TW201206888A - Bi-functional quinoline analogs - Google Patents

Abstract

Provided are compounds of Formula I: wherein X is: R1 and R2 together with the phenyl to which they are bound may form a bicyclic, fused heterocyclic ring, and all other variables are as defined herein, as well as their use in treating pulmonary inflammation or bronchoconstriction and compositions comprising and processes for preparing the same.

Description

201206888 VI. Description of the Invention: [Technical Field] The present invention relates to a novel anti-inflammatory tracheal dilator compound, a composition comprising the same, a method of treatment and use thereof, and a method for the preparation thereof. [Prior Art] The chronic inflammatory process constitutes a respiratory disease such as chronic obstructive pulmonary disease (COPD) and asthma. These diseases involve active inflammation in the bronchial airways, lung parenchyma and pulmonary blood vessels of the lungs. The inflammatory process in this disease is characterized by an increase in the number of activated immune cells (such as macrophages, neutrophils, eosinophils, and lymphocytes), and the release of self-immune and resident lung cells. Pro-inflammatory signaling molecules, namely cytokines and chemokines. The mechanisms of the disease are not the same, but chronic inflammation is a potential mechanism toward both. COPD is closely related to exposure to harmful particles and gases from external circumstance (such as tobacco smoke) and exposure to wood burning flames, and is characterized by oxidative stress and harmful cathepsins and proteases. balance. These processes can lead to specific pathologies such as goblet cell metaplasia and mucus hypersecretion (causing bronchitis), alveolar wall destruction (causing emphysema) and inappropriate tissue repair and smooth muscle thickening (resulting in small airway remodeling) (remodeling)) (For comments, see Molfino & Jeffery, Pulm. Pharmacol. The r _ 2 007; 20:462-72). In asthma, the allergic immune mechanism causes a chronic inflammatory process that leads to airway hyperresponsiveness and structural changes in the bronchial airways (called remodeling) -5 - 201206888, such as airway smooth muscle thickening and goblet cell hyperplasia (for review, see Hamid & Tulic, Annu. Rev. Physiol. 2009; 71:489-507). A tracheal dilating agent that improves lung function and improves exhaled airflow is a standard care for relieving symptoms in the treatment of respiratory diseases. Inhaled long-acting beta 2 adrenergic receptor agonist (LAB A ), such as salmeterol or formoterol, or inhaled long-acting toxic receptor receptor antagonist ( LAMA), such as tiotropium, is a common prescription drug used to alleviate symptoms. Inflammation is a major process that causes many respiratory diseases, and anti-inflammatory treatments may be effective and have the potential to affect the development of the disease. Phosphodiesterase-4 (PDE4) is a ubiquitous enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP). The use of selective inhibitors to inhibit the enzymatic activity of PDE4 increases the cellular content of cAMP, which has an anti-inflammatory effect in many immune and resident lung cell types (Spina, Brit. J. Pharmacol. 2 0 0 8) ;1 55:3 08- 1 5 ). The use of the PDE4 inhibitor roflumilast (r0flumilast) has been shown to have clinical anti-inflammatory activity, showing a decrease in exacerbation and an appropriate increase in lung function in patients with COPD (Rabe ei a/., Zancei 2005; 3 66 :5 63 -71 ; Calverly et al., Am. J. Respir. Crit. Care Med. 2007 ;176:154-61). In addition, roflumilast improves lung function in patients with severe and symptomatic COPD treated with salmeterol or tiotropium, but due to side effects (including nausea, headache, diarrhea, and weight) Reducing) and still have dose limitations (Fabrib et al., Lancet 2009; 3 74:695-703; Calverly et al., 201206888

Lancet 2 0 0 9; 374:685-94). Forest Research Institute's product Daxas (roflumilast) has been approved as an oral PDE4 inhibitor for daily use in the treatment of COPD. However, it is acknowledged that Daxas has a number of unfavorable event messages despite the evidence of consistent efficacy, and this unfavorable event message once led the committee to reject the approval based on the overall poor risk-benefit ratio. When the possibility of side effects is reduced by limiting exposure to the systemic circulatory system, local delivery of the PDE4 inhibitor thus provides effective anti-inflammatory activity in the lung. In addition, direct local delivery allows PDE4 inhibitors to have higher local concentrations, higher than achievable concentrations by oral administration, and thus has the potential to further improve anti-inflammatory efficacy. PCT Publication W02004/1 03 998 relates to a quinoline derivative of formula (I) as a phosphodiesterase inhibitor:

This application also relates to the use of the compounds described for the treatment of inflammatory diseases. C.J. Lunnis, et al., Quinolines as a novel structural class of potent and selective PDE4 inhibitors:

Optimisation for oral administration, Bio or g & Med. Chem 2009) 19: 1380-1385 Reveal the following compounds: 201206888

And its analogs wherein the 4-amino substituent is modified, the linking group attached to the 4-substituent is modified, the main formamide is modified, and the porphyrin 8_ substituent is modified. Two of these analogues are as follows:

M.D. Woodrow, et al., Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration, Bioorg & Med. Chem Letters (2009) 19: 5261-5265 reveals the following compounds:

And analogs thereof, including analogs defined by the following chemical formulas, wherein each variable is as defined in the literature: 201206888

Traditional therapeutic agents for the treatment of inflammatory respiratory conditions suffer from limited efficacy and side effects data such as side effects. Therefore, there is still a need in the prior art for new drugs designed to treat respiratory conditions including inflammatory respiratory conditions such as asthma, COPD, chronic bronchitis, bronchiectasis, cystic fibrosis, and the like. SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula I:

Wherein: X is a substituted benzene ring selected from the group consisting of: 201206888

HO R1 and R1 Z are a bond or a group selected from the group consisting of or

(R4)a R1 is CH20H, CH2CH2OH, N(H)C(0)H, or

An alkyl group, and R 2 is H; or R 1 and R 2 together with the attached phenyl group form a bicyclic fused heterocyclic ring having 9 or 10 ring atoms, wherein 1 or 2 ring atoms are selected from N, 0 and S, Wherein the bicyclic fused heterocyclic ring is optionally substituted with one or two or three additional substituents each independently selected from the group consisting of alkyl, keto and oxime H;

R3 is selected from Cm alkyl, C4-12 alkenyl, C4-12 alkynyl, R8-0-R8, R8-N(R7)-R8, C3.6 cycloalkyl, R8-C3. 6 cycloalkyl, R8-C3.6 cycloalkyl-Het, C3.6 cycloalkyl-R8, R8-C3.6 cycloalkyl-R8, C6-IG extended aryl, R8-C6 -IG aryl, C6-1Q aryl-R8, R8-C6-l () aryl-R8, R8-C6-,. Stretching group -0-R8, R8-C6.l0 aryl-N(R7)-R8, R8-C6-1() aryl-C6.1() aryl, Het, R8-Het, Het-R8, R8-Het-R8, R8-0-Het, R8-C6.i aryl-O-Het, R8-C6-io aryl-C(0)-Het, R8-C6. 1() aryl-N(R7)-Het' R8-Het-C6. Stretching base, R8-C6•丨. An aryl-Het, and a R8-0-R8-C6.1Q aryl group; wherein the alkylene group or the alkynyl group is optionally arbitrarily 1, 10.10 to 201206888 2 or 3 Substituting a halo group, a keto group, and a substituent of OR7; wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of a dentate group, an alkyl group, and an OR7;

Het is a 5-6 membered saturated or unsaturated monocyclic heterocyclic ring, or a 8-10 membered saturated or unsaturated, bicyclic heterocyclic group wherein one or two ring atoms are selected from the group consisting of N and fluorene. And S, and wherein the monocyclic or bicyclic heterocyclic group is optionally substituted by 1, 2 or 3 substituents selected from halo, s, alkoxy, keto and OH; Y is C(o ), OC(O), C(0)N(R7), C(0)N(R7)CH2, 0C(0)NR7CH2 'n(r7)c(o), or n(r7)c(o) n(r7); a is 0, 1, 2, 3, or 4; R4 is selected from halo, alkyl, and OR7; R5 is deuterium or alkyl; b is 1, 2, 3, 4, or 5 : R6 is selected from the group consisting of halo, alkyl, haloalkyl, OR7, fluorenyl-haloalkyl, R8-OR7, fluorene-R8-OR7, c(o)alkyl, o-r8-c(o)alkyl , CON(R7)2, R8-CON(R7)2, R8-N(R7)2, n(r7)c(o)alkyl, N(R7)C(0)N(R7)2, N( R7)S02 alkyl, R8-S02N(R7)2, and CN» or two R6 on an adjacent carbon together with the attached phenyl group form a bicyclic heterocycle having 9 or 10 ring atoms, wherein 1 or The two ring atoms are selected from N, 0 and s; R7 is hydrazine or alkyl; and R8 is C 丨. 丨〇 alkyl, C 2-10 extended alkenyl, or C 2 - anthranyl ' -11 - 201206888 wherein each R8 is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR7; the prerequisite is two C8 extensions of any of the R8 groups of any definition of R3 The total number of carbon atoms of the group, C2.1Q extended alkenyl group or C2-1G alkynyl chain is not more than 12; R9 is hydrazine or C^-Cs alkyl; or a pharmaceutically acceptable salt thereof. In one system, the invention provides a compound of the formula:

(R6)b-- ΝΗ Ο

And pharmaceutically acceptable salts thereof, wherein all variables are as defined above.

In another aspect, the invention provides a composition comprising a compound of formula I or hydrazine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In a system, the composition is suitable for inhalation. In another aspect, the invention provides a method comprising administering an effective amount of a compound of formula I or hydrazine or a pharmaceutically acceptable salt thereof to a human. In another aspect, the invention provides a method of treating inflammatory or bronchoconstriction of the lungs of a human in need thereof. The method comprises administering an effective amount of a compound of formula I or I' or a pharmaceutically acceptable salt thereof to a human. -12- 201206888 In another aspect, the present invention provides a method for the treatment of a human in need of a disease associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including Bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, bronchiolitis, and transplant-related fines Bronchitis, nasal inflammation, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or treatment of rhinovirus. The method comprises administering a therapeutically effective amount of a compound of formula I or hydrazine or a pharmaceutically acceptable salt thereof to a human. In one system, the invention provides a method of treating chronic obstructive pulmonary disease (COPD) or asthma in a human in need thereof, using a compound of formula I or guanidine or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a compound of formula I or hydrazine, or a pharmaceutically acceptable salt thereof, for use as a medicament. In another aspect, the invention provides a compound of formula I or guanidine, or a pharmaceutically acceptable salt thereof, for use in a method of treating inflammation or contraction of the trachea of a human lung. In another aspect, the present invention provides a compound of Formula I or hydrazine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COPD) in humans. , asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, pancreatic bronchi Inflammation, bronchiolitis associated with transplantation, sinusitis, and respiratory tract-related -13106002888 tracheobronchitis, or prevention of respiratory-related pneumonia, or treatment of nasal inflammatory disease. In one system, the invention provides a compound of formula I or guanidine, or a pharmaceutically acceptable salt thereof, for use in a method of treating a condition associated with chronic obstructive pulmonary disease (COPD) or asthma in a human. In another aspect, the invention provides the use of a compound of formula I or guanidine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammation or bronchoconstriction in the lungs of a human. In another aspect, the present invention provides the use of a compound of Formula I or I', or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a disease associated with reversible or irreversible airway obstruction in humans. , chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection, cystic fibrosis , emphysema, pneumonia, bronchiolitis, bronchiolitis associated with transplantation, nasal inflammatory disease, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or treatment of sinusitis. In another aspect, the present invention provides a composition comprising a compound of formula I or hydrazine or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of inflammation or bronchoconstriction of the lungs of a human. In another aspect, the present invention provides a composition comprising a compound of Formula I or hydrazine, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in human therapy and reversible or irreversible respiratory tract Obstruction-related diseases, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis - 201206888), acute bronchitis, chronic bronchitis, Cystic fibrosis, emphysema, pneumonia, bronchiolitis, sinusitis, and respiratory inflammation, or prevention of respirators associated with pneumonia, or detailed instructions for treatment of the invention are also available as long-acting The bifunctional activity of the β2 adrenergic inhibitor is controlled by a single tube dilatation and anti-inflammatory activity for inhalation to control both symptoms. The complementary or synergistic inhibitor of the two molecular message transduction pathways binds to the receptor adenylate cyclase activity via the action of the G protein, resulting in a cyclic PDE4 enzyme of the cell. It is also used to inhibit the cAMP content responsible for cAMP cells. Inhalation of a molecule with β2 agonism can provide synergistic anti-inflammatory activity, thus reducing the agent: a mixture of single-function reagents, and the small environment of a single lung should also increase the occurrence of this molecule. The higher the exposure dose from the locally delivered lung to the whole body will significantly reduce the chance of side effects caused by systemic circulation. Herein, the following terms are defined as follows: "Compound of the present invention" means cough bronchitis after infection with a compound of the formula I, and tracheobronchial sinusitis associated with transplantation. The steroid agonist and PDE4 can simultaneously provide inflammatory activity by the interaction of the bronchial compounds. When P agonizes f, the beta agonist will increase AMP. Inhibition of decomposing enzymes while maintaining fines and PDE4 inhibition [and possible synergy (quantity. Compared to the possibility of placing functional compounds together to maximize the luminosity and duration of lung retention in other tissues and utensils or Salts, particularly -15-201206888 are pharmaceutically acceptable salts thereof. "Compounds of formula I" mean compounds which are referred to herein as structural formulas of formula I or I' (formulas of formula I' are formulae A subgroup of the compounds of formula I. The compound of formula I comprises a solvate and a hydrate (i.e., an adduct of a compound of formula I with a solvent). In these systems, the compound of formula I comprises When one or more centers are in the palm, the term is intended to encompass racemic mixtures, individual stereoisomers, including optical isomers (mirroromers and non-image isomers) and geometric isomers (cis-/ Further, the compound of the formula I also contains the tautomeric form of the formula. "Alkyl" is a straight chain or branch having from 1 to 8 carbon atoms. The hydrocarbon chain of the chain (ie Cu alkyl), or usually 1 to 6 carbons Subunit (i.e., c, .6 alkyl) unless otherwise specified. When the compound of Formula I contains more than one alkyl group, each alkyl group may be the same or different. Examples of suitable alkyl groups include, but not Limited to methyl ("Me"), ethyl ("Et"), 1-propyl (n-propyl), isopropyl, n-butyl, isobutyl (2-methyl-1-propyl) , second butyl (2-butyl), tert-butyl (-C(CH3)3), n-pentyl, 2-pentyl, 3-pentyl, hexyl, octyl, etc. "alkenyl" is a linear or branched hydrocarbon chain having at least one degree of unsaturation (ie, a carbon-carbon double bond) and having 2 to 8 carbon atoms (ie, C 2-8 alkenyl), or usually 2 to 6 carbon atoms (ie, C 2 ) -6 alkenyl), unless otherwise specified. When the compound of formula I contains more than one alkenyl group, each alkenyl group may be the same or different. Examples of suitable alkenyl groups include 'but are not limited to, ethoxylated groups (ethylene or vinyl) (-CH = CH2), suspected C. 201206888 (-CH2CH = CH2), 5-hexenyl (-ch2CH2CH2CH2CH = CH2), etc. "Alkynyl" is having at least one carbon-carbon bond. Straight chain or branch Hydrocarbon chain, and optionally also one or more carbon-carbon double bonds, and having 2 to 8 carbon atoms (ie C2.8 alkynyl), or more usually 2 to 6 carbon atoms (ie C2_6 alkyne) Unless otherwise indicated, the number of carbon atoms. When the compound of formula I contains more than one alkynyl group, each alkynyl group may be the same or different. Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-CeCH) , propargyl (-CH2CsCH), etc. "Alkyl" means a saturated straight or branched divalent hydrocarbon radical having from 1 to 12 carbon atoms ("C!.12 alkyl") unless otherwise Indicate the number of carbon atoms. When the compound of formula I contains more than one alkylene group, the individual alkyl groups may be the same or different. Typical alkylene groups include, but are not limited to, methyl (-CH2-), ethyl (-CH(CH3)- or -CH2CH2-), propyl (eg, -CH(CH2CH3)-, -CH2CH(CH3)- or -CH2CH2CH2-), butyl group (e.g., -CH2CH2CH2CH2-), and the like. In a system, the alkyl group is linear. "En stretched alkenyl" means an unsaturated straight or branched divalent hydrocarbon radical having at least one carbon-carbon double bond and having from 2 to 12 carbon atoms ("c2.12 alkenyl") unless otherwise indicated The number of carbon atoms. When the compound of formula I contains more than one alkenyl group, the individual alkenyl groups may be the same or different. Typical alkenyl groups include, but are not limited to, 1,2-extended vinyl groups (_Ch = CH-) and (-ch2ch = chch2ch2-). In a system, the stretching base is linear. -17- 201206888 "Extend alkynyl" means an unsaturated straight or branched divalent hydrocarbon group having at least one carbon-carbon bond, and optionally also having one or more carbon-carbon double bonds, and having 2 Up to 12 carbon atoms ("C2.12 exetylene") unless otherwise specified. When the compound of formula I contains more than one alkynyl group, each alkynyl group may be the same or different. Typical alkynyl groups include, but are not limited to, 1,2-extended ethynyl (-C=C-) and (-CH2C^CCH2CH2-). In a system, the alkynyl group is linear. "Alkoxy" means a fluorenyl-alkyl group wherein "alkyl" is as defined above. "Halo" or "halogen" is synonymous and means fluoro, chloro, bromo, and iodo. In one system, the halo group is fluorine, chlorine or bromine. "Haloalkyl" is a straight or branched hydrocarbon chain substituted with one or more halogens (fluoro, chloro, bromo, and iodo) having from 1 to 8 carbon atoms (ie, Cl-8 haloalkyl) Or, usually 1 to 6 carbon atoms (i.e., <^.6 haloalkyl) unless otherwise specified. The haloalkyl group contains a perhaloalkyl group such as a trifluoromethyl group. When the compound of formula I contains more than one haloalkyl group, each haloalkyl group may be the same or different. Examples of suitable haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, trifluoromethyl, dichloromethyl, dichloroethyl and the like. "Ketyl" as used herein means a group = 0, and which is bonded directly to the carbon atom of the hydrocarbon ring or C, N or S of the heterocyclic ring to form an oxide, -N-oxide, mill and yam. "Cycloalkylene" means a divalent saturated or partially unsaturated monocyclic non-aromatic ring having from 3 to 6 carbon atoms (C3.6 cycloalkyl) unless otherwise indicated . When the compound of formula I contains more than one -18-

201206888 When cycloalkyl groups are extended, the respective cycloalkyl groups may be the same or different. Indeed, examples include cyclopropyl, cyclobutyl, and cyclopentyl. The cycloalkylene group also optionally contains 1 or 2 substituent alkyl groups, which may be the same or different, and optionally, a hydroxyl group, a hydrazine-alkyl group, a ketone group, an amine group (e.g., NH2) such as N. ( Η )alkyl), and dialkylamino (eg, Ν (: any subgroup thereof. In one system, a cycloalkyl group is not "arylene" means a divalent monocyclic or fused bicyclic ring 6 to 10 carbon atoms (C6-1Q extended aryl), unless otherwise a number of carbon atoms. When the compound of formula I contains more than one individual aryl group, the same or different. The aryl group also includes optionally one or two extended aryl groups, which may be the same or different, and a group, a meridine, a fluorene-homocarbyl group, an amine group (e.g., NH2), N (anthracene). And a dialkylamino group (for example, anthracene (alkane). In one system, the aryl group is a phenyl group, and the aryl group is an unsubstituted phenyl group. ""Heterocycle" is synonymous, meaning a monocyclic saturated or partially unsaturated or aromatic ring having 5, 6, atoms, wherein 1, 2, 3, or 4 ring atoms are each, ◎ and S Miscellaneous And all remaining ring atoms are ('heterocyclyl has 5, 6, 9 or 10 ring atoms, the c ring atoms are each independently selected from the group consisting of ruthenium, osmium and s, when the heterocyclic group is included 2 or more heteroatoms (deuterium, deuterated cycloalkyl, and exocyclic hexyl substituted ring derived from halo 'alkyl, alkylamino (formula) 2), or substituted. When the ring has a different aryl group, the substituent comprising a phenyl substituent is selected from a halogen group, an alkylamino group (e.g., oxime) 2), or a fused double ring in a system. 9 or 10 rings are independently selected from Ν: μ 1, 2 or 3 in a system. For all systems and S), each -19-201206888 heteroatoms may be the same or different. When two or more heterocyclic groups are contained, examples in which each heterocyclic group may be the same group include, but are not limited to, furyl, tetrahydrofuran, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyridyl, pyrrole Pyridyl, diolanyl, oxazolidinyl, oxa, thiazolyl, isothiazolyl, imidazolyl, imidazolinylpyrazolyl, pyrazoline , pyrazolidine, triazolyl, tetrahydropyranopyl, tetrahydropyranyl, pyridyl, dihydro, dioxo, morpholinyl, dithianyl (sulfur Demorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, pyridazinyl, fluorenyl, isodecyl, fluorenyl benzofuranyl, dihydrobenzofuranyl, isophenyl And furyl, carbazolyl, benzimidazolyl, benzoxazolinyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, fluorenyl, quinazolyl, quinolinyl, iso a porphyrin group, a tetrahydroisophyllinyl group, a decahydroporphyrin group, an octahydroisoquinolyl group, an anthracene, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a phthalazinyl group, etc. It can be bonded via any or a ring heteroatom (eg, N). "Heterocyclene" means a heterocyclic group as defined herein. For example, a heterocyclic group includes: a compound of the formula I or different. a heterocyclic thiol group, a thienyl aryl group, a pyrroline ova group, a heterogeneous D Sodium, imidazolidinyl, oxazolyl, piperidyl U, steep, dithianyl, oxazinyl, triazinyl, porphyrinyl, benzothienobenzoxazolyl, benzopyranyl , salinyl, tetrazoline, pyridazinyl, thionaphthyl (divalent -20 as defined by ring carbon atoms - 201206888

Preferably, the heterocyclic group in the compound of formula I is a monocyclic saturated or partially unsaturated ring having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are independently A hetero atom selected from n, fluorene and S and all remaining ring atoms are C. With respect to the "optionally substituted" with respect to a particular group of the compound of formula I, the word B (for example, an optionally substituted alkylene group) means that the group has no substituent and that the group has the indicated number of substitutions. Base, unless otherwise specified, usually up to 4 substituents. Unless otherwise specified, when "substituted" is used simultaneously with a group having several available substitution positions or simultaneously with two or more substitutable groups When present, the substituents can be attached to any available C or heteroatom. Throughout the specification and examples, the compounds are appropriately named according to the standard IUPAC nomenclature. In some chemical structural formulas, when the carbon atoms are not When there are a sufficient number of linkages - 201206888 variables or bonds to produce a valence of 4, it should be noted that the remaining carbon substituents that need to generate valence 4 are hydrogen. Similarly, in some chemical structural formulas, When the chemical bond of the drawing does not specifically specify a terminal group, it is indicated by the prior art that the bond is a methyl group (Me, -CH3). In one aspect, the invention includes a compound of formula I:

Wherein: X is a substituted benzene ring selected from the group consisting of:

Z is a bond or a group selected from the group consisting of:

R1 is CH2OH, CH2CH2OH, N(H)C(0)H, or an alkyl group, and R2 is Η; or R1 and R2 together with the attached phenyl group form a bicyclic fused heterocyclic ring having 9 or 10 ring atoms. Wherein 1 or 2 ring atoms are selected from the group consisting of N, hydrazine and S, wherein the bicyclic fused heterocyclic ring is optionally independently selected from alkyl, keto and 0H via one, two or three respective -22-201206888 Substituted by an additional substituent; R3 is selected from the group consisting of C4-12 alkylene, C4.12 alkenyl, c4.12 alkynyl, R8-0-R8, R8-n(r7), r8, C3_6 Alkyl, r8_c3 6 cycloalkyl, R8-C3.6 cycloalkyl-Het, C3-6 cycloalkyl-R8, r8_c3 6 cycloalkyl-R8, phenyl, r8-phenyl , phenyl-R8, R8-phenylene-R8, R8·phenylene-r8, r8. phenyl-N(R7)-r8, phenylene phenylene, Het, R8- Het, Het-R8, R8_Het-R8, R8 〇 Het, R8-phenylene-hydrazine-Het, r8_phenylene_C(0)-Het, R8-phenylene. N(R7)-Het, R8_Het-phenylene, R8-phenylene-Het, and r8〇r8_phenylene; wherein the alkyl, alkenyl or alkynyl group is optionally arbitrarily selected from 1, 2 or 3 , keto group, and OR7 The substituent group; wherein each of the groups optionally present extending over the teeth 2, 3 or 4 groups selected from, alkyl, and the substituent OR7;

Het is a 5-6 membered saturated or unsaturated monocyclic heterocyclic ring, or a 8-10 membered saturated or unsaturated bicyclic extended heterocyclic ring wherein one or two ring atoms are from N, 〇 And the monocyclic or bicyclic heterocyclic group in s, and Si are optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, decyl, alkoxy, keto and oxime H; Y is C(O), 0C(0), C(〇)N(R7), c(0)N(R7)CH2, oc(o)nr7ch2, n(r7)c(o), or n(r7)c (o)n(r7); a is 0, 1, 2, 3, or 4; R4 is selected from halo, alkyl, and OR7; R5 is deuterium or alkyl; -23- 201206888 b is 1, 2 , 3, 4, or 5;

R6 is selected from the group consisting of halo, alkyl, haloalkyl, OR7, fluorene-halogen, R8-OR7, 0-R8-0R7, C(O)alkyl, o-r8-c (〇), CON(R7)2, R8-CON(R7)2, r8-n(r7)2, N(R7)c(〇), N(R7)C(0)N(R7)2, N(R7 )S02 alkyl, R8-S02N(R7)2, and CN

Or two R6 groups on adjacent carbons together with the attached phenyl group form a bicyclic heterocyclic ring having 9 or 10 ring atoms, wherein 1 or 2 ring atoms are selected from N, 0 and S; R7 is hydrazine or alkane And R8 is a Cl.lQ stretching base, a C2-10 stretching base, or a C2-10 stretching base ' wherein each R8 is optionally 1, 2 or 3 selected from a halogen group, a ketone group, and an OR7 Substituted by a substituent; the prerequisite is a carbon atom of a C丨-丨〇 alkyl group, a C2-丨〇 extended alkenyl group, or a fluorene-anthracene alkynyl chain of two R8 groups in any definition of R3 The total number is not more than 12;

R9 is hydrazine or hydrazine-3-alkyl; or a pharmaceutically acceptable salt thereof. In other systems, the invention provides a compound of formula II (a) and formula (b):

II(8) -24- 201206888

Or a pharmaceutically acceptable salt thereof;

X is a substituted benzene ring selected from the group consisting of: V R1 and R1 R1 are CH2〇H, CH2CH2〇H, N(H)C(0)H, or N(H)S(〇2)CH3, and R2 Is H; or R1 and R2 together with the attached phenyl group form a bicyclic ring selected from the group consisting of

Fused heterocycle:

R3 is selected from the group consisting of C4-12 stretching, C4-12 stretching, C4-12 stretching alkynyl, R8-0-R8, R8-C3.6 cycloalkyl-Het, R8-phenylene, R8 - Benzene-25- 201206888 ke-O-R8, R8-phenylene-phenylene, Het, R8-Het, R8-0-Het, R8-phenylene-C ( Ο ) -Het, R8- Het-phenylene, R8-phenylene-Het, and R8-0-R8-phenylene; wherein the alkyl, alkenyl or alkynyl groups are optionally arbitrarily selected from 1, 2 or 3 Substituting a halo group, a keto group, and a substituent of OR7; wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halo, alkyl, and OR7;

Het is a 5-6 membered saturated or unsaturated monocyclic heterocyclic ring, or a 8-10 membered saturated or unsaturated bicyclic heterocyclic group wherein 1 or 2 ring atoms are selected from N, 0. And S, and wherein the monocyclic or bicyclic heterocyclic group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of a dentate group, an alkyl group, an alkoxy group, a ketone group and OH; Y is C(O) ), OC(O), C(0)N(R7), C(0)N(R7)CH2, oc(o)nr7ch2, n(r7)c(o), or n(r7)c(o) n(r7): a is 0, 1, 2, 3, or 4; R4 is selected from halo, alkyl, and OR7; R5 is deuterium or alkyl; b is 1, 2, 3, 4, or 5 R6 is selected from the group consisting of halo, alkyl, haloalkyl, OR7, 0-haloalkyl, R8-OR7, 0-R8-0R7, C(O)alkyl, 0-R8-C(0)alkyl , CON(R7h, R8-CON(R7)2, R8-N(R7)2, N(R7)C(0)alkyl, N(R7)C(0)N(R7)2, N(R7) S〇2 alkyl, R8-S02N(R7)2, and CN» or two R6 on an adjacent carbon together with the attached phenyl group form a bicyclic heterocycle having -26-201206888 9 or 10 ring atoms, Wherein 1 or 2 ring atoms are selected from N, 0 and S; R7 is a fluorene or a hospital base; and R8 is a Ci.iq stretching group, a C2.1G stretching group, or a C2-10 stretching alkyne group. R8 is optionally substituted by 1, 2 or 3 substituents selected from halo, keto, and OR7; the prerequisite is that the two R8 groups of any definition of R3 are Calkyl alkyl, C2. The total number of carbon atoms of the 1Q extended alkenyl group or the C2.1G extended alkynyl chain is not more than 12.

Other systems independently comprise a compound of formula 111(a), 111(b), III(c), III(d), and III(e), or a pharmaceutically acceptable salt thereof, respectively:

-27- 201206888

Wherein X, R1, R2, R4, R5, R6, R8, a, b, Het and all other variables are as defined in the above formula. In the systems exemplified in the formula III (b) 'HI (c), and III (d), there is another system in which the Het is selected from the group consisting of piperidine and piperazine. In each of the systems shown by the formula 111(a) '111(b) '111(c), and III(d), there is another system in which R8 is a Cs alkyl group. Another system comprises a compound of formula IV (a), or a pharmaceutically acceptable salt thereof: -28- 201206888

(R6)b NH O

The OH variant is as defined in formula II above.

Another system comprises a compound of formula IV (a), or a pharmaceutically acceptable salt thereof:

0H

R5 IV(b) wherein X, R1, R2, R4, R5, R6, R8, a, b, and all other variables are as defined above in Formula II. Another system comprises a compound of formula IV (b), or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R4, R5, R6, a, b, and all other variables are as set forth above in Formula II Definitions, and R8 is C2.8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, wherein each R8 is optionally 1, 2 or 3 selected from halo, keto, and OR7 Substituted by a substituent. Another system comprises a compound of formula IV (b), or a pharmaceutically acceptable salt thereof: -29- 201206888

As defined in the above formula π. Other independent systems contain the formulas v(a), V(b), V(c),

And a compound represented by V(d), a pharmaceutically acceptable salt thereof:

R7

-30- 201206888

Wherein X, R1, R2, R4, R5, R6, a, b, and all other variables are as defined above in Formula II, and R3 is selected from alkyl, C2-10, alkenyl, or C2.1Q alkyne a group wherein each R3 is optionally substituted with 1, 2 or 3 substituents selected from a halogen group, a ketone group, and OR7. Other systems comprise a compound of the formulae V(a), V(b), V(c), and V(d), or a pharmaceutically acceptable salt thereof, wherein Χ'ΙΙ1, ! ^2! ^4,! ^, ^6, a, b, and all other variables are as defined above in Formula II, and R3 is selected from C4-1()alkyl, C4.1Q, alkenyl, or C4.1Q alkynyl . Still other systems comprise a compound of the formulae V(a), V(b), V(c), and V(d), or a pharmaceutically acceptable salt thereof, wherein Χ, Ι^, Ι12, Ι14, R5' R6, a, b, and all other variables are as defined in Formula II above, and R3 is C4.!. Alkyl. Another system comprises a compound of the formulae V(a), V(b), V(c), and V(d), or a pharmaceutically acceptable salt thereof, wherein X, R1, R2 -31 - 201206888, R4 , R5 'r6, a, b, and all other variables are as defined above in Formula II, and R3 is R8-〇R8, and R8 is independently in each example Cl-ίο alkyl, c2.1 () an alkenyl group, or a c2.1() alkynyl group, wherein each R8 is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR7; the prerequisite is R3 The total number of carbon atoms of the 匕.10) alkyl, c2.1Q extended alkenyl, or C2.IG alkynyl chain of the two R* groups of any definition is not greater than 12. Another system is a compound of formula VI, or a pharmaceutically acceptable salt thereof:

Wherein X, R1, R2, R5, R6, R8, a, b, and all other variables are as defined above in Formula II. Among the various groups of compounds and pharmaceutically acceptable salts thereof described herein, other systems are additionally included. Each group contains one or more of the following compounds per se or a combination thereof: (a) wherein R3 is selected from C4.12 alkylene, C4-12 extended alkenyl, C4-12 extended

Alkynyl, R8-0-R8, R8-C3-6 cycloalkyl-Het, R8-phenylene, rL phenyl-O-R8, R8-phenylene-phenyl, Het, R8- Het, R8-〇_

Het, R8-phenylene-C(0)-Het, R8-Het-phenylene, R8-phenylene

Het, and R8-〇-R8-phenyl compound. -32- 201206888 (b) wherein R8 is, in each of the examples, a compound selected from the group consisting of C!.6 alkylene, C3.6 extended alkenyl, and C3.6 extended radical; (c) wherein R3-Y is R8 a compound of phenyl-NHC (0); (d) a compound (e) wherein R3-Y is R8-phenyl-N(CH3)C(0) wherein R3-Y is R8-0-R8- a compound of phenyl-NHC ( Ο ); (f) a compound wherein R 3 -Y is R 8-0-R 8 -phenyl-N ( CH 3 ) C ( Ο );

(g) a compound wherein R3-Y is R8-phenyl-C(〇)NHCH2; (h) a compound wherein R3-Y is R8-phenyl-C(Ο)N(CH3)CH2; Wherein R3-Y is a compound of R8-0-R8-phenylene-c(o)nhch2; (j) wherein R3-Y is r8-o-r8-phenylene-C(0)N(ch3) a compound of ch2; (k) wherein X is a compound selected from the group consisting of:

HO 1) wherein X is a compound selected from the group consisting of: -33- 201206888

m) wherein X is a compound selected from the group consisting of:

η) wherein X is a compound selected from the group consisting of:

〇) wherein R 5 is an alkyl group; R 6 is OR 7 ; R 7 is an alkyl group: and b is a compound of 1; P) a compound wherein R 9 is a methyl group; and q) a compound wherein R 9 is hydrogen. As mentioned above, it is a prerequisite that the total number of carbon atoms of the CMo alkyl, C2-1Q alkenyl, or C2-1G alkynyl chain of two R8 groups in any definition of R3 is not more than 12 » for example, When R3 is -R8-0-R8- 'If the first R8 group is an exoethyl (-CH2-CH2-) chain, then the largest of the R8 groups in the R3 group has the largest carbon atom The number will be 1〇. It is to be noted that, for this purpose, the number of carbon atoms in the chain is not counted in the number of carbon atoms in the chain. For example, a 3,3-dimethylbenzyl chain will be considered to have a chain of 6 carbon atoms. In one system, the compound of the invention is defined as wherein R1 is 201206888 CH2OH, N(H)C(0)H, or N(H)S(〇2)CH3, and R2 is H. In the "special system", the compound of the invention is defined as wherein the rule 1 is CH2OH and R2 is ruthenium. In a system, 'the compound of the invention is defined as wherein... and R2 together with the attached phenyl group form a bicyclic fused heterocyclic ring having 9 or 10 ring atoms, wherein one or two ring atoms are selected from the group consisting of ruthenium and osmium. And S, and the bicyclic fused heterocyclic ring is optionally substituted by one, two or three additional substituents each independently selected from the group consisting of alkyl, keto and oxime. The phrase "one, two or three additional substituents" is used to mean that there are one, two or three substituents other than those in the formula I in which R1 and R2 are bonded to the same phenyl ring. In the system, wherein R1 and R2 together with the attached phenyl group form a bicyclic fused heterocyclic ring having 9 or a ring atom, wherein one or two ring atoms are selected from the group consisting of ruthenium, osmium and S, and the double ring is thick The heterocyclic ring is optionally substituted with an additional substituent selected from the group consisting of an alkyl group, a ketone group and an anthracene. In this system, the compounds of the invention are defined as wherein R1 and R2 are formed together with the attached phenyl group:

In one system, the compound of the invention is defined wherein R3 is selected from the group consisting of C4-12 alkyl, C4-12 extended alkenyl, C4-12 alkynyl, R8-〇-R8, and R8-N(R7)-R8 Wherein the alkylene, alkenyl or alkynyl group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, keto, and OR7, respectively. The alkylene group of the R3 may be a straight chain or a branched chain. In -35- 201206888 - in the system 'R3 is selected from C5.8 alkyl, (5-8 an alkenyl group, C5.8 alkynyl group, R8-〇-R8, and R8_N(R7)_R8, wherein each R8 Is a Ci 4 alkylene group, a C2.4 alkenyl group, or a c2.4 alkynyl group, wherein each of the alkyl, alkenyl and alkynyl groups is optionally exemplified by one or two selected from halo, keto, and Substituted by a substituent of OR 7. The alkyl, alkenyl or alkynyl group of R8 may also be straight or branched. In one system, R3 is defined as each alkyl, alkenyl and alkynyl group and Each R8 group is unsubstituted. In a particular system, 'R3 is an unsubstituted C5-8 alkylene group. In a preferred system, R3 is an unsubstituted linear C5 alkylene group. In a preferred system, R3 is an unsubstituted linear C6 alkylene group. In the preferred system, R3 is an unsubstituted linear Cs alkyl group. In a particular system, r3 is unsubstituted. Linear C5 alkynyl. In one system, the compound of the invention is defined as wherein R3 is selected from C3-6 cycloalkyl, R8-C3-6 cycloalkyl, C3.6 cycloalkyl- R8, R8-c3-6 cycloalkyl-R8, c6.1Q extended aryl, R8-CH. , c6-10 aryl-R8, r8-C6-1Q extended aryl-R8, r8_C6_iq extended aryl group_0_R8, rS-Cwg extended aryl-n(R7)-R8, R8-C6.l() Aryl-C6.1G exoaryl, Het, R8-Het, Het-R8, R8-Het R8, r8 〇Het, R8-c6 1 〇 aryl-O-Het, R8-C6.丨G 延芳.c(〇)-Het, and R8_C6•丨〇 aryl-N(R7)_Het. In one system, R3 is selected from the group consisting of r8_C6_i() extended aryl, R8-C6-i. aryl group _ R8, Het, R8_Het, R^-Het-R8, R8-C6.i〇 aryl-〇-Het, and r8-c6-1g extended aryl_N(R7)_Het. In one system, R3 is Selected from r8·phenylene, R8-phenylene-R8 'Het, R8-Het, R8-Het-R8, R8-phenylene-Het-Het, and rS·phenyl-N(R7)- Het. 201206888 In a special system, R3 is selected from the group consisting of R8-phenylene, R8-phenylene-RS,

Het, R8-Het, R8-Het-R8, R8-phenylene-Het-Het, and R8-phenylene-N(R7)-Het. In a special system, R3 is selected from the group consisting of 尺8_ phenyl,

Het, and R8_Het. In a preferred system, R3 is selected from the group consisting of r8_phenyl, Het, and R8-Het, and R8 is an unsubstituted straight or branched c, 1*6

An alkyl group, a C3-6 extended alkenyl group, or a c3.6 extended alkynyl group. In a preferred system, R3 is selected from the group consisting of R8-phenylene, Het, and R8-Het, and R8 is an unsubstituted linear Cu alkyl group, c3.6 an alkenyl group, or a c3-6 extension. Alkynyl. In one system, Het is a 6-membered saturated heterocyclic group, wherein one ring atom is Ν' and one ring atom is selected from C, Ν, Ο and S, wherein the heterocyclic group is optionally halogenated, Alkyl, alkoxy, keto or hydrazine is substituted ~ times. In a particular system, Het is a 6-membered saturated heterocyclic group wherein - one ring atom is N, and one ring atom is selected from C, Ν, Ο is S, and all other ring atoms are C, and Wherein the heterocyclic group is optionally substituted once with a halogen group (particularly C1), an alkyl group, an alkoxy group (particularly 〇CH3), a ketone group or hydrazine H. In a particular system, Het is an unsubstituted, heterocyclic ring group. In a preferred system, Het is an unsubstituted 6-membered saturated heterocyclic group wherein 1 or 2 of the ring atoms are N, and all other ring atoms are in a system wherein C is a R3 containing a Het group. R3 can be bonded to Y via any suitable carbon or heteroatom. However, the variables R3 and Y should be chosen from each other's point of view to avoid creating a system that is clearly unstable or ineffective according to the knowledge of those familiar with organic chemistry. For example, when R3 is Het and Het is a nitrogen-containing heterocyclic group bonded to Y via N, those skilled in the art -37-201206888 will understand that Y is not, for example, n(r7)c(o) or n(r7)c(o)n(r7), because this system will cause the NN bond. In a system, the compound of the invention is defined as wherein Y is C(0) or N(R7)C(0) or C(0)N(R7)CH2. In a particular system, γ is C(O) or N(R7)C(0). In a preferred system, γ is c(0). In a better system, Y is N(H)C(0). Y (and a group bonded to the phenyl group via γ) may be bonded to the ortho, meta or para position of the phenyl group. In a system, Y is the position of the bond or para position between the phenyl groups. In a preferred system, Y is the position of the bond to the para position of the phenyl group, as shown in the following formula I'

And pharmaceutically acceptable salts thereof, wherein all variables are as defined herein, including the particular and preferred systems of the various variables described herein. In a system, the compound of the invention is defined as wherein a is 0, 1 or 2, more particularly 0 or 1, preferably hydrazine. In these systems, wherein a is 1, 2, 3 or 4, R4 is selected from the group consisting of halo, alkyl, and fluorene R7. In the special system, wherein a is 1, 2, 3 or 4, and R4 is selected from the group consisting of F, CM, Br, methyl, ethyl, isopropyl, OH, OCH3 and OCH2CH3. In a system, the compounds of the invention are defined as wherein R5 is alkyl, especially CH3. -38- 201206888 In a system, the compound of the invention is defined as wherein b is 1'2 or 3', especially 1 or 2. In a preferred system, b is one. In one system, the compound of the invention is defined as wherein R6 is selected from halo, alkyl, haloalkyl, OR7, deutero-haloalkyl, R8-〇R7, 0_r8_OR7, C(0)alkyl, fluorene -R8_c(〇)alkyl, (:01^(117)2, 118-con(r7)2, r8-n(r7)2, n(r7)c(o)alkyl, N(R7)C( 0) N(R7)2, N(R7)S〇2 alkyl, R8_s〇2N(R7)2, and CN. In one system, R6 is selected from halo, alkyl, haloalkyl, OR7, o - haloalkyl, r8_〇r7, and CN. In one system, r6 is selected from the group consisting of halo, alkyl, haloalkyl, OR7, fluorenyl-haloalkyl, and CN. In a special system, R6 is selected from the group consisting of f, (: 1, Br, alkyl, haloalkyl, fluorene R7, hydrazine-haloalkyl, and CN. In a preferred system, R6 is selected from the group consisting of F, Cl, Br, CH3, CH2CH3, CF3, OH, 0CH3, OCH2CH3, and CN. In a preferred system, R6 is 0CH3. In one system, the compound of the invention is defined as two of the R6 on the adjacent carbon and the attached phenyl group. Together, a bicyclic heterocyclic ring having 9 or 10 ring atoms is formed, wherein one or two ring atoms are selected from N, 0 and S and all other ring atoms are C. In one such system, the phase The two R6 groups on the carbon together with the attached phenyl group form a benzofuran beta in a system wherein the compound of the invention is defined as wherein R7 is hydrazine or Cm alkyl; more particularly hydrazine or C,.3 alkyl. In a system, R7 is hydrazine or methyl. A clear example of a compound of formula I is shown in the examples below. Preferred compounds of formula I are selected from the group consisting of: -39- 201206888 (R) -6- [[3-[[4·[5-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroisoquinolin-5-yl)ethyl]amino]] 1-alkynyl]phenyl]amine-methylmethyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylporphyrin-3·carboxamide

(R) -6-[[3-[[6-[[2-(3-carbamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]hexyl]aminecarboxylidene]benzene Sulfhydryl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carbamimidoxime

6-[3-[[4-[2-[[2-hydroxy-2-(8-hydroxy-2-keto)-1,2-dihydroisoquinolin-5-yl)ethyl]amino] Ethyl]piperazin-1-yl]carbonyl]benzenesulfonyl]-4-(3-methoxyphenylamino)methylquinoline-3-carboxamide

-6-[[3-[[4-[2-[[2-hydroxy-2-(8-hydroxy-2-keto)-1,2-dihydroisoquinolin-5-yl)ethyl]amine Ethyl]phenyl]aminomethane]phenyl]sulfonyl]-4 _[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide- 40- 201206888

Nh2 : and 6-[[3-[[3-[2-[[(R))-2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroisospor-5-) Ethyl]amino]amino]propyl]-N-methylbenzamideamino]methyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8 -methylquinin-3-formamide

And pharmaceutically acceptable salts thereof. The compound of formula I can exist as a free base or a salt, especially a pharmaceutically acceptable salt. For a review of pharmaceutically acceptable salts, see Berge et al. 5 J. Pharma S ci. (1977) 66: 1-19 o A pharmaceutically acceptable salt formed from an inorganic or organic acid, for example, a hydrochloride salt, Hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, amine sulfonate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate , fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, citrate, ascorbate, palmitate, salicylate, Stearates, citrates, alginates, polyglutamates, oxalates, oxalic acid acetates, gluconates, benzoates, alkyl or aryl sulfonates (eg, methyl sulfonate) Acid salt, ethanesulfonate, besylate, p-toluenesulfonate or naphthalene-41 - 201206888 sulfonate), and 2-hydroxyethanesulfonate; with amino acids (eg, lysine, spermine) A complex formed by an acid, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, or the like. The compound of the invention may also be in the form of a salt with an elemental anion such as chlorine, bromine or iodine. For therapeutic use, the salt of the active ingredient of the compound of formula I will be pharmaceutically acceptable, i.e., it will be pharmaceutically An acceptable salt derived from an acid. However, salts which are not pharmaceutically acceptable acids are also useful, for example, for the preparation or purification of pharmaceutically acceptable compounds. For example, trifluoroacetate can be used for this purpose. All salts are within the scope of the invention, whether or not derived from a pharmaceutically acceptable acid. In one system, the compound of formula I is in the form of a trifluoroacetate salt. In a system, the compound of formula I is in the form of a hydrochloride. "Chiral" B means a molecule with the property of two mirror partners not overlapping, but "achiral" B is the numerator of two mirror partners that can overlap. "Stereoisomer" refers to a compound having the same chemical structure but having a different spatial arrangement of atoms or groups. "Non-image isomer" means a stereoisomer having two or more palm centers and whose molecules are not mirror images of each other. Non-image isomers have different physical properties such as melting point, boiling point, spectral properties, and reactivity. Mixtures of non-imagewise isomers can be separated under high resolution analysis steps such as electrophoresis and chromatography. "Mirror image isomer" means that the two stereoisomers of the compound are mirror images that are mutually incapable of overlapping each other. The stereochemical definitions and conventions used herein are generally based on S. P.

