nerve cell damage during oxygen deficiency, function as a neuroprotective agent, and can be used to treat cerebral ischemia or middle frame nervous system damage (B.5 Denyer, JC Expert Opinion on Therapeutic

Pints ’1998, 8, 1237_125〇). This compound solution can be used to treat eye diseases (hu, T-C, Potter, D.E. Research Communications in armacology and Toxicology, 2001, 6, 263-275). Examples of cerebral ischemia that can be treated or prevented by the compounds of the present invention include temporary ischemic attack, stroke, such as embolization stroke, ischemic stroke, plug stroke, hemorrhagic stroke or lacunar stroke, subarachnoid hemorrhage, cerebral vasospasm , Asphyxia, drowning, cardiac arrest and subdural hemorrhage after birth. Examples of central nervous system injuries that can be treated with the compounds of the present invention include external 87682 200412948 brain injury, neurosurgery (surgical trauma), neuroprotective effects of head injury, internal pressure increase, cerebral edema, hydrocephalus and spinal cord injury . Ocular diseases treated or prevented by the compound of the present invention include drugs, cataracts, diabetic cataracts, diabetic neurodegenerative diseases, ischemic retinopathy, diretinal hemorrhage, retinitis staining, acute glaucoma, especially acute ¥ Glaucoma, chronic glaucoma, especially chronic atmospheric glaucoma, degeneration of spots, retinal artery occlusion, and retinitis. In view of its inhibitory effect on the release of nerve conductors, the compounds of the present invention can be used for 乂 / oral treatment of sudden diseases. Examples of sudden illnesses that can be treated or prevented by the compounds of the present invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial burst, complex sub-burst, and partial burst-continuous general burst), and general bursts including tonicity / clonicity Bursts (mapileptic seizures), Absence bursts (small epileptic seizures), Burst myoclonus, Non-tonic bursts, Bursts and tonic dry hair, Lennox Gastaut disease , Western syndrome (juvenile spasms), multiple obstructive bursts and burst prevention (anti-burst agents). Furthermore, the compounds of the present invention can be used for the treatment of tinnitus, itching such as itching sensations, neurogenic and psychogenic itching, and urinary tract diseases such as urinary incontinence and irritant syndromes. The compound solution of the present invention can be applied to diseases generally related to blocking of L-type # 5 channel, such as cardiac blood vessels, gas control, and anti-bronchial contraction diseases such as prevention and treatment of hypersensitivity, allergies, bronchospasm, dysmenorrhea, esophageal spasm , Premature birth, gastrointestinal peristaltic disease and cardiovascular disease, wherein the cardiovascular disease is selected from hypertension, myocardial ischemia, angina pectoris, congestive heart loss for 5 weeks, myocardial infarction and recurrence. 87682 -56- The compound of the present invention can prevent the occurrence of this condition preventively if appropriate. &gt; An oral therapeutically effective amount of the invented human, eight mouthpieces are administered to cheek patients. The typical dose is about 0.001 to 500 per A kg of beans per month. According to the activity of a specific compound, the age, weight and disease of the individual to be treated, / b, the type and severity of the disease, and the number of administrations and Depending on the path. Better Nan Zhihao said that the dosage I was from 5 mg to 2 g. [Embodiments] + The following examples illustrate the present invention. It is not intended to limit the invention. In this regard-it is important to understand the specific analysis used in the example paragraph: it is designed to provide indications that inhibit N_ channel activity. There are many assays that can determine the activity of a given compound as an N-type Kodo antagonist and the resulting negative value for any particular assay is therefore not conclusive. Examples Examples of the compounds of the present invention are the above-mentioned compound numbers 65 to 65. The compounds were prepared as follows. Example 1 in 4- (4-bromophenyl) -pyridine-3-carbaldehyde (0.050 g, 0.19 mmol) (Thomas, AD; Asokan, CV ·, Journal of the Chemical Society, Perkin Transactions 1,2001 , 20, 2583-2587) in benzene (3 liters) was added with 3,5-difluorobenzylamine (22 µl, 0.19 mmol) and hydrothioacetic acid (13 µl, 0.19 mmol) Moore). The reaction mixture was heated at reflux for 15 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous NaHC03 solution and saturated brine in this order. The organic layer was dehydrated with MgS04. MgS04 was removed by filtration and the filtrate was evaporated in vacuo. After vacuum drying, 2- [4- (4-bromophenyl) -pyridin-3-yl] -3- (3,5-difluorobenzyl) was obtained as a pale yellow solid. -Pyrazolidine-4- 87682 -57- 200412948 ketone. HPLC (Method A) retention time 4.13 minutes (丨 Rong ··

MeCN / H20 / 0.05% NH4OH, 5,95% gradient H20 for 0-6 minutes. dry

Waters Xterra 50x4.60 mm ID, C18 reverse phase, flow rate: 1.5 halo / min). Mass spectrum (ES +) m / z 461, 463 (M + H). Example 2 Using a procedure similar to that described in Example 1, starting from 2,3,4-trifluorobenzylamine, 2- [4- (4-bromophenyl) -pyridin-3-yl] was obtained as a pale yellow solid. _3- (2,3,4_Di ^ »5 digascarbyl)-sedazidin-4-one. HPLC (Method A) retention time 4.17 minutes. Mass i (ES +) m / z 479,481 (M + H) 〇 Example 3 Using a procedure similar to that described in Example 1, starting from 2,5-difluorobenzylamine, 2- [4- (4-Bromophenyl) -pyridin-3-yl] -3- (2,5-difluoroethanyl) monopyridin-4-one. HPLC (Method A) retention time was 4.07 minutes. Mass spectrometry (ES +) m / z 461,463 (M + H) 〇 Example 4 Using a procedure similar to that described in Example 1, from 3,4-dimethyldioxyphenethylamine hydrochloride and methylamine (40% aqueous solution ), And heated to 45 ° C for 64 hours and then to 80 C for 6 hours to obtain 3- (2-benzo [ι, 3] dioxopentyl-5-ylethyl) -2- as a yellow oil [4- (4-bromophenyl) _pyridine-3_ylthiazolidine_4_one. HPLC (Method A) retention time 4.01 minutes. Mass spectrum (ES +) m / z 484 (M + H) 〇 Example 5 Step 骡 1 Using a procedure similar to that described in Example 1, from 4-bromopyridine_3_formaldehyde, isobutylamine, and 87682 -58- 200412948 chlorothio group Start with acetic acid, heat at 80 ° C for 16 hours and purify by flash column chromatography (dissociated with isohexane / ethyl acetate i: 丨) to obtain 2_ (4_bromo ^ bifluorene> 3-yl) as a pale yellow solid. ) -3-isobutyl-distazolidin_4_one. HPLC (Method A) retention time was 3.55 minutes. Mass spectrum (ES +) m / z 315, 317 (M + H). Step 2 2_ (4_Mo-Ebbit_3yl) -3_isobutyl-thiazolidinone (0.10 g, 0.32 pen moles) and phenylboronic acid (0.041 g, 0.34 millimoles) The 1-propane solution was flushed with nitrogen and stirred at room temperature for 20 minutes. Add Pd (OAc) 2 (Q.001g "4.45 Emory) ,?卩 113 (0 003 g, 95 millimoles) and 2 ^ 20 20: 03 (0.2 ml '0.38 millimoles). The reaction mixture was flushed with nitrogen and then heated to 80 ° C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHC03 and brine and dried over MgS04. MgSO was removed by filtration and the filtrate was concentrated in vacuo. The residue was subjected to flash column chromatography (iso-hexane / ethyl acetate 1: 1 dissolution) and dried under vacuum to obtain 3-isobutyl-2- (4_benzylide) -3-yl as a yellow solid- Far away bite-4-one. HPLC (Method A) retention time was 3.74 minutes. Mass spectrum (ES +) m / z 313 (M + H). Example 6 Using a procedure similar to that described in Step 2 of Example 5, starting from 3,4-methylenedioxyphenyllithium benzoate, 2- (4-benzo [1,3] dioxetane) was obtained as a yellow oil. -5-yl-eridin-3-yl) -3-isobutyl-dipridin-4-one. HPLC (Method A) retention time was 3.64 minutes. Mass spectrum (ES +) m / z 357 (M + H). Example 7 Using a procedure similar to that described in step 2 of Example 5, starting from 2-p thiophene boronic acid, 3-isobutyl-2- (4-pyridin-2-yl-pyridin-3-yl) was obtained as a yellow oil. Xazolide-4- 87682 -59- 200412948 exposure. HPLC (Method A) retention time 3.48 minutes. Mass spectrum (ES +) m / z 3 19 (M + H). Example 8 Using a procedure similar to that described in Example 1, since 2 -Cyclohexyl-1 -fluorenyl-ethylamine was started and the product was purified by flash column chromatography (iso-hexane / ethyl acetate 1: 1 dissociation) to obtain 2- [4- (cardibromophenyl) as a solid Pyridine-3-yl] -3_ (2-cyclohex-1-fluorenyl-ethyl) -thiazolidine-4-one. HPLC (method A) retention time 4.59 minutes. Mass spectrum (ES +) m / z 443, 445 (M + H) 〇__ Example 9 Using a procedure similar to that described in Step 5 of Example 5, 2- (4-bromo-pyridin-3-yl) -3-isobutylpyrazolidine-4-one and Pyridin-4-ylboronic acid was started and purified by flash column chromatography (isohexane / acetic acid acetate 1: 4 followed by ethyl acetate followed by ethyl acetate / methanol 19: 1) to obtain 2- [2] as a yellow oil. 4,4f] bipyridin-3-yl-3-isobutylpyridin-4-one. HPLC (method A) retention time 3.05 minutes. Mass spectrum (ES +) m / z 314 (M + H). Example 10 4-chlorophenylboron Acid (0.045 g, 0.29 mmol) added to 2_ (4-bromopyridine-Hongji) _3_isobutylπseptundum_4 __ (〇.075 g, 0.24 mmol) -In a stirred solution of dimethoxyethane (1 ml) and the solution was degassed. K2C03 (0.090 g, 0.65 mmol), water (0.3 ml) and Pd (PPh3) 4 (0.0 10 g '9 mol) and the mixture was heated to 85. 