TW201206927A - Bi-functional pyrazolopyridine compounds - Google Patents

Abstract

This invention provides compounds of the formula: wherein X is wherein 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, their use in pulmonary inflammation or bronchoconstriction therapy and compositions comprising and processes for preparing the same are provided.

Description

201206927 VI. OBJECTS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel anti-inflammatory tracheal dilator compounds, compositions comprising the same, methods and uses thereof, and methods for their preparation. [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. COP D is closely related to exposure to harmful particles and gases from external environments (such as tobacco smoke) and exposure to wood burning flames, and is characterized by oxidative stress and harmful imbalances between cathepsins and proteases. . 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 a review, see Molfino & Jeffery, Pw/m. Pharmacol. Γ/ier. 2007; 20:462-72). In asthma, allergic immune mechanisms cause chronic inflammation, leading to airway hyperresponsiveness and structural changes in the bronchial airways (called remodeling), such as airway smooth muscle thickening and goblet cell growth 201206927 (see Hamid & Tulic, hnw for review) /?ev. Corpse?;·〇/. 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 (LABA), such as salmeterol or formoterol, or inhaled long-acting muscarinic receptor antagonist (LAMA) For example, 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 monophosphate adenosine (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,··. Pharmacol. 2 00 8 ; 5 5 : 3 0 8 - 1 5 ) » The use of the oral P DE4 inhibitor roflumilast has been shown to have anti-inflammatory activity in the clinic, showing a worsening of the disease and an appropriate increase in lung function in patients with COPD (Rabe Etal ·, Lancet 2 0 0 5 ; 366:563-71 ; Calverly et a l., Am. J. Cr!·. Care Mec/. 2007 ; 1 76: 1 54-6 1 ). 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) There is still a dose limit (Fabbri " a/·, Lancei 2009; 3 74:69 5 -703; Calverly et al., Lancet 2009; 3 74:6 8 5-94). Forest 201206927

Research Institute's product Daxas (roflumilast) has been approved as an oral PDE4 inhibitor for daily use in the treatment of COP D. However, the fact is acknowledged that Dax as has consistent evidence of consistency, but there are still many adverse event messages, and this unfavorable event message once led the committee to refuse 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 than those achievable by oral administration, and thus has the potential to further improve anti-inflammatory efficacy. PCT Publication No. WO2005/090348 to GSK relates to a compound of the formula (I) as a PDE4 inhibitor and a pharmaceutically acceptable salt thereof: /R3 ΗΝ Ο

—W where (in particular) = W is Ar, -CR4R5Ar or a group (y) or (yi), where ··

Ar is

201206927 wherein A, B, D, E, and F are C-R6, N or N + -0-, and R6 is especially H, halo, Cm alkyl, ... r7r8n-s(o)2-, ... R7R8N-CO-, ... r7r8n-,... -ch2-nr7r8, -ch2-ch2-nr7r8,... -ch2-co-nr7r8, ... and all other variables As defined in the literature.

Hoffmann-La Roche PCT Publication W02007/0231 10 is a P3 8 Map kinase inhibitor of the formula la or lb:

Wherein (in particular): R1 is aryl or heteroaryl; R4 is H, Cm alkyl, hydroxy, amine, hetero-Cm alkyl, hetero-Cm alkoxy, heteroalkylamino, heterocyclic , heterocyclyl-Cm alkyl, hydroxy C3.6 cycloalkyl, C3.6 cycloalkyl-Cu alkyl, Cm alkylsulfonyl, Cu alkylsulfonylamino, aryl, heteroaryl, aryl-Cm alkyl, heteroaryl-Cu alkyl, Cu alkoxy, heteroaryl-Cu alkoxy, -(CHRb)rC(= 〇)-Rc, -(CHRb)r-0-C ( = 0) -Rc, -(CHRb)r-NH-C( = 0)-Rc or -so2-rc ; X and Y are N, or one of X and Y is N and the other is CRd ; W is a key, 0, S(0)m, CH2, or NRf; A is 0, CH2, S(0)m, C(=0), NRh, or CH(ORh); all other variables are as As defined in the literature. -8 - 201206927

PCT Publication of Glaxo Group Limited W02008/015416 for PDE4 inhibitors of formula (I):

Where Ar is

Where '· Q1 is NH or NMe, and Q2 is -C(O)- ' -s(0)2-, -C(0)NH or -C(0)NMe-, or Q1 is a bond or -〇 -, and Q2 is a bond, or Q1 is -C(O)-, and Q2 is -NH or NMe, or Q1 is -S(〇h-, and Q2 is -NH, NMe, or a bond; L is (CH2)n or -(CH2)m-0-(CH2)m-; R5 is hydrazine, methyl, ethyl, n-propyl, isopropyl, -CH2CH2OH, -CH2CH(Me)OH, -C H2 CH 2 C Η 2 Ο Η, -CH2CH2OMe, or -CH2CH2CH2OMe; and 艮6 is a Cm alkyl group or a Cm alkane substituted with an OH or OCu alkyl group. All other variables are as defined in the literature.

PCT Publication of Glaxo Group Limited 2008/01 5437 for PDE4 inhibitors of formula (I): -9 - 201206927

Where: Ar is

Where: Q1 is NH or NMe, and Q2 is -C(O)-, -S(0)2-, -C(0)NH or -C(0)NMe-, or Q1 is a bond or -〇- And Q2 is a bond, or Q1 is -C(O)-, and Q2 is -NH or NMe, or Q1 is -S(0)2-, and Q2 is -NH, NMe, or a bond; Q3 is One bond, NH or NMe: L is (CH2)n_-(CH2) „1-0-(CH2)m-; R5 is Η, methyl, ethyl, n-propyl, isopropyl, -CH2CH2OH, - CH2CH(Me)OH, -CH2CH2CH2OH, -CH2CH2OMe, or -CH2CH2CH2OMe; and is a Cm alkyl group or a Cm alkyl group substituted with an OH or OCu alkyl group; all other variables are as defined in the literature. 201206927

PCT Publications of Glaxo Group Limited W02009/1 001 66, W02009/1001 67, W02009/1 001 69 and W02009/0 1 97871 are related to the dual pharmacophores of formula (I) - PDE4-muscarinic antagonism Agent: ^NH R5a R5 R3

ΌΝΚ Yes, (xCR6 W02009/100166

:and

All variables therein are as defined in the respective publications. Traditional therapeutic agents for treating inflammatory respiratory conditions suffer from limited efficacy and undesired side effects data. 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, C〇PD, chronic bronchitis, bronchiectasis, cystic fibrosis, and the like. -11 - 201206927 SUMMARY OF THE INVENTION In summary, the present invention provides a compound of formula I: R? OH HN^

Where: X is selected from:

R1 is ch2oh, ch2ch2oh, n(h)c(o)h, n(h)s(o2)ch3, and R2 is Η: or R1 and R2 together with the attached phenyl group form 9 or 10 ring atoms a bicyclic fused heterocyclic ring wherein 1 or 2 ring atoms are selected from N, 0 and S and the remaining ring atoms are C, wherein the bicyclic fused heterocyclic ring is optionally independently selected by one, two or three Substituted from an additional substituent of an alkyl group, a keto group and OH; R3 is selected from the group consisting of c4.l2 alkylene, (:4.12 an alkenyl group, <:4-12 an alkynyl group, R4-〇-R4, R4-N(R8)-R4, C3-6 cycloalkylene, R4_C3.d_ cycloalkyl 201206927, C3-6 extensible ring base-R4, R4_C3-6 extension ring base-R4, C6-1() Aryl group, R4-C6-1Q aryl group, C6-1G aryl group-R4, R4_C6 iq aryl group _r4, r4_ C6-1() aryl group-〇_R4, r4 C6 iq aryl group _n(r8)_r4, r4_C6·丨〇 aryl-C6-1G extended aryl, Het, R4-Het, R^Het-Cn. aryl, Het-R4, R4-Het-R4, R4_ 〇_Het-R4_C6". Aryl group _Het, r4_C6-丨. aryl-C(〇)-Het, and R4-C6.1q aryl group N(R8)_Het; Base, alkenyl, alkynyl, cycloalkyl, or aryl Desirably substituted with hydrazine, 2 or 3 substituents selected from halo, keto, and indole 118;

Het is a 5-6 membered saturated or unsaturated extended heterocyclic group wherein 1 or 2 ring atoms are selected from N, 0 and S, and wherein the heterocyclic group is optionally 1, 2 or 3 selected from halogen Substituted by a substituent of a group, an alkyl group, an alkoxy group, a ketone group and a hydrazine H; R is a Ci.1C| stretching group, a C2-10 stretching group, or a C2-1Q stretching group, wherein each R4 is optionally Substituted by 1, 2 or 3 substituents selected from halo, keto, and OR8; prerequisites are alkyl, C2-1() alkylene of two R4 groups of any definition of R3 The total number of carbon atoms of the base, . or (: 2.10 ankynoyl chain is not more than 12; Y is c(o), c(o)n(r8)ch2, n(r8)c(o), oc(o)n (r8)ch2, n(r8)c(o)n(r8)ch2, or so2n(r8)ch2; R5 is an alkyl group; R6 is H or an alkyl group; and R7 is selected from an unsubstituted C3-6 ring An alkyl group, a substituted C3-6 cycloalkyl group, and a heterocyclic group selected from the following formulas (i), (ii), and (iii): -13- 201206927

Wherein Z is 0, s, S(0)2, NH or N-R7a, and R7a is selected from the group consisting of alkyl, C(O)alkyl, C(0)NH2, C(0)N(H)alkyl And C(0)N(alkyl)2; and R8 is H or alkyl. In one system, the invention provides a compound of formula I, shown:

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 I' 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. 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 due to sac fibers) Bronchiectasis caused by a disease other than the disease), acute bronchitis-14-201206927, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, bronchiolitis, and transplantation-related fines Bronchitis, sinusitis, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or treatment of sinusitis. The method comprises administering an 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 η-Λα thereof, for use in a method of treating inflammation or bronchial constriction in a human lung

Em ο 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 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, pan Bronchiolitis, bronchiolitis associated with transplantation, sinusitis, and tracheobronchitis associated with respirators, or prevention of pneumonitis associated with respirators, or methods of treating sinusitis. In one system, the invention provides a compound of formula I or I', 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. -15-201206927 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 invention provides the use of a compound of formula I or hydrazine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for 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, panbronchiolitis, bronchiolitis associated with transplantation, nasal inflammatory disease, and tracheobronchitis associated with respirators, or prevention of respirators-related pneumonia, or treatment of sinusitis. In another aspect, the 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 in 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 Obstructive-related diseases, chronic obstructive pulmonary disease (COP D), 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, sinusitis, and tracheobronchitis associated with respirators, or prevention of respiratory-related pneumonia, or treatment of sinuses inflammation. -16- 201206927 DETAILED DESCRIPTION OF THE INVENTION One aspect of the invention provides a compound of formula 1:

OH

I hn-r7

Or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of:

R1 is CH2OH, CH2CH2OH, N(H)C(0)H, N(H)S(〇2)CH3, and R2 is Η; or R1 and R2 together with the attached phenyl group form 9 or 10 rings a bicyclic fused heterocyclic ring of an atom wherein one or two ring atoms are selected from N, fluorene and S and the remaining ring atoms are C, wherein the bicyclic fused heterocyclic ring is optionally independently one, two or three independently Substituted by an additional substituent selected from the group consisting of alkyl, keto and OH; R3 is selected from the group consisting of 〇4.12 alkyl, Cm-alkenyl, C4-Q stretching, R4-0-R4, R4-N (R8 )-R4, C3-6 cycloalkyl, r4-C3.6 cycloalkyl, 匸3-6 cycloalkyl-R4, R4-C3_6 cycloalkyl-r4, phenyl, R, Phenyl, phenylene _R4, R4-phenylene _R4, R4-phenylene '0'R4' R4· -17- 201206927 phenyl-N(R8)-R4, r4_ phenyl Phenyl, Het, R4-Het, R4-Het-phenylene, Het.R4, R4_Het-R4, R4-〇-Het, R4-phenylene-O-Het, R4-phenylene-c(〇 —Het, and phenyl-N(R8)-Het, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl group is optionally 1, 2 or 3 selected from a halogen group Substituted by a keto group, and a substituent of 0r8;

