TWI301487B - Novel compounds for use as modulators of chemokine receptor activity - Google Patents

Description

1301487

A7 B7 V. INSTRUCTIONS (The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. Chemokines in a variety of diseases and disorders, including asthma and allergic diseases And plays an important role in immune and inflammatory responses in autoimmune diseases such as rheumatoid arthritis and atherosclerosis. These small secretory molecules are 8-14 kDa protein super families in positive expansion. It is characterized by a conserved type of 4 cysteine-type motifs. The chemical hormone superfamily can be divided into two main groups, each exhibiting a characteristic tectonic master, namely the Cys-X-Cys (C-X_C) family and Cys-Cys (CC) family. They are distinguished by single-amino acid insertion and sequence similarity between the NH-proximal cysteine residues. C-X-C chemical hormones include several Strong neutrophil chemotherapeutic and activators such as interleukin-8 (1 L-8) and neutrophil-activated peptide 2 (NAP-2). c-C chemical hormones including monocytes and lymphocytes a powerful chemical attractant of cells, but not neutrophils, such as humans Nuclear cell chemoattractant protein 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (regulation of activation, normal T expression and secretion), inflammatory properties of eotaxin and giant scorpion cells Protein 1 and 1 (MIP-1 and MIP-1). Studies have shown that the role of chemical hormones is mediated by the G-protein-coupled receptor subfamily, including CCR1, CCR2, CCR2A, Receptors such as CCR2B, CCR3, CCR4, CCR5, OCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent a good target for drug development because these can be modulated. Applicable to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1301487 A7 _____B7 V. Invention Description I 2~] The receptor agent can be used to treat the disorders and diseases mentioned above. a compound of the formula (丨)

Wherein m is 0, 1, 2 or 3; each R1 independently is a halogen, cyano, nitro, carboxy, hydroxy, C3-C6 cycloalkyl, CrCs alkoxy, alkoxycarbonyl, Ci-Cs halane Base, CrC6 haloalkoxy, -NR9R10, C3-C6 cycloalkylamino, 〇 "(: 6 alkylthio 'Ci-C6 alkyl thiol' Ci_C6 alkylamino group, continuation amine 〇2 NH2), alkylsulfonyl, -qC^NRHR12, -NR13C(0)-(NH)PR14, phenyl, or Ci_C6^, optionally containing a thiol or alkoxycarbonyl substituent; p is 0 Or 1 ; Z.1 table a bond or a base (CHDq-, where q is 1 or 2; Z2 is a bond or a CH2 group, but the conditions are different when Z1 and Z2 are different ; ' 'Q oxygen or sulfur atom or CH2 or NH base; R2 surface base-5- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1301487 A7 B7

η is 〇, 1 or 2; -CH2〇H or each R3 independently represents ^^^6 alkyl, (^-(^ alkoxycarbonylcarboxy; _ R4, R5, R6 and R7 each independently represents a hydrogen atom or a Ci_Ce alkane a group, or R4, R5, R6 and R7, which are linked to the next two carbon atoms of the CrCU to form a 4 to 7-membered saturated carbon ring, or R5, R7 a hydrogenogen ' and R4 and R8 together with the carbon atom to which they are attached form a 5- to 6-membered saturated carbocyclic ring; R8 represents a hydrogen atom 'C i - C 6 alkyl group or is bonded thereto as defined above R4; R9 and R1G each independently represent a CrC6 alkyl group, or R9 and R1. Together with the nitrogen atom to which they are attached, form a 4- to 7-membered saturated heterocyclic ring; R1 1 and R1 2 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group containing a C 1 _ c 6 alkoxycarbonyl group; a hydrogen atom of C13 or a C?-C 6 alkyl group; a hydrogen atom of R14, or optionally a group, a Ci-C6 alkoxy group SC". Alkoxycarbonyl substituted (^-(:6 alkyl; Γ~R15 retort, CrQ alkoxy, CrG alkylcarbonyl, (^-(:6 alkoxy), CrC6 alkoxycarbonyl -cl^ base or the following base·· _NR17R18 -6-

1301487 A7 _____B7 Z, invention description (4~) one ^ -NHSO2CH3 ? -C(0)NR17R18 ^ -NHC(0)NR1 8 v -0C(0)NR17R18, -〇CH2-C(0)NR17R18,-NHC (0)0R19 or -NHC(0)R20; t is 0,1,2 or 3; each R1 6 independently represents halogen, cyano, nitro, acid group, hydroxy c 3 · c 6 cycloalkyl, CrCe alkane Oxygen, CrCs alkoxycarbonyl, CrCs haloalkyl, oxy, -NR21R22, C3-C6 cycloalkylamino, CrCs thiol 'Ci-Cg-based complex' Ci_C6 alkyl-based amine, continuous amine (S02NH2), Ci-Cs alkanesulfonyl, _c(o)nr23r24, -nr25c(o) (NH)VR26, phenyl, or, optionally, a C C6 alkyl group containing a carboxyl group *Cl-C6 alkoxycarbonyl group R17 and R18 each independently represent a hydrogen atom, or optionally a CrG alkyl group having a substituent or alkoxycarbonyl substituent, or R17 together with R18 and the nitrogen atom to which they are attached form a 4- to 7-membered saturated carbon Ring; R19 represents a hydrogen atom, or optionally a carboxyl group or a Ci-Cs alkoxycarbonyl substituent tCrCs alkyl; R represents a Ci-Cs alkyl group 'C2-C6 fluorenyl' C3-C6 cycloalkyl, adamantyl, a C5-C6 cycloalkenyl group, a phenyl group or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one selected from the group consisting of a hetero atom among oxygen and sulfur, each of which optionally contains one or more substituents selected from the group consisting of: schiffyl, thiol, keto, halogen, tertyl, C i - C 6 Alkyl, ci - c 6 methoxy 'Ci-C6 thiol group, Ci-C6 alkyl group, Ci-C6 oxiranyl phenyl and -NHC(0)-R27; R21 and R22 are each independently Hydrogen atom or CrCs alkyl, or ruler 21 and 1^2 -7- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1301487 A7

Together with the nitrogen atom to which they are attached, a 4- to 7-membered saturated heterocyclic ring is formed; R23 and R24 each independently represent a hydrogen atom or, as the case may be, a C i -alkoxycarbonyl group; 0 or 1; R25 represents a hydrogen atom or an alkyl group; R26 represents a hydrogen atom, or optionally a carboxyl group, a Cl_C6 alkoxy group or a Ci_c6 alkoxycarbonyl substituent of ¢^-(36 alkyl; and an alkyl group, an amine group ( _nh2) or phenyl; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, an alkyl group or an alkyl moiety in a substituent may be linear or branched. And when RlG (or Rl7*Rl8, or R) is saturated with a ring, the only hetero atom contained in the RfG is R9, and the nitrogen atom attached to R10 (or R" and Ri8, or !^1 and r22) In the meaning of .0, the 'sufficient' and the saturated or unsaturated 5- to heterocyclic ring system may be aliphatic or aromatic. The integer m is preferably 1 or 2. Each R1 is independently Halogen (such as chlorine, fluorine, bromine or iodine), cyano, nitro, fluorenyl 'Chuckyl' C3 - C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl)' Ci -C6 is preferred, CrC4 alkoxy (eg, decyloxy) , ethoxy, n-propoxy or n-butoxy-), CrCf, preferably, Ci-q, alkoxycarbonyl (such as oxime carbonyl or ethoxy, several ^), C 〗 - c 6, Preferred ci-C4, haloalkyl (such as trifluoromethyl), Cls-C6? preferred, haloalkoxy (such as trifluoromethoxy), -NR9R10, (: 3-(:6 naphthenic) Amine (such as cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), Cl-c6, preferably -8 - this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 1301487 A7 B7 V. Description of the invention (6 C1-C4 alkylthio (such as methylthio or ethylthio), Cl-c6, preferably Ci-C4' mercaptocarbonyl (such as methylcarbonyl, B Carbocarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), Ci-, preferably, alkylcarbonylamine (such as methoxycarbonylamine or ethoxy) Carbonyl) sulfonamide, Ci-C6, preferably CrG alkyl sulfonyl (such as methyl sulfonyl 'ethyl hydrazine, n-propyl sulfhydryl, isopropion hydrazine: yl, n-butyl Achievement g Shengji, the positive performance or the continuation of the base), - (^ (CONRHr12, -NR13C(0)-(NH)pR14, benzene Base, or Cl-C6, preferably 匕-^alkyl (such as methyl 'ethyl' n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or n-hexyl Depending on the case, it contains a carboxyl group or a Cl-c6 group, preferably a ^^-匚4, alkoxycarbonyl group (such as a methoxycarbonyl group or an ethoxycarbonyl group). Preferably, each ιί1 is independently halogen (especially chlorine or Fluorine), cyano, nitro ' ci - C6 alkoxy (especially methoxy), ci - c 6 alkylcarbonyl (especially methylcarbonyl) SCi-C: 6 alkylcarbonylamine (special Methylcarbonylamine). Each of R1 is a halogen atom. Preferably, Q is an oxygen atom. Each R3 independently represents ^6, preferably CrC: 4, alkyl (such as decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or N-hexyl), CrC6, preferably CrC: 4, alkoxycarbonyl (such as oxime carbonyl or ethoxycarbonyl), -CH2〇H or a thiol group. Preferably, Han 3 is a thiol group, a methoxycarbonyl group, an ethoxycarbonyl group, and a -CH2OH^ group. R4, R5, R6 and R7 each independently represent a hydrogen atom or Ci_C6, preferably a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) Base, n-pentyl or n-hexyl), or R4, r5, r6 and Han 7

Loading

Line -9- 1301487 A7 B7

Ci_C4 of two carbon atoms attached to each other is bonded to form a 4- to 7-membered saturated carbocyclic ring (such as cyclohexyl or preferably cyclopentyl), or R5, R6 and R7. Each of the hydrogen atoms of the watch and the ruler 4 and the ruler 8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring (preferably a cyclopentyl group). R8 represents a hydrogen atom, CrC6, preferably a C1-C4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or Link to R4 as described above. R9 and R1g each independently represent a hydrogen atom or CrQ, preferably a Ci_C4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-Hexyl), or Han 9 and R1G together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring (preferably pyrrolidinyl or piperidinyl). , R11 and R12 each independently represent a hydrogen atom, or, preferably, a pipe, an alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, The n-pentyl or n-hexyl group optionally contains CrC6, preferably an alkoxycarbonyl substituent. R13 represents a hydrogen atom or CVC6, preferably c-C4 alkyl (eg, decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) ). R14 represents a hydrogen atom, or Ci-C6, preferably c-C4, alkyl (such as methyl, ethyl, n-propyl, isopropyl & n-butyl, isobutyl, tert-butyl) The pentyl or n-hexyl group optionally contains the following oxime carboxyl group, Cl_c6, preferably alkoxy group *Ci-C6, preferably an alkoxycarbonyl group. -10-