0 for 15 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous NaHC03 solution and brine and dehydrated with MgSCU. The MgS04 was removed by filtration and the filtrate was evaporated in vacuo The residue was purified by flash column chromatography (solved with isohexane / ethyl acetate 2: 3 87682 -60- 200412948) after vacuum drying to obtain 2- [4- (4-chlorophenyl) as a pale yellow solid. ) -Pyridoxine: -3-yl] -3-isobutylpyrazolidin-4-one. HPLC (method A) retention time 4.00 minutes. Mass spectrum (ES +) m / z 347, 349 (M + H). Example 11 Using a procedure similar to that described in Example 10, starting from 4-fluorophenylboronic acid and purifying by flash column chromatography (isohexane / ethyl acetate 3 followed by 1: 1 dissociation), 2_ [ 4- (4-fluorophenyl) -pyridin-3-yl]- 3-isobutylpyrazolidin-4-one. HPLC (Method A) retention time 3.81 minutes. Mass spectrum (ES +) m / z 33 1 (M + H). Example 12 Using a procedure similar to that described in Example 10, starting from 3-bromophenylboronic acid and purifying by flash column chromatography (iso-hexane / ethyl acetate 9: 1 followed by 4: 1), a pale yellow solid was obtained. 2- [4- (3-Bromophenyl) -pyridin-3-yl] _3-isobutylpyrazolidin-4-one. HPLC (Method A) retention time 4.01 minutes. Mass spectrum (ES +) m / z 391,393 (M + H). Example 13 Using a procedure similar to that described in Example 10, starting with 4-trifluoromethoxyphenylboronic acid and purifying by flash column chromatography (using Isohexane / ethyl acetate 3: 2 dissociation) to obtain 3-isobutyl-2- [4- (4-trifluoromethoxyphenyl;) _ pyridin-3-yl] -pyridine as a yellow oil -4_one. HPLC (Method A) retention time 4.12 minutes. Mass spectrum (ES +) m / z 397 (M + H) ° Example 14 Using a procedure similar to that described in Example 10, starting with 4-methylphenylboronic acid and purifying by flash column chromatography (using isohexane / ethyl acetate Esters 3: 2 dissociated) to obtain pale yellow 87682 -61-200412948 3-isobutyl-2- (4 -p-tolyl-p-pyridine-3 -yl) -τιthio_4_ ketone. HPLC (Method A) retention time was 3.97 minutes. Mass spectrum (ES +) m / z 327 (M + H) ° Example 1 5 Using a procedure similar to that described in Example 10, starting from 4- (trifluoromethylsilyl) phenylboronic acid and purifying by flash column chromatography ( (Isohexane / ethyl acetate 3: 2 dissociation) to obtain 3-isobutyl-2- [4- (4-trifluoromethylsilyl-phenyl) -anodo-3-yl] as a pale yellow solid -Li Jundian-4-one. HPLC (method A) retention time 4.0 min. Mass spectrum (ES +) m / z 385 (M + H). Example 16 Using a procedure similar to that described in Example 10, starting from 4-methyl p-sphenyl; 5-pentanoic acid and purified by flash column chromatography (iso-hexane / ethyl acetate 3: 2 followed by 1: 1 dissolution) To obtain 3-isobutyl-2- [4- (4-methylsulfanyl-phenyl) -pyridin-3-yl] -vτcetinol> 4-one as a pale yellow solid. HPLC (Method A) retention time 4.01 minutes. Mass spectrum (ES +) m / z 359 (M + H). Example 17 Using a procedure similar to that described in Example 10, starting with 4-ethylphenylboronic acid and purifying by flash column chromatography (dissociation with isohexane / ethyl acetate 7: 3 followed by 3: 2), a pale yellow color was obtained. 2- [4- (4-ethyl-phenyl) -pyridin-3-yl] isobutyl, sedazin-4-one as a solid. HPLC (Method A) retention time 4.20 minutes. Mass spectrum (ES +) m / z 341 (M + H) 〇 Example 1 8 Step 1 Add n-butyl M (2.5 M, 22.5 ml, 56.3 ¾ mole) to diisopropyl 87682 -62- 200412948 amine (9.56 Ml, 68.1 mmol) of tetrahydrofuran (200 ml) in a -78 ° C solution. The reaction was stirred at -78 ° C for 30 minutes and at 0 ° C for 30 minutes. The reaction was cooled to -78 ° F and a solution of 3 · bromopyridine (5 ml, 51.2 mmol) in tetrahydrofuran (15 ml) was added. The reaction mixture was stirred for 10 minutes and dimethylformamide (15.8 ml, 222 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 hour and at room temperature for 30 minutes. Saturated NaHC03 (2 mL) was added and the reaction was poured into saturated NaHC03 (200 mL) and stirred for 16 hours. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ether (300 ml) and washed with saturated NaHCO3 (200 ml) and brine. The organic layer was separated and dehydrated with MgS04. MgS04 was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in hot isohexane, filtered and the filtrate was cooled to 0 ° C. The light-colored solid was separated, collected by filtration, and purified by flash column chromatography (iso-hexane / ethyl acetate 2: 1), and dried under vacuum to obtain 3-bromo-pyridine-4-carbaldehyde as a colorless solid. 4 NMR (400 MHz, CDC13) 5 10.36 (1Η), 8.91 (1Η), 8.71 (1Η), 7.71 (1Η). Step 骡 2 Using a procedure similar to that in Example 1, starting from 3-bromo-pyridine_4_formaldehyde and isobutylamine, heating to 80 ° C for 6 hours, and purifying by flash column chromatography (using isohexane) / Ethyl acetate 4: 1), followed by dispersing with isohexane to obtain 2- (3-bromopyridin-4-yl) -3_isobutylthiazolidine-4-one as a colorless solid. HPLC (Method A) retention time 3.60 minutes. Mass spectrum (ES +) m / z 315, 317 (M + H). Step 骡 3. 2,2-Dimethoxyethane (1 ml of 2 · (3 · bromoxandinyl) -3-isobutylpyrazolidin-4-one (0.20 g, 0.63 mmol) ) To the stirred solution, add renmethoxymethoxy acid (0.116 g, 0.76 mmol), k2CO3 (0.237 g, 1.71 87682 -63- 200412948 mmol) and water (2 ml). The solution was degassed and Pd (pph3) 4 (0.029 g, 0.03 mmol) was added. The mixture was then heated to 85 ° C for 16 hours. Add CH2C12 (8 ml) and water (5 ml) to the mixture and continue stirring for 30 minutes. The mixture was filtered and the filtrate was dried over MgS04. MgS04 was removed by filtration and the solution was concentrated in vacuo. The residue was purified by flash column chromatography (iso-hexane / ethyl acetate 4: 1 followed by 2: 1 followed by 2: 3) and dried under vacuum to obtain a solid. The solid was dispersed in isohexane and then dissolved in ether. HC1 dioxane solution (4M) was added and the solvent was evaporated in vacuo. After vacuum drying, 4_ (3_isobutyl_4-oxo ^ pyridin_2_yl) -3_ (4_methyl) was obtained as a yellow solid. Oxy-phenyl) -pyridine hydrazone; chloride. HPLC (Method A) retention time was 3.77 minutes. Mass spectrum (ES +) m / z 343 (M + H). Example 19 A procedure similar to that in Example 18, Step 3 was started from 4-chlorophenylboronic acid to obtain 3- (4-chloro-phenyl) _4- (3_isobutyl_4_oxo-pyrazole) as a colorless solid. Pyridin_2_yl) _pyridine; chloride. HPLC (Method A) retention time 4_03 minutes. Mass spectrum (ES +) m / z 347, 349 (M + H). Example 20 The procedure similar to that in step 18 of Example 18 was started from 4-fluorophenylboronic acid to obtain 3- (4-fluoro · phenyl) -ζμ (3-isobutyl-4-oxo 4 succinate) as a colorless solid. Yodo-2-yl) -p ratio Yodo radium; chloride. HPLC (Method A) retention time was 3.83 minutes. Mass spectrum (ES +) m / z 331 (Μ + Η). Example 21 The procedure similar to that in Example 3, step 3, was started from 4-methylphenylboronic acid to obtain 4- (3-isobutyl-4 -oxo-pyridine-2-yl)- 3-p-tolyl-synthesized ytterbium; chloride. HPLC (Method A) retention time was 4.06 minutes. Mass 87682 -64- 200412948 Spectrum (ES +) m / z 327 (M + H). Example 22 2.5 M of n-butyllithium (22.5 ml, 56.3 mmol) was added to -78 of tetrahydrofuran (200 ml) of diisopropylamine (9.56 * l, 68.1 mmol). (:: solution. The reaction was stirred at -78 C for 30 minutes and stirred at 30 ° C. The reaction was cooled to -78 ° C and 2-bromopyridine (5 ml, 52.4 mmol) was added. ) Solution of tetrahydrofuran (15 ml). The reaction mixture was stirred at _78 for 4 hours, during which the solution became light orange. Dimethylformamide (5 · 8 ml, 204 mmol) was added. And the reaction was stirred at -78 C for 30 minutes and stirred at room temperature for 2 hours. Saturated NHW1 (60 mL) was added and the reaction was stirred at room temperature for 16 hours. The organic layer was separated and vacuum: concentrated. The residue was dissolved in ether and saturated with Wash with NaHC03 and saturated brine. Separate the organic layer and dehydrate with MgSCU. Remove MgS04 by filtration and concentrate the filtrate in vacuo to obtain a red oil. The oil was purified by flash column chromatography (isohexane / ethyl acetate 9: 1 followed by 4 : 1 dissociation) and vacuum drying to obtain 2_ (2-bromoelide_3_yl) -3-isobutylπsetumol-4-one as a colorless solid. 