Het is a 5-6 membered saturated or unsaturated extended heterocyclic group wherein one or two ring atoms are selected from the group consisting of ruthenium, osmium and S, and wherein the heterocyclic group is optionally 1, 2 or 3 selected from halogen Substituted by a substituent of a group, an alkyl group, an alkoxy group, a ketone group and an OH; r4 is a Ci-w alkylene group, a c2-1()-alkenyl group, or a C2-IG alkynyl group, wherein each R4 is optionally Substituted by 1, 2 or 3 substituents selected from halo, keto, and OR8; the prerequisite is that one of the R groups of any of the R groups has a Ci.io extension, C2-10 The total number of carbon atoms of the base or C2.10 alkynyl chain is not more than 12; Y is c(0), C(0)N(R8)CH2, n(r8)c(o), oc(o)n( R8)ch2, n(r8)c(o)n(r8)ch2, or so2n(r8)ch2; R5 is a hospital base; R6 is H or an alkyl group; R7 is selected from an unsubstituted c3_6 cycloalkyl group, a substituted C3_6 cycloalkyl group, and a heterocyclic group selected from the following formulas (i)' (ii), and (iii):

Wherein z is 0, s, s(0)2, NH or N-R7a, and -18-201206927 R7a is selected from the group consisting of alkyl, C(〇)alkyl, c(0)NH2, C(0)N ( H) an alkyl group, and C(0)N(alkyl)2; and R8 is an anthracene or an alkyl group. Also included in the description of each group of compounds and pharmaceutically acceptable salts thereof herein, wherein R1 and R2 together with the attached phenyl group form a bicyclic fused heterocyclic ring selected from the group consisting of:

ΗΟ Other systems provide compounds of formula 11(a) and formula 11(b): -19- 201206927

HO

OH

X is selected from:

or

R1 is -CH2-OH, -NH-CHO, or -NH-SOz-C^-Cj alkyl, and R2 is Η; or R1 and R2 together with the attached phenyl ring form a bicyclic fused selected from the group consisting of Heterocycle:

R4 is a Cuq alkylene group, a C2-1()-alkenyl group, or a C2-1Q-exetylene group, wherein -20-201206927 each R4 is optionally 1, 2 or 3 selected from a halogen group, a ketone group, and an 8 Substituted by a substituent; R5 is alkyl; R6 is η or alkyl, and R8 is η or alkyl; or a pharmaceutically acceptable salt thereof. Another system provides a compound of the formula:

R1 is -CH2-OH, -NH-CHO, or -NH-SOz-CrCs alkyl' and R2 is hydrazine; or R1 and R2 together with the attached phenyl ring form a bicyclic fused heterocyclic ring of the formula :

R4 is C丨-丨〇alkyl, C2.丨〇 alkenyl, or C2-丨〇 alkynyl' wherein 21 - 201206927 each R4 is optionally selected from halo, ketone by 1, 2 or 3 Substituted, and substituted with a substituent of OR8; R5 is a hospital base; R6 is an anthracene or a hospital base' and R8 is an anthracene or alkyl group: or a pharmaceutically acceptable salt thereof. Other systems provide the compounds of formula IV, V, VI, VII, and VII:

-22- 201206927

R1 is -CH2-OH, -NH-CHO, or -NH-S02-CH3, and R2 is Ηt or R1 and R2 together with the attached phenyl ring form a bicyclic fused heterocyclic ring of the formula:

-23- 201206927 R4 is c^oalkyl and Cn. Strive alkenyl, or c2·,. An alkynyl group, wherein each R4 is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR8; R5 is a deutero group; R6 is an anthracene or an alkyl group, and R8 is a hydrazine or an alkane Base: or a pharmaceutically acceptable salt thereof. In the Jg description of each group of compounds and pharmaceutically acceptable salts thereof herein, another system is also included, wherein the group represented by the following formula:

A single molecule having both bifunctional activity as a long-acting β2 adrenergic receptor agonist and a PDE4 inhibitor can simultaneously control both symptoms by bronchodilating and anti-inflammatory activity. Such compounds will also provide additive or synergistic anti-inflammatory activity by complementary interactions of the two molecular signaling pathways. When a beta agonist binds to a receptor via the action of a G protein, the beta agonist will increase adenylate cyclase activity, resulting in an increase in cyclic AMP of the cell. Inhibition of the PDE4 enzyme is also useful for maintaining the cAMP content of the cell by inhibiting the enzyme responsible for cAMP breakdown. Inhalation of a molecule having both a 卩2 agonist and PDE4 inhibitory activity provides an additive effect and a possible synergistic anti-inflammatory activity, thereby reducing the dose. The placement of a single bifunctional compound of -24-201206927 into the lung environment should also increase the chance of this molecule to interact to a maximum compared to a mixture of monofunctional reagents formulated together. The relative exposure to the whole body via the locally delivered lung and the length of the lung stay will significantly reduce the chances of side effects caused by exposure to other tissues and organs through systemic circulation. In this paper, the following terms are defined as follows: Said. "Compound of the invention" means a compound of formula I or a salt thereof, especially a pharmaceutically acceptable salt thereof. "Compound of the formula I" means a compound of the formula wherein the compound of the formula I or I' is represented by the formula (the compound of the formula 是 is a group of the compounds of the 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, when the compound of the formula contains one or more pairs of palms, the term "this term is intended to cover racemic mixtures, individual stereoisomers" contains optical isomers (mirroromers and non-images). Structure) and a mixture of geometric isomers (cis-/trans-isomerism) and stereoisomers. Further, the compound of the formula I also contains the tautomeric form of the formula. "Institutional" is a straight or branched hydrocarbon chain of 1 to 8 carbon atoms (ie, C, -8 alkyl), or usually 丨 to 6 carbon atoms (ie Ci6 alkyl) unless otherwise The number of carbon atoms. When the compound of the formula contains more than one alkyl group, each alkyl group may be the same or different. Examples of suitable alkyl groups include, but are not limited to, methyl ("Me"), B. Base ("Et"), propyl (n-propyl), isopropyl, n-butyl, isobutyl (2-methyl-hydrazine-propyl), second butyl (2-butyl), third (-C(CH3h), n-pentyl, 2pentyl, 3-pentyl, hexyl, octyl, etc. -25- 201206927 "Alkenyl" is having at least one degree of unsaturation (ie carbon-carbon double bond) a linear or branched hydrocarbon chain having from 2 to 8 carbon atoms (i.e., C2-8 alkenyl), or usually 2 to 6 carbon atoms (i.e., C2-6 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, vinyl (ethylene or vinyl) (-CH = CH2), allylic (-CH2CH=CH2), 5-hexyl (_CH2CH2CH2CH2CH=CH2), etc. "Alkynyl" is a straight or branched hydrocarbon chain having at least one carbon-carbon bond, and optionally also one or more a carbon-carbon double bond, and having 2 to 8 carbon atoms (i.e., C2-8 alkynyl), or more usually 2 to 6 carbon atoms (i.e., C2-6 alkynyl) unless otherwise specified. 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 (-C=CH), propargyl (-CH2CsCH) Etc. "Alkyl" means a saturated straight or branched divalent hydrocarbon radical having from 1 to 12 carbon atoms ("Ch, 2 alkyl") unless otherwise specified as the number of carbon atoms. Where the compound comprises more than one alkylene group, the respective alkylene groups may be the same or different. Typical alkylene groups include, but are not limited to, methyl (-CH2-), ethyl (<: Η((:Η3)- or -CH2CH2-), propyl (for example -CH(CH2CH3)-, -CH2CH(CH3)- or -CH2CH2CH2-), butyl (for example -CH2CH2CH2CH2-, -C(CH3) ) 2CH2-) and so on. In one system, an alkylene group is linear. In one system, an alkylene group is branched. "Extend alkenyl group" means an unsaturated straight or branched chain having at least one carbon-carbon double bond. a valence hydrocarbon group having from 2 to 12 carbon atoms ("C2.12 olefinic group") -26 to 201206927, unless otherwise specified. When the compound of formula I contains more than one alkenyl group, each extension The alkenyl groups may be the same or different. Typical alkenyl groups include, but are not limited to, 1,2-extended vinyl (-CH=CH-) and (-CH2CH=CHCH2CH2-). In a system, the alkenyl group is linear. "Alkynyl" means an unsaturated straight or branched divalent hydrocarbon radical having at least one carbon-carbon bond, and optionally also one or more carbon-carbon double bonds, and having from 2 to 12 carbons Atom ("C2.12 alkynyl") 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 tri CCH2CH2-). In the monolith, 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, Chs haloalkyl), or Usually 1 to 6 carbon atoms (i.e., Cu haloalkyl) unless otherwise specified. The haloalkyl group includes a perhaloalkyl group such as a trifluoromethyl group. When the compound of formula I contains more than one haloalkyl group, the individual haloalkyl groups 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 = oxime, and the C, N*s' which forms a carbon atom or a heterocyclic ring directly bonded to a hydrocarbon ring forms an oxide, -N-oxide, ruthenium and anthracene. -27-201206927 "Cycloalkyl" means a saturated or partially unsaturated monocyclic non-aromatic ring having from 3 to 6 carbon atoms (C3.6 cycloalkyl) unless otherwise specified. Clear examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group also includes a cycloalkyl group optionally substituted by 1 or 2 substituents which may be the same or different and are selected from the group consisting of a halogen group, an alkyl group, a hydroxyl group, a fluorenyl group, and a ketone group. , an amine group (for example, NH 2 ), an alkylamino group (for example, N(H) alkyl group), a dialkylamino group (for example, N(alkyl) 2 ), C(0)NH 2 , C(0)N(H) alkane. And C(0)N(alkyl)2, or any subgroup thereof. "Cycloalkylene" means a divalent saturated or partially unsaturated monocyclic non-aromatic ring having from 3 to 6 carbon atoms ((: 3-6 cycloalkyl) unless otherwise indicated The number of atoms. When the compound of formula I contains more than one cycloalkyl group, each of the cycloalkyl groups may be the same or different. A clear example of a cycloalkyl group includes a cyclopropyl group, a cyclobutene butyl group, and a cyclopentene group. And a cyclohexyl group. The cycloalkyl group also includes a cycloalkyl group optionally substituted by 1 or 2 substituents, which may be the same or different and selected from a halogen group, an alkyl group, and a hydroxyl group. , 0-alkyl, keto, amine (eg NH2), alkylamino (eg N(H)alkyl), and dialkylamino (eg N(alkyl) 2), or any subgroup thereof In one system, a cycloalkyl group is unsubstituted. "Extended aryl" means a divalent monocyclic or fused bicyclic aromatic ring having 6 to 10 carbon atoms (C6.lc) Aryl) unless otherwise specified as a different number of carbon atoms. When the compound of formula I contains more than one aryl group, the respective aryl groups may be the same or different. Examples include a phenylene group and an extended naphthyl group. The aryl group also includes an extended aryl group optionally substituted with 1 or 2 substituents, which may be the same or different, and are selected from a halogen group, an alkyl group, -28- 201206927 hydroxy, fluorenyl-alkyl, amine (eg nh2), alkylamino (eg N(H)alkyl), and dialkylamino (eg N(alkyl) 2), or any of its In one system, the aryl group is a phenyl group. In one system, the aryl group is an unsubstituted phenyl group. "Heterocyclyl" or "heterocycle" is synonymous, meaning a single ring. And a saturated or partially unsaturated or aromatic ring having a fused bicyclic ring having 5, 6, 9 or 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are each independently selected from N, 〇 And a hetero atom of S and all remaining ring atoms are C. In one system, the heterocyclic group has 5, 6, 9 or 10 ring atoms, wherein 1, 2 or 3 ring atoms are each independently selected from fluorene. , Ο and S heteroatoms. In all systems, when a heterocyclic group contains 2 or more heteroatoms (Ν, Ο and S), each hetero atom may be the same or different. In all systems, when formula I When two or more heterocyclic groups are contained, each heterocyclic group may be the same or different. Examples of the heterocyclic group include, but are not limited to, furyl, tetrahydrofuranyl, thienyl, tetrahydroindolyl, sulfur oxidized four Hydrothienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, diolanyl, oxazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazole Pyridyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, piperidyl, dihydropiperidyl, tetrahydropyranyl, pyridyl, dihydropyridyl, piperidine Pyridyl, dioxoalkyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, anthracene Azinyl, fluorenyl, isodecyl, fluorenyl, porphyrin, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothienyl, oxazolyl, benzene Imidazolyl, benzoxazolinyl, benzoxazolyl, benzisoxazolyl, benzothiazole-29-201206927, benzotriazolyl, benzopyranyl, Mercapto, quinazinyl, quinalhenyl, isoquinolinyl, tetrahydroporinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, porphyrinyl, pyridazinyl, A oxazolinyl group, a quinoxaline group, a naphthyl group, a pterylidene group, a thianaphthalenyl group, or the like. The heterocyclic group can be bonded via any available ring carbon atom or ring hetero atom (e.g., N). "Heterocyclene" means a divalent heterocyclic group as defined herein. For example, a heterocyclic group includes:

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 the group consisting of ruthenium, osmium, and S and all remaining ring atoms are C. The phrase "optionally substituted" with respect to a particular group of the compound of formula I (for example, an optionally substituted alkylene group) means that the group has no substituent, and that the group has the indicated number of substituents, Usually up to 4 substituents unless otherwise specified. Unless otherwise specified, when substituted, the substituent may be present at the same time as a group having several available substitution positions of -30-201206927 or simultaneously with two or more substitutable groups. Linked 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 formulas, 'when a carbon atom does not have a sufficient number of linkage variables or bonds When the valence number of 4 is generated, it is indicated that the remaining carbon substituent which is required to generate the valence of 4 is hydrogen. Similarly, in some chemical structural formulas, when the chemical bond drawn does not specifically specify a terminal group, according to the prior art The custom 'is indicated that the bond is methyl (Me, -CH3). In one aspect, the invention includes a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein: R1 is CH2OH, CH2CH2OH, N(H)C(0)H, N(H)S(〇2)CH3' and R2 is Η; or R1 and R2 are attached thereto The phenyl groups together 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 ruthenium, osmium and S and the remaining ring atoms are C, wherein the bicyclic fused heterocyclic ring is optionally The ground is replaced by one, two or three additional substituents each independently selected from the group consisting of alkyl, fluorenyl and OH; -31 - 201206927 R3 is selected from the group consisting of C4.12 stretching base, C4-12 stretching base, 〇4·12 stretching alkynyl, r4-o-r4, r4-n(r8)-r4, c3.6 cycloalkyl, R4-c3.6 cycloalkyl, C3-6 ring-ring-R4 , R4-C3-6 cycloalkyl-R4, C6·1. Aryl group, R4-C6-丨0 aryl, C6-1Q aryl-R4, R4-C6·丨. Aryl-R4, R4-C6-, Q-exoaryl-O-R4, R4-CH. Aryl-n(r8)-r4, ana 4-(:6-10 extended aryl-C6-oxime. aryl, Het, R4-Het, Het-R4, R4-Het-R4, R4-O -Het, R4-C6, aryl-Het, R4-C6, aryl-C(0)-Het, and R4-C6-io-aryl-N(R8)-Het Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl group is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR8;

Het is a 5-6 membered saturated or unsaturated extended heterocyclic group wherein one or two ring atoms are selected from N, 0 and S, and wherein the heterocyclic group is optionally substituted by 1, 2 or 3 Substituted by a substituent of a group, an alkyl group, an alkoxy group, a ketone group and OH; R4 is a Cmo alkylene group, a C2-10 alkenyl group, or a C2-10 alkynyl group, wherein each R4 is optionally passed through 1, 2 Or 3 substituents selected from the group consisting of halo, keto, and OR8; prerequisites are C 丨-丨〇 alkyl, C 2 · decene of two R 4 groups of any definition of R 3 The total number of carbon atoms in the base or 匚 2' 丨〇 alkynyl chain is not more than 1 2 ; Y is c(o), c(o)n(r8)ch2, N(R8)C(0), 〇-C (〇) N(R8)CH2, n(r8)c(o)n(r8)ch2, or so2n(r8)ch2; R5 is a hospital base; R6 is H or an alkyl group; -32- 201206927 R7 is selected from An unsubstituted C 3 ·6 cycloalkyl group, a substituted c 3.6 ring hospital group, and a heterocyclic group selected from the following formulas (1), (ii), and (iii):

Wherein Z is hydrazine, S, S(0)2, NH or N-R7a, and R7a is selected from the group consisting of alkyl, C(O)alkyl, C(0)NH2, C(0)N(H)alkyl And C(0)N(alkyl)2; and R8 is an anthracene or an alkyl group. In a system, the compound of the invention is defined as wherein R1 is CH2OH, N(H)C(0)H, or N(H)S(02)CH3 and R2 is Η. In a particular system, the compounds of the invention are defined wherein R1 is CH2OH and R2 is deuterium. In one system, the compound of the invention is defined as wherein the R1 and R2 together with the attached phenyl 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 a ketone group, a keto group and QH. "One, two or three additional substituents, "B" means that in addition to the formula -1 in which R1 and R2 are bonded to the same benzene ring -0H, there are one, two or three substituents. Wherein, wherein |^ and R2 together with the attached phenyl group form a bicyclic-extracted heterogastric stomach having 9 or 10 ring atoms, wherein one or two ring atoms are selected from the group consisting of ruthenium, osmium and S' and the bicyclic ring is fused The heterocyclic ring is optionally substituted by an additional substituent selected from the group consisting of an alkyl group, a ketone group and OH. In this system, the compound of the invention is defined as wherein the R1 and R2 together with the phenyl group of the m-mesh form the following: 33- 201206927

In a system, the compound of the invention is defined wherein R3 is selected from the group consisting of C4-12 alkyl, 〇4.12, alkenyl, C4.12 alkynyl, R4-〇-R4, and R4-N(R8)- R4, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, keto, and OR8, respectively. The alkyl, alkenyl or alkynyl group in R3 may be straight or branched. In one system, R3 is selected from the group consisting of C5.8 alkyl, C5-8 extended alkenyl, C5-8 extended alkynyl, R4-0-R4, and R4-N(R8)-R4, wherein each R4 is Cm stretched. An alkyl group, a C2.4 alkylene group, or a C2.4 alkynyl group, and each of the alkyl, alkenyl and alkynyl groups is linear or branched, and optionally one or two selected from a halogen group, The keto group, and the substituent of OR8 are substituted. As stated above, it is a prerequisite that the total number of carbon atoms of the alkylene group, the C2-1()-alkenyl group, or the C2-1()-alkenyl chain of the two R4 groups in any definition of R3 is not more than 12 . For example, when R3 is -R4-indole-R4-, if the first R4 group is an exoethyl (-CH2-CH2-) chain, then the carbon atom of the second R4 group in the R3 member The maximum number will be 10. The alkyl, alkenyl or alkynyl group of R4 may also be straight or branched. In one system, R3 is defined as each alkyl, alkenyl and alkynyl group and each R4 is straight or branched, but is substituted with no halo, keto, and OR8. In a particular system, R3 is an unsubstituted linear or branched C5-8 alkylene group. In a preferred embodiment, R3 is an unsubstituted linear C5 alkylene group. In a preferred system, R3 is an unsubstituted linear C6 alkylene group. In a preferred system, R3 is an unsubstituted linear C7 alkylene group. In a particular system -34-201206927, R3 is an unsubstituted linear C5 alkynyl group. In one system, the compound of the invention is defined as wherein R3 is selected from the group consisting of C3-6 cycloalkylene, R4-C3_6 cycloalkyl, C3.6 cycloalkyl-R4, R4-(:3.6 Cycloalkane -R4, (:6.1() extended aryl, R4-C6.1Q extended aryl, (: 6-10 extended aryl-R4, R4-C6-1G extended aryl-R4, R4-C6-1 ( ) aryl-O-R4, R4-C6-1() aryl-N(R8)-R4, R4-C6_1Q extended aryl-C6.1() aryl, Het 'R4, Het, Het -R4, R4-Het-R4, R4-0-Het, R4-C6.10 exoaryl-O-Het, R4-C6_1G extended aryl-C(0)-Het, and R4-C6_1Q extended aryl- N(R8)-Het. In a particular system, R3 is selected from the group consisting of C6_丨〇 aryl, R4-Cn, aryl, RtCn, aryl-R4, Het, R4-Het, and R4- Het-R4. In a special system, R3 is selected from the group consisting of R4-C6-1() extended aryl, Het, R4-Het, and R4-Het-R, in a special system, and R3 is selected from R4- Phenyl, R4-phenylene-R4, Het, R4-Het, and R4-Het-R4. In a special system, R3 is selected from the group consisting of R4-phenylene, Het, and R4-Het. - In a particular system, R3 is selected from the group consisting of R4-phenyl, Het, and R4-Het, and R4 is an unsubstituted straight or branched Cu alkyl, C3-6 alkylene Or a C3-6 alkynyl group. In a preferred system, R3 is selected from the group consisting of R4-phenylene, and R4-Het, and R4 is an unsubstituted straight or branched Cm alkyl group, C3.6 is an alkenyl group or a 〇3_6 stretching group. In a preferred system, R3 is an R4-C6_1() extended aryl group, especially a R4-phenylene group. In one particular system, R4 is not Substituted straight or branched Cu alkyl, C3.6 alkenyl, or C3-6 extended alkynyl, more particularly R4 is unsubstituted straight or branched (:1.6 alkyl). In a preferred system, R3 is R4-phenylene, and R4 is selected from the group consisting of -CH2-, -(CH2)5-, -CH(CH3)CH2--35-201206927, and -C(CH3)2CH2- In a preferred system, the R3 is selected from

In a system, H et is a 6-membered saturated heterocyclic group wherein one of the ring atoms is N, and one ring atom is selected from C, fluorene, fluorene and S' wherein the heterocyclic group is optionally halogenated. , alkyl, alkoxy, keto or hydrazine H is substituted once. In a particular system, Het is a 6-membered saturated heterocyclic group wherein one ring atom is N, one ring atom is selected from C, Ν, Ο is S, and all other ring atoms are C, and The heterocyclic group is optionally substituted once with a halogen group (especially C1), an alkyl group, an alkoxy group (particularly OCH3), a ketone group or OH. In a particular system, Het is an unsubstituted heterocyclic group. In a preferred system, Het is an unsubstituted 6-membered saturated heterocyclic group wherein 1 or 2 ring atoms are N and all other ring atoms are C. In systems where R3 comprises 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 a mutual point of view to avoid creating a system that is clearly unstable or ineffective based on 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 will understand that Y is not, for example, N(R8)C(0) or N(R8). C(0)N(R8) because this system will cause the NN bond. In a system, the compound of the invention is defined as wherein Y is c(o), c(o)n(r8)ch2, n(r8)c(o), or 0-C(0)N(R8)CH2 » In a special system 'Y is c(0) or c(0)n(r8)ch2. In a preferred system, Y is c(o)n(r8)ch2. In a preferred system, γ is c(o)n(h)ch2. -36- 201206927 Thus, in a preferred system, the invention provides a compound of formula I':

And pharmaceutically acceptable salts thereof, all of which are as defined herein, and include all specific and preferred systems of the variables described herein. When Y is bonded to the ring of R3 (e.g., an extended aryl group such as a phenyl group or a heterocyclic group), Y may be bonded to the ortho, meta or para position of the R3 ring. In the integral system, Y is the position or alignment between the bond and the R3 ring. In one system, the compounds of the invention are defined as wherein R5 is alkyl, especially Cm alkyl, more particularly -CH2CH3. In one system, the compounds of the invention are defined as wherein R6 is alkyl, especially Ch alkyl, more particularly -CH2CH3. In one system, R6 is in one system and R7 is selected from unsubstituted C3.6 cycloalkyl, substituted C3.6 cycloalkyl. Substituted cycloalkyl means halo, alkyl, hydroxy, fluorenyl-alkyl, keto, NH2, N(H)alkyl, N(alkyl)2, C(0)NH2, C(0 a cycloalkyl group substituted with N(H)alkyl, and C(0)N(alkyl)2. In one system, R7 is a heterocyclic group selected from the group consisting of formula (i), (ii), and (Hi).