1301487 A7 B7

R represents a radical, C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), Ci-Ce, preferably Cm C4 pit Base group (such as methyl group, ethyl group, n-propyl group, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C" C6, preferably C^ C: 4, alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), CrCs alkoxycarbonyl (^-(: 6 alkyl, preferably ^-^ alkoxycarbonyl^-. alkyl (such as methoxycarbonyl) Methyl or oxiranyloxyethyl), or the following groups: -NR17R18, -NHS02CH3, -C(0)NR17R18, -NHCCC^NRHr1, -0C(0)NR17R18, -〇CH2_C(0)NR17R18, -NHC( O) OR19 or -NHC(0)R20 〇 preferably 1115 (: 1-(:4 alkoxy (particularly methoxy), CrC# alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl) ,Ci-Cd alkoxycarbonyl c-C4 alkyl (especially oxime oxycarbonylmethyl or methoxycarbonylethyl), -C(〇) NR17R18, -NHS02CH3, -NHC(0)NR17R18, or, especially | J, -NHC(0)R20 ο Each R16 independently of the surface #素 (such as chlorine, fluorine, bromine or broken), cyano, nitro, to the base 'meal base CyC6 cycloalkyl (cyclopropyl 'cyclobutyl, cyclopentyl or cyclohexyl), Ci_C6, preferably, Ci-C4 alkoxy (eg, methoxy, ethoxy, n-propoxy or positive) Butoxy), Ci-Cs, preferably, CVC4, alkoxycarbonyl (such as methoxycarbonyl or hydrazine carbonyl), preferably Cl_C4 'halo-radical (such as trifluoromethyl), & _ C6, preferably, Ci-Ce oxime oxo (such as trifluoromethoxy), -nr21rP, CyC6 cycloalkylamino (such as cyclic diamine, cyclobutylamino, cyclopentylamino or cyclohexyl) Amino), Ci-Cs, preferably C1-C4 sulfur-based (such as thiol or ethylthio), Ci_C6, preferably Cj -11- This paper scale applies to China National Standard (CNS) A4 specification ( 210X297 mm) 1301487 A7 B7 V. INSTRUCTIONS ( ) C4, alkylcarbonyl (eg methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexyl) Carbonyl), Cr c6, preferably, alkylcarbonylamino (such as methoxycarbonylamino or ethoxycarbonylamino), sulfonamide, preferably c"c4 alkylsulfonyl (such as a Sulfonyl, ethyl sulfonyl, n-propyl sulfonyl Isopropyl sulfonyl, n-butylsulfonyl, n-pentylsulfonyl or n-hexylsulfonyl), -C(0)NR23R24, -nr25c(o)-(nh)vr26, phenyl, or, preferably. CrG alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) which optionally contains a carboxyl group or a Ci-Cs, The preferred Ci-C4 'burning oxygen group (such as methoxyne group or ethoxy group) substituent. Preferably, each R 16 is independently an apparently functional (especially gas or fluorine), a cyano group, a CrC4 alkoxy group is a methoxy group, a dQ alkoxycarbonyl group (particularly a methoxycarbonyl group), a CrC4 haloalkyl group. (especially trifluoromethyl), CrG alkylcarbonyl (especially methylcarbonyl), phenyl or c^-c^alkyl (such as methyl or tert-butyl). R17 and R18 each independently represent a hydrogen atom or Cl-C6, preferably Κ4, an alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, positive The pentyl or n-hexyl group optionally contains the following substituents or, more preferably, CrC6, preferably a CrG alkoxycarbonyl group, particularly a fluorenyl group or a R 1 7 and R 1 8 and The nitrogen atoms attached together form a 4- to 7-membered saturated heterocyclic ring (preferably pyrrolidinyl salidazilide). R represents a ruthenium atom or Ci-C<5' prefers CPC4, alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl) Or n-hexyl) as the case may include the following substituents: carboxyl or, better, -12- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)! 3〇1487 A7 B7 V. Description of the invention (1〇

CrCs, preferably Κ4, alkoxycarbonyl, especially methoxycarbonyl. , preferably Ci-Cs, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), c2-c6 , preferably c2_c4 fluorenyl, c3-c6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), adamantyl, c3-c6 cycloalkenyl, phenyl or saturated or unsaturated 5 a toluene heterocyclic ring system comprising at least one (one, two, three or four heteroatoms) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, each optionally comprising one or more (eg, one, two, three or four) substituents independently selected from the group consisting of nitro, hydroxy, keto, halogen (eg, fluorine, gas, bromine or iodine), carboxy, Κ6, preferably alkane Base (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl 'n-pentane or n-hexyl) 'Ci-C6, preferably C1-C4, burnt Oxyl (e.g., methoxy, ethoxy, n-propoxy or n-butoxy), C1-C 6, preferably c 1 - C 4, alkylthio (e.g., methylthio or ethanesulfide) Base), ci -C6, preferably Ci-C4, alkylcarbonyl (eg fluorenylcarbonyl) Ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarboxy), Ci-C6 'preferably Ci-C4, anthracenyloxycarbonyl (eg methoxyl group or Ethoxycarbonyl), phenyl and -NHC(0)-R27. The saturated or unsaturated 5- to 10-membered heterocyclic ring system may be monocyclic or polycyclic (e.g., bicyclic) and may include up to four independent heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of ring systems that may be used include pyrrolidinyl, piperidinyl, fluorenyl, decidyl, far phenyl, hetero-U, thiophene, pyrrolyl, furyl, carbazolyl, Mercapto, quinolyl, benzimidazolyl, tripentyl, tetrakisyl and P are the decyl groups. -13-

A7 B7 1301487 V. INSTRUCTIONS (11 R21 and R22 each independently represent a hydrogen atom or CrCs, preferably Cl_c4, alkyl (such as methyl 'ethyl, n-propyl, isopropyl, n-butyl, isobutyl , a third butyl group, n-pentyl or n-hexyl), or R21 and R2 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring (more than a bite base or a mountain R23 and R24 each independently represent a hydrogen atom or, preferably, Ci-Cd, an alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) , n-pentyl or n-hexyl), as the case may be, preferably κ4, an alkoxy substituent. R25 represents a hydrogen atom or CrQ is preferred Ci-C*, alkyl (such as fluorenyl, ethyl, positive Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) R26 represents a hydrogen atom, or CVC6, preferably an alkyl group (eg methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), optionally containing the following substituents: carboxy, CVC6, preferably alkoxy or (^-(:6, preferably , alkoxycarbonyl. R27, Ci-Cs, preferably, alkyl (such as decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or N-hexyl), amine or phenyl. Preferred compounds of the invention include Ν-[2-(3-{[1-(3,4-dichlorobenzylpiperidyl)aminohydroxypropyloxy]乙'基}Ethylamine 'N-[5-Gas-2-(3-{[1-(3,4-2-chlorobenzyl)-4-piperidinyl]amine-based - 14 - this paper size Fitted S National Standard (CNS) A4 Specification (210X297^17

Loading

1301487 A7 B7 V. INSTRUCTION DESCRIPTION (12 2 -Hydroxypropyloxy)phenyl]acetamide, Ν-[2-(3-{[1-(3,4-dichloroindenyl)-4 -piperidine Aminobutyryl-2 -methylphenyl]acetamidamine, Ν-[4-(3-{[1-(3,4-dichloroindenyl)-4- Piperidinyl]amino-2-bromopropoxy)[1,1-biphenyl]-3-yl]acetamidamine, >^[3-ethylindenyl-2-(3-{[1 -(3,4-dichloroindenyl)-4-ylidenyl]amino}-2-hydroxypropoxy)-5-methylphenyl]acetamidamine' Ν-[2-(3-{ [1-(3,4-dichloroindolyl)-4-benzaridinyl]amino-2-hydroxypropyl)-4-phenylphenyl]acetic acid amine Ν-[2-(3·{[ 1-(3,4_dioxamethyl)-4-piperidinyl]amino}-2-hydroxypropoxy)·5-fluorophenyl]acetamidamine, N-[2-(3-{ [i-(3,4-dichlorobenzyl)-4-indenyl]amino}-2-ylpropoxy)-5-cyanophenyl]acetamide, Ν-[2-( 3-{[1-(4-Chlorobenzyl)-4-indenyl]aminobi-2-(ylpropoxy)phenyl]acetamide, N-[2-(3-{[ 1- (4-Benzylbenzyl)-4-piperidinyl]aminopiperyloxy)phenyl]isobutylamide, N-[2_(3-{[ 1-(4- gasbenzyl)-4 -piperidinyl.]aminodibu 2_hydroxypropoxy)benzene -2,2-dimethylpropanamide, N-[5-gas-2·(3-{[1-(4-chloroindolyl)-4-piperidinyl]amino}-2 -hydroxypropoxy)phenyl]acetamidine, Ν-[2-(3-{[1·(4- gas fluorenyl)-4, piperidinyl]amino-2-hydroxypropyloxy) -5-methylphenyl]acetamide, Ν_[2-(3·{[1-(4-)-benzyl)-4dipiperidinyl]amino}-2-hydroxypropoxy-15- Paper scale applicable to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1301487 A7 ___B7 V. Description of invention (13 ) 'Base'-4-methylphenyl]acetamide, Ν-[2-(3- {[1-(4-Chloromethyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4-aphthylphenyl]ethanoamine' Ν-[2-(3-{ [1-(4-Hydrazinyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5-cyanophenyl]acetamide, N-(2-{[(2S) -3-({[l-(4-chlorophenyl)methyl]-4-piperidinyl}amino)-2-hydroxypropyl]oxy}phenyl)acetamide bis(trifluoroacetate) , N-(2-{(2R)-3-[l-(4-carbobenzyl)-piperidin-4-ylamino]-2-hydroxy-2-methylpropoxy}-phenyl) Acetamide, Ν-(2-{[3-({1·[(4-)phenyl)methyl]-4-piperidinyl}amino)-2-hydroxy-2-methylpropyl] Oxy}phenyl) Indoleamine, N-(2-{(2S)'-3_[l-(4_gasbenzyl)-piperidin-4-ylamino]-2-hydroxy-2-methylpropoxy}-benzene Ethylamine, N-{2-[((2S)-3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino) 2-hydroxypropyl)oxy]- Phenyl}acetamidamine, N-{2-[((2S)-3-{[1-(4-))]]]]]] ]-4-fluorophenyl}acetamidamine, N-{4_fluoro-2-([(2S)-3-{[l-(4-fluoroindolyl)-4piperidinyl]amino}- 2-anilinylpropyl)oxy]-phenyl}ethinamine^1^{2-[(2 5)-3-{[(3&)-1-(4-acetobenzyl)pyrrolidine Amino-2-yl-4-ylpropanyloxy]-4-aerophenyl octaamine 'N-{2-[(2S)-3-{[(3R)-l-G4-chlorobenzyl Pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamidamine, Ν-[2-(3-{[1-(4-fluoroindolyl)- 4 - BTS base group] Amino group - 2 · Meridian base - 2 · -16- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

1301487 A7 B7___ V. INSTRUCTIONS (14) Methylpropoxy)phenyl]acetamidamine, Ν-[2-(3-{[1·(4-chlorobenzyl)-4-indanyl]amine }}-2-trans-yl-2-methylpropoxy)-4-fluorophenyl]acetamidamine 'N-[4-fluoro-2-(3-{[1-(4-fluoroindolyl)) 4-piperidyl]amino-2-hydroxy-2-methylpropoxy)phenyl]acetamide, Ν-[2-(3-{[1-(4-]-chloroindolyl)-4 - benzylidene]amino}·2-hydroxypropoxy)-4·methylphenyl]acetamidamine, Ν-[2-(3-{[1_(4-fluoroindolyl)-4_Brigade Pyridyl]amino}-2-hydroxypropoxy)-4-methylphenyl]acetamidamine, Ν-[2-(3-{[1-(4-]-chloroindolyl)-4-piperidine Amino]-2-hydroxypropyloxy)phenyl]benzamide, N-[2-(3-{[i-(4-fluoroindolyl)-4piperidinyl]amine 2-hydroxypropyloxy)phenyl]benzamide, N-[2-(3-{[(3S)-l-(4-chlorobenzyl)pyrrolidinyl]amino)-2-hydroxypropoxy Phenyl]benzamide, N-[2-(3-{[(3R)-l-(4-oxabenzyl)pyrrolidinyl]amino}-2-hydroxypropoxy)phenyl Benzoylamine, Ν-[2-(3-{[1-(4-bromoindolyl)-4-piperidinyl]amino-2-hydroxypropyloxy)phenyl]benzamide, Ν-[2-(3·{[1 -(4-fluoro-)-4-piperidinyl]amino-2-hydroxy-2-methylpropoxy-yl)phenyl]benzamide-[2-(3-{[1- (4-fluorobenzyl)-4,piperidinyl]amino}-2-hydroxy-2-methylpropoxy)phenyl]benzamide, 1^[2-(3-{[(311 )-1-(4_气#基)Pyrrolidinyl]amino}_2_Kilyl-17- This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1301487 A7 B7 V. Invention Description (15) -2-methylpropoxy)phenyl]benzamide, Ν-[2·(3·{[1-(4-bromomethyl)-4-piperidyl]amino}- 2_peptidyl- 2-methylpropoxy)phenyl]benzamide, Ν·[2-(3-{[1-(4-芊-yl)-4-piperidyl]amino}- 2-hydroxypropoxy)-4_methoxyphenyl]acetamidamine, N-[2-(3-{[l-(4-carbo)-4-piperidyl]amino}- 2-hydroxypropoxy)-6-fluorophenyl]acetamidamine, N-[2-fluoro-6-(3_{[l-(4-fluoroindolyl)-4-piperidinyl]amino} 2-hydroxypropoxy)phenyl]acetamidamine, 2-(3-{[1-(4-)-yl)-4-piperidinyl]amino}-2-hydroxy-2-methyl Propyl)-N-methylbenzamide, · 1(2-{3-[1:(3,4-dioxabenzyl)-piperidin-4-ylamino]-2-hydroxypropane Oxyl} Phenylguanamine, Ν·(2-{3-[1-(3- gas-4-fluorobenzyl)piperidin-4-ylamino]-2-hydroxypropoxy}phenyl)benzamide Amine, Ν-(2-{3-[1-(3,4-difluorobenzyl)-piperidine-4-ylamino]-2-hydroxypropoxyphenyl)benzamide, hydrazine -(2-{3-[1-(3,4-dichlorobenzyl)-piperidin-4-ylamino]-2-hydroxypropyloxy}-6-methylphenyl)acetamidamine, Ν-(2-{3-[1-(4-fluorobenzyl)-acridin-4-ylamino]-2-hydroxypropyloxy}-6-methylphenyl)acetamide, N - ( 2 - { 3 - [ 1 - ( 4 -Bromobenzyl)-piperidin-4diylamino]-2-hydroxy-2-indolylpropoxy}phenyl)acetamide, Ν-( 2-{3-[1-(3,4_二气爷基)-17 guanade-4-ylamino]-2-3⁄4 base - -18 - This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) 1301487 A7 B7 V. INSTRUCTIONS (16 ) 2 -Methylpropoxy}phenyl)acetamide, Ν-(2-{3-[1-(3 - gas-4 -fluoro) Mercapto)piperidin-4-ylamino]2-hydroxy-2-methylpropoxy}phenyl)ethinamide, Ν-(2-{3-[1_(3,4_difluoro) Base)-Brigade bite _4-ylamino]-2-boryl-2-methylpropoxy}•phenyl)acetamidine, 2-{3-[1-(4-bromoindole) )-piperidin-4-ylamino]-2-hydroxypropoxydiphenyl-methylbenzamide, 2-{3·[1-(3,4 -diqi)--- 4-Aminoamino]-2-3⁄4ylpropoxy}-> 1-methylbenzamide, 2-{3-[1-(4-carboyl)-piperidin-4-ylamine ]]2-hydroxypropoxy}-N-methylbenzamide, 2-{3-[1-(4difluorobenzyl)-piperidin-4-ylamino]-2-hydroxypropyl Oxy}-N-methylbenzamide, 3.5-dimethyl-111-pyrrole-2-carboxylic acid (2-{3-[1-(4-bromobenzyl)-piperidin-4-yl) Amino]-2-hydroxypropoxy}phenyl)decylamine, 3.5-dimethyl-111-pyrrole-2-carboxylic acid (2-{3-[1-(3-a))-anthracene 4-aminoamino]-2-3⁄4ylpropoxy}phenyl)-bristamine, 3.5-dimethyl-111-pyrrole-2-carboxylic acid (2-{3-[1-(3-fluorobenzyl) )-(裱--4-amino-yl)-2-pyridinyloxy}phenyl)-bristamine, Ν-(2-{3-[1·(4-bromo-aryl)- shouting- 4-Aminoamino]-2-ylpropoxy]-phenyl··) acetamidine, : Ν·(2-{3_[1-(3 - chloro-4-fluoro))- shouting~淀-4-ylamino]-2-3⁄4ylpropoxy}-phenyl)acetamidine, Ν-(2-{3_[1-(3,4-difluorobenzylpiperidin-4-yl) Amino]-2-hydroxy-19- This paper size is applicable National Standard (CNS) A4 Specification (210 X 297 mm) 1301487 A7 B7 V. Description of the Invention (Propoxy}-epi) Ethylamine, and Ν-(2-{3-[1-(4_Fluorine) Alkyl)-piperidinylamino]_2-hydroxypropoxy}-phenyl)ethinamine. The present invention further provides a process for the preparation of a compound of the formula (1) as defined above, which comprises: (a) a compound of the formula (11)