1H NMR (400 MHz, CDC13) 5 10 · 34 (1Η), 8.57 (1Η), 8.17 (1Η), 7.43 (1Η). Step 2 In 2- (2-bromo-bite-3-yl) -3-isobutylpyridine _4_ ketone (0.689 g, 3.70 mol) To a solution of isobutylamine (0.44 ml, 4-44 mmol) in benzene (20 ml) at 80 ° C was added hydrothioacetic acid (0.31 ml, 4.44 mmol). The reaction was heated to 80 ° C for 16 Hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHC03 solution and brine, dried over MgS04. The MgS04 was removed by filtration and the filtrate was concentrated in vacuo. Purified by column chromatography (iso-hexane / ethyl acetate 2 ·· 1 dissociation) to obtain solid 87682 -65- 200412948. A second impure fraction was obtained, which was dispersed by isohexane and dried under vacuum to obtain colorless needles. 2- (2-bromo-pyridin-3-yl)> 3-isobutyloxetine-cardione. 4 NMR (400MHz, CDC13) 5 8 · 36 (1Η), 7.43 (1Η), 7.33 (1Η), 5.95 (1Η), 3.64_3 · 70 (3Η), 2.43 (1Η), 1.93-2_00 (1Η), 0.92 (6Η) 〇 Step 3 in 2- (2 • 澳-π Biyodo-3-yl) -3-isobutyl- π plug mouth _4_ isocyanate (0.10 g, 0-32¾ mole) of ι, 2-dimethoxyethane (2 ml) Stirred solution: Zhong Gongkou 4-bromophenylboronic acid (0.076 g, 0.38 mmol) , K2CO3 (0. U8 g, 0.86 mmol) and water (2 ml). The solution was degassed and Pd (pph3) 4 ((K0i7 g, 0 · 02 φmol) was added. The mixture was heated at 85 ° C for 16 hours. Add CH2C12 (8 ml) and water (5 ml) to the mixture and continue stirring for 30 minutes. The mixture was filtered and the filtrate was dehydrated with MgS04, filtered to remove MgS04 and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (iso-hexane / ethyl acetate 4: 丨 then 3: j followed by 2 ·· 1 dissolution). The purified product was dissolved in ether and the addition of a solution of HC1 in dioxane (4M) resulted in a colorless precipitate. The precipitate was collected by filtration, and then dispersed in isohexane and dried with real ganoderma to obtain 2- (4-bromo-phenyl) -3- (3-isobutyl-4-oxo_soulamido-2-yl)-as a colorless solid. p pyridinidine; chloride. HPLC (Method A) retention time 4.04 minutes. Mass spectrum (ES +) m / z 391, 393 (M + H). Example 23 A procedure similar to that in Step 3 of Example 22 was started from 4-methoxyphenylboronic acid to obtain 3- (3-isobutyl-4-oxo · thiazolidin-2-yl) -2- ( 4 • methoxy-phenyl) -pyridine; chloride. HPLC (Method A) retention time was 3.69 minutes. Mass spectrum (ES +) m / z 343 (M + H). 87682 -66- 200412948 Example 24 A procedure similar to Step 3 of Example 22 was started from the deduction of chlorophenylboronic acid to obtain 2- (4-chloro-phenyl) _3_ (3_isobutyloxy-pyrazolidine) as a colorless solid _2_yl) _pyridoxine; chloride. HPLC (Method A) retention time was 3.97 minutes. Mass spectrum (ES +) m / z 347, 349 (M + H). Example 25 A procedure similar to that in Step 22 of Example 22 was started from fluorophenylboronic acid to obtain 2- (4-fluoro-phenyl) _3_ (3_isobutyl_4_oxo_oxazole} _ as a colorless solid. 2_based) _ Edianlu; chloride. HPLC (Method A) retention time was 3.75 minutes. Mass spectrum (ES +) m / z 331 (M + H). Example 26 A procedure similar to that in Step 3 of Example 22 was started from 4-methylphenylboronic acid to obtain 3- (3-isobutyl · 'oxo-thiazolidine-2_yl) -2-pair _Tolyl · Orbital cadmium, vapor. HPLC (Method A) retention time was 3.88 minutes. Mass spectrum (ES +) m / z 327 (Μ + Η). Example 27 Similar to the procedure of Example 10, starting from 4-trifluoromethylphenylboronic acid, and purified by flash chromatography (dissociated with isohexane / ethyl acetate 3: 2) to obtain 3-isobutyl as a pale yellow oil. -2- [4- (4-trifluoromethyl-phenyl) _pyridine_3_yl] _pyrazolidone. HPLC (Method A) retention time was 408 minutes. Mass spectrum (ES +) m / z 381 (M + H). Example 28 Similar to the procedure of Example 10, starting from 4-cyanophenylboronic acid and purified by flash chromatography (isohexane / ethyl acetate 2 · 3 followed by 1: 1 dissolution), a pale yellow solid -67- was obtained. 87682 200412948 4- [3- (3- (3-Butyl-4-oxooxetyridine_2_yl) _t-bite_4_yl] -benzonitrile. HPLC (Method A) retention time was 3.57 minutes. Mass spectrum (ES +) m / z 338 (M + H). Example 29 A procedure similar to that of Example 10 was started from 4-methoxyphenylboronic acid and purified by flash chromatography (with isohexane / ethyl acetate 2: 3 followed by 1: 1 dissolution) to give 3-isobutyl-2- [4- (4-methoxy_phenylpyridyl] _pyrazolidine_cardione as a pale yellow solid. HPLC (method A) retention Time 3.77 minutes. Mass spectrum (ES +) m / z 343 (M + H). Example 30 A procedure similar to that of Example 10 was started with 4-acetamidophenylboronic acid and purified by flash chromatography (using isohexane / Ethyl acetate 2: 3 followed by 1: 1 dissolution) to obtain 3-isobutyl-2- [4- (4-vinyl-phenyl) _pyridin-3-yl] -pyrazolidine- 4-keto. HPLC (method A) retention time 4.05 minutes. Mass spectrum (ES +) m / z 339 (M + H) 〇 Example 3 1 in 2 _ (3-> odor p ratio 111 _ 4_ group)- 3-isobutyl far-zero azo-4-S isopropyl (0.20 g '0.63 mmol) and 4-bromophenylboronic acid (0.153 g, 0.76 mmol) K2CO3 (0.237 g, 1.71 mmol) and water (2 ml) were added to the ethane (2 ml) solution. The solution was degassed and then treated with Pd (PPh3) 4. The reaction was heated to 85 ° C for 16 hours CH2C12 (8 mL) and water (5 mL) were added and the mixture was stirred for 30 minutes. The mixture was filtered using a phase separation tube (1ST, Isolute). The organic layer was dehydrated with MgS04. The MgS04 was removed by filtration and the filtrate was concentrated in vacuo. Residue The material was purified by flash column chromatography (iso-Tiger / ethyl acetate 4 ·· 1 followed by 2: 1 to 1 ·· 1 to 87682 -68-200412948 2: 3) and then purified by preparative reverse phase hplC (solvent : MeCN / H2O / 0,05% NH4〇H, 5-95% gradient Η20 · 6 minutes, column: Waters Xtena 50x19 mm inner diameter, C18 reverse phase, flow rate: 17 ml / min) 'to obtain a colorless solid. Solid Dissolved in ether and added HC1 dihenane solution (4M) to obtain a colorless precipitate, which was collected by filtration and then dispersed in ether. After vacuum drying, 3_ (4_bromo_phenyl) _4_ (3_iso Butyl_4-oxo'fluoride-2-yl) -pyridinium chloride; chloride. HplC (Method A) retention time 4.07 minutes. Mass spectrum (ES +) m / z 391,393 (M + H). ; Example 32 To a solution of 2- (2-bromopyridin-3-yl) -3-isobutylpyrazolidine_4_one in toluene (5 ml) and ethanol (1 liter), 4_ethyl was added晞 基Phenylboronic acid and 2M Na2CO3 (2 liters). The reaction mixture was degassed and pd (pph3) 4 was added. The reaction was then heated to 100 ° C for 16 hours. Add ch2C12 (8 ml) and water (5 ha) to the mixture and continue stirring for 30 minutes. The mixture was filtered and the filtrate was dehydrated with MgSCU. MgS04 was removed by filtration and the filtrate was concentrated in vacuo. The residue was separated by flash column chromatography with isohexane / ethyl acetate (4: 1 to 丨: 丨). The residue was dissolved in diethyl ether and 4M HC1 / dipurinane was added. The precipitate was collected by filtration, dispersed in ether and dried under vacuum to obtain 4- (3-isobutyl_4-oxo-thiazolidine 2-yl) -3- (4-ethylenyl_phenyl) _ as a colorless solid. Pyridine hydrazone; chloride. HpLC (Method A) residence time was 4.04 minutes. Mass spectrum (ES +) m / z 339 (M + H). Example 33 Using a procedure similar to that described in Example 32, starting from 4- (trifluoromethyl) _phenylboronic acid, 3- (3-isobutyl_4-oxo-pyrazolidine_2_ was obtained as a colorless solid. ) _2_ (4-trifluoromethyl-phenylpyridine hydrazone; chloride. Ηρχ (method A) retention time 87682 -69- 200412948 between 4.06 minutes. Mass spectrum (ES +) m / z 381 (M + H) Example 34 Using a procedure similar to that described in Example 32, starting from 4-cyanophenylboronic acid, 2- (4-cyano-phenyl) -3- (3-isobutyl-4-oxo was obtained as a colorless solid. Substituted-pyrazolidin-2-ylpyridinium pyridine; chloride. Hplc (method A) retention time 3.58 minutes. Quality (ES +) m / z 338 (M + H). Example 35 Uses similar to those described in Example 32 Procedure, starting from 4-vinylphenyl heteroacid "to obtain 3- (3-isobutyl-4 · oxo-dissolve-2 · yl) -2- (4-vinyl- Phenyl) -pyridine hydrazone; Chloride. HPLC (Method A) Retention time 3 97 minutes. Mass spectrum (ES +) m / z 339 (M + H). Example 36 4- (4-Bromomethylpyridine-3 -A solution of formic acid (0.083 g, 0.315 mmol) and isoamylamine (0.033 g, 0.38 ¾ mole) was heated in benzene to 60. 