, NH or N-R7a, and wherein Z is Ο, S, S(O) -37- 201206927 R7a is selected from the group consisting of alkyl, C(0)alkyl, C(0)NH2, C(0)N(H And an alkyl group, and C(0)N(alkyl)2. In a system, 'R7 is a heterocyclic group represented by the formula (ii):

In a system, 'R7 is a heterocyclic group represented by the formula (ii), wherein Z is hydrazine, S, S(0)2, NH or N-R7a, and R7a is selected from methyl, ethyl and n-propyl. Base, isopropyl, C(O)methyl, C(0)NH2, C(0)N(H)methyl, and C(0)N(methyl)2 »

In a system, the compound of the invention is defined wherein R8 is 11 or Ci-4 alkyl; more particularly H or Cn alkyl. In a system, r8 is an indole or a methyl oxime. A clear example of a compound of formula I is shown in the examples of the text. Preferred compounds of formula I are selected from the group consisting of: N-[[l,6-diethyl-4-[(tetrahydro-2Η-piperidin-4-yl)amino]-1H-D-pyrazole [3,4-b]pyridin-5-yl]methyl]-3-[2-[[(R)_2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquine Phenyl-5-yl)ethyl]amino]propyl]benzamide

•38- 201206927 (R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4- b](J is more than 5-amino)methyl]-3-[[[2-di-yl-2-(8-yl-2-yl)-1,2-dihydroquinolin-5- Ethyl]amino]methyl]benzamide

(R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine- 5-yl]methyl]-4-[[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl]ethyl]amino]methyl Benzylamine

(R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine- 5-yl]methyl]-4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino] Pentyl]benzamide

(R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]d ratio -5-5-yl]methyl]-8-[[2-amino-2-(8-yl-2-yl)-1,2-dihydroquinolin-5-yl)ethyl]amino ] octylamine-39- 201206927

HN〇

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., J. PAflrma (1 97 7) 66: 1 - 19. Pharmaceutically acceptable salts formed from inorganic or organic acids include, for example, 'hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, amine sulfonate, phosphate, phosphoric acid. Hydrogen salt, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate , pyruvate, citrate, ascorbate, palmitate, salicylate, stearate, citrate, alginate, polyglutamate, oxalate, oxalate acetate, glucose a diacid salt, a benzoate salt, an alkyl or aryl sulfonate (such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or naphthalenesulfonate), and 2-hydroxyl An ethanesulfonate; formed with an amino acid (eg, aminic acid, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.) Complex. The compounds 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 is a salt derived from a pharmaceutically acceptable 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, trifluoroacetic acid -40-201206927 salt can be used for this purpose. All salts, whether derived from a pharmaceutically acceptable acid, are within the scope of the invention. In one system, the compound of formula I is in the form of a trifluoroacetate salt. In one system, the compound of formula I is in the form of the hydrochloride salt. “Chiral” B means a numerator with the property that two mirror partners cannot overlap, whereas “achiral” B means a numerator in which two mirror partners 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 Terms (1 984) McGraw-Hil 1 Bοok Company, New York; and E1 iel, E · and Wi 1 en, S., Stereochemistry of Organic Compounds (1 9 9 4) John Wiley & Sons, Inc., New York. 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 50-41 - 201206927 :50 mixture of the mirror image isomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or processes that have no stereoselectivity or stereospecificity. The "racemic mixture" and "racemate" are meant to mean a molar mixture of two mirror-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 recognize that guanidine, guanamine, guanidine, urea, thiourea, heterocycles and the like may 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. It is within the scope of the invention to include all mixtures of the mirror image isomers and the non-an image isomers, including mixtures containing mirror image isomers and mixtures rich in non-image isomers. 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 enantiomerically rich mixture comprises at least about 75 % of the specified mirror image isomers', preferably at least about 85%, of the specified mirror image isomers. In a system, the mixture enriched in the mirror image is substantially free of another mirror image isomer. Similarly, a mixture that is enriched in a non-image isomer type is a mixture of non-an image isomers in which the amount of the specified non-image isomer is greater than -42 to 201206927. 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-mirror isomer. In a system, the mixture rich in non-image isomers is substantially free of all other non-image isomers. Those skilled in the art will appreciate that "substantially free" means that the amount of other non-image isomers is less than 5% 'preferably less than 1%, more preferably less than 0.1%. In another system, no other non-image isomers will be present, or any other non-image isomer will be present below detectable enthalpy. Stereoisomers can be separated using techniques known in the art, including high performance liquid chromatography (HP LC) and crystallization of palm salts. For illustrative purposes, a clear example of a mirror image isomer within the scope of the invention comprises: N-[[l,6-diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino] -1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[[(R)-2-hydroxy-2-(8-hydroxy-2-keto-)- 1,2-dihydroquinolin-5-yl)ethyl]amino]propyl]benzamide

And N-[[l,6-diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]-1H-pyrazolo[3,4-b]H ratio steep-5 -yl]methyl]-3-[2-[[(S)-2-]-yl-2-(8-light-yl-2-keto-1,2-dihydroquinolin-5-yl) Amino]propyl]benzamide-9-201206927

In one system, the present invention provides a mixture of image-enriched forms comprising (R)-N-[[l,6-diethyl-4-[(tetrahydro-2H-pyran-4-) Amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[5-[[2-hydroxy-2-(8-hydroxy-2-one) 1,2-dihydroquinolin-5-yl)ethyl]amino]pentyl]benzamide

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 man-made difference (conformational polymorphism) between different conformational conformers of the same molecule. Caused by. Herein, the polymorphism of the crystal also includes the ability of the hydrate or solvate of the compound to exist in different crystal structures. The polymorphs of the present invention may differ in stacking (configuration) (c〇nf〇rmati) due to differences in crystal stacking (stacking polymorphism) or stacking differences between different conformational conformers of the same molecule 〇nai) polymorphic) exists. The present invention includes 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 exist in the form of a crystalline form -44-201206927 solid. Herein, the amorphous solid refers to an ordered solid in which the position of the atom in the solid is not long distance. This definition is equally applicable to the case where the crystal size is 2 nm or less. Additives, comprising a solvent, can be used to produce the amorphous form of the invention. The present invention includes all amorphous forms of the compounds of formula I and their pharmaceutically acceptable salts. 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. Use The compounds of the invention exhibit bifunctional activity in the form of a pharmacophore phosphodiesterase 4 inhibitor (PDE4i) and a beta agonist. Without being limited 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 inhibiting the PDE4 enzyme and possibly other pro-inflammatory mechanisms to enhance the 3', 5'-loop single dish The cytosolic content of adenosine monophosphate (cAMP) and the reduction of bronchodilation (by (3 adrenergic receptor agonist group). The downstream signaling pathway can also be produced simultaneously with the same cell by regulating the two targets. Interactions further produce a positive cooperative anti-inflammatory effect. Local delivery of a single bifunctional compound with dual activity of PDE4i and beta agonist provides the benefit of combination and conjunctive treatment. In particular, such bifunctional compounds Cooperative anti-inflammatory or tracheal dilation can be provided by simultaneously modulating the same route. The bifunctional -45-201206927 compound of the invention can be provided in the same microenvironment that cannot be guaranteed by individual compounds that are combined or conjunctively treated. The role of treatment. In addition, this bifunctional compound provides reduced non-target effects (off-target e Ffect) 'Thus reduce the risk of adverse events associated with individual PDE4i or beta agonist 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 to treat respiratory diseases. Further details regarding such combination therapies utilizing the compounds of the invention are described below. Accordingly, the compounds of the invention may be used as a medicament, particularly for the treatment of clinical conditions which require treatment with PDE4i or beta agonists. Inflammation of the lungs or bronchoconstriction and treatment of various respiratory diseases. For a review of the therapeutic activity of PDE4i in the treatment of respiratory diseases, see 'For example, Kroegel & Foerster, Phosphdiesterase-4 inhibitor as a novel approach for the treatment of respiratory disease : cilomilast, Expert Op in. Inves tig. Drugs (2007) 1 6:1 09- 12 4 ; Dastidar et al·, Therapeutic benefit of PDE4 inhibitors in inflammatory diseases, Curr Op in Investig Drugs (2007) 8:364-372 ; Krymskaya, et al., Phosphodiesterases regulat e airway smooth muscle function in health and disease, Cwrr. Top. Z) ev. 5z'o/. (2007) 79:61-74; and Spina, PDE4 inhibitors: current status, Brit. J · Pharmacol. 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 respiration - 46-201206927 obstruction, chronic obstructive pulmonary disease (COPD) (including acute exacerbation of COP D), 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 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 respirators associated tracheobronitis and/or prevention of respirator-associated pneumonia in patients using respirators. With regard to the treatment of acute exacerbations 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 a mammal, such as a human, which must be treated with a PDE4i or beta agonist. As used herein, "treating and treating," B means reversing, alleviating, inhibiting, or preventing the development of one or more symptoms of a disorder or condition or the disorder or condition. In a system, the invention provides A method for treating a respiratory disease. In one system, the present invention provides a method for treating a disease associated with reversible or irreversible airway obstruction in a mammal, particularly a human, in a particular system. Method for treating COPD in mammals (especially humans) in need. In a particular system, the present invention provides a frequency for reducing the acute exacerbation of c〇PD in mammals (especially humans) in need thereof. , severity or duration or method of treating one or more symptoms of acute exacerbation of c〇PD. In one system, the invention provides a method of treating asthma in a mammal, particularly a human, in need thereof. The present invention provides a bronchiectasis (including vesicular fibrosis) in a mammal, particularly a human, in need of treatment Method for bronchiectasis caused by external conditions. In one system, the present invention provides a method for treating bronchitis (including acute and chronic bronchitis) in a mammal, particularly a human, in need thereof. The present invention provides a method of treating cough after viral infection in a mammal, particularly a human, in a desired system. In one system, the present invention provides a method of treating cystic fibrosis in a mammal, particularly a human, in need thereof. In one 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 system, the present invention provides a method for treating pancreatitis in a mammal, particularly a human, in need thereof. In one system, the present invention provides a transplant-related mammal (especially human) associated with transplantation. The method of bronchiolitis (including bronchiolitis associated with lung and bone marrow transplantation). In the system, the present invention provides a method for treating a 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 present invention provides a therapeutic need Methods for the treatment of nasal inflammation in mammals (especially humans) also provide compounds of the invention for use in the treatment of drugs, particularly for the treatment of mammals (e.g., humans) - 48-201206927, which must be PDE 4 i or β A agonist-treated disorder. In one system, the invention provides a method of treating a respiratory disease. In a system, a disease associated with reversible or irreversible airway obstruction is provided for treating a mammal, particularly a human, in need thereof. A compound of the invention. In a particular system, a compound of the invention for use in the treatment of a chronic obstructive pulmonary disease (C Ο PD ) in a mammal, particularly a human, in need thereof. 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 the 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 treating a mammal (especially a human) in need thereof is provided. In a system, a compound for bronchitis (including acute bronchitis and chronic bronchitis) for treating a mammal (especially 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, 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 in a mammal, particularly a human, in need thereof. In a system, a compound of the invention for use in the treatment of pneumonia of a mammal, particularly a human, in need thereof is provided. In a system, a compound of the present invention for treating bronchiolitis in a mammal (especially human) or a bronchiolitis associated with transplantation (including bronchiolitis associated with lung and bone marrow transplantation) is provided. In a system, a compound of the invention associated with a respirator-related tracheobronchitis or a respirator-associated pneumonia is provided for use in a patient who uses a respirator at -49-201206927. In the system, a compound of the invention for use in the treatment of a nematode of a mammal, particularly a human, in need thereof. The invention also provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a mammalian (e.g., human) condition which requires treatment 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, the use of a compound of the invention 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 Nasal treasure inflammation. As used herein, the term "effective amount" refers to a cell culture, tissue, system, or mammal (including human) organism or medicine sufficient to cause, for example, a researcher or clinician in a subject to be administered. The amount of the compound of the invention to be reacted. The scope of the phrase 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. -50- 201206927 Or the amount of biological action desired. For example, a compound of the invention is used in an amount effective to treat a condition in which treatment with a PDE4i or beta agonist is effective 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 (such as cilomilast or roflumilast) and other beta agonists (such as 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 pg. The selection of a particular dosage for a patient will be determined by a healthcare professional, clinician or veterinarian with prior knowledge of 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 . In a preferred embodiment, the dosage of the compound of the invention for treating 70 kg of human will range from about 50 to about 75 0 . If the compound is administered in a different route, the above recommended dosage can be adjusted using conventional dosimetry. Suitable dosages for other routes of administration can be determined by those skilled in the art in light of the above-described general techniques in the technical fields described above and in the teachings of the Japanese Patent Publication No. 51-2012069. 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 one) 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" refers to any combination of a compound of the invention or two or more compounds of the invention in a pharmaceutical composition. The pharmaceutically acceptable excipient, diluent or carrier must be acceptable from the standpoint of compatibility with the other ingredients of the formulation and will not be deleterious 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 according to the desired route of administration using conventional techniques. See Remington’s, Pharmaceutical -52- 201206927