Wherein m, η, Zi, Z2, Han 1 and 3 are all defined in formula (1); reacting with compound of formula (III): loading Q, R2; or

R4, R5 R6, R7, and R8 are all defined in formula (I)

Line (b) Compound of formula (IV): -20- This paper scale applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1301487

Wherein m, n, 1, 1, Z2, R1, r3, r4, r5, r6, r7, which are defined in formula (I); react with a compound of formula (v) and R8 I^-Q-R2 ( v) wherein L1 represents a hydrogen atom or a leaving group (such as L i when Q is CH2) and is defined in Q and R (I), or (C) is a compound of formula (VI)

(VI) wherein m, η, zi, Z2, R1 and R3 are all defined in formula (1), and the compound of formula (VII) is reacted -

7 >2 . (VII) -21 - 1301487 V. INSTRUCTIONS (19

R4, R R6, R7 and R8 are all as defined in formula (1). After (a), (b) or (c), the compound of formula (1) is converted to another compound of formula (I) and/or Or a pharmaceutically acceptable salt forming a compound of formula (I). The present invention is conveniently carried out in a solvent such as an organic solvent such as an alcohol (e.g., methanol or ethanol) k (e.g., toluene) or acetonitrile, such as at 15. (: or higher temperature, for example, in the range of 20 to 120 ° C. Formula (II), (III), (IV), (V) 'VI (VI) and (VII) are all commercially available. The compound of formula (I), which is well known in the literature or which can be readily prepared by known techniques, can be converted to another compound of formula (J) using standard procedures. = For example, <>"Table-NHC(0)CH3 compound is converted to another compound of the formula (^^5) by hydrolysis reaction in hydrochloric acid. Readers of the present invention are aware of the initiators of the present invention. Some of the functional groups in the intermediate compounds, such as hydroxy or amine groups, may need to be protected with a protecting group. Thus, the formula (the preparation of the compound may include the removal of one or more protecting groups in a suitable step. May) B-based protection and deprotection is contained in "pr〇tective Groups in Organic

Chemistry'', edited by JWF· McOmie, Plenum Press (1973) and Protective Groups in Orgaaic^ynthesis, 2nd edition, TW·Greene and PGM· Wuts, Wiley-Inlerscience (1991) 0 above (I) The compound can be converted into its pharmaceutically acceptable salt or solvate 'preferred acid addition salt such as hydrochloric acid i, hydrobromide, sulphate, B-22- CNS) ΜSpecifications (21G><297 public) V. Description of the invention (2〇) acid salt, butyl succinate, cis-butane, tartrate, bar acid salt, oxalate, Methanesulfonate or p-toluenesulfonate. The compound of formula (I) can exist as a non-image isomer. It is to be understood that the present invention encompasses the use of all geometric and % isomers of the compound of formula (1) and mixtures thereof, including racemates. The use of tautomers and mixtures thereof also form an aspect of the invention. Preferred optical isomers are (8 Å mirror image isomers. The compound of the touch (I) has activity as a pharmaceutical, in particular, a chemical hormone receptor (particularly MIP-1 alpha chemical hormone receptor) activity. Formulations, and can be used to treat autoimmune-type 'inflammatory' proliferative and hyperproliferative diseases and

Epidemiology/medium diseases include rejection of transplanted organs or tissues and acquired immune deficiency syndrome (AID illusion. U. Examples of such symptoms are: (1) (respiratory) airway diseases, including chronic obstructive pulmonary disease (c) 〇pD) such as non-recoverable COPD, · asthma, especially long-term or spasmodic asthma (such as 'late-onset asthma and airway hyperreactive bronchitis; acute, allergic, atrophic rhinitis, and chronic rhinitis including cheese Nasal nose, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and drug-induced nasal mucosa nasal growth including glubus, fibrinous and pseudomembranous rhinitis and membranous rhinitis; seasonal rhinitis including neuropathic rhinitis (hay fever), and vascular motility, &inflammation; sarcoidosis, farmer lung and related diseases, fibrotic lung and spontaneous interstitial pneumonia; (7) (bone and eye) rheumatoid arthritis Serum-negative spondyloarthropathy (including joint adhesion spondylitis, cowile 5-arthritis and Reiter, s disease),

This paper scale applies to China National Development (CNS) A4 specification ($10X297 mm) 1301487 A7 B7 V. Invention description (Z)

Behcet's disease, Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, specific dermatitis, contact dermatitis and other eczema dermatitis, sebum dermatitis, flat skin moss (Lichen planvs ), pemphigus, large cancer pemphigus, large, vesicular epidermis, ramie therapy, angiodermas, vasculitis 'erythema' skin eosinophilia, uveitis, clustered baldness and spring combined membrane (4) (gastrointestinal tract) abdominal disease, proctitis, eosinophilic gastroenteritis, obese cell disease, Crohn's disease, ulcerative colitis, food-related allergies that are far from the influence of the intestine, such as Migraine, rhinitis and wet therapy; (5) (other tissue and systemic diseases) recurrent sclerosis, atherosclerosis, acquired asthmatic syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's chronic thyroid Inflammation, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, high IgE syndrome, leprosy nodular leprosy, sezary syndrome and spontaneous thrombocytopenic purpura (6) (Allograft rejection) acute and chronic, occurring, for example, after transplantation of the kidney, heart, liver, lung, bone marrow, skin and cornea, and chronic graft versus host disease; (7) cancer, especially non- - vesicular lung cancer (NSCLC) and squamous sarcoma; (8) accompanied by increased chemical hormone water, diseases that kill angiogenesis (eg, NSCLC); and..., (9) cystic fibrosis, stroke, heart , brain, limbs and septicemia re-injection damage. > -24- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1301487

Accordingly, the present invention provides the use of a compound of formula (i) as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof, in therapy. In another embodiment, the present invention provides a use of a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for use in therapy. As used in this specification, the term "treatment" includes, and prevents, unless otherwise specified. The words "therapeutic, and, and, therapeutically," should also have a corresponding cognition. The present invention also provides a method for treating a patient suffering from an inflammatory disease or at risk, including The patient is administered a therapeutically effective amount of a compound of the formula (][] or a pharmaceutically acceptable salt or solvate thereof, which is a patient suffering from an airway disease or is at risk of developing the disease. A method of treating the disease comprising administering to the patient a therapeutically effective amount of a compound of formula (J) or a pharmaceutically acceptable salt or solvate thereof, for use in the above therapeutic use, at a dosage The compound may be mutated in the range of 〇·_亳克/kg to 3G mg/kg, depending on the compound to be administered, the dosage form, the desired treatment and the adaptation disorder. The compound and its pharmaceutically acceptable salt or solvate may be used in its own form. However, it is usually used in the form of a pharmaceutical compound in which the compound of the formula (I)/salt/solvate (live)忮 ingredients) combined with medicinal acceptable The adjuvant, diluent or carrier. The pharmaceutical composition preferably comprises from 0.05 to 99% to (% by weight), more preferably from 〇 to 8% to 25%, depending on the mode of administration.