Parker, Ed.,

McGraw-Hill Dictionary of Chemical 201206888

Terms ( 1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic COMPOUNDS (1 994) John Wiley & S o ns, Inc., N e w Yo rk. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule relative to its palm center. Particular stereoisomers may also be referred to as mirror image isomers, and mixtures of such isomers are often referred to as mirror image isomer mixtures. The 50:50 mixture of mirror image isomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or processes that are not stereoselective or stereospecific. "Drug mixture" and "racemate" B mean an equimolar mixture of two mirror image isomers. "Tautomer" means the movement of a hydrogen atom resulting in a stereoisomer type of two or more structures. The compounds of formula I may exist in different tautomeric configurations. Those skilled in the art will appreciate that guanidine, guanamine, guanidine, urea, thiourea, heterocycles and the like can exist as tautomeric forms. All possible tautomeric forms of oxime, guanamine, guanidine, urea, thiourea, heterocycle, etc. of all systems of formula I are within the scope of the invention. The tautomers may exist in a balanced manner, and it will be appreciated by those skilled in the art that the description of a single tautomer in the chemical formulas mentioned may be equally extended to all possible tautomers. It is to be understood that all mirror image isomers, non-image isomers, and racemic mixtures, tautomers, polymorphs, polymorphs of the compounds of the formula I and their pharmaceutically acceptable salts All are covered within the scope of the invention. All mixtures of the mirror image isomer and the non-image isomer, including the rich -43-201206888

Mixtures containing mirror image isoforms and mixtures enriched in non-image areomers are encompassed within the scope of the invention. A mixture rich in mirror image is a mixture of mirror image isomers in which the ratio of mirror image isomers to another mirror image isomer is greater than 50:50. More particularly, the mixture enriched in the image isomer form comprises at least about 75% of the specified mirror image isomer, preferably at least about 85% of the specified mirror image isomer. In a system, the mixture rich in mirror image is substantially free of another mirror image isomer. Similarly, a mixture rich in non-image isomers is a mixture of non-image isomers in which the amount of the specified non-image isomer is greater than the amount of each other non-image isomer. More particularly, the mixture enriched in the non-image isomer type comprises at least about 75% of the specified non-image isomer, preferably at least about 85% of the specified non-image isomer in one system, enriched The mixture of non-image isomers is substantially free of all other non-image isomers. For illustrative purposes, clear examples of mirror image isomers within the scope of the present invention include:

(11)-6-[[3-[[8-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroisoquinolin-5-yl)ethyl]amine) Amino] octyl]amine carbazino]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

And (8)-6-[[3-[[8-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroiso-44- 201206888 sin-5-yl) Ethyl]amino]octyl]amine-carbamoyl]phenyl]sulfonyl]_4_[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

In one system, the present invention provides a mixture enriched in a mirror image isoform, which comprises (R)-6-[[3-[[4-[5-[[2-hydroxy-2-(8-hydroxy]- 2-keto-1,2-dihydroisoquinolin-5-yl)ethyl]amino]pentyl-1-alkynyl]phenyl]aminocarboxyl]phenyl]sulfonyl]-4- [(3-Methoxyphenyl)amino]_8-methylsalthion-3-carboxamide

Or a pharmaceutically acceptable salt thereof as the main isomer. The compounds of formula I and their pharmaceutically acceptable salts may exist in different polymorphic or polymorphic forms. Herein, the polymorphic nature of the crystal means the ability of the crystalline compound to exist in different crystal structures. The polymorphic nature of the crystal may be due to the difference in crystal stacking (stack polymorphism) or the heterogeneity between the different conformational conformers of the same molecule (conformational polymorphism) Caused by. Herein, the polymorphism of the crystal structure also includes the ability of the hydrate or solvate of the compound to exist in different crystal structures. The polymorphic form of the present invention may be due to the difference in stacking between the crystal stacks -45 - 201206888 stacks (stacked polymorphism) or stacking differences between different conformational isomers of the same molecule (configuration ( Conformational ) polymorphic) exists. The present invention encompasses all polymorphic and polymorphic forms of the compounds of formula I and their pharmaceutically acceptable salts. The compound of formula I, and pharmaceutically acceptable salts thereof, may also be present in the form of an amorphous solid. As used herein, an amorphous solid refers to an ordered solid in which the position of the atoms in the solid is not long. This definition applies equally to cases where the crystal size is 2 nm or less. Additives, comprising a solvent, can be used to produce the amorphous form of the present invention. The present invention includes all amorphous forms of the compound of formula I and pharmaceutically acceptable salts thereof. The compounds of the invention may also be in the form of a prodrug. More specifically, the compound may exist in the form of an in vivo cleavable ester of the compound of formula I or a salt of the ester. Examples of suitable esters include acetates, pivalates, tartrates, maleates, succinates, and the like. Uses The compounds of the present invention exhibit bifunctional activity in the form of dual pharmacophores phosphodiesterase 4 inhibitors (PDE4i) and (3 agonists. Without limiting to any particular theory, it is believed that the compounds of the invention may be used in vivo. To reduce inflammation in the lungs (by increasing the cytoplasmic content of 3',5'-cyclic adenosine monophosphate (cAMP) by inhibiting PDE4 enzymes and possibly other pro-inflammatory mechanisms) and reducing bronchiectasis By the adrenergic receptor agonist group), by adjusting the two targets, the downstream signaling pathway of -46 - 201206888 can interact with the same cells to produce a positive cooperative anti-inflammatory effect. Local delivery of a single-type bifunctional compound with dual activity of PDE 4 i and β agonist provides a combination and conjugtive treatment. In particular, such bifunctional compounds can be adjusted simultaneously by the same Provides a cooperative anti-inflammatory or tracheal dilation effect. The bifunctional compound of the present invention can be used without treatment or combination (conj uncti ve) Individual compounds provide a co-processing effect in the same microenvironment. In addition, such bifunctional compounds provide reduced non-target effects (0 ff_ target effect), thereby reducing the risk of adverse events associated with individual PDE4i or LABA compounds. However, if desired, the dual active compounds of the compounds of the invention may still be combined with other pharmaceutically and non-pharmacological treatments conventionally used in the treatment of respiratory diseases. Further details regarding such combination therapies utilizing the compounds of the invention are described below. Thus, the compounds of the invention are useful as medicaments, particularly for the treatment of clinical conditions which require treatment with PDE4i or beta agonists, which include treatment of pulmonary inflammation or bronchoconstriction and various respiratory diseases. PDE4i for the treatment of respiratory diseases For a review of possible therapeutic activities, see, for example, Kroegel & Foerster, Phosphdiesterase-4 inhibitor as a novel approach for the treatment of respiratory disease: cilomilast, Expert Op in. Investig. Drugs (200 7 ) 16:109-124 ; Dastidar Eta 1., Therapeutic be Nefit of PDE4 inhibitors in inflammatory diseases, Curr Op in Investig Drugs ( 2 0 0 7 ) 8:364-372 ; Krymskaya, et al., -47- 201206888

Phosphodiesterases regulate airway smooth muscle function in health and disease, Cur r. Top. Dev. Biol. ( 2 0 0 7 ) 7 9 : 6 1 - 7 4 ; and S pi na, PD E4 i nhi bitors : c ur r ent Status, Brit. J. P/iarmaco/· 2008; 155:308-15. In particular, the compounds of the invention are useful in the treatment of a variety of respiratory conditions in humans in need thereof, such as diseases associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (C Ο PD ) (including acute exacerbations of COPD) ), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, pancreas Bronchitis, and bronchiolitis associated with transplantation (including bronchiolitis associated with lung and bone marrow transplantation). The compounds of the invention may also be used in the treatment of ventilator-related tracheobronchialitis and/or prevention of respirator-associated pneumonia in patients using a respirator. With regard to the treatment of acute exacerbation of COPD', the compounds of the invention may be used to reduce the frequency, severity or duration of acute exacerbation of COPD, and/or to reduce the frequency, severity or duration of one or more symptoms of acute exacerbation of COPD. The therapeutic uses and methods described herein are by administering an effective amount of a compound of the invention (a compound of formula I or a pharmaceutically acceptable salt thereof) to a patient in need of treatment (usually a mammal, preferably a human) The steps are carried out. In one aspect, the invention provides a method of treating a condition in which a mammal, such as a human, must be treated with a PDE4i or beta agonist. As used herein, "treating and treatment" is meant to reverse, retard, inhibit or prevent the development of a disorder or condition or one or more symptoms of the disorder or condition. In one system, the invention provides a method of treating a respiratory disease. In one system, the invention provides a method of treating a condition associated with reversible or irreversible airway obstruction in a mammal, particularly a human, in need thereof. In a particular system, the invention provides a method of treating COPD in a mammal, particularly a human, in need thereof. In a particular system, the invention provides a method for reducing the frequency, severity or duration of acute exacerbation of COPD or treating one or more symptoms of acute exacerbation of COPD in a mammal, particularly a human, in need thereof. In one system, the present invention provides a method of treating asthma in a mammal, particularly a human, in need thereof. In one system, the present invention provides a method of treating bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis) in a mammalian, particularly a human, in need thereof. In one system, the present invention provides a method of treating bronchitis (including acute and chronic bronchitis) in a mammal, particularly a human, in need thereof. In one system, the present invention provides a method of treating a cough after viral infection in a mammal, particularly a human, in need thereof. In one system, the invention provides a method of treating cystic fibrosis in a mammal, particularly a human, in need thereof. In the system, the invention provides a method of treating emphysema in a mammal, particularly a human, in need thereof. In one system, the invention provides a method of treating pneumonia in a mammal, particularly a human, in need thereof. In one embodiment, the invention provides a method of treating bronchiolitis in a mammal, particularly a human, in need thereof. In one system, the present invention provides a method of transplantation-related trochanteritis (including bronchiolitis associated with lung and bone marrow transplantation) in mammals (especially humans) required for treatment of -49-201206888. In one system, the present invention provides a method of treating tracheobronchitis associated with a respirator and/or preventing pneumonia associated with a respirator in a human in need of a respirator. In one system, the invention provides a method of treating nasal inflammation in a mammal, particularly a human, in need thereof. Also provided are compounds of the invention for use in the treatment of drugs, particularly those which are useful in the treatment of mammals (e.g., humans) for treatment with PD E4i or beta agonists. In one system, the invention provides a method of treating a respiratory disease. In a system, a compound of the invention for use in treating a mammal, particularly a human, in a condition associated with reversible or irreversible airway obstruction is provided. In a particular system, a compound of the invention for use in the treatment of chronic obstructive pulmonary disease (COPD) in a mammal, particularly a human, in need thereof is provided. In a system, a compound of the invention is provided for a mammal, particularly a human, in need thereof to reduce the frequency, severity or duration of acute exacerbation of COPD or to treat one or more of the acute exacerbations of COPD. In a system, a compound of the invention for use in the treatment of asthma in a mammal, particularly a human, in need thereof is provided. In a system, a compound for bronchiectasis (including bronchiectasis due to a condition other than cystic fibrosis) for a mammal (especially a human) in need thereof is provided. In a system, a compound for the treatment of bronchitis (including acute bronchitis and chronic bronchitis) in a mammal, particularly a human, in need thereof is provided. In a system, a compound for coughing after infection with a virus for a mammal (especially a human) in need thereof is provided. In a system -50-201206888, a compound for the treatment of cystic fibrosis of a mammal, particularly a human, in need thereof is provided. In a system, a compound of the invention for use in the treatment of emphysema of a mammal, particularly a human, in need thereof is provided. In a system, a compound of the invention for use in the treatment of pneumonia in a mammal, particularly a human, in need thereof is provided. In a system, a compound of the present invention for treating bronchiolitis (especially human) or bronchitis associated with transplantation (including bronchiolitis associated with lung and bone marrow transplantation) is provided. In a system, a compound of the invention for treating a ventilator-related tracheobronchitis or preventing respirator-associated pneumonia is provided for treating a patient using a respirator. In a system, a compound of the invention for use in the treatment of sinusitis in a mammal, particularly a human, in need thereof is provided. The invention also provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a condition in which a mammalian, such as a human, must be treated with a PDE4i or beta agonist. In a system, the use of a compound of the invention for the manufacture of a medicament for the treatment of a respiratory disease is provided. In a system for providing a medicament for the manufacture of a medicament for the treatment of a disease associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, asthma Bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), bronchitis (including acute bronchitis and chronic bronchitis), cough after viral infection, cystic fibrosis, emphysema, pneumonia, Bronchiolitis, bronchiolitis associated with transplantation (including bronchiolitis associated with lung and bone marrow transplantation), tracheobronchitis associated with respirators, or for prevention of pneumonitis associated with respirators, or for treatment Sinusitis. -51 - 201206888 As used herein, the term "effective amount" refers to a cell culture, tissue, system, or mammal (including humans) sufficient to cause, for example, a researcher or clinician in a subject to be administered. The amount of the compound of the invention reacted biologically or pharmaceutically. The scope of the term also includes an amount effective to enhance normal physiological function. In a system, the effective amount is the amount of the desired drug concentration in the secretions and tissues of the airway and lungs, or the expected physiological response in the blood of the patient to be treated when the composition is administered by inhalation. Or the amount of biological action desired. For example, a compound of the invention is used in an amount effective to treat a condition which must be treated with a PDE4i or beta agonist in an amount sufficient to treat the particular condition in a patient to be administered. In one system, an effective amount is an amount of a compound of the invention sufficient to treat COPD or cystic fibrosis in a human. The correct and effective amount of a compound of the invention will depend on a number of factors including, but not limited to, the species, age and weight of the patient being treated, the condition and severity of the condition in need of treatment, and the bioabsorption rate of the particular compound being administered. , efficacy and other properties, the nature of the blend, the route of administration, and the delivery device, and will ultimately be determined by the judgment of the participating medical staff or veterinarian. Further consultation on appropriate doses can be obtained by considering the usual doses of other PDE4i (eg, cilomilast or roflumilast) and other beta agonists (eg salmeterol). All potency differences between these compounds and the compounds of the invention as well as the bifunctional properties of the compounds of the invention are also contemplated. The estimated dose of a compound of the invention administered topically to the airway surface of a patient (e.g., by inhalation) to treat a 70 kg human can range from about 20 to about 1 000 pg. The selection of a particular dosage for a patient will be determined by a healthcare professional, clinician or veterinarian with prior knowledge of 201206888 in the prior art, based on a number of factors including those described above. In a particular system, the dosage of a compound of the invention for treating 70 kg of human will range from about 50 to about 75 0 pg. In a preferred system, the dose of the compound of the invention for treating 70 kg of human will be from about 50 to about 75 μg g. If the compound is administered in a different route, the above recommended dosage can be used. Adjusted by traditional dose calculation. Suitable dosages for other routes of administration can be determined by those skilled in the art in light of the above-described teachings in the art and in the art. Delivery of an effective amount of a compound of the invention may require delivery of a single dosage form or multiple unit doses (either simultaneously or separately during a specified period (e.g., 24 hours)). The dose of the compound of the present invention (in the form of the composition alone or in the composition containing the same) can be administered in a manner of from 1 to 10 times per day. In general, the compounds of the invention (either alone or in the form of a composition comprising the same) will be administered 4, 3, 2, or optimally once a day (24 hours). Composition Although the compound of the present invention can be administered alone, it is preferably present in the form of a composition, particularly a pharmaceutical composition (combination). Accordingly, in another aspect, the present invention provides a composition, particularly a pharmaceutical composition (eg, a pharmaceutical composition for inhalation), comprising as an active ingredient a compound of the present invention, and a pharmaceutically acceptable excipient, diluent or Carrier. As used herein, "active ingredient" means a combination of any of the compounds of the invention or two or more compounds of the invention in a pharmaceutical composition. The pharmaceutically acceptable excipients, diluents or carriers are compatible with the other ingredients of the blend. -53 - 201206888 must be acceptable and not harmful to the recipient. Generally, a pharmaceutically acceptable excipient, diluent or carrier for use in a pharmaceutical formulation is "non-toxic", meaning that it is safe to take at the dose delivered by the formulation and is "inert", indicating Its therapeutic activity on the active ingredient does not produce an appreciable response or an undesired effect. Pharmaceutically acceptable excipients, diluents and carriers are well known in the art and may be selected using conventional techniques depending on the desired route of administration. See Remington's, Pharmaceutical Sciences, Lippincott Williams &Wilkins; 2 1st Ed (Can, 1, 2005). Preferably, the pharmaceutically acceptable excipient, diluent or carrier is according to the FDA General Regarded As Safe (GRAS). The pharmaceutical composition of the present invention comprises a pharmaceutical composition suitable for topical administration and administration to the respiratory tract (including the nasal cavity and sinus, the external airway of the mouth and chest, and the lung), including the use of various types of dry powder inhalers, pressurized quantitative inhalation. An aerosol delivered by a softmist inhaler, a nebulizer, or an insufflator. The most appropriate route of administration can be determined by several factors, including the patient and the condition or disorder being treated. The compositions may be presented in unit dosage form or in a bulk dosage form, such as in the case of inhaler-quantified blends, and may be made by any method known in the pharmaceutical arts. Generally, the method comprises the step of mixing the active ingredient with a carrier, diluent or excipient and optionally one or more accessory ingredients. In general, the compositions are prepared by mixing the active ingredient with one or more liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients -54-201206888, or Both, and then if necessary, are shaped to form the desired blend. In a preferred embodiment, the composition is a pharmaceutical composition for inhalation suitable for inhalation and delivery to the lumen of the inner branch. Typically, the composition is in the form of an aerosol comprising particles delivered using a nebulizer, a pressurized metered dose inhaler (MDI), a micro-mist inhaler, or a dry powder inhaler (DPI). The aerosol blend used in the method of the invention may be a liquid (e.g., a solution) suitable for administration as a nebulizer, a micro-mist inhaler, or MDI, or a dry powder suitable for administration in MDI or DPI. The aerosol used to administer the drug to the respiratory tract is usually polydisperse; that is, it contains particles of different sizes. Particle size distribution is usually described by mass median aerodynamic particle size (MMAD) and geometric standard deviation (GSD). In order to optimize drug delivery to the inner bronchial space, the MMAD ranges from about 1 to about 10 μηι, preferably from about 1 to about 5 μηι, and the GSD is less than 3', preferably less than about 2. When inhaled into the lungs, aerosols with MMAD above 10 μη are usually too large. Aerosols with a GSD greater than about 3 are not suitable for delivery to the lung when delivering a high ratio of drug to the oral cavity. In order to obtain these particle sizes in powder blends, the particles of the active ingredient can be reduced in size using conventional techniques, such as micronization or spray drying. Other non-limiting examples of methods or techniques that can be used to prepare particles suitable for breathing include spray drying, precipitation, supercritical fluids, and freeze drying. The desired fraction can be separated by air fractionation or screening. In a system, the particles will be crystalline. For liquid blends, the particle size is determined by selecting a particular type of nebulizer, micro-mist inhaler, or MDI. • 55- 201206888 Aerosol particle size distribution is detected using previously known devices. For example, the Anderson multi-stage impact sampler or other suitable method, such as the US Pharmacopoeia Chapter 601, is specifically exemplified as a device for identifying aerosols ejected by quantitative and dry powder inhalers. The dry powder composition for topical delivery to the lung by inhalation may be formulated to be free of excipients or carriers, and instead comprise only active ingredients in the form of a dry powder having a suitable particle size suitable for inhalation. The dry powder composition may also contain a mixture of the active ingredient and a suitable powder base (carrier/diluent/excipient material) such as a monosaccharide, disaccharide, or polysaccharide (e.g., lactose or starch). Lactose is generally a preferred excipient for dry powder blends. When a solid excipient such as lactose is used, typically the excipient will have a particle size that is much greater than the active ingredient to aid in dispersing the blend in the inhaler. Non-limiting examples of dry powder inhalers include sump multi-dose inhalers, pre-quantitative multi-dose inhalers, capsule inhalers, and single-dose disposable inhalers. The sump inhaler contains multiple doses (e.g., 60 times) in a single container. Prior to inhalation, the inhaler is activated to allow the inhaler to be metered into a dose of medication from the reservoir' and ready for inhalation. Examples of sump-type DPIs include, but are not limited to, AstraZeneca's Turb〇haler® and Vectura's ClickHaler®. In a pre-quantized multi-dose inhaler, the individual doses are separately prepared to be contained in different containers. The inhaler is activated prior to inhalation to allow a new dose of the drug to be released from the container and ready for inhalation. Examples of multi-dose DPI inhalers include, but are not limited to, 'GSK's Diskus®, Vectura's Gyrohaler®, and Valois' Prohaler®. During inhalation, the patient's respiratory airflow accelerates the release of powder from the device and into the mouth -56-201206888. For capsule inhalers, the blend is present in the capsule and stored outside the inhaler. The patient places the capsule in the inhaler, activates the inhaler (pierces the capsule), and then inhales. Examples include RotohalerTM ( GlaxoSmithKline ) and S pinhal erTM ( Novartis ).

HandiHalerTM (IB), TurboSpinTM (PH&T). For single-dose disposable inhalers, the patient activates the inhaler to prepare for inhalation, inhalation, and then discards the inhaler and packaging material. Examples include TwinCerTM (U Groningen), OneDoseTM (GFE), and Manta InhalerTM (Manta Devices). Typically, dry powder inhalers utilize the turbulent nature of the powder route to disperse excipient-drug aggregates and deposits of active ingredient particles. In the lungs. However, some dry powder inhalers utilize cyclone dispersion chambers to produce particles of the size that are desired to be aspirated. In the cyclone dispersion chamber, the drug enters the coin-shaped dispersion chamber in a tangential manner, causing the air passage and the drug to move along the outer circular wall. As the drug blend moves along the circular wall, it bounces around and spreads out of the mass by impact. The air passage is spirally moved toward the center of the dispersion chamber and is discharged vertically. Particles having a small aerodynamic size can travel along the air path and exit the dispersion chamber. In fact, the function of the dispersion chamber is like a small jet honing device. Depending on the nature of the blend, larger lactose particles can be added to the blend to help disperse via impact with the API particles.

The TwincerTM single-dose disposable inhaler appears to operate using a coin-shaped cyclone dispersion chamber (called an “air classifier”). See Rijksuniversiteit Groningen, US Published Patent - 57- 201206888 2006/02370 1 0 » The literature published by the University of Groningen has revealed the use of this technique to effectively dose 60 mg of pure micronized colistin mesylate Delivered in the form of a respirable dry powder. In a preferred system, the aerosol blister is delivered as a dry powder using a dry powder inhaler wherein the particles released by the inhaler have a MMAD of from about 1 μηη to about 5 μηη and a GSD of less than about 2. Suitable examples of dry powder inhalers and dry powder dispersion devices for delivering the compounds and compositions of the present invention include, but are not limited to, US 7,520,278; US 7,322,354; US 7,246,61 7 ; US 7,23 1,920; US 7,2 19,665; US 7,207 , US 3, 522, 3 85; US 6,845,772; US 6,637, 43 1 ; US 6,329,034; US 5,45 8,1 3 5 ; Revealed by /0237010. In one system, the pharmaceutical formulation of the present invention is a dry powder for inhalation that is delivered to a Diskus®® device. The Diskus® device includes an elongated strip formed of a substrate having a plurality of grooves distributed along the length direction and a cover plate that seals the groove but is peelable to define a plurality of containers in each container There is a reversible blend, and the blend contains a predetermined amount of the active ingredient per se or a mixture of the active ingredient with one or more carriers or excipients such as lactose and/or other therapeutically active agents. Preferably, the strip is sufficiently flexible to be wound into a roll. The cover and the substrate will preferably have leading end members that are not sealed to each other, and at least one of the leading end members is configured to be coupled to the winding device. Moreover, preferably, the gasket between the substrate and the cover extends over the entire twist. To produce an inhalation dose, the cover may be preferably stripped from the substrate from the first end of the substrate by the length. -58- 201206888 In one system, the pharmaceutical formulation of the present invention is a dry powder for inhalation that is delivered as a single-dose disposable inhaler (particularly a TwinCerTM inhaler). The TwinCerTM inhaler comprises a foil laminated bulb having one or more grooves and a cover that seals the groove but is peelable to define one or more containers. Each container has an inhalable blend and the blend contains a predetermined amount of the active ingredient itself or a mixture of the active ingredient with one or more carriers or excipients such as lactose. The cover plate will preferably have a leading end member that is configured to protrude from the inhaler body. The patient will operate the device and administer the aerosol composition as follows: 1) removing the outer wrapper, 2) pulling up the foil tab to expose the drug in the blister, and 3) inhaling the drug from the blister. In another system, the pharmaceutical composition of the present invention is a dry powder for inhalation, wherein the dry powder is prepared into microparticles as disclosed in PCT Publication No. WO2009/0 1 528 6 or W02007/1 1 488 1 to NexBio. Such microparticles are usually prepared by adding a counterion to a solution of the compound of the invention in a solvent; adding an anti-solvent to the solution; gradually cooling the solution to a temperature below about 25 ° C to form a compound containing the compound The composition of the microparticles. The microparticles containing the compound can then be separated from the solution by any suitable method, such as precipitation, filtration or freeze drying. Counterions, solvents and antisolvents suitable for the preparation of microparticles of the compounds of the invention are disclosed in WO 2009/015286. In another system, the pharmaceutical compositions of the invention can be delivered in the form of a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include US 5,2 6 1,5 3 8 ; US 5,544,647 ; US 5,622,1 63 ; US 4,955,371; 178 3,565,070; 1; 33,361,306 and 1; 86,116,234-59 - 201206888 and US 7,108,159. In a preferred system, the compounds of the invention may be delivered in a dry powder form using a metered dose inhaler wherein the released particles have a MMAD of from about 1 μm to about 5 μm and a GSD of less than about 2 for delivery to the inner bronchus by inhalation. Or a liquid aerosol composition of the lungs may, for example, be formulated into an aqueous solution or an aqueous suspension or prepared to be delivered in a pressurized pack (eg, a metered dose inhaler, a micro-mist inhaler, or a nebulizer using a suitable liquefied propellant) Sol. Such an aerosol composition suitable for inhalation may be a suspension or solution, usually containing the active ingredient together with a pharmaceutically acceptable carrier or diluent (such as water (distilled or sterile water), saline, highly permeable saline, or Ethanol) and optionally one or more other therapeutically active agents. The aerosol composition delivered by the pressurized metered dose inhaler typically additionally comprises a pharmaceutically acceptable propellant. Examples of such propellants include fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof, especially hydrofluorocarbons such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, It is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may be free of excipients or may optionally contain other modulating excipients known in the art, such as a surfactant such as oleic acid or lecithin, and an anti-solvent such as ethanol. The pressurized blend will typically be contained in a small metal canister (e.g., a small aluminum can), sealed with a valve (e.g., a metering valve), and mounted to an actuator with an interface. In another system, the pharmaceutical compositions of the present invention are delivered in liquid form using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include -60-201206888 U.S. Patent Nos. 6,253,762, 6, 4 1 3,497, 7,601, 3 3 6, 7,481,995 ' 6,743, 4 1 3, and 7,105,152 By. In a preferred system, the compounds of the invention are delivered in the form of a dry powder using a metered dose inhaler wherein the particles released have an MMAD of from about 1 μηι to about 5 μηη and a GSD of less than about 2. In one system, the aerosol blend is suitable for aerosolization with a jet nebulizer or a supersonic nebulizer (containing a static and vibrating perforated plate sprayer). The liquid aerosol composition for atomization may be prepared by dissolving the solid particle granules with an aqueous carrier or by reconstituting the solid granules with an aqueous carrier, or may be added with an aqueous carrier such as an acid or alkali metal buffer salt and osmotic pressure. A reagent such as a regulator is prepared together. It can be sterilized using in-process techniques such as filtration, or techniques at the end of the process, such as heating in a hot pot or gamma radiation. It can also be presented in unsterilized form. The patient may be sensitive to the pH, osmolality, and ion content of the nebulized solution. These parameters should therefore be adjusted to be compatible with the active ingredient and tolerated by the patient. The optimum solution or suspension of the active ingredient will contain a chloride ion concentration > 30 mM 'pH 4.5-8.0 ' and a molar osmotic pressure of about 800-1 600 mOsm/kg. The pH of the solution can be controlled by titration with a common acid (e.g., hydrochloric acid or sulfuric acid) or a base (e.g., sodium hydroxide) or using a buffer. Frequently used buffers include citrate buffers, acetate buffers, and phosphate buffers. The buffer strength can range from 2 mM to 50 mM. The compositions may be administered using a nebulizer or other nebulizer which is commercially available to break up the blend into particles or droplets suitable for deposition in the respiratory tract. Non-limiting examples of nebulizers that can be used for aerosol delivery of the compositions of the present invention - 61 - 201206888 Examples include pneumatic jet nebulizers, ventilated or breath-enhanced jet nebulizers, or ultrasonic nebulizers (including static and vibrating perforated plate nebulizers) Particles that are not suitable for inhalation by using a high velocity air stream to burst through the water column can strike the walls or aerodynamic baffles. A ventilated or breath-enhanced nebulizer operates in substantially the same manner as a jet nebulizer, except that the inhaled air passes through the main droplet-producing zone as the patient inhales to increase the nebulizer output rate. In an ultrasonic nebulizer, the piezoelectric crystal vibrates Surface instability occurs in the drug reservoir such that droplets are formed. In a multi-well plate sprayer, the pressure 产生 generated by the sonic energy forces the liquid through the mesh where it is broken into droplets via the Rayleigh breaking mode. The sonic energy can be supplied by a vibrating horn or a vibrating plate driven by a piezoelectric crystal, or by a mesh hole vibrating itself. Non-limiting examples of nebulizers include any single fluid or two-fluid atomizer or nozzle that produces droplets of suitable size. The single fluid atomizer operates by forcing liquid through one or more holes where the jet of liquid breaks up into droplets. The two-fluid atomizer operates by forcing both gas and liquid through one or more holes, or by jetting a jet of liquid against another liquid or gas jet. The choice of nebulizer that aerosolizes the aerosol blend is important for administration of the active ingredient. Different nebulizers have different potencies depending on their design and operating principles and are sensitive to the physical and chemical properties of the blend. For example, two blends with different surface tensions may have different particle size distributions. In addition, the properties of the conjugate, such as pH, osmolality, and dispersed ionic content, can affect the resistance of the drug, and thus the preferred system meets some range of properties described. In a system, the formulation for nebulization uses a suitable nebulizer to transport the space within the bronchus in the form of an aerosol having an MMAD of from about 1 μm to about and a GSD of less than two. In order to be most effective and to avoid the side effects of the upper respiratory tract, the aerosol should not have an MMAD greater than about 5 μηη and a GSD greater than about 2. If the MMAD of the aerosol is greater than about or the GSD is greater than about 2, a large proportion of the agent may be deposited in the upper air to reduce the amount delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is less than about 1 μηη, the large ratio may still be suspended in the inhaled air and may then be present during exhalation. The compounds of the invention may also be administered by transbronchoscopy in the form of transbronchoscopic lavage. The nasally designed compositions are designed to contain aerosols, solutions, solutions, solutions, sprays, mists and drops. Aerosol blends for nasal administration are formulated in much the same way as aerosol compositions for inhalation, but particles of inoperable size will preferably be used for nasally administered formulations. Micron-sized particles to visible droplets. For nasal delivery, the particle size in the range of 10–500 μηι can be used to stay in the nasal cavity. In another aspect, the invention provides a method of treating a human condition in need thereof, comprising administering to the human a pharmaceutical composition comprising a compound of the invention, wherein the compound is administered in an effective amount. In a comparative system, the method comprises administering a package of the form of the inhalation composition, preferably 5 μm, to the whole body, not to 5 μm, and the particles of the substance are washed (the suspension may have , ensuring that the respiratory body contains about -63 - 201206888 20 to about 1 000 pharmaceutical composition of the compound of the invention. In another aspect, the invention provides a treatment for a human in need thereof associated with reversible or irreversible airway obstruction Disease, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection, cystic Fibrosis, emphysema, pneumonia, bronchiolitis, bronchiolitis associated with transplantation, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or treatment of nasal fever a method comprising administering to a human a pharmaceutical composition comprising a compound of the invention, wherein the compound is administered in an effective amount. Said method comprising administering to a composition for inhalation a pharmaceutical composition comprising from about 20 to about 1 000 pg of a compound of the invention. A preferred unit dose of the compound of the invention comprises an effective amount of the active ingredient or A suitable blend of components. It will be understood that in addition to the ingredients specifically mentioned above, the compositions of the present invention may comprise other conventionally used agents of this type in the prior art. The compositions of the present invention may be treated according to The combination of the special condition required and the desired route of administration is formulated as a compact, controlled release or sustained release form. Since the free base of the compound is generally less soluble in the aqueous solution than the salt, the free base composition comprising the compound of formula I is available. Providing more sustained release of the active agent delivered to the lung by inhalation. The particulate active agent in the lung that is not dissolved in the solution does not cause a physiological reaction, but may be a deposit form of the bioabsorbable drug, and then gradually Dissolved in a solution. In another example, the blend can be used in both the free base and the salt form of the compound of the present invention to provide immediate release. And sustained release of the active ingredient for dissolution into mucus secretions such as the nose. Compositions The compounds of the invention may be formulated and/or used with other therapeutically active agents. Other therapeutic activities that may be formulated or used with the compounds of the invention Examples of agents include, but are not limited to, anti-inflammatory agents, anticholinergic agents, peroxisome proliferator-activated receptor (PPAR) gamma agonists, PPAR δ agonists, epithelial sodium channel resistance Broken agent (ENaC blocker) 'kinase inhibitors (eg p38 MAPK, PI3K, JNK, ERK, IKK2), anti-infectives, and antihistamines. Thus, in another aspect, the invention provides an effective amount of the present invention A composition of a compound of the invention and one or more additional therapeutically active agents, wherein the other therapeutically active agent is selected from the group consisting of an anti-inflammatory agent, an anticholinergic agent, a P2Y2 receptor agonist, a PPAR gamma agonist, a PPAR δ agonist, ENaC Blockers, kinase inhibitors (eg, p38 MAPK, PI3K, JNK, ERK, IKK2), anti-infectives, and antihistamines. The use of a compound of the invention in combination with one or more other therapeutically active agents reduces the dosage of the compounds of the invention required to treat respiratory tract disorders, thereby reducing the likelihood of undesirable side effects due to beta agonists absorbed throughout the body. Anti-inflammatory agents suitable for use in combination with the compounds of the invention include corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), particularly phosphodiesterase (PDE) inhibitors. Examples of corticosteroids useful in the present invention include oral administration -65-201206888

Or inhaled corticosteroids or their prodrugs. Clear examples include, but are not limited to, ciclesonide, desisobutyryl-ciclesonide, budesonide, flunisolide, mometasone And its vinegar (such as mometasone furoate), fluticasone propionate, fluticasone furoate, beclomethasone, methyl prednisolone ), prednisolone, dexamethasone, 6α, 9ct-difluoro-17α-[(2-furylcarbonyl)oxy]-ΐΐβ-hydroxy-16α-methyl-3-one Base-androstene-1,4-diene-17β·S-fluoromethyl thioformate, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-keto-17α-propenyloxy - androst-1,4-diene-17β-thiocarbamic acid S-(2-keto-tetrahydro-furan-3S-yl) ester, beclomethasone ester (eg 17-propionate or 17,2 dipropionic acid vinegar), fluoromethic acid, triamcinolone acetonide, rofleponide, or any combination or subgroup thereof . Preferred corticosteroids for formulation or use with the compounds of the invention are selected from the group consisting of ciclesonide, desisobutyryl-ciclesonide, budesonide, mometa. Mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subgroup thereof. NS AIDs for use in the present invention include, but are not limited to, sodium cromoglycate, nedocrosin Nedocromil sodium, phosphodiesterase (PDE) inhibition -66-201206888 (eg, theophylline, amin 〇phy 11 ine, PDE 4 inhibitor, PDE3/PDE4 mixed inhibitor or PDE4/ PDE7 mixed inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (eg 5 L 0 and FLAP inhibitors), nitric oxide synthase (iNOS) inhibitors, protease inhibitors (eg tryptase inhibitors) , neutrophil elastase inhibitors, and metalloproteinase inhibitors), β2-integrin antagonists and adenosine receptor agonists or antagonists (eg, adenosine 2 a agonists), Intracellular hormone antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis (e.g. prostaglandin D2 (CRTh2) receptor antagonist). PDE4 inhibitory Qi, PDE3/PDE4 mixed inhibitor or PDE4/PDE7 mixed inhibitor may be any compound known to inhibit PDE4 enzyme or found to be useful as a PDE4 inhibitor, and any compound that is a selective PDE4 inhibitor (ie Compounds that do not significantly inhibit other members of the PDE family). Examples of well-defined PDE4 inhibitors for formulation and use with the compounds of the invention include, but are not limited to, roflumilast, pumafentrine, arofylline, cilomilast (cilomilast) ) 'to fi mi last, toomilmilast, tolafentrine, picl amilast, ibudilast, apus ( apremilast), 2-[4-[6,7--ethoxy-2,3-bis(transmethyl)-1.naphthyl]-2-pyridyl]-4-(3-pyridyl) )-1 (2H)-fluorenone (butyl 2585), 1^-(3,5-monochloro-4-|] is more than 11)-1-[(4-phenylphenyl)methyl]-5 -hydroxy-α-keto-1H-indole-3-acetamide (AWD-12-281), 4-[(2R) -2-[3-(cyclopentyloxy)-4-methoxy Phenyl]-2-phenylethyl-67- 201206888 base]-pyridine (CDP-840), 2-[4-[[[[2-( 1,3-benzodioxa-5-yloxy) ))-3-pyridyl]carbonyl]amino]methyl]-3-fluorophenoxy]-(2R)-propionic acid (CP-671305), N-( 4,6-dimethyl-2· Pyrimidinyl)-4-[4,5,6,7-tetrahydro-2-(4-methoxy-3-methylphenyl)-5- (4-methyl-1-piperidin Base)-1H-indol-1-yl]benzenesulfonamide (2E)-2-butenedioate (YM-393059), 9-[(2-fluorophenyl)methyl]-N- Benzyl-2-(trifluoromethyl)-9H-indole-6-amine (NCS-613), N-(2,5-dichloro-3-pyridyl)-8-methoxy-5-quinoline Formamide (D-4418), N-[(3R)-9-amino-3,4,6,7-tetrahydro-4-keto-1-phenylpyrrolo[3,2,1- ][1,4]benzodiazepin-3-yl]-3H-indol-6-amine (PD-168787), 3-[[3-(cyclopentyloxy)-4-methoxybenzene Methyl]-N.ethyl-8-(1-methylethyl)-3H-indole-6-amine hydrochloride (V-U294A), N-(3,5-dichloro-1- Oxy-4-pyridyl)-8-methoxy-2-(trifluoromethyl)-5-sormine formamide (Sch3 51591), 5-[3-(cyclopentyloxy)·4 ·Methoxyphenyl]-3-[(3-methylphenyl)methyl]-(3S,5S)-2-piperidone (^0712), 5-[2-[(1R,4R) 4-amino-1-(3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexyl]ethynyl]pyrimidin-2-amine, 6-[3-(dimethylamine A) Mercapto) phenylsulfonyl]-4-(3-methoxyphenylamino)-8-methylquinolin-3-carboxamide (GSK-2 5 6 06 6 ), cis-[4 -cyano-4 - (3-cyclopropylmethoxy-4- Fluoromethoxyphenyl)cyclo-1-ol], and 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl-1-(2- Methoxyethyl)-2(1H)pyridone (T-440), and any combination or subgroup thereof. The leukotriene antagonist and the leukotriene synthesis inhibitor include zafirlukast, montelukast sodium, zileuton 201206888 zileuton, and pranlukast.