Sciences, Lippincott Williams &Wilkins; 21st Ed (2005/1 /5). Preferably, the pharmaceutically acceptable excipient, diluent or carrier is according to the FDA Generally 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 nasal cavity and nasal treasure, external airway of the mouth and chest) and lungs' including utilization of various types of dry powder inhalers, pressure quantification An aerosol delivered by an inhaler, 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 combination is by uniformly and intimately admixing the active ingredient with one or more liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients ' or both' and The product is prepared by molding the desired mixture as necessary. 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 present 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. -53- 201206927 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 μηη, preferably from about 1 to about 5 μηι, and the GSD is less than 3, preferably less than about 2. Aerosols with MMAD above 10 μηη are usually too large when inhaled into the lungs. An aerosol having a GSD greater than about 3 is 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 the powder blend, 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 respiration 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. The aerosol particle size distribution is detected using prior art devices. For example, the Anders on 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 dosing 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, a disaccharide, or a polysaccharide such as lactose or starch. Lactose -54 - 201206927 is usually the 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 container. Prior to inhalation, the patient activates the inhaler so that the inhaler is metered from the reservoir to a dose of medication and is ready for inhalation. Examples of sump-type DPIs include, but are not limited to, Turbohaler® from AstraZeneca and ClickHaler® from Vectura. In pre-quantitative multi-dose inhalers, individual doses are separately packaged in separate containers, and the inhaler is activated prior to inhalation to release a new dose of the drug 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 oral cavity. 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 (piercing the capsule), and then inhales. Examples include RotohalerTM (GlaxoSmithKline), SpinhalerTM (Novartis), HandiHalerTM (IB), TurboSpinTM (PH&T). For a single dose disposable inhaler, the patient activates the inhaler to prepare for inhalation, inhalation' 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 the shaped-drug aggregates and deposit the 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 Public Patent 2006/0237010. The literature published by the University of Groningen has revealed that the use of this technique effectively delivers a 60 mg dose of pure micronized colis tin mesylate as a breathable 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 an 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 7,3 22,3 54 ; US 7,246,6 1 7 ; US 7,23 1,920; US 7,2 1 9,6 65 ; US 7, 207,330 ; US 6,880,555 ; US 5,522,3 85 ; US 6,845,772 ; -56- 201206927 US 6,637,43 1 ; US 6,329,034 ; US 5,458,1 35 ; US 4,805,8 1 1 ; And the disclosure of US Published Patent No. 2006/0237010. In one system, the pharmaceutical composition of the present invention is a dry powder for inhalation prepared by a Diskus®-type 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 one or more containers, each The 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 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. 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 recesses and a cover that seals the groove but is peelable to define a plurality of 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 (e.g., lactose). The cover plate will preferably have a guide end member that is configured to protrude from the inhaler body. The patient will operate the device and deliver the aerosol composition as follows: 1) removing the outer wrapper, 2) pulling up the foil tab to expose the drug in the bulb, and 3) inhaling the drug from the bulb. -57-201206927 In another system, the pharmaceutical composition of the present invention is a dry powder for inhalation, wherein the dry powder is prepared into a microparticle, as disclosed in PCT Publication No. WO2009/01 5286 or WO2007/1 1488 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. "Equilibrium ions, solvents and antisolvents suitable for the preparation of microparticles of the compounds of the invention have been disclosed in WO2009/0] 52 8 6. In another system, the pharmaceutical compositions of the present 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 5,26 1,53 8 ; US 5,544,647 ; US 5,622,1 63 ; US 4,95 5,3 7 1 ; US 3,565,070; US 3,361,306 and US 6,116,234 and The one disclosed in US 7,108,159. In a preferred embodiment, the compounds of the invention may be delivered in a dry powder form using a metered dose inhaler wherein the released particles have a MNiAD of from about 1 μηι to about 5 μπι and a GSD of less than about 2. A liquid aerosol composition for delivery to the inner bronchus or lung by inhalation may, for example, be prepared as an aqueous solution or an aqueous suspension or prepared to be packaged in a pressurized pack (eg, a metered dose inhaler using a suitable liquefied propellant, micro-mist inhalation) Aerosol delivered by a device or sprayer. 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 therapeutic activities -58-201206927. 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 surfactants such as oleic acid or lecithin, and anti-solvents such as ethanol. The pressurised blend will typically be contained in a small metal canister (e.g., a small aluminum can), sealed by a valve (e.g., a metering valve), and mounted to an actuator with an interface. In another system, the pharmaceutical composition of the present invention is delivered in a liquid form using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in U.S. Patent Nos. 6,2, 53,762, 6, 4, 3,497, 7,601, 3, 3, 7,48,995, 6,743, 4, 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 are liberated from about 1 μηη to about 5 μηη MMAD and less than about 2 GSD. 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 by techniques in the process (in-Pr〇ceSS) (e.g., -59-201206927 filtration) or at the end of the process (e.g., heating in a hot pot or gamma irradiation). 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 &gt; 30 mM' pH 4.5-8.0' and a molar osmotic pressure of about 800-1600 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. &quot;Buffers 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 include pneumatic jet nebulizers, aerated or breath-enhanced jet nebulizers, or ultrasonic nebulizers (including static and vibrating perforated plate sprayers). Jet nebulizers use high velocity air flow. Droplets are produced by bursting through the water column. Particles that are not suitable for inhalation can hit the walls or aerodynamic baffles. The vented or breath-enhanced nebulizer operates substantially the same way as the 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 ultrasonic jet nebulizers, the vibration of the piezoelectric crystal creates surface instability in the drug reservoir, causing droplet formation. 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 vibrating plate driven by a piezoelectric crystal -60-201206927 body, 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 a nebulizer that aerosolizes the aerosol blend is important to 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, molar osmotic pressure, and dispersed ionic content, can affect the tolerance of the drug, and thus the preferred system meets some range of properties described. In a preferred system, the formulation for nebulization is delivered to the space within the inner bronchus using a suitable nebulizer in the form of an aerosol having an MMAD of from about 1 μηι to about 5 μπι and a GSD of less than 2, in order to be most effective and To avoid the side effects of the suction and the whole body, the aerosol should not have an MMAD greater than about 5 μηη and should not have a GSD greater than about 2. If the MMAD of the aerosol is greater than about 5 μχη or the GSD is greater than about 2, a large proportion of the agent may deposit in the upper airway, reducing the amount of drug 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, a large ratio of particles may still be suspended in the inhaled air and may then be exhaled during exhalation. -61 - 201206927 The compounds of the invention may also be administered by transbronchoscopic lavage. Compositions designed for nasal administration include aerosols, solutions, suspensions, sprays, micro-fogs, and drops. Aerosol compositions for nasal administration can be formulated in much the same manner as aerosol compositions for inhalation, except that particles of non-inhalable size will be preferred for nasal administration. Typically, particles of about 5 microns in size can be used to visually droplets. Therefore, for nasal delivery, a particle size in the range of 10 to 500 μm can be used to ensure retention in the nasal cavity. In another aspect, the invention provides a method of treating a respiratory condition in a human 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 preferred embodiment, the method comprises administering a pharmaceutical composition comprising from about 20 to about 1 000 pg of a compound of the invention in the form of an inhalation composition. In another aspect, the invention provides a treatment for a human in need thereof, a disease associated with reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COP D), asthma, bronchiectasis (including due to cystic fibrosis) Bronchiectasis caused by the condition), acute bronchitis, chronic bronchitis, cough after viral infection, cystic fibrosis, emphysema, pneumonia, bronchiolitis, bronchiolitis associated with transplantation, and breathing Any of the related tracheobronchitis 'or prevent respirator-associated pneumonia' or a method of treating nasal stagnation </ RTI> the method comprising administering to the human a pharmaceutical composition comprising a compound of the invention, wherein the compound is Effective amount of investment. In a preferred system, the method comprises administering a pharmaceutical composition comprising from about 20 to about 1000 pg of a compound of the invention in the form of a composition for inhalation of -62 to 201206927. Preferred unit dose blends of the compounds of this invention are those which comprise an effective amount of the active ingredient or a suitable component thereof. 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 can be formulated into a compact, controlled release or sustained release form depending on the desired and desired route of administration of the particular condition to be treated. 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 can be used to provide more sustained release of the active agent delivered to the lung by inhalation. The particulate active agent which is not dissolved in the solution in the lung does not cause a physiological reaction, but may be in the form of a deposit of the bioabsorbable drug, and then gradually dissolves in the solution. In another example, the blends can be used in both free base and salt forms of the compounds of the invention to provide both immediate and sustained release of the active ingredient for dissolution into mucus secretions such as the nose. Compositions Compounds of the Invention It can be formulated and/or used with other therapeutically active agents. Examples of other therapeutically active agents that may be formulated or used with the compounds of the invention include, but are not limited to, anti-inflammatory agents, anticholinergic agents, peroxisome proliferator-activated receptors (PPAR) gamma Agonists, PPAR δ agonists, epithelial sodium channel blockers (ENaC blockers), kinase inhibitors (eg, p38 ΜΑΡΚ, PI3K, JNK, ERK, IKK2), anti-infectives, and antihistamines. -63- 201206927 Accordingly, in another aspect, the invention provides a composition comprising an effective amount of a compound of the invention and one or more additional therapeutically active agents, wherein the additional therapeutically active agent is selected from the group consisting of anti-inflammatory agents, anticholinergic properties Agents, P2Y2 receptor agonists, PPAR gamma agonists, PPAR δ agonists, ENaC blockers, kinase inhibitors (eg, p38 ΜΑΡΚ, 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 diseases, thereby reducing the likelihood of undesirable side effects due to absorption of the P agonist 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 for use in the present invention include oral or inhaled corticosteroids or prodrugs thereof. Clear examples include, but are not limited to, ciclesonide, desisobutyryl-ciclesonide, budesonide, flunisolide, mometasone And its esters (such as mometasone furoate), fluticasone propionate, fluticasone furoate, beclomethasone, methylprednisolone (methyl prednisolone), prednisolone, dexamethasone, 6〇1,9〇1-difluoro-17〇1-[(2-furylcarbonyl)oxy]-110-hydroxyl -16〇1-methyl-3-keto-androstene-1,4-diene-17β-thiocarboxylic acid S-fluoromethyl ester, 6α,9α-difluoro-Πβ-hydroxy-16α-methyl- 3-keto- 17α-propoxy-androstene-indole, 4-dien-17β-thiocarbamic acid S-(2-keto-tetrahydro-furan-3S-yl) ester, chlorinated 64 - 201206927 beclomethasone ester (eg 17-propionate or 17,21-dipropionate), fluoromethyl ester, triamcinolone acetonide, rofleponide, or any combination thereof or Subgroup. Preferred corticosteroids for formulation or use with the compounds of the invention are selected from the group consisting of ciclesonide, desisobutyryl-ciclesonide 'budesonide', and mometastat. Mometasone, fluticasone propionate, and fluticasone furoate, or any combination or subgroup thereof. The NS AID used in the present invention includes, but is not limited to, sodium cromoglycate, nedocromil sodium, and pDE inhibitors (eg, theophylline, aminophylline, PDE4 inhibitor, PDE3). /PDE4 mixed inhibitor or PDE4/PDE7 mixed inhibitor), leukotriene antagonist, leukotriene synthesis inhibitor (such as 5 LO and FLAP inhibitor), nitric oxide synthase (iNOS) inhibitor, protease inhibitor (eg, tryptase inhibitors, neutrophil elastase inhibitors, and metalloproteinase inhibitors), β2_integrin antagonists and adenosine receptor agonists or antagonists (eg, adenosine 2a agonists), cells A hormone antagonist (such as a chemokine antagonist) or a cytokine synthesis inhibitor (such as a prostaglandin D2 (CRTh2) receptor antagonist). PDE4 inhibits [[, PDE3/PDE4 mixed inhibition [J Qi! j or PDE4/PDE7 mixed inhibitors can be any compound known to inhibit PDE4 enzymes or found to be useful as PDE4 inhibitors, and for selective PDE4 inhibition Any compound of the agent (ie, a compound that does not significantly inhibit other members of the PDE family). An exemplary package of PDE4 inhibitors for formulation and use with the compounds of the invention -65-201206927 includes, but is not limited to, roflumilast, pumafentrine, arophylline (west) Cimolast, tofimiUst, ogiemilast, tolafentrine, piclamilast, ibudilast, apus Apremilast, 2-[4-[6,7-diethoxy-2,3-bis(radiomethyl)-1-naphthyl]_2_卩 than d]-4-(3 - Deuterium steep base)-1(2H)-pyridazinone (T2585), N-(3,5-dichloro-4-pyridyl)-1-[(4-fluorophenyl)methyl]-5- Hydroxy-α-keto-1H-indole-3-acetamide (AWD-12-281), 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxy Phenyl]-2-phenylethyl]-pyridine (CDP-840), 2-[4-[[[[2-(1,3-benzodioxa-5-yloxy)-3-) Pyridyl]carbonyl]amino]methyl]-3-fluorophenoxy]-(2R)-propionic acid (CP-671305), &gt; 1-(4,6-dimethyl-2-pyrimidinyl) -4-[4,5,6,7-tetrahydro-2-(4-methoxy-3-methylphenyl)-5-(4-methyl-1-piperazinyl)-1Η-吲哚-1-yl Benzene sulfonamide (2E)-2-butenedioate (YM-393059), 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)- 9H-indole-6-amine (NCS-613), N-(2,5-dichloro-3-pyridyl)-8-methoxy-5-salrogylcarboxamide (〇-4418), heart [ (311)-9-Amino-3,4,6,7-tetrahydro-4-keto-1-phenylpyrrolo[3,2,1-][1,4]benzodiazepine- 3-yl]-3H-indole-6-amine (PD-168787), 3-[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]-N-ethyl-8 -(1-methylethyl)-3H-indole-6-amine hydrochloride (V-11294A), N-(3,5-dichloro-1-oxy-4-pyridyl)-8- Oxy-2-(trifluoromethyl)-5-carbolinecarbamamine (Sch3 51591), 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[( 3-methylphenyl)methyl]-(3S,5S)-2-piperidone (HT-0712), 5-[2-[(lR,4R)-4-amino-1-(3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexyl]ethynyl]pyrimidin-2-amine-66- 201206927 ,6-[3-(dimethylaminocarbamimidino)phenylsulfonate Base]_4_(3-methoxyphenylamino)-8-methylquinolin-3-carbamidamine (GSK-256066), cis-[4-cyano-4-(3-cyclopropyl-methyl) Oxy-4-difluoromethoxyphenyl) ring already::!_ Alcohol], and 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)_i-naphthyl]4-(2-methoxyethyl)-2(1H)-pyridinone (T-440), and any combination or subgroup thereof. The leukotriene antagonist and the leukotriene synthesis inhibitor comprise zafirlukast, montelukast sodium, zileuton, and praniukast. 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 ( For example, anhydrous atropine 'atropine sulfate, atropine oxide or HCl salt, methylatropine nitrate, homatropine hydrobromide, atropine methyl bromide (homatropine) Methyl bromide), hyoscyamine hydrobromide, hyoscyamine sulfate, scopolamine hydrobromide, scopolamine methyl bromide, or any combination thereof Or subgroup. 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, aclidinium bromide, gluco-67-201206927 glucopyrrolate (Robinul), isopropamide iodide, mepenzolate bromide, dextrochlorine Tridihexethyl chloride, hexocyclium methylsulfate, cyclopentolate HC1 salt, tropine hydrazine 1*0?丨03111丨(16), trihexyphenidate (11^116\ 7?11611丨(1丫1)11(:1 salt, pirenzepine, telenzepine, and methoctramine, or any combination or subgroup thereof. Preferred anticholinergic agents which are formulated and used together with the inventive compounds include ipratropium (bromide), oxitropium (bromide) and tiotropium (bromide), or Any combination or subgroup thereof. Examples of ENaC receptor blockers that are formulated and used together with the inventive compounds 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 Compounds disclosed in WO2004/073629, WO2005/018644, WO2006/022935, WO2007/018640, and WO2007/146869. Examples of kinase inhibitors include the following inhibitors: NFkB, PI3K (phosphatidylinositol 3-kinase) (CAL-263 (oral), Trial trove and Calistoga web site), p38-MAP kinase (SB-681323); Singh et al., J Clin Pharmacol. 2 010 Jan; 50(1):94 -100) Anti-infective agents for formulation and use with the compounds of the invention comprise antiviral agents and antibiotics. Examples of suitable antiviral agents include Tami flu® and Relenza®. Examples of suitable antibiotics include, but are not limited to, aztreonam-68-201206927 (aztreonam) (arginine or lysine), fosfoonicin, and aglycosides such as tobramycin, or Any combination or subgroup thereof. Antihistamines (i.e., quinone 1-receptor antagonists) for formulation and use with the compounds of the invention include, but are not limited to: ethanolamines such as diphenhydramine HCl salt, carbinoxamine cis Butarate, doxylamine, clemastine fumarate, and dimenhydrinate; ethylenediamines, such as pyri 1 amine Mitpyramine, tripelennamine HC1 salt, tripelennamine citrate, and antazoline; fenamines such as benamin ( Pheniramine), chloropheniramine, bromopheniramine, dexchlorpheniramine, triprolidine, and acrivastine; For example, methapyrilene; piperazines such as hydroxyzine HC1 salt, hydroxyzine pamoate, cyclizine HC1 salt, cyclizine Acid salt, meclizine HC1 salt and cetirizine HC1 salt; 峨 steep class, such as astemose, levocabastine HC1 salt, loratadine ), decarboethoxy loratadine, tefenadine-69 - 201206927 (terfenadine), and fexofenadine HC1 salt; tricyclic and tetracyclic, such as Pru Promethazine, chlorpromethazine, trimeprazine, and azatadine; and azelastine HC1 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, the compounds of the invention are used in combination with one or more anti-inflammatory agents, particularly PDE4i or inhaled corticosteroids. 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: a single pharmaceutical composition, such as the compositions described above, or 2) a separate pharmaceutical composition, each comprising a Or a variety of active ingredients as a component. The components of the composition may be administered separately separately, first by administering the present invention -70-201206927 and then administering other therapeutically active agents, 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 butoxy end group (B 〇c) 2 0 Dibutyl terephthalate BOP Benzotriazol-1-yl-oxy-III -(dimethylamino)-squamous hexafluorophosphate·Cbz benzyl argon carbonyl DCC NN,-dicyclohexylcarbodiimide DCE dioxirane-71 - 201206927 DCM dichloromethane DIEA N,N-diisopropyl Ethylethylamine DME Dimethoxyethane DMF Dimethylformamide DMSO Dimethyl Maple Et Ethyl EtO Ac Ethyl acetate EtOH Ethanol Et3N and TEA Triethylamine ESI Electrospray Free g 克h H2 H2 Hydrogen H ATU 2-(1Η-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate HPLC high performance liquid chromatography iPrOH isopropanol LAH hydrogenation Aluminum lithium 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 min ' -72- 201206927 m L ml mmol Mole MS or ms mass spectrometry MsCl methane sulfonium chloride Ms mesylate (or salt) N positive, linear NaBH(OAc)3 sodium triethoxy hydride hydride NaCNBH s sodium cyanoborohydride NaN3 sodium azide PDC dichromate pyridinium Pd(OH)2/C phosphatidazole carbon carbon Ph phenyl PMP 1 ,2,2,6,6-pentamethylpiperidine PPh3 triphenylphosphine Pt02 uranium oxide Py mouth Π 基 Π or Π 症 rt or r. t · room temperature (also known as ring temperature) t - B u third butyl TBAF tetrabutylammonium fluoride TBS tert-butyl Dimethyl decyl TBSC1 tert-butyldimethylmethyl chlorohydrin TFA trifluoroacetic acid THF tetrahydrofuran TLC or tic thin layer chromatography δ low magnetic field direction and tetramethyl decane distance ppm -73- 201206927 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 scheme.