1301487 A7 B7 V. Inventive Note (23) w, still more preferably 0.10 to 70% w, and even more preferably 0.10 to 50% w of the active ingredient, all based on the total composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, together with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical composition can be applied topically in the form of a solution, a suspension, a sevoflurane aerosol and a dry powder formulation (eg, to the lungs and/or airways or skin) or ingots, capsules, syrups, powders or granules. The form is administered orally; or it is administered in the form of a solution or a suspension, or is administered subcutaneously, or is administered orally or transdermally in the form of a suppository. The invention has thus far been further explained with reference to the following illustrative examples in which 1 H NMR spectra were recorded on a Varian Unity Inova 400. An intermediate solvent peak (β η 7.27 ppm) of chloroform-d was used as an internal standard. Low resolution mass spectrometry and correct mass determination were recorded on a Hewlett-Packard 1100 LC-MS system with an APCI/ESI ionization chamber. All solvents and commercial agents are laboratory grade and are used in the form received. The nomenclature of the compounds was generated using ACD/IUPAC Name Pro. Example 1 - 1 6 Starting material: 1-(3,4-dioxamethyl)-4-piperidylamine i) 4-piperidylamino decanoic acid tert-butyl ester in 1-benzyl- 4-piperidinamine (13.10 g, 68.84 mmol) in di-methane methane-26- This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1301487 A7 B7 V. Invention description (24 ) &quot ; ~" — (100 ml) / triethylamine (2 ml) was added with dibutyl butyl carbonate (11.6 g, 53·16 mmol) and the solution was stirred at room temperature for 2 hours. . Water was added to the solution, the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was taken up in ethanol. To the solution was added 20% palladium hydroxide (500 g) and the mixture was hydrogenated under 50 psig hydrogen (ρ & device) for 48 hours. The mixture was filtered through a pad of diatomaceous earth. The solid was washed with two portions of hot ethanol and concentrated to give 8.85 g of product. APCI-MS: m/z 201 [MH+] 4 NMR (400 MHz, CD3ODH 2.97-3:39 (1H, m), 3 (2H, m) 2·55·2·62 (2H, m), 1.8- 1.84 (2H, dd), 1·42 (9H, s), 1.27-1 37 (2H, m) ii) 1·(3,4·Dichlorobenzyl)-4-spotting amine in 4-bred bite Add 12-diox-4·(gasmethyl)benzene to a solution of tert-butyl carbamic acid (400 mg, 2·〇 mmol) / DMF (25 ml) / triethylamine (2 ml) 390 mg, 1.99 millimoles). After the solution was stirred at room temperature for 3 hours, it was concentrated by venting. A solution of the solid in methylene chloride (3 mL) was added to trifluoroacetic acid (6 ml) and stirred at room temperature for 2 hr. After the solution was diluted with methylene chloride, it was washed with two portions of water. The combined aqueous washes were taken to pH 10 with 2M NaOH and extracted with diethyl ether. The ether was dehydrated (Na.sub.2SO.sub.4). APCI-MS m/z 2 5 9 [ MH+ ] iH NMR (400 MHz, CD3OD)d 7.4Ϊ (1Ή,d),7·36 (1H,br d), 7·13 (1H,dd),3· 42 (2H, s), 2·^7·3·01 (1H, m), 3 (2H, m), 2·55-2·62 (2H, m), 1·41-1·55 (2H ,dd),1.31-1.54 (2H,m) -27- This paper scale applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) 1301487 A7 B7 V. Description of invention (Example 1 Ν·[2_(3 -{[1-(3,4-dioxalylpiperidinyl)aminohydroxypropyloxy)phenyl]acetamidamine ^ Ν_乙醯基_2_(2,3_epoxyoxypropoxy The mixture of aniline (12 g, 0.58 mmol) and the above starting material (150 mg, 0.58 mmol) in ethanol (1 mL, 99.5 %) was refluxed for 3 hr. The residue obtained was purified by silica gel column chromatography (eluent: methylene chloride/methanol 15 : EtOAc) /z 466[MH+] 4 NMR (400 MHz, CD3ODH 8·0 (1H, dd), 7·5 (1H, d), 7·45 (1H, d), 7.23 (1H, dd), 6.89-7.08 (4H, m), 4.15 (1H? m)5 3.9-4.1 (2H,m) 3.40 (2H, S), 2.97-3.11 (1H, m), 3 (2H, m), 2.55-2.68 (2H, m), 1.39-1.55 (2H, dd), 1.31-1.44 (2H, m), 2.17 (3H, s) 〇 The following compounds were synthesized in a similar manner to the method described in Example 1. Example 2 N-[5 -Chloro-2-(3-{[l-(3,4 - 2) Benzyl)-4-piperidinyl]aminobi-2-hydroxypropoxy)phenyl]acetamide--APCI-MS: m/z 500 [MH+] Example 3: - Ν-[2 -(3-{[1-(3,4-dioxabenzyl)-4-acridinyl]aminobi-2-hydroxypropyloxy)-5-methylphenyl]acetamidamine > -28 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1301487 V. Description of invention (26) APCI-MS: m/z 480 [MH+] Example 4 Ν·[4-( 3-{[1-(3,4-dichloroindolyl)-4-actopyridinyl]amino-4-b-4-ylpropoxy)[1,Γ-biphenyl]-3-yl]B Guanamine., APCI-MS: m/z 542 [ΜΗ+] Example 5 N-[3-'Ethyl-2-(3-{[l-(3,4-dichloroindenyl)-4 -piperidinyl]amino}-2-hydroxypropoxy)-5-methylphenyl]acetamide APCI-MS: m/z 522 [MH+] Example 6 Ν-[2_(3-{[ 1-(3,4-dioxamethyl)-4-ylide-based]amino}_2- Alkyloxy)-4·^benzene Tomb] Ethylamine APCI-MS: m/z 484 [ΜΗ+] Example 7 Ν-[2-(3-{[1-(3,4 - Digasbenzyl) 4-)-piperidinyl]amino}-2-hydroxypropoxy)-5-fluorophenyl]acetamide APCI-MS: m/z 484 [MH+] Example 8 Ν-[2-( 3-{[1-(3,4-dioxabenzyl)-4-piperidinyl]aminobi-2-hydroxypropyloxy-5-5-tomb-phenyl]ethylamine APCI-MS J m/ z 491 [MH+], Example 9, 'Ν-[2-(3-{[1-(4-)-benzyl)-4-piperidinyl]aminobi-2-hydroxypropyloxy)phenyl ]Ethylamine-29- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1301487 A7 B7 V. Invention description (27) One " APCI-MS : m/z 432 [MH+] Implementation Example 1 0 Ν-[2-(3·{[1-(4-Chloromethyl)-4-tramethylene]amino}-light-propoxyl)phenyl]isobutylamide, APCI- MS: m/z 460 [MH+] Example 1 1 Ν-[2-(3-{[1-(4-chloroindolyl)-4-piperidinyl]amino}_2-hydroxypropoxy)benzene Base]-2,2-dimethylpropanamide APCI-MS ·· m/z 474 [MH+] Example 1 2 N-[5 - gas-2-(3-{[l-(4-gas) Mercapto)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]acetamide APCI-MS m/z 466 [MH+] Example 1 3 Ν-[2-(3-{[1-(4·chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropyloxy)-5 -methylphenyl]acetamide APCI-MS ·· m/z 446 [MH+] Example 1 4 Ν-[2-(3-{[1-(4-)-benzyl)-4-piperidinyl Amino}-2-hydroxypropoxy)-4-methylphenyl]acetamidamine--APCI-MS: m/z 446 [MH+] Example 15: 'Ν-[2-(3-{ [1-(4 - sage)-4 - brittle base] amino-based propyl propyl) - 4 - phenyl phenyl] ethyl amide - 30 - This paper scale applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1301487 A7 _B7____ V. Description of invention (28) APCI-MS: m/z 450 [MH+] Example 1 6 Ν-[2-(3-{[1-(4 - gas 芊4-(piperidinyl)amino}_2-hydroxypropoxy)-5-cyanophenyl]acetamide, APCI-MS: m/z 457 [MH+] Example 1 7 to 6 3 Starting material epoxy A: N-{2-[(2S) oxiranylmethoxy]phenyl}acetamidine (2S)-2-[(2-nitrophenoxy) A The base epoxy pentoxide (1.17 g, 6 mmol) was dissolved in ethyl acetate (50 mL). Pt/C (0.50 g) was added, and stirred at room temperature under atmospheric pressure in a hydrogen atmosphere for 3 hours. The catalyst was filtered off and washed with b acetate (10 ml) on a filter. Acetic anhydride (1.23 g, 1.13 ml, 12 mmol) and ethyl bis(isopropyl)amine (1.55 g, 2.05 mL, 12 mmol) were added to the solution. After the reaction mixture was stirred at room temperature for 3 hours, it was extracted with 1M NaOH (2 X 50 ml) and brine (2 X 50 ml) and then dried over Na. The solvent was evaporated and the title compound (jjjjjjjjjjj 1 H NMR (400 MHz, CDC13): d 8.36 (m; 1H), 7.89 (br s, 1H), 6.8-7.0 (m, 3H), 4.35 (dd, -lH, J=2.5, J=11.3) , 3.95 (dd, 1H, J=5.9, J=11.3), 3·39 (m, 1H), ^Z^5 (t, 1H, J=4.8), 2.78 (dd, 1H, J=2.7, J =4.8), 2.22 (s, 3H). :~ APCI-MS : m/z 208[MH+]

Epoxide·· B -31 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1301487 A7 B7 V. Invention description (29 i) [(2R)-2 -methylepoxyacetamidine (methyl) 4-methyl-methyl phthalate ester (S)-2-methyl-dehydroglycerol (〇1 gram, u millimolar), diammonium pyridine (0.5 mg, 3.8 micromolar The ear was cooled in an ice bath in triethylamine (2 mL) and toluenesulfonate (0.217 g, 1.14 mmol) was added in one portion over 1 min. Seal the flask and keep it at -ίο. (The whole was taken overnight. The reaction mixture was evaporated and evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The product (heptane / EtOAc 1 : 2) gave 145 mg (5 3%) of subtitle compound. lH NMR (400 MHz, CDC13): δ 7.80 (2 Η, d, J 8.4 Hz), 7.36 (2H, d, J 8.1 HZ), 4.04 (1H, d, J 10·7 Hz), 3.95 (1H, d, J 10.7 Hz), 2.70 (1H, d, J 4.7 Hz), 2.64 (1H, d, J 4· 6 Hz), 2.46 (3H, s), 1.36 (3H, s) 〇 ii) N-(2-{[(2R)-2-indolyl oxiranyl]methoxy}phenyl) acetamidine The amine was added to [(2R)-2-indenyl oxiranyl] in 2-ethylaminosyl (90.5 mg, 0.598 mmol) and post-acid hydrazine (234 mg, 0.718 mmol). A solution of 4-toluenesulfonate (145 mg, 0.598 mmol) / DMF (1 mL). After the mixture was stirred at room temperature for 4 hours, it was dissolved between ethyl acetate and water. After extraction, the combined organic pine is dehydrated and hollowed out. The residue was purified on EtOAc (EtOAc /EtOAc (EtOAc) ,

4 NMR (400 MHz, CDC13): β 8.38-8.31 (1H, m), 8.02 (1H, bs), 7.04-6.97 (2H, m), 6.93-6.86 (1H, m), 4·11 (1H, d,J -32- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

Binding

1301487

10.9 Hz), 4.01 (1H, d, J 10.9 Hz), 2.95 (1H, d, J 4.7 Hz)? 2.78 (d, J 4.7 Hz), 2.21 (3H, s), 1·48 (3H, s) .

Epoxide·· C 1) [ ( 2 S) - 2 -Methyl oxiranyl]methyl _ 3 nitrobenzene phthalate is added to the powder in a dried 1000 ml three-necked flask. Molecular sieves (8.0 g, 4A) and CH2C12 (440 ml, dehydrated on molecular sieves). Add D-(-)-diisopropyl tartrate (3 liters, 14 2 mmol) and 2-methyl-2-propan-1-ol (20 mL, 240 mmol) and mix Cool to -2 () C. Tetraisopropoxide (3.5 ml, 119 mmol) was added to several milliliters of CHAh and the mixture was stirred at -20 °C for 3 minutes. The hydrogenated cumene peroxide (75 liters, about 430 millimoles) was dropped during the period of 5 hours while maintaining the temperature at -2 0 °C. The mixture was stirred at this temperature overnight. Trimethylphosphine (4 mM, 34 mM) was added dropwise at -50 °C during the period of 15 hours. Add triethylamine (50 ml, 360 mmol) and hydrazine (3.48 g, 28.5 mmol) followed by 3-nitrobenzenesulfonium chloride (47 g, 212 mmol) / CH2Cl2 (400 mL) solution. Increase the temperature to -1〇. (: and the mixture was stirred at this temperature overnight. After the external cooling was removed, the reaction mixture was filtered through > 5 Celite®. The organic phase was passed through 1% tartaric acid (5 liters) The organic phase was dehydrated (MgS〇4) and evaporated to give about 150 g of a yellow oil. The crude material was chromatographed (1).公斤 氧化 爹 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 庚 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 8.8 8.8 8.8 8.8 Purification is used. lH NMR (400 MHz, CDC13): d 8.79-8.75 (1H, m); 8.52 (1H, -33 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm)

Binding

1301487 A7 ___ B7 V. INSTRUCTIONS (31) "" ddd, J 1.1 2.3 8.3 Hz); 8.25 (1H, ddd, J 1.1 1.8 7.8 Hz); 7.81 (1H, t, J 8.5 Hz); 4.28 ( 1H,d,J 11.3 Hz); 4·05 (1H,d,J 11.3

Hz); 2.73 (1H, d, J 4.4 Hz); 2.67 (1H, d? J 4.4 Hz); 1.56 (3H, s), ii) N-(2-{[(2S)-2_methyl ring Oxyethane]methoxy}phenyl)acetamide The compound obtained in a) was added to a flask (24 57 g, 9 〇 mmol), 2-ethylamino-phenol (13.59 g, 90) Millol), Cs2C03 (35.1 g, 108 mmol, powder anhydrate) and DMF (90 mL). The flask was sealed and the mixture was stirred with a magnetic stir bar at room temperature for 2 hours. A concentrated precipitate formed and the starting material was converted over 2 hours. The mixture was partitioned between Et 〇Ac / water (400 + 400 mL). The organic phase was collected and the aqueous phase was washed with EtOAc (2×200 mL). The combined organic phases were extracted with water (200 mL), 1M EtOAc (2. The organic solution was dried over Na 2 SO 4 and concentrated in vacuo. The crude material was purified on EtOAc (Heptane /EtOAc 5:1 to 1:1). The optical purity was determined to be 97.4% based on HPLC (ChiralpckT M, isohexane/isopropanol 95:5). !H NMR (400 MHz, CDC13): S 8.39-8.32 (1H, m); 8.00 (1H, bs); 7.05-6.97 (2H,m); 6.9^5-6.88 (1H,m); 4.12 (1H , d, AB, J 11.0 Hz); 4.02 (1H, d, AB, J UarfeHz); 2.96 (1H, d, J 4.6 Hz); 2.79 (1H, d, J 4.8 Hz); 2.22 (3H, 3) ; 1:49 (3H, s)