0 for 90 minutes. Add Thioacetic acid (0_038 g, 0.41 mmol) and the mixture was heated to 80 ° C for 16 hours. The solvent was removed in vacuo and the residue was dispersed in ether. After vacuum drying, 2_ [4_ (4-Bromo_phenyl) _pyridine_3_yl] -3 (3-methyl-butyl) -thiazolidine-4-one. HPLC (method A) retention time 4.29 minutes. Mass spectrum (ES +) m / z 405, 407 (Μ + Η). Example 37 4 · (4-Bromophenyl) -Edian_3_formaldehyde (0.083 g, 0.32 mmol), 2,2,3,3, A solution of 3-pentafluoropropylamine (〇104, 0.7 mmol) and hydrothioacetic acid (0.032 g, 0.35 mmol) was heated in toluene at 56 t for 72 hours and heated at 8 (TC 36 hours. The solvent was evaporated in vacuo and the residue was purified by chromatography using a flash column 87682 -70- 200412948 (iso-hexane / ethyl acetate 1: 1 dissolution) and dried under vacuum to obtain 2- [4_ (4- Bromophenyl) -pyridin-3-yl] -3- (2,2,3,3,3-pentafluoropropylettoline-4-one. HPLC (Method A) retention time 3.75 minutes. Mass spectrometry (ES +) m / z 467,469 (M + H). Example 38 4- (4-bromophenyl) -pyridine-3-carboxaldehyde (0.50 g, 0.19 mmol) benzene (1 mmol) ) Was heated to and add 5 0 ° C ethylamine (2M solution in tetrahydrofuran, 0.19 ml, 0.38 mmol). The solution was heated to 50 ° C for 15; minutes and | hydrothioglycolic acid (0.01 8 g, 0.19 mmol). The reaction was then heated to 80 ° C for 72 hours. KAO3 aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was dehydrated with MgSCU. MgS04 was removed by filtration and the filtrate was concentrated in vacuo. The residue was dispersed in diethyl ether and dried under vacuum to obtain 2- [4- (4-bromophenyl) _pyridine_3_yl] _% ethylpyrazolidine_4_one as an off-white solid. HpLc (method A) retention time 3.75 minutes. Mass spectrum (ES +) m / z 363, 365 (m + h). Example 3 9 Similar to the procedure described in Example 36, starting from 3,3-dimethylbutylamine, 2- [4, (4-bromophenyl ratio lake_3_kib 3- (3-bromophenyl ratio) _ (3- 3,3-dimethyl-butyl) acetophenone. HPLC (Method A) retention time 4 shoulder minutes. Mass spectrum (ES +) m / z 419, 421 (M + H). The procedure described in Example 36, starting from cyclopentylamine, yielded an off-white solid phenyl), "Pyridol_3yl] dongcyclopentyl_sound money 4 different. HPLC (10,000 to A) retention time was 417 minutes. Mass spectrum 彻, 彻 (M + H) 0 '87682 -71 200412948 Example 4 1 Similar to the procedure described in Example 36, starting from aminomethylcyclopropane to obtain 2- [4- (4-bromo Phenyl) -pyridin-3-yl] cyclopropylmethyl-pyrazolane-4-one. HPLC (Method A) retention time was 3.99 minutes. Mass spectrum (ES +) m / z 389, 391 (M + H). Example 42 Similar to the procedure described in Example 36, starting from 3- (isopropoxy) _propylamine, 2- [4- (4-bromophenyl) _pyridine_3_yl] _3_ (3-Isoamyloxypropyl) -pyrazolidine. 4-one. HPLC (Method A) retention time was 4.09 minutes. Mass spectrum (ES +) m / z 435, 437 (M + Η). Example 43 Similar to the procedure described in Example 36, starting from propylamine, 3- propyl-2- [4- (4-bromophenyl) _pyridine_3_yl] _thiazolidine was obtained as a colorless solid. _4_ketone. HPLC (Method A) retention time 3.95 minutes. Mass spectrum (es +) m / z 375, 377 (M + H). Example 44 A procedure similar to that described in Example 10 was started from 3-methylphenylboronic acid to obtain 3-isobutyl_2_ (4_ M-tolyl_pyridine_3_yl) _thiazolidine_4_ is different. HPLC (Method A) retention time was 3.96 minutes. Mass spectrum (ES +) m / z (M + H). Example 45 Similar to the procedure described in Example 10, starting from 2,4-dimethylbenzeneboronic acid, 2- [4- (2,4-dimethylbenzylpyridine_3_kib 3-Isobutyl_pyrazolane-4-one. 1 ^ 1 ^ (Method 8) retention time 4.15 minutes. Mass spectrum (£ 8 +) 111 / ^ 87682 -72- 200412948 341 (M + H). Example 46 Similar to the procedure described in Example 10, starting from 2-methylphenylboronic acid, 3-isobutyl-2- (4-o-tolyl-pyridin-3-ylpyrazolidine_4-one was obtained as a colorless oil. HPLC (Method A) retention time of 3.95 minutes. Mass spectrum (ES +) m / z 327 (M + H). Example 47 of m-chloroperoxybenzoic acid (0.071 g, 0.28 mmol) Methanol (5 ml) was added to a 4-volume solution to 2- [4- (4-bromo-phenylpyridine-3_yl] -3_isobutyl ^ oxazoline_4_one in chloroform (2.25 ml) and methanol (2 25 ml) of -70. (: In solution. The reaction mixture was stirred for 5 hours. The reaction was quenched with saturated aqueous NaHC03 and extracted with CHAh. The organic layer was washed with brine and dehydrated with MgS04. The MgSCU was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dissolved in ethyl acetate / methanol 19: 1) and dried in vacuo To obtain 4- (4-bromo-phenyl) -3- (3_isobutyl 4,4-dioxo_ 丨 * 4 * _oxazolidine_2_yl) -pyridine, a colorless solid; chloro Compound. HPLC (method A) retention time 3 55 minutes. Mass spectrum (ES +) m / z 407, 409 (M + H). Example 48 4- (4-bromophenyl) -pyridine_3_formaldehyde (〇1〇 Gram, 0.38 millimolar) and 2-butylamine (0_028 grams, 0.38 millimolar) in benzene and heated it on the ribs for 2 hours. Add hydrothioglycolic acid (0_035 grams, 0.38 millimolar) ) And the mixture was heated at 80.0 for 16 hours. Additional hydrothioacetic acid (0.035 g, 0.38 mmol) was added and the mixture was heated to 90X: 6 hours followed by 70. It was heated for 4 days. Evaporated in vacuo The solvent and the residue were purified by flash column chromatography to obtain 2 • [Heart (Bromide 87682 -73- 200412948 phenyl) -pyridin-3-yl] -3-second butyl-pyrazolidine 4-one. HPLC (method A) retention time 4.04 minutes. Mass spectrum (ES +) m / z 391,393 (M + H). Example 49 The procedure described in Example 49 was started, starting with cyclohexylamine and the product starting with Diethyl ether dispersion to obtain 2- [4- (4-bromophenyl) _pyridin-3-yl] -3-cyclohexyl as an off-white solid -p Sai Jundian-4-嗣. HPL C (Method A) retention time 4.2 3 minutes. Mass spectrum (ES +) m / z 417, 419 (M + H) 〇 Example 50 ^ Step 1 3-Bromopyridine-4- A benzene solution of formaldehyde (1.09 g, 5.45 mmol) and cyclopentylamine (0.46 g, 5.45 mol) was heated at 70 ° C for 90 minutes. Hydrothioglycolic acid (0.50 g, 5.45 mmol) was added and the reaction was heated to 70 ° C for 4 days. Vacuum evaporation> Cereal was obtained. Oily 2-(3-&gt; odor-ρ ratio 矣 -4 -yl) -3 -cyclopentyl-vr plug _ 4 _ ketone. HPLC (Method A) retention time was 3.55 minutes. Mass spectrometry (ES +) m / z 327, 329 (M + H) 〇Step 2 3,4-methylenedioxyboronic acid (0.061 g, 0.37 mmol) and 2- (Bromo- Bite-4-yl) -3-cyclopentyl-carazolidin-4-one (0.10 g, 0.31 mol) in a solution of 1,2-dimethoxyethane (1 ml) gas. K2CO3 (0.114 g, 0.82 mmol) water (0.4 ml) &amp; Pd (PPh3) 4 (002 g, 17 μmol) was added and the mixture was heated to 85 ° C for a period of time 16 hours. The mixture was treated with a saturated aqueous solution of NaHC03 (30 ml) and Cl ^ Ch and stirred for 30 minutes. The organic layer was separated and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (dissolved with isohexane / ethyl acetate / methanol 10: 10: 1) and crystallized from methanol. After vacuum drying, 2-876-87-74-200412948 colorless solid was obtained. Benzo [1,3] dioxocyclopent-5-yl-epine-4-yl) -3-cyclopentylthiazolidine-4-one. HPLC (Method A) retention time was 3.76 minutes. Mass spectrum (Es +) m / z 369 (M + H). Example 5 1 Similar to the procedure described in Example 5 0, step 2, starting from 4-cyanophenylboronic acid, 4_ [4- (3-cyclopentyl-4-oxopyrimazine_2_ ) _Pyridine_3- the group l · benzonitrile. HPLC (Method A) retention time was 3.65 minutes. Mass spectrum (ES +) m / z 279 'No molecular ions were observed. Example 52. Similar to the procedure described in step 2 of Example 50, starting from 4- (N, N-dimethylamino) _phenyldiboronic acid, 3_cyclopentyl_2- [3- ( 4-Dimethylamino-phenyl) p-pyridin-4-yl] -π-seduline_4_one. HPLC (Method A) retention time was 3.65 minutes. Mass spectrum (ES +) m / z 279, no molecular ions (M + H) were observed. Example 53 Similar to the procedure described in step 50 of Example 50, starting from 4- (trifluoromethyl) _phenylboronic acid, 3-cyclopentyl-2_ [3- (4_trifluoromethylbenzene) was obtained as an off-white solid. ) Pyridin-4-yl] · oxazolidin-4-one. HPLC (Method A) retention time was 416 minutes. Mass spectrum (ES +) m / z 393 (M + H). Example 54. Similar to the procedure described in step 50 of Example 50, starting from 4-methoxyphenylboronic acid, and obtaining cyclopentyl-2- [3_ (4_methoxyphenyl) as a colored solid. p-bito_4_yl] Setone bite-4_one. HPLC (Method A) retention time 3.84 minutes. Mass spectrum (ES +) m / z 355 (M + H). Example 55 ^ 87682 -75- 200412948 Similar to the procedure described in step 50 of Example 50, starting from 4- (methylthio) -phenylboronic acid to obtain 3-cyclopentyl-2- [3- (4 -Methylthio-phenyl) pyridin-4-yl] -pyridine-4-one. HPLC (Method A) retention time was 4.06 minutes. Mass spectrum (ES +) m / z 371 (M + H). Example 56 Similar to the procedure described in step 50 of Example 50, starting from 4-ethylphenylboronic acid, 3-cyclopentyl-2- [3- (4-ethyl-phenyl) pyridine- 4-yl] -pyrazolidin-4-one. HPLC (Method B) retention time 4.29 minutes (solvent J MeCN / H20 / 0.05% HC02H, 5-95% gradient Η20 · 6 minutes, column: Waters Xterra 50x4.60 mm inner diameter, C18 reverse phase, flow rate: ι · 5 ml / min). Mass spectrum (ES +) m / z 3 53 (M + Η). Example 57 Similar to the procedure described in Example 50, Step 2, starting from 4-bromobenzic acid, 2- [3- (4-bromophenyl) p-bito-4-yl] -3- Cyclopentyl-p-septundine_4_ ketone. 