Wherein: γ is c(o), c(o)nhch2, n(r7)c(o)nhch2, oc(o)nhch2-74-201206927, or so2nhch2; PG is a suitable protecting group, such as hydrazine or TBS; And all other variables are as defined above. In general, the method for preparing the compound of the present invention comprises the following steps: a) Reductive alkylation of Compound 3 or a salt thereof with Compound 4 or a salt thereof to prepare Compound 5 or a salt thereof And b) arbitrarily deprotecting compound 5 or a salt thereof to prepare a compound of formula I or a salt thereof. Compound 1 is coupled with an acid under standard conditions (e.g., HATU coupling, mixed anhydride, DCC coupling, etc.) to give the indoleamine compound 2. Compound 1 is coupled with a phosgene equivalent (eg, carbonyldiimidazole or 4-nitrophenyl chloroformate) at a lower temperature (-7 8 ° C to 0 ° C) to obtain an activated species, which can then be The appropriately substituted alcohol or amine is reacted at a higher temperature (room temperature to 100 ° C) to give a urethane or urea compound 2, respectively. Compound 1 has been disclosed in the literature. Compound 2 is oxidized under standard conditions (Dess-Martin, PDC, Swern) to give the corresponding carbonyl compound 3. Alternatively, if an appropriately substituted carbonyl-containing acid can be obtained, then compound 3 can be formed directly from compound 1 under standard conditions (e.g., HATU coupling, mixed anhydride, DCC coupling, etc.). Alternatively, compound 2 or 3 can be formed directly if an appropriately substituted hydrazine chloride or sulfonium chloride is obtained. Compound 4' has been disclosed in the literature, and is coupled with compound 3 under reductive alkylation conditions (e.g., NaCNBH3 or NaBH(OAc)3) in a suitable solvent (e.g., alcohol or DMF) to give the corresponding compound 5. Compound 5 is converted to the compound of the invention by removing any protecting groups. TBS is usually used to protect the base from -75 to 201206927, and in these cases it is deprotected using conventional techniques, such as TBAF. In another system, the compound of the present invention can be prepared by displacement of the leaving group as shown in Scheme 2. Reaction diagram 2

Wherein: Y is c(o)nhch2, n(r8)c(o)nhch2, oc(o)nhch2' or S02NHCH2; PG is a suitable protecting group, such as hydrazine or TBS: LG is a suitable leaving group, for example Bromide, chloride, iodide, OMs, or 0-triflate; and all other variables are as defined above. Generally, the method for preparing the compound of the present invention comprises the following steps: a) Compound 6 or a salt thereof is coupled with Compound 4 or a salt thereof by alkylation reaction to prepare Compound 5 or a salt thereof; and b) Compound 5 is optionally obtained Or a salt thereof is deprotected to prepare a compound of the formula -76-201206927 or a salt thereof. 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 6. For example, the conversion of the alcohol of 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 room temperature. Alternatively, the conversion of the alcohol of Compound 2 to bromide can be carried out under standard conditions (e.g., CBr4 and PPh3). Alternatively, compound 6 can be formed directly under standard conditions by coupling compound 1 with an appropriately substituted acid containing a leaving group. Compound 6 is then coupled with Compound 4 at a high temperature (eg, from about 50 to about 150 ° C) in a suitable solvent (eg, DMSO or DMF) using a suitable base (eg, K 2 CO 3 , DIEA, or PMP) to provide compound compound 5 Deprotection can then be carried out as described above in Reaction Scheme 1 to provide a compound of Formula I. Reaction Figure 3

Wherein: Y is c(o)nhch2, n(r8)c(o)nhch2, oc(o)nhch2, -77-201206927 or so2nhch2; PG is a suitable protecting group such as hydrazine or TBS; PG1 is suitable protection The group, for example, Cbz or Boc; and all other variables are as defined above. Generally, the method for preparing the compound of the present invention comprises the following steps: a) Compound 8 or a salt thereof is coupled with compound 9 or a salt thereof to prepare compound 5 or a salt thereof And b) arbitrarily deprotecting compound 5 or a salt thereof to prepare a compound of formula I or a salt thereof. Further, according to this system, Compound 1 can be coupled with a commercially available or known suitably protected amino acid to prepare Compound 7. Suitable protecting groups include Boc or Cbz. Compound 1 phosgene equivalent (such as carbonyl diimidazole or 4-nitrophenyl chloroformate) is coupled at a lower temperature (_ 7 8 乞 to 〇 it) to activate the substance 'which can then be suitably substituted The alcohol or amine is reacted at a higher temperature (room temperature to 100 ° C) to give compound 7 with a urethane or urea, respectively. Alternatively, Compound 7 can be formed directly if an appropriately substituted hydrazine chloride or sulfonium chloride is obtained. The protecting group can be removed under standard conditions to obtain compound 8. Compound 8 is reacted with bromide 9 at a higher temperature (e.g., from about 50 to about 150 ° C) in the presence of neat or in a suitable solvent (e.g., DMSO or DMF) to produce compound 5. The intermediate compound of Formula 7 (wherein Y is N(R8)C(0)) can be prepared from the corresponding Compound 10 according to the following Reaction Scheme 4. These intermediate compounds 7 can then be used to prepare the compounds of formula I as described above (wherein γ is N(R8)C(0)). -78 - 201206927 Reaction Figure 4

N R4 Η PG1, R3

R5 N N R4 wherein: Y is N(R8)C(0); PG1 is a suitable protecting group, such as Cbz or Boc; and all other variables are as defined above. Compound 10 is coupled with a mono-protected diamine under standard conditions (e.g., HATU coupling, mixed anhydride, DCC coupling, etc.) to give the indoleamine compound 7. Compound 10 has been disclosed in the literature. Compound 10 can also be used to prepare compound 2 (wherein Y is N(R8)C(0)) according to the reaction shown in Figure 5 below. Reaction Figure 5

Where: Y is c(o) or n(r8)c(o); and all other variables are as defined above. Compound 1 is coupled with an amino-alcohol under standard conditions (e.g., H ATU coupling, mixed anhydride, DCC coupling, etc.) to give the indoleamine compound 2. The order of the steps of the above reaction is not strictly limited to the practice of the invention -79-201206927, and these steps can be carried out in any suitable order as known to those 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 solely by the scope of the following patent application. In the following examples, the compounds are appropriately named in accordance with the IUPAC standard nomenclature. The naming convention for the 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(1H)-one

Add NaN3 (266 mg, 4.1 mmol) to (R)-8-(benzyloxy)·5-[2-bromo-1-[(t-butyl) Methylmercapto)oxy]ethyl]quinolin-2(1Η)-one (1 g, 2.05 mmol) was taken in a solution of DMF (20 mL) and warmed to 80t for 3h. The resulting solution was poured into H20 (80 mL) and extracted with EtOAc (3 X 50 mL). The organic layer was rinsed with H20 (2×1 〇〇mL) and brine (1 〇〇mL) to Na2S The title compound (1.37 g) was obtained as a yellow solid. The compound was used directly without further purification. ES/MS theory 値 (C24H31N403Si + ): 451.2, experimental 値: w/ζ = 451·3 (M + H)+. Intermediate 2: (R)-S-[2-Amino-1-[(t-butyldimethylmethyl)oxy]-80- 201206927