Epoxide: D N-{4-fluoro-2-[(2S)oxiranyl methoxyoxy]phenyl}acetamide-34- This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm)

Binding

1301487 A7 B7 V. INSTRUCTIONS ( ) Manufactured from (2S)-2-[(5-fluoro-2, sure phenoxy)methyl]oxirane according to the procedure described for epoxide: A. APCI-MS: m/z 226[MH+] 4 NMR (400 MHz, CDC13): d 8.30 (dd,1H,J=5.2, J=9 0) 7.71 (br·S,1H), 8.6-8.8 (m , 2H), 4.36 (dd, 1H, J=2 3 J=11.3), 3.90 (dd, 1H, J=6.3, J=11.3), 3.40 (m, 1H), 2.97 (t 1H, J=4.4) , 2.78 (dd, 1H, J=2.7, J=4.8), 2.21 (s, 3H) 〇

Epoxide: E N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}benzamine N-(2-hydroxyphenyl)benzamide (159 mg, 〇·75 mmol), 2-(gasmethyl)-2-methyloxirane (1.60 g, 15 mmol) and gasified thallocidate (27 mg, 0.12 m) The mixture of moles was stirred at 70-75 ° C; 6 hours off. After cooling to room temperature, water (2 ml) was added and the mixture was shaken and shaken. Extracted with di-methane (2.times.5 mL), and combined organic extracts were washed with aqueous NaOH (2M, 5 mL) and water (1 mL). Dehydration with NazSCU, evaporation of solvent and flash chromatography on EtOAc EtOAc (EtOAc:EtOAc 62%). APCI-MS: m/z 284[MH+] 'H NMR (400 MHz, CDC13)-: ί 8.68 (br. S5 1H), 8.54 (m 1H), 7.94, (m, 2H), 7.4-7.6 (10) ), 7.07 (m, 2H), 6.92 (m, 1H), 4.19 (d, 1H, J = 10.7), 4.06 (d, lH; J 10.7), 2.92 (d, 1H, J = 4.6), 2.78 ( d, 1H, J = 4.6). ’

Epoxide: F -35- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1301487

AT _ B7 V. INSTRUCTIONS (33) " N-Methyl-2-[(2-methyl-2-oxiranyl)methoxy]benzamide according to N-{2-[ (2-Methyl-2-oxiranyl)methoxy]phenyl}benzamide The method described is from 2-hydroxy-N-methylbenzamide (according to Cohen et al., J. Prepared by Am. Chem. Soc., 1998, 20, 6277-6286. APCI-MS : m/z 284[MH+] 'H NMR (400 MHz, CDC13) · ^ 8.68 (br. S, 1H), 8.54 (m, 1H), 7·94 (m, 2H), 7.4-7.6 (m, 3H), 7.07 (m, 2H), 6.92 (m, 1H), 4.19 (d, 1H, J = 10.7), 4.06 (d, lH, J 10.7), 2.92 (d, 1H,

J=4.6), 2.78 (d, 1H, J=4.6), 1.51 (s, 3H) oxime epoxide: G N-[4-methyl-2-(2-oxiranylmethoxy) Phenyl]acetamide will be N-(2-oxindole-4-ylphenyl)acetamide (10 g, 60 mmol), 2-(bromopurinyl)oxirane (9.86 g, A mixture of 72 mmol, 6.0 mL) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 mL) The reaction mixture was then diluted with ethyl acetate and extracted with aqueous HCl (1.5%), saturated aqueous NaH.sub.3, and brine. The solvent was distilled off and the title compound was obtained by flash chromatography on EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) . APCI-MS : m/z 222[MH+]- 'H NMR (400 MHz, CDC13) : , ^8.20 (d, 1H, J=8.2)? 7.78 (br. s,1H),6·79 (d, 1H, J=8.2), 6.70: (s, 1H), 4.32 (dd, 1H, J=2.5, J=11.4), 3.93 (dd, 1H, J=5.9, J=11.4), 3.38 (m, 1H) ), 2.94 (t, 1H, J=4.8), 2.77 (dd, 1H, 1=2.7^=4.8), 2.29 (s, 3H), 2.19 (s5 -36- This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1301487 A7 B7 V. Description of invention (34 3H) Epoxide: Η Ν-[4-methoxy-2-(2-oxiranylmethoxy)phenyl] Acetamide is substituted with potassium carbonate from N-(2-hydroxy-) according to the method described for N-[4-methyl-2-(2-oxiranylmethoxy)phenyl]acetamide. Prepared from 4-methoxyphenyl)acetamide APCI-MS: m/z 238 [MH+] ln NMR (400 MHz, CDC13): ά 8.20 (d, 1H, J = 8.8), 7.62 (br. s, 1H), 6.4-6.6 (m, 2H), 6.70 (s, 1H), 4.32 (dd, 1H, J=2.5, J=11.3), 3.91 (dd, 1H, J=6.1, J=ll. 3), 3.77 (s, 3H), 3.37 (m, 1H), 2.94 (t, 1H, J = 4.8), 2.76 (dd, 1H, J = 2.7, J = 4.8), 2·18 (s, 3H) 〇· Epoxide: I i) 2- Amino-3-fluorophenol was added to a solution of 2,6-difluoronitrobenzene (iioo mg, 6.9 mmol)/anhydrous methanol (2 liters) with sodium (180 mg, 7.8 mmol)/ Anhydrous methanol (8 ml) solution. The solution was stirred overnight. After concentration, water was added and the solution was extracted with EtOAc (EtOAc), EtOAc (EtOAc) To a yellow residue/dichloromethane (1 liter) solution was added boron tribromide (1M, methylene chloride, 10 ml) and stirred at room temperature overnight. Then, water was added to stir the solution for 60 minutes. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were dehydrated with MgS(R) 4, dried over EtOAc (EtOAc m. The residue was taken up in B and washed with 2 argon argon and water. The mixture of glutamic acid and sodium hydroxide was combined with -37-1301487 A7 ______B7__ V. Inventive Note (35) 6M HCl was neutralized, extracted with diethyl ether, dehydrated with MgS〇4 and evaporated to give a yellow residue on a silica gel. The product was obtained by flash chromatography using Et〇Ac••heptane®:3 as a decanting agent (72 mg, 46 mmol), which was suspended directly in water with Pd/C (140 mg). - Ethanol 〇 ml). Sodium hydride (53 mg) was added over a period of $ minutes and the suspension was stirred at room temperature (i.times.) and filtered through a pad of Celite to remove the catalyst. The filtrate was acidified with 6 M hydrochloric acid to destroy any residual borohydride, neutralized with 2M sodium hydroxide and then extracted with diethyl ether. The ether extract was dehydrated and evaporated with Mgs(R). APCI-MS : m/z 128.2 [MH+] u) -fluoro-6·(2-oxiranylmethoxy)phenyl]acetamide in 2-amino-3-fluorophenol (3〇〇 In milligrams, 2.36 millimoles) acetic anhydride was added to the stirred solution in water-methanol (10 halo) until all of the 2-amino- 3 -fluorine was consumed. The solution was concentrated to a residue containing hydrazine-(2-fluoro-6-hydroxyphenyl)etheneamine. Ν-(2-Fluoro-6-hydroxyphenyl)acetamide (399 mg ' 2.36 mmol) and potassium carbonate (652 mg, 4 72 mmol) in a mixture of DMF (5 liters) Epichlorohydrin (388 mg, 2.8 mmol) was added and the mixture was stirred at 70 ° C for 3 hours. Water and ethyl acetate were added, the organic phase was separated, dehydrated and concentrated. The residue obtained was purified by EtOAc (EtOAc:EtOAc) - . APCI-MS,: m/z 226[MH+] 'Η NMR (400 MHz, CDC13) : δ ΊΛ5 (m, 1H), 6.87 (br. s, 1H), 6·6-6·8 (m , 2H), 4.30 (dd, 1H, J=2.3, J=11.3), 3.93 (dd, 1H, J=5.7, J-11.3), 3.34 (m, 1H), 2.91 (t, 1H, J=4.4 ), 2.75 -38- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1301487 A7 B7

V. Description of invention (36

(dd, 1H, J=2.8, J=4.8), 2.20 (br·s, 3H) oxime epoxide: J N-(2-oxiranylmethoxy-phenyl)-benzamide To a stirred solution of N-(2-hydroxyphenyl)-benzamide (0.81 g, 3.80 mmol) and ruthenium citrate (1.61 g, 4.94 mmol) in acetonitrile was added to the table bromide (0) · 63 ml, 7.60 millimoles). After 4 hours, the reaction mixture was partitioned between diqi methane and water. After evaporating the organic solvent, the residue was crystallised from EtOAc (EtOAc:EtOAc: EtOAc: 1H),8·55 (bs,1H), 7.94 (d,2H),7.53 (m,3H),7.08 (bs,2H),6·96 (bs,1H),4.42 (d,1H),4.02 , (m, 1H), 3.41 (bs, 1H), 2.96 (s, 1H), 2.80 (s, 1H) 〇

Epoxide: KN-methyl-2-oxiranylmethoxy-benzoguanamine in 2-hydroxy-N-mercaptobenzamide (0.5 g, 3.31 mmol, according to Cohen, Seth M et al., J. Am. Chem. Soc., (1998), 120(25), 6277-6286) and cesium carbonate (2.16 g, 6-62 mmol) in acetonitrile Alcohol (0.274 ml, 3.31 mmol). The mixture was heated at 5 (TC) for 2 hours, cooled to room temperature and then partitioned between water (50 mL) and di-methane (100 m, liter). The methane layer was dried and evaporated. Obtained 0.43 g (64%) of solid product 1. APCI-MS ·· m/z 208 [MH+] 4 NMR (400 MHz, CDC13): β 8.20 (dd, 1H), 7.85 (bs, 1H), -39 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1301487 A7 B7 V. Description of invention (37 7.42 (m, 1H), 7.11 (m, 1H), 6.95 (dd, 1H), 4.46 (dd, 1H), 4.11 (dd, 1H), 3.41 (m, 1H), 3.02 (d, 3H), 2.97 (t, 1H), 2.84 (dd, 1H) 〇 epoxide: L, N-(2-methyl-6-oxiranylmethoxy-phenyl)-acetamide, 3-methyl-2-acetamidophenol (0.165 g, 1 Torr), and A mixture of epichlorohydrin (1.84 g, 20 mmol) was scrambled at 70 ° C to give a clear solution. Then vaporized triethylbenzylammonium (0.15 g, 1 mmol) and at 12 5 Continue stirring in C: drop for 15 minutes. After cooling to room temperature, add 1 NaOH solution and extract the solution with dioxan. Organic extract After washing with water, it is dehydrated. After distilling off the methane, the obtained brown oil is purified by EtOAc EtOAc (EtOAc) 0.54 millimolar. APCI-MS : m/z 208 [MH+] epoxide: Μ 3,5-dimethyl-111-pyrrole-2-carboxylic acid (2-oxiranylmethoxy) Phenol)-acetamide is similar to epoxide··L from 3,5-dimercapto-biha-2-deca-(2-phenyl)-acetamide (300 mg, 1·) Preparation of the compound 0 - , APCI-MS: m/z 287 [MH+] H NMR (400 MHz, CDC13): H46, (m,1H), 8.31 (m,1H), 6.99 (m, 2H), 6.87 (m, 1H), 5.85 (m, 1H), 4.34 (m, 1H), 3.92 (m, 1H), 3.36 (m, 1H), 2.91 (m, 2H), 2.71 ( m,1H),2.47 (m, -40- This paper size applies to the Chinese National Standard (CNS) A4 specification (21QX297 public 羡)'1 -------- 1301487 A7 _______B7 V. Description of invention (38) 3H), 2.25 (m, 3H) (1) 3,5-Dimethyl-111-pyrrole-2-carboxylic acid (2-phenyl)-acetamide 2-aminophenol (545 mg, 5 m Mohr), 3,5-dimethyl-1H-pyrrole-2-carboxylic acid (ii) (695 m Stirring, 5 mmol) and HATU (1900 mg, 5 Bo mole) were placed in DMF (20 mL). Diisopropylethylamine was added to pH 8. The mixture was stirred overnight and concentrated. The residue was purified on EtOAc (EtOAc /EtOAc (EtOAc) APCI-MS : m/z 231 [MH+] lU NMR (400 MHz, CDC13) : ^ 9.22 (s, 1H)5 7.63 (s, 1H), 7.11 (m, 2H), 7.03 (m, 1H), 6.88 (m, 1H), 5.88 (s, 1H), 2.44 (s, 1H), 2.24 (s: 1H). (ii) 3,5-Dimercapto-111-indol-2-carboxylic acid in ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich) (504 mg, 3 mmol) in THF Add NaOH (480 mg, 12 mmol) / H20 (12 mL) to the solution in /H20/Me0H (5:1 ··1,30 mL). The mixture was mixed overnight at 75 Torr. The homogeneous mixture was extracted with diethyl ether. Saturated KHS04 solution was added to the aqueous layer until the pH was about 3. The solution was then extracted with digas methane. The extract was dehydrated with MgS〇4 and evaporated. The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc: , 4 NMR (400 MHz, CDC13): ά 8.75· (s, 1H), 5.83 (s, 1H), 2.25 (s, 1 Η), 2.38 (s, 1 Η).