1 ^ 1 ^ (Method 8) Retention time 4.19 minutes. Mass spectrometer 8 +) 111/240, 405 (M + H). Example 58 Similar to the procedure described in step 50 of Example 50, starting from 3,4-dimethylphenylboronic acid, 3-cyclopentyl-2- [3- (3,4-dimethyl- Phenyl), Biyodo_ 4-yl] -pyrazolidin-4-one. HPLC (Method A) retention time 4.24 minutes. Mass spectrum (ES +) m / z 353 (M + H). Example 59 4-Ethylamidophenylboronic acid (0.96 g, 6.48 mmol) and 3-bromoanedioic acid (1.0 g '5.4 mmol) of 1,2-dimethoxyethane (1.0 ml) ) Solution removes 87682 -76- 200412948 gas. K2CO3 (1.412 g, 14.6 mmol) of water (4 ml) and Pd (PPh3) 4 were added and the reaction was heated to 40 ° C for 72 hours followed by 80 °. (: Heating for 1 hour. The reaction was cooled to room temperature, treated with KAO3 solution and CH2C12 and stirred for another 30 minutes. The mixture was filtered through a phase separation tube (1ST, Isolute). The CH2C12 was removed by vacuum evaporation. The residue was subjected to flash column chromatography Purified (iso-hexane / ethyl acetate 1: 1 dissociation) and dried under vacuum to obtain 3- (4-ethylenylphenyl) -pyridine-4-carbaldehyde. HPLC (method A) retention time, 3.70 minutes. Mass spectrum (ES +) m / z 210 (M + H). Example 60 'Cyclopropylamine (0.019 g, 0.33 mmol) and 3- (4-vinylphenyl) -pyridine-4-carboxylic acid A solution of benzene (1 ml) was heated at 60 ° C for 90 minutes. Hydrothioglycolic acid (0.030 g, 0.33 mmol) was added and the mixture was heated at 60 ° C for 16 hours and 80 ° C for 8 hours. Additional hydrothioacetic acid (0.030 g, 0.33 mmol) was added and the reaction was heated at 80 ° C for 16 hours. The mixture was diluted with ch2C12 and filtered through a phase separation tube (1ST, Isolute). Vacuumed Remove CH2C12. The residue was purified by flash column chromatography and dried under vacuum to obtain 3-cyclopropyl-1 2- [3- (4-ethylfluorenyl-phenyl) -P biyodo-4- as a colorless oil. base] &lt; Salial-4-one. HPLC (Method A) retention time 3.67 minutes. Mass spectrum (ES +) m / z 323 (M + H). -Example 61 Using a procedure similar to that described in Example 60, starting from cyclobutylamine, 3 · cyclobutyl-2- [3- (4-ethenylphenyl) · []] Junjun-4-one. HPLC (Method A) retention time was 3.89 minutes. Mass spectrum (ES +) m / z 337 (M + H). Example 62 -77- 87682 200412948 Using a procedure similar to that described in Example 60, starting from isopropylamine, 3-isopropyl-2- [3- (4-vinylphenyl) _pyridyl was obtained as a pink oil. ] -Pyrazolidine_4_one. : ^ 1 ^ (Method 8) Retention time 3.82 minutes. Mass spectrum $ 8 +) 111/2325 (M + H). Example 63 Using a procedure similar to that described in Example 60, starting from the second butylamine, 3-second butyl-2- [3- (4_ethylfluorenylphenyl) _p ratio lake_4_ was obtained as a colorless oil. Base] Sejun bite 4-ketone. 1 ^ 1 ^ (Method 8) Dwell time 3.97 minutes. Mass spectrum (^ +;) 111/2 Yu 39 (M + H). Example 64 Using a procedure similar to that described in Example 60, starting from 1-ethylpropylamine, 3 · (1-ethyl-propyl) -2- [3- (4-vinylphenyl) was obtained as a coloring oil. Yuanjunji_4_one. HPLC (method A) retention time 4.16 minutes. Mass spectrum (ES +) m / z 353 (Μ + Μ) 〇 Example 65 Step 1 3-Bromopyrimidin-2-carboxaldehyde ( 0.50 g, 2.62 mmol (US Patent 4,876,271) and isobutylamine (0.31 ml, 3.14 mmol) in benzene (10 ml) was heated to 80 C for 30 minutes and then added Hydrothioglycolic acid (0.22 ml, 314 mmol) and heating was continued for 16 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHC03 solution and brine, and washed with MgS 〇4 was dehydrated. MgS04 was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in benzene (10 liters) and hydrothioacetic acid (0.22 ml, M mmol) was added. The mixture was heated to 8 (rc). It took 16 hours. The solvent was removed in vacuo and 87682 -78- 200412948 residues were dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHC03 solution and saturated brine and dehydrated with MgS04. MgS04 and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dissolved with isohexane / ethyl acetate 9 ·· 1), and dried with real chilli to obtain 2- (3-bromofluoren-2- ) -3-isobutyl-pyrazolidone. HPLC (method A) retention time minutes. Mass spectrum (ES +) m / z 318, 320 (M + H) 〇 Step 2 Similar to Example 22 described in Step 骡 3 Procedure, starting from 4-acetamidophenylboron; acid and 2- (3-bromopyrimidin-2-yl) -3-isobutyl ^ thiazolidine-4-one and by flash column chromatography Purification (iso-hexane / ethyl acetate 9: 1 dissociation) to obtain 3 · isobutyl-2- [3- (4-vinyl · phenyl) -pyrimphen-2-yl] -oxazole as a yellow oil Pyridin-4-one. HPLC (Method A) retention time 4.45 minutes. Mass spectrometry (ES +) m / z 344 (M + H). Activity example Inhibition of N-type # 5 channel in IMR32 cells. Human neuroblastoma The cell line IMR32 has been used by several groups to study calcium channels in low-throughput analysis by electrophysiology or fluorescence techniques (Carbone, E., et al. (1990) Pflugers Arch 41 6: 1 70-1 79; Rafferty, M., et al. (2000) patent WO 00/06559; Seko, T., et al. (2001) General Biomedical Chemistry (11: 2067-2070). It has been shown that undifferentiated IMR3 2 cells constitutively show L-type calcium channels, while differentiated IMR32 cells show both N- and L-type channels. Therefore, undifferentiated IMR32 cells can be used to analyze L-type calcium channels and differentiated cells analyzed in the presence of 5 // M nitrendipine can be used to study N-type channels. 87682 -79- 200412948 The development of FLEXstation ™ was performed by media flux analysis of undifferentiated and differentiated IMR3 2 cells labeled with Fluo-4. Voltage-driven calcium channel opening is stimulated by KCI polarizing cells, which can be added by the fluid system of FLEXstation. The amount of influx obtained by injecting cells into the cells was recorded by fluorescence. The analysis was confirmed with a known ion channel blocker. IMR32 cells were grown in EMEM supplemented with 10% fetal bovine serum, 2 mM lutamine, 1% NEAA, 100 U / ml penicillin, and 100 μg / ml streptomycin. In order to differentiate IMR3 2 cells, 1 mM dibutylfluorenyl cAMP and 2.5 / zM bromodeoxyuridine were added to the cells and the culture medium and the cells were maintained for 7-9 days. After washing the bars with Ca2 + / Mg2 + free Hanks buffered saline solution (HBSS), the cells were detached from the tissue culture medium using enzyme free cell lysis buffer (In vitro gen). The cells were then resuspended in analysis buffer (HBSS containing Ca2 + / Mg2 + and 20 mM HEPES supplemented, pH 7.4) to obtain a total volume of 40 ml. Add 2 // M Fluo_4 and 50 # M Carbosulfan and then incubate the cells at 25 ° C for 30 minutes. After centrifuging for 1 minute at 1000 rpm in Heraeus Megafuge 1_0 (rotor 2704), the cell pellet was resuspended in 40 ml of analysis buffer supplemented with 50 // M carbesulfamide and incubated for another 30 minutes at 25 ° C. The cells were centrifuged as described above and resuspended in analysis buffer supplemented with carbesulfamide. Take 200,000 cells and divide into 96-well plates containing 0.001-100 // Μ test compound (for N-type analysis, add 5 // Μ pairs of zepine to each hole), repeat three times . The final volume of compounds and cells in the analysis buffer was 200 μl. The cell-containing disc was centrifuged in a Heraeus Labofuge 400E (rotor 8 177) at 300 rpm for 1 minute without restriction. 87682 -80- 200412948 The disc was then analyzed using FLEXstation. The excitation and emission wavelengths are 494 and 525 nm, respectively. The calcium response was stimulated by the addition of 50 microliters of 250 mM KC1 (50 mM final concentration) by the FLEXstatiOn fluid device. SOFTmax Pro (Molecular Device Corporation) was used to calculate the fluorescence change of each hole due to calcium influx and therefore the IC5G of each compound. The results are shown in the following table. j Dagger 1 IQo (^ M) J (N-type # 5 channel) / 1 0.59 2 0.54 3 0.27 4 0.89 5 3.98. · 6 3.76 7, 6.24 8 0.74… 1 9 0.00 10 0.60 11 1.29 -12 2.07 13 1.21 14 0.49 15 0.79 16 _ 0.96 17 0.88 '18 K40 19 0.53' 20 4.15 21 0.52 22 0.70 23 8.93. 24 1.26 -81- 87682 200412948 87682 Compound IQo (fiM) (N-type calcium channel) 25 4.92 26 1.96 I 27 1.28 28 17.62 29 14,80 30 0.52. 31 0,50, 32. 0.53. 33 0.56 34 16.41 35 L33 36 2.71. 37 · L58 '38 2.31 39 9,73 40 0r63T 41 1,30 42; 5.14 43 1.01 44 4.83 45 4.26 46 6,67 47 3.97; 48 0.21 49 132 50 2J9 51 2,69 it