Intermediate 1 (1.37 g) was dissolved in MeOH (20 mL) and Pd(OH) 2/C (20°/.w/w' 2 8 8 mg' 0.41 mmol) was added. A nitrogen gas bubble was bubbled through the solution for 5 minutes. The resulting suspension was attached to a balloon filled with h2 and stirred overnight. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc Chromatography (9:1, CH2Cl2MeOHMeOHMeOHMeOH Es/MS theory 値 (Ci7H27N203Si + ) : 335.2, experimental 値: /z = 335.2 (M + H)+. Intermediate 3: (R)-5-(2-azido-1-hydroxyethyl)-8-(benzyloxy)quinoline-2(1H)-one

TBAF (1.0 M THF solution, 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 concentrated. The title compound (137 mg, EtOAc) ES/MS theory 値 (Cl8H17N403 + ) : 337.1 , experimental 値·· w/z = 337.2 (M + H)+. Intermediate 4: (R)-5-(2-Amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one -81 - 201206927

The title compound was synthesized according to a method similar to that described for Intermediate 2, using Intermediate 3 as a substrate. ES/MS theory 値 (ChHmNzO/): 221.1, experimental 値: w/z = 221.1 (M + H)+. Intermediate 5: (R)-l-[4-(Benzyloxy)_3_[[(t-butyldimethylmethyl)oxy]methyl Iphenyl]-2-bromoethanol

TBSC1 (5 g, 33.2 mmol) and hydrazine (3.7 g, 55.4 mmol) were added to the stirred solution of (R)-4-(2-bromo-1-hydroxyethyl)-2- at room temperature (Hydroxymethyl) hydrazine (10 g, 27.7 mmol) in a solution of CH2C12 (200 mL). The resulting suspension was stirred for 1 hour, then Η 2 Ο (200 mL) was added to allow the reaction to be taken and the aqueous layer was extracted with CH2C12 (3 X 100 mL). The combined organic layer was washed with EtOAc (EtOAc) (EtOAc) The compound was used directly without further purification. ES/MS theory 値 (C22H3: 473.1, experimental 値: w/z = 473.1 (M + Na)+. Intermediate 6: (R)-[l-[4-(benzyloxy)_3_[[(third Butyldimethylmercapto)oxy]methyl]phenyl]_2-bromoethoxy](t-butyl)dimethyl decane

201206927 The title compound was synthesized according to a method similar to that described for Intermediate 5, except that an excess of TB SCI and a higher reaction temperature were used. Intermediate 7 : (R)-2-azido-1-丨4·( Benzyloxy&gt;-3·丨丨(t-butyldimethylmethylsulfonyloxy)methyl]phenyl]ethanol

The title compound was substituted with (R)-8-(benzyloxy)-5-[2-bromo-1-[(t-butyldimethyl hydrazide) using Intermediate 5 according to a procedure similar to that described for Intermediate 1. Synthesis of ethoxy]ethyl]quinoline·2(1Η)-one” ES/MS theory 値(C22H31N3Na03Si + ) : 436.2, experimental 値:w/z = 436.2 (M + Na) + ο t 8 : (R)-4-(2-Amino-1-hydroxyethyl tert-butyldimethylmethyl)oxy]methyl]phenol

The title compound was synthesized according to a method similar to that described for Intermediate 2, using Intermediate 7 as a substrate. ES/MS theory 値 (C&quot;H27NNa03Si + ) : 3 20.2, experimental 値: w/z = 320.2 (M + Na) + 〇 intermediate 9 : (R)-N-[2-(benzyloxy)-5 -(2_bromo-1_hydroxyethyl)phenyl 1-carboxamide-83- 201206927

(R)-l-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.2 g, 5.7 mmol) in THF: toluene (1:1, 5 mL) 2 (1% w/w) was reacted overnight at 45 psi and room temperature on a Parr shaker. The next morning, Pt02 was removed by filtration with celite. 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 mixed solution of the aniline. The reaction was allowed to proceed at 0 ° C for 30 minutes, then warmed to room temperature and the reaction was continued for 2 hours. The reaction mixture was concentrated to almost dryness, followed by water. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHC03 and brine to dry Na.sub.2SO.sub.sub.sub.sub.sub. Chromatography (1:1 hexanes /EtOAc) ES/MS theory 値 (Cl6H17BrN03+): 350.0, experimental 値: mtz = 3 50 (M + H) + » Intermediate 10 : (R)-N-[5-(2-azido-buhydroxyethyl) -2-(benzyloxy)phenyl]carbenamide

The title compound was synthesized according to a method similar to that described in Intermediate 1, using Intermediate 9 as a substrate. ES/MS theory 値 (C16H17N403 + ): 313.1, experimental 値: w/z = 313 (M + H)+. -84- 201206927 Intermediate 11 : (R)-N-[5-[2_azido[(t-butyldimethylmethyl)oxy]ethyl]-2-(benzyloxy)benzene Methotrexate

The title compound was synthesized according to a procedure similar to that described for the intermediate 5, which was obtained by substituting the intermediate 10 for (R)_4_(2-bromo-di-ylethyl)- 2 -(ylmethyl) hydrazine. ES/MS theory 値 (C22H3lN4〇3Si + ) : 42 7.2 'Experimental 値: m / 2 = 4 2 7 ( M + Η ) + 〇 Intermediate l2 : (R)-N-[5-[2·Amino "(T-butyldimethylmethyl)oxy]ethyl hydrazine-2-hydroxyphenyl]carboxamide

The title compound was synthesized by substituting Intermediate 1 1 for Intermediate 1 according to a method similar to that described for Intermediate 2. E S / M S theory 値 (C15H27N203Si + ) : 31 1.2, experimental 値: m / z = 3 1 1 (Μ + Η) +. Intermediate I3 : (R)-l-[3-Amino-4-(benzyloxy)phenyl]bromoethanol

(R)-l-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.200 g '0.569 mmol) in 1:1 THF·· toluene (5 mL) with 1% (w/w) Pt〇2 was reacted overnight at 45 psi and room temperature on a Parr shaker. The next morning, pt〇2 was removed by filtration with -85-201206927 celite. The product was concentrated to give the title compound. ES/MS Theory Cl (Cl5H) 7BrN02 + ) : 3 22.0, Experimental 値: speak &quot;=322 (M + H)+. Intermediate 14 : (R)-l-[3-Amino-4-(benzyloxy)phenyl]azidoethanol

The title compound was substituted for (R)-8-(benzyloxy)-5-[2-bromo-1-[(t-butyldimethyl hydrazide) using Intermediate 13 according to a procedure similar to that described for Intermediate 1. Synthesized from oxy]ethyl]quinolin-2(1H)-one. ES/MS theory 値 (C15H17N402 + ): 285.1, experimental 値: w/z = 285 (M + H)+. Intermediate 15 : (R)-8-(Benzyloxy)-5-indole-2-bromo-l-[(t-butyldimethylmethyl)oxy]ethyl]quinoline·2 (1Η) _ketone

The title compound was synthesized according to a method similar to the one described in the intermediate 5, using the intermediate hydrazine in the substituting (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. ES/MS theory 値 (C21H3 ^4041 + ) : 3 99.2, experimental 値: m/z = 399 (M + H) + ° Intermediate I6 : (R)-N-[5-[2-azido- 1-[(Tertiary butyldimethylhydrazino)oxy]ethyl]-2·(benzyloxy)phenyl]methanesulfonamide 86 - 201206927

Methanesulfonium chloride (0.044 mL, 0.569 mmol) was added to a stirred solution of the intermediate 1 5 (275 mg, 0.5 69 mmol) in pyridine (1 mL) at 0 °C. The resulting mixture was warmed to room temperature to monitor whether the reaction was complete by LC/MS. After 1 hour, 1 equivalent of MsCl' was added followed by 0.5 equivalents after 1 hour for a total of 2.5 equivalents. After another one hour, H20 (50 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was extracted with CH2C12 (4×25 mL). The combined organic layers were washed with saturated NaHC03 and brine, dried over Na.sub.2SO.sub. The title compound (197 mg, 72%, 3 steps) ES/MS theory 値(C22H33N404SSi + ): 477.2, experimental 値: m/z = 477 (M + H)+. Intermediate 17: (R)-N-[S-[2-Amino-1-[(t-butyldimethylmethyl)oxy]ethyl]-2-hydroxyphenyl]methanesulfonamide

The title compound was synthesized according to a method similar to the one described in Intermediate 2, using Intermediate 16 in place of Intermediate 1. The compound was used directly without further purification. ES/MS theory 値 (C15H29N204SSi + ) : 361 _2, experimental 値: m/z = 361 (M + H)+. Intermediate IS: 3-(2-hydroxy-2-methylpropyl)benzoic acid -87- 201206927

CH3MgBr (3.0 M in THF, 11.2 mL, 33.7 mmol) was slowly added to a stirred solution of 3-(2-ketopropyl)benzoic acid (2 g, 1 1.2 mmol) The resulting suspension was warmed to room temperature in a solution of THF (100 mL) and then stirred overnight. The reaction mixture was diluted with h2o (50 mL) then 5 N EtOAc (pH &lt;3&gt;&lt;3&gt;) to allow the reaction to be quenched. The aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with H.sub.2 (100 mL) and brine (100 mL). The title compound (1.36 g, 62%) ES/MS theory Cu (CuHMNaO,): 217.1, experimental 値: = 217.2 (M + Na)+. Intermediate 19: Methyl 3-(2-amino-2-methylpropyl)benzoate

At (TC), chloroethion (〇·845 mL, 13.4 mm〇l) and concentrated H2S〇4 (3 mL, 55.2 mmol) were added to the stirred intermediate 18 (1.3 g, 0.69 mm ο 1) In a solution of glacial acetic acid (3 m L), the resulting mixture was allowed to warm to room temperature and then stirred for further 2 hours. The reaction mixture was poured into ice, and K2C03(s) (pH ~ 4) was added to make it alkaline. The aqueous layer was extracted with EtOAc (3 X 50 mL). EtOAc EtOAc (EtOAc) Add 'thiourea (904 mg, n·9 mm〇l). The reaction mixture is warmed to 95 ° C for 3 hours 'cooling' and then concentrated. The residue is dissolved in 201206927

MeOH (20 mL) was bubbled with HCl (g) over 5 min. The resulting solution was heated under reflux overnight, cooled and then concentrated. The residue was diluted with EtOAc (100 mL) and EtOAc (EtOAc). Saturated NaHC03 (pH &gt; 10) was added to make the aqueous layer basic, followed by extraction with CHC13 (3 X 50 mL). The combined organic layer was washed with EtOAc EtOAc m. The compound was used directly without further purification. ES/MS theory 値 (Ci2H18N02 + ): 208.1, experimental 値: w/z = 208.2 (M + H)+. Intermediate 20: methyl 4-(5-hydroxypent-1-yn-1-yl)benzoate

Methyl 4-iodobenzoate (13.1 g, 60 mmol), PdCl 2 (PPh3) 2 (2.0 g, 3 mmol), and Cul (855 mg, 4·5 mmol) were added to TEA (60 mL). The mixture was degassed by vigorously passing N2 bubbles into the solution while stirring. Pen-4-yn-1-ol (5.5 g, 66 mmol) was added in a syringe. The mixture was heated at 90 ° C overnight. After cooling, the crude mixture was concentrated on a rotary evaporator and suctioned under high vacuum for one hour. The oil was taken up in EtOAc EtOAc (EtOAc)EtOAc. 4 NMR (4 0 0 Μ H z, CD C13) δ 7.9 5 (dd, 2 Η, · / = 9.0,1 · 5 Hz), 7.44 (dd, 2H, "/ = 9.0, 1.5 Hz) 3.90 (s - 3H) &gt; 3.85 (m, 2H), 2.57 (t, 2H, J = 5.5 Hz), 1.87 (m, 2H), 1.42 (t, 1H, J = 5.5 Hz); ES/MS theory値(C丨3HI5 03 + ): -89 - 201206927 219.1, experimental 値: w/z = 219 (M + H)+. Intermediate 21: 4-(5-Hydroxypent-1-yn-1-yl)benzoic acid