Amine: N -41 - ^ paper scale suitable for s s home standard (CNS) A4 specification (2l 〇 x 297 mm) 1301487 A7 B7 V. Description of invention (39

1-(4-oxooctyl)-methanoline hydrochloride in tert-butyl 4-piperidinylcarbamate (2.02 g, 1 〇 1 mmol) and triethylamine (10 ml) in anhydrous DMF (100 1-Chloro-4-(gasmethyl)benzene (1.61 g, 10 mmol) was added to the stirred solution in ML). After stirring the solution overnight at room temperature, the solvent was removed by hollowing out. The residue was taken up in dioxane (150 ml) and trifluoroacetic acid (30 ml). After 3 hours at room temperature, the solution was diluted with di-methane (150 mL) and extracted with water (2 X 15 mL). The pH of the combined aqueous extract was adjusted to 10 via the addition of 2M Na〇H. The solution was extracted with diethyl ether (3 X 100 mL). The title compound (1.91 g, 8.5 mmol, 85%) was obtained. iH NMR (400 MHz, CDC13): J 7·2·7·3 (m, 4H), 3.41 (s, 2H), 2.76 (m, 2H), 2.63 (m, lH), 1.98 (m, 2H) , 1.76 (m, 2H), 1.3-1.6 (m, 4H). APCI-MS: m/z 225[MH+]amine··〇(3S)-l-(4-- aryl)-3-indolylamine from (3 s )pyrrole according to the method described for amine··N Prepared from tributyl butyl carbamic acid. APCI-MS: m/z 211[MH+] 4 NMR (400 MHz, CDC13): j 7.2-7.3 (m, 4H), 5·55 (d, 2H), 3·49 (m, 1H), 2.66 ( m,2H),2·41^»,1H), 2.29 (dd,1H), 2.18 (m,1H),1·68 (br·s,2H),1.48 (m,4H)

Amine: P (3R)-l-(4-chloroheptyl)-3_p than sulphate-42- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1301487 A7 B7 V. Description of invention (40) Prepared from (3R) pyridinyl carboxylic acid tert-butyl ester according to the method described for amine: N. APCI-MS: m/z 211[MH+] 1 H NMR (400 MHz, CDC13): 汐7.2-7.3 (m, 4H), 5.55 (d, 2H), 3·49 (m, 1H), 2.66 (m) , 2H), 2·41 (m, 1H), 2.29 (dd, 1H), 2.18 (m, 1H), 1.68 (br·s, 2H), 1.48 (m, 1H)

Amine··················································· Med. Chem. 1992, 35, 4334-4343) and triphenylphosphine (2.41 g, 9.18 mmol) were dissolved in dry THF (25 mL). The solution was cooled to 0 ° C and a solution of 4-gasphenol (1.18 g, 9·18 mmol) in anhydrous THF (10 mL) was added followed by diethyl azodicarboxylate (1.60 g, 9· 18 millimoles, 1.45 ml). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed by venting and the residue was stirred with diethyl ether / n-heptane (1:2, 50 mL). The solid was filtered to oxidize triphenylphosphine, and the solution was extracted with aqueous NaOH (1 Μ, 3×7 5 mL). The solvent was evaporated and the title compound was obtained eluting with EtOAc EtOAc EtOAc (EtOAc) . Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred at room temperature. The solution was concentrated in vacuo and purified to purified crystals eluted elut elut elut elut elut APCI-MS : m/z 212[MH+] ', -43- This paper size is applicable to China National Standard (CMS) A4 specification (210X297 mm) 1301487 A7 __ _Β7 V. Invention description (41 ) ^ ~ lU NMR ( 400 MHz, CDC13) : d 7.19 (m, 2H)? 6.84 (m, 2H), 4.25 (m, 1H), 3.17 (m, 1H), 2.7-2.9 (m, 4H), 1.97 (m, ih) , 1.7-1.9 (m, 2H), 1.53 (m, 1H).

Amine·· R 1-(4-bromobenzyl)-4-piperidinylamine in 4·bromofluorenyl bromide (1·〇g, 4.1 mmol) in di-methane (2 mL) and To the solution in isopropylethylamine (1 ml) was added 4 - butyl amidocarboxylate (1.0 g, 5.0 mmol). The solution was stirred at room temperature. The solvent was evaporated and 25 mL of 50% TF A / dichloromethane was then evaporated. The mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After the toluene was removed, the aqueous phase was adjusted to pH 1 3 with NaOH. The aqueous phase was then extracted three times with dichloromethane and the combined extracts were dried and evaporated to give a pale yellow oily product (0.96 g, 3. 6 mmol). APCI-MS : m/z 269[Μ+] NMR (400 MHz, CDC13) : ά 7.42 (d, 2H), 7.18 (d, 2H), 3.43 (s, 2H), 2.78 (m, 3H), 2.43 (bs, 2H), 2.10 (t, 2H), 1.82 (m, 2H), 1.44 (m, 2H). The following amines (S, T, U) are synthesized in a manner similar to that described for the amine R. · · · · Amine: S ' 1-(3,4-difluoroindolyl)-4-piperidinamine ~ APCI-MS : m/z 227 [MH+]

Amine: T -44 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1301487 A7 ______B7 V. Description of invention (42) 1- (3-Air-4-fluorobenzyl)-4 - Shout bite amine APCI-MS : m/z 243 [MH+]

Amine: U 1 ·(4·fluoroindolyl)-4-piperidinamine, APCI-MS: m/z 209 [MH+] Example 1 7 1^_(2-{[(23)-3-({ [1-(4-Carboxymethyl)methyl]-4-piperidinyl}amino)-2-(p-propylpropyl)oxy}phenyl)acetamide bis(trifluoroacetate) 1_(4芊 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) , 3 57 mM) solution in ethanol (50 mL, 99.5%) was refluxed for 4 hours. The solution was distilled under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) eluting APCI-MS: m/z 432 [MH+] Example 1 8 N-(2-{(2R)-3-[l-(4·gasbenzyl)--salt-4-ylamino]-2- 1-(4-Galyzyl)piperidinamine (62 mg, 0.276 mmol) and N-(2-{[(2) via benzyl-2-methylpropoxy}-phenyl)acetamide A solution of R)-2-methylepoxyethyl hydrazinyl]methoxy}phenyl)acetamide (6 ιιη, 0.276 mmol) in ethanol (1:1 liter) was placed in a sealed tube. The bottle was stirred at 80 ° C for 4 hours. The reaction mixture was diluted with water and purified by reverse phase HPLC to afford 13 mg (yield: EtOAc) Its optical purity is in Chiralpak AD - Tube -45-

1301487 A7 B7 V. INSTRUCTIONS (43) The column was determined to be 86% ee by HPLC. APCI-MS: m/z 446.1 [M+] Example 1 9 Ν-(2-{[3·({1-[(4-chlorophenyl)methyl)-4-piperidyl)amino)- 2-Hydroxy-2-methylpropyl]oxy}phenyl)acetamidamine was prepared from the racemic epoxide in a similar manner to that described in Example 18. , APCI-MS · m/z 446.1 [M+] Example 2 0 N-(2-{(2S)-3-[l-(4-carboyl)-piperidin-4-ylamino]-2 ·Hydroxy-2-indolylpropoxyphenyl)acetamidin from N - { 2 - ((( 2 S ) - 2 -methyloxirane) in a manner similar to that described in Example 18 (Methoxy)phenyl}acetamide prepared, > 98% yield. APCI-MS: m/z 446.1 [M+] General procedure (Example 2 1 - 4 3 ) Add epoxide/DmS solution (O.iM, to amine/EtOH drop (0.1M '0.23⁄4 liters). 0.2 ml). The reaction mixture was heated at 8 ° C for 24 hours. Example 2 1 1{2-[((2 8)-3_{[1-(4~fluoroindolyl), 4, piperidinyl]aminobi-2-phenylhydroxy)oxy]-phenyl} Acetamine APCI-MS: m/z 416 [MH+] , Example 2 2 N-{2-[((2S)-3-{[1-(4- gas 竿 1) _4, succinyl) amine Base}_2_经•46- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- 1301487 A7 B7 V. Description of invention (44) propyl) oxygen Kebu 4-fluorophenyl}acetamide APCI-MS: m/z 450 [MH+] Example 2 3 N-{4 -Fluoro-2- [ [(2S)-3-{[l-(4- Fluoromethyl)·4;piperidinyl]amino-2-hydroxypropyl)oxy]-phenyl}acetamide APCI-MS: m/z 434 [MH+] Example 2 4 N-{2- [((2S)-3-{[(3S)-l-(4-Chloromethyl)pyrrolidinyl]amino} 2-hydroxypropyl)oxy]-4-fluorophenyl}acetamidamine APCI -MS : m/z 436 [MH+] Example 2 5 N - {2-[((2))--[[(3R)]-1-(4-chlorobenzyl)pyrrolidinyl]amino-2- Hydroxypropyl)oxy]-4-fluorophenyl}acetamide APCI-MS: m/z 436 [MH+] Example 2 6 Ν-[2-(3-{[1-(4-fluorobenzyl) -4 - acridinyl]aminobi-2-hydroxy-2-methylpropoxy)phenyl]acetamide APCI-MS : m/z 430 [MH+] 2 7 N-[2-(3-{[ 1-(4-lactyl)-4 - keate]amino} - 2 - phenyl to 2-methylpropoxy)·4- Fluorophenyl]acetamide APCI-MS : m/z 464 [ΜΗ+] : - Example 2 8 N-[4-fluoro-2-(3-{[l-(4-fluorobenzyl Y-4) -piperidinyl]aminobi-2-hydroxy- -47- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1301487 A7 B7 V. INSTRUCTION DESCRIPTION (45) 2-Methylpropoxy)phenyl]acetamide APCI-MS: m/z 448 [MH+] Example 2 9 Ν-[2-(3-{[1 -(4- seroaki)-4-azino]aminohydroxypropyloxy-4-methylphenyl]acetamide APCI-MS: m/z 446 [MH+] Example 3 Ν [2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4-methylphenyl]acetamide APCI-MS : m/z 430 [MH+] Example 3 1 N-[2-(3-{[lj4-chlorobenzyl)-4-piperidinyl]aminobi-2-phenylpropoxy)phenyl]phenylhydrazine Amine APCI-MS: m/z 494 [MH+] Example 3 2 Ν-[2-(3-{[1-(4-fluorobenzyl)-4)piperidinyl]amino}-2-hydroxypropoxy Phenyl]benzamide APCI-MS: m/z 478 [MH+] Example 3 3 N-[2-(3-{[(3S)-l-(4· benzyl)pyrrolidinyl) Amino}-2-hydroxypropoxy)phenyl]benzamide: APCI-MS: m/z 480 [ΜΗ+] : ' Example 3 4 N-[2-(3-{[( 3R)-l-(4-Chlorobenzyl)pyrrolidinyl]aminobi-2-hydroxy-48- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