-82- 200412948 Compound ‘iC50_ (N-type calcium channel)’ 52 l〇M ,, 53 137 54 2.38 55 0.78 56 0.35 57 1.27 58 1, 17 59 0.58; 60 3.56 61 L09 62 2.13 63 0.93 87682-83-

Claims (1)

Please pick up the patent Fanyuan: a kind of the following manufacturing for use, in which: the compound of formula (1) or its prodrug or combined medicine γ e &gt; Or prevent double N-type transfer, please handle loose ,, .X 迢 &quot; Zhou Yizhi's pharmaceutical products 0 ,, R2 R—N ^ / Z 0) li} ^ γ ™ ^ 3 Z is -S- , -S (〇) -CrC6 alkyl or -C〇_ (c, -S02-, _〇_ or _NR, where R is hydrogen, l-Csfe group); R is hydrogen or cvc6 ^ group; R2 is Hydrogen, fluorine or Ci-c6fluorenyl; Y4- (CRM ^ X4. (C ^ 2) n... (CRy2) mA (CR ^) m-il-(CRy?) M-A- (CRy2 w ( Cn, wherein: -p, m, and n are each independently an integer of 0 to 4; -A is an aryl group, a heteroaryl group, a carbocyclyl group, or a heterocyclic group; · χ3 is,, s-, _NR,-_s (〇), _s〇2, _〇c〇, each Co-, _NR'eC〇-, -CO-O-, -CO-S- or -CO-NR,-, wherein R 'is hydrogen, Cl_c6 Alkyl, C2_c6 fluorenyl or c2_C6 alkynyl; _χ4 is -0-, _S_, -NR'-, -S (0)-or _scv, where R is nitrogen, Ci-Q alkyl, c2_c6 alkenyl or c2_c6 alkynyl;-each Ry is the same or different and is hydrogen, Ci_C6 alkyl, C2-C6 alkene , CVC6 alkynyl: aryl, aryl or heteroaryl; R3 represents aryl, heteroaryl, heterocyclyl or carbocyclyl; and R is -CrXpArA-CVXrCs, where: the heart is a chemical bond, radical, c2-C6 Fluorenyl ^ C2-C: 6-X 87682 block; when Q is a chemical bond, X i is a chemical bond and when q is a Ca-xenyl group, G-c0-xenyl or C2_Cg-alkynyl, X i represents a chemical bond or -S -, He, ... so_, .s〇2 ... Cms_m -CO-NR ·, _s_c〇_, _〇c〇, _nr, _c〇, reverse "· c〇_〇-, C0-NR, _R" _C0_0_ _C〇〇R ”c〇nr, -CO-NR 'heart c〇 as' ... 〇c〇 to prepare nr, c〇〇, where each R' is the same or different and represents hydrogen, phenyl, CrC, alkane Group, c2_.c6 fluorenyl or CyC6 alkynyl and are individualized, are the same or different and represent Ci_c6 alkynyl, [246 fluorenyl or c2_Cdt alkynyl; _Arl is heteroaryl, heterocyclyl, aryl, carbon Cyclic group, heteroaryl-Ra_, heterocyclyl-Ra_, aryl-Ra- or carbocyclyl-Ra-, wherein Ra is CVC alkynyl, K6 fluorenyl or c2-c6 alkynyl; -C2 C, c6 alkylene, c2-c6 alkenyl, 4C2-C6 alkynyl;-X2 is a chemical bond or -0-, _S-, _NR, _, ... s〇y, _c〇_, -C0_s-, -C0_0_, _C0_NR, _, _s_CO-, 〇_ (: 〇-, -NR'_C〇_, _CO-〇-R "_c〇 Office, -CO- NR'_R &quot; -CO-〇-, -C〇_〇-r "_c〇_nr, ..._ c〇NR, R" c〇-NR, _NRf_c〇〇 or -0-CO-NR'-, where Each R is the same or different and represents hydrogen, phenyl, Ci-C6 alkyl, CVC6 alkenyl or CrC6 alkynyl and each R "is the same or different and represents Ci-C6 alkylene, C2-C6 alkylene Or c2-c6 alkynyl; and -C3 is CVC6 alkynyl, c2-C6 alkynyl, or C2-C6 alkynyl. For example, for the application in the scope of patent application, Z is -S-, -O-, or -so-. For example, for the application of patents No. 1 or 2, R1 is hydrogen or -CH3. 1· 2. 3.87682 -2- 200412948 4. The use according to any one of the aforementioned patent applications, wherein I is hydrogen or unsubstituted C! -C4 alkyl. 5. The use according to any one of the foregoing claims, wherein each Ry is the same or different and is hydrogen or unsubstituted Cl-C4 alkyl or phenyl. 6_ Use according to any one of the foregoing patent claims, wherein A is aryl or or heteroaryl, which is unsubstituted or selected from 1, 2 or 3 selected from Ci-C4 alkyl, Cl-C4 '^ tioxy, autogen, via NH2, NH (Ci-C2alkyl) or N (Cl_C2alkyl) 2 substituent. ; 7. Use as in any of the foregoing patent applications, wherein X3 is _〇 一 _s_, -S〇_, _s〇2- or _NH_c〇j 8. · As in any of the foregoing patent applications Uses, where P is ο or 1; and / or melons are 0 or 1; and / or η is 1 or 2. 9. Use according to any one of the aforementioned patent applications, wherein &amp; is -〇_ or -S-〇10 · Use according to any one of the aforementioned patent applications, wherein Υ is of formula-(CH2) mO ( CH2) a base of n-, or _A-X3- (CH2) m-, wherein Ry, A, X3, m, and η are as defined in any one of claims 1 or 5 to 8. 11 · The use according to any one of the aforementioned patent applications, wherein R3 is aryl, 4aryl or carbocyclic, which is unsubstituted or 1, 2 or 3 selected from halogen starting group, cyano group, CVC6 alkyl, Ci-C6 alkyl, sulfur-filled, C2-C6 alkenyl, c2-C6 alkoxy, C2-c6 alkenylthio, c2-C6 alkynyl, C2-C ^ oxy, c2-Cd sulfur Group, c3_c6 carbocyclyl, c3-C6 carbothione, c3_c6 carbosulfanyl, -NH-CO- (CVC6 alkyl), 87682 200412948 -CO-NH-CCVG alkyl), _NR, R "( Where R, & R &quot; are each independently hydrogen or CVC6 alkyl) and -Si (R "') 3 (wherein each R", independently Ci-c4 alkyl) are substituted with' wherein the substitution on R3 is basically As unsubstituted or substituted with 1, 2 or 3 other substituents selected from the group consisting of 素 prime and acyl group. 1 2 · The use as in any one of the aforementioned patent applications, where (^ is a chemical bond or C1- C 6 elongation. '13. Use as described in item 12 of the aforementioned patent application, where q is a chemical bond or unsubstituted CrC4 alkylene. 14. Use as in any of the foregoing application patent scope, Where &amp; is a chemical bond or -〇 -,, -S-CO-, -0-co-, or -NH-CO-.-15. Use as described in any of the aforementioned patent applications, wherein Ari is a heteroaryl group, a heterocyclic group, an aryl group , Carbocyclyl or heteroaryl- (C ^ -C: 2 alkyl) _, which is unsubstituted or carries 1, 2 or 3 selected from halogen, Cl_C4 alkyl, Hydroxyl, CrC * alkoxy, -NR, R "and -NH-CO-R (wherein R 'and R" are the same or different and are selected from the group consisting of hydrogen and unsubstituted Ci_c4 alkyl group). 16. Use as described in item i5 of the scope of patent application, where Ari is pyridyl, mouth, phenyl, benzimidazolyl, fluorenyl-methyl, pyridyl-methyl, sulfanyl ~ methyl-methyl Base ', molyl, ammonium, sulfonyl, p-bihadynyl, 1-benzodicyclocyclohexyl, 1,3-benzodioxycyclopentyl or phenyl or having 3 to 6 slave atoms Saturated or unsaturated hydrocarbon rings, each of which is unsubstituted or substituted with 1, 2 or 3 cyclic groups selected from fluorine, via a group, -OCH3, and -NH_CO_CH3. 1 7 · If applied The application of item 6 of the patent, in which Ar1 is pyridyl, ^ 87682 -4- 200412948 Phenyl, benzimidazolyl, furyl_methyl, ^^, triphenylene, phenyl, or 1,3-benzodioxycyclopentyl, which is an unsubstituted gem-like radical There are 1, 2 or 3 substituents selected from the group consisting of fluorine, hydroxyl, -OHCH and -NH-CO_CH3. h 18. If the use of any of claims 1 to 11 of the scope of patent application, ^ N r C 2 is C1-C4 alkylene, which is unsubstituted or selected from one or two Substituent substitution. And 19. If the scope of patent application is for the use of any of items 1 to 11 or 18, -iL jcti X2 is a chemical bond or -O-, -S-, -CO-O-, -Q-CO_, sc〇, -CO-S-, or -NH-CO 〇20. As the scope of application for patents 1 to 11, 1 The use of any one of items 8 or 19, wherein C3 is a CVC4 alkyl group or a CVC4 fluorenyl group, which is unsubstituted or fine—or multiple such as 1, 2, or 3 selected from the group consisting of hydroxyl, _NH2, -NH ((VCVJ ^), Alkynyl) 2 and halogen substituents. 