Anticholinergic agents for formulation or use with a compound of the invention include, but are not limited to, muscarinic receptor antagonists, particularly antagonists comprising a pan-antagonist and an M3 receptor. Exemplary compounds include alkaloids of belladonna plants, such as atropine, scopolamine, homatropine, hyoscyamine, and various forms thereof, including salts (eg, anhydrous) Atropine, atropine sulphate, atropine oxide or HCl salt, methylatropine nitrate, homatropine hydrobromide, homatropine methyl bromide ' hyoscyamine hydrobromide, hydrazine; hyoscyamine sulphate, scopolamine hydrobromide, scopolamine methyl bromide, or any combination thereof or Subgroups of other anticholinergic agents for formulation and use with the compounds of the invention include, but are not limited to, methantheline, propantheline bromide 'anisotropine methyl' Bromide) or Valpin 50, acridinium bromide, glucose D (glycopyrrolate) (Robinul), Isoproamide iodide, mepenzolate bromide, tridihexethyl chloride, hexocyclium methylsulfate, cyclopentolate HC1 salt, tropine Indoleamine (-69-201206888 tropicadmide), trihexyphenidyl HC1 salt, pirenzepine, telenzepine, and methoctramine, or any combination or subgroup thereof. Preferred anticholinergic agents for formulation and use with the compounds of the invention include ipratropium (bromide), oxitropium (bromide) and tiotropium (bromo) Compound, or any combination or subgroup thereof.

Examples of ENaC receptor blockers for formulation and use with the compounds of the invention include, but are not limited to, amiloride and its derivatives, such as US Patent 6,858,615 to Parion Sciences, Inc, and PCT Publication W02003 /070 1 82 , W 0 2 0 0 4/0 7 3 6 2 9 , W02005/0 1 8644, W02006/02293 5, WO2007/0 1 8640, and the compounds disclosed in WO2007/146869.

Examples of kinase inhibitors include the following inhibitors: NFkB, PI3K (phosphatidylinositol 3-kinase) (CAL-263 (oral), Trial trove and Calistoga web site), p3 8-MAP kinase (SB-68 1 323) ( 口月艮): Singh et al., J Clin Pharmacol. 2 0 10 Jan; 5 0(1 ): 94-1 00 ) « Anti-infective agents for formulation and use with the compounds of the invention comprise antiviral agents And antibiotics. Examples of suitable antiviral agents include Tamiflu® and Relenza®. Examples of suitable antibiotics include, but are not limited to, aztreonam (arginine or lysine), fosfomycin, and aglycosides such as tobramycin, or any combination thereof or Subgroup. -70- 201206888 Antihistamines (i.e., Η 1 -receptor antagonists) for formulation and use with the compounds of the present invention include, but are not limited to: ethanolamines such as diphenhydramine HC1 salt 'carbimethamine (carbinoxamine) maleate, doxylamine, clemastine antibutmentate, and dimenhydrinate;

Ethylenediamines, such as pyrilamine, metpyramine, tripelennamine, HC1 salt, tripelennamine citrate, and antazoline (antazoline) ; hospital amines, such as pheniramine, chloropheniramine, bromopheniramine, dexchlorpheniramine, triprolidine, and Acrivastine; oral ratio, such as methapyri 1 ene; piperazines, such as hydroxyzine HC1 salt, hydroxyzine pamoate, race Cyclizine HC1 salt, cyclizine lactate, meclizine HC1 salt and cetirizine HCI salt: piperidines, such as astmisole, levamisole Levocabastine HC1 salt, loratadine, descarboethoxy loratadine, terfenadine, and fexofenadine HC1 salt -71 - 201206888 Tricyclic and tetracyclic classes, such as promethazine, chlorpromethazine, trimeprazine, and azatadine; and azelastine An HCl salt, or any combination or subgroup thereof. In the above methods of treatment and use, the compounds of the invention may be used alone or in combination with one or more other therapeutically active agents. In general, any therapeutically active agent having a therapeutic effect in a disease or condition treated with a compound of the invention may be used in combination with a compound of the invention, provided that the particular therapeutically active agent is compatible with the treatment using the compound of the invention. Typical therapeutically active agents suitable for use in combination with the compounds of the present invention comprise the agents described above. In a preferred system, a compound of the invention is used in combination with one or more anti-inflammatory agents, particularly PDE4i or an inhaled corticosteroid. In a preferred embodiment, the compounds of the invention are used in combination with one or more anticholinergic agents, particularly muscarinic (M3) receptor antagonists. In another aspect, the invention provides a method of treatment and use as described above, comprising administering an effective amount of a compound of the invention and at least one additional therapeutically active agent. The compounds of the invention may be used in conjunction with, or in combination with, at least one additional therapeutically active agent in any suitable therapeutic combination. Administration of a compound of the invention with one or more other therapeutically active agents can be administered concomitantly in the following forms: 1) a single pharmaceutical composition, such as the compositions described above, or 2) separate pharmaceutical compositions, each comprising a Or a variety of active ingredients as a component. The components of the composition can be administered separately separately, first by administering the present invention -72-201206888 and then administering the other therapeutically active agent, and vice versa. When a compound of the invention is used in combination with another therapeutically active agent, the dosage of each compound may differ from the dosage of the compound of the invention when used alone. Suitable dosages will be readily determined by those skilled in the art. In order to achieve the desired combination therapeutic effect, the appropriate dosage of the compound of the invention, other therapeutically active agents, and associated timing of administration will be selected and will be within the skill and judgment of the participating physician, clinician or veterinarian. Synthetic Methods The present invention also provides a process for the preparation of the compounds of the present invention and a process for the preparation of the synthetic intermediates used in the process, the details of which are set forth below. Some abbreviations and acronyms are used to describe the method of synthesis and experimental details. Although most of them are known to those skilled in the art, some of these abbreviations and acronyms are listed in the table below. Abbreviations Definition AIBN Azobisisobutyronitrile Bn Benzyl B 〇c Third butoxycarbonyl (Boc) 20 Dibutyl butyl dicarbonate BOP benzotriazole-1 yl-oxy·tris-(dimethyl Amino)-plutonium hexafluorophosphate Cbz benzyloxycarbonyl DCC N,N'-dicyclohexylcarbodiimide DCE Dichloroethane DCM Dichloromethane DIEA Ν, Ν-diisopropylethylamine DME Dimethoxy Ethylethane DMF dimethylformamide-73- 201206888 DMSO dimethyl sulphate Et Ethyl EtO Ac Ethyl acetate EtOH Ethanol E13 N and TEA Triethylamine ESI Electrospray free g g h h2 gas HATU 2- (1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate HPLC high performance liquid chromatography IBX 2-iodobenzoic acid iPrOH Propanol LAH lithium aluminum hydride M molar concentration mg mg Me methyl MeOH methanol m / z or m / e mass / charge ratio MH + mass plus one MH ' mass minus one MIC minimum inhibitory concentration min minutes m L ml mmol mm Ear MS or ms mass spectrometry MsCl methane sulfonium chloride Ms mesylate (or salt) N positive, linear NaBH(OAc)3 sodium triethoxy hydride hydride sodium NaCNBH3 Sodium cyanoborohydride NaN3 sodium azide NMP N-methyl-2-piperidone PDC dichromate pyridinium -74- 201206888

Pdr〇H)2/C Phenol oxidized platinum carbon Ph phenyl PMP 1,2,2,6 ,6 -pentamethylacridine PPhi - phenylphosphine PtO. uranium oxide Py Π ratio n pyridine or pyridine rt or rt Room temperature (also known as ring temperature) t-Bu • Z1 butyl TB AF fluorinated tetrabutyl TBS butyl dimethyl fluorenyl TBSC1 first-butyl dimethyl decyl chloride TFA trifluoroacetic acid THF Tetrahydrofuran TLC or tic thin layer chromatography δ Low magnetic field direction and ppm of tetramethyl sand courtyard In the following synthesis steps, in order to prepare some of the compounds of the present invention, it is necessary to place a protecting group at the reaction site of the intermediate. Those skilled in the art will readily be able to determine the advantageous conditions for the use of protecting groups, suitable protecting groups for use depending on the compound and reaction conditions, and methods for introducing and removing such protecting groups. Suitable protecting groups include TBS, Bn, and Boc. Conventional techniques for introducing and removing the protecting group are equally applicable to the reaction of the present invention. A common procedure for preparing one of the compounds of the present invention is shown in the following reaction schemes. Figure 1-75-201206888 Reaction Scheme 1

Wherein: R7 on compound 1 is H; -76- 201206888 Y is c(o) ' oc(o), or n(r7)c(o); PG is a suitable protecting group such as H or TBS; Other variables are as defined above. In general, a method of preparing a compound of the present invention comprises the steps of: a) performing a reductive alkylation reaction of Compound 3 or a salt thereof with Compound 6 or a salt thereof to prepare Compound 7 or a salt thereof; and b) optionally allowing Compound 7 or The salt is deprotected to prepare a compound of formula I or a salt thereof. Compound 1 (wherein R7 is Η) is coupled with an amine under standard conditions (e.g., HATU coupling, mixed anhydride, DCC coupling, etc.) to give the decylamine compound 2. Compound 1 has been disclosed in the literature, and the amine can be obtained commercially or by standard methods, including those described above. Compound 2 was oxidized under standard conditions (Dess-Martin, PDC, Swern) to give the corresponding carbonyl compound 3. Compound 4, which has been disclosed in the literature, is converted to compound 5 by treatment with NaN3 in a suitable solvent (e.g., D M F ) at elevated temperature (about 50 to about 120 ° C). Compound 5 can be reduced to the corresponding amine compound 6 under standard hydrogenation conditions (e.g., Pd/carbon at atmospheric pressure for 1 to 24 hours). Amine compound 6 is coupled with compound 3 under reductive alkylation conditions (e.g., NaCNBH3 or NaB Η(0 A c)3) in a suitable alcoholic solvent to provide the corresponding compound 7. Compound 7 is converted to the compound of the invention by removal of any protecting groups. The use of a third butyl dimethyl fluorenyl protecting group is generally deprotected in these cases using conventional techniques, such as deprotection with -77-201206888 TBAF. As will be appreciated by those skilled in the art, the above process can also be carried out as a salt of intermediate compound 1-7, or a compound of formula I can be prepared first, followed by conversion of the compound of formula I to the desired salt using conventional salt formation techniques. form. If a protected carbonyl group is available to form R3, the compound can be prepared according to the procedure shown in Figure 2.

Wherein: R7 on compound 1 is Η; Υ is c(o), oc(o), or n(r7)c(o); PG1 is a suitable carbonyl protecting group such as dioxane, acetal or condensate Ketones; and all other variables are as defined above. According to Reaction Scheme 2, Compound 1 (wherein R7 is H) is coupled with an amine under standard conditions (e.g., HATU coupling, mixed anhydride, DCC coupling, etc.) -78-201206888 to give the corresponding decylamine compound 8. Compound 8 was deprotected to give the corresponding carbonyl compound 3. Compound 8 can be deprotected using conventional deprotection techniques depending on the protecting group employed. In another system, the compound of the present invention can be prepared by displacement of the leaving group as shown in Figure 3 of the reaction. Reaction Figure 3

Where: PG is a suitable protecting group, such as hydrazine or TBS; -79- 201206888

The appropriateness of the G-based separation is that acetoic acid sulfonyl fluoride is as defined in the example three peaks ο ' S Μ Iο and all other variables are as defined above. In general, the process for preparing the compound of the present invention comprises the steps of: a) coupling of compound 9 or a salt thereof to compound 6 or a salt thereof to prepare compound 7 or a salt thereof: and b) optionally deprotecting compound 7 or a salt thereof, The compound of formula I or a salt thereof is prepared. More specifically, according to this system, the alcohol in compound 2 can be converted to a suitable leaving group under standard conditions to give compound 9. For example, the reaction of the alcohol in compound 2 to the mesylate can be carried out by treating compound 2 with MsCl and a suitable base (e.g., TEA or pyridine) in a suitable solvent (e.g., CH2C12) at ambient temperature. Alternatively, the conversion of the alcohol in compound 2 to bromide can be carried out under standard conditions (e.g., CBr4 and PPh3). Compound 9 is then coupled with compound 6 at a high temperature (e.g., from about 50 to about 150 ° C) in a suitable solvent (e.g., DMSO or DMF) with a suitable base (e.g., K2C03, DIEA or PMP) to afford compound 7. Compound 7 can then be deprotected as described above in Scheme 1 to yield a compound of formula I. In another system, the compound of formula I (wherein Y is C(0)N(R7)CH2) can be prepared from another intermediate compound 2' and 3' as shown in Reaction Scheme 4. -80- 201206888

Reaction Figure 4

Wherein: R7 on compound 1 is an alkyl group, R7 on compound 12 is a hydrazine or an alkyl group; Υ is c(o)n(r7)ch2; -81 - 201206888 LG is a suitable leaving group such as Br, Cl , I, O-Ms '0-triflate; and all other variables are as defined above. More specifically, according to this system, the ester in the compound 1 can be converted into an alcohol. For example, the conversion of the alcohol of Compound 10 to the mesylate can be carried out by treating Compound 10 with MsCl and pyridine at ambient temperature in a suitable solvent such as CH2C12. Alternatively, the conversion of the alcohol of compound 10 to bromide can be carried out under standard conditions (e.g., CBr4 and PPh3). Next, the compound 11 can be reacted with an amine R7NH2 (wherein R7 is a hydrazine or an alkyl group) to obtain a compound 12. Alternatively, compound 11 can be reacted with the azide at a temperature (e.g., from about 50 to about 150 ° C) in a suitable solvent (e.g., DMSO or DMF), and then with H2 and a suitable catalyst (e.g., Pd/). C) Reduction in a suitable alcohol solvent affords compound 12 wherein R7 is hydrazine. Compound 12 can then be reacted with a suitable acid or active acid in the same manner as described above for the conversion of compound 1 to compound 2 as shown in Figure 1, to give compound 2. In another system, intermediate compound 7 can be prepared in the reverse order of the amine by replacing the halide ion on the potential guanidine-agonist group, as shown in Figure 5. -82- 201206888 Reaction Picture 5

Wherein: PG is Η or TBS; pG2 is a suitable leaving group such as B〇c or Cbz; PG3 is hydrazine or benzyl; and all other variables are as defined above. Further, according to this system, the acid in Compound 1 can be coupled with a mono-protected diamine (commercially available or known) to prepare Compound 13. Suitable protecting groups include Boc or Cbz. The protecting group can be removed under standard conditions to give compound 14. Reaction of Compound 14 with Protected Bromide 4 at elevated temperature (e.g., about 50 to about 150 ° C) in a suitable solvent (e.g., -83 - 201206888 DMS 0 or DMF) affords compound 7 Protected variant, compound 7 ' in another system, a compound of formula I (wherein Y is C(0)N(R7) or N(R7)C(0)N(R7)) can be reacted according to the reaction Figure 6 converts the acid compound 1 to the corresponding aniline (compound 15) and further converts the aniline compound 15 to the desired intermediate compound 2 or intermediate compound 8. Reaction Figure 6

Wherein: R7 on compound 1 is H; Y is C(0)NH or N(R7)C(0)NH; and all other variables are as defined above.

More specifically, according to this system, the acid in the compound 1 (wherein R7 is H) can be converted into the corresponding amine compound 15. For example, the conversion reaction can be carried out at a high temperature (eg, 4 〇.c to reflux temperature) in a suitable solvent (eg, third butanol) with diphenylphosphonium arsenide, a suitable base (eg, TEA or DIEA 201206888). Acid 1 was treated to give a third butyl carbamate. Deprotection under standard conditions (e.g., TFA in DCM or HCl in MeOH at -20 °C to room temperature) affords compound 15. Compound 15 can then be reacted with a suitable acid or a reactive acid species as in the reaction of compound 12 of Figure 4 to give compound 2 or 8 above (wherein γ is CONH). Alternatively, the aniline compound 15 is coupled with a phosgene equivalent (eg, carbonyldiimidazole or 4-nitrophenyl chloroformate) at a low temperature (-78 ° C to 〇〇c) to obtain an activated species, which can then be combined with The appropriately substituted amine is reacted at a higher temperature (room temperature to °C) to give compound 2 or 8 (wherein Y is N(R7)C(0)NH). Those skilled in the art will appreciate that 'substituted aniline of compound 15 can also be used to prepare compound 2 or 8 ' and finally obtain a compound of formula 1 (where Y is C(0)N(R7) or N(R7) C(0)N(R7) and R7 is not Η)0 In another system, 'intermediate compound 18 can be prepared by adding a thiol to compound 16 and subsequently performing an oxidation reaction, as shown in Figure 7 .

Reaction Figure 7

Νη2 where: • 85· 18 201206888 R5 on compound 16 is CH3 and R6 is OCH3; and all other variables are as defined above. According to Reaction Scheme 7, compound 16 is coupled with an alkyl mercaptan in the presence of a palladium catalyst to give the corresponding thioether compound 17. The oxidation reaction of Oxone gives the corresponding oxime, which is then oxidized under standard conditions (Dess-Martin, PDC, S w e r η ) to give the corresponding carbonyl compound 18. The order of the above steps of the reaction is not critical to the practice of the invention, and these steps can be carried out according to any suitable order of the person skilled in the art to provide a compound of formula I. The above detailed description is to be understood by the following examples, which are not intended to limit the scope of the invention. The invention is defined only by the scope of the claims below. In the following examples, the compounds were appropriately named in accordance with the IUPAC standard nomenclature. The naming convention for novel compounds is exemplified by the following examples. [Embodiment] Intermediate 1: (R) -5-[2-azido-1-[(t-butyldimethylmethyl)oxy]ethyl]-8-(benzyloxy)quina Porphyrin-2(1Η)-one

Add NaN3 (266 mg, 4.1 mmol) to (R)-8-(benzyloxy)-5-[2-bromo-1-[(t-butyl dimethyl) at room temperature A solution of decyl)oxy]ethyl]quinolin-2 (1H)-one (1 g, 2.05 mmol) in DMF (20 mL) and warmed to 80 ° C for 3 hours

At the time of 201206888. The resulting solution was poured into H20 (EtOAc) (EtOAc)EtOAc. The combined organic layers were washed with H20 (2×1 00 mL) water (100 mL), dried over Na2S04 (s), and concentrated to afford compound (1.37 g) as a yellow solid. The compound was used directly without step-wise purification. ES/MS Theory 値 (C24H31N403Si+) : 451. Test: w/z = 45 1 ·3(Μ + Η)+. Intermediate 2: (R) -5-[2-Amino-1-[(t-butyldimethyl-oxy)ethyl]-8-hydroxyquinoline-2 (1Η)-one intermediate 1 ( 1.37g ) dissolved in MeOH ( 20 mL )

Pd(OH)2/C (20% w/w, 28 8 mg, 0.41 mmol). The foam was passed through the solution for 5 minutes. The resulting suspension was attached to a balloon and stirred overnight. The reaction mixture was filtered and concentrated with EtOAc EtOAc EtOAc. Chromatography (9:1'</RTI>> ES/MS Theory 値 (C"H27N203Si+ ) : 3 3 5. Test: w/2 = 3 3 5.2 (M + H)+. Intermediate 3: (R) -8-(benzyloxy)-5-(1-((Third);

Base oxime)oxy)-2-(methylamino)ethyl)quinoline-2 (1H (3 X and salt headings, solid) Adding TfNN h2 to brown 0.1% is light 2, real Dimethyl-ketone

-87- 201206888 (R) -8-(Hydroxyl)-5- (2-di-1,3-(t-butyldimethylmethyl decyloxy)ethyl) porphyrin-2(1H)-one (1.5 g, 3.1 mmol) The solution formed in methylamine/tetrahydrofuran (2.0 mL, 16 mL, 32 mmol) was taken to 100 in a sealed tube. C (oil bath) was heated for 3 days. The mixture was allowed to cool to room temperature, concentrated, and purified by flash chromatography (methylene chloride / methanol / ammonium hydroxide) using a 25 g Silicycle SiliSep flash column. The desired fraction is concentrated under reduced pressure to give the title compound. ES/MS theory 値(C25H35N203Si+ ) : 439·2 , experimental 値: w/z = 43 9.3(M + H)+. Intermediate 4: (R) -5-(1-((t-butyldimethylmethyl)oxy)-2-(methylamino)ethyl)-8-hydroxyquinoline·2 (1Η )-ketone

Intermediate 3 was dissolved in MeOH (25 mL) and Pd/C (10% w/w, 100 mg). The resulting suspension was attached to a balloon filled with H2 and stirred for 7 hours. The reaction mixture was filtered with EtOAc EtOAc (EtOAc) ES/MS theory 値 ( Ci8H29N2〇3Si+) : 349.2, experimental 値: m/z = 349·2(Μ + Η)+ 0 Intermediate 5: (R) -5-(2-azido-1-hydroxyl Ethyl)-8-(benzyloxy)quinoline-2 ( 1Η )-ketone-88- 201206888

A solution of TBAF in 1 M (THF) (0.443 mL, 0.443 mmol) was added to a solution of Intermediate 1 (200 mg, 0.443 mmol) in THF (4 mL) . The resulting mixture was stirred overnight and then concentrated. Chromatography (1:3, hexanes / EtOAc (EtOAc): EtOAc (EtOAc: EtOAc: EtOAc 3 7·2(Μ + Η)+. Intermediate 6 : ( R ) - 5 - ( 2 -amino-1-hydroxyethyl)-8 -hydroxyquinoline-2 (1Η)-one

The title compound was synthesized according to a method similar to that described in Intermediate 2, using Intermediate 5 as a substrate. ES/MS theory 値 (C11H13N2O3): 221.1, experimental 値: = 221.2 (Μ + Η)+. Intermediate 7: (R)-1-[4-(Benzyloxy)-3-[[(t-butyldimethylmethyl)oxy]methyl]-phenyl]-2 -bromoethanol

Add TBSC1 (5 g, 33.2 mmol) and imidazole (3.7 g' 55·4 mmol) to the stirred solution at room temperature from (R) _丨_[4-(benzyloxy)- -89- 201206888 3-(Hydroxymethyl)phenyl]-2-bromoethanol (10 g, 27.7 mmol) in CH2C12 (200 mL). The resulting suspension was stirred for 1 hour, then H20 (200 mL) was added to quench. The aqueous layer was extracted with CH2C12 (3×100 mL). The combined organic layer was washed with EtOAc EtOAc EtOAcjjjjjj This compound was used directly without further purification. ES/MS theory 値 (C22H31BrNa03Si+): 473.1, experiment 値: = 473.1 (M+Na) +. Intermediate 8: (R)-2-azido-1-[4.(benzyloxy)-3-[[(t-butyldimethylmethyl)oxy]-methyl]phenyl] Ethanol

The title compound was substituted for (R)-8-(benzyloxy)-5-(2-bromo-1-((t-butyldimethyl hydrazide) using Intermediate 7 according to a procedure similar to that described for Intermediate 1 Synthesized from oxy)ethyl)quinolin-2 (1Η)-one. ES/MS Theory 値 (C22H3iN3Na03Si+): 436.2, Experimental 値: w/z = 436.2 (M + Na) +. Intermediate 9: (R)-4-(2-Amino-1-hydroxyethyl)-2·[[(t-butyldimethylmethyl)oxy]methyl]phenol

The title compound was synthesized according to a method similar to that described in Intermediate 2, using 201206888 Intermediate 8 as a substrate. ES/MS theory 値 (Cl5H27NNa03Si+) : 3 2 0 · 2, experimental 値: /η/z = 3 2 0 · 2 ( M + N a )+ ° Intermediate 10 : ( R) -N-[2-( Benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl]carboxamide

(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.2 g, 5.7 mmol) in THF: toluene (1:1, 5 mL) 1% w/w) was reacted on a Parr shaker at 45 psi and at room temperature overnight. Pt02 was removed by filtration through celite the next morning. The filtered solution was cooled to 〇 ° C, and a solution of acetic anhydride (0.161 mL, 0.569 mmol) and formic acid (0·043 mL' 1.140 mmol) was added dropwise to the stirred solution. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hr. The reaction mixture was concentrated to near dryness and water was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHC03 and brine, dried over Na.sub.2SO (s) and concentrated. Chromatography (1:1 hexanes /EtOAc) E S /M S theory 値 (C16H17BrN03+) : 350.0, experimental 値: w/z = 350(M + H)+. Intermediate 1 1 : ( R) -Ν-[5·(2-azido-1-hydroxyethyl)-2-(benzyloxy)phenyl]carboxamide -91 - 201206888

The title compound of Bn was synthesized by a method similar to that described for Intermediate 1, using Intermediate 10 as a substrate. ES/MS theory C (C16H17N403+): 313.1 ′ Experimental 値: w/z = 313(M + H)+. Intermediate 12: (R)-N-[5-[2-azido-1-[(t-butyl dimethyl)

Mercapto)oxy]ethyl]-2·(benzyloxy)phenyl]carboxamide

, 〇-TBS

I

The title compound of Bn was synthesized according to a method similar to that described in Intermediate 7, using the intermediate 1 1 in place of (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. . ES/MS theory 値 (C22H31N4 〇 3Si+): 427.2' Experimental 値: w/z = 427 (M + H)+.

Intermediate 13: (R)-N-[5-[2-Amino-1-[(t-butyldimethylmethyl)oxy]ethyl]-2-hydroxyphenyl]carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 2, using Intermediate 12 instead of Intermediate 1. ES/MS theory値

Ci5H27N203 Si+) : 311.2, experimental enthalpy: m/z = 311 (M + H) + • 92- 201206888 Intermediate 14: (R) -l-[3-amino-4-(benzyloxy)phenyl] ·2_Bromoethanol

(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.200 g, 0.569 mmol) in 1:1 THF: toluene (5 mL). % w/w) was reacted overnight at 45 psi and at room temperature on a Parr shaker. Pt〇2 was removed by filtration through celite the next morning. The product was concentrated to give the title compound. ES/MS theory 値 (C15H17BrN〇2+): 322.0, experimental 値: m/z = 322 (M + H)+. Intermediate 15: (R) -1-(3-amino-4-((oxy)phenyl)-2-azideethanol

The title compound was substituted for (R)-8-(benzyloxy)-5-[2-bromo-1-[(t-butyldimethyl hydrazide) using intermediate 14 according to a procedure similar to that described for Intermediate 1. Synthesized from oxy]ethyl]quinolin-2 (1H)-one. ES/MS theory 値 (C15H17N402+: M: 285.1 'Experiment 値: = 28 5 (M + H)+. Intermediate 16: (R) -8-(benzyloxy)-5-[2-bromo-1- [(Tertiary butyldimethylmethyl)oxy]ethyl]quinoline-2 (1H)-one-93- 201206888

The title compound was synthesized according to a method similar to that described in Intermediate 7 using the intermediate 15 instead of (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. ES/MS theory 値 (C21H31N402Si+): 399.2, experimental 値: w/z = 399 (M + H)+. Intermediate 17: (R)-N-[5-[2-azido-1-[(t-butyldimethylmethyl)oxy]ethyl]-2-(benzyloxy)phenyl Methionamide

Ο I Bn at 0 °C > Adding chlorinated chlorine (〇_〇44 mL, 0.569 mmol) to a stirred mixture of intermediate 16 (275 mg, 0.569 mmol) in pyridine (10 mL) In the solution. The resulting mixture was warmed to room temperature and the reaction was monitored by LC/MS. After 1 hour, an additional 1 part of methanesulfonyl chloride was added, followed by one hour and then 〇 5 equivalents to make a total of 2.5 eq. After another hour, water (50 m L) was added and stirred at room temperature for 2 hours. The aqueous layer was extracted with C Η 2 C12 ( 4 X 2 5 m L ). The combined organic layers were washed with saturated NaHC EtOAc (br.) and brine and dried and evaporated. Chromatography (1:1 hexanes /EtOAc) ES/MS Theory 値 (C22H33N404 SSi+): 477.2, Experimental 値: /n/z = 477(M + H) + 201206888 Intermediate 1 8 : ( R ) -Ν·[5-[2-Amino-1 _ [(yl)oxy]ethyl]-2-hydroxyphenyl]methanesulfonamide

.TBS 0 〇 it Η

—S-N

II Ο

The HO title compound was synthesized by substituting the intermediate 1 with the intermediate 17 of the intermediate 2. No further purification is required. ES/MS theory 値 (C φ 36 1 .2 'Experiment 値: w/z = 361(M + H)+. Intermediate 19 : ((6-bromohexyl)oxy) ( 矽 将 嗤 (1.1 g , 16.56 mmol) and 9.1 mmol, added to a stirred solution of 6-bromohexanol in CH2C12 (80 mL) overnight, followed by H20 (1 mL) to give CH2Cl2 ( 3 X 50 mL) extraction. The combined ones were dried with Na; 2S 〇 4, and concentrated to give the title compound. This compound can be used directly without the need for an intermediate 20: (6-hydroxyhexyl) aminocarbamic acid third butyl dimethyl hydrazine

A similar method, using this compound directly using 15H29N204SSi+): tert-butyl) dimethyl TBS-C1 ( 1.37 g, (1.5 g, 8, 28 mmol 1. Mix of mixing: reaction quenching. The layers were washed with brine (2.6 g) and purified for EtOAc. EtOAc: <RTI ID=0.0>&&&&&&&&&&&&&&& 2.348 mmol) and K2C03 (0.5 90 g - 4.27 mmol) were mixed with 1:1 EtOAc (EtOAc) (EtOAc (EtOAc). The mixture was washed with EtOAc (3 mL) (EtOAc) (M + H) + Intermediate 2 1 : 6 · (Methylamino) hexan-1 -ol 中间 An intermediate 20 (2.14 mmol) was added to a stirred solution containing 95% LAH at 〇 °C ( 0.426 g, 10.68 mmol) in 10 mL of anhydrous THF. This mixture was then heated to 80 ° C and heated at reflux for 3 hours. After 3 hours, the reaction mixture Cool to 〇 ° C, add water ( 0.426 mL) ' 20% (w / v) NaOH ( 0.426 mL) ' and water (1-215 mL) in sequence. Stir at room temperature for 15 minutes, then add MgS04, and After stirring for 30 minutes, the mixture was filtered with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj + H) + Intermediate 22: 1-Benzyl-4-((6-((t-butyldimethylmethyl)oxy)hexyl)oxy)piperidine-96- 201206888 at 0 °C Add NaH solid (60% w/w in mineral oil, 352 mg, 4.6 mmol) to a stirred solution of 1-benzyl-4-hydroxypiperidine (841 mg, 4.4 mmol) in DMF (50 The resulting solution was stirred for 5 minutes, then the intermediate 19 (2.6 g, 8.8 mmol) was added. The mixture was warmed to room temperature and then warmed overnight at 70 ° C. It was then poured into Η 2 0 (1 0 0 | mL) and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with EtOAc (EtOAc)EtOAc. Chromatography (1:3, EtOAc /EtOAc) ES/MS theory 値 (C24H44N02Si+): 406.3, experimental 値: /η/ζ = 406.3 (M + H)+. Intermediate 23: 4-((6-((Tertiary butyldimethylmethyl)oxy)hexyl)oxy)piperidine

Intermediate 22 (157 mg, 0.387 mmol) was dissolved in MeOH (5 mL) followed by 10% (w/w) Pd/C (41 mg, 0.0387 mmol). The reaction vessel is connected to a 3-way valve that is connected to a balloon filled with hydrogen. The vessel removes the gas 3 times and then returns to the hydrogen. The resulting suspension was stirred with EtOAc EtOAc m. This compound was used without further purification. ES/MS theory 値 (Ci7H38N〇2Si+) : 316.3, experimental 値: m/z = 316·3(Μ + Η) + 201206888 Intermediate 24: 4-(6-((T-butyl dimethyl fluorenyl) )oxy)hexyl)piperazine-1 -carboxylic acid benzyl ester wide tTCbz Intermediate 19 (2.6 g' 8.8 mmol) was added to the stirred column

Benzene-1_ benzyl formate (1·1 mL' 5.87 mmol) in CH3CN (80 mL). The reaction mixture was heated under reflux overnight, cooled and then sat NaHCI (EtOAc) The aqueous layer was extracted with EtOAc (3 EtOAc)EtOAc. The title compound (1.78 g, 70%) ES/MS theory 値 (C24H43N203 Si + ): 435.3, experimental 値: m/z = 435.2 (M + H)+.

Intermediate 25: 1-(6-((t-butyldimethylmethyl)oxy)hexyl)piperazine

The broad fjlH title compound was synthesized according to a method similar to that described for Intermediate 23 using Intermediate 24 as a substrate. ES/MS theory C (C16H37N2OSi+): 301.3, experimental 値: w/z = 301·3 (Μ + Η)+. Intermediate 26: 6-(butyl-3-(3-acetyl-1-yloxy)hexyl acetate -98- 201206888

1-Bromo-6-(but-3-ynyloxy)hexyl (1.5 g, 6.4 mmol, according to Procopiou, P. et al., J Med Chem 2009 52 (8), 22 80-22 8 8 Preparation) A solution was formed in DMF (25 mL) and treated with tetra-n-butyl ammonium acetate (2.9 g, 9.7 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was partitioned between water and diethyl ether. The aqueous layer was extracted three times with diethyl ether. The combined extracts were washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated Intermediate 27: tert-butyl 4-aminophenylethylaminocarbamate

Di-tert-butyl dicarbonate (1.60 g, 7.34 mmol) was added to 2-(4-aminophenyl)ethylamine (1·0 g, 7.34 mmol) in EtOAc (20 mL) In the solution formed. After stirring for 18 hours, the reaction mixture was washed with EtOAc EtOAc EtOAc EtOAc (EtOAc) > 2H ) > 6.77 ( br t > J = 5.4 Hz > 1 H ), 6.46-6.49 ( m > 2H ) ' 4.83 ( s, 2H) > 2.99-3.0 5 ( m · 2H) ' 2.47-2.51 ( m ' 2H) ' 1.37 ( s ' 9H). ES/MS theory 値 (C13H20N2NaO2): 259.1, experimental 値·· w/z 25 9.1 ( M + N a ) +. 99· 201206888 Intermediate 28: 4-(2-(methylamino)ethoxy)phenethylaminocarbamic acid tert-butyl ester

Add 2-(methylamino)ethanol to a solution of N-Boc-p-phenylphenethylamine (750 mg, 3.16 mmol) and triphenylphosphine ( 1.655 g, 6.308 mmol) in THF (30 mL) (0.3 8 mL » 4.75 mmol) followed by DIAD (1.25 mL, 6.31 mmol). After stirring at room temperature for 7 2 /j, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc (C丨6H27N203+): 295.2, experimental 値: m/z = 295.2 (M + H)+. Intermediate 29: 4-( 4'-Amino-[1,1'-biphenyl]-4-yl)butyric acid methyl ester

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (158 mg, 0.723 mmol) solid and Pd at room temperature (PPh3) 4 (38 mg, 0.033 mmol) was added to methyl 4-(4-iodophenyl)butanoate (200 mg, 0.657 mmol) in dimethoxyethane / 2M Na2C03 (3 mL, 2: 1) In the solution formed. The resulting mixture was degassed with argon, followed by heating at 110 ° C for 30 minutes using a microwave. The reaction mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) (EtOAc)EtOAc. Things. Chromatography (9:1, CH2Cl2 /MeOH) ES/MS theory 値 (Ci7H2〇N〇2+) ·· 270.2, experiment 値: m/z = 270.2 (M + H)+. Intermediate 30: 4-( 3'-Amino-[1,1-biphenyl]-4-yl)butyric acid methyl vinegar

The title compound was substituted with 4-(4,4,5,5-tetramethyl-1,3,2. dioxonium) according to a method similar to that described for Intermediate 29. Synthesized by heterocyclic pentan-2-yl) phenylamine. ES/MS theory Ci ( Ci7H2 〇 N 〇 2+ ) : 270.2, experimental 値: ί / ζ = 270 · 2 (Μ + Η) +.

Intermediate 31 : 5-(4-Aminophenyl)pent-4-yn-1-ol, νη2

-101 - 1 -iodoaniline (10 g, 45 mmol), /carbon (2·86 g, 1.35 mmol* 5% w/w), PPh3 (1.4 g, 5.4 mmol), Cul ( 5 13

Mg, 2.7 mmol), and Κ2〇03 (15 g, 5.4 mmol) were added to DME (50 mL) and H20 (50 mL). Nitrogen gas bubbles were bubbled through the solution by vigorous agitation to degas the mixture. Pent-4-yn-1-ol (10.5 mL' 114 mmol) was added in a syringe. The mixture is at 85. (: heating down. After cooling, water (1 mL) and EtOAc (200 mL) were added.

Extracted with EtOAc. The organic layer and the aqueous layer were neutralized with IN HC1, respectively. The aqueous layer was extracted with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (6 g, 76%). 1H NMR (400 MHz, CDC13) δ 7.19 ( dd > 2 Η > J = 8.9 > 1.5 Hz ) > 6.58 ( dd > 2H > J = 8.9 > 1.5 Hz ) > 3.85 (t > 2H · J = 8.0 Hz) , 3.75 ( brs > 2H ) , 2.55 (t, 2H > 7 = 8.0 Hz ) * 1 .86 ( m > 2H ) ; ES/MS theory 値 (

CiiHi4N0+): 176.1, experimental 値: m/z = 176.1 (M + H)+. Intermediate 32: 2,2,2-Trifluoro-N-(4-iodophenyl)acetamidine, jaVCF3 4 -iodoaniline (0.250 g, 1.147 mmol) was cooled to 〇°c in 5 mL anhydrous THF. TFA anhydride (2.294 mmol, 0.482 g, 0.319 mL) was then added dropwise over 5 minutes. The mixture was allowed to react at 〇 〇 C for 15 minutes, then warmed to room temperature and the reaction was continued for 40 minutes. The reaction mixture was purified by concentration of solvent and TFA. Then placed under high vacuum for the night. ES/MS theory 値 (C8H5F3INO): 314.9, experiment 値: m/z = 3 1 6 (M + H)+. Intermediate 33: 2,2,2-trifluoro-N-(4-iodophenyl)-N-methylacetamide

-102- 201206888 Intermediate 32 (1.0 g, 3.175 mmol) in 20 mL of acetone with CH3I (6.3 5 0 mmol, 0.9 0 1 g, 0 · 3 9 5 mL) and K2 C Ο 3 (

6.350 mmol' 0.876 g) was mixed and then heated under reflux at 80 °C for 2 hours. The purification of the reaction mixture consisted of the addition of 1x sat. NaHC.sub.3 to EtOAc (EtOAc). The product was used directly in the next step without purification. ES/MS Theory 値 (C9H7F3INO): 328.95, Experimental 値: w/2 = 3 3 0 (M + H)+. Intermediate 34: 2,2,2-trifluoro-indole (4-iodo-2-methylphenyl)acetamide

The title compound was synthesized according to a method similar to that described in Intermediate 3 2 using 4-iodo-2-methylaniline as a substrate. ES/MS theory 値 (C9H7F3INO): 3 28.95, experimental 値: w/z = 3 30 (μ + Η)+. Intermediate 35: 2,2,2-Trifluoro-indole-(4-iodo-3-methylphenyl)acetamidamine YF3 The title compound was used according to a procedure similar to that described for Intermediate 3, using 4- Iodo-3-methylaniline was synthesized as a substrate. ES/MS theory 値(C9H7F3INO): 328.95, experimental 値·· w/z = 330(M + H)+. Intermediate 36: 2,2,2-trifluoro-N-(4-(5-hydroxypenta-butyn-1-yl)benzene-103- 201206888 base)-N-methylacetamide

Intermediate 33 (0.377 g, 1.147 mmol) was mixed with PdCl2(PPh3)2 (0.02294 mmol»0.016 g) in 10 mL TEA, then the mixture was degassed with N2 for 5 min. Then Cul (0.01147 mmol, 0.002 g) and pent-4-yn-1-ol (1.147 mmol, 0.115 g) were added, followed by a reaction at 50 ° C for 4 hours. The purification of the reaction mixture was carried out by adding 1x saturated NaHC03 to the reaction mixture, which was taken to elute with 4×25 ml of EtOAc, and then washed with 1× water and 1× saturated NaCl, dried over Na 2 SO 4 and then concentrated. The product was purified by chromatography on EtOAc (EtOAc)EtOAc ES/MS theory 値 ( Ci4HmF3N02) : 285.1, experimental 値: w/z = 286(M + H)+ » Intermediate 37: 2, 2, 2-trifluoro-heart (4-(5-hydroxypenta-1) -alkyn-1-yl)-2-methylphenyl)acetamide

The title compound was synthesized by substituting the intermediate 34 for the intermediate 3 in a similar manner to that described for the intermediate 36. E S / M S theory C ( CMH14F3N02) : 285.1, experimental 値: m / z = 286 (Μ + Η) +. Intermediate 38: 2,2,2-Trifluoro A-( 4_( 5_hydroxypenta-1_yne·1_yl)-3-methylphenyl)acetamidamine -104 - 201206888

The title compound was synthesized by substituting the intermediate 35 for the intermediate 33 according to a method similar to that described for the intermediate 36. ES/MS theory 値 (C14H14F3N02): 285.1, experimental 値: = 28 6 (M + H)+. Intermediate 39: 2,2,2-Trifluoro-N-(4-(6-hydroxyhex-1-yn-1-yl)benzene φ-yl)acetamide

Intermediate 32 (2.7 g, 8.5 mmol, prepared according to Melissaris, AP and Litt, Μ.H., J 〇rg Chem 1 994, 59, 5 8 1 8-5 82 1 ) in DMF (26 mL) The solution was treated sequentially with tetra-n-butylammonium acetate (3.8 g, 13 mmol) and yttrium (II) acetate (57 mg, 0.26 mmol). The mixture was degassed with nitrogen then treated with 5-hexyn-1-ol (0.93 mL, 8.5 mmol). After stirring at room temperature for 4 hours, the following reagents were further added: tetra-n-butylammonium acetate (1 g), palladium (II) acetate (57 mg), and 5-hexyn-1-ol (1 mL). After stirring at room temperature overnight, the mixture was partitioned between diethyl ether and water. The aqueous layer was extracted 4 times with diethyl ether. The combined organic extracts were washed twice with water and aq. EtOAc EtOAc EtOAc EtOAc Partially cured. ES/MS theory 値 (Ci4Hi5F3N〇2+ ) : 286.1 , experimental 値: w/z = 286.2(M + H)+ » -105- 201206888 Intermediate 40 : N- ( 4 · ( 5-bromopenta-1- Alkyn-1-yl)phenyl)-2,2,2-trifluoroacetamide

N-(4-(5-chloropent-1-ynyl)phenyl)-2,2,2-trifluoroacetamide (10 mmol, using 5-chloropentyne in a similar manner to Intermediate 39 The solution of 3-pentyn-1-ol was prepared by treatment with 3-pentanone (200 mL) with lithium bromide (1 〇eq, 100 mm ο 1 ). The mixture was heated under reflux for 16 hours and then concentrated to dryness under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The concentrated organic layer was again taken up in 3-pentanone (200 mL) and EtOAc (EtOAc) The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The crude product was purified by automated flash gel chromatography using 40 g s i i i i y c 1 e S i 1 i S e ρ flash column (hexane/ethyl acetate). The desired fraction was concentrated under reduced pressure to give the title compound as pale white solid. ES/MS theory 値 (C13H12BrF3NO+): 3 34 ·0, experimental 値: zw/z = 3 3 4 · 1 (M + Η) +. Intermediate 41 : 1-( 5 -Chloropent-1-on-1-yl)-4 -nitrobenzene

4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine) -106- 201206888 pin (II) (〇·30 g, 〇_43 mmol) and copper iodide (I) (0.18 A mixture of tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under argon for 10 min. The mixture was then heated to 55 ° C and treated with 5-chloropentyne (12 mL, 1 10 mmol) via a syringe. After stirring for 30 minutes, another portion of dichlorobis(triphenylphosphine)palladium(Π)(〇·1〇g) and 5-chloropentyne (1 mL) were added. After stirring for an additional 30 minutes, the mixture was allowed to cool to room temperature then filtered over Celite. The filtrate was concentrated to dryness under reduced pressure to give 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was used in the next step without further purification. ES/MS theory CH (CHHHC1N02+): 224.1, experimental 値: w/z = 224.2 (M+H)+. Intermediate 42: 1-(5-bromopent-1-yne-i-yl)-4-nitrobenzene

The title compound was synthesized by a method similar to that described for the intermediate 40, using φ as the substrate. ES/MS theory 値 ( : 268.0, experimental 値: w/z = 268.1 (M + H) +. Intermediate 43 : 1-( 4-aminophenyl)-5-bromopentan-1-one