1301487 A7 B7_._ V. INSTRUCTIONS (46) Propoxy)phenyl]benzamide APCI-MS ·· m/z 480 [MH+] Example 3 5 Ν_[2-(3-{[1- (4.Bromoindolyl)·4-piperidinyl]aminohydroxypropyloxy)phenyl]benzamide APCI-MS : m/z 540 [ΜΗ+] Example 3 6 Ν·[2-( 3-{[1-(4-chlorobenzyl)-4-piperidinyl]aminobi-2-hydroxy-2-methylpropoxy)phenyl]benzamide APCI-MS : m/z 508 [MH+] Example 3 7-[2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-mercaptopropoxy)benzene Benzoylamine APCI-MS : m/z 492 [MH+] Example 3 8 N-[2-(3 - { [(3R) - 1-(4-)-)-pyridinyl]amino 2-hydroxy-2-methylpropoxy)phenyl]benzoguanamine APCI-MS: m/z 494 [MH+] Example 3 9 N - [ 2 - (3 - {[ 1 _( 4 - Bromobenzyl)-4-piperidinyl]aminobi-2-hydroxy-2-methylpropoxy)phenyl]benzoguanamine APCI-MS: m/z 554 [MH+] - ♦ Example 4 0 Ν-[2-(3-{[1·(4 - Benzyl)-4-3⁄4 yl)]amino hydroxypropoxy-49- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1301487 A7 B7 V. Description of invention (47) Benzyl-4-methoxyphenyl]acetamide APCI-MS : m/z 462 [MH+] Example 4 1 Ν-[2-(3-{[1-(4 - gas fluorenyl) )-4-piperidinyl]amino}-2-hydroxypropoxy)-6-phenylphenyl]ethenolamine APCI-MS ·· m/z 450 [MH+] Example 4 2 N-[2 - Fluorin-6-(3·{[1-(4-fluoroindolyl)-4-piperidinyl]aminobi-2-yl-p-propoxy)phenyl]acetamide APCI-MS : m/z 434 [MH+] Example 4 3 2-(3-{[1-(4-)-]]-]]]] Methionamide APCI-MS: m/z 446 [MH+] Example 4 4 N-(2-{3_[l-(3,4-dichlorobenzyl)------ ]-2-3⁄4 propylpropoxyphenyl)benzamide in N-(2-oxiranyloxyphenyl)benzamide solution (〇·2 ml '0.1Μ in DMSO) Add 1-(3,4 -diqieryl) shouting mercaptoamine (〇·2 ml, 〇·1Μ ethanol)... The resulting mixture was heated at 75_8 〇〇c for 24 hours. The ethanol was removed and the substrate was purified in preparative 1 C/ms. APCI-MS: m/z 529 [MH+] ?~ The following Example 4 5 - 6 3 was synthesized in a similar manner to the method described in Example 4 4 . -50- 1301487 A7 B7 V. INSTRUCTION DESCRIPTION (48) Example 4 5 Ν-(2-{3-[1_(3 -Ga-4-fluoroindolyl)piperidinyl-4-ylamino-2-hydroxyl Propoxy}phenyl)benzamide APCI-MS : m/z 513 [MH+] Example 4 6 Ν-(2-{3-[1-(3,4-difluorobenzyl)-piperidine 4--4-aminoamino]·2-hydroxypropyloxyphenyl)benzamide APCI-MS : m/z 496 [MH+] Example 4 7 Ν-(2_{3-[1-(3,4 -Chloropurinyl)-piperidin-4-ylamino-2-polyhydroxyloxy}-6-methylphenyl)acetamide APCI-MS: m/z 481 [MH+] Example 4 8 Ν ·(2-{3-[1-(4-Fluoroindolyl)-piperidin-4-ylamino]-2-hydroxypropyloxy}-6-nonylphenyl) Ethylamine APCI-MS : m/z 430 [MH+] Example 4 9 Ν-(2_{3-[1-(4-bromobenzyl)-piperidine-4-amino]-2-hydroxy-2-methylpropoxy }phenyl)benzamine APCI-MS ·· m/z 490 [M+] - Example 5 0, Ν-(2-{3-[1-(3,4-dichloroindenyl)----- -3⁄4ylamino]-2-3⁄4yl-2-methylpropoxy}phenyl)acetamide APCI-MS : m/z 481 [MH+] -51 - This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1301487 A7 B7 49 V. Description of the invention (Example 5 1 Ν-(2-{3-[1-(3-Gao-4-fluorobenzyl)piperidin-4-ylamino]-2_hydroxy_2_ decylpropoxy}phenyl)acetamidine Amine APCI-MS: m/z 464 [MH+] Example 5 2 Ν-(2·{3-[1-(3,4·Difluoro-yl)-tradoxy-4-ylamino]-2 Methyl-2-methylpropoxy}-phenyl)acetamide APCI-MS: m/z 448 [ΜΗ+] Example 5 3 2-{3-[1-(4-bromoindolyl)-旅淀-4_基胺基]-2-3⁄4 propyloxybu N-methylbenzamide APCI-MS ·· m/z 476 [M+] Example 5 4 2-{3·[1- (3,4-di-benzyl)--salt_4_ylamino]_2·^-propenyloxy-N-methylbenzamide APCI-MS : m/z 467 [Μ+] Example 5 5 2-{3_[1-(4-Chlorobenzyl)-yliden-4-ylamino]-2-pyridyloxy} _N-mercaptophenylamine APCI-MS : m/ z 432 [MH+] - Example 5 6 i-2-{3-[1-(4-fluorobenzyl)-brazin-4-ylamino p2-pyridyloxybu-N-methylbenzene Indole APCI-MS : m/z 416 [MH+] ' -52- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1301487 A7 B7 V. Invention description (5Q) Example 5 7 3 ,5-Dimethyl-11_pyrrole-2-carboxylic acid (2-{3-[1-(4-bromobenzyl)-piperidin-4-ylamino) ]-2-hydroxypropoxy}phenyl)guanamine APCI-MS: m/z 456 [MH+] Example 5 8 3,5-Dimethylhydrazine - 0 pirox-2 竣(2-{3- [1-(3-Gasinyl)-joutan_4-ylamino]-2-3⁄4ylpropoxy}phenyl)S&amine APCI-MS: m/z 512 [MH+] Example 5 9 3,5-Dimethyl_H_pyrrole-2 -carboxylic acid (2_{3-[1-(3-fluorobenzyl)-piperidin-4-ylamino]-2-per propenyloxy} Benzoamine APCI-MS: m/z 495 [MH+] Example 6 0 Ν-(2-{3-[1-(4-bromoindolyl)-piperidin-4-ylamino]-2 -hydroxypropoxy}-phenyl)acetamide APCI-MS ·· m/z 476 [MH+] Example 6 1 Ν-(2-{3-[1_(3-chloro·4-fluorobenzyl) -piperidin-4-ylamino]-2-hydroxypropoxyphenyl)acetamide APCI-MS: m/z 450 [MH+ small example 6 2· Ν-(2-{3-[1 -(3,4-difluorobenzyl)-piperidinedi-4-ylamino]-2-hydroxypropoxy}-phenyl)acetamide APCI-MS : m/z 434 [MH+]^ -53 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1301487 A7 B7 V. Description of invention (51) Example 6 3 Ν-(2_{3_[1-(4·Fluorofluorenyl)- Piperidin-4-ylaminobi-2-hydroxypropyloxy}-benzyl) Ethylamine APCI-MS ·· m/z 416 [ΜΗ+] THP -1 chemotaxis assay Introduction This assay measures the chemotactic response of MIR-1 alpha chemical hormones in the human monocyte cell line THP-1. The compounds of the examples were evaluated for their ability to suppress the chemistries of standard concentrations of ΜΙΡ-1α chemical hormones by their suppression. Method ΤΗΡ - 1 cell 4 cells The cells were rapidly thawed from the freezing solution at 37 ° C and resuspended in a 25-cent flask containing 5 ml of supplemental Glutamax and 10% heat-activated fetal bovine serum. Antibiotic-free RPMI-1640 medium (RPMI + 1 0% HIFCS). The medium was discarded on the third day and fresh medium was added. The THP·1 cell line was routinely cultured in RPMI-1640 medium supplemented with 10% heat-activated fetal bovine serum and glutamax without antibiotics. The optimal growth of the cells requires that they be transferred once every three days with a minimum colonization density of 4 X 105 cells/ml. One-neutralization assay The cells were removed from the flask and washed by centrifugation in RPMI + 1 O'% HIFCS + glutamax. The cells were then resuspended in fresh medium (RPMI + 10% HIFCS + glutamax) at 2 X 107 cells/ml and added to Calcein-54- this paper scale for Chinese National Standard (CNS) A4 specification (210 X 297) 1301487 A7 B7 V. INSTRUCTIONS (52) A Μ (5 μl of stock solution to 1 ml of the final concentration of 5 X 1 〇-6 。. After gentle mixing, the cells are immersed in 3 7 30 minutes in a C02 incubator at ° C. The cells were then diluted to 50 ml with medium and washed twice by centrifugation at 400 x g. The labeled cells were then resuspended in cells of 1 X 1 〇7 cells/ml. Concentration and soaking with an equal volume of ΜIP-1α inhibitor (丨〇·1 〇M to 1 0 ·6 Μ final concentration) in a humidified C〇2 incubator at 3 7 °C for 3 〇 minutes. The system was implemented with a Neuroprobe 96-well-developing plate in an 8 micron filter (cat·n· 101 - 8 ). Add 30 μl of various concentrations in the lower hole of the plate in three replicates. a chemical sputum agent for the antagonist or vehicle. Then carefully place the filter on top of it, then add 2 to the surface of the filter. 5 μl of cells pre-soaked with the corresponding concentration of antagonist or vehicle. The plate was then immersed in a humidified COi incubator at 37 ° C for 2 hours, after which it was removed by adsorption on the surface. The cells were centrifuged at 2 rpm for 2 minutes, and the cells were removed and quantified by the light associated with the cells associated with Calcein-AM. The glory unit of the reagent blank indicates cell bleed and normalizes the sputum to % osmotic rate by comparing the camp 値 with a known number of fluorescent cells of the labeled cells. The effect of the antagonist is to be permeable. The number of cells is calculated as % inhibition compared with the vehicle. -55- ______ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) Application for the continuation case number 090113763

(The above are filled by this bureau.) Chinese manual replacement page of the year of February) % ^明—Patent specification I, invention m Chinese as a chemical hormone receptor activity predicate novel compound English novel compounds for use as modulators OF CHEMOKINE RECEPTOR ACTIVITY Name Nationality 1. Thomas Eriksson 2 · Thomas Sklinstedt TOMAS ERIKSSON TOMAS KLINGSTEDT 3. Tesfar Dimo West TESFALEDET MUSSIE - Inventor, said that everyone lives in Sweden, residence in Sweden Longde City S-22187 Name (Name)

Swedish company AstraZeneca AB ASTRAZENECA AB Binding line Nationality Sweden III. Applicant Residence, residence (office) Representative Name Sweden Saitete S-15185