21. For the application of item 1 in the scope of patent application, wherein the compound of formula (I) is a compound of formula (IA), its prodrug and its pharmaceutically acceptable salt: Y is a group of the formula-(CH2) m〇 (CH2)-, -A 'or _A-X3_ (CH2) m, where A is phenyl, pyridyl, or pyrrolyl, which is unsubstituted or substituted by 1, 2 or 3 substituents selected from -CH3,-(: Η2-(: Η3, -OCH3, -OCH2-CH3, halogen, and hydroxyl. Substitution; X3 is -0-, -S〇2 ·, or -NH- CO-; and m is 0 or 1; 87682 200412948 R3 is phenyl, pyrenyl, furyl, fluorenyl, benzocuryl, cyclopentyl, 1,4-benzodioxycyclohexyl, 13 -Benzodioxycyclopentyl or 2,3-dihydrobenzofuranyl, which is unsubstituted or substituted with 1, 2 or 3, selected from the group consisting of 'hydroxyl, CVC6 alkyl, Cl_C6 alkoxy, 1 &lt; 6 alkylthio, c2-c6 fluorenyl, C2-C6 fluorenyl, c2-c6 thiol, C2-C6 thiol, C2-C6 thiol, 〇2-(^ 6 thiol, () 3- (1; 6 carbocyclyl, c3_c6 carbocyclyloxy, C3-C6 ^ epthio, -NH-CO-CCrC ^ alkyl), _c0-NH · (Ci_C6: fe group), and -NR R '(wherein r' and r "are each independently hydrogen or phenyl group). The substitution on R3 is basically unsubstituted or another 1, 2, or 3 selected from _ prime and hydroxyl. Other substituents; and R 4 is -〇1-11-eight 1 * 1 or-€ 2- 乂 2- € 3, where: -C ^-(CH2)-,-(CH2) 2KCH2) 3-; -Xι is a chemical bond or -Ο -, -S-, -S_CO_ or -O-CO-; -Ar1 is phenyl, pyridyl, thienyl, benzimidazolyl, furyl_methyl, 1,3 -benzyloxycyclopentyl Or ι, 4_benzodioxocyclohexyl, which is unsubstituted or carries 1, 2 or 3 on a cyclic group selected from the group consisting of fluorine, via ~ Cinyl, _OCH3, -N (CH3) 2 and- NH-CO-CH3 group substitution; -C2 is a straight chain unsubstituted alkyl group; one is a chemical bond or 〇_, -s-, _ (: 〇-〇- or _nh-co-〇-; and. .3 is Ci-C4 alkyl, which is unsubstituted or substituted on the primary carbon with (a) one. 22. per group or (b) 1, 2, or 3 self-substituted substituents. The use of item 21, wherein r3 is phenyl, pyrimidine, sulfanyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzyloxy% hexyl, 1,3-benzo Dioxocyclopentyl or 2,3-dihydrobenzofuran 87682 -6-200412948 group 'which is unsubstituted or substituted with 1, 2 or 3 selected from halogen, c 1 -c: 4 alkyl, C2_c4 fluorenyl CrQ alkoxy, CrC4 alkane Group, c2_c4fluorenyloxy, 〇3 &lt; 6 carbocyclyl, C3-C6 carboepoxy, _nh_CCKCi-C2 alkyl) and -NCCrC6 alkyl) 2 substituents, the substitution on R3 is basically Substituted or further substituted by 1, 2 or 3 other substituents selected from halogen and via a substituent. 23. 24. 25. 26. 27. 28 The use according to any one of the aforementioned patent applications, wherein γ is the base of formula -A_. For example, for the application in the scope of patent application No. 23, A is unsubstituted other than dnayl or unsubstituted fluorenyl. For example, for the application in the scope of patent application No. 24, wherein A is an unsubstituted pyridyl group and the compound of formula (I) is a salt in which the pyridyl group on γ has a positive charge on the nitrogen atom. For example, the use of any one of the scope of the patent application, where &amp; is benzyl, fluorenyl, furanyl or 1,3-benzodioxycyclopentyl, which is unsubstituted or 1, 2, or 3 selected from halogen, hydroxy, cyano, Ci_C4 alkyl, Ci-C4 alkyloxy, CVC4 alkylthio, C2-C4 alkenyl, -NR, R ', (wherein R' and R "are each independently hydrogen Or Cl_C4: ^ group) and _ with (11 ",) 3 groups (wherein each group is independently SCrC4 alkyl) substituents, the substitution on I is basically unsubstituted or 1, 2 Or 3 other substituents selected from the group consisting of i element and hydroxyl group. The use as in any of the aforementioned patent application parks, wherein X is a chemical bond or -0- or -S-. As in any one of the aforementioned patent applications, where Ar1 is eridinyl, pyrrolidinyl, 1,3-benzodioxycyclopentyl or cyclohexyl, unsubstituted, which is not substituted by 87682 200412948, unsubstituted C3-C6 cycloalkyl or phenyl, which is unsubstituted or substituted with 1, 2 or 3 selected from halogen, CVC4 alkyl, CrC4 alkoxy, C1-C4, thiol and aryl—the Ar The substitutions above are basically unreplaced. 29. The use according to any one of the aforementioned patent applications, 'where χ2 is a chemical bond or -0_, -S-or -CO-0 ·. 30. The use according to any one of the aforementioned patent applications, wherein (: 3 is a CVC4 alkyl group or a C2-C4 fluorenyl group, which is unsubstituted or has 1, 2 or 3 selected from a hydroxyl group and a halogen group. Substituent substitution. 31. The use according to any one of the scope of the aforementioned patent application, wherein the compound of formula (I) is a compound of formula (IAf), a prodrug thereof and a pharmaceutically acceptable salt thereof: Z is a or -SO- group; Y is a group of the formula -A-, wherein a is an unsubstituted or unsubstituted phenyl group; R3 is a phenyl group, a thienyl group, a pyridyl group, or 1, 3-benzodioxycyclopentyl, which is unsubstituted or substituted with 1, 2 or 3 selected from halogen, hydroxyl, CKC4 alkyl, ci-c 4 alkoxy, ci-c 4 alkylthio, C 2 c 4 alkenyl, -NR'R ". (Where r 'and R, each independently is hydrogen or CVC6 alkyl) and Si (R'M) 3 (where R ,, is independently CVC4 alkyl) Substituent Substitution 'The substitution on R3 is essentially unsubstituted or substituted with 1, 2 or 3 other substituents selected from: Nansu and 87682 hydroxy; R4 is -Ci-x ^ Ani-cvXrC ^, where :-Ci is a chemical bond or an unsubstituted iCl-C4 alkylene;-when 01 is a chemical bond, 11 is a chemical bond and when (: 1 is unsubstituted (: 1-C4 alkylene, Xi is a chemical bond or 〇 or -S-; 1-An is unsubstituted pyridyl, pyridinyl, 13-benzodioxycyclopentyl or cyclohexyl, unsubstituted C3-C6 cycloalkyl. Or unsubstituted or substituted with 1, 2 or 3 selected from halogen, CVC4 alkyl, C2-; C4 alkenyl "CVC: 4 alkoxy, C VC4 alkylthio and -N (CH3) 2 are substituted with substituents. The substitutions on ^ 1 ^ are basically unsubstituted;-(: 2 is C "C4 alkylene, which is unsubstituted or substituted by one or two -X2 is a chemical bond or -0, -S_ or -C0_0-; and -CggCpC4 alkyl or CrC4 alkenyl, each of which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a hydroxyl group and a nanin. 3 2 · —a preparation of the formula (Γ) or a salt thereof or a pharmaceutically acceptable salt thereof, Among them, R1, R3 and R4 are as defined in any one of items 1 to 31 of the scope of patent application, and Z is as defined in item 2 of the scope of patent application and γ is the base of formula _ eight_, where A is a heteroaryl group, but Provided that when B is s, 1 is nitrogen, γ is unsubstituted pyridyl, and R3 is bromophenyl, R4 is a formula Ci_Xi octa ^, wherein the radical 1 is a 3- to 6-membered carbocyclic ring. 87682 -9- 33.200412948 If the compound of the scope of patent application No. 32, wherein γ is the beauty of the formula _A_, where A is unsubstituted pyridyl or fluorenyl; and &amp; 3 is aryl, heteroaryl, Heterocyclyl or carbocyclyl, which is unsubstituted or substituted with one, two or three selected from fluorine, chlorine, hydroxyl, Cl-c0 alkyl, Cl_C0 alkoxy, Ci_C6 ^ thio, c2-c6 alkenyl , C2_c6 alkoxy, c2_C6 thiol :, C2_ = alkynyl, C2-C6 alkynyl, c2-c6 alkynyl, c3_c ^ ring, c3, C6 carboepoxy, CVC6 carboepthio _nh_c〇_ (Ci_C6 alkyl / .-co-NH- (Cl_C6 alkyl), _NR'R ”(where R, and R, each independently are chlorine or alkyl) and Si (R”,) 3 (where R &quot;, is independently a Ci ^ C4 alkyl) substituent, and the substitution on R3 is essentially unsubstituted or substituted with i, 2 or 3 other substituents selected from halogen and hydroxyl. 34. If you apply The compound in the scope of the patent No. 32 or 33 is a compound of the formula (IB) or a prodrug thereof or a pharmaceutically acceptable salt thereof: This wide N ^^ (IB) where: 1-R3 'y * 2, 3 | R3 , Y, and z such as Definition of item S3; and R4 is -CVXi-Ar !, or -C2_X2, _c3, or Ci_C6 alkyl or C2_c6 晞 one group in which Cl, Xi, C2 and C3 are as defined in item 32 or 33 of the scope of patent application; and -Aι &gt; is a heterocubyl, heterocyclyl, aryl, carbocyclyl, heteroaryl_ &amp;, or hetero% group -R-'R is Cl_C6 alkylene, C2_C6 alkylene, or C2-C6 Alkynyl, where when Aq is unsubstituted phenyl or via one or two selected from methyl, ethyl, methoxy, ethoxy, phenoxy, chlorine, bromine, and terminal 87682 -10- 200412948 When the phenyl group is substituted with a substituent, both Ci &amp; Xi are chemical bonds or Ci is a methyl group and -0- ,, -NR,-, -SO-, _s〇2-, {Οι, -CO -0 -... C0_NR jC〇_, 4C〇, _NR, c〇_, -CO-〇-R ,, -CO_〇 ..._ c〇_NR, R ,, c〇〇, _c〇〇r "_c〇 _ R &quot; CO-NR R'-CO-NR'-, -O-CO-NR,-or -NR, -C0-0-, where each R 'is the same or different and represents hydrogen, phenyl, or alkane Group, CrC6 埽 group or CrC6 block group and each R "is the same or different and represents c" c6 group, C ^ C6 group, or 〇2-(^ 6 group; and 2 ' -0_, _8_, "^ &amp; '_, -80-, -802-,-. 0-,-. 