A mixture of intermediate 42 (200 mmol) was dissolved in a mixture of methylpyrrolidine/dichloromethane (1:1,800 mL) and treated with tin(II) chloride dihydrate (218 g, 960 mmol) 30 g each time). The exothermic -107-201206888 reaction mixture was cooled in an ice-water bath. After the tin chloride addition was completed, the cooling bath was removed and the mixture was returned to room temperature. After stirring for 45 minutes, the mixture was added portionwise to a mixture of ice and concentrated ammonium hydroxide solution to quench the reaction. The slurry was filtered through a fritted glass funnel and rinsed with dichloromethane. The filtrate was concentrated under reduced pressure and diluted with diethyl ether. The organic layer was washed with water 4 times, and then washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was quickly precipitated in ethyl acetate. The solid was collected by filtration on a EtOAc EtOAc (EtOAc)EtOAc. Another portion of the title compound was then collected from the concentrated ethyl acetate filtrate. ES/MS theory 値 (CiiHisBrNO) · 258.0, experimental 値: /^/ζ = 258·1(Μ + Η)+. Intermediate 44: Ν-(4-(5-bromopentenyl)phenyl)-2,2,2-trifluoroacetamide

The title compound was synthesized by a method similar to that described for Intermediate 3, using Intermediate 43 as a substrate. eS/MS theory 値 ( Ci3Hi4BrF3N02+) : 3 52.0, experimental 値: w/z = 3 52·1 (Μ + Η) + intermediate 45: Ν-(4-(2-(4-bromobutyl))丨,3_dithiolane-?-yl)phenyl)-2,2,2-trifluoroacetamide-108- 201206888

丨, 2-ethanedithiol (1·〇mL, 12 mmol) and boron trifluoride diethyl etherate (2.0 mL, l6 mm〇i) were added to the intermediate 44 (2 9 g, 8.2 mmol) In a solution of dichloromethane (3 〇 mL). After stirring at room temperature for 1 hour, the mixture was poured into an aqueous sodium hydrogencarbonate solution. The resulting aqueous layer was extracted with EtOAc (EtOAc) EtOAc. ES/MS theory Ci ( Ci5Hi8BrF3NOS2+) : 428.0 ' Experimental 値: m/z = 428·1(Μ + Η) + ο Intermediate 46: 5-(3-nitrophenyl)pent-4-yn-1- alcohol

The title compound was synthesized according to a method similar to that described for Intermediate 39, using 3 - moth nitrobenzene as the substrate to obtain the β ε S / MS theory 値 (C"Hi2N03+): 206.1, experimental 値: w/z = 206.2 (Μ + Η) + 〇 intermediate 47 : 5-( 3-aminophenyl)pent-4-yn-1-ol

The solution of intermediate 46 (16 mmol) in ethanol (80 mL) was then taken up in 10% aqueous hydrochloric acid (4 mL) and iron powder, and then placed in an oil bath of -109-201206888 95 °C. After heating under reflux for 90 minutes, the mixture was subjected to LC/MS analysis to confirm that the reaction was completed, and the mixture was subjected to hot filtration with a Celite celite pad and eluted with methanol. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by automated flash chromatography using a 40 g sili. The desired fraction was concentrated under reduced pressure to give the title compound: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Intermediate 48: 6-(4-Aminophenyl)hex-5-block-1-ol

Add a solution of intermediate 39 (8.5 mmol) in IPA (20 mL) to a solution of potassium hydroxide (1.4 g, 26 mmol) in IPA (150 mL) at 1 °C. It was then heated under reflux for 3.5 hours and then concentrated to dryness under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted three times with dichloromethane. The combined extracts were concentrated to dryness under reduced pressure and the residue obtained was purified by rapid flash chromatography, using 25 g s s s S S S S S S The desired fraction was concentrated under reduced pressure to give the title compound as pale yellow oil. ES/MS theory 値 (C12H16NO+): 190.1, experimental 値: m/z = 1 90.2 (M + H)+. Intermediate 49 : 5-(4-(Methylamino)phenyl)pent-4-yn-1-ol -110- 201206888

The intermediate 3 6 (0.22 1 g, 0.7752 mmol) was reacted with K2C03 (0-77 52 mmol &lt;RTIgt; The reaction mixture was subjected to purification: EtOAc (EtOAc m.) The product was purified by eluting with EtOAc (EtOAc)EtOAc. ES/MS theory 値 (C 1 2 Η 15 Ν Ο ) : 189.1, experimental 値: w / 2t = 190 (M + H) +. Intermediate 50: 5-(4-Amino-3-methylphenyl)pent-4-yn-1-ol

The title compound was synthesized according to a method similar to that described for Intermediate 49, using Intermediate 37 as a substrate. ES/MS theory 値 (C 12H 15 NO ) : 189.1. Experimental 値: m/z = 190 (M + H) +. Intermediate 51 : 5-(4-Amino-2-methylphenyl)pent-4-yn-1-ol

The title compound was synthesized according to a method similar to that described for Intermediate 49, using Intermediate 38 as a substrate. ES/MS theory C (C12H15NO): 1 89.1, experimental 値: w/z = 190 (M + H)+. -111 - 201206888 Intermediate 52: 1-(4-((6-Bromohexyl)oxy)butyl)-4-nitrobenzene 4-(4-nitrophenyl)butan-1-ol (2.0 g a mixture of 10 mmol), tetra-n-butyl sulphate (〇_丨7 g, 0.5 mmol), and 1,6-dibromohexanin (3.2 mL, 20 mmol) in dichloromethane (10 mL) Treatment with aqueous sodium hydroxide (10 M '1 m L) with stirring. The reaction mixture was stirred at room temperature for 6 days. The organic layer and the aqueous layer are separated. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by automated flash gel chromatography using a 40 g Silicycle SiliSep flash column (hexane/ethyl acetate). The desired fraction was concentrated under reduced pressure to give the title compound as a pale-yellow oil (0.72 g, 20%). ES/MS theory C (C16H25BrN03+): 358.1, experimental 値: w/z = 3 5 8·2 (Μ + Η)+. Intermediate 53 : 1-(2-(( 6-bromohexyl)oxy)ethyl)-4-nitrobenzene

The title compound was synthesized according to a method similar to that described for the intermediate 52, using 2-(4-nitrophenyl)ethanol in the same manner as the 4-(4-nitrophenyl)butan-1-ol. ES/MS theory 値 (C14H21BrN03 + ) : 3 3 0. 1, Experimental 値: w/z = 330.1 (M + H)+. -112- 201206888 Intermediate 54: Acetic acid 6_ ((4-(4-(2,2,2-trifluoro-N-methylethylamino)phenyl)butan-3·'yn-1-yl) Oxy)hexyl ester

The title compound was synthesized by substituting the intermediate 26 for the intermediate 33 according to a method similar to that described for the intermediate 36. ES/MS theory 値 (C21H27F3NO4·1·): 414.2, experimental 値: zw/z = 414.3 (M + H)+. Intermediate 55: 6-(4-(4-(2,2,2-trifluoro-N-methylethylamino)phenyl)butoxy)hexyl acetate

Intermediate 54 (1.2 g, 2.9 mmol) in methanol was taken from palladium / carbon (10% w/w, 50 mg). The mixture was shaken under 50 psi of hydrogen for 2 hours and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound (1 g, m. ES/MS theory 値(C2iH3iF3N〇4+ ) : 418.2 , experimental 値: w/z = 41 8·3(Μ + Η)+. Intermediate 56: 6-(4-(4-(methylamino)phenyl)butoxy)hexan-1-ol oxime -113- 201206888 The title compound was used according to a method similar to that described for Intermediate 49. The intermediate 55 is synthesized as a substrate. ES/MS theory 値 (C17H30NO2+): 280.2, experimental 値: m/z = 280.3 (M + H)+. Intermediate 57 : 4-(4-((6-((T-butyldimethylmethyl)oxy)hexyl)oxy)butyl)-N-methylaniline

Intermediate 5 6 (0.92 g, 3.3 mmol) in dichloromethane with butyl dimethyl decyl chloride (0.75 g, 5.0 mmol), DMAP (50 mg), and triethylamine (1.4 mL) , 10 mmol) treatment. After a few minutes, another portion of tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol) and triethylamine (1 mL) were added. The mixture was filtered through a pad of Celite and concentrated. The residue was purified by automated flash grit chromatography using a 40 g sili. The desired fraction was concentrated under reduced pressure to give the title compound, m. ES/MS theory 値 (C23H44N02Si+): 394.3, experimental 値: /n/z = 394.4 (M + H)+. Intermediate 58: 6-((11-Hydroxyundecyl)thio)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-114 - 201206888

The title compound was synthesized according to a method similar to that described in Org. Lett. 2004, 6 (24), 45 87-4590. Add 6-iodo-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide (1.0 g &gt; 2.3 1 mmol) to a round bottom flask, dry Dioxane (23 mL) and z_-Pr2NEt (0.8 1 mL '4·62 mmol). A catalytic amount of Pd2(dba)3 (63 mg, 0.07 mmol) 'Xantphos (80 mg &gt; 0.14 mmol) and 11-mercapto-1-111 alcohol (494 mg, 2.42 mmol) were then added. The mixture was evacuated and then back to nitrogen (3 cycles). The mixture was heated under reflux for 2 hours (HPLC confirmed the reaction was completed). The reaction mixture was then returned to room temperature&apos; followed by filtration and concentration. The crude product was used directly in the next step without further purification. ES/MS Theory 値 (C29H40N3O3S+) : 510.3, Experimental 値: m/z = 510.4 (M + H) + ° Intermediate 59 ·· 6- (( 3-Bromophenyl)thio)-4- ( ( 3 -Methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized by substituting 3-bromothiophenol for 1 1 -mercapto-1 -undecanol in a similar manner to that described for the intermediate 58 to -1 - 201206888 ES/MS Theory 値 (C24H21BrN302) S+): 494·1, experimental 値: w/z = 494.1 (M + H)+. Intermediate 60: 6-((4-Bromophenyl)thio)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in the above-mentioned compound (5), which was obtained by substituting 4-bromothiophenol for 1 1 -mercapto-1 -undecanol. ES/MS Theory 値 (C24H21BrN302S+): 494.1, Experimental 値: w/z = 494.1 (M + H) + 〇 Intermediate 61: 6-((11-Hydroxyundecyl)sulfonyl)-4-( (3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

Oxone (2.8 g) was added to a solution of intermediate 58 (2.31 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for 3 days and then poured into 10% Na2SO3. Chloroform was added, the layers were separated, and the aqueous layer was extracted twice with chloroform. The organic layer was combined, washed once with brine, dried over anhydrous magnesium sulfate and evaporated at low pressure. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut ES/MS theory 値 (C29H4QN3 〇 5S+): 542.3, experimental 値: = 542.4 (M + H)+. Intermediate 62: 6-((3-Bromophenyl)sulfonyl)-4_((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 61 using Intermediate 59 as a substrate. ES/MS theory 値 (C24H2iBrN304S+): 526.0, experimental 値: w/z = 526·1 (μ + Η) + ο Intermediate 63 : 6-((4-bromophenyl)sulfonyl)-heart (( 3-methoxyphenyl)amino)-8-methylquinolin-3-carbamide

The title compound was synthesized by a method similar to that described for Intermediate 61 using Intermediate 60 as a substrate. ES/MS theory 値 (C24H2iBrN3〇4S+): 526.0, experimental 値: / / 2 = 526.1 (Μ + Η) + -117- 201206888 Intermediate 6 4 : 6 - ( ( 4,-(hydroxymethyl)- [1,1 '-biphenyl]-3-ylsulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

2M Na2C03 (1.4) was added to a suspension of intermediate 62 (0.95 mm〇i) and 4_(methylidene)phenylboronic acid (290 mg, 1_90 mmol) in DME (10 mL) at room temperature. mL ' 2.85 mmol ) and PdCl 2 ( PPh 3 ) 2 ( 33 mg, 0.005 mmol). The reaction mixture was stirred under reflux for 2 hours and then cooled to room temperature. After adding 60 mL of chloroform, a white precipitate formed which was collected by filtration. The crude product was purified by flash column chromatography eluting elut elut elut elut elut ES/MS theory 値 (C3iH28N3 〇 5S+): 554.2, experimental 値: m/z = 554.3 (M + H)+. Intermediate 65 : 6-(( 4 '·(Hydroxymethyl)biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquin Porphyrin-3-carboxamide

-118-201206888 The title compound was synthesized according to a procedure similar to that described in Intermediate 64 using Intermediate 63 (1.38 mmol) as the substrate. The crude product was quickly precipitated in 15 mL of ethyl acetate for 10 min. After cooling to rt, EtOAc (EtOAc m.) ES/MS Theory 値 (C31H28N3 05 S+ ): 5 54.2 , Experimental 値: w/z = 5 54.3 (M + H)+. Intermediate 66: 6-((4'-(3-hydroxypropyl)biphenyl]_4_yl) fluorenyl.)-4-((3-methoxyphenyl)amino)-8-A Glycosyl-3-carbamamine 0〆

The title compound was synthesized by a method similar to that described for the intermediate 65, using 4-(3-propylpropyl)phenylboronic acid in place of 4-(ylmethyl)phenylboronic acid. ES/MS theory 値 (C33h32N3 〇 5S+ ): 5 82.2, experimental 値: = 582·3 (Μ + Η)+. Intermediate 67: 6-((4'-(3-hydroxypropyl)-[υ,-biphenyl]_3_yl)sulfonyl)-4-((3-methoxyphenyl)amino) _8_Methyl porphyrin _3_Procarbamide-119- 201206888

The title compound was synthesized by substituting 4-(3-hydroxypropyl)phenylboronic acid for 4-(hydroxymethyl)phenylboronic acid in a similar manner to that described for Intermediate 64. ES/MS theory 値 (c33H32N305 S+ ): 582.2 ′ Experimental 値: w/z = 582.3 (M + H)+. Intermediate 68: 6-((4,-(5-Hydroxypentyl).[u,-biphenyl]-4-yl)alkyl)-4-((3-methoxyphenyl)amino )_8_methylquinoline_3_formamide

The title compound was used in a similar manner to that described for Intermediate 65, using 3-[4-(4,4,5,5-tetramethyloxaborolan-2-yl)phenyl]pentane-1 - The alcohol is synthesized by substituting 4_(hydroxymethyl)phenylboronic acid. ES/MS theory 値 (C35H36N3 〇 5S+): 610.2, experimental 値: w/z 610·3 (Μ + Η)+. Intermediate 69:6·((4,-(5-Hydroxypentyl)-[丨,1,-biphenyl]-3-yl)mine®1yl)_4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-methyl 201206888

The title compound was synthesized by substituting 4-(5-pyridyl)phenylboronic acid with 4-(5-pyridyl)phenylboronic acid in a similar manner to that described in Intermediate 64. ES/MS theory 値 (c35h36N3OsS+ ): 610_2, experimental 値: w/z = 610·3 (Μ + Η)+. Intermediate 70: (8-Hydroxyoctyl)amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-A Guanamine

Add HATU (116 mg, 0.305 mm ο 1 ) and DIEA (0.106 mL '0.61 mmol) to 3-[[3-aminomethylmercapto-4-[(3-methoxy) at room temperature Phenylphenyl)amino]methylquinolin-6-yl]sulfonyl]benzoic acid (100 mg '0.203 mmol) in a solution of DMF (2 mL). After 5 minutes, 8-aminooctanoicol (0.35 mL, 0.244 mmol) was added and the resulting mixture was stirred for a further hour. The reaction mixture was poured into 10% (w/v) EtOAc (EtOAc)EtOAc. The combined organic layer was washed with h20 (2×100 mL) and brine (1 0G mL). dried with Na2S04 (s) and concentrated to give a brown semi-solid (129 mg): chromatography (9:1, CH2Cl2/ MeOH, -121 - 201206888 0.1% EtOAc (m.). ES/MS theory 値 (c33H39N406 Si+): 619.3, experimental 値: w/z = 619.3 (M + H)+. Intermediate 71 : 6-[[3-[(6-Hydroxyhexyl)aminecarguanylidene]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methyl Quinoline-3-carboxamide

The title compound was synthesized by a method similar to that described for the intermediate 70, using 6-aminohexanol in place of 8-amino octanol. Es/MS theory 値(C31H35N4〇6S+ ) : 591.2 , experimental 値: w/z = 591.3 (M + H)+. Intermediate 72: 6-[[3-[[4-( 5 hydroxypent-1-yn-1-yl)phenyl]amine carbazyl]phenyl]indole]]_4_[(3_methoxy Phenyl)amino]_8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described for the intermediate 7 y, using the intermediate 3 1 instead of 8-amino octanol. ES/MS theory 値 (C36H33N406S+) : 649 2, experimental 値: = 649 3 (M + H) + -122- 201206888 Intermediate 73 : 6- ( ( 3- ( 4- 4- 5- Alkyn-1-yl)phenyl)(methyl)amine-methylmethyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3 -Procarbamide

The title compound was synthesized according to a method similar to that described for Intermediate 70, using Intermediate 49 instead of 8-amino octanol. ES/MS theory 値 (C37H34N406S): 662.2, experimental 値: w/z = 663 (M + H)+. Intermediate 74 ·· 6-(( 3-(4- 4-(5-hydroxypent-1-yn-1-yl)-2-methylphenyl)aminecarboxamido)phenyl)sulfonyl)- 4-((3-Methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 70, using Intermediate 50 instead of 8-amino octanol. ES/MS theory 値 (C37H34N406S): 662.2, experimental 値: w/z = 663 (M + H)+. Intermediate 75: 6-((3-((4-(5-)-Pentyl-1-yl-1-yl)-3-methyl 201206888-phenyl)amine-methylphenyl)phenyl)sulfonyl) -4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized by substituting the intermediate 51 for the intermediate 70 according to a method similar to that described for the intermediate. Es/MS theory値

C37h34n4o6s): 662.2, experimental 値: w/z = 663 (m + h)+. Intermediate 76: 6-((3-(4-(6-Hydroxyhex-1-yn-1-yl)phenyl)amine),phenyl)sulfonyl)-4_((3_A) Oxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized by substituting the intermediate 48 with 8-amino octanol in a similar manner to that described for the intermediate 7 〇. Es/ms theory 値 (C37H35N406S+) : 663.2 'Experimental 値:; „/ζ = 663.3(M + H)·* Intermediate 77 : 6- ( ( 3_ ( ( 3- ( 5 _ _ Phenyl)amine-methylmercapto)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-124- 201206888

The title compound was synthesized according to a method similar to that described for Intermediate 70, using Intermediate 47 instead of 8-amino octanol. ES/MS theory 値(C36H33N4〇6S+ ) : 649.2, experimental 値:= 649.3(M + H) + intermediate 78:6-( (3_( (4_(4_(6. Base) oxy)hexyl)oxy)butyl)phenyl)(methyl)aminecarboxyl)phenyl)sulfonyl)-4((3-methoxyphenyl)amino) _8_ methyl sormine-3-caraamine

It was synthesized by substituting the intermediate 57 for 8-aminooctyl alcohol. ES/MS theory 値 (C48H63N4〇7SSi+ ) : 867.4 , experimental 値: w/z = 8 67·6(Μ + Η)+. Intermediate 79 · 6-((3_((4-(4)((6-hexyl))))))))))))))))))))) ((3-Methoxyphenyl)amino)·8-methylquinoline_3_formamide-125- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 5 using Intermediate 78 as a substrate. Es/MS theory 値 (C42H49N407S+): 753.3, experimental 値: w/2 = 753.4 (M + H)+. Intermediate 80: 6-[[3·[[6-hydroxyhexyl](methyl)amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amine-based b _methylquinoline-3_formamide

The title compound was synthesized by substituting the intermediate 21 for 8-aminooctyl alcohol according to a method similar to that described for the intermediate 70. ES/MS theory 値 (C32H37N406s+): 605.2, experimental 値: w/z = 605 (Μ + Η)+ &gt; Intermediate 81:6·( (3-( 4'-(hydroxymethyl))_[ι , ι,-biphenyl]-4-yl)amine-tertyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline_3_A Guanamine

-126-

201206888 The title compound was obtained according to the procedure similar to the one described in Intermediate 70 (4'-amino-[1,1'-biphenyl]-4-yl)methanol-substituted amino octyl. ES/MS Theory 値 (c38H33N4〇6S+ ) : 673.2 値··》ί/ζ = 673·2(Μ + Η)+ » Intermediate 82 : 4-[3-[[3-aminomethylmethyl-4- [(3-Methoxyphenyl)]-8-methylporphyrin-6-yl]-indenyl]benzhydrylamino]phenethylamino-tributyl ester oxime 2 The title compound is based on the intermediate A similar method of 70 was synthesized by substituting the intermediate 27 for 8-aminooctyl alcohol. 4 NMR ( 400 MHz, DMSO-d6 ) δ 1 0· 80 ( s,1 Η ) ' (s,lH) , 9.09 (s,lH) , 8.25-8.39 (m,3H), (dJ= 7.9 Ηζ· 1H) &gt; 8.04 ( s &gt; 1H ) . 7.87 ( d

8.0 Hz * 1H ) , 7.72-7.80 ( m, 2H ) , 7.69 ( d ’ J

Hz - 2H ) &gt; 7.20 ( d &gt; J = 8.4 Hz - 2H ) - 7.11 ( t 8_0Hz, lH) , 6_88 (t, J = 5.4Hz, lH) ' 6.60-6 m, 2H) , 6.52 (d , / / 8.3 Hz, 1H ) , 3.6 〇 ( s ' , 3.08-3 .1 8 ( m &gt; 2H ) , 2.65-2.73 (m, 5H) , ^40 9H ) » ES/MS Theory 値 (C38H4 〇N507S + ) : 71〇.3 ' Real: m/z = 7 1 0.3(M + H)+ 〇, so that the experimental amino acid is made so that 10.46 8.2 1 &gt; J == 8.4 &gt; J = .68 ( 3H ) -8-methylquinolin-6-yl)sulfonyl)-#_methylbenzamide amino)ethoxylated phenylethylaminocarbamic acid tert-butyl ester

The title compound was synthesized by substituting the intermediate 28 with 8-aminooctyl alcohol according to a method similar to that described for the intermediate 7 〇. ES/MS theory 値 (C41H46N508 s+): 768.3, experimental 値: w/z = 768·3(Μ + Η) + intermediate 84:6-( (3-(4·( (6-((3) Dimethyl decyl)oxy)hexyl)oxy)piperidine-hydrazino-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline 3-carbamamine

The title compound was synthesized by a method similar to that described for the intermediate 70, using the intermediate 23 instead of 8-amino octanol. ES / MS theory 値 (C42H57N4 〇 7SSi+ ) : 789.4 , experimental 値: / „ / ζ = 78 9.3 (Μ + Η) +. Intermediate 85: 6-( (3_(4-(6_((t-butyl) Dimethyl fluorenyl) -128- 201206888 oxy)hexyl)piperazine-hydrazinyl-phenyl)phenyl)anthraceneoxyphenyl)amino)-S-methylsalthene-3-carboxamide )-4-( ( 3- A

The title compound was synthesized by substituting the intermediate 25 to the 8-amino octanol to give the compound (C4iH56N506SSi+): 774.4, 774. Intermediate 86: 4-(4,-(3-((3-Aminomethyl)-4-phenyl)amino)-8-methylquinolin-6-yl)sulfonyl) 0 V: Method to make ES/MS theory ml: ml z = -((3-methoxybenzamide)-[1,1 '-biphenyl]-4-yl)butanoic acid methyl ester

The title compound was synthesized by substituting the intermediate of the intermediate 70 for the amino-octanol. (C42H39N4〇7s+) : 743 3, Experimental 値: Intermediate 87 : 4-( 3,_( 3_ (( 3_Aminomethylphenyl-4-phenyl)amino)-8-methylquinolin-6- () sulfonyl) -129- 〇 also called the method, so that the ES / MS theory 値 743.4 (M + H) + - ((3-methoxycarbamoyl) - 201206888

The title compound was synthesized by substituting the intermediate 30 for 8-aminooctyl alcohol according to a method similar to that described for the intermediate π. ES/MS theory 値(C42H39N4〇7S+) : 743 3, experimental 値: w/z = 743·4(μ + η) + intermediate 88 : 6· ( ( 3_ ( 4 · ( 6-hydroxyhexyl) oxygen ())piperidinyl carbonyl)phenyl)sulfonyl)-4((3-methoxyphenyl)amino)_8_methylsalthene-3-carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 5, using Intermediate 84 as a substrate. ES/MS theory 値 (C36H43N4〇7S+): 675.3, experimental 値: m/z = 675.2 (M + H)+. Intermediate 89: 6-((3-(4-(6-Hydroxyhexyl)piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)- 8-methylquinoline-3·carbamamine-130- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 5, using Intermediate 85 as a substrate. ES/MS theory C (C35H42N5 〇 6S+): 660.3, experimental 値: w/z = 660.3 (M + H)+.

Intermediate 90: 6-((3-((4,-(4-hydroxybutyl)-[1,1,-biphenyl]-4-yl)aminecarboxamido)phenyl)sulfonyl)- 4-((3-Methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

Add LiAlH4 solid (29 mg, 0.713 mmol) to a stirred solution of the intermediate 8 6 (265 mg, 0.35 7 mmol) in THF (5 mL). Then, H2〇 (0.029 mL) '15% (w/v) NaOH (0.029 mL) and H20 (0.087 mL) were added in that order, followed by stirring for further 1 hour. The resulting suspension was diluted with EtOAc (EtOAc EtOAc EtOAc. Chromatography (9:1, CH2Cl2 /MeOH) ES/MS theory 値 (C41H39N4 〇 6S+): 715.3, experimental 値: m/z = 715·4(Μ + Η) + -131 - 201206888 Intermediate 91 : 6- ( ( 3- ( 4 '- ( 4 -hydroxybutyl)-[1,1'-biphenyl]-3-yl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8 -methylsporphyrin-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 90 using Intermediate 87 as a substrate. Es/MS theory C (C41H39N406S+): 715.3, experimental 値: w/z = 715·4 (Μ + Η)+. Intermediate 92: 6-[[3-[[4-( 5-Hydroxypentyl)phenyl]aminocarbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amine -8-methylquinolin-3-carbamamine

Pd(OH)2 (20% on activated carbon, 250 mg) was added to a solution of intermediate 72 (250 mg, 0.38 mmol) in MeOH/THF (1:1) (10 mL). The solution was hydrogenated via a balloon for 5 hours. The Pd was filtered through a celite pad. The filtrate was then concentrated in vacuo to give title crystall ES/MS theory - ( -132- 201206888 C36H37N4 〇 6S+): 653.2, experimental 値: w/z = 65 3·3 (Μ + Η)+. Intermediate 93: 6-[3-[[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl]-benzenesulfonyl]-4-(3-methoxyphenylamino)- 8-methylquinoline-3-carboxamide

At room temperature, in 2-(piperazin-1-yl)ethanol (16 mg, 丨.22 mmol), 3-[3-aminocarbazin-4-(3-methoxyphenylamino) -8-methylquinolin-6-flavoring base] benzoic acid (500 mg, 1.02 mmol), and BOP (540 mg, 1.22 mmol) in a mixture of 3 mL DMF φ was added TEA (0.34 mL &gt; 3.06) Mm). The reaction mixture was stirred overnight. Water was added and the precipitate was collected by filtration. The filter cake was washed with CH2C12 and dried to give the title compound. ES/MS theory 値 (C31H34N506S+): 604.2, experimental 値: w/z = 6 04.2 (M + H)+. Intermediate 94: 6-[[3-[[4-(2-Aminoethyl)phenyl]aminemethylmercapto]phenyl]sulfonyl]-4-[(3-methoxyphenyl) Amino]-8-methylquinoline-3-carboxamide

TFA (0.5 mL) was added dropwise to a suspension of intermediate 82 201206888 ( 382 mg &lt;RTI ID=0.0&gt;&gt; After stirring for 5 hours, the reaction mixture was concentrated in vacuo to give a brown residue. A portion of the residue was taken from a silica gel-carbonic resin and used directly in the next step without further purification. ES/MS theory C (C33H32N505S+): 610.2, experimental 値: m/z = 610·2 (Μ + Η)+. Intermediate 95: 6-((3-(2-(4-(2-Aminoethyl)phenoxy)ethyl)(methyl)aminecarboxamido)phenyl)sulfonyl)-4 -((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 94 using Intermediate 83 as a substrate. Es/MS theory C (C36H38N5〇6S+) : 66 8.2 5 ′ Experimental 値: = 668.2(Μ + Η)+. Intermediate 96: 4·((3-Methoxyphenyl)amino)-8-methyl-6-((3-(piperazin-1-carbonyl)phenyl)sulfonyl)quinoline-3 _mercaptoamine

The title compound was synthesized according to a method similar to that described for the intermediate 7 y, using a mixture of adiamine and octanyl alcohol. Es/MS theory - (-134- 201206888 C29H3〇N505S+): 560.2, experimental 値: = 560.2 (M + H)+. Intermediate 97: 4-((3-Methoxyphenyl)amino)-8-methyl-6-((3-(4-(3-(2-)-propylpropyl)benzylidene) Piperazine-1-carbonyl)phenyl)sulfonyl)quinoline-3·carboxamide

Add HATU (82 mg, 0.217 mmol), DIEA (0.103 mL &gt; 0.59 mmol), and 3-(2-ketopropyl)benzoic acid (39 mg, 0.21 7 mmol) to stirring at room temperature Intermediate solution 96 (110 mg, 0.197 mmol) in DMF (2 mL). The reaction mixture was stirred for 40 min then poured into H.sub.2 (50 mL). The resulting precipitate was filtered, washed with H20 and dried to give crude diamine ( 256 mg). The title compound (85 mg, 64%) ES/MS theory値

C39H38N507S+): 720.3, experimental enthalpy: m/z = 720.2 (M + H) + » Intermediate 98 : 6- ( ( 3- ( 3-( 5 br) Aminomethyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-135- 201206888

A suspension of intermediate 77 (0.65 g, 1.0 mmol) and carbon tetrabromide (1·〇g, 3.0 mmol) in dichloromethane (14 mL) was subjected to ultrasonication for 5 min, then in an ice-water bath cool down. Then, a solution of triphenylphosphine (0.52 g, 2.0 mmol) in tetrahydrofuran was added by a syringe, the cooling bath was removed, and the mixture was stirred at room temperature overnight. Ethanol was added to the mixture to quench the reaction, and concentrated under reduced pressure to give a foam. The foam was taken up in tetrahydrofuran (15 mL) and treated with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol) as previously described. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The crude product was again taken up in tetrahydrofuran (15 mL) and was taken eluted with EtOAc (EtOAc) After stirring at room temperature overnight, the mixture was concentrated at a reduced pressure. The residue was taken up in acetone to form a suspension and filtered. The concentrated filtrate was purified by automated flash grit chromatography using 40 g of &lt;RTIgt;S&lt;1&gt;&gt; i c y c 1 e S i 1 i S e p fast column (hexane/ethyl acetate). The desired fraction was concentrated under reduced pressure to give the title compound, m. ES/MS Theory 値 (C36H32BrN405 S+ ) : 71 1 · 1 , Experimental 値: m/z = 7 1 1 · 2 (Μ + Η)+. Intermediate 99: 6-((3-(4-4-(4-(6-bromohexyl)oxy)butyl)phenyl)(methyl)aminecarboxamido)phenyl)sulfonyl)- 4-((3-Methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-136- 201206888

The title compound was synthesized by substituting Intermediate 79 for Intermediate 77 according to a procedure similar to that described in Intermediate 98. ES/MS theory 値 (C42H48BrN406S+): 815.3, experimental 値: w/z = 815·4(Μ + Η) + intermediate 100: (R) -3-(2-( (2-(8-(benzyloxy)) Keto-2-yl-1,2-dihydroquinolin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)amino)-2-methyl Propyl)methyl benzoate

Add methyl 3-(2-amino-2-methylpropyl)benzoate g, 4.82 mmol) to the pure (R)-8-(benzyloxy)·5_(2_bromo-indole-(( Third butyl dimethyl decyl oxy) ethyl) quinolin-2 (1 Η)-one ( 1.57 g ' 3.22 mmol). The resulting mixture was heated to 95. (: </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 615.3, Experimental 値: m/z = 615_3 (M + H) + -137- 201206888 Intermediate 101: (R) -3-(2-( (2-(8-(benzyloxy))-2-yl) - 1,2-Dihydroquinolin-5-yl)-2·((t-butyldimethylmethyl)oxy)ethyl)amino)-2-methylpropyl)benzoic acid

LiOH solid (370 mg, 15.4 mmol) was added to a stirred mixture of EtOAc/MeOH/H20 (15 mL, 3/1/1). In the solution. The reaction mixture was stirred overnight, then adjusted to pH 1 with 1 N HCl. The aqueous layer was extracted with EtOAc (EtOAc m. Recrystallization (CH.sub.2Cl.sub.2/.sub.2). ES/MS theory 値 (C35H45N205Si+): 601.3, experimental 値: w/z = 60 1 ·3(Μ + Η)+. Intermediate 102: (R)-N-(4-(5-((2-tert-butyldimethylmethyl)oxy)-2-(8-hydroxy-2-keto-1), 2-Dihydroquinolin-5-yl)ethyl)(methyl)amino)pent-1-yn-1-yl)phenyl)-2,2,2-trifluoroacetamide

-138- 201206888 Intermediate 40 (0.30 g, 0.90 mmol) and intermediate 4 (375 mg '1.1 mmol) in DMF (5 mL); diisopropylethylamine (0.47 mL, 2.7 mmol) The amount of tetra-n-butylammonium iodide (100 mg) was treated. The mixture was heated in a 55 ° C oil bath for 3 days. The mixture was concentrated at low pressure and purified by automated flash gel chromatography using a 12 g silicycle silisep. The desired fraction is concentrated under reduced pressure to give the title compound. ES/MS Theory 値 (C3 丨 H39F3N304 Si+ ) : 602.3 , Experimental 値: w/z = 602.4 (M + H)+. Intermediate 103: (R) -5-(2-((5-(4-aminophenyl)pent-4-yne-1-yl)(methyl)amino)-1-((Third Dimethyl decyl)oxy)ethyl)-8-hydroxyquinoline-2(1H)-one

The title compound was synthesized according to a method similar to that described for Intermediate 49, using Intermediate 102 as a substrate. ES/MS theory 値 (C29H4 〇 N3 03 Si+): 506.3, experimental 値: w/z = 506.4 (M + H)+. Intermediate 1〇4: (R) -N-(4-(2-(4-((2-tert-butyldimethylmethyl))oxy)-2-(8-hydroxy-2-) Ketopropyl-1,2-dihydrosin-5-yl)ethyl)amino)butyl)-1,3-dithiolan-2-yl)phenyl-139- 201206888 -2, 2,2-digas acetamide

The title compound was synthesized by substituting the intermediate 4 5 for the intermediate 9 8 according to a method similar to that described for the intermediate. ES / MS theory 値 ( C32H43F3N3 〇 4S2Si+:) : 68 2.2' Experimental 値: w/z = 682_4 (M + H) + 〇 intermediate 105: (1^)-(4-(2-(4-amino) Phenyl)-1,3 -thiolane-2-yl)butyl)(2-((t-butyldimethylmethyl)oxy)-2-(8-hydroxy- 2- Ketopropyl-1,2-dihydroquinolin-5-yl)ethyl)carbamic acid tert-butyl ester

A solution of intermediate 104 (0.41 g, 0.60 mmol) in THF (5 mL) EtOAc (EtOAc (EtOAc) Treatment with #-dimethylaminopyridine (DMAP, 50 mg). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness under reduced pressure. The residue was taken up in EtOAc (5 mL)EtOAcEtOAc The mixture was stirred in an oil bath at 40 ° C and then concentrated under reduced pressure. MeOH (5 mL - 140 - 201206888) was added and the mixture was heated in a 40 ° C oil bath for 2 days. The mixture was concentrated under reduced pressure and the mixture was partitioned between 1N aqueous hydrochloric acid and dichloromethane. The aqueous layer was basified to pH 10 with concentrated aqueous ammonium hydroxide and then extracted three times with dichloromethane. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by automated flash gel chromatography using a 25 g Silicycle SiliSep flash column (dichloromethane / methanol / ammonium hydroxide). The desired fraction was concentrated under reduced pressure to give the title compound as white powder. ES/MS theory 値 (C35H52N3 05 S2Si+): 6 86.3, experimental 値: m/z = 498.2 (M-TBS-i_Bu + H) +.

Intermediate 106: (foot)-8-camto-5-(2,2,3,3-tetramethyl-18-(4-nitrophenyl)-4,14-dioxa-7-nitrogen Hetero-3-oxaoctadecan-5-yl)quinoline-2 ( 1H)-one

The title compound was synthesized by substituting the intermediate 5 2 for the intermediate 4 5 according to a method similar to that described for the intermediate. ES / MS theory 値 ( C33H50N3 〇 6Si+) : 612.4, experimental 値: w / z = 612.5 (M + H) +» Intermediate 1 〇 7: (R) - (2-(8-((3rd butyl) Carbocarbonyl)oxy)-2-keto-1,2-dihydroquinolin-5-yl)-2-((t-butyldimethylsilyl)oxy)ethyl)(6-( 4-(4-nitrophenyl)butoxy)hexyl)carbamic acid tert-butyl ester-141 - 201206888

A solution of intermediate 106 (0.53 g, 0.87 mmol) in dichloromethane (5 mL) EtOAc EtOAc (EtOAc: , #-dimethylaminopyridine (DMAP, 20 mg) treatment. The reaction mixture was stirred at room temperature overnight and then concentrated to dryness under reduced pressure. The residue was purified by automated flash gel chromatography using a 25 g Silicycle SiliSep flash column (hexane/ethyl acetate). The desired fractions are concentrated under reduced pressure to give the title compound as a colourless oil. ES/MS theory C (C43H66N3O10Si+): 812.5, experimental 値: m/z = 812·6(Μ + Η)+. Intermediate 108: (R) -(6-(4-(4-Aminophenyl)butoxy)hexyl)(2-(8-((tert-butoxycarbonyl)oxy)-2-one) 1,3 -Dihydrosin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)aminocarboxylic acid tert-butyl ester

A suspension of Pd/C (10% w/w, 15 mg) and intermediate 107 (0.25 g, 〇·31 mmol) in MeOH (4 mL) was stirred with a hydrogen balloon for 30 min. The mixture was filtered through a Celite algae pad - 142 - 201206888 and concentrated under reduced pressure. The title compound was obtained as a white foam (0-13 g, 54%). ES/MS Theory 値 (C43H68N308Si+): 782.5 'Experimental 値: w/z = 782.6 (M + H)+. Intermediate 109 : ( R) -8-hydroxy-5- ( 2,2,3,3 -tetramethyl-16-(4-nitrophenyl)-4,14-dioxa-7-aza -3-oxahexadecane-5-yl)quinoline-2 (1H)-one

〇

The title compound was synthesized by substituting the intermediate 53 for the intermediate 52 according to a method similar to that described for the intermediate 168. ES/MS theory 値 (C3iH46N3〇6Si+): 584.3, experimental 値: w/z = 584·4 (Μ + Η) + 〇 intermediate 110: ( R ) - ( 2- (8 (3) Alkylcarbonyl)oxy®)-2-keto-1,2-dihydroquinolin-5-yl)-2-((t-butyldimethylsilyl)oxy)ethyl)(6- (4-nitrophenylethoxy)hexyl)amine tert-butyl acid

The title compound was synthesized according to a method similar to that described for Intermediate 1 to 7 using Intermediate 109 as a substrate. ES/MS theory 値 -143- 201206888 C41H62N3O10Si+) : 784.4, experimental 値: m/z = 784.5 (M + H)+. Intermediate 111: (R) -(6-(4-Aminophenylethoxy)hexyl)(2-(8-((t-butoxycarbonyl)oxy)-2-one-1,2 -Dihydroquinolin-5-yl)-2-((t-butyldimethylammonyl)oxy)ethyl)carbamic acid tert-butyl ester

The intermediate 1 1 〇 (0.38 mmol) in methanol (9 mL) was treated with iron(III) chloride hexahydrate (10 mg) and decolorized activated carbon (100 mg). When the mixture was heated to reflux, a hydrazine monohydrate (1.0 mL) was added dropwise using a syringe. After heating at reflux for 2 hours, the mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc The desired fraction was concentrated under reduced pressure afforded title compound (l. ES/MS theory 値 (C36H56N306Si+ ): 654.4, experimental 値: w/z = 654.5 (M + H)+» Intermediate 112: 4-[(3-methoxyphenyl)amino]-8-methyl -6-[[3-[(8-ketooctyl)amine-carbamoyl]phenyl]sulfonyl]quinoline-3-formamide-144- 201206888

Dess-Martin reagent (105 mg, 0.249 mmol) was added to a stirred solution of intermediate 70 (77 mg, 0.124 mmol) in DMF (2 mL). The resulting solution was stirred for 3 hours and poured into saturated NaHC03 (50 mL). The precipitate was filtered, washed with H20jjjjjjjj This compound was used without further purification. ES/MS theory 値(C33H37N406S+ ) : 617.2 , experimental 値: m/z = 617.3 (M + H)+. Intermediate 1 13 : 4-[(3-Methoxyphenyl)amino]-8-methyl-6-[[3-[(6-ketohexyl)aminemethanyl]phenyl]sulfonate Quinoline-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 71 as a substrate. ES/MS theory 値 (C31H33N4 〇 6S+): 5 89.2, experimental 値: w/z = 5 89·2 (Μ + Η)+. Intermediate 114: 4-[(3-Methoxyphenyl)amino]-8-methyl-6-[[3-[methyl(6-ketohexyl)aminemethane]phenyl]sulfonate Mercapto]quinoline-3-carboxamide-145-, 0,0201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 80 as a substrate. ES/MS theory C (C32H35N406S+): 603.2, experimental 値: w/z = 603 (M + H)+. Intermediate 115 : 4-[( 3 -Methoxyphenyl)amino]-8 -methyl[[4-( 5-ketopentyl-1-yne-indole-yl)phenyl]aminecarboxamide Phenyl]sulfonyl]quinoline-3-carboxamide

The title compound is based on the intermediates! A similar method as described in i 2 was synthesized using the intermediate 72 as a substrate. ES/ms theory C (C36H31N406S+): 647·2, experimental 値: w/z = 647 6(m + h)+. Intermediate 116: 4-((3-methoxyphenyl)amino)_8-methyl_6_(( 3-(methyl(4-(5-ketopentyl))) Phenyl)amine carbenyl)phenyl)sulfonyl)quinoline-3-carboxamide-146- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 73 as a substrate. ES/MS theory C (C37H32N406S): 660.2, experimental 値: w/z = 661 (M + H)+.