SONYA CELEBIOGLU This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

A BCD Patent Application No. 01, 485, and,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, N^Z2 R4 R6 2 Ν H R8 OH (0 wherein m is 1 or 2; each R 1 independently represents a halogen; Z1 represents a bond or a group (CH2)q, where q is 1; Z2 represents a bond or a CH2 group, but The restriction condition is that Z1 and Z2 are different when the table is a bond; Q is an oxygen atom; R2 is based on R 15 η is 0 or 1; each R3 independently represents a hydrogen atom; R4, R5, R6 and R7 each independently represent a hydrogen atom; R8 represents a hydrogen atom or a Κ6 alkyl group; R15 represents -C(0)NR17R18 or -NHC(0)R2G ; t is 0,1 or 2; each R16 is independently halogen, cyano, hydroxy, (^-"alkoxy, ☆ outside the paper 3 勒|^1 6*) 毅家标准(CNS) A4 specification ( 210 X 297 ft.) A8 B8 C8 D8 1301487 VI. Patent application range C6 alkyl group 'phenyl or CpCs alkyl group; R17 and R18 each independently surface hydrogen atom or Cl_c6 alkyl group; R2G table CrC6 alkyl group, benzene Or a pyrrolyl group, each of which is optionally substituted with two groups selected from the group consisting of Ci-C6 alkyl groups. 2. A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the R15 form -NHC(0)R20. 3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein each R16 independently represents a halogen, a cyano group, a C1-C4 alkoxy group, a Ci-c* A carbonyl group, a phenylalkyl group. 4. A compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof according to the scope of the claims of the invention, which is selected from the group consisting of: Ν-[2-( 3-{[1- (3,4-dichlorobenzylpiperidinyl)aminohydroxypropyloxy]phenyl}acetamidamine, Ν·[5-chloro-2-(3-{[1-(3,4-dichlorobenzyl) 4-(piperidinyl)amino}-2.hydroxypropoxy)phenyl]acetamide, N_[2-(3-{[1-(3,4-dichlorobenzyl)-4 -piperidinyl]amino-2-hydroxypropyloxy-5-methylphenyl]acetamidamine, N·[4-(3-{[1_(3,4-di-benzyl)-4 -piperidinyl]amino-2-bromopropoxy)[1,1-biphenyl]-3-yl]acetamidamine, Ν-[3·acetamido-2-(3-{[l -(3,4-dioxabenzyl)-4-piperidinyl]amino}_2-hydroxypropoxy)-5-methylphenyl]acetamidamine, Ν·[2-(3-{ [ 1-(3,4-dichlorobenzyl)-4-piperidinyl]aminobi-2-hydroxypropyloxy)-4-fluorophenyl]acetamidamine, N-[2-(3_{ [1- (3,4-Dichlorobenzyl)-4-piperidinyl]aminopurine 2-hydroxyl paper 73⁄4 is the guide 63⁄43⁄4⁄4 wash standard (CNS) A4 size (210 X 29_7 shelving) 1301487 A8 B8 C8 D8 夂Patent application range Propyloxy)-5-fluorophenyl]acetamide, Ν_[2·(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amine }-2-hydroxypropoxy)-5-cyanophenyl]acetamidamine, [1-(4-cyclobenzyl)-4-piperidinyl]amine }}-2-hydroxypropoxy)phenyl]acetamidamine, N _[ 2 - (3 - {[ 1 - ( 4 - benzyl)-4 -piperidinyl]amino hydroxypropyloxy Phenyl]isobutylamine, N-[2_(3-{ [1-(4-chlorobenzyl)-4piperidinyl]amino}-2-hydroxypropoxy))]-2 ,2-dimethyl-propanolamine, N-[5-gas-2-(3-{[l-(4-hehenhenyl)-4-piperidyl)amino}_2·hydroxypropoxy Phenyl]acetamidamine, N-[2-(3-{ [1-(4-chlorophenyl)-4 - shiezing]amino}-2-hydroxypropoxy)-5-methyl Phenyl]acetamide, Ν-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino-2-hydroxypropyloxy)-4-methylphenyl Acetamine, Ν·[2-(3-{ [1·(4- gasbenzyl)-4·piperidinyl]aminobi-2-hydroxypropyloxy)-4-fluorophenyl] Indoleamine, N-[2-(3-{ [1-(4-chlorobenzyl)-4-piperidinyl]amino-2-hydroxypropyloxy)·5-cyanophenyl]acetamide , N-(2_{[(2S)-3-({[l-(4-Chlorophenyl)methyl)-4-piperidinyl)amino)-2-ylpropyl]oxy}phenyl Ethylamine bis(trifluoroacetate), N-(2-{(2R)-3-[l-(4-chlorobenzyl)-piperidin-4-ylamino]-2-hydroxy-2 -methylpropoxy}-phenyl Acetamide, Ν-(2-{[3-({1-[(4-chlorophenyl)indolyl)-4-piperidinyl}-amino)------ 210 X 297 PCT) 1301487 - C8 ---------D8______ - VI. Patent pending 2-hydroxy-2-methylpropyl]oxy}phenyl)acetamide, N-(2 -{(2S)-3-[l-(4-Chloro-yl)-choke-4-ylamino]-2-transyl-2-mercaptopropenyl}-phenyl)acetamide, N-{2-[((2S)-3-{[l-(4)fluorobenzyl)-4-piperidinyl]amino-2-hydroxy-2-yloxy)-phenyl}acetamide , N-{2-[((2S)-3-{[l-(4-chloro; yl)-4) succinyl]amino-2-hydroxypropyl)oxy]-4-fluorophenyl Ethylamine, Ν-{4-fluoro-2-[((2S)-3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino-2-hydroxypropyl)oxy Phenylamine, N-{2-[((2S)-3-{[(3S)-l-(4-chloroindolyl)pyrrolidinyl]amino}-2-hydroxypropyl Oxy]-4-fluorophenyl}acetamidamine, N-{2-[((2S)-3-{[(3R)-l-(4-chlorobenzyl)pyrrolidinyl]amino) 2-hydroxypropyl)oxy]-4-fluorophenyl}acetamidamine, Ν-[2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}_2 _hydroxy-2-mercaptopropoxy)phenyl]acetamidine , N-[2·(3-{ [1-(4-Chlorobenzyl)-4-piperidinyl]amino]>2-hydroxy-2-mercaptopropoxy]-4-fluorophenyl] Acetamine, N-[4_fluoro-2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}·2-hydroxy-2-methylpropoxy Phenyl]acetamide, Ν-[2-(3-{[1-(4-chlorobenzyl)·4-piperidinyl]amino}-2-hydroxypropoxy)-4-methyl Phenyl]acetamide, Ν-[2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino-hydroxypropoxy)-4-methylphenyl] Indoleamine, N - [ 2 - (3 _ { [ 1 - (4 - chlorobenzyl) - 4 -piperidinyl] amino} -2- hydroxy propyl paper paper will be 6 · home standard (CNS) A4 Specification (210X297轸) A8 B8 C8 D8 1301487. VI. Patent application range oxy)phenyl]benzamide, Ν-[2-(3-{[1-(4-fluoroaryl)-4 - ϋ定]Amino}-2-pyridyloxy)phenyl]benzoguanamine, !^-[2-(3-{[(3 8)-1-(4-benzyl)pyrrole Acryl]amino}_2-hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[(3R)-l-(4-)-)-peptidyl] Amino}_2-pyridyloxy)phenyl]benzamide, Ν-[2-(3-{[1-(4-bromo-aryl)-4-♦)-amino}_2_ P-propoxy)phenyl]benzamide, N-[2-(3-{ [1-(4-chloroindolyl)-4-piperidinyl]amino}-2-hydroxy_ 2 - Mercaptopropoxy)phenyl]benzamide, N-[2-(3-{ [1-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- Methylpropoxy)phenyl]benzamide, N-[2-(3-{[(SR)-1-(4-benzyl)pyrrolidinyl]amino-2-hydroxy-2- Methylpropoxy)phenyl].benzamide, N - [2 - (3 - { [ 1 - (4 · bromobenzyl)-4 -piperidinyl]amino} - 2 -hydroxy-2 - mercaptopropoxy)phenyl]benzamide, Ν-[2-(3-{[1-(4-)-yl)-4-anthracene]-amino}-2-yl-propyl Oxy)-4-methoxyphenyl]acetamidamine, Ν[[(3-{[1-(4-)-benzyl)-4-piperidinyl]amino}-2-hydroxypropoxy ,6-fluorophenyl]acetamide, Ν-[2-fluoro-6-(3·{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxyl Propyl)phenyl]acetamidine, 2·(3_{Π-(4-chlorobenzyl)-4·piperidinyl]amino}-2-hydroxy-2 - A paper-based standard (CNS) Α4 specifications (210X297 will be) 1301487 as B8 - C8 -___;______D8__ VI. Patent application range propyloxy)-N-methyl Methionamine, n-(2-{3-[1-(3,4-dibenzyl)-acridin-4-ylamino]-2-hydroxypropoxyphenyl)benzamide , Ν-(2-{3-[1-(3-chloro.4-fluorobenzyl)acridin-4-ylamino]-2-hydroxypropenyl}benzyl)benzamide, Ν- (2-{3-[1-(3,4-difluorobenzyl)-piperidin-4-ylamino]-2-hydroxypropyloxy}-phenyl)benzamide, Ν-(2 ·{3-[1-(3,4_Dioxabenzyl)-piperidine-4-ylamino]-2-hydroxypropoxy}-6-methylphenyl)acetamide, Ν-( 2-{3-[1_(4_fluorobenzylidin-4-ylamino)-2-hydroxypropyloxy}-6-methylphenyl)acetamidine, Ν-(2-{3-[ 1·(4-bromo-aryl)- 喊°定-4-ylamino]-2-yl-2-ylpropoxy}phenyl)acetamidamine, Ν-(2-{3-[ 1·(3,4-Dichloroindenyl)-piperidin-4-ylamino]-2-hydroxy-2-methylpropoxy}phenyl)acetamidamine, Ν ·( 2 - { 3 - [ 1 - (3- gas-4 -fluorobenzyl)piperidin-4-ylamino]-2-hydroxy-2-methylpropoxy}phenyl)acetamide, Ν-(2-{3 -[1-(3,4-difluorobenzyl)-acridine_4.ylamino-hydroxy-2-methylpropoxy}-phenyl)acetamidamine, 2 - { 3 ·[ 1 - (4-dibenzyl)-piperidin-4-ylamino] -2·hydroxypropoxy-S}-N-methylbenzamide, 2-{3_[1-(3,4-dichlorobenzyl)-piperidin-4-ylamino]-hydroxypropoxy }·Ν-mercaptobenzamine, 2· { 3-[ 1-(4-Chlorobenzyl)-pyridin-4-ylamino]-2-hydroxypropyloxy-based paper home standard (CNS) A4 size (210X297拎藿). 1301487 A8 B8 C8 D8 VI. Patent application base}-:^-Methylbenzamide, 2-{3-[1-(4-fluorobenzyl)-piperidine- 4·ylamino]-2-hydroxypropoxy}-N-methylbenzamide, 3,5-^-methyl-lH-p ratio slightly 2-rebel (2-{3-[ 1-(4-bromo-aryl)-piperidin-4-ylamino]-2-hydroxypropoxy}phenyl)decylamine, 3,5-dimercapto-1 Η-p ratio -2 - Wei acid (2 - { 3 _[ 1 - (3-chlorobenzyl)-piperidin-4-ylamino]-2-hydroxypropoxy}phenyl) decylamine, 3,5-dimethyl 1Η-pyrrole-2-carboxylic acid (2-{3-[1-(3-fluorobenzyl)-piperidin-4-ylamino]-2-hydroxypropyloxy}phenyl)decylamine, N- (2 - { 3 - [ 1 - ( 4 - bromobenzyl cyano-4-ylamino) - 2 - hydroxypropoxy} - phenyl) acetamidine, Ν · (2-{3-[ 1 _(3·Chloro_4_fluorobenzyl)-piperidin-4-ylamino]-2-hydroxypropoxy}- Ethylamine, Ν - (2 - { 3 _ [ 1-(3,4 -difluorobenzyl)-piperidin-4 ·ylamino]· 2 -hydroxypropoxyphenyl) Amine, and hydrazine - (2 - { 3 - [ 1 - ( 4 - fluorobenzyl) - azin-4-ylamino] - 2 - hydroxypropoxy phenyl) acetamide. 5. A process for the preparation of a compound of the formula 1 or a pharmaceutically acceptable salt or solvate thereof, which comprises, (a) using a compound of the formula (II), a paper-based standard (CNS) ) A4 size (10) x 衿 )) 1301487 Patent application range 8 8 8 8 ABCD Z NK (II) wherein m, η, Z1, Z2, R1 and R3 are all reacted with a compound of the formula (III) as defined in the formula (I): 〇, /R8 (HI) FT pR7 R' FT R6 Q, R2, R4, R5, R6, R7, and R8 are all as defined in formula (I); or (b) are compounds of formula (IV): R4 R6 (IV) wherein m, n, Z1, Z2, R1, R3, R4, R5, R6, R7, and R8 are all as defined in formula (I); and react with compound of formula (V) L^Q-R2 (V) where L1 represents a hydrogen atom or a detached group and Q and R2 are those defined in formula (I); or the paper has 3 sides|^1 city 61) 毅家标准(CNS) A4 specification (210X297耠) · A8 B8 C8 D8 1301487, patent application range (c) using compound of formula (VI) Wherein m, η, Z1, z2, and RMUR3 are all those defined in formula (1) and react with a compound of formula (VII). H〇, /R Wherein Q, R2, R4, R5' R and R8 are all as defined in formula (I); and, as appropriate, after (a), (b) or (c), the pharmaceutically acceptable compound forming formula (I) is acceptable Salt or solvent compound. 6. A pharmaceutical composition for treating a human disease or condition in which a chemical hormone receptor activity modulation is beneficial, comprising a compound of formula (I) according to any one of claims 1 to 4, or A pharmaceutically acceptable salt or solvate in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. 7. A compound of the formula (1), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 4, which is for use in the treatment of a human disease in which the modulation of its chemical hormone receptor activity is beneficial or Symptoms. 8. If the compound of any one of the patent applications ranged from item 4 to 4 or its medicinal paper can be used, the standard (CNS> A4 specification (210 X 29_7矜)_1301487 A8 B8 C8 D8, the scope of application An arsenic salt or a solvate for use in the manufacture of a pharmaceutical product for use as a chemical hormone by m ^c.1 / «η. sexual modulating agent 9 as claimed in any one of claims 1 to 4 of the claim. A compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for the treatment of a human disease or symptom which is beneficial for the modulation of its chemical hormones. ίο· ^ Patent Application No. 1 A compound of the formula (1), or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of rheumatoid arthritis. 11·=Application for a patent scope! A compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease. 12·=Application of a compound of the formula (1) according to any one of the claims (1) Acceptable salts or solvates for the manufacture of asthma A pharmaceutical compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of relapsing sclerosis. A medical composition having an inflammatory disease or a patient at risk of developing an inflammatory disease, comprising a therapeutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof, or any one of the formula (1) Solvent 15. A treatment for an airway disease or a risk of developing an airway disease = a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof as claimed in any one of the four items Or dissolve = medical doctor's medical doctor's first 8 8 8 8 A BCD 1301487 VI. Application for patent range. This Paper Bullying Standard (CNS) A4 Specification (21〇X297i)