0-8- -CO-0 ·, _c〇-NR'-, _S_CO-, _〇_c〇_, _NR, -C〇_, -C〇-〇-R "_CO_〇_, -C0- NR'R ”-C0_0-, _CO_〇_R” _C〇_ NRf &quot; ^ -CO-NR ^ R ^ CO-NR ^ &gt; -NR ^ CO-O ^ t -O-CO-NR ^ 'where Each R is the same or different and represents hydrogen, phenyl, Cl-C6 alkyl, C ^ C: 6 alkenyl or CrC6 alkynyl, and each R "is the same or different and represents C1-C6 alkylene, c2-C6 alkenyl or c2_c6 alkenyl. 35 2_ [4- (4-bromo_phenyl) -pyridin-3-yl] -3- (3,5-difluoro · fluorenyl) -pyrazolidine-4-one 2- [4- (4- Bromo-phenyl) -pyridine_3-yl] -3- (253,4-trifluoro-benzyl) -pyrimazole, 4 • pyridine is the same as 2- [4- (4-bromo-phenyl) -pyridine- 3-yl] -3- (2,5-difluoro · benzyl) · pyrazolidine-4-one 3- (2 · benzo [1,3] dioxocyclo-5-yl-ethyl &gt;; 2- [4- (4-Bromo-phenyl) is called drolidin-3-yl] -oxazolidin-4-one 3-isobutyl-2- (4-phenyl-exo 1: syndrome-3 -Yl) -p-sepyl-p--4-one 87682 -11-200412948 2- (4-benzo [1,3] dioxopentyl-5-yl-pyridin-3-yl) -3-isobutyl -Thiazolidine-4 -pyridine with 3-isobutyl_2- (4 -telephen-2-yl-exo b lake-3-yl) -pyrene-4-one 2- [4- (4 -Bromo-phenyl) _pyridin-3-yl] -3- (2-cyclohex-1-enyl-ethyl) -pyrimidine-4-one 2_ [4,4 '] bipyridine-3- Propyl-3-isobutyl-pyrazolidin-4-one 2- [4_ (4 -murine-benzyl) -p biyodo-3-yl] -3-isobutyl-ρ plug u-4 -Pyridine with 2- [4- (4-fluoro-phenyl) _pyridin-3-yl] -3-isobutyl-pyrazolidine; -4-one-2- [4- (3-bromo-benzene ) _Pyridin-3-yl] -3-isobutyl-pyrazolidin-4-one 3-oxetyl-2- [4- (4-trifluoromethoxy-phenyl) -Edian -3 -yl] plug mouth settling -4 -Iso 3-isobutyl-2- (4-p-tolyl-pyridin-3-yl) -pyrimazin-4-one 3-isobutyl- 2- [4- (4-trifluorosilyl-phenyl) -pyridin-3-yl] -thiazolidine-4-one 3-isobutyl_2- [4- (4-methylsulfanyl · Phenyl) "Bizheng_3_yl] —Sejundian_4_one 2- [4_ (4-ethyl-phenyl) -shodian_3_yl] _3_isobutyl-distantylol &lt; _Heartone 4- (3-isobutyl-4 · oxo-sedazolidine_2_yl) -3- (4-methoxy-phenyl) _pyridoxine; chloride 3- (4- Chloro-phenyl) _4_ (3_isobutyl-4-oxo_pyrazolidin-2-yl) -pyridinium pyrene; chloride 3_ (4-fluoro-phenyl) -4- (3-isobutyl -4_oxetazosin-2-yl) -pyridine; 4- (3-isobutyl-4-oxo-thiazolidine-2_yl) _3_p-tolyl-pyridine; Chloride 87682 -12- 200412948 2_ (4-bromo_phenyl) -3- (3-isobutyl-4-oxo-pyrazolidine-2_yl) -pyridinium chloride; chloride 3_ (3_iso Butyl-4-oxo-pyrazolidine_2_yl) _2_ (4_methoxy-phenyl) _pyridine; gaseous 2 弋 4_gas-phenyl) -3- (3_iso Butyloxo_thiazolidine-2_yl) _pyridine; chloride 2 gas 4-fluoro_phenyl) _3 · ( 3_isobutyl_4_oxo_thiazolidine_2_yl) _pyridinium pyridine; chloride (3X-butyl-cardio-oxo-π-sexiadian-2 -yl) -2 -p-tolyl -ρ ratio bite tweezers; gaseous well 3 butyl-2- [4- (4-trifluoromethyl-phenyl) -ethenyl_3-yl] _0 cetoxamine_4-one 4_ [3- ( 3-isobutyl-4-oxo-predazol-2-yl) -pyridine_4-yl] nitrile 3 isobutyl-2- [4- (4-methoxy-phenyl) -τι Biyodo-3-yl] -P selenium-4-one 3isobutyl · 2- [4- (4-ethylethyl-phenyl) -ϊτ 比 路 _3_ 基]-嗤 唉 _ 4_Identical (4 丨 can-benzyl) -4- (3-isobutyl-4 -oxo-π-septamidine-2 -yl) -Edian tweezers; chloride 4- (3-isobutyl 4--4-oxo-pyrazolidin-2-yl) -3- (4-vinyl-phenyl) -pyridine; 3-chloro 3-isobutyl · 4-oxo-pyrazolidine_ 2_yl) _2- (4-trifluoromethyl-phenyl) _pyridine hydrazone; gaseous 2_ (4-cyano-phenyl) -3- (3-isobutyl-4_oxo_thiazolidine -2-yl) _pyridinehydrazone; chloride 3- (3-isobutyl-4-oxo-oxazolidin-2-yl) -2- (4-vinyl-phenyl) -pyridinehydrazone; gas Compound Zhu 82 -13- 200412948 2- [4- (4-Bromo-phenyl) -bamboo 1: lake-3-yl] -3- (3-methyl-butyl) -P Yodo-4-one 2- [4- (4-bromo-phenyl) -exo-3-yl] -3- (2,2,3,3,3-pentafluoro-propyl) _mouth plug Junyodo-4 -fluorene 2- [4 · (4-bromo-phenyl) -exo I: Yodo-3-yl] _3_ethyl-Xuanjundian-4-one 2- [4- (4-bromo -Phenyl) -pyridin-3-yl] -3- (3,3-dimethyl-butyl thiazolyl-4 -pyridine with 2- [4- (4-mo-phenyl) ratio -3 -Yl] -3-cyclopentyl-septamidine. 4-ketone 2- [4- (4-bromo-phenyl) -pyridin-3-yl] -3-cyclopropylmethyl-pyrimidine; wow Pyridyl-ζμketone 2_ [4- (4-bromo-phenyl) -pyridin-3-yl] -3- (3-isopropoxy-propyl) -oxazoline-4 -pyridine 3-allyl 2--2- (4- (4-bromo-phenyl) -pyridin-3-yl] -thiazolidine-4-one 3-isobutyl-2- 2- (4-m-tolyl-p ratio · 3 -Yl) -distant η-zo-4--4- 2- [4- (2,4-dimethyl-phenyl) -pyridin-3-yl] -3-isobutyl-pyrazolidin-4-one 3-isobutyl- 2- (4-o-tolyl-leaf 1: Hydro-3-yl) -ρ septundo-4- 酉 with 4_ (4_bromo-phenyl) -3- (3- Isobutyl-1,4-dioxo-1 λ * 4 * -pyrazolidine_ 2-yl) -pyridinehydrazone; chloride 2- [4- (4-bromo-phenyl) -pyridin-3-yl] -3-second butyl-thiazolidin-4-one 2_ [4- (4- Bromo-phenyl) -pyridyl] -3-cyclohexyl-pyrazolidin-4-one 2 (3 -incorporated [ι, 3] dioxopentyl than lake 4-yl) -3-ring Amyl-υ plug mouth seat _ 4-酉 with 4_ [4- (3-cyclopentyl-4-oxo-pyrazolidin-2-yl) -pyridin-3-yl] -fluorene nitrile 3-ring Pentyl_2_ [3 _ ('dimethylamino-phenyl) _pyridine_4_yl] _thiazolidine_4_one 3-cyclopentyl-2- [3- (4-trimethylol-benzene ) -P-bito-4-yl] -p-sedetyl-4-one 3cyclopentyl-2- [3- (4-methoxy-phenyl) -ubito-4-yl]- petidine-4-one 87682 -14- 200412948 3-cyclopentyl-2- [3- (4-methylthio-phenyl) -pyridin-4-yl] -thiazolidine-4-one 3 -Cyclopentyl-2- [3- (4-ethyl-phenyl) -pyridin-4-yl] -pyrazolidin-4-one 2- [3- (4-bromo-phenyl) -pyridine_ 4 · yl] -3-cyclopentyl-pyrazolidin-4-one 3 · -cyclopentyl-2 2- [3- (3,4-dimethyl-phenyl) -p ratio lake-4-yl ] 塞 Jun 淀 -4- 酉 Same as 3-isobutyl-2- 2- [3- (4 -Ethyl-phenyl) -ρBiYodo-4-yl] -Far θ Sitting Lake-4- 酉 Same as 3 -Cyclopropyl-2- [3- (4-vinyl-phenyl) -pyridine: 4-yl] -oxazolidine -4-keto 3-cyclobutyl-2- [3- (4-ethylfluorenyl-phenyl) -pyridin-4-yl] -pyrazolidin-4-one 3-isopropyl-2- [3 -(4-Ethyl-phenyl) -pyridine-4-yl] -thiazolidine-4-one 3-second butyl-2- [3- (4-vinyl-phenyl) -pyridine-4 -Yl] -pyrazolidin-4-one 3- (1-ethyl-propyl) -2- [3- (4-ethylenyl-fluorenylpyridine-4 -yl) -Keto 3-isobutyl-2_ [4- (4-vinyl-phenyl) -pyrimidin-3-yl] -thiazolidine-4-one 2- {4- [4- (1, 2-di # 成 基 -ethyl) -phenyl] 4 比 岸 -3-yl} -3-isobutyl-p-sepam-4 -one 2- {4_ [4_ (2-hydroxy-ethyl) -phenyl l · pyridin-3-yl} -3-isobutyl-thiazolium-4- 4-pyridine with 2- {4- [4- (1- Hydroxy-ethyl) -phenyl l-pyridine_3-yl} -3-isobutyl-pyrimazolium-4-ketoneΓ 2- {4- [4- (2,2-difluoro-vinyl) -Phenyl] -pyridin-3-ylb 3-isobutyl-thiazolidine-4-one 3-isobutyl-2- [4- (4-trifluorovinyl-phenyl) _pyridine · 3_ -Yl] -pyrazolidine-4 -pyridine with 2- {4- [4- (1-fluoro-vinyl) -phenyl l · 17 -15- 200412948 3-isobutyl-2- [3 ♦ ethenyl_phenyl) _pyridine_2_ylbucetin-4_one; or a prodrug thereof or a pharmaceutically acceptable salt thereof. 36 · —A kind of pharmaceutical composition, including the following formula—, compound of formula (U) or its prodrug or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or diluent: R4-N Z ⑼ YZ, Y, R, R and R are as defined in items i to 35 of the scope of patent application, but with the following conditions: (a) when Z * s, R1 is hydrogen and R4 is 2. (4-methoxy Bundle ethyl), Y-R3 is not 4-benzyloxyphenyl or 4-pyrrolidinylphenyl; (b) when Z is S and Ri is hydrogen, YrR; not _phenyl_〇_A2_r , Where A2 is CVC5 alkylene and R ^ i_pyrrolidinyl, piperyl, renmorphinyl, 1-piperidinyl, or 4-alkyl_1-piperidinyl; and (... ! Is hydrogen and R4 is -CVX ^ C: 3 where C2 is unsubstituted CVC3 alkylene, X2 is · 0- and C3 is unsubstituted CrC2 alkyl,-烷基 -R3 is not phenoxy Phenyl, benzyloxyphenyl, phenylhydrothiophenyl, benzylbenzyl, 4-chlorobenzyloxyphenyl or 4-nitrophenoxyphenyl. 37. Such as the scope of application for patent No. 36 Pharmaceutical composition in the form of lozenges, capsules, dragees, tablets, aqueous or oily suspensions, dispersible powders or granules, or sublingual lozenges 3 8. The pharmaceutical composition according to the scope of patent application 'item 36, which is a form suitable for non-fine intestinal, nasal or transdermal administration or administration by inhalation. 39 · —If the scope of patent application is 36 The compound of formula (II) or its 87682-16 · 200412948 prodrug or its medicinal properties as defined in the item is used to treat the human or animal body. 40 .—% of patients suffering from remission, Type calcium channel regulation ..., the method comprises administering to the patient an effective amount of two: a pharmaceutically acceptable salt of a compound of formula (I) of any one of Fanyuan items 1 to 31. Medicine 41. If you apply for the method of any one of the scope of the patent range 1 to 3 in the patent scope, the 40th type, in which &amp; type is pain. The use of the item or, such as the application of calcium channel modulation, specifically the disease i 87682 17- 200412948 柒. Designated Representative Chart: (1) The designated table chart in this case is: () Figure. (2) Brief description of the component representative symbols in this representative map: 捌 If there is a chemical formula in this case, please reveal the best display Inventive chemical formula: 87682