Intermediate 117: 4- 3-methoxyphenyl)amino)-8-methyl-6-(( 3-((2-methyl-4)(5-ketopentyl)-alkynyl-yl) Phenyl)amine carbaryl)benylamine

The titled mouth was synthesized according to a method similar to that described for the intermediate U 2 by using the intermediate 74 as the substrate ι = human _ and IF as the substrate. ES/MS theory c ( c37h32n4 〇 6S) : 66 〇 2, experimental 値: ... = 66i (m + h) +. Amino)-8-methyl(-1-yl)phenyl)amine-brenyl intermediate 118: 4.((3.Methoxyphenyl 3-((3-methyl-4.) 5 _ketopenta-indole-alkyne) benzyl)sulfonyl)quinoline_3_formamide-147- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 7 5 as a substrate. e S / MS theory 値 (C37H32N4 〇 6S) : 660.2' Experimental 値: „j/z = 661(Μ + Η)+» Intermediate 119: 4-((3-methoxyphenyl)amino)- 8-methyl-6-((3-((4)(6-ketohexyl-1-yn-1-yl)phenyl))aminomethyl)phenyl)sulfonyl)quinoline-3-yl Guanamine

The title compound was synthesized according to a method similar to that described in Intermediate </ RTI> 2, using Intermediate 76 as a substrate. Es/ms theory 値 (C37H33N4〇6S): 661.2' Experimental 値: w/z = 6631 (M + H)+. Intermediate 120: 4-[(3-Methoxyphenyl)amino]-8-methyl-6_[[3_[[4-(5-ketopentyl)phenyl]aminecarboxylidene]phenyl ]sulfonyl]quinoline-3_carbamamine 201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 92 as a substrate. ES/MS theory c ( c36h35n4o6s + ) : 6512 , experimental 値: w / z = 6513 (m + h) +. # Intermediate 121 ·····((3-methoxyphenyl)amino)-8-methyl-6-((3-(4-((6-ketohexyl))oxy)piperidine-丨_carbonyl)phenyl)sulfonyl)quinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described for the intermediate 1 1 2 and φ was obtained using the intermediate 88 as a substrate. ES/MS theory 値 (C36H4iN4〇7S+): 673.3, real. Test: w/z = 673.3 (M + H)+. Intermediate 122: 4-((3-Methoxyphenyl)amino)-8-methyl-6-((3-(4-(6-ketohexyl)piperazine-1-carbonyl)phenyl )sulfonyl)quinoline-3-carboxamide-149- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 and using Intermediates 8 9 as a substrate. e S / M S theory C (C35H4 〇 N506S+): 658.3, experimental 値: w/z = 658.3 (Μ + Η)+. Intermediate 123: 6-((3-((4,-Methyl)-[1,1,-biphenyl]-4-yl)amine,carinyl)phenyl)sulfonyl)-4-( 3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized by a method similar to that described for the intermediate 丨丨 2, using Intermediate 81 as a substrate. Es/ms theory C (C38H3iN406S): 671.2, experimental 値: w/z = pi.2(Μ + Η)+. Intermediate 124: 4-((3-Methoxyphenyl)amino)_8-methyl_6_(( 3-((4'-(4-ketobutyl))-[], _biphenyl ]_4_yl)aminemethanyl)phenyl)sulfonyl)porphyrin-3·carbamamine 201206888

The stomach compound was synthesized by a method similar to that described for the intermediate 1 1 2, using IBX in place of the Dess-Martin reagent and using the intermediate 90 as a substrate. ES/MS theory 値 (C41H37N406S+) : 713.2 'Experimental 値: w/z = 713.3(Μ + Η)+β Intermediate 125: 4-((3-methoxyphenyl)amino)-8-methyl -6-(( 3-( (4'-(4-ketobutyl)-[ι,κ-biphenyl]_3_yl))aminomethyl)phenyl)alkyl)quino-3- Methionine/

The title compound was synthesized according to a method similar to that described in Intermediate 24, using Intermediate 9 1 as a substrate. Es/MS theory C (C41H37N406S + ) : 713.2, experimental 値: w/z = 713.4 (Μ + Η)+. Intermediate 126: 4-((3-Methoxyphenyl)amino)·8-methyl-6-(( ll-keto^^-alkyl)sulfonyl)quinoline-3-carboxamidine Amine-151 - 201206888

The title compound was synthesized by a method similar to the intermediate i i 2 using an intermediate 61 as a substrate. Es/MS theory C (C29H38N305S+): 540.3, experimental 値: m/z = 540.4 (M + H)+. Intermediate 127: 6-((4'-Methylamino-[n,-biphenyl]_3_yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-A Quinoquinoline-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 1 1 2 using Intermediate 64 as a substrate. ES/MS theory 値 (C3iH26N3 〇 5S+): 552.2, experimental 値: w/z = 552·3 (Μ + Η)+. Intermediate 128: 6-((4,-Methylamino-[1,1biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)_8_A Quinoline·3_carbamamine

The title compound was synthesized according to a method similar to that described for the intermediate 1 1 2 to give -152 to 201206888 using the intermediate 65 as a substrate. Es/ms theory 値 (C3iH26N305S+): 552.2' Experimental 値: w/z = 552.2 (M + H)+. Intermediate 129: 4-((3-Methoxyphenyl)amino)·8-methyl_6-((4'-(3-ketopropyl)-[丨,〗 '-biphenyl] _4•yl)sulfonyl)quinoline-3_carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 1 24, using Intermediate 66 as a substrate. ES/MS theory 値 (C33H30N3O5S): 580.2, experimental 値: w/z = 580.3 (Μ + Η)+. Intermediate 130: 4-((3-Methoxyphenyl)amino)-8-methyl-6-(( • 4'-(3-ketopropyl)-[1,1 biphenyl]- 3-yl)sulfonyl)quinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Intermediate 1 24 using Intermediate 67 as a substrate. ES/MS theory 値 (C33H30N3O5S+): 5 80.2, experimental 値: = 5 80.3 (Μ + Η)+. -153- 201206888 Intermediate 131: 4-((3-Methoxyphenyl)amino)-8-methyl-6-((4'-(5-ketopentyl)biphenyl]-4- Sulfhydryl)quinoline-3_carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 1 24 using Intermediate 68 as a substrate. Es/MS theory C (C35H34N305S+): 608.2, experimental 値: m/z = 608.3 (M + H)+. Intermediate 132: 4-((3-Methoxyphenyl)amino)-8-methyl-6-((4'-(5-ketopentyl)biphenyl]-3-yl)sulfonate Quinoline-3-carbamamine

The title compound was synthesized according to a method similar to that described for Intermediate 1 24 using Intermediate 69 as a substrate. ES/MS theory 値 (C35H34N305S+): 608.2, experimental 値: w/z = 60 8.3 ( Μ + Η+) 〇 intermediate 133: 4-((3-methoxyphenyl)amino)-8-A Base-6-(( -154- 201206888 3- (4-ketopiperidin-1-carbonyl)phenyl)sulfonyl)quinoline-3-carboxamide

DIEA (0.3 19 mL, 1.83 mmol) was added to the stirred solution of 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8- Methyl-Sialolin-6-yl]sulfonyl-yl]benzoic acid (300 mg, 0.61 mmol) in DMF (6 mL). After 5 minutes, 1,4-dioxa-8-azaspiro[4.5]nonane (0.156 mL, 1.22 mmol) was added and the obtained mixture was stirred for 1.5 hours. The reaction mixture was poured into H20 (50 mL) and filtered. The filter cake was rinsed with H20 and dried to give a yellow solid. The solid was dissolved in THF (6 mL). The reaction mixture was heated to 50 ° C and stirred overnight. The resulting mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic layer was washed with EtOAc EtOAc EtOAc (EtOAc) This compound was used without further purification. ES/MS theory 値(C3〇H29N4〇6S+ ) : 573_2 , experimental 値: w/z = 5 73·2(Μ + Η)+. Intermediate 134: 6-[[3-(Hydroxymethyl)phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]·8-methylsalthene-3-carboxamidine Amine-155- 201206888

Add LAH (158 mg, 3_96 mmol) to 3-[[3-aminomethylmethyl-4-[(3-methoxyphenyl)amino]-8- Methylquinoxa-6-yl]sulfonyl]benzoic acid methyl ester (500 mg, 0.99 mmol) in THF (10 mL). After stirring for 20 minutes, H20 (0.158 mL), 15% (w/v) NaOH (0 · 1 5 8 mL), and H20 (0.474 mL) were added in that order. The resulting suspension was stirred for 1 hr then EtOAc (EtOAc)EtOAc. This compound was used directly without further purification. ES/MS theory 値 (C25H24N305S + ) : 478.1, experimental 値: m/z = 478.1 (M + H) + ° Intermediate 135: methanesulfonic acid 3-[[3-carbamoyl-4-[ (3) -Methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzyl ester

To a stirred solution of intermediate 134 (330 mg, 0. 697 mmol) was added to a stirred solution of EtOAc (0.06 mL, 1.449 mmol) and DIEA (0. The reaction was monitored by LC/MS. EtOAc (m.p. The resulting reaction mixture was stirred for an additional 1 hour then sat. NaHC03 (50 mL) was then applied to the suspension. The aqueous layer was extracted with CH2C12 (3×20 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc. This compound was used without further purification. ES/MS theory 値 (C26H26N307S2+): 556.1 ′ Experimental experiment: m&quot; = 55 6.1 (M + H)+. Intermediate 136 : 4-[(3-Methoxyphenyl)amino]-8-methyl-6-[[3-[(methylamino)methyl]phenyl]sulfonyl]quinoline 3-carbamamine

Methylamine (2Min THF, 4.1 mL, 8.28 <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> was added to a solution of intermediate 135 (460 mg, 0.828 mmol) in THF (10 mL). The reaction mixture was warmed to 60 ° C and stirred overnight. The resulting solution was cooled to room temperature and then diluted with H20 (50 mL). The aqueous layer was extracted with EtOAc (3 X 30 mL). The combined organic layers were washed with H20 (50 mL) and brine (50 mL), dried over Na2S s 4 (s) and concentrated to give a yellow solid (3 80 mg). The title compound (135 mg, mp. ES/MS theory 値 (C26H27N404S+): 491.2 ′ Experimental 値: w/z = 491·2(Μ + Η)+. -157- 201206888 Intermediate 137: 4-[(3-Methoxyphenyl)amino]-8-methyl-6-[[3-[[3-(2-ketopropyl)phenylcarbonyl) (methyl)amino]methyl]phenyl]sulfonyl]quinoline-3-carboxamide

Add 3-(2-ketopropyl)benzoic acid (33 mg, 0.185 mmol) and DIEA (0.097 mL, 0.555 mmol) to EtOAc (100 mg, 0.204 mmol) In a solution formed by DMF (2 mL). The reaction mixture was stirred for 5 minutes and HATU (78 mg - 0.204 mmol) was added. The resulting solution was stirred for 3 hours and then poured into H20 (50 mL). The precipitate was filtered, EtOAcjjjjjjjjj ES/MS Theory 値 (C36H35N406S+): 651.2, Experimental 値: m/z = 651.4 (M + H) + ° Intermediate 138: 2-[4-[3-[3-Aminomethyl]-4 -(3-methoxyphenylamino)-8-methylquinolin-6-sulfonyl]benzimidyl]piperazin-1-yl]ethyl ester

Add MsCl (105 μί, 1.36 mmol) to a solution of intermediate 93 (410 mg, 0·68 mmol) in CH2C12 at 0 °C, then add -158-201206888 to TEA (284 eL'2.0 mm〇l ). The reaction mixture was stirred for 30 minutes and poured into 0.5 N HCl (aq). The aqueous layer was washed with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub. The combined organic layers were washed with brine, dried and dried ES/MS g g値 (C32H36N5O8S2&quot;1&quot;) ’· 682.2, experimental 値: =682·3(Μ + Η)+.

Intermediate 139: 6_[3-[4-[2-[2-(Tert-butyldimethylmethyloxy)-2-(8-hydroxy-2-keto-1,2-dihydroquine) Phenyl-5-yl)ethylamino]ethyl]piperazine-1-carbonyl]benzenesulfonyl]-4-(3-methoxy-phenylamino)-8-methylquinoline-3 ·Metformamide, guanidine

DIEA (276 pL, 1.59 mmol) was added to a solution of intermediate 138 (360 mg, 0.53 mmol) and intermediate 2 (209 mg, 0.53 mmol) in 3 mL DMSO at 50 °C. The reaction mixture was stirred for 1 hour and water was added. The solid was collected by filtration and purified to purified title crystal ES/MS theory 値 (C48H58N708Ssi+): 9 2 0.4, experimental 値: m/z = 920.3 (M + H)+. Intermediate 140 : ΓΛ) -6-[[3-[[4-[2-[[2-[8-(Benzyloxy)-2-oneyl-1,2-dihydroquinolin-5-yl) ]-2·[(Tertiary dimethyl dimethyl fluorenyl)oxy] -159- 201206888 ethyl]amino]ethyl]phenyl]amine-methylmethyl]-phenyl]sulfonyl]-4 -[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

Intermediate 94 (206 mg, 0.258 mmol) and 8-(benzyloxy)-5-[2-bromo-1-[(t-butyldimethylmethyl)oxy]ethyl]quinoline- 2 (1H)-ketone (115 mg, 0.235 mmol), sodium sulphate (20 mg &gt; 0.133 mmol), and Κ2〇〇3 (97 mg, 0.705 mmol) in anhydrous acetonitrile (1. 〇mL) and anhydrous DMF (0.5 mL) of the mixture was mixed and heated in a microwave oven at 1 °C for 2 hours. The reaction mixture was poured into H20 and extracted with EtOAc. Flash chromatography (0-1 5% MeOH / EtOAc) 'H NMR (400 MHz &gt; DMSO-d6) δ 10.81 ( s &gt; 1H) &gt; 10.54 (brs &gt; 1H ) , 10.45 (s, lH) &gt; 9.09 ( s &gt; 1H ) , 8.36 (d , J = 1.7 Hz, 1H) &gt; 8.29-8.34 ( m &gt; 2H ) « 8.27 ( d &gt; J =10.0 Hz, 1H) &gt; 8.2 1 ( dt &gt; J = 7.8 - 1.3 Hz &gt; 1H ), 8.02 -8.05 ( m &gt; 1H) &gt; 7.8 5 -7.8 9 ( m &gt; 1H) &gt; 7.78 ( brs &gt; 1H ) '7.75(t&gt;y=7.9Hz&gt; 1H) &gt; 7.67 ( d &gt; J = 8.4 Hz , 2H) &gt; 7.5 4-7.5 8 ( m - 2H ) , 7 · 3 3 - 7.4 0 ( m, 2 H ),

7.27-7.3 3 ( m &gt; 1H ) - 7.14-7.20 (m&gt; 3H) &gt; 7.11 ( t &gt; J =8.1 Hz &gt; 1H ) &gt; 7.09 ( d &gt; J = 8.3 Hz &gt; 1H ) &gt ; 6.62-6.68 (m, 2H) - 6.54 ( d - J = 9.9 Hz - 1 H ) &gt; 6.5 0 -6.54 ( m -160- 201206888 &gt; 1Η ) &gt; 5.26 ( s &gt; 2Η ) , 5.09- 5.17 (m,1Η) &gt; 3.60 ( s ,3H ) &gt; 2.72-2.86 ( m &gt; 3H ) , 2.71 ( s,3H) - 2.59-2.68 ( m &gt; 3H ) , 0.78 ( s,9H ) , 0.00 ( s,3H ) , -0.2 1 (s,3H). ES/MS theory 値 (C57H61N6 08SSi+): 1017.4, experimental 値: m/z = 1017.5 (M + H+). Intermediate 141: ( R ) -6-( (3-( (2-(4-(2-( (2)

Benzyloxy)-2-keto-1,2-dihydroquinolin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)amino)ethyl) Phenoxy)ethyl)(methyl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylsalthene-3-carboxamidine amine

The title compound was synthesized by substituting the intermediate 95 for the intermediate 94 according to a method similar to that described for the intermediate. ES/MS Theory 値 (C60H67N6O9SSi+) : 1 07 5.45 - Experimental 値: w/z = 1 0 7 5.4 (M +Η) + Intermediate 142: ( R) -6-( (3-(4-(3- (2-((2-(8-(Benzyloxy)-2-keto-1,2-dihydroquinolin-5-yl)-2-((t-butyldimethylmethyl))oxy) Ethyl)amino)amino-2-methylpropyl)benzhydryl)piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amine- 161 - 201206888 基)-8-Methylquinoxaline-3-caraamine

The title compound was synthesized according to the analog intermediate 101 similar to that described in Intermediate 97 to replace the 3-(2-ketopropyl)benzoic acid to synthesize the ES/MS theory (C64H72N709 SSi+): 1142.5, experiment fi =1 142· 5(Μ + Η)+ 〇Intermediate 143: (R) ·6.( (3_( (3.(2_( (2_(8_))))) -yl)-2-((t-butyldecyl)oxy)ethyl)amino)-2-methylpropyl)-indole-methylamino)methyl)phenyl)sulfonyl) -4-((3-methoxyphenyl)-8-methylquinolin-3-carboxamide method to give. I : m/z (benzyloxydimethyl cn Mace methionyl)amine 0〆

The title compound was synthesized by substituting the intermediate 96 in a similar manner to the intermediate 1 42. ES/MS (C6iH "N6Na08SSi+) : 1095.5 'Experimental 値: /η/ζ = (M + Na ) +. Method, make the theory 値1095.4 -162- 201206888 Intermediate 144 : ( R ) -6-[[3- [[4-[2-[[2-[8-(Benzyloxy)-2-keto-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl]amino]ethyl Phenyl]amine-mercapto]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

NH 0 yNH2

Intermediate 140 (135 mg, 0.133 mmol) was combined with TBAF (1M / THF, 0.4 mL) and acetic acid (23.times.) in anhydrous acetonitrile (2M) and stirred at room temperature. After 18 hours, the reaction mixture was concentrated in vacuo to a brown oil. The solid was filtered and washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ), 10.46 (s, lH), 9.09 (s, lH) &gt; 8.37 ( s * 1H ) , 8.32 (s, 1 H ) , 8.30 ( brs, 1 H ) , 8. 1 6-8·24 ( m , 2H ) , 8.03 ( s , 1H) « 7.86 ( d &gt; / = 7.9 Hz · 1H ) &gt; 7.77 ( brs « 1H ) -7.76 (dd- J = 7.6· 15.6 Hz* 1H) , 7 · 6 6 (d, "/ = 8 · 3 Hz, 2H), 7.55 ( d &gt; J = 7.6 Hz &gt; 2H ) , 7.32 - 7.41 ( m &gt; 2H ) » 7.26 - 7.32 ( m &gt; 1 H ) &gt; 7.07-7.23 ( m » 5H ), 6.61-6.69 ( m,2H) , 6.49-6.5 9 ( m,2H) , 5.28 ( s, 2H ) &gt; 5.03 ( t &gt; J = 6.1 Hz &gt; 1H ) - 3.60 ( s &gt; 3H ), -163- 201206888 3. 1 5-3.1 9 ( m,2H ) , 2·70 ( s,3H) &gt; 2.62-2.81 ( m · 7H) . ES/MS theory 値 (C51H47N608S+): 903.3, experimental 値: m/z = 903.3 (M + H+ ). Intermediate 145: (R) -6-((3-((2-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(((((((((((((((((((((((((((((((((((( -2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)phenoxy)ethyl)(methyl)aminecarboxyl)phenyl)sulfonyl )-4-((3-Methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

A solution of Intermediate 141 (0.3769 g, 0.3505 mmol) in MeOH (7 mL) was degassed for about 10 minutes by passing N2 as a bubble. The solution was cooled to 〇 ° C' and Pd/C (0.3850 g, 10 wt ° /.) was slowly added. The flask was flushed and filled with H2 for 3 times, then stirred under H2 (1 atm, balloon). The reaction mixture was warmed to room temperature and the reaction was monitored by LC-MS. After 72 hours, the reaction mixture was filtered over Celite pad. The filter cake was rinsed with 1:1 DCM/MeOH. The filtrate was concentrated, and the residue was dissolved in 3:1 MeOH / EtOAc. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; Placed in a Η 2 atmosphere. The progress of the reaction was monitored by L C - M S . After 2 4 hours, the reaction mixture was filtered through a pad of &lt -164- 201206888 The residue was purified by EtOAc EtOAcjjjjjjj ES/MS theory 値 (C53H61N609SSi+): 985.4, experiment 値: m/z = 985·5(Μ + Η)+. Intermediate 146: (R) -6-( (3-(4-(3-(2-(2-(8-(benzyl)

Oxy)-2-keto-1,2-dihydroquinolin-5-yl)-2-hydroxyethyl)amino)-2-methylpropyl)benzylidene)piperazin-1- Carbonyl)phenyl)sulfonyl)-4((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

The title compound was synthesized by a method similar to that described for Intermediate 1 44 using Intermediate 142 as a substrate. ES/MS theory 値 (C58H58N709S+): 1028.4, experimental 値: w/z = 1028·3(Μ + Η) + intermediate 147: ( R) -6-( ( 3- ( 3-(2-(2-( 2-(8-(Benzyloxy)-2-keto-1,2-dihydroquinolin-5-yl)-2-hydroxyethyl)amino)· 2-methylpropyl)-indole- Methyl benzamino)methyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-165- 201206888

The title compound was synthesized by a method similar to that described for Intermediate 1 44 using intermediate M3 as a substrate. ES/MS theory 値 (C55H54N6Na〇8S+): 981.4, experimental 値: w/z = 981.4 (M + Na Intermediate 148: (R) -6-[[3-[[8-[[2-[( Tributyldimethylmercapto)oxy]-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]octyl]amine formazan Phenyl]sulfonyl]4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

Add glacial acetic acid (0.005 mL, 0.089 mmol) and intermediate 2 (50 mg, 0. 149 mmol) to a stirred mixture of intermediate 1 12 (55 mg, 0.089 mmol) in DMF (2 mL) ) in the solution formed. The resulting solution was stirred for 3 hours, then NaBH( ΟAc) 3 (57 mg &gt; 0.267 mmol) was added portionwise. The reaction mixture was stirred overnight and poured into saturated NaHC03 (40 mL). The precipitate was filtered, washed with EtOAcjjjjjjjj This compound was used without further purification. ES/MS Theory 値 -166- 201206888 (C50H63N6O8SSi+ ) : 93 5.4, Experimental 値: m/z = 93 5.4 ( M+H+). Intermediate 149: (R) -6-[[3-[[6-[[2-[T-butyldimethylmethyl]yloxy]-2-(8-yl-yl-2-one-)丨,2-dihydroquinoline _5-yl)ethyl]amino]hexyl]amine carbaryl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]- 8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in the intermediate i 4 8 using the intermediate 1 1 3 in place of the intermediate 丨丨 2 to obtain the ❶ES/MS theory 値(C48H59N608SSi+ ) : 907.4, experimental 値: = 907.4 ( M+ H+). Intermediate 150: (R)-6-[[3-[[4-[[2-[(T-butyldimethylmethyl)oxy)-2-(8-hydroxy-2-keto)- 1,2-dihydroquinoxazol-5-yl)ethyl]amino]piperidin-1-yl]carbonyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino ]-8 -Methylquinin-3_Artemisinide

The title compound was synthesized by substituting Intermediate 133 for Intermediate 1 12 according to a procedure similar to that described for Intermediate 148. ES/MS theory 値 (C47H55N608SSi+): 891.4, experimental 値: 891.4 (M + H) + intermediate 151: (R) -6-( (3-( 4,-(4-( (2-(( Tributyldimethylmercapto)oxy)-2-(5-hydroxy-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl Ethyl)amino)butyl)-[1,1'-biphenyl]-4-yl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide

The title compound is based on a procedure similar to that described for the intermediate 148, using (R)-8-(2-amino-1-((t-butyldimethylmethyl)oxy)ethyl)- The 5-hydroxy-2H-benzo[b][l,4]oxazine-3(4H)-ketone is substituted for the intermediate 2 and is synthesized by substituting the intermediate 124 for the intermediate i丨2. ES/MS theory 値 (C57H63N609SSi+) : 1 03 5.4, experimental 値: m/z =1 03 5 ·6(Μ + Η)+. Intermediate 152: (R)_6-((3-( (4'-(4-(2-tert-butyldimethylmethyl))oxy)-2-(5-hydroxy-3 - Ketos-3,4-dihydro-2 Η-benzo[b][ 1,4 ]oxazol-8 -yl)ethyl)amino)butyl)-[丨,丨' _biphenyl]- (3)-aminocarbamido)phenyl)sulfonyl)-4_((3-methoxybenzene-168-201206888)amino)-8-methylquinolin-3-carbamide

The title compound was synthesized by substituting the intermediate 125 for the intermediate 124 according to a method similar to that described for the intermediate 1 48. ES/MS theory 値 (C57H63N609SSi+ ) : 1 03 5.4, experimental 値: w/z = 1 03 5.6 (M + H)+. Intermediate 153: (11)-6-[[3-[[4-[5-[[2-[(T-butyldimethylmethyl))oxy]-2-(8-hydroxy-2 - Ketopropyl-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]aminecarbamyl]phenyl]-sulfonyl]-4-[ ( 3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in the intermediate 148, using Intermediate 1 15 instead of Intermediate 1 12 . ES/MS theory 値 (C53H57N608SSi+): 965.4, experimental 値: m/z = 965·4(Μ + Η) + ο Intermediate 154: (R) -6-( (3-( 4-(5-(( (2-((Third-169-201206888 butyldimethylhydrazo)oxy)-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl Amino)pent-1-yn-1-yl)-2-methylphenyl)amine-carbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino) _8_methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in the intermediate 148, using Intermediate 1 17 instead of Intermediate 1 12 . ES/MS theory 値 (C52H56N609SSi): 978.4, experimental 値: w/z = 979 (M + H)+. Intermediate 155: (R)-6-((3-(4-(6-(2-((tert-butyldimethyl)methyl)oxy)-2-(8-hydroxy-2-) Ketopropyl-1,2-dihydroquinolin-5-yl)ethyl)amino)hex-1-yn-1-yl)phenyl)aminecarboxyl)phenyl)sulfonyl)-4- ((3-Methoxyphenyl)amino)-8-methylporphyrin-3-carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 148, using Intermediate 1 1 9 instead of Intermediate 1 1 2 . ES/MS theory 値 (C54H59N608SSi+ ) : 979.4 ′ Experimental test: w/z = 9 -170- ° 201206888 (M + H)+. Intermediate 156 : ( R ) -6-( ( 3- ( 4-(4-(2-(2-(2-(2-(2-(2-(2-((((((((((((((((( Ketopropyl-1,2-dihydroquinolin-5-yl)ethyl)(methyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxyl)phenyl)sulfonyl )-4-((3-Methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described for Intermediate 70, using Intermediate 103 instead of 8-amino octanol. ES/MS theory 値(C54H59N608SSi+ ) : 979.4 , experimental 値: w/z =

979·6(Μ + Η)+. Intermediate 157 : ( R) -6- ( ( 3- ( 3- ( 3- ( 5- ( 3- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Ketopropyl-1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxyl)phenyl)sulfonyl)-4- ((3-Methoxyphenyl)amino)-8-methylquinolin-3-carbamidamine-171 - 201206888 〇/

a mixture of intermediate 98 (0.35 g, 0·48 mmol) and intermediate 2 (0.24 g '0.72 mmol) in DMF (4.5 mL) eluted with diisopropylethylamine (25 mL) (50 mg) treatment. The mixture was at 5 5 . Heat in a C oil bath for 1 9 hours. The mixture was concentrated at low pressure and purified by automated flash gel chromatography using a 25 g Silicycle SiliSep flash column (dichloromethane / methanol / ammonium hydroxide). The desired fraction was concentrated under reduced mpqqqqqqqq ES/MS theory 値 (C53H57N608SSi+): 965.4, experimental 値: w/z = 965·5 (Μ + Η)+. Intermediate 158: (R) - (2-((t-butyldimethyl)methyl)oxy)-2-(8-yl-yl-2-mercapto-1,2-carbazin-5 -yl)ethyl)(4-(2-(4-(3-((3-methoxyphenyl)amino))-8-methylquinoline- 6-yl)sulfonyl)benzamideamino)phenyl)-L3-dithiolan-2-yl)butyl)carbamic acid tert-butyl ester

Add DMAP (20 mg), HATU (1 10 mg, 0.29 mmol) -172 - 201206888 and DIEA (0.15 mL, 0_87 mmol) to 3-[[3-aminocarbazin-4-[(3) -Methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoic acid (144 mg, 0,29 mmol) and intermediate 105 (0.18 g, 0.35 mmol) in NMP (3 mL) in the mixture formed. The reaction mixture was stirred in EtOAc EtOAc EtOAc (EtOAc) , 27%). ES/MS theory

値(C60H71N6O10S3Si+ ) : 1 159.4, experimental 値: w/z = 1 1 59·6(Μ + Η)+. Intermediate 159: (R) -(2-(8-((t-butoxycarbonyl)oxy)-2-one-1,2-dihydroquinolin-5-yl)-2-(( Third butyl dimethyl fluorenyl) oxy) ethyl) (6-(4-(4-(3-((3-methoxyphenyl)- 4-((3-methoxyphenyl)). Amino)_8-methylquinolin-6-yl)sulfonyl)benzamideamino)phenyl)butoxy)hexyl)carbamic acid tert-butyl ester

0

The title compound was synthesized by substituting the intermediate 108 with 8-aminooctyl alcohol according to a method similar to that described for the intermediate 70. ES/MS theory 値(C68H87N6〇l3SSi+ ) : U55.6 , experimental 値: m/z = 1 256(M + H)+. -173- 201206888 Intermediate 160: (R) - (2-(8-((T-Butoxycarbonyl)oxy)-2-one-1,2-dihydroquinolin-5-yl)- 2-((Tertiary butyldimethylmethyl)oxy)ethyl)(6-(4-(3_((3-methoxymethyl)amino)-) 8_Methylquinoline·6•yl)sulfonyl)benzhydrylamino)phenylethoxy)hexyl)carbamic acid tert-butyl ester

The title compound was synthesized according to a method similar to that described for Intermediate 70, using Intermediate 111 instead of 8-amino octanol. ES/MS theory 値(C6IH75N6〇llSSi+ ) : 1127.5 , experimental 値: w/z = 1 1 27.7(M + H)+. Intermediate 161: (r) _6-((3_((4_(5-(8- hydroxy-2-indolyl-1,2-dihydroquinolin-5-yl)-2,2,3,3_4 Benzyl-4,14-dioxa-7-aza-3-salt-seventh -18-yl)phenyl)(methyl)amine-methylphenyl)phenyl)sulfonyl)-4-( (3-methoxyphenyl)amino)-8-methylquinoline_3_carbamamine 0

The title compound was synthesized by substituting the intermediate 99 with the intermediate 99 according to a procedure similar to that described for the intermediate 157. ES/MS buried 値 (C54H73BrN609SSi+): 1 069.5, experimental 値: w/z = 1〇69 7 (M + H)+. Intermediate 162: (R) -6-((3-(4-(5-((2)(( butyl dimethyl decyl)oxy))-2-(5-hydroxy-3-one) Base-3,4 -~ is -N 2H-benzo[b][l,4]oxazin-8-yl)ethyl)amino)pentan-1-alkyne-yl)-2-methyl Phenyl)amine-carbamoyl)phenyl)sulfonyl)-4((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

The title compound was synthesized according to a method similar to that described for the intermediate compound, </ RTI> </ RTI> <RTIgt; ES/MS theory 値 (C53H58N609SSi): 982.4' Experimental 値: w/z = 98 3 (Μ + Η)+. Intermediate 163: (R) -6-((3-(4-(5-(5-(2-tert-butyldimethylmethyl))oxy)) 2_(5-hydroxy-3-one Base_3,4·dihydro-2Η-benzo[b][l,4]oxazin-8-yl)ethyl)amino)pent-1-yn-1-yl)-3-ylbenzene Aminomethyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-175- 201206888

The title compound was synthesized by substituting the intermediate 118 for the intermediate 124 according to a method similar to that described for the intermediate 151. ES/MS theory 値 (C53H58N6O9SSO. 982.4, experimental 値:; ti/z = 983(M + H)+. Intermediate 164: (R) -6-( (3-( 6-( (2-(( Tert-butyl-methyl-methyl)oxy)-2-(6-carbyl-3-indolyl-3,4-diamino-2Η-benzo[b][l,4]oxazin-8 -ethyl)ethyl)amino)hexyl)amine,carinyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-yl Guanamine

The title compound was used according to a method similar to that described for Intermediate 1 49, using (R)-8-(2-amino-1-((t-butyldimethylmethyl) oxy)ethyl)-6 -Hydroxy-2H-benzo[b][l,4]oxazine-3(4H)-one is synthesized by substituting intermediate 2. ES/MS Theory 値 (C47H59N6〇9SSi+ ): -176- 201206888 91 1.4, Experimental 値: m/z II 91 1·5(Μ + Η)+ 〇 Intermediate 165: (R) -6-( (3- ((4-(5-((2-T-butyldimethylmethyl)oxy)-2-(6-hydroxy-3-keto-3,4-dihydro-2H-benzo) [b][l,4]oxazin-8-yl)ethyl)amino)pentan-1-yne-indole-yl)phenyl)aminocarboxamido)phenyl)sulfonyl)-4-( (3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

OH

The title compound is based on a procedure similar to that described for the intermediate 1 5 3 using (R)-8-(2-amino-1-((t-butyldimethylmethyl)oxy)ethyl)- 6•Hydroxy-2H-benzo[b][l,4]oxazin-3(4H)-one is synthesized by substituting intermediate 2. ES/MS theory 値 (C52H57N609SSi + ): _ 969.4, experimental 値: = 969·5 (Μ + Η)+. Intermediate 166: (R) -6-[[3-[[4-[5-[[2-[3-[[((t-butyl dimethyl decyl) oxy)methyl]-4-) Hydroxyphenyl]-2-hydroxyethyl]amino]pentyl]phenyl]aminocarboxylidene]phenyl]sulfonyl]-4_[(3-methoxyphenyl)amino]8 - Methylquinoline-3-carbamamine-177- 201206888

The title compound was synthesized according to a method similar to that described for the intermediate 148, using Intermediate 9 in place of Intermediate 2 and Intermediate 1 2 〇 in the intermediate. ES/MS theory 値 (C5iH62N5 〇 8ssi+): 932.40 * Experimental 値: m/z = 93 2.4 (M + H) + =

Intermediate 167: (R) -6-[[3-[[6-[[2-[(T-butyldimethylmethyl))oxy]-2-(3-carbanoyl-4) Phenylphenyl)ethyl]amino]hexyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)aminopyr8-methylquinolin-3 Formamide

The title compound was synthesized by substituting the intermediate 13 for the intermediate 2 according to a method similar to that described for the intermediate 1 49. Es/MS theory 値 (C46H59N608Ssi+): 883 4, experimental 値: w/z = 883 (m + h)+. Intermediate 168: (R) -6-((3-((6-(6-(2-butyldimethyl)methyl)oxy)-2) (3-carbamimidyl) 4-hydroxyl Phenyl)ethyl)amino)hexyl)(methyl)aminecarbamido)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline -3-methanamine-178- 201206888 TBS, ο

The title compound was synthesized by substituting the intermediate 1 1 4 with the intermediate 1 1 4 for the intermediate 1 1 3 (C47H6〇N6〇8SSi): 896.4, Experimental 値# Intermediate 169 : ( R ) .6-( ( 3- ((6-Dimethyldecyl)oxy)-2-(5-hydroxy-3-([b][l,4]oxazine-8-yl)ethyl)amino)alkyl)phenyl )) A similar method described in (3-methyl-methyl quinolin-3-carbamide), resulting in .ES/MS theory 値: /n/z = 897 (Μ + Η ) + ((2-((t-butyl keto)-3,4-dihydro-2-indole-phenylhexyl)(methyl)amine methoxyphenyl)amino)-8 -

The title compound is based on the intermediates! 5 j is synthesized by substituting the intermediate 1 1 4 for the intermediate 丨 2 4 (C48H6〇N609SSi): 942.4, experimental 値

Intermediate 170: (R) -6-((3-((6-dimethylmethyl)oxy)_2) (5_hydroxy_3_ and [b][l,4] oxazin-8-yl Ethyl)amino)alkyl)sulfonyl)- 4-((3-methoxyphenyl). A similar method to give. ES/MS theory ml: mlz = 925(M + H)+ Bismuth((2-((t-butyl keto)-3,4-dihydro-2H-phenylhexyl)amine,carbenyl)anilino)-8-methylsalthion _ -179- 201206888 3 - formazan Amine 0〆

The title compound was synthesized by substituting the intermediate 1 1 3 for the intermediate 1 24 according to a method similar to that described for the intermediate 151. ES/MS theory 値 (C47H58N609SSi): 91〇.4 ′ Experimental 値: w/z = 911(M + H)+. Intermediate 171 : ( R) -6-[[3-[[4-[5-[[2-[(T-butyldimethylmethyl))oxy]-2-(3-carbamido) -4-hydroxyphenyl)ethyl]amino]pent-1-ynyl]phenyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3.methoxyphenyl)amino ]-8-methylporphyrin-3-carboxamide

The title compound was synthesized by substituting the intermediate 13 for the intermediate 2 according to a method similar to that described for the intermediate 153. ES/MS theory 値 (C5iH57N6 〇 8SSi+): 941.4, experimental 値: w/z = 941 (M + H)+. Intermediate 172: (R) -6-((3-(4-(5-(2-tert-butyldimethyl)methyl)oxy)-2 (5-hydroxy-3-) Keto-3,4-dihydro-2H-benzo[b][l,4]oxazol-8-yl)ethyl)amino)pentan-1-ynyl-1-yl)phenyl)amine A Mercapto)phenyl)sulfonyl)-4-((3-methoxyphenyl-180- 201206888)amino)-8-methylquinolin-3-carboxamide 0

The title compound was synthesized by substituting the intermediate 1 15 for the intermediate 124 according to a method similar to that described for the intermediate 151. ES/MS theory 値 (C52H56N609SSi) ·· 968.4, experiment 値·· w&quot; = 969(M + H)+. Intermediate 173: (R)-6-[[3-[[6-[[2-[3-[[(t-butyldimethylmethyl))]oxy]methyl]-4-hydroxyphenyl Hydroxyethyl]amino]hexyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

The title compound of TBS and 〇々 HO was synthesized by substituting the intermediate 9 for the intermediate 2 according to a method similar to that described for the intermediate 1 49. ES/MS theory 値 (C46H60N5O8SSi+): 870.4, experimental 値: w/z = 870 (M + H) + intermediate 174 : ( R) -6-[[3-[[4-[[2-[3- [[(T-butyldimethylmethyl)oxy]methyl]-4-hydroxyphenyl]-2-hydroxyethyl]amino]piperidin-1-yl-2012-06888 base]carbonyl]benzene Sulfhydryl]-4-[(3-methoxyphenyl)amino]-8-methylporphyrin-3-carboxamide

The title compound was synthesized by substituting Intermediate 9 for Intermediate 2 according to a method similar to that described for Intermediate 150. ES/MS theory C (C45H56N508SSi+): 854.4, experimental 値: /w/z = 854 (M + H)+. Intermediate 175: (R) _6-[[3-[[6-[[2-[(T-butyldimethylmethyl))oxy]-2-(4-hydroxy-3-(methylsulfonate) Amidino)phenyl)ethyl]amino]hexyl]aminecarboxyl]phenyl]sulfonyl]·4·[(3-methoxyphenyl)amino]-8-methyl salicin 3-carbamamine

The title compound was synthesized according to a method similar to the one described in Intermediate 149, using Intermediate 18 instead of Intermediate 2. ES/MS theory 値 (C46H61N609S2Si+): 93 3.4, experimental 値: w/z = 93 3 (Μ + Η)+. Intermediate 176: (R) Tert-butyldimethylmethyl)oxy]methyl]-4-hydroxyphenyl]_2-hydroxyethyl]amino]hexyl](methyl)aminecarbamyl] Phenyl]sulfonyl]3-methoxyphenyl)amine-182 - , 0 201206888 base]·8-methylquinoline-3_carboxamide

The title compound was synthesized according to the intermediate 1 1 4 substituted with the intermediate 1 1 4 (C47H62N5〇8SSi+): 884.4' Experimental intermediate 177: (R) -6- ( ( 2-mercapto)oxy)-2-(6-hydroxy-3-keto[b][l,4]oxazin-8-yl)ethyl)amino)deca-((3-methoxy) A similar method as described for phenyl)amino)-8-methylquina is made. ES/MS theory 値: mtz = 884 (M + H) + ((t-butyldimethyl-3,4-dihydro-2H-benzo-alkyl)sulfonyl)-4-lin-3 -Procarbamide

The title compound is based on the use of (R)-8-(2-amino-1-((t-butylethyl)-6-hydroxy-2H-benzo[bni,4]oxazine with the intermediate 1 4 8 - Substance 2 and using intermediate 126 instead of intermediate shirt ES/MS theory 値 (C45H64N508SSi+): =862·6(Μ + Η)+. The similar method, such as dimethyl decyl)oxy) 3 ( 4H )-keto-substituted intermediate J 1 1 2 to obtain "862.4, experimental 値: m/z -183- 201206888 Intermediate 178: (R) -6-( (4,-(3-( (2-(( Tributyldimethylmercapto)oxy)-2-(5-hydroxy-3-keto-3,4-dihydro-2H-benzo[1?][1,4]indole -8 -yl)ethyl)amino)propyl)-[1,1'-bi]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8- Methylquinoline-3-carbamide

The title compound was synthesized by substituting the intermediate 129 for the intermediate 91 according to a method similar to that described for the intermediate. ES/MS theory 値 (C49H56N5 08SSi+) : 902.4, experimental 値: m/z = 902·5(Μ + Η) + Intermediate 179: (R) -6-( (4,-(3-( (2- ((Tertiary butyldimethylmethyl)oxy)-2-(5-hydroxy-3-keto-3,4-dihydro-2-indole-benzo[b][l,4]oxazine- 8-yl)ethyl)amino)propyl)-[1,1'-biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8 -methylquinolin-3-carbamidamine

184-201206888 The title compound was synthesized according to a method similar to that described for the intermediate 1 2 5 by using the intermediate 1 30 instead of the intermediate 9 1 . ES/MS theory 値 (C49H56N508SSi+): 902.4, experimental 値: w/2= 902.5 (M + H) + 〇 intermediate 180: (R) -6-( (4,-(5-( (2-(( Tert-butyldimethylmercapto)oxy)-2-(5-hydroxy-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- Ethyl)amino)amino)pentyl)-[1,1,-biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8- Quiquinolin-3-carboxamide

The title compound was synthesized by a method similar to that described for the intermediate 1 2 5 using the intermediate 1 3 1 instead of the intermediate 91. The crude product was purified by EtOAc EtOAc (EtOAc) ES/MS theory 値 (C51H6GN508SSi+): 93 0.4, experimental 値: m/z = 930.5 (M + H)+. Intermediate 181: (R) -6-((4,-(5-((2-tert-butyldimethylmethyl)oxy)-2-(5-hydroxy-3-keto)- 3,4-Dihydro-2H-benzo[1)][1,4]oxazol-8-yl)ethyl)amino)pentyl)-[1,1'-biphenyl]-3- 185- 201206888 sulphonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline _ 3 -carboxamide 0

The title compound was synthesized according to a method similar to that described for the intermediate 1 2 5 by using the intermediate 1 3 2 instead of the intermediate 9 1 . ES / MS theory 値 (C5lH60N5O8SSi+): 930.4, experimental 値: m/z = 930.5 (M + H) + Example 1: (foot)-6-[[3-[[8-[[2-hydroxy-2- (8-Hydroxy-2-keto-1,2-dihydroquinoline-5-yl)ethyl]amino]octyl]amine-mercapto]phenyl]sulfonyl]-4-[(3) -Methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

A solution of TBAF (1.0 M in THF, 0.244 mL, 0.244 mmol) was added to a solution of Intermediate 148 (76 mg, 0.08 13 mmol) in THF (2 mL). After stirring overnight, glacial acetic acid (0.023 mL, 0.407 mmol) was added and stirring was continued for 16 hours. The reaction mixture was concentrated and purified with EtOAcjjjjjj -186- 201206888 . 'η NMR ( 400 MHz &gt; DMSO-d6 ) δ 11.90 ( m,1H), 11.18 (m,lH) , 10.49 (m,2H) , 9_33 (brs,lH), 9.03 ( s, 1H) &gt; 8.92 ( s * 1H ) , 8.7 5 ( t, 1H, · / = 5.7 Hz) , 8.35-8.06 (m, 4H) &gt; 7.90-7.5 5 ( m - 2H ) - 7.30-7.13 ( m &gt; 2H ) &gt; 6.98 ( d &gt; 1H &gt; J = 8.1 Hz) , 6.76 (dd , 1H, "7 = 2.2, 8.2 Hz) , 6.70 (m, lH) &gt; 6.58 ( m &gt; 2H ) ,6_14(m,lH) ,5.33(m,lH) ,3.64(s,3H)

, 3.28 ( dd, 2H, J = 6.7, 13.1 Hz ) » 3.15-2.89 ( m » 2H ) , 2.74 ( m, 3H) , 2.54 ( s, 3H) , 1.73 - 1.26 ( s, 12H) ; ES/MS Theoretical 値(C44H49N6〇8S+) : 821.2, experimental 値:m/z = 821.3(M + H)+ = Example 2: (R) -6-[[3-[[6-[[2-hydroxy-2- (8-Hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]hexyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3- Methoxyphenyl)amino]-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 149 as a substrate. *H NMR (400 MHz, DMSO-d6) δ 11.90 (m, 1H), 10.93 (m &gt; 1H), 10.50 (m, 2H), 9.07 (m, lH), 8.92 (m, lH) &gt; 8.80 ( m - 1H ) &gt; 8.64-7.67 ( m &gt; 12H ) &gt; 7.17 ( m &gt; 1H ) , 6.99 (d, lH, J = 7_9) , 6.73 (m, -187- 201206888)

1H ) , 6.60 (m, 2H) &gt; 6. 1 3 ( brs - 1 H ) &gt; 5.30 ( m &gt; 1H )&gt; 3.65 ( s « 3H ) , 3.31 (m, 2H) , 3.02 (m, 3H), 2.72 ( m &gt; 2H ) , 1.69-1.26 (m, 8H) ; ES/MS theory 値 ( C42H45N608S+) : 793.3, experimental 値: m/z = 793·3 (Μ + Η)+. Example 3: (R) -6-[[3-[[4-[[2-hydroxy-2·(8-hydroxy-2-keto-l,2-dihydroquinolin-5-yl)ethyl) Amino] piperidine l-yl]carbonyl]phenyl]sulfonyl]-4-[(3.methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate compound 150 as a substrate but without glacial acetic acid. NMR ( 400 MHz, DMSO-d6 ) δ 1 1 ·13 ( brs,1H ), 10.5 1 ( brs &gt; 1Η ) &gt; 9.05 ( s - 1Η ) ' 8.78 ( m , 2Η ), 8.38 ( m &gt; 2Η ), 8.05(m,2H) ' 7.75 ( m &gt; 3H ) »7.18

(m, 2H), 6.99 (d « 1H &gt; 7 = 8.2 Hz) ' 6.72 ( m &gt; 2H ), 6.61 ( m, 2H) &gt; 6.20( brs ' 2H ) ' 5.3 3 ( m,1H ) , 4.54(m,lH), 3.68(s,3H) &gt; 3.54-2.75 ( m , 7H ) , 2.70 ( s, 3H ) , 2.05 ( m, 2H) ' 1.52 ( m, 2H). ES/MS Theory 値 (C41H41N608S+): 777.3 ′ Experimental 値: w/z = 777.3 (M + H)+. -188- 201206888 Example 4: (R)-6-[[3-[[4-[5-[[2-hydroxy-2-( 8-hydroxy-2-keto)-1,2-dihydroquinoline -5-yl)ethyl]amino]pent-1-ynyl]phenyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]- 8-methylquinoline-3-carboxamide 2,2,2-trifluoroacetate.

The title compound was synthesized according to a method similar to that described for Intermediate 1 48, using Intermediate 6 in place of Intermediate 2 and Intermediate 1 1 5 instead of Intermediate 1 1 2 . *H NMR (400 MHz &gt; DMSO-d6) δ 11.07-10.9 1 ( m , 1Η ) ' 1 0.68- 1 0.5 9 ( m,1Η) ,1 0.56-1 0.46 ( m,2Η) , 9.〇7 (s ' 1H) , 8 · 7 2 - 8.5 2 ( m, 2 Η ), 8 · 4 3 - 8 · 2 6 ( m, 3 Η ) &gt; 8.26-8.12 ( m * 2H ) &gt; 8. 1 1 -8.02 ( m » 1H ) , 7.79 ( d' 4H « J = 8.85 Hz ), 7.43 ( d, 2H &gt; J = 8.74 Hz ), 7·22-7.06 ( m &gt; 2H ) &gt; 7.04-6.93 ( m * 1H ) 1 6.72-6.63 ( ^ ' 2H ) , 6.63 - 6.5 1 ( m, 2H ) &gt; 6.24-6.12 ( m · ih ) ' 5.3 3 - 5.2 5 ( m,1 H ) ,3.6 0 ( s,3 H ) ,3 · 1 8 - 3 · 〇8 (quasi' 4H ) , 2.71 ( s,3H ) , 2.54 ( s,2H) 5 2.00-1.87 ( ^ ' 2H ) ; ES/MS theory 値 ( C47H43N608S+ ) : 851 .3, experimental 値: m/z = 85 1 .3(M + H)+ « Example 5: ( R ) -6-[[3-[[4-[5-[[2-hydroxyl -2- (8-hydroxyindole-189- 201206888 1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]amine-methylmethyl]phenyl]sulfonate Mercapto]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carbamide

TBAF (1.0 M) (1.036 mL, 1.036 mmol) was added to a solution of intermediate 153 (500 mg, 0.518 mmol) and acetic acid (0.5 mL) in EtOAc (15 mL). The solution was stirred at room temperature overnight. 7N MeOH/NH4 was then added to the acidic mixture to neutralize. All solvents were removed under vacuum and the resulting solid was suspended in MeOH (30 mL) and filtered. The solid was treated with a Me OH / water mixture (1:1) (40 mL) and was shaken for 5 min. The residual solid was filtered, washed with EtOAcqqqqqqq 'H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 10.59 (s, 1H), 9.06 (s, 1H), 8.3 4 (d, 1H, "/ = 1.74 Hz) &gt; 8.28 ( s &gt; 2H ) - 8. 1 7 ( t &gt; 2H » J = 8.5 1 Hz ) &gt; 8.03 -7.98 ( m - 1H ) , 7.88-7.82 (m,1H) , 7.73(t, 4H &gt; J = 8.08 Hz) , 7.37 ( d - 2H &gt; 7 = 8.71 Hz) , 7.06 (m, 2H) , 6.89 ( d, 1 H &gt; J = 8.12 Hz) , 6.61 ( dd, 2H &gt; J = 8.52 , 1.64 Hz) , 6 · 4 9 ( dd, 2 H, · / = 13.94, 5.62 Hz) &gt; 5.05-4.99 ( m - 1H ) , 3.57 ( s, 3H) &gt; 2.69 (m, 6H) &gt; 2.43 ( t &gt; 2H &gt; J = 6.98 Hz) , 1.71-1.61 (m -190- 201206888 , 2H) ; ES/MS theory 値 (C47H43N608 S+) : 851.3, experimental 値: mlz = 851·3 (Μ + Η) + ; CHN analysis theory C ( C47H46N608S_2H20 ) (MW = 8 86.3 0 ) : 0 = 63.64% ; Η = 5.2 3 % ; Ν = 9 · 4 8 %. Experimental 値: C = 6 3 · 5 0 %, Η = 4.7 5 %, Ν = 8.98%. Example 6: (R) -6-[[3-[[4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto)-

1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]amine-methylmethyl]phenyl]sulfonyl]-4-[(3-methoxy Phenyl)amino]-8-methylquinoline-3-carbamide hydrochloride, hydrazine

ΝΗ 2 II ^ Example 4 was replaced with the hydrochloride salt using Dowex exchange resin. 'H NMR (400 MHz, DMSO-d6) δ ppm 11.07-10.91 (m &gt; 1 H ) &gt; 10.68-10.59 (m&gt; 1H) &gt; 1 0.5 6 - 1 0.4 6 ( m &gt; 2H ), 9.07 ( s, 1H) &gt; 8.72-8.5 2 ( m &gt; 2H ) &gt; 8.43 -8.26 ( m &gt; 3H ) - 8.26-8. 12 ( m &gt; 2H ) &gt; 8.1 1-8.02 ( m &gt; 1H), 7.79 (d, 4H, J = 8.85 Hz), 7.43 (d &gt; 2H &gt; J = 8.74 Hz) &gt; 7.22-7.06 ( m &gt; 2H ) &gt; 7.04-6.93 ( m &gt; 1H ) , 6.72-6.63 (m, 2H), 6.63-6.5 1 ( m, 2H ) - 6.24-6.12 ( m - 1H ) &gt; 5.3 3 -5.25 ( m &gt; 1H ) , 3.60 (s, 3H) , 3.18- 3.08 (m, 4H ) &gt; 2.71 ( s - 3H ) , 2.54(s, 2H) - 2.00- 1.8 7 ( m - 2H) ; ES/MS Theory 値 (C47H43N608S+) : 851.3, Experiment 値-191 - 201206888 : Mlz = 85 1 .3(M + H)+ » Example 7: (R) -6-( (3-( 4-(6-((2-)-) -mercapto-1,2-aminosulfate-5-yl)ethyl)amino)hexan-1-yl-1-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4 -((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

〇〆

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate compound 15 5 as a substrate. *H NMR ( 400 MHz, dmso-d6 ) δ 11.25 ( s,1 Η ) , 10.64 (s &gt; 1 Η ) &gt; 1 0.50 ( m &gt; 2Η ) &gt; 9.03 ( s - 1 Η ) &gt; 8.57 ( m , 2H) , 8.43 ( s, lH) &gt; 8.36 ( s &gt; 1H ) &gt; 8.32 ( m &gt; 1H )&gt; 8.22 ( d &gt; J = 7.9 Hz · 1H ) , 8.18-8.10 (m , 2H), 7.92 ( d &gt; J = 7.9 Hz &gt; 1H ) , 7.8 6-7.73 ( m &gt; 3H ) &gt; 7.47-7.36 ( m &gt; 2H ) &gt; 7. 1 7 ( t &gt; J = 8.4 H z &gt; 2 H ) &gt; 6.98 ( d &gt; J = 8.2 Hz &gt; 1H ) , 6.72 (m, 2H) &gt; 6.60 ( m &gt; 2H ), 6.15 ( bs - 1H ) &gt; 5.3 1 ( m &gt; 1H ) - 4.80 ( bs &gt; 1H ), 3.60 ( s, 3H) &gt; 3.46-2.77 ( m &gt; 4H ) &gt; 2.5 0-2.45 ( m ^ 2H ) , 2.7 1 ( s &gt ; 3H ) , 1.84 - 1.74 ( m &gt; 2H ) , 1.62-1.54 (m &gt; 2H ) ; ES/MS theory 値 (C48H45N6〇8S+) : 8 65.3, experimental 値: w/z = 8.65 ·4 (Μ + Η)+. -192- 201206888 Example 8: ( R) -6- ( ( 3- ( 4-(4-(2-hydroxy-2-(2-hydroxy-2-)-2-hydroxy-2-keto-1,2-dihydroquinoline) -5-yl)ethyl)(methyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4-((3-methoxy) Phenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 1 56 as a substrate. NMR ( 400 MHz &gt; DMSO-d6 ) δ 10.79 ( s, 1 Η ) , 10.61 (s, 1 Η ) , 1 0.34- 1 0.25 ( m &gt; 2 Η ) , 9.09 ( s, 1 Η ) &gt; 8.3 9-8.28 ( m,3H) , 8.23-8.16 ( m,2H) , 8.05 -8.02 ( m &gt; 1H ) - 7.87 ( m &gt; 1H ) &gt; 7.8 1 -7.74 ( m &gt; 4H ) - 7.39

(d, 2H, J = 8.4 Hz), 7. 13-7.08 ( m &gt; 2H ) &gt; 6.92 ( d , 1H, / = 8.0 Hz) , 6.67-6.61 ( m, 2H ) , 6.54 - 6.47 ( m &gt; 2 H ) &gt; 5.10 ( m &gt; 1H ) , 3_60(s, 3H) &gt; 2.71 ( s &gt; 3H ) , 2.67-2.59 ( m,5H ) - 2.39-2.27 ( m - 4H ), 1.69 - 1 .5 8 ( m &gt; 2H ) ; ES/MS theory 値 (C48H45N608S+): 865.3, experimental 値: w/z = 865.4 (M + H)+. Example 9: ( R) -6- ( ( 3- ( 3-( 5-(2-hydroxy-2-(2-hydroxy-2-keto)-1,2-dihydroquinolin-5-yl) Ethyl)amino)amino-1-acetyl-1--1-193-201206888 phenyl)amine carbhydryl)phenyl)sulfonyl)-4-fhk (3-methoxyphenyl)amine -8-methylquinoline-3-carboxamide

The title compound was synthesized according to the same procedure as described in Example 1 using the intermediate substance 157 as a substrate. ,1Η) , 10.54 1Η ), 8.36 ( s 3Η ), 8.04 ( s 丨(m, 4H ), weep, 2H ) , 6.92 , 6.55-f ;.4 9 ( m * 2.82 ( m,2H 9 ( m, 2H),

'H NMR ( 400 MHz &gt; DMSO-d6 ) δ 10.80 ( s,1 Η ) ^ (s,1 Η ) ,1 0.35 ( bs,2H ) &gt; 9.09 ( s ,1H ) - 8.32 ( s &gt; 1 H &gt; 8.24-8.1 5 ( m , 1H) &gt; 7.91-7.83 ( m - 1H ) &gt; 7.80-7. 7.37 ( t &gt; 1H &gt; J = 8.0 Hz ) , 7.18-7.06 (m, 2H) , (d » 1H » J = 8.0 Hz ) · 6.63 ( m &gt; 2H ) , 2H) &gt; 5.11 ( m &gt; 1H ) , 3.59(s,3H) , 2.82( )· 2.71 ( s &gt; 3H ) , 2.67 ( m, 2H) , 2.59 ( m,:

1.77- 1.73 (m, 2H); ES/MS theory 値 (C47H43N6 〇 8S+) 851.3, experimental 値: w/z = 851.4 (M + H)+. Example 10: (1〇-6-[[3-[[4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl) Ethyl]amino]pentyl]phenyl]aminocarbazinyl]phenyl]sulfonyl]4-[(3-methoxyphenyl)amino]-8-methylquinoline-3 -Procarbamide 2,2,2-trifluoroacetate-194- 201206888

Cf3co2h η Ο

The title compound was synthesized according to the method similar to that described in Example 4, using the intermediate 12 hydrazine instead of the intermediate 115. NMR ( 400 MHz, DMSO-d6) δ 1 1.02-10.90 (m,1 Η), 10.53-10.49 (m,1 Η), 10.48-10.43 (m,2H) » 9.12-

9.03 ( m,1H) &gt; 8.60-8.44 ( m &gt; 2H) » 8.41-8.28 (m&gt; 2H ) · 8.24-8.19 ( m &gt; 1H ) - 8.17-8.13 ( m - 1H ) &gt; 8.09-8.03 ( m,iH) , 7.93 -7.8 5 ( m,1H) , 7.83 -7.73 ( m,2H ) 1 7.7 1 -7.64 ( m &gt; 2H ) ' 7 · 2 5 - 7 · 1 8 ( m ' 2 H ) ' 7.17-7.10 (m,2H) , 7.03-6,93 (m,1H) ,6.71-6.61 ( m ' 2H ) , 6.60-6.52 ( m,3H ) &gt; 6.18-6.12 (m&gt; 1H) ' 5.34-5.25 ( m,1H) , 3.60 ( s,3H) ' 3.13-2.91 ( m ' 4H ) &gt; 2.71 ( s - 3H ) - 2.62-2.56 ( m » 1H ) , 1.72-1.55 (m &gt; 4H 1.3 8- 1.27 ( m &gt; 2H ) ; ES/MS theory 値 ( C47H47N6 〇 8S+) : 855.31, experimental 値: w/z = 85 5.4 (M + H)+. Example 11: 6-[3-[[4-[2-[[2-i-yl-2-(8-carbyl-2-indolyl-1,2-hydroquinolin-5-yl)ethyl) Amino]ethyl]piperazin-1-yl]carbonyl]benzenesulfonyl]-4-(3-methoxyphenylamino)-8-methylsalrin-3-carboxamide-195 - 201206888

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 139 as a substrate. !H NMR ( 400 MHz &gt; DMSO-d6 ) δ 10.80 ( s,1Η ) , 10.50 (s &gt; 1Η ) &gt; 10.45( s' 1Η) &gt; 9.08 ( s &gt; 1H ) &gt; 8.38 ( s

, 1H) &gt; 8.30 ( s &gt; 1H ) , 8.17 (d, lH, &gt; 7 = 9.2 Hz), 8.00 ( s &gt; 1H ) - 7.78 ( m &gt; 2H ) - 7.70 ( m - 2H ) &gt 7.16 (s,lH) ,7_14(s,lH) &gt;6.98(d&gt;1H&gt; J = 7.6 Hz) &gt; 6.71 ( d - 1H &gt; J - 9.6 Hz ) - 6.67 ( s &gt; 1H ) &gt ; 6.60 ( m , 1H) &gt; 6.53 ( d &gt; 1H &gt; J = 7.6 Hz ) &gt; 6. 16 ( s &gt; 1H ),

5.53 ( brs, 1H) , 3 · 6 6 ( brs, 7 H ) , 3 . 1 5 - 3 · 0 4 ( m, 6 H ), 2.70 (brs ° 6H) &gt; 2.39 ( brs &gt; 2H ) ; ES/MS theory値

(C42H44N708S+): 806.3, experimental 値: w/z = 806.3 (M + H) + Example 12: Γ and ;-6-[[3-[[4-[2-[[2-hydroxy-2- (8 -hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]ethyl]phenyl]aminocarboxyl]phenyl]sulfonyl]-4-[ ( 3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide-196-, 0 201206888

The nh2 intermediate 144 (119 mg) was dissolved in a mixture of EtOH (2 mL) and THF (3.5 mL) and hydrogenated in the presence of 10% Pd/C at room temperature and ring pressure. After completion, the reaction mixture was filtered, and then purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Η ), 10.53 ( s, 1H ) , 10.51 ( brs, 1H ) , 9.04 ( s, 1H ), 8.73 ( brs &gt; 2 H ) , 8.41 (s, 1H ) &gt; 8.35 ( s &gt; 1H) &gt; 8.33 (s,lH) &gt; 8.23 ( d &gt; J = 7.7 Hz &gt; 1H ) . 8.16 ( d * y = 10.0 Hz &gt; 1H ) &gt; 8.10 ( s &gt; 1H ) &gt; 7.91 ( d &gt; J = 8.0 Hz · 1H) , 7.74 - 7.83 ( m, 4H) , 7.2 8 ( d, "/ = 8 · 6 H z, 2 H ) &gt; 7.10-7.19 (m > 2H) &gt; 6.99 ( d &gt ; J = 8.1 Hz &gt; 1H ) *

6 · 6 9 - 6 · 7 3 ( m, 2 H ) , 6 · 5 7 _ 6 · 6 2 ( m, 2 H ) , 5.3 3 ( d, &gt; / = 7.7 Hz &gt; 2H) , 3.61 ( s, 3H) * 2.83-3.50 ( m &gt; 7H ), 2.71 ( s, 3H ). ES/MS theory 値 (C 4 4 H41 N 6 0 8 S + ) : 813.3 , experimental 値: = 813.3 (M + H)+. Example 13: 6-[[3·[[3-[2-[[(R))-2-hydroxy-2-(8-hydroxy-2. keto-1,2-dihydroquinolin-5-yl) Ethyl]amino]propyl]-N-methylbenzamideamino]methyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8- Methylquinoline-3·carbamamine-197- 201206888

The title compound was synthesized according to a method similar to that described in the intermediate 148, using Intermediate 6 in place of Intermediate 2 and Intermediate 1 137 in Substituting Intermediate 1 1 2 . 'H NMR ( 400 MHz ' DMSO-d6) δ 11.08 ( brs · ιη) 10.49 ( m, 2Η) , 9.〇5 ( m,1Η) ' 8·69 ( m ' 2Η) 8.37 (m, 2H), 8.l4(m'lH), 8.01(m,lH), 7.81 (m &gt; 2 H ) , 7.61 ( m ' 2H) &gt; 7.52-7.07 ( m &gt; 5H) 6.99 (d&gt;1H&gt; J = 8.2 Hz) » 6.85-6.52 (m&gt; 3H) » 6-2° (m, lH), 5.32 (m, lH), 4_78 (ra, 2H) . 4.57 (111 , 3H), 3.58 ( m, 4H) , 3.3 9 - 2 · 9 5 ( m,4 H ), 2.89 ( m,2H), 2.69 (s,3H), 1.03 (m,3H) :ES/MS_n· 値(C47H47N6〇8S+ ) : 85 5.3 ' Experimental 値: m/Mus 85 5.4(M + H)+ » Example 14: (R) -6-[[3-[[6-[[2-hydroxy-2-( 8-hydroxy-2-yl)* 1,2-dihydroquinolin-5-yl)ethyl]amino]hexyl](methyl)amine-methyl phenyl]sulfonyl]-4-](3-methoxyphenyl)amino ]-8-Methyl Porphyrin-3_Procarbamide-198- 201206888

The title compound was synthesized according to a method similar to that described in Example 4, using Intermediate 1 1 4 instead of Intermediate 1 15 . 'H NMR (400 MHz) DMSO-d6 δ 11.10-10.96 (m-1H), 10.48-10.39 (m, 1H), 9.03 (s, 1H), 8.63-8.43 (m

, 2H ) , 8.43 - 8.2 8 ( m, 2H ) , 8. 1 8 - 7.9 6 ( m, 2 H ), 7.67 ( m, 5H) &gt; 7.23 -7.05 ( m - 2H ) &gt; 7.0 1-6.90 ( m &gt; 1H ) , 6.78 -6.65 ( m,2H ) &gt; 6.61-6.48 ( m &gt; 2H ), 6.22-6.03 ( m &gt; 1H ) , 5 · 3 2 - 5 · 2 3 ( m,1 H ) , 3.6 6 ( s, 3H ) , 3.43 -3 .3 8 ( m,1 H ) &gt; 3 .1 3-2.99 ( m &gt; 3H ) , 2.97 (m, 2H) , 2.81 ( s, 3H &gt; 2.67 ( s &gt; 3H ) , 1.71-1.54 (m, 2H) &gt; 1.51-1.39 (m - 2H) &gt; 1.36- 1.22 ( m &gt; 2H ) , 1 · 1 3-0.9 1 ( m , 2H); ES/MS theory 値 (C43H47N608S+): 807.3, experimental 値: w/z = 8 07 (M + H)+. Example 15: ( R) -6- Ethyl)amino)hexyl)oxy)piperidin-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline- 3-carbamide-199- 201206888

The title compound was synthesized according to a procedure similar to that described in Example 13 using the intermediate 1 2 1 instead of the intermediate 1 3 7 . 'H NMR ( 400 MHz &gt; dmso-d6 ) δ 11.56 ( brs, 1 Η ), 10.48 ( s, 1 Η ) , 9.16 ( brs, 1 Η ) , 8.99 ( s, 1 Η ), 8.64 ( brs &gt; 1 Η ) , 8.48 ( d &gt; J = 22.5 Hz &gt; 2H ) , 8.26 ( d

-y = 9.9 Hz &gt; 1H ) &gt; 8. 1 7 ( s &gt; 1H ) &gt; 7.94-7.77 ( m &gt; 1H ), 7.75 - 7.61 (m, lH) &gt; 7.48-7.19 ( m &gt; 3H ) &gt; 7. 1 5 ( d &gt; J = 8.3 Hz - 1H ) &gt; 7.00 (d - J = 7.9 Hz &gt; 1H) &gt; 6.89 - 6.77 ( m &gt; 1H ) &gt; 6.78-6.64 ( m &gt; 1H ) - 6.55 ( d &gt; J = 9.5

Hz, 1H) , 6.19 ( brs, 1 H ) , 5.44 ( dd &gt; J = 10.2, 2.8 Hz, lH) &gt; 4.67 ( d &gt; J = 6.7 Hz &gt; 1H ) - 4.52 ( d &gt; ./ = 7.9 Hz &gt; 1H ) &gt; 4.20-0.69 ( m &gt; 29H ) ; ES/MS Theory 値 ( C47H53N609S+ ) : 8 77.4, Experimental 値: &&quot;=877·4(Μ + Η) + Example 16 · (R) -6-((3-(4-(6-((2-)-yl-2-yl-2-(2-dihydroquinolin-5-yl)) Ethyl)amino)hexyl)piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamidine Amine-200- 201206888

The title compound was synthesized according to a procedure similar to that described in Example 13 using the intermediate 1 22 instead of the intermediate 1 3 7 . H NMR (400 MH z, dmso-d6 ) δ 1 2. 50 ( brs 1 1H ) y 1.58 ( bi s &gt; 1 η ), 10.5 1 ( brs 1 1H ) , 9.56 ( s &gt; 1H) 9 .90 (s, 1H), 8.76 ( s, 1H ) &gt; 8.61 (s, 1 H ) , 8. 4 1- .29 (m, 1H) , 8. 06 ( s, 1H) -7.97 -7.65 ( m &gt; 4H ) ) • 43 -7.23 (m, 4H ) , 7.17 (d 5 jr = 8. 2 Hz , 1H) , 7.04 (d , J = 8.2 Hz, 1 H ), 7.01-6.88 ( m, 2H ), 6.54 (d &gt; J = 9.8 Hz, 1H) &gt; 5.52 (d, &lt;; =1 JO Hz, 1H ) , 4. 80- .2 1 (m , 29H ); ES/MS Theoretical 値 ( C46H52N7O8 s+ ) 8 62.4, experimental 値: w/z = 862.3 (M + H) + 〇

Example 17: 6-((3-(4-(3-(2-(2-(R)-2-hydroxy-2-(8-hydroxy-2-keto)-1,2-dihydroquinolin-5 -ethyl)ethyl)amino)propyl)benzhydryl)piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8 - Methylquinoline-3-carboxamide

The title compound was synthesized according to a procedure similar to that described in Example 13 using subst. 'H NMR ( 400 MHz, dmso-d6 ) δ 11.02 ( s,1Η ) , 10.49

(d &gt; J = 18.1 Hz - 2H ) , 9.05 ( s &gt; 1H ) , 8.73 ( s &gt; 2H ) &gt; 8.4 1 ( s &gt; 1H ) &gt; 8.32 ( s &gt; 1H ) &gt; 8.15 ( Dd- J = 9.9 &gt; 5.2 Hz - 1H ) , 8.05 ( s, 1H) &gt; 7.91 -7.59 ( m &gt; 4H ) , 7.37 ( d &gt; J = 42.3 Hz, 4H ) , 7.24 - 7.1 1 ( m &gt; 2H ), 6.99 ( d » 7 = 8.2 Hz, 1H ) - 6.8 3 -6.66 ( m &gt; 2H ) , 6.60 (t &gt; J = 9.7 Hz &gt; 2H ) &gt; 6.2 1 ( s &gt; 1H ), 5.41-5.25 (m, 1 H ) , 4.13 - 2.91 (m, 17H), 2.68 (s, 3H) - 1 . 1 2 ( s , 3H) ; ES/MS theory 値 (C5〇H5〇N709S+) : 924.3, experimental 値: w/z = 924.3 (M + H)+. Example 18: (R)-6-((3-(4-(3-(2-(2-)-yl-2-(2-hydroxy-2-keto-1,2-dihydroquinoline) -5-yl)ethyl)amino)-2-methylpropyl)benzylidene)piperazine-1 -carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 12, using Intermediate 146 as a substrate. 'H NMR ( 400 MHz - dmso-d6 ) δ 10.77 ( s - 1Η ) &gt;10.38 (brs,1 H ) , 9.08 ( s,1H) , 8.38 ( s,1H ) , 8.29 ( s -202-

201206888 &gt; 1Η ) , 8.18(d, / =10.0 Hz, 1Η) &gt; 7.99 ( s 7.86 ( s - 1H ) - 7.75 ( d &gt; J = 14.7 Hz &gt; 5H ), (m,7H) &gt; 6.95 (d &gt; J = 8.0 Hz &gt; lH) &gt; 6.71 8.1 Hz, 1H) &gt; 6.65 ( s &gt; 1H ) &gt; 6.53 ( d &gt; J = 2H ) » 5.26-4.92 ( m &gt; 1H ) &gt 3.8 7-2.5 7 ( m &gt; 1 .3 0-0.84 ( m » 6H ) ; ES/MS theory 値 (C5) H52N7 93 8.4, experimental 値: w/z = 93 8.3 (M + H)+. Example 19: (R) -6-((3-((3-(2-(2-hydroxy-yl-2-indolyl-1,2-)-pyridin-5-yl)ethyl)amine -2_)-N-methylbenzhydrylamino)methyl)phenyl)sulfonyl)-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide, 1 Η ), 7.46-7.08 (d &gt; J = 6.6 Hz, 20H ), 09S+ ): 2- (8·hydroxymethylpropyl 4-((3-

The title compound was synthesized according to the analog intermediate 1 47 similar to that described in Example 18'. 1 Η NMR ( 400 MHz, dm; so -d 6 ) δ 11.17 ( brs · 10.51 ( s &gt; 1H) , 9.03 (s &gt; 1H) , 8·65 ( d 1 J = , 2H ), 8 • 38 ( d, J = 24. , 5 Hz, 2H ) - 8.1 1 ( d Hz,1 H ) j '8.02 (s &gt; 1 H) &gt; 7.82 (s,1 H ) ,Ί .Ί m,8H ) 5 7.00 (d &gt; J = 8. 1 Hz , 1H ) , 6.67 ( 46.0 , 25.2 Hz ' 4H ) , 6. 3 6-6.07 ( m,1H ), go, use 1 Η ), 46.4 Hz &gt; J = 9.5 1-7.06 ( dd &gt; J = 5.38-5.21 -203- 201206888 (m &gt; 1Η ) &gt; 5.03 -2.5 8 ( m &gt; 1 8H ) , 1.23 ( s,3H), 1.06 (s, 3H); ES/MS theory 値 (C48H49N608S+): 869.3, experimental 値: w/z = 869.4(M + H)+. Example 20: ( R ) -6- ( ( 3- ( 4 '- ((2-Hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-[1,1'-biphenyl -4-yl)amine-carbyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 13 using Intermediate 123 instead of Intermediate 137. 'H NMR ( 400 MHz &gt; dmso-d6) δ 11.03 ( brs &gt; 1H), 10.65 ( s &gt; 1H ) , 10.51 ( s, 1H) , 10.46 ( s, 1H ), 9.06 ( s &gt; 3H ) &gt; 8.40 ( s &gt; 1 H ) &gt; 8.34 ( s &gt; 2H ) &gt; 8.25 ( d &gt; J = 7.6 Hz - 1H ) &gt; 8.08 (d&gt; J = 6.0 Hz &gt; 2H) &gt; 7.91 ( d, *7 = 7.4 Hz, 2H) - 7.8 6-7.69 ( m &gt; 5H ) &gt; 7.61 ( d

&gt; J = 6.5 Hz &gt; 2H ) &gt; 7.18-7.09 ( m - 2H ) &gt; 6.97 ( d &gt; J = 7.4 Hz &gt; 1H ) &gt; 6.69 ( d &gt; J = 9.5 Hz &gt; 2H ) , 6.57 (d, J = 9.9 Hz &gt; 2H ) &gt; 6.25-6.10 (m &gt; 1H) &gt; 5.35 ( d &gt; J = 9.3 Hz - 1H ) , 4.42 - 2.3 4 ( m, 12H ) ; ES / MS theory - (-204- 201206888 C49H43N608S+): 875.3, experiment 値: speak &quot;=875.1 (M + H) +. Example 2 1 : ( R ) - 6 - ( ( 3 - ( 4 ' - 4 - ( 4 - hydroxy-3-keto-3,4-dihydro-21-- Benzo[1&gt;][1,4]oxazol-8-yl)ethyl)amino)butyl)-π,1'-biphenyl]-4-yl)aminecarboxamido)phenyl)sulfonate Mercapto)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate compound 15 as a substrate. 1H NMR ( 400 MHz, dmso ) δ 1 1. 1 9 ( brs, 1 Η ) , 10.73 (s, lH) , 10.18-10.01 (m, 2H) , 9.17 (s, lH), 8.53 ( s, 3H) , 8.47 ( s, 2H) , 8.3 7 ( d, J = 8.1 Hz,

1H) , 8.22 (s, lH) , 8.10-7.83 (m, 5H), 7.81 (d, J = 8.6 Hz ' 2H ) , 7.74 ( d, · / = 8.2 Hz, 2H ) &gt; 7.42 ( d , • / = 8.1 Hz, 2H) &gt; 7.27 ( t &gt; J = 8.0 Hz · 1H ) , 7.03 (d, J = 8.5 Hz, 1H), 6.87-6.78 ( m, 2H ) &gt; 6.77-6.63 (m &gt ; 2H ) , 6.10-5.93 (m, lH) » 5.16 ( d &gt; J = 9.9 Hz , 1H ) - 4.77- 1.68 ( m &gt; 1 8H ) ; ES/MS theory 値 ( C51H49N609 S + ) : 92 1 .3, Experimental 値: m / z = 921 .3 (M + H) + 〇 Example 22 : ( R ) -6- ( ( 3- ( 4 '- ( 4- ( 2- 2- 2- 5--205- 201206888 Hydroxy-3-keto-3,4-dihydro-2-benzo[1?][1,4]oxazin-8-yl)ethyl)amino)butyl) -Π,1'-biphenyl]-3-yl)amine,carboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylsalthene- 3-methylamine

The title compound of HOtC was synthesized according to a method similar to that described in Example 1, using the intermediate 1 5 2 as a substrate to obtain "H NMR ( 400 MHz, dmso-d6 ) δ 1 1 . 07 ( brs » 1 H ), 10.61 ( s 1H ) , 1 0.04-9.88 ( m, 2H ) , 9· 05 (S , 1 H ) &gt; 8.63-8.29 丨(m ,5H ) &gt; 8.26 ( d, J -- = 7.4 Hz &gt; 1 H ), 8.11 ( d &gt; j =9. 5 Hz, 2H ) , 7.91 (d, J = 7.9 Hz , 1 H ) &gt; 7.85-7. 70 丨(m ,3H ) &gt; 7.59 ( d, J = 8.0 Hz y 2H ), 7.53-7.38 ( m , : 2H ), 7.34 ( d &gt; J = 8. 1 Hz , 2H ) &gt; 7.15 (t , · / = 7 • 9 H z,1H : ) .6.91 ( d , J =8.4 Hz 9 1 H ), 6.70 ( d , J =8. 3 Hz, 2H ) , 6.57 (t, J = f ?.4 Hz , 2H ) , 6.00-5.81 (m , 2H ) ), 5.04 ( d , J = = 9.9 Hz &gt; 1 H ), 4.61-4.45 ( m &gt; 2H ), 4.17-1.49 ( m , 1 5H ) ES/MS theory 値 ( c5 1 H 4 9 n6o9s+ ) : 921.3 » Experimental 値: m/z = 92 1 ·3(Μ + Η)+ » Example 2 3 : (R) -6-( (3-((6-((2-hydroxy-2-)) -hydroxyl-3·fluorenyl·3,4-dihydro-2H-benzene [b][l,4]喔ΐ晓-8-yl] oxime ethyl)amino 201206888) hexyl)amine carbhydryl)phenyl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide

OH 0〆

The title compound was synthesized according to a method similar to that described in Example 1 using Intermediate 1 64 as a substrate. NMR ( 400 MHz, DMSO-d6 ) δ 10 · 9 7 ( brs, 1 Η ), 10.62 ( s, 1H) , 9.27 ( brs, 1 H ) , 9.06 ( s, 1 H ), 8.75 ( t, J = 5.7 Hz,1H ) &gt; 8.54 ( brs &gt; 1H ) - 8.47 ( brs - 1 H ) , 8.3 7-8.2 8 ( m,2H ) , 8 _ 1 1 ( d, / = 7.4 H z

, 1H) &gt; 8.03 ( s &gt; 1H ) &gt; 7.79 ( m &gt; 2H ) - 7.69 ( t &gt; 7 = 7.6 Hz, 1H) &gt; 7.22 ( s &gt; 1H ) &gt;7.16(t&gt;J = 8.2 Hz - 1H ) , 7_09 (s, lH) , 6.96 (s, lH) &gt; 6.72 ( d &gt; 7 = 8.0 Hz, 1H) &gt; 6.65 ( s - 1H ) &gt; 6.58 ( d &gt; J = 8.0 Hz &gt;

1H ) &gt; 6.5 1 ( d &gt; / = 2.8 Hz &gt; 1H ) &gt; 6.34 ( d &gt; J = 2.8 Hz , 1H) &gt; 6.03 ( brs &gt; 1H ) &gt; 5.06 ( dm &gt; J = 8.7 Hz, 1 H

), 4.5 3-4.45 ( ABq - J = 18.0 Hz &gt; 2H ) &gt; 3.64 ( s &gt; 3H

), 3.29 (ABq, "/ = 6.4 Hz, 2H), 3.09-3.01 (m &gt; 1H ) · 2.96-2.82 ( m &gt; 2H ) , 2.70 ( s, 3H) , 1.66 - 1.50 ( m -207- 201206888 , 4H) &gt; 1.3 8- 1.2 8 ( m &gt; 4H ). ES/MS theory C (C41H45N609S+): 797.3, experimental 値: w/z = 797·4(Μ + Η)+. Example 24: (R)-6-((3-(4-(4-(5-(2-hydroxy-2-(6-hydroxy-3-keto-3,4-dihydro-2H-benzo[ b][l,4]oxazol-8-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4-(( 3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 1 65 as a substrate. 'H NMR (400 MHz &gt; DMSO-d6 ) δ 11.08 ( brs &gt; 1 Η ), 10.63 ( d &gt; J = 5.1 Hz - 1H ) , 9.31 (brs, 1H) &gt; 9.05 ( s , 1H) &gt; 8.7 1 ( brs &gt; 1H ) &gt; 8.61 ( brs &gt; 1H ) &gt; 8.40-8.3 1 (m, 2H) &gt; 8.21 (d&gt; J = 8.2 Hz&gt; 1H) &gt; 8.09 ( s &gt; 1H ) &gt; 7.91 ( d &gt; J = 8.2 Hz &gt; 1H ) , 7.80-7.75 (m, 2H), 7.43 (d - ./=8.6 Hz &gt; 1H) , 7.14 (t, J = 8.4 Hz, 1H) , 6.69-6.68 ( m,2H ) ,6 · 5 8 ( d,·· = 7.9 Hz - 1H ), 6.54 (d&gt;y = 2,8Hz&gt; 1H), 6.34 (d, J = 2.8 Hz, 1H) 1H ) , 2.71 ( s, , 6.08 ( brs, 1 H ) , 5.09 ( dm,·· = 10.2 Hz, 1H ), 4.5 5-4.46 ( ABq &gt; J = 15.2 Hz &gt; 2H ) &gt; 3.65 ( s &gt; 3H) &gt; 3.17-3.05 ( m &gt; 2H ) &gt; 3.00-2.8 9 ( m &gt; -208- 201206888 3H ) &gt; 2.5 8 -2.45 ( m - 2H ) - 1.99- 1.8 5 ( m &gt 2H ). ES/MS Theory 値 (C46H43N6〇9S+) : 8 5 5.3, Experimental 値: w/z = 8 5 5·4(Μ + Η)+.

Example 25: (R)-6-((3-((2-(4-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-) 5-yl)ethyl)amino)ethyl)ethyl)phenoxy)ethyl)(methyl)aminemethylmercapto)phenyl)sulfonyl)-4-((3-methoxyphenyl)amine -8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate compound 1 45 as a substrate. *H NMR (400 MHz, DMSO-d6): δ 11.00 (brs &gt; 1Η),

10.50 ( s &gt; 1Η ) &gt; 10.44 ( s &gt; 1H ) &gt; 9.0 4 ( s - 1H ) &gt; 8.66 (brs &gt; 1 H ) &gt; 8.40 ( s - 1H ) &gt; 8.32 ( s &gt; 1H ) &gt; 8. 14 ( d , 1H &gt; J = 10.0 Hz) &gt; 8.0 3 -8.00 ( m &gt; 1H ) , 7.91 (s, 1H ) , 7.80-7.66 (m, 4H) , 7.19-7.10 (m, 4H), 6.99-6.97 ( m &gt; 2H ) , 6.84 - 6.82 ( d &gt; 1 H &gt; J = 7.2 H z ) &gt; 6.74-6.70 ( m &gt; 2H) - 6.60-6.55 ( m &gt; 2H) &gt; 6.17 ( brs &gt; 1H ) &gt; 5.31 ( br d &gt; 1H ' J = 9.2 Hz) , 4.237 (m, 2H) , 4.00 ( m, 2H) , 3.83 ( m, 1H) , 3.65 ( s,3H), 3.53 ( m,1H) &gt; 3.04-2.8 8 ( m &gt; 4H ) &gt; 2.69-2.63 ( m - -209- 201206888

4H) , 2.54 ( s, 3H) ; ES/MS theory 値 (C47H47N6O9S : 87 1.3 1, experimental 値: /w/z 871.3 (M + H) + » Nor I _ 3 _ (淫 淫 26: ( R ) -6-[[3-[[4-[5-[[2-hydroxy_2-[4-hydroxyethylidenemethyl)phenyl]ethyl]amino]]pentyl]phenyl]aminecarboxamide ]]][[3-methoxyphenyl)amino]-8-methylquinoline-3_yield, 2,2,2-trifluoroacetate, hydrazine

Cf3co2h

, r Λ . Solution, and add HF/pyridine (30% (w/w) in water, 0" at room temperature for 1 hour, then add NH3 (2.0 M MeOH Μ # , 10 mL) to neutralize all under vacuum Solvents were purified by preparative HPLC eluting with EtOAc (EtOAc: EtOAc (EtOAc) -d6) δ 11.13-10.97 (m&gt; 1H)

, 10.46 ( s, 1H) &gt; 9.49-9.34 ( m - 1H ) , 9.06 ( s, 1H ) &gt; 8.5 5-8.44 ( m &gt; 2H ) , 8.40 (s, lH) &gt; 8.3 8 - 8.3 3 ( m

, 1H) * 8.32 ( s * 1H ) , 8.21 (m, lH) , 8.08 (s, lH ), 7_90 ( dd, / = 7.97 « 1.09 Hz, 1H) , 7.84 - 7.8 0 ( m , 1 H ) , 7.77 ( d,·/ = 7.82 Hz,1H ) , 7.68 ( d &gt; J = 8.48 Hz, 2H) , 7.21 (d, J = 8.52 Hz - 2H ) , 7.14 (m -210- 201206888 ,1Η ) ,7.08 - 7.03 ( m &gt; 1Η) &gt; 6.76 ( d &gt; J = 8.20 Hz &gt; 1H ) &gt; 6.68 ( m &gt; 2H ) , 6.61-6.55 (m, 1H), 6.00 (bs, 1H ) , 4.8 3 -4.73 ( m &gt; 1H) &gt; 4.49 ( s ' 2H) - 3.61 ( s &gt; 3H ) , 3.12-3.00 (m, lH) , 2.99-2.87 (m, 4H) &gt; 2.71 (s, 3H &gt; 2.58 ( m &gt; 2H ) , 1 · 6 9 -1 · 5 6 ( m, 4 H ), 1.3 9- 1 .29 ( m &gt; 2H ) ; ES/MS theory 値 (C 4 5 Η 4 8N 5 O 8 S + ): 8 1 8.3, experimental 値: w/z = 8 1 8 · 4 (Μ + Η)+. Example 27: (R)-6-[[3-[[6-[[2-(3-Methylamino-4-hydroxyphenyl)-2-hydroxyethyl]amino]hexyl]aminecarboxamide Phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

NH,

OH Ι:χ^

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 167 as a substrate. lU NMR (400 MHz &gt; DMSO-d6 ) δ 1 1.05 - 1 0.97 ( s &gt; 1Η ) &gt; 9.99 -9.89 ( s &gt; 1H ) &gt; 9.57-9.41 ( s - 1H ) , 9.12 ( s, 1H ), 8.74 - 8.63 ( m, 1H ) , 8 · 5 8 - 8 · 4 9 ( m, 2 H ), 8.3 3 - 8.26 ( m &gt; 3H ) - 8.18-8.14 ( m - 1H ) &gt; 8.1 1 ( m &gt; 5H ) &gt; 7.9 1 ( s &gt; 1H ) &gt; 7.72-7.66 ( d &gt; 1H &gt; J = 9.2 Hz) &gt; 7.65 -7.5 5 ( m &gt; 1H ) &gt; 7.12 ( m &gt; 1H ) &gt; 6.96-6.8 9 ( m , 1H) , 6.87 (m, lH) , 6.73 - 6.65 (d, lH, J = 8.3 Hz -211 - 201206888 ), 6. 58-6.47 6.12-5 • 89 ( s, 1H ) &gt; ( S , 2H ), 4.87- 4.73 ( d,1H, J = 8.8 ) -3.64 ( s,4H ) 1.10-2.83 (m &gt; 4H ) 2.72 ( s ,3H ) &gt; 1.75-1. 49 ( m,4H )&gt; 1.38 (m 4H ) ♦ ES/MS theory 値(C 4 0 H4 5 n6o8s+) : 769.3 , real: test 値·· m / z ==769 (M + H )+. Example 28: (R)-6-((3-(6-((2-(3-carbamoyl)-4-hydroxyphenyl)-2-hydroxyethyl)amino)hexyl) (methyl) Aminomethyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylporphyrin-3-carboxamide, 0

标题^N HO. The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 168 as a substrate. 'H NMR ( 400 MHz, dmso-d6) δ 10.98-10.77 ( s - 1Η ), 1 0.09-9.99 ( s,1H) , 9.63 -9.52 ( s,1H) , 9.10-8.99 ( s &gt; 1H ) &gt 8.43-8.21 ( m &gt; 5H ) &gt; 8.19-8.08 ( m &gt; 1H ), 8.06-7.94 ( m,1H ) &gt; 7.8 3 -7.60 ( m &gt; 5H ) ,) &gt; 7.20- 7.08 ( m &gt; 1H ) , 6.90-6.78 ( m,2H ) &gt; 6.77-6.62 ( m -2H ) &gt; 6. 1 1-5.95 ( s &gt; 1H ) - 4.84-4.63 ( m &gt; 1H ) , 3.66 ( s,3H ) , 3.02-2.91 ( m,4H ) , 2.8 7-2.7 5 ( m,5H ), 2.68 ( s,3H) , 1.39-1.17(m,4H) ,1.73-1.51 ( m, -212 - 201206888 4H ) ; ES/MS Theory 値 (C41H46N608S ) : 7 82.3 1 - Real: m/z = 78 3 (M + H) + 〇 Example 29 : ( R) -6- ( ( 3- ( 6- ((2-Hydroxy-2-(5-(3-)-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxo-8-yl)ethyl))hexyl)amine Mercapto)phenyl)sulfonyl)-4-((3-methoxy)amino)-8-methylquinolin-3-carbamoin

The title compound was synthesized according to a method similar to that described in Example 1 using the material 1 70 as a substrate. ]H NMR ( 400 MHz, dmso-d6 ) δ ppm 10.98-10.89 ( s )&gt; 1 0.04-9.92 ( s &gt; 1H ) &gt; 9.12-9.0 1 ( s &gt; 1H ), 8.70 ( m - 1H) , 8.43-8.22 ( m , 2H) &gt; 8.17-7.97 ( 2H ) , 7.8 6-7.62 ( m,2H ) - 7.22-7.09 ( m &gt; 1H 6.96-6.8 5 ( m &gt; 1H) &gt; 6.7 8 -6.49 ( m &gt; 4H ) &gt; 6.05-5. m,1H) &gt; 5.10-4.97 ( m &gt; 1H ) , 4 · 5 3 ( d,2 H, J = 3.65-3.61 ( s - 3H) &gt; 3.04-2.8 3 ( m &gt; 5H) &gt; 2.70 ( s ), 2.50 (s, 2H) &gt; 1 .69 - 1 .45 ( m - 5H ) &gt; 1 .32 ( m ); ES/ MS theory 値(C41H44N609S ) ·· 796.3, experiment ttj/z = 79 7(M + H)+. In use, 1 Η S. 82-m , ), 84 ( ), , 5H , 5H 値·· -213 - 201206888 Example 30: (R) -6-( (3-( 6-(2-hydroxy-2-(5-hydroxy-3 keto-3,4-dihydro-2H-benzo[bUl] ,4]oxazin-8-yl)ethyl)amino)hexyl)(methyl)amine-carbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino) -8-methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 1 69 as a substrate. *H NMR ( 400 MHz &gt; dms ο - d 6 ) δ 1 1.0 5 - 1 0.8 6 ( s,1 Η ), 1 0.04-9.90 ( s,1H) , 9.11 - 9.01 ( s,1H) , 8.45- 8.27 ( m · 2H ) - 8.09-7.96 ( m &gt; 1H ) &gt; 7.85 -7.62 ( m &gt; 4H ), 7.21-7.08 ( m,1H) , 6.97-6.84 ( m,1H) ' 6.79-6.65 ( m,2H) &gt; 6.63-6.48 ( m - 2H ) &gt; 6.00-5.84 ( m &gt; 1H ), 5.09-4.97 ( m,1H ) , 4.59-4.46 ( m ' 2H ) ' 3.67 ( s, 3H ) &gt; 3.23-2.93 ( m &gt; 8H ) ' 2.8 8 - 2.7 6 ( m,4 H ) - 2.70 (s &gt; 4H ) , 1.69-1.41 (m, 4H) · 1.41 -1.24 ( m · 3H ) ; ES/MS theory 値 (C42H46N6 〇 9S): 810.3, experimental 値: w/z = 8 1 1 (M + H)+. Example 31: (R) ·6-[[3-[[4-[5-[[2-(3-carbamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]]- Alkynyl]phenyl]aminocarbazinyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide-214 - 201206888

The title compound was synthesized according to a method similar to that described in Example 1 using intermediate compound 171 as a substrate. 1H NMR (400MHz, DMSO-d6) δ 10.64 ( s,1Η ) , 10.07 (s,lH) &gt; 9.6 1 ( s &gt; 1Η ) &gt; 9.07 ( s &gt; 1Η ) , 8.53 (brs

, 2H) &gt; 8.29 ( m &gt; 4H ) &gt; 8.18 ( d - 1H - J = 2.0 ) &gt; 8.06 (s,lH) &gt; 7.88 ( m &gt; 1H ) &gt; 7.77 ( d &gt; 4H &gt ; J = 8.8 Hz )&gt; 7.43 ( d &gt; 2H &gt; J = 8.7 Hz ) , 7.11 (t,lH,J= 8.4

Hz) , 6.94 ( dd &gt; 1H &gt; J = 2.1, 8.3 Hz) , 6.87 ( d &gt; 1 H -/ = 8.2 Hz ) , 6.65 (m, 2H) , 6.5 (d, lH, J = 8.4

Hz) &gt; 6.07 ( brs - 1 H ) &gt; 4.76 ( m, 1 H ) , 3.59 (s, 3H) , 3.27 ( m, 2H ) , 2 · 93 ( s, 2H ) , 2.70 ( s, 3H ) , 1.33 ( m &gt; 2H ) , 0.92 (q, 2H &gt; J = 7.4 Hz) ; ES/MS theory 値 (C45H43N608S+ ) : 827.3 , experimental 値: m/z = 827_3(M + H)+. Example 32: (R)-6-((3-(4- 4-(5-(2-hydroxy-2-(5-hydroxy-3-keto-3,4-dihydro-2H-benzo[ b][l,4]oxazol-8-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4-(( 3-methoxyphenyl)amino)-8-methylsalthion-3-carboxamide-215- 201206888 ο

The title compound was synthesized according to a method similar to that described in Example 5, using intermediate 1 72 as a substrate. 'Η NMR ( 400 MHz, dmso-d6) δ 11.15-10.99 ( s, 1Η), 1 0.64 ( s &gt; 1 H ) - 9.98 ( s &gt; 1 H ) , 9.05 (s, lH) &gt; 8.60- 8.5 1 ( m &gt; 2H ) - 8.3 1 ( m &gt; 4H ) , 8.13 - 8.02 (m, 1H) , 7.78 ( m &gt; 5H ) , 7.42 ( d &gt; J = 8.57 Hz, 2H) , 7.20- 7.06 ( m &gt; 1 H ) &gt; 6.9 1 ( s &gt; 1H ) &gt; 6.74-6.49 ( m &gt; 4H ), 6.13-5.81 (brs, 1H) , 5.13 - 5.00 (m, 1H) , 4.54 ( d, J = 4.42 Hz, 2H ) , 3.64 - 3.5 8 ( s &gt; 3H ) , 3.19 - 2.89 ( m , 5H ) , 2.70 ( s, 2H ) , 2 · 5 8 - 2 · 5 1 ( m, 2 H) , 2.00-1.80 (m, 2H); ES/MS theory 値 (C46H42N609S): 8 54.3 , experimental 値: = 855 (M + H)+. Example 33: (R) -6-((3-((4-(5-(2-(2-)-(2-(5-)-yl-2-yl)-(2-yl-2-yl-1,2- Ethyl)amino)amino)pentan-1-yl-1·yl)phenyl)(methyl)aminecarbenyl)phenyl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide-216- 201206888 ο

The title compound was synthesized according to a procedure similar to that described in Example 13 using the intermediate 1 16 in place of the intermediate 1 3 7 .

1H NMR ( 400 MHz, dmso-ds ) δ ppm 11.00-10.87 ( s &gt; 1H ), 10.49 ( s, 1H ) , 9.05 ( s, 1H ) , 8.68 -8.5 0 ( brs, 2H ) , 8.29 ( s, 2H) , 8.13 ( d, J = 9.97 Hz, 1H ), 7.83 ( s, 2H) , 7.70-7.4 1 ( m, 4H ) &gt; 7.19-6.90 ( m &gt; 6H ) , 6.78-6.47 ( m, 4H &gt; 6.27-6.03 ( m &gt; 1H ), 5.3 3 -5.20 ( m,1H) , 3.67-3.60 ( m,3H) ,3.3 6 -3.3 3 ( s,3H) ,3.04(m,5H) - 2.71 ( s &gt; 3 H ) &gt; 2.47 ( m &gt; 2H ) , 1.96- 1.74 ( m &gt; 2H ) ; ES/MS theory 値 ( C48H44N608S) · _ 864.3, experimental 値·· m/z = 865 ( M + H)+.

Example 3 4 : ( R ) -6-( (3-( 4-(5-( 2 -hydroxy-2 -( 8 -hydroxy-2-indolyl-1,2 - a gas quinoline _- 5- Ethyl)amino)amino)pent-1-yl-1-yl)-2-methylphenyl)amine-carboxanyl)phenyl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide-217- 201206888

The title compound was synthesized according to a method similar to that described in Example 5, using the material 1 54 as a substrate. 'H NMR ( 400 MHz, dmso-d6 ) δ 11.16-10.98 (s - 1H 10.58-10.41 ( s &gt; 1H ) , 10.19 ( s « 1H ) , 9.06 ( s , 8.67-8.56 ( m - 2H) &gt; 8.47-8.03 ( m &gt; 5H) , 7.78 J = 7.88 Hz > 3H) - 7.45-7.10 ( m &gt; 4H ) &gt; 6.99 ( d 8.16 Hz, 1H) , 6.79-6.5 3 ( m,3H ) &gt; 6.3 1-6.09 ( 1H ) &gt; 5.3 8 -5.25 ( m &gt; 1H ) , 3.6 3 - 3 6 2 ( m,3 H 3.26-3.04 ( m &gt; 4H ) &gt; 2.7 1 ( s,3 ) &gt ; 2.61-2.52 ( m &gt;&gt; 2.22 ( s &gt; 3H ) &gt; 2.11-1.83 ( m &gt; 2H ) ; ES/MS (C48H44N608S) : 864.3, experimental time: w/z = 865 (M + H) + Example 35: ( R) -6- ( ( 3 - ( ( 4- ( 5 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( [b][l,4]oxazin-8-yl)ethyl)pent-1-yn-1-yl)-2-methylphenyl)aminecarboxamido)phenyl)yl)-4- ((3-Methoxyphenyl)amino)-8-methylquinoline-3-methyl! In use [), 1H) (d, &gt; J = m » ), 4H ) 値〇 5- Hydroxylamine sulfonamide-218- 201206888

The title compound was synthesized according to a method similar to that described in Example 5, using intermediate compound 162 as a substrate.

'HNMR( 400 MHz&gt; dmso-de) δ 11.28-11.04 ( 2 &gt; 1Η), 10.25-10.13 ( 2 ' 1Η) ' 10.04-9.91 ( 2,1Η) , 9.10-8.98 (m ' 1H) « 8.78- 8.5 0 ( m - 2H ) , 8.4 6 · 8.3 2 ( m, 2 H ) , 8.27-8.23 ( d ' J = 7.49 ' 1H ) &gt; 8.15-8.03 ( m &gt; 1H ), 7.94-7.70 ( m ' 3H) ' 7.44-7.11 ( m,4H) , 6.98-6.85 ( m ' J = 8.30 ' 1H ) , 6.80-6.49 ( m,4H ) ,5.14-4.99 ( m ,1H) &gt; 4.63 -4.45 ( m &gt ; 2H ) , 3.63 ( s, 3H) - 3.19 - 2.89 ( m, 5H) , 2.71 ( s, 3H) &gt; 2.49 ( m &gt; 4H ) . 2.22 (s' 3H) ' 2.00-1.82 (m, 2H ); ES/MS theory 値 (C47H44N6〇9S): 868.3, experimental 値: w/z = 869 (m + h)+. Example 36: (R) -6-((3-((4_(5_((2_(hydroxy)-2-(2-hydroxy-3-keto-3,4-dihydro-2H-benzo[b][i] , 4]oxazine·8-yl)ethyl)amino)pent-1-yn-1-yl)-3-methylphenyl)aminecarboxamido)phenyl)sulfonyl)-4-( (3-methoxyphenyl)amino)-8-methylquinoline-3-formamide-219- 201206888

The title compound was synthesized according to the method similar to that described in Example 5, using the intermediate 1 63 as a substrate to give a &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&& 1H) , 9.98 ( s, 1H ) , 9.05 ( s, 1H ), 8.77-8.51 ( m, 2H) , 8.43-8.29 ( m, 3H) , 8.24 - 8.18 ( d, J = 7_9 1H ) , 8.08 ( s , 1H), 7.92-7.73 (m, 3H), 7.71-7.68 (s, 1H), 7.65-7.60 (d, J = 8.4 1H), 7.37 (d &gt; J = 8.42 Hz » 1H ) , 7.21 - 7.06 (m,1H) , 6.92 (d, J = 8.47 Hz, 1 H ) , 6.72-6.66 ( m,2H ) , 6.60-6.54 ( m ,2H) &gt; 5.14-5.00 ( m - 1H ) » 4.54 ( d » J = 4.05 Hz, 2H ) , 3.61 (s, 3H) , 3.11 (m, 4H) , 2.72 - 2.68 (s, 3H) &gt; 2.6 1 -2.48 ( m &gt; 2H ) , 2.4 0 - 2 · 3 4 ( s,3 H ) - 2.02- 1.86 ( m,2H) ; ES/MS theory 値 (C47H44N609S ) : 868.3 . Experimental 値: w/z = 869 (M + H)+. Example 37: (R) -6-((3-((4-(2-(4-(4-(2-(2-(2-(2-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxy-2-phenyl-2-yl-2-yl-2-yl-2-yl-2-yl-2-yl) 5-yl)ethyl)amino)butyl)-1,3-dithiolan-2-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4-(3 -Methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-220- 201206888

Intermediate 158 (90 mg, 0.08 mmol) was taken in dichloromethane and treated with trifluoroacetic acid (0.50 mL). After stirring for 30 minutes, the mixture was concentrated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssss The mixture was allowed to stand at room temperature overnight and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) *H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1 Η), 10.57 ( s, 1H) , 10.48 ( m &gt; 2H ) &gt; 9.06 ( s &gt; 1H ), 8.50 ( bs &gt; 2H ) &gt; 8.40 ( s &gt; 1H ) , 8.33 (m, 2H) &gt; 8.22 (d, lH, J = 8.0 Hz), 8.12 (d, lH, J = 9.6 Hz), 8.08 ( s &gt; 1H ) - 7.89 ( d &gt; 1H &gt; J = 7.6 Hz ) , 7.83 - 7.71 (m, 4H ) , 7.64 ( m, 2H ) , 7 · 1 7 - 7 · 1 1 ( m, 2 H ), 6.97 (d1 1H ' J — 8.4 Hz), 6.68 (m, 2H), 6.60-6.56 (m, 2H) &gt; 5.27 ( m &gt; 1H ) &gt; 3.6 1 ( s - 3H ) - 3.45-3.39 (m &gt; 2H ) &gt; 3.3 4-3.28 ( m &gt; 2H) - 3.10-2.85 ( m &gt; 2H ) , 2.71 ( s, 3H) , 2.5 7-2.43 ( m, 2H) &gt; 2.40-2.30 ( m &gt; 2H ) , 1.62 (m, 2H), 1.26 (m, 2H); ES/MS theory 値 (C49H49N608S3+): 945.3, experimental 値: m/z = 945·5 (Μ + Η) + -221 - 201206888 Example 38 : ( R) -6- Ethyl)amino)hexyl)oxy)butyl)phenyl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)- 8-methylquinoline-3-carboxamide

The concentrated reaction mixture containing intermediate 159 was taken in dichloromethane (5 mL)EtOAc After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The residue was taken up in THF (1 mL) and EtOAc (EtOAc) The mixture was stirred in a 40 ° C oil bath overnight and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (bs, 1 Η) 10.48 (m, 2 Η), 9.05 ( s, 1 Η) &gt; 8.5 1 ( bs &gt; 2H ), 8.41 (s, lH) &gt; 8.33 ( m &gt; 2H ) 1 8.21 ( d · 1H « J = 7.6 Hz ) . 8. 14 ( d J 1H - J = 9.6 Hz ) , 8·09 ( s, 1H), 7.89 ( d &gt; 1 H - J = 8.0 Hz ) ' 7.83-7.73 (m,4H) &gt; 7.67 (m &gt; 2 H ) , 7.22 - 7.11 (m' 4H) ' 6.97 (d,1H,= -222- 201206888 8.0 Hz) ,6.69 (m, 2H), 6.58 (m, 2H) &gt; 5.2 9 ( m &gt; 1H ) &gt; 3.6 1 ( s &gt; 3H ) &gt; 3.3 9-3.29 ( m &gt; 4H ) , 3.14 - 2.79 (m , 2H ) , 2.71 ( s, 3H) , 2 · 6 0 - 2.4 3 ( m, 4 H ), 1.68- 1.43 ( m, 1 OH ) &gt; 1.3 6-1.25 ( m - 2H ) ; ES/MS theory 値 (C52H57N609S+): 941.4, experimental 値: m/z = 94 1.5 (M + H)+.

Example 39: (R) -6- (3-(4-(2-(6-(2-hydroxy-2-(8-)-(2-hydroxy-2-(8-)-amino-2-indolyl-1,2- oxaquine咐-5-yl)ethyl)amino)hexyl)oxy)ethyl)phenyl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino )-8-methylquinoline-3-carboxamide

The intermediate 1 60 is synthesized as a substrate. 1 H NMR ( 400 MHz, dms ο - d 6 ) δ 1 1 . 0 4 ( s, 1 Η ) , 10.48 (m, 2H) &gt; 9.06 ( s &gt; 1H ) - 8.53 ( s &gt; 2H ) - 8.40 ( s -1H ) , 8.33 (m, 2H) &gt; 8.21 ( d &gt; J = 7.8 Hz &gt; 1H ), 8.15 ((!,·· = 9.9 Hz,1H) &gt; 8.08 ( s - 1H ) &gt; 7.89 ( d &gt; J = 7.9 Hz &gt; 1H ) - 7.80-7.70 ( m &gt; 2H ) , 7.67 (d, "7=8.4 Hz, 2H) - 7.24 ( d &gt; J = 8.5 Hz - 2H ), 7.14 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H) &gt; 6.69 ( m &gt; 2H ) &gt; 6.63 - -223- 201206888 6.53 (m, 2H) , 5.30 (m, lH) , 3.94(bs,lH) &gt; 3.61 (s,3H) &gt; 3.56 ( t » J = 7.0 Hz &gt; 2H ) , 3.39 (1, "/ = 6.4 Hz, 2H), 3.26-2.83 (m, 5H ) &gt; 2.79 ( t &gt; J = 6.9

Hz, 2H), 2.71 (s, 3H), 1.56 (m, 4H) &gt; 1.27 ( m &gt;4H); ES/MS theory 値 (C5 〇 H53N609S+) : 913.4, experimental 値: m/z = 913.3 ( M + H) + 〇 Example 40: ( R) -6-( (3-( 4-(4-(6-(2-(2-)-(2-(2-(2-(2-) 2-Dihydroporphyrin-5-yl)ethyl)amino)hexyl)oxy)butyl)phenyl)(methyl)aminemethylmercapto)phenyl)sulfonyl)-4- ((3) -Methoxyphenyl)amino)-8-methylquinoline-3-carbamimidoxime

The substance 161 was synthesized as a substrate. The crude product was purified by EtOAc EtOAc EtOAc. *H NMR ( 400 MHz &gt; dmso) δ 11.04 ( s &gt; 1Η) - 10.51 ( m

, 1H) &gt; 9.07 ( s * 1H ) , 8.53 (m, 2H) &gt; 8.32 ( m &gt; 2H ) &gt; 8.15 (d &gt; 7 = 9.9 Hz * lH) » 7.93 ( s - 1H ) &gt; 7.80 (s &gt; 1H ) , 7.68 (s, lH) , 7.62 - 7.39 (m, 3H) &gt; 7.17 - 7.10 (m, 2H) &gt; 7.03 ( m &gt; 2H ) &gt; 6.98 ( d &gt; ./ = 8.0 Hz &gt; -224- 201206888 1 Η ) - 6.86 ( m &gt; 2Η ) &gt; 6.7 5 ( m &gt; 1 Η ) &gt; 6.64 ( s &gt; 1 Η ) , 6.55 (m, 2H) &gt; 5.30 ( m « 1H ) , 3.61 (s, 3H), 3.35 ( s &gt; 3H ) , 3.29 - 3.19 ( m, 4H ) &gt; 3.14-2.87 ( m * 4H) &gt; 2.72 ( s &gt; 3H ) - 2.24 ( m &gt; 2H ) , 1.60 (m, 2H) , 1.44 (m, 2H) &gt; 1 .30 ( m &gt; 1 OH ) ; ES/MS theory 値 ( C53H59N609S + ) ·· 95 5.4, experimental 値·· m/z = 95 5.4(M + H)+.

Example 41: (R)-6-[[3-[[6-[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]hexyl]amine A Mercapto]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carbamide

The title compound was synthesized according to a method similar to that described in Example 1 using Intermediate 173 as a substrate. 1H NMR (400 MHz &gt; DMSO-d6) δ 1 1.24- 1 1.08 ( s &gt; 1Η ) &gt; 9.49-9.3 2 ( s - 1Η ) , 9.03 ( s, 1H) &gt; 8.84-8.71 ( m &gt; 1 H ) &gt; 8.34 ( m &gt; 5H ) , 8.06 (s, 2H) , 7.81 (d, 2H,

J = 8.0 Hz ) &gt; 7.69 ( t &gt; 1H - J = 7.8 Hz ) , 7.33 ( s, lH ), 7.18 ( s, 1H ) , 7.03 ( d, 1H &gt; J = 8.2 Hz) &gt; 6.75 ( d &gt; 1H &gt; J = 8.2 Hz) &gt; 6.68 ( s &gt; 1H ) &gt; 6.61 ( d &gt; 1H J

=7.8 Hz) &gt; 5.05 ( m &gt; 1H ) &gt; 4.80 ( d &gt; 1H - J = 8.4 Hz ), 4.45 - 4.27 ( m &gt; 2H) &gt; 3.64 ( s &gt; 3H) - 3.28 ( d &gt; 2H -225- 201206888 -J = 6.19 Hz ) &gt; 2.93 ( s &gt; 4H ) &gt; 2.70 ( s &gt; 3H ) &gt; 1.79- 1.47 ( m,4H ) , 1.33 ( s,4H ) ; ES /MS theory 値 (C40H46N5O8S+): 756.3, experimental 値: m/z = 7 5 6 (M + H)+. Example 42: (R)-6-[[3-[[4-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]]amino]amino]piperidin-1 -yl]carbonyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate material 1 74 as a substrate. 'H NMR ( 400 MHz &gt; DMSO-d6) δ 11.1 9-11.05 (s,1 H ) » 9.53-9.34 ( s &gt; 1 Η ) &gt; 9.05 (s , 1H) '8.89- 8.70 ( m, 1 Η ) , 8.70-8.5 7 ( m, 1H) , 8.42 ( s, 2H ), 8_05 ( s , 1H ) , 7.89-7.62 ( m, 5H ) , 7.36 ( m , 1H ) * 7.19 ( m , 3H ) , 6.77 ( d,2H ,y =: 8.22 Hz), 6.73 ( s,1 H ), 6.66-6.55 ( m,1 H ) -4.86- 4.79 ( m, 1H ), 4.50 ( s, 2H ) &gt; 6.19- 5.9 1 ( m &gt; 1H) &gt; 3.68 ( s , '3H ), 3.53-3.31 (m, 2H ) &gt; 3.21-2.93 ( m , 3H ),: 2.71 ( s , 3H ) &gt; 1.71-1.39 ( m &gt; 2H ), 2.32-1 • 83 ( m ' 2H ) ; ES/MS Theory 値 (C39H42N508S+): 740.3 , Experimental 値: m/z = 740(M + H) + -226- 201206888 Example 43 : ( R) -6-[[3-[[6-[[2-hydroxy-2-[4-hydroxy-3-(methylsulfonylamino)phenyl]ethyl]amino]hexyl]amine formazan Phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide

ΝΗ Ο

The title compound was synthesized according to a method similar to that described in Example 1 using Intermediate 1 75 as a substrate. NMR (400 MHz, DMSO-d6) δ 11.15-10.93 (s, 1H), 10.13-9.90 (s &gt; 1 Η ) , 9.02 (s, 1 Η ) , 8.72 ( s &gt; 2 Η ) &gt; 8.5 7-8.42 ( m &gt; 2H ) , 8.26 ( s, 2H) &gt; 8.12-8.05 ( d &gt; 1H &gt; J = 7.7 Hz ) &gt; 8.02 ( s &gt; 1H ) , 7.8 3 - 7.7 3 ( d, 2 H,

J = 7.1) &gt; 7.71-7.63 ( t &gt; Ui J = 7.8 Hz ) &gt; 7.21 ( s &gt; 1H )&gt; 7.18-7.10 (m&gt; 1H) &gt; 7.07-6.98 ( m &gt; 1H ) &gt ; 6.88 ( d , 1H, / = 8.3 Hz) &gt; 6.75 -6.67 ( d &gt; 1H &gt; J = 8.3 Hz ), 6.63 ( s &gt; 1H ) &gt; 6.59-6.5 3 ( d &gt; 1H &gt; J - 7.8 Hz ) &gt; 4.79- 4.69 ( m &gt; 1H ) &gt; 3.61 ( s &gt; 3H ) &gt; 3.32-3. 1 9 ( m &gt; 2H ),

3.19-3.10 ( m &gt; 2H ) &gt; 2.92 ( brs &gt; 4H) - 2.67 ( brs &gt; 2H

)&gt; 1.53 ( m &gt; 4H ) &gt; 1 .3 0- 1.24 ( m &gt; 4H ) , 0.91 (t, 3H &gt; J = 7.32 Hz ) ; ES/MS theory 値 (C4〇H47N6〇9S2+ ) : 8 1 9.3, experimental 値: m/z = 8 1 9 (M + H)+. Example 44: (R)-6-[[3-[[6-[[2-hydroxy-2-(4-hydroxy-3-(hydroxy-227-201206888 methyl)phenyl)ethyl]amino]] Hexyl](methyl)aminemethylmercapto]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]methylquinoline-3-carboxamide

The title compound was synthesized according to a method similar to that described in Example 1 using intermediates 276 as a substrate. 1H NMR (400 MHz, DMSO-d6) δ 1 1.06- 1 0.93 ( s · 1Η ) &gt; 9.48-9.39 (s&gt; 1Η) , 9.07 ( s, 1H) &gt; 8.62-8.27 ( m &gt; 4H) &gt 8.16-7.98 ( m &gt; 1H ) , 7.69 ( m,5H) » 7.42-7.27 (m ' 1H) , 7.25-6.98 ( m,2H ) , 6.8 1 · 6 · 6 6 ( m,3 H ) &gt 6.66-6.5 0 ( m &gt; 1H ) &gt; 6.12-5.90 ( m &gt; 1H ) &gt; 4.82-4.74 (m'lH) - 4.49 ( s . 2H ) &gt; 3.68 ( s &gt; 3H ) &gt; 3.00 ( s &gt; 5H) &gt; 2.84 ( m &gt; 2H ) , 2.71 (s, 3H) , 1.72-1, 55 (m, 3H ) , 1.54- 1.42 ( m, 2H ) &gt; 1.42- 1 .3 0 ( m &gt; 2H ), 1.11-0.91 ( m ' 2H) ; ES/MS theory 値 (CUH48N508S+): 770.3, experimental 値: w/z = 770(M + H)+ 〇 Example 45: (R) ' 6-( (11-(2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)--alkyl)sulfonate 4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carbamamine-228- 201206888

The title compound was synthesized according to a method similar to that described in Example 13 using Intermediate 126 instead of Intermediate 137. 'H NMR (400 MHz, DMSO-d6) δ 10.92 ( brs &gt; 1 Η ), 10.50 ( s &gt; 1 Η ) , 10° 46 (brs, lH) &gt; 9.07 ( s &gt; 1 H ),

8.5 1 ( brs 2H ) &gt; 8.33 ( s &gt; 1H ) &gt; 8.30 ( s &gt; 1H ) &gt; 8.14

(d &gt; 7 = 10.2 Hz, 1H ) &gt; 7.99 ( s &gt; 1H ) &gt; 7.79 ( s - 1H )-7.20-7.1 3 ( m &gt; 2H ) - 6.98 ( d &gt; J = 7.9 Hz - 1H ), 6.69-6.5 7 ( m,3H) , 6.14 ( brs,1H) , 5.29 ( dm,·· = 7.0 Hz, 1H) , 3.65 (s, 3H) , 3.19 - 3.15 (m, 2H) &gt; 3. 1 1-2.90 ( m,5H ) , 2.75 ( s,3H) ,1.6 6 -1 · 5 3 ( m, 2H ) &gt; 1.44- 1.34 ( m &gt; 2H ) &gt; 1.30-1.14 ( m &gt ; 14H). ES/MS theory 値 (C40H50N5O7S+): 744.3, experimental 値: m/z = 744.5 (M + H)+. Example 46: (R) -6-((11-(2-hydroxy-2-(6-hydroxy-3-keto-3,4-dihydro-2H-benzo[b][l,4]] Oxazin-8-yl)ethyl)amino)undecylsulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamidine Amine-229- 201206888

0〆

The title compound was synthesized according to a method similar to that described in Example 5, using Intermediate 1 77 as a substrate. 'H NMR (400 MHz, DMSO-d6) δ 11.06 ( brs, 1 Η ), 10.62 ( s, 1 Η ) , 9.06 ( s, 1 Η ) &gt; 8.60 ( brs &gt; 1 Η ), 8.49 ( brs &gt; 1 Η ) , 8.3 4 - 8 _ 3 2 ( m,2 Η ) , 8.02 ( s,1H) , 7.80 ( s,1H) &gt; 7.20 (t&gt; J = 9.0 Hz&gt; 1H) &gt; 6.7 1- 6.66 (m, 3H) -6.51 (d &gt; y = 2.7 Hz &gt; 1H) &gt; 6.34 ( d &gt; J = 2.3 Hz - 1 H ) &gt; 5.06 ( dm &gt; J = 7.8 Hz - 1H) &gt; 4.52-4.44 ( ABq &gt; J = 15.7 Hz, 2H ) , 3.69 ( s - 3H ) , 3.20-3.16 ( m, 2H) &gt; 3. 10-3.00 ( m &gt; 1 H ) &gt; 2.95 -2.84 ( m - 2H ) , 2.75(s,3H) ,1.66-1.51 (m,2H) &gt; 1.45-1.33 (m,2H) &gt; 1.32-1.13 ( m &gt; 14H ). ES/MS theory 値 (C39H50N5O8S+): 748.3, experimental 値: w/z = 748.5 (M + H)+. Example 47: (R) -6-( (4,-((2-(2-(-)-yl-2-yl)-(2-dihydroquinolin-5-yl) Amino)methyl)-[1,1'-biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline -3 - methotrexate-230- 201206888

The stomach compound 1 was synthesized according to a method similar to that described in Example 13 except that NMP was used instead of DMF and the intermediate i27 was used instead of the intermediate is?. The crude product was purified by PREP-HPLC toiel

*Η NMR ( 400 MHz - DMSO-d6) δ 11.22 ( brs &gt; 1Η) ' 10.49 ( brs, 2H) , 9.15 ( brs, 1H) , 9.03 ( s, 1H), 8.42 ( s &gt; 1 [H ) , 8.37 ( s ,1 H ), 8.17 (S ,1 H ), 8.10 ( d,J r ==9. 8 Hz, 1 H ), 8.05 (s, 1H) &gt; 8.04- 8.00 ( m &gt; 1H y 7.8 1 ( d, J = 7.8 Hz, 2H ) , 7. , 73- 7.68 ( m , 3H ) , 7. 12 (d &gt; y -: 7.8 Hz, 1H) , 7. 06 ( t, J = 8.2 Hz,1 H ), 6. 96 ( d,J =8.2 Hz,1 H ) '6.70 ( s,1H ) &gt; 6.64- 6.54 ( m, 3H ), 6.22 ( brs ' 1H ) ,5 • 36 (dm,v ^ = 8.3

Hz, 1H), 4.32 (brs, 2H), 3.69 (s, 3H), 3.27-2.98 (m, 2H), 2.71 (s, 3H). ES/MS Theory 値 (C42H38N5〇7S+): 75 6.3 ′ Experimental 値: w/z = 75 6.4(M + H)+. Example 48: (R)-6-((4,-(((2-hydroxy-2-(2-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amine) Methyl)biphenyl]_4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carbamide-231 - 201206888

The title compound was obtained by a method similar to that described for Intermediate 18, using NMP instead of DMF and using Intermediate 128 instead of Intermediate 137. The crude product was purified by PREP-HPLC toiel

*Η NMR ( 400 MHz, DMSO-d6 ) δ 1 1 . 17 ( brs,1Η ), 10.50 ( brs,2Η) , 9.12 ( brs,2Η) , 9.06 ( s,1Η), 8.41 (s' ih) &gt 8.37 ( s · 1H ) , 8.13 - 8.06 (m, 2H), 7.92 ( d . j = 7.8 Hz - 2H ) , 7.8 6 - 7.7 9 ( m,3 H ) - 7.66 &quot;, 7=7.8 Hz , 1H), 7.26 (1,·· = 7.8 Hz, 1H), 7.12 (¢1-./ = 7.8 Hz &gt; 1H) - 6.9 7 ( d &gt; J = 8.2 Hz &gt; 1H )

• 6.83 (d&gt; J = 8.2 Hz&gt; 1H) &gt; 6.70-6.63 ( m » 2H ), 6.56 (d· j = 10.2 Hz - 1H) &gt; 6. 1 9 ( brs &gt; 1H ) , 5.35 ( dm » J = 7.8 Hz &gt; 1 H ) &gt; 4.30 ( s - 2H ) , 3.61 (s, 3H) ' 3.16-2.96 (m, 2H) , 2.72 (s, 3H) °ES/MS Theory 値 (C42H38N5〇 7S+): 756.3, experimental 値: = 756.4 (M + H) + Example 49: ( R ) -6- ( ( 4 '- ( 3- ( ( 2-hydroxy-2- ( 5-hydroxy-3- keto) -3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyl)amino)propyl)-[1,1,-biphenyl]-4-yl Sulfomethyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide-232- 201206888

The title compound was synthesized according to a method similar to that described in Example 1 using Intermediate 1 78 as a substrate.

1H NMR (400 MHz, DMSO-d6) δ 11.20 ( brs &gt; 1 Η ), 9.97 (s, 2H) - 9.04 ( s &gt; 1 Η ) &gt; 8.63 ( brs &gt; 1 Η ) &gt; 8.53 (brs &gt; 1Η &gt; 8.4 1 ( s &gt; 1Η ) &gt; 8.37 ( s - 1Η ) - 8.09 ( s &gt; 1Η ) &gt; 7.87 (d&gt; J = 8.6 Hz&gt; 1H) - 7.83 ( brs &gt; 1H ) , 7.69 (d, J = 8.2 Hz, 1 H ) , 7 · 3 9 · 7 · 3 4 ( m, 2 H ), 7.27 ( t &gt; J = 8.0 Hz - 1H ) &gt; 6.91 (d&gt; J = 8.6 Hz&gt ; 1H) &gt; 6.86-6.8 1 ( m &gt; 1H ) &gt; 6.7 1-6.65 ( m - 2H ) &gt; 6.55 ( d « J = 8.6 Hz &gt; 1H ) &gt; 5.92 ( brs &gt; 1H) &gt ; 5.04 ( dm &gt; J = 7.5

Hz,1H ) &gt; 4.5 7-4.48 ( ABq - J = 14.9 Hz &gt; 2H ) , 3.62 ( s, 3H) &gt; 3. 12-3.02 ( m &gt; 1H ) , 3.01-2.90 (m, 3H) , 2.73 -2.66 ( m &gt; 2H ) , 2.71 ( s, 3H) &gt; 2.03 - 1.90 ( m &gt; 2H) . ES/MS theory 値 (C43H42N508S+): 78 8.3, experimental 値: w/z = 7 8 8.2 (M + H)+. Example 50: (R)-6-((4'-(3-((2-hydroxy-2-( 5-hydroxy-3-keto-3,4-dihydro-2H-benzo[b]][ 1,4]oxazol-8-yl)ethyl)amino)propyl)biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl-233- 201206888)amine ))-8-methylquinoline-3-carboxamide 0 ΗΝ person 1 0^

标题 1^ϊ^'ΝΗ ο gtpNH2 The title compound was synthesized according to the method similar to that described in Example 1 using the intermediate 1 79 as a substrate. 'H NMR ( 400 MHz, DMSO-d6 ) δ 1 1 .14 ( brs, 1 Η ) ' 9·98 ( s, 2H ) , 9.04 ( s, 1H ) , 8.64 ( brs &gt; 1H ) ' 8.56 (brs , lH) , 8.42 (s'lH) , 8.35 (s'1H) '8.15(s &gt; 1H ) 1 8.0 1 ( s &gt; 1H ) 1 7.99-7.93 ( m ' 1H ) , 7.82 ( s ' 1H) 1 7.71 -7.63 ( m &gt; 3H ) - 7.39 ( d &gt; ^ = 7.4 H z &gt; 2 H )1 7.07 ( t - 7 = 8.1 Hz &gt; 1H ) - 6.91 ( d &gt; J = 8.6 Hz » 1H) , 6.70 ( s, 1H) , 6.65 - 6.52 ( m, 3H ) &gt; 5.91 ( brs , 1H) , 5.05 ( dm , " / = 7 · 9 Hz , 1 H ) , 4 · 5 7 - 4.4 9 ( AB q 1 J = 14.8 Hz, 2H) &gt; 3.6 1 ( s &gt; 3H ) &gt; 3.12-3.03 ( m &gt; 1 H ) &gt; 3.03 -2.89 ( m &gt; 3H ) , 2.72 - 2.67 ( m , 2H ) , 2.71 (s' 3H) , 2.06-1.91 (m, 2H). ES/MS theory 値 (C43H42N508S+): 788.3, experimental 値: w/z = 788.2 (M + H)+. Example 51: (R) .6-((4'-(5-(2-hydroxy-2-(5-hydroxy-3-keto-3,4-dihydro-2Η-benzo[b][ l,4]oxazol-8-yl)ethyl)amino)pentyl)biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8 -methylquinoline-3-carboxamide-234- 201206888

The title compound was synthesized according to a method similar to that described in Example 1 using the intermediate compound 180 as a substrate.

'H NMR (400 MHz &gt; DMSO-d6) δ 11.12 ( brs, 1 Η), 9.98 (s, 2H) &gt; 9.05 ( s &gt; 1H ) &gt; 8.56 ( brs &gt; 1H ) &gt; 8.46 (brs, 1H) , 8.40 ( s, 1H ) , 8.36 ( s, 1H) , 8.07 ( s , 1H) , 7.85 (d, J = 8.2 Hz, lH) , 7.82 (s, lH), 7.78 ( d &gt; y = 8.3 Hz &gt; 1H ) , 7.66 (d, J = 7.8 Hz, 1H), 7.27-7.23 (m, 1H) &gt; 7.1 2 ( s &gt; 1 H ) , 6.99 (s, 1H)

&gt; 6.91 ( d &gt; J = 8.6 Hz - 1H ) - 6.82 ( d &gt; J = 8.6 Hz - 1H ), 6.70 - 6.62 (m, 2H) &gt; 6.5 6 ( d &gt; J = 8.6 Η z &gt ; 1 H ), 5.9 1 ( brs &gt; 1H ) &gt; 5.04 ( dm &gt; J = 7.4 Hz &gt; 1H ) , 4.57 - 4.49 ( ABq &gt; J = 14.5 Hz , 2H ) , 3.6 1 ( s &gt; 3H ) , 3.08- 2.99 (m, lH) , 2.96-2.85 (m, 2H) &gt; 2.71 ( s &gt; 3H ), 2.63 ( t &gt; J = 7.2 Hz > 2H ) &gt; 1 .72- 1.5 5 ( m &gt; 4H ) &gt; 1.38-1 .27 ( m &gt; 2H ). ES/MS theory 値 (C45H46N508 S+): 816.3, experimental 値: w/z = 816.3 (M + H)+. Example 52: (R)-6-((4'-(5-(2-hydroxy-2-(5-hydroxy-3-keto)-3,4-dihydro-2H-benzo[b][ l,4]oxazin-8-yl)ethyl)amino) -235- 201206888 pentyl)biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl)amine Base)-8-methylquinoline-3-carboamine 0

The title compound was synthesized according to a method similar to that described in Example 1 using intermediates 181 as a substrate. · 'H NMR (400 MHz, DMSO-d6) δ 1 1 _ 14 ( brs, 1 Η ), 9.98 ( s, 2H ) , 9.04 ( s, 1H ) , 8.64 ( brs, 1H ) , 8.56 (brs, 1 H ) ), 8.42 ( s , 1 H ) &gt; 8. 35 ( s &gt; 1 H ) , 8. 15 (S , 1 Η ), 8.0 1 (s , 1 H ), 7. 99. • Ί 93 ( m , 1 H ) -7.82 (S ,1 Η ), 7.65 (d &gt; J = 3.2 H :z, 1 H ) , 7.61 ( d &gt; J =Ί 7.4 Hz , 2Η) 7 • 39 (d,, 7 = 7. 4 Hz , 2H ) &gt; 7.07 ( t &gt; J = 8.1 Hz, 1 H ) j 6 • 91 ( d, J : — 1 8.6 Hz , 1 H ), 6.70 (s &gt; 1 Η ) , 6 .65- 6 .52 (m, 3H ) , ^ 5.9 1( b rs,1 H ) , 5 • 04 ( dm &gt; J = 7.4 Hz - 1H) &gt; 4.57 -4 .49 丨(AB q, J = 14.5 Hz j 2H ) - 3. 6 1 ( s » 3H ) -3.08 -2. 99 (m ,1 H ), 2.96 -2. 85 (m,2H ), 2.71 (s, 3H ), 2 • 63 (t, J = 7.2 Hz, 2H), 1.72-1. 55 ( m , 4H ) &gt; 1.3 8 -1.27 (m , 2H ). ES/MS Theory C ( C 4 5 H 46N; 5〇8s + ): 8 1 6.2 ί &gt; Experiment 値 :m /z =

8 1 6.3 (M + H)+. EXAMPLE 5 3 to 60 0-236-201206888 Other compounds of Formula I which can be prepared using the general synthetic routes described above include: (R) -6-(3-( (4-(4-(4-( 2-Hydroxy-2 -(8-carbyl-2-ylidene-1,2-dihydroquinolin-5-yl)ethylamino)butyl)phenyl)-N-methylpiperidine- 1-Methylamino)methyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinoline-3-carboxamide

〇

〇

Nh2 53

(R) -6-( 3-( 4-( 4-(4-(2-)-yl-2-(8-yl)-indenyl-1,2-dihydrosin-5-yl) Ethylamino)butyl)phenyl)piperidine-1-carbonyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinolin-3-carbamidine Amine

1,2-Dihydrosalin-5-yl)ethylamino)butyl)cyclohexyl)piperidine-1-carbonyl)phenylsulfonyl) 4-(3-methoxyphenylamino) -8-methylquinoline-3-carboxamide-237- 201206888 0〆

5 5 (R) -6- ( 3- ( 4- 4-(4-(4-(2-hydroxy-2-(8-hydroxy-2-one)

1,2-dihydroquinoxa-5-yl)ethylamino)butyl)phenyl)-N-methylpiperazine-1-carboxamido)methyl)phenylsulfonyl) -4-(3-methoxyphenylamino)-8-methylquinoline-3-carbamimidoxime

1,2-dihydroquinolin-5-yl)ethylamino)butyl)phenyl)-N-methylpiperidine-1-carboxamido)methyl)phenylsulfonyl) -4-(3-methoxyphenylamino)-8-methylquinolin-3-carboxamide 0

Again o^

Nh2 57- phenyl-5-yl)ethylamino)butyl)phenyl)piperazine-1-carboxylic acid 3-(3-aminocarbamimid-4-(3-methoxyphenylamino)-8 -methylsialolin-6-ylsulfonyl-238- 201206888

3-(3-Aminomethylindol-4-(3-methoxyphenylamino)-8-methylquinoline·6-ylsulfonyl)benzylaminocarboxylic acid (R) -6-(2 -hydroxy- 2-(8-hydroxy-

2-keto-1,2-dihydroquinolin-5-yl)ethylamino)hexyl ester

(R) -6-( 3-( 5-( 5-(2-hydroxy-2-(8-hydroxy-2-keto)-1,2-di 59-hydroquinolin-5-yl)ethylamino) Pentyl)porphyrin-1-carbonyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylsorpene-3-cartoamine

Biological Examples Inhibition of PDE4B4 Enzyme Activity The inhibitory activity of the test compound was determined using the PDE Glo assay (Promega, V1361). Prepare PDE-Glo reaction buffer (1 -239-201206888 mL 5X buffer + 4 mL water), and 150 nM solution of the test compound dissolved in the reaction buffer, followed by serial dilution of 1:3 in the reaction buffer in. The final concentration used in the assay did not exceed 0.1% DMSO using DMSO in the starting dilution of the test compound. Human recombinant PDE4B2 (BPS Bioscience) was added to the solution of the test compound in the reaction buffer at a concentration of 0.12 nM per reaction. The enzyme and test compound were pre-incubated for 10 minutes at room temperature. Next, 50 nM enzyme-loaded cAMP was added to initiate the enzyme reaction, and the reaction was terminated after 1 hour. Stop buffer (1 mL 5X Stop Buffer + 3.9 mL water + 100 μί 100 mM IBMX (ICN Chemicals in DMSO)) was added to each reaction tank to terminate the reaction. Add detection buffer (1 mL 5X PDE-Glo Detection Buffer + 3.96 mL Water + 40 μί PKA (supplied in kit)) to the cAMP-enzyme-test compound mixture. This secondary reaction is in the chamber. Warm for 20 minutes. An equal volume of Kinase Glo reagent was then added to the reaction mixture. After 10 minutes, the luminescence luminescence was measured using a luminometer (EnVision, reading luminosity every 0.1 seconds). There is a direct correlation between the luminescence enthalpy and the cAMP concentration in the reaction mixture. Data were plotted against relative light units (RLU) versus measured compound concentrations, and IC50 was determined using a non-linear curve fitting method using a single point binding mode using GraphPad Prism 5.0. The IC5Q measurement of the above compounds is shown in column 1 (PDE4 IC5〇) of Table 1 below. P-2 Adrenergic Receptor Binding Assay The test compound was incubated with Chinese-240-201206888 hamster oocytes (CHO) expressing human recombinant P-2 adrenergic receptor for 120 minutes. The binding of the test compound to the p 2 adrenergic receptor was measured by measuring the amount of radiolabeled 酉[3H] ( - ) CGP-12 177 (0.3 nM) displaced by the receptor by a scintillation counter. A concentration response curve of the test compound was prepared, and IC5G (the molar concentration of the compound when 50% inhibition of the maximum reaction of the compound was produced) was measured. The above analysis was carried out using the flow of the original description based on the analysis of J 〇 s e p h e ί &lt;3 / ·, ( 2 0 0 4 ) JVa μ «· - Sc λ _ d r c is 369:525-532. The IC5Q measurement of the above compounds is shown in column 2 (β2 IC50) of Table 1 below. Functional agonism of human recombinant β 2 adrenergic receptors expressed in Chinese hamster oocytes (CHO) Test compounds were incubated with CHO cells expressing human recombinant Ρ-2 adrenergic receptor for 30 minutes. The agonistic response of the receptor was measured by detecting the increase in the concentration of cyclic AMP in the cells relative to the control group by using a homogeneous time resolved fluorescence (HTRF) format. The compound was judged to be a "complete" or "partial" agonist based on the maximum concentration of cAMP accumulation relative to the control compound isoproterenol ("complete" agonist in this assay system). A concentration response curve of the test compound was prepared, and EC5q (the molar concentration of the agonist at 50% of the maximum response of the agonist) was measured. The above analysis was carried out using the flow of the original description based on the analysis of Baker, J.G. (2 0 0 5 ) ζ_ί_ ·/_ , · 1 44 : 3 1 7-3 2 2 . -241 · 201206888 The EC5Q measurement of the above compounds is shown in column 3 (β2 EC50) of Table 1 below. Inhibition of tumor necrosis factor a (TNF-ct) induced by lipopolysaccharide (LPS) released from human peripheral blood mononuclear cells (PBMC) Human whole blood was taken out by the donor and cell purification was started within 2 hours. Peripheral blood mononuclear cells (PBMC) were purified using standard Ficoll gradient purification techniques at a concentration of 1 〇〇, and the sputum cells/slots were placed in 96-well microplates. (3-2 adrenergic receptor agonists also have an anti-inflammatory effect on some immune cells expressing the receptor, which inhibits the production of tumor necrosis factor alpha (TNF-α) in this assay. Therefore, PBMC is in beta-2 Adrenergic receptor antagonist ICI-118551 [3-(Isopropylamino)-1-[(7-methyl-4-dihydroindolyl)oxy]butan-2-ol] (10 μΜ) Pre-incubation for 30 minutes in the presence of PDE4-directed activity of the test compound and pre-incubation without ICI-118551 to determine the conjugate activity guided by PDE4 and β-2 receptors. Dissolved in DMS0 and diluted in buffer (final DMS0 concentration 0.1% ν / ν), then added to the cell suspension and pre-incubated for 1 hour at 37 ° C. Then add LPS solution (0.4 ng / The cells were incubated for an additional 6 hours. At the end of the incubation, the cell supernatant was collected and TNF-α was measured using the Procarta Cytokine Assay Kit (Affymetrix, Santa Clara, CA) according to the manufacturer's instructions. Using MiraiBio Masterplex QT ν4·0 Software (MasterPlex Version 1.0.1.18 Copyright 2008, Hitachi Software Engineering Co., Ltd Analytical data, extrapolated the mean fluorescence intensity (MFI) to the 201206888 TNF-α concentration, and measured the average enthalpy of the re-groove. Using the software GraphPad Prism 5 for Windows (version 5.02) (GraphPad Software, San Diego CA) The inhibition curve of each test compound in the presence or absence of ICI-118551 was measured using a non-linear curve fitting method in a single-point binding mode to measure the IC50. The EC5Q measurement of the above compounds is shown in column 4 of Table 1 below. (PBMC TNF EC5〇) φ Lipopolysaccharide (LPS)-induced neutrophil aggregation to the lungs of Lewis rats The rats were anesthetized with 4% isoflurane and placed at an angle of 30° on the supine Position, open the mouth to expose the trachea. Introduce the 22·caliber needle with the syringe into the trachea, and deliver the suspension of the test compound (200 μΐ volume / 400 g) to the lung about 1 cm above the tracheal protuberance. The rats were allowed to return to awake. After 2 hours, the awake animals were placed in the chamber and exposed to aerosolized LPS (1.0 mg/mL) at a rate of 3.0 L/min for 20 φ minutes. After exposure to LPS 4 Intraperitoneal injection of excess pentobarbital Rats were euthanized (pentobarbital) (90 mg/kg). Bronchoalveolar lavage (BAL) was then performed by inserting a 14-caliber blunt needle into the exposed trachea. Five 5 ml PBS washes were collected from the lungs, placed in a Falcon tube, and then centrifuged at 1 600 g for 10 minutes at 4 °C. The supernatant was discarded, and the cells were resuspended in PBS, and the total number of cells was measured based on a 10 μΐ resuspended cell sample stained with trypan blue blue dye, and counted using a +C〇Untess® cell counter (Invitrogen). Differential cells on cytospinned cells stained with May-Grunwald a n d G i e m s a solution -243- 201206888

Count to measure the number of neutrophils in the BAL wash. Manual eye counting is performed to measure the percentage of cells in the lysed sample (measuring macrophages, neutrophils, eosinophils, T-lymphocytes, and eosinophils, respectively). The total number of various cell types in each sample was measured. Usually, each experimental group contains a minimum of 6 rats, and the mean 値 ± SEM number of neutrophils in each group is measured. The degree of neutrophil inhibition caused by the direct administration of the test compound to the lung was measured as compared with the control group treated with the vehicle and exposed to LPS. Statistical analysis for measuring significant differences between groups was performed using the one-way variation analysis (ANOVA) using the software GraphPad Prism 5 for Windows (5.02) 3⁄4 (GraphPad Software, San Diego CA). Compounds of Examples 5, 8, 10, 1 2, 2 4, 2 6 , 2 7 , and 3 5 were tested in this analysis, except for the compound of Example 26, all of which showed a dose of 300 pg/kg. There is greater than 40% neutrophil inhibition.

Inhibition of choline-induced bronchoconstriction in Dunkin-Hartley guinea pigs Dixon-Hartley (available from Charles River Laboratories, male, 500 to 800 g) was anesthetized with 4% isoflurane and placed in supine 30 ° ° position, open the mouth to expose the trachea. A 22-gauge needle with a syringe was introduced into the trachea, and the suspension of the test compound (200 μΐ volume) was delivered to the lungs at a distance of -244-201206888 1 cm above the tracheal protuberance. The in vivo bronchial protection of the test compound against acetylcholine (ACh)-induced bronchoconstriction was performed in the conscious guinea pig 4 hours after administration of the test compound in the trachea using the Whole Respiratory Measurement System (WBP) (Buxco Research Systems) carry out testing. Pulmonary function is measured in this system and is indicated by the enhanced PAUSE (Penh), which has been widely used in scientific research and preclinical drug screening as an alternative to measuring lung tolerance in conscious animals. (Chong α/., /. Pharmnacol. Toxicol. Methods 1 998; 39: 163-168. Pennock et al., J. Appl. Physiol. 1 9 79; 46: 399-406). The guinea pig was placed in the WBP system and exposed to an aerosol of 0.9% saline solution or ACh solution (4 mg/mL) for 1 minute. Continuous recording of lung function measurements immediately after saline or Ach challenge for 20 minutes (expressed in Penh and at maximum expiratory flow rate/maximum inspiratory flow rate X pause time) results in airway response (Penh) versus relative The area under the curve (AUC) of the reaction time (20 minutes) is expressed. The airway reaction of guinea pigs was measured 24 hours before the start of evaluation of φ of the test compound to determine the basal reaction before compound treatment. Thus, each animal can be used as its own control group in assessing the bronchial protection of the test compound, and the efficacy of the test compound is calculated as the percentage inhibition of the airway reaction compared to this number. The analysis of the duration of bronchial protection was also measured by challenge the animals for 24 hours after administration of the test compound. Typically, each experimental group contained a minimum of 6 guinea pigs and the mean 値 ± SEM inhibition pen of each group was measured. The statistical analysis used to measure significant differences between groups is based on the one-factor variation analysis (ANOVA) using the software GraphPad -245 - 201206888

Prism 5 for Windows (version 5.02) (GraphPad Software, San Diego CA). Compounds of Examples 5 and 12 were tested in this assay and showed greater than 75% bronchial protection at 4 hours at doses below 125 pg/kg.

Example # PDE4 IC5〇β2 IC5〇β2 EC5〇PBMC TNF ECso 1 + + + + + + + + 2 + + + + + + + + 3 + + + + + + + + + + + + + + + + + 5 + + + + + + + + 6 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 11 + + + + + + + + 12 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 17 +10 + + + + + + 18 + + + + + + + + 19 + + + + + + + + 20 + + + + + + + + 2 1 * ★ + + + + 22 * * + + + + + + 23 + + + + + + + +

-246- 201206888

Example # PDE4 IC5〇β2 IC5〇β2 ECs〇PBMC TNF ECso 24 氺氺+ + + + + 25 + + . + + + + 26 + + • + + 27 + + + + + + + + 28 + + - + + + + 29 + + + + + + + + 30 + + + + + + + + 3 1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 35 氺氺+ + + + + + 36 氺氺+ + 氺氺+ + 37 + + + + + + + + +38 + + + + + + + + + + + + + + + + + + + 40 氺氺+ + + + 氺φ 4 1 + + + + + + + + 42 + + + 氺氺+ + 43 + + + + + + + + 44 + + _ _ + + 45 + + + + + + + + 46 + + + + + + + 47 + + - _ + + 48 + + + + + + + + 49 氺氺+ + 氺氺+ + 50 氺氺+ + * * + + 5 1 氺氺+ + + + + + 52 氺氺本氺-247- 201206888

Dry powder blends Dry powder blends for inhalation administration of one or more of the compounds of the invention can be prepared in the following manner: The particles (API) of the compounds of the invention are micronized using conventional methods including, but not limited to, jet honing The mass median aerodynamic particle size (MMAD) is about 2 and the GSD &lt; distribution of about 2.5. The micronized particles are then mixed with a conventional dry powder excipient such as lactose. Examples of suitable forms of commercially available lactose include Lactohale LH100 (including &gt; 60 micron particles), and Lactohale LH200 (containing large (&gt; 60 micron) lactose particles mixed with lactose "microparticles" (&lt;10) Micron)). A typical blend will contain less than 10% API with the remainder being a dry powder excipient. This bulk blend can be filled to multiple doses of DPI, such as Valois Prohaler, which is designed to deliver the desired dose -248-

Claims (1)

201206888 VII. Application for Patent Park: 1. A compound of formula I: Wherein χ is a substituted benzene ring selected from the group consisting of: Η0\^Λ〆 And Ri Z is a bond or a group selected from the group consisting of: or (R4)a R1 is CH2OH, CH2CH2OH, N(H)C(0)H, or 1^(11)3(02)(^-(:3 alkyl, and R2 is Η; or R1 and R2 The linked phenyl groups together form a bicyclic fused heterocyclic ring having 9 or 1 ring atoms, wherein 1 or 2 ring atoms are selected from the group consisting of fluorene, 0 and S, wherein the bicyclic fused heterocyclic ring is optionally subjected to one or two Or three additional substituents each independently selected from the group consisting of alkyl, keto and oxime; R3 is selected from (: 4.12 alkyl, C4-12 alkenyl, C4-12 extended, R8 -0-R8, R8-N(R7)-R8, C3-6 cycloalkyl, r8-c3-6 exocyclic graft-249- 201206888, R8-C3_6 cycloalkylene_Het, c3-6 Cycloalkyl-R8, R8-C3-6 cycloalkylene-R8, C6-1G extended aryl, r8_c6.ig extended aryl, C6-1Q extended aryl-R8, R8-C6, aryl -r8, r8-C6.i. aryl-O-R8, R8-C6-1() aryl-N(R7)-R8, r8-C6-iq aryl-C6.1() Aryl, 1,118-Het, Het-R8, R8-Het_R8, R8-〇-Het, R8-C6-1() aryl-oxime Het, R8-C6-丨g aryl-c (〇)-Het, R8-C6.1() aryl-N(R7)-Het, R8-Het-C6-i aryl, R8-C6.1Q aryl-Het, and R8- 0-R8-C6-10 An aryl group, wherein the alkyl, alkenyl or alkynyl group is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, keto, and OR7; Optionally substituted with 1, 2, 3 or 4 substituents selected from halo, alkyl, and hydrazine R7: Het is a 5-6 membered saturated or unsaturated monocyclic heterocycle, or 8- a 10-membered saturated or unsaturated, bicyclic heterocyclic group wherein 1 or 2 ring atoms are selected from the group consisting of N, 0 and S, and wherein the monocyclic or bicyclic heterocyclic group is optionally subjected to 1, 2 or 3 Substituted by a substituent of a halo group, an alkyl group, an alkoxy group, a ketone group and OH; Y is c(0), OC(O) 'C(0)N(R7), C(0)N(R7) CH2, 0C(0)NR7CH2, n(r7)c(o), or n(r7)c(o)n(r7); a is 0, 1, 2, 3, or 4; R4 is selected from a halogen group , alkyl, and OR7; R5 is hydrazine or alkyl; b is 1, 2, 3, 4, or 5; R6 is selected from halo, alkyl, haloalkyl, OR7' 0-haloalkyl, R8 - -250- 201206888 OR , 〇-R8-OR7, c(0)alkyl, 〇_r8_c(〇)alkyl, c〇n(R7)2, r8-C〇N(R7)2, r8_n(R7 2, N(R7)C(0)alkyl, N(R7)C(0)N(R7)2, n (R7)S〇2 alkyl, R8-S02N(R7)2, and CN t or two R6 on the adjacent carbon together with the attached phenyl group form a bicyclic heterocycle having 9 or 10 ring atoms, wherein 1 or 2 ring atoms are selected from N, Ο and S; R7 is fluorene or alkyl: and R8 is C丨·丨0 alkyl, C2-10 extended alkenyl, or C2-i〇 alkynyl, Wherein each R8 is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR7; the prerequisite is that the two R8 groups of any definition of R3 are Cio alkyl, C2 The total number of carbon atoms of the -1 () alkenyl group or the C2-1G alkynyl chain is not more than 1 2; R9 is hydrazine or (: 丨-(: 3 alkyl; or a pharmaceutically acceptable salt thereof). 2. The compound of claim 1, wherein R3 is selected from the group consisting of C4·丨2 alkyl, c4-12 extended alkenyl, C4_u alkynyl, R8-〇-R8, R8-N(R7)-R8, C3.6 Cycloalkyl, r*_C3_6 cycloalkyl 'R8-C3_6 cycloalkyl-Het, C3_6 cycloalkyl-r8, r8_c3-6 extended fluorenyl _r8, phenyl, R8- Phenyl, phenyl-R8, r8_phenyl-R8, R8-phenylene-O-R8, R8-phenylene-N(R7)_r8, phenyl-phenylene, Het, R8-Het, Het-R8, R8-Het-R8, R8-〇_Het, R8-phenylene-Het, R8-phenylene-C(0)-Het' R8-phenylene-N (R7)-Het, R8-Het-phenylene, R8-phenylene-Het, and R8-fluorene-R8-phenylene; or a pharmaceutically acceptable salt of 251 - 201206888. 3. If the compound of claim 1 is selected from the formula II (〇 or formula II (b): Or a pharmaceutically acceptable salt thereof; wherein: 10 X is a substituted benzene ring selected from the group consisting of: And Ri R1 is CH2OH, CH2CH2OH, N(H)C(0)H, or N(H)S(02)CH3, and R2 is H; or R1 and R2 together with the attached phenyl group are selected from the group consisting of Bicyclic fused heterocycle: -252- 201206888 HO R3 is selected from C4•丨2 alkylene, C4_丨2 alkenyl, C4_丨2 alkynyl, R8-0-R8, R8-C3.6 cycloalkyl-Het, R8-extension Phenyl, R8-phenylene-O-R8, R8-phenylene-phenylene, Het, R8-Het, R8-0-Het, R8-phenylene-C(0)-Het, R8- Het-phenylene, R8-phenylene-Het, and R8-0-R8-phenylene; wherein the alkyl, alkenyl or alkynyl groups are optionally arbitrarily selected from 1, 2 or 3 Substituted by a halogen group, a ketone group, and a substituent of OR7; Wherein the phenyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halo, alkyl and OR7; Het is a 5-6 membered saturated or unsaturated monocyclic heterocyclic group. (heterocyclene) or a 8-10 membered saturated or unsaturated, bicyclic heterocyclic group wherein 1 or 2 ring atoms are selected from the group consisting of N, 0 and S, and wherein the monocyclic or bicyclic heterocyclic group is optionally subjected to 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, alkoxy, keto and OH; Y is C(O), OC(O), C(0)N(R7), C (0) N(R7)CH2, oc(o)nr7ch2, n(r7)c(o), or n(r7)c(o)n(r7); a is 0, 1, 2, 3, or 4 R4 is selected from halo, alkyl, and OR7; -253- 201206888 R5 is an anthracene or an alkyl group; b is 1, 2, 3, 4, or 5; r6 is selected from a halogen group, an alkyl group, a halogen , OR7, Ο-halogen; or7, 〇-R8-〇R7, C(O)alkyl, 〇-R8-C(0)alkyl, R8-C〇N(R7)2, R8-N ( R7)2, n(r7)c(o) n(r7)c(o)n(r7)2, n(r7)so2 alkyl, r8-so2n(r7) » or two R6 on adjacent carbon a bicyclic heterocyclic ring having 10 or more ring atoms together with a phenyl group attached thereto, wherein 1 or 2 ring atoms are N, 0 and s; R7 is Η An alkyl group; and r8 is an alkylene group, a c2-l()-alkenyl group, or a c2-10 wherein each R8 is optionally substituted with 1, 2 or 3 substituents selected from the group 'OR7': prerequisites The total number of carbon atoms of the C2O alkyl group, C2_1Q extended alkenyl group, or &lt; base chain of any two R8 groups of R3 is not more than 12. 4. A compound as claimed in claim 1 or a salt thereof, wherein R1 is CH2OH and R2 is H. 5. The compound of claim 1 or a salt thereof, wherein R1 and R2 are taken together with the attached phenyl group or a bicyclic fused heterocyclic ring of 1 ring atom, wherein one or two are selected from the group consisting of N, 0 and S, and the bicyclic fused heterocyclic ring are optionally substituted with an additional substituent of a group, a keto group and OH. 6. The compound of claim 1 or its substituent, R8-CON(R7)2, 2, and CN have 9 subunits selected from the group consisting of an alkynyl group, a keto group, and a definition] 2 - 1 0 acetylene pharmaceutically pharmaceutically acceptable salt having 9 ring atoms selected from the group consisting of alkane pharmaceutically acceptable -254-201206888, wherein R1 and R2 together with the attached phenyl group form the following 7. The compound of any one of claims 1 to 6, wherein R3 is selected from the group consisting of alkyl, C4.12, alkenyl, C4.12, alkyne, or a pharmaceutically acceptable salt thereof. a group, R8-〇-R8, and r8_N(R7)_r8, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by 1, 2 or 3, respectively, selected from a dentate group, a keto group, and an OR7 group. Substituted by the base. The compound of any one of claims 1 to 6, wherein R3 is selected from C5.8 alkyl, (5-8 an alkenyl group, C5_8 alkynyl group), or a pharmaceutically acceptable salt thereof , R8_〇_R8, and r8_n(r7)_r8, wherein each R8 is a Ci·4 stretching base 'C2-4 stretching base, or C2.4 stretching alkynyl group, wherein each alkyl group, an alkenyl group and a stretching group The alkynyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of a halogen group, a ketone group, and an OR7. 9. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable thereof And a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of R8-, wherein R3 is an unsubstituted C5-8 alkylene group. The compound of any one of claims 1 to 6 wherein R3 is selected from the group consisting of R8- Phenyl, R8-phenylene-R8, Het, R8-Het, R8-Het-R8, R8-phenylene-O-Het, and R8-phenylene-N(R7)-Het. The compound of any one of claims 1 to 6, wherein R3 is selected from the group consisting of R8·phenylene, R8-255-201206888, phenyl-R8, Het, or a pharmaceutically acceptable salt thereof. R8-Het' R8_Het-R8, rL phenylene 〇.Het, and R8-phenylene-N(R The compound of any one of claims 1 to 6, wherein R3 is selected from the group consisting of R8-phenylene, He1, and R8-Het, or a pharmaceutically acceptable salt thereof. 13. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is C(〇) or n(R7)C(0). The compound of any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein a is hydrazine. The compound of any one of claims 1 to 6, or pharmaceutically acceptable thereof And a pharmaceutically acceptable salt thereof, wherein b is 1. 17. as claimed in claims 1 to 6 The compound of any one of the invention, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the group consisting of F, Cl, Br, alkyl, halogen-based, OR7, 〇-_, and CN® 18. The compound of any one of clauses 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R6 is 〇CH3. 19. A compound selected from the group consisting of: (R) -6-[[ 3-[[8-[[2- Benzyl-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]octyl]aminecarboxyl]phenyl]sulfonyl]-4 -[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide; (foot)-6-[[3-[[6-[[2-hydroxy-2- (8-Hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]hexyl]amine-mercapto]phenyl]sulfonyl]_4_[ -256- 201206888 ( 3-methoxyphenyl)amino]-8-methylsalvin-3-carboxamide; (R) -6-[[3-[[4-[[2-hydroxy-2-( 8- Hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]piperidin-1-yl]carbonyl)phenyl]sulfonyl]-4-[(3-A) Oxyphenyl)amino]-8-methylquinolin-3-carboxamide; (R) -6-[[3-[[4-[5-[[2-hydroxy-2-( 8- Hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]aminocarboxyl]phenyl]sulfonyl]-4 -[(3-methoxyphenyl)amino]-8-methylquinolin-3_formamidine•amine; (1〇-6-[[3-[[4-[5-[[2- Hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]pentan-1-yl]phenyl]amine-methylmethyl]phenyl Sulfhydryl]-4-[(3-methoxyphenyl)amino]-8-methylquinin-3-carboxamidine (11)-6-[[3-[[4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)) Amino]pentyl-1-alkynyl]phenyl]aminocarbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline -3-methyl hydrazine • amine; (R) -6-( (3-((4-(6-(2-(2-)-) Hydroquinolin-5-yl)ethyl)amino)hexan-1-yn-1-yl)phenyl)aminecarboxamido)phenyl)sulfonyl)-4-((3-methoxybenzene) (amino)-8-methylsalthion-3-carboxamide; (R) -6-((3-((4-(5-(2-hydroxy-2-)-2-hydroxy-2-) · Keto-1,2-dihydroquinolin-5-yl)ethyl)(methyl)amino)pent-1-yn-1-yl)phenyl)aminecarboxamido)phenyl)sulfonate 4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; -257- 201206888 (R) -6- ( (3-( 3- (5-((2-hydroxy-2-(8-hydroxy-2-keto)-1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1-yl) Phenyl)amine-methylmercapto)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6 -[[3-[[4-[5-[[2-hydroxy·2·( 8-hydroxy-) 2-keto-1,2-dihydrosin-5-yl)ethyl]amino]pentyl]phenyl]aminocarbazino]phenyl]sulfonyl]-4-[ (3-A Oxyphenyl)amino]-8-methylquinolin-3·carbenamide; 6-[3-[[4-[2-[[2-hydroxy-2-(8-hydroxy-2-one) 1,2-dihydroquinolin-5-yl)ethyl]amino]ethyl]piperazin-1-yl]carbonyl]benzenesulfonyl]-4-(3-methoxyphenylamine -8-methylquinoline-3-carboxamide; hydrazine; -6-[[3-[[4-[2-[[2-hydroxy-2-(8-hydroxy-2. keto)- 1,2-dihydroquinolin-5-yl)ethyl]amino]ethyl]phenyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl) Amino]-8-methylquinoline-3-carboxamide; 6-[[3-[[3-[2-[[(R))-2-hydroxy-2-(8-hydroxy-2-one) 1,2-dihydroquinolin-5-yl)ethyl]amino]propyl]-indole-methylbenzamideamino]methyl]phenyl]sulfonyl]-4-[( 3-methoxyphenyl)amino]-8-methylsalthion-3-carbamide; (R) -6-[[3-[[6-[[2-hydroxy-2-( 8- Hydroxy-2-keto-1,2-dihydroporphyrin-5-yl)ethyl]amino]hexyl](methyl)amine-methylmethyl]phenyl]sulfonyl]-4-[(3) -Methoxyphenyl)amino]-8-methylquinolin-3-carboxamide; (R) -6- ( ( 3- ( 4- ( (6-((2-Hydroxy-2-(8-hydroxy-2-keto)-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)piperidin-1- Carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; -258- 201206888 (R) -6-( (3-(4-(6-(2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)piperazine -1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; 6- ( ( 3- ( 4 - ( 3- ( 2- ( ( R ) -2-hydroxy-2-( 8-hydroxy-2-keto-1,2·dihydrosin-5-yl)ethyl)amino)propyl) Benzyl hydrazino) piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl) φ amino)-8-methylquinoline-3-carboxamide (R) -6-((3-(4-(3-(2-(2-)-yl-2-(8-yl)-2-keto-1,2-dihydroquinolin-5 -ethyl)amino)amino)-2-methylpropyl)benzylidene)piperazine-1-carbonyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amine (8)-methyl-thaloline-3-carboxamide; (R)-6-((3-((3-(2-(2-)-) Keto group-1,2-di Hydroquinolin-5-yl)ethyl)amino)-2-methylpropyl)-indole-methylbenzamideamino)methyl)phenyl)sulfonyl)-4-(3- Methoxy phenyl phenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6- ( ( 3- ( 4 '- ( ( ( 2- ( ( ( ( ( ( ( -hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)biphenyl]-4-yl)aminecarboxyl)phenyl)sulfonyl) 4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6- ( ( 3 - ( ( 4 '- ( 4- ( ( 2-hydroxy-2-(5-hydroxy-3-keto-3,4-dihydro-2Η-benzo[b][l,4]oxazin-8-yl)ethyl)amino)butyl Biphenyl]-4-yl)amine-carbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide ; -259- 201206888 (R) -6-( (3-( 4,-(4-(4- 2-)-yl-2-(5-carbyl-3-keto-3,4-dihydro- 2H-benzo[b][l,4]oxazol-8-yl)ethyl)amino)-butyl)-[1,1'-biphenyl]-3-yl)aminecarboxamido)phenyl Sulfhydryl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6-( (3- ( 6- ( (2 - thiophene-2- (6 - 3--3-mercapto-3,4-dihydro-2H-benzo[bni,4]oxazin-8-yl)ethyl)amino)hexyl)aminecarboxyl)phenyl)sulfonyl) 4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6· ( (3- ( 4-(5-( ( 2 -transyl- 2-(6-carbyl-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyl)amino)penta- 1-Alkyn-1-yl)phenyl)amine carbhydryl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-methyl Indoleamine; (7?) -6-((3-((2-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-yl-2-yl-2-yl-2-yl-2-yl-2-yl-2-yl) Sialolin-5-yl)ethyl)amino)ethyl)phenoxy)ethyl)(methyl)aminecarboxyl)phenyl)sulfonyl)-4-((3-methoxybenzene) (amino)-8-methylquinolin-3-carboxamide; (R)-6-[[3-[[4-[5-[[2-hydroxy-2-[4-hydroxy-3] -(hydroxymethyl)phenyl]ethyl]amino]pentyl]phenyl]aminocarbazinyl]phenyl]sulfonyl]-4 ·[(3-methoxyphenyl)amino]- 8-methylquinoline-3-carboxamide; (R) -6-[[3-[[6-[[2-(3-carbamido-4-hydroxyphenyl)-2-hydroxyethyl) Amino]hexyl]amine-methylindenyl]phenyl]sulfonate 4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide; (R) -6- ( ( 3- ( 6- ( ( 2- (3-Methylamino-4-hydroxyphenyl)-2-hydroxyethyl)amino)hexyl)(methyl)amine-methylmethyl)phenyl-260- 201206888 )sulfonyl)-4-( (3-methoxyphenyl)amino)-8-methylquinoline-3-carbamide; (R) -6-( (3-( 6-(2-hydroxy-2-(5) -hydroxy-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxazol-8-yl)ethyl)amino)hexyl)aminecarboxamido)phenyl) Sulfhydryl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6-( (3-( 6-( ( 2-hydroxy-2-(5-hydroxy-3-ketoφ-yl-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyl)amino)hexyl (methyl)amine carbaryl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6-[[3-[[4-[5-[[2-(3-carbamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]pent-1-ynyl]benzene Aminomethyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide; (R) -6- ( (3-( (4-(5-( ( 2 -trans-yl-2-(5-carbyl-3-keto-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyl)amine) φ 1--1-yn-1-yl)phenyl)amine-carbyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinin-3- Methionine; (R) -6-((3-(4-(5-(2-hydroxy-2-(8-hydroxy-2-indolyl-1,2-)-salt-5-yl) Ethyl)amino)pentan-1-yl-1-yl)phenyl)(methyl)aminecarbenyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amine (8)-methyl-quinoline-3-carboxamide; (R)-6-((3-((4-(5-(2-hydroxy-2-(8-hydroxy-2-one))) -1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1-yl)-2-methylphenyl)amine-carboxanyl)phenyl)sulfonyl) -4-((3-methoxybenzene-261 - 201206888 based R amine CX) / yl-3 alkynyl-1- ketopentyl hydroxylamine 醯5-} sulfo-C-yl}-2-ethyl} Benzene 2--8-yl; oxazinamide C carbamide 5-4]amine 3 /(V 1 \1/ 3-4bl phenyl quinone J quinquin 3-4 methyl CH-. ί 2 A C -2-86-hydrogen} --6, monomethylaminophenyl methoxymethylamine hydrazone I 3 I phenyl quinylmethyl R hydroxy hydroxy propyl t£[aniline^ S ) 碡methyl 2H-3-phenyl-yl m ) ^ Diyloxy 1-methyl 4 I - 5 3 ^ ^ (yl-1C ketopenta 4-ylamine oxime; &gt; ))5醯ethyl-Φ Benzene-3 -»} oxo-8-ylquinoxalyl-Φ amine-8-azine oxo R 2 -yloxy hydrazine 3/ hydroxy»3/ ketone I 2 I base Amine\)/ylethyl Nlyyl I 5 - porphyrin salyl hydrazide * \) / ring 3-R heteroc C thio C alkoxy (4 aniline 彳 δ) group (3 2-phenyl-( Phenyl phenyl methionine C quinolate 6-yl C methyl C sulfonamide hydrazine methyl hydroxy quinolinol hydrocarbyl hydrazine diamine 1.2, phenyl phenyl} -S yl-2-butyl} hydroxy oxymethyl - NJ / 3 base C hex CI ) 4 I group } amine group > mercapto sulfonate} } phenyl phenyl R- phyl benzene {-2 ethyl group ethoxy hydroxy amide amine I I 3 I oxaquine Methylmorpholine quinolimium I 2 3 -yl fluorenylmethylamine \1/ phenyl -6 yl} Amino) fluorenyl sulfonyl}) phenyl-2-ylhexyl hydroxyoxymethoxyphenyl)amine (8)-methyl-quinoline-3-carboxamide; (R)-6-((3-((4-(4-(6-(6-(2-)-) -2-keto-1,2-dihydroquinolin-5-yl) (amino) hexyl) oxy) butyl) phenyl) (methyl) amine carbyl) phenyl) sulfonyl) -4-262-201206888 ((3-methoxyphenyl)amine (8)-6-methylquinoline-3-carboxamide; (11)-6-[[3-[[6-[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)) Phenyl]ethyl]amino]hexyl]amine-carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-methyl Indoleamine; (R)-6-[[3-[[4-[[2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]]amino]amino]piperidin-1 -yl]carbonyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carboxamide; (11)-6-[[ 3-[[6-[[2-hydroxy-2-[4-hydroxy-3-(methylsulfonylamino)phenyl]ethyl]amino]hexyl]aminecarboxylidene]phenyl]sulfonate 4-[(3-methoxyphenyl)amino]-8-methylquinolin-3-carbamamine; (11)-6-[[3-[[6-[[2- Hydroxy-2-(4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino)hexyl](methyl)aminecarbenyl]phenyl]sulfonyl]-4-[ ( 3- Methoxyphenyl)amino]-8-methylporphyrin-3-carboxamide; (R) -6- ( ( 11- ( 2 - phthalyl-2-(8-)-yl-2- Mercapto-1,2_ dihydrogen Quinoline-5-yl)ethyl)amino)undecylsulfonyl)-4-((3-methoxyphenyl)amino)-8-methylsalrin-3-carboxamidine Amine; (R) -6-((11-(2-hydroxy-2-(6-hydroxy-3-keto-3,4-dihydro-2H-benzo[b][l,4] evil) Pyrazin-8-yl)ethyl)amino)undecylsulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carbamide (R) -6- ( ( 4 '- ( ( 2 hydroxy-2-( 8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino) Methyl)-[1,1'-biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-formamidine Amine; -263- 201206888 (r) _6·( (4'-( (2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl) Amino)methyl)diphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carbamide; R) -6-((4'-(3-((2-hydroxy-2-(5-hydroxy-3-keto)-3.4-dihydro-2H-benzo[b][l,4]oxazine -8-yl)ethyl)amino)propyl)biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3 -carbamamine; (R) -6-((4'-(3-((2-hydroxy-2-(5-hydroxy-3-keto)-3.4-dihydro-2H-benzo[bni,4]oxazin-8-yl)) Ethyl)amino)propyl)-[1,1'-biphenyl]-3-yl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methyl saliva (R) -6-((4'-(5-((2-)-yl-2-(5-amino-3-yl)-3.4-dihydro-2H-benzene And [b][l,4]oxazin-8-yl)ethyl)amino)pentyl)biphenyl]-4-yl)sulfonyl)-4-((3-methoxyphenyl) Amino)-8-methylquinoline-3-carboxamide; (R) -6-((4'-(5-((2-)-yl-2-yl) · 3.4-Dihydro-2H-benzo[b][l,4]oxazol-8-yl)ethyl)amino)pentyl)-[1,1'-biphenyl]-3-yl)sulfonate Mercapto)-4-((3-methoxyphenyl)amino)-8-methylquinolin-3-carboxamide; (R) -6-(3-( (4- (4- 4-(2-Phosyl-2-(8-carbyl-2-keto-1,2-dihydroquinolin-5-yl)ethylamino)butyl)phenyl)-N-methyl Piperidine-1-carboxamido)methyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinolin-3-carboxamide; -264- 201206888 - Keto-1 - : quinolinone D-butyl-2-carbamidine -2--A1yl; sulfonyl: quinolyl-hydroxy-(R)-6-(3-(4-(4-(4-(2-hydroxy-2-)-2-hydroxy-2-yl-1,2 -dihydroquinolin-5-yl)ethylamino)butyl)phenyl)piperidinylcarbonyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methyl (R)-6-(3-(4-(4-(4-(2-hydroxy-2-)-2-hydroxy-2-yl-1,2-dihydroquinoline- 5-yl)ethylamino)butyl)cyclohexyl)piperidinyl 1-carbonyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methyl quinolin-3 Methionine; (R)-6-(3-(4-(4-(4-(2-hydroxy-2-(8-hydroxyketo)-1,2-dihydroquinolin-5-yl)) Ethylamino)butyl)phenyl)-N-piperazine-1-carboxamido)methyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8- (Qu) -6-(3-((4-(4-(4-(2-(2-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(2-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(2-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(2-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-( Phenyl-5-yl)ethylamino)butyl)phenyl)-N-piperidin-1-carboxamido)methyl)phenylsulfonyl)-4-(3-methoxyoxene phenyl) Amino)-8-methylquinolin-3-carbamidamine; (R)-4-(4-(4-(2-hydroxy-2-(8-hydroxy-2-keto)-1 2 Hydrogen sulfin-5-yl)ethylamino) butyl) phenyl) piperazine-1-carboxylic acid 3 3-aminemethyl benzyl-4-(3-methoxyphenylamino)-8- Methylquinolin-6-ylmercapto)benzyl ester; 3-(3-Aminomethylindol-4-(3-methoxyphenylamino)-8-methylphenyl-6-ylsulfonyl Benzylaminocarbamic acid (R)-6-(2-hydroxy-2.(8-yl-2-keto-1,2-dihydrosin-5-yl)ethylamino)hexyl ester; (R) -6-( 3-( 5-( 5 · ( 2 -)-yl-2-( 8 -transyl-2 -嗣-265- 201206888 1,2-dihydroporphyrin-5-yl) Amino)pentyl)porphyrin-1-carbonyl)phenylsulfonyl)-4-(3-methoxyphenylamino)-8-methylquinoline-3-carbamide; or A pharmaceutically acceptable salt thereof. 20. A composition comprising a compound according to claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 2 1. The composition of claim 20, wherein the composition is suitable for inhalation. A composition according to any one of the claims of the present invention, which further comprises a therapeutically active agent selected from the group consisting of an anti-inflammatory agent, an anticholinergic agent, and a peroxisome proliferator-activated agent. Peroxisome proliferator-activated receptor agonists, epithelial sodium channel blockers, kinase inhibitors, protease inhibitors, anti-infectives, and antihistamines. 23. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use as a medicament. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in a method for treating inflammation or bronchoconstriction in the lungs of a human. 25. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with reversible or irreversible airway obstruction in humans, chronic obstructive pulmonary disease Disease (C0PD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchi-266-201206888 inflammation, cough after viral infection, cystic fibrosis, lung Emphysema, pneumonia, panbronchiolitis, bronchiolitis associated with transplantation, sinusitis, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or methods of treating sinusitis. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with chronic obstructive pulmonary disease (COPD) or asthma in a human. method. The use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating inflammation or bronchoconstriction of the lungs of a human. 28. The use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in human therapy and reversible or irreversible respiratory tract Obstructive-related diseases, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, cough after viral infection , cystic fibrosis 'emphysema, pneumonia, panbronchiolitis, bronchiolitis associated with transplantation, nasal inflammatory disease, and tracheobronchitis associated with respirators' or prevention of respirators-related pneumonia, or treatment Nasal treasure inflammation. 29. A pharmaceutical composition comprising a compound of any one of clauses 19 to 19, or a pharmaceutically acceptable salt thereof, for use in the manufacture of an inflammatory or bronchoconstrictor for treating a human lung A pharmaceutical composition comprising a compound according to any one of claims -19 to 19, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a drug, and the drug For the treatment of human diseases associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchi Inflammation, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, panbronchiolitis, bronchiolitis associated with transplantation, nasal inflammatory disease, and tracheobronchitis associated with respirators, Or prevent pneumonia associated with respirators or treat sinusitis. -268- 201206888 Four designated representatives: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 201206888 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. : -4-