LiOH (2 g, 83 mmol) was added dropwise to H20 (30 mL) EtOAc. The resulting mixture was stirred at 42 ° C for 4 hours. After cooling, water (100 mL) and EtOAc (200 mL). The mixture was extracted with EtOAc. The organic layer and the H20 layer were neutralized with IN HC1, respectively. The aqueous layer was extracted with EtOAc and EtOAc (EtOAc) evaporated. The material was concentrated with EtOAc (EtOAc)EtOAc. 4 NMR (400 MHz &gt; DMSO-d6) δ 13.05 (brs, 1 Η), 7.88 (dd, 2 Η, &lt;/ = 8.5, 1.5 H z ), 7.4 7 (dd ' 2 H, J = 8 · 5, 1 . 5 H z), 4 · 5 5 (brs, 1H) &gt; 3.50 (t &gt; 2H &gt; ./ = 5.5 Hz) &gt; 2.50 (m &gt; 2H) &gt; 1.68 (m , 2H) ; ES/MS theory 値((:121〇3 + ) : 205.1, experimental 値:m/Z = 205 (M + H)+. Intermediate 22: l-(5_chloropenta-1·yn-1-yl )_4-nitrobenzene

4-iodonitrobenzene (25 g' 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran ( The mixture in 300 mL) and triethylamine (150 mL) was degassed under a argon atmosphere for 10,100,069, for 10 minutes. The mixture was then heated to 55 ° C. </ RTI> treated with 5· chloropentyne (12 mL, 110 mm 〇l) via a syringe. After stirring for 30 minutes, another portion of dichlorobis(triphenylphosphine)palladium(II) (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 and then filtered through a pad of Celite. The filtrate was concentrated to dryness under reduced pressure to give 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was used without further purification. ES/MS theory 値 (ChHhCINO/): 224.1, experimental 値: m/z = 224.2 (M + H)+. Intermediate 23: 1-(5-Bromopent-1-yn-1-yl)_4_nitrobenzene

A solution of the crude intermediate 22 (about 200 mmol) in 3-pentanone (1 L) was treated with lithium bromide (1 〇 eq, 1 74 g, 2 moles). The mixture was heated under reflux for 30 minutes and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1% aqueous hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness The residue was again placed in 3-pentanone (1 L) and heated under reflux overnight in the presence of lithium bromide (250 g). The mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. 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 used directly without further purification. ES/MS theory 値 (CUHHB1TN02 + ): 268.0, experimental 値: m/z = 268.1 (M + H)+. Intermediate 24: 4-(5-bromopent-1-yn-1-yl)aniline -91 - 201206927

The crude intermediate 23 (200 mmol) mixture was dissolved in a mixture of jV-methylpyrrole D-dichloromethane (1:1 '800 mL) and anhydrous tin (II) chloride (2 1 8 g, 96) 0 mmol) treatment (30 g each time). The exothermic 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. The slurry was filtered through a funnel of sintered glass 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 brine 1 brine, dried over anhydrous magnesium sulfate, filtered, and evaporated The residue was taken up in ethyl acetate and filtered with a EtOAc. The filtrate was concentrated and the residue was quickly precipitated from benzene and filtered. Repeat the concentration-fast precipitation cycle 5 times. After the last iteration, the concentrated filtrate was purified by automated flash gel chromatography (hexane/ethyl acetate). The desired fraction is concentrated to a smaller volume and then treated dropwise with methanesulfonic acid until no more material precipitates. The solid was collected by EtOAc (EtOAc) elute elute £3/1^ Theory 値 ((: 丨丨1^丨38 to +): 240.0, experimental 値: /«/2 = 240.1 (M + H)+ 〇 Intermediate 25 : N-(4-(5- Chloropent-1-yn-1-yl)phenyl)-2,2,2-trifluoroacetamide

-92- 201206927 2,2,2-Trifluoro-N-(4-iodophenyl)acetamidamine (3.2 g, 10 mmol, according to Melissaris, AP and Litt, MH J Org Chem 1 994, 59, 5818- 5821 Preparation), Dichlorobis(triphenylphosphine) (II) (0.14 g, 0.2 mmol), Triphenylphosphine (19 mg '0.07 mmol), and Iodinated. Copper (I) (0.019 g, 0.1 mmol) The mixture in triethylamine (50 mL) was degassed under argon for 1 min while stirring in a 55 ° C oil bath. The mixture was then treated with 5-chloropentyne (1.1 mL, 10 mmol). After heating for 4 hours, the mixture was allowed to cool to room temperature and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give crude title compound. ES/MS theory 値 (C14H14C1F3N0 + ) : 290.1, experimental 値: m/Z = 290.1 (M + H) + ο Intermediate 26 : N-(4-(5-bromopent-1-yn-1-yl) Phenyl)-2,2,2-trifluoroacetamide

A solution of intermediate 25 (ca. 10 mmol) in 3-pentanone (200 mL) was taken up in lithium bromide (10 eq, 100 mmol). The mixture was heated under reflux for 16 hours and then concentrated to dryness under reduced pressure. The residue was taken in ethyl acetate and washed with water. The concentrated organic layer was again taken up in 3-pentanone (200 mL). The mixture was concentrated to dryness under reduced pressure. 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 fast-purification chromatography using a 40 g SiliSep flash column (hexane/ethyl acetate). The desired fraction was concentrated to give the title compound as a white solid. ES/MS theory 値 (C丨3Hi2BrF3NO + ) : 33 4.0, experimental 値: /w/z = 334.1 (M + H)+ » Intermediate 27 : l-(4-((6-Bromohexyl)oxy) Butyl)-4-nitrobenzene

4-(4-Nitrophenyl)butan-1-ol (2.0 g, 10 mmol), tetra-n-butylammonium hydrogen sulfate (0.17 g, 0.5 mmol), and 1,6-dibromohexane (3.2 mL) A mixture of 20 mmol) in dichloromethane (10 mL) wasEtOAc. The reaction mixture was stirred at room temperature for 6 days. The organic layer and the aqueous layer are separated. The water layer was extracted three times by the dichlorocarbyl plant. 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 4 〇 g SiliSep flash column (hexane/ethyl acetate). The desired fraction was concentrated in vacuo to give the title compound as a pale-yellow oil (0.72 g &lt; 20° /.). ES/MS Theory 値(C|6H25BrN03 + ): 358,1, Experimental 値:ζη/ζ = 358·2 (M + H)+. Intermediate 28: 3-(((1,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4-b]pyridine -5-yl)methyl)amino)·4-ethoxycyclobutene-3-ene-1,2-dione-94- 201206927 r^〇

5-(Aminomethyl)-l,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)·ΐΗ-pyrazolo[3,4-b]pyridin-4-amine A suspension of dihydrochloride (〇·6〇g, 1.6 mmol) in ethanol (8 mL) was obtained eluted with diisopropylethylamine (DIEA, 0.57 mL, 3.3 mmol) to give a clear homogeneous mixture. Cool in an ice-water bath. Next, 3,4-diethoxycyclobut-3-en-1,2-dione (TCI America, 0.41 g, 0.36 mmol) was added dropwise with a syringe. After the addition was completed, the mixture was returned to room temperature and stirred overnight. The precipitated solid was collected by EtOAc (EtOAc) elute ES/MS theory 値 (C22H30N5O4 + ): 428.2, experimental 値: m/z = 428.3 (M + H)+. Intermediate 29: N-丨[1,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]-1 pyrazolo[3,4-bIpyridine-5- Methyl 3-(2-ketopropyl)benzamide

Add HATU (202 mg, 0.531 mmol) and DIEA (0.294 mL ' 1.69 mmol) to a stirred solution of 3-(2-ketopropyl)benzoic acid (86 mg, 0.483 mmol) in DMF. (5 mL) in the solution formed. After 5 minutes, 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pipe-95-201206927-an-4-yl)-lH-pyrazole[3, 4-b]pyridine-4-amine (200 mg, 0.531 mmol). The resulting solution was stirred for additional 2 hours. The reaction mixture was poured with EtOAc EtOAc m. The combined organic layers were washed with H20 (2×1 mL) and brine (100 mL), dried Na2S04 (s) and concentrated to give a yellow oil (3 76 mg). Chromatography (9:1, CH2Cl2MeOHMeOHMeOHMeOH ES/MS theory 値 (C26H34N503+): 464.3, experiment 値: w/z = 464.3 (M + H)+. Intermediate 30: N-[[l,6-diethyl-4-anthracene (tetrahydro-2H-piperidin-4-yl)amine]·1H-pyrazolo[3,4-b]pyridine- 5-yl]methyl]-3-mercaptobenzamide

The title compound was synthesized according to a method similar to that described for the intermediate 29, using 3-(meth) benzoic acid in place of 3-(2- propyl propyl) benzoic acid. ES/MS theory 値 (C24H30N5O3 + ) : 43 6.2, experimental 値: w/z = 436.2 (M + H)+. Intermediate 31: N-[[l,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]- 1H-pyrazoloindole 3,4-b]pyridine_ 5-methyl]-4-methylmercaptobenzamide

The title compound was synthesized according to a method similar to that described for Intermediate 29, using 3-(2- propyl propyl) benzoic acid in place of methyl benzoic acid. ES/MS theory 値 (c24H30N5O3 + ) : 43 6.2, experimental 値: w/z = 436.2 (M + H)+. Intermediate 32: N-[丨1,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amine-based 1H-pyrazolo[3,4-b]pyridine-5 -yl]methyl]-4-(5-hydroxypent-1-yn-1-yl)benzamide

The title compound was synthesized by a method similar to that described for Intermediate 29, using Intermediate 21 instead of 3-(2- propylpropyl)benzoic acid. ES/MS theory 値 (C28H36N503 + ) : 490.3, experimental 値: w/z = 490.4 (M + H) + ο Intermediate 33 : 8-bromo-N-[[l,6-diethyl-4-[ (tetrahydro-2 Η-pyran-4-yl)amino]-1Η-pyrazoloindole 3,4_b]pyridin-5-yl]methyl]octylamine

The title compound was synthesized by a method similar to that described for Intermediate 29, using 8-bromo-octanoic acid instead of 3-(2-ketopropyl)benzoic acid. Es/MS theory 値 (C24H39BrN5〇2 + ) : 508.2, experimental 値: m/z = 508.2 (M + H) + -97- 201206927 Intermediate 34 : N-[[l,6 -diethyl·4- [(tetrahydro-2H-piperazin-4-yl)amino]-111-pyrazolo[3,4-1)1pyridin-5-yl]methyl]-4-(5-hydroxypentyl) Benzylamine ο ΗΝ0

Pd(OH)2 (200 mg) was added to a solution of intermediate 32 (200 mg, EtOAc. 40 mmol) in THF / MeOH (5 mL each). The solution was treated with Η 2 for 3 hours under a ring pressure. The reaction mixture was then filtered through a pad of c e 1 i t e. The c e 1 i t e pad was rinsed with EtOAc (EtOAc) (EtOAc). ES/MS theory 値 (C28H4 〇 N5 〇 3 + ) : 494.3, experimental 値: m / z = 494.4 (M + H) +. Intermediate 35: 1-(4-(5-Bromopent-1-yn-1-yl)phenyl)-3-((1,6-diethyl-4-((tetrahydro-2H-pyran)) -4·yl)amino)-1Η-pyrazolo[3,4-b]pyridine-5(yl)methyl)urea

A suspension of the intermediate 24 methanesulfonate (1.4 g, 4.2 mmol) in dichloromethane (50 mL) was purified eluting eluting Triphosgene (0.93 g' 3 · 2 mmol) -98 - 201206927 treatment, followed by 5-(aminomethyl)-l,6-diethyl-N-(tetrahydro-2H-pyran-4- Treatment with -1 Η-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (1.3 g, 3.4 mmol). Methanol was added to the mixture to quench the reaction and concentrate under low pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a 5% aqueous potassium hydrogensulfate solution and a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure. The crude residue was purified by automated flash gel chromatography using a SiliSep flash column (dichloromethane / methanol / ammonium hydroxide). The desired fractions were concentrated in vacuo to give the title compound as pale brown. ES/MS theory 値 (C28H36BrN602 + ) : 5 67.2 , experimental 値: w/z = 567.2 (M + H)+. Intermediate 36: N-[[l,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]-1H-pyrazoloindole 3,4-b]pyridine- 5·yl]methylbu 4-(5-ketopentyl)benzamide

Dess Martin reagent (43 2 mg, 1.02 mmol) was added to a solution of intermediate 34 (250 mg, 0.51 mmol) in THF (5 mL) and DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under EtOAc (EtOAc m. ES/MS theory 値 (C28H38N503 + ) : 492.3, experimental 値: speak /2 = 492.3 (M + H)+. -99- 201206927 Intermediate 37 : (R)-N-(4-(5-((2-((tert-butyldimethylmethyl))oxy)) 2-(8-hydroxy-2-one) 1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl-1-ynyl-1-yl)phenyl)-2,2,2-trifluoroacetamide

A mixture of intermediate 26 (0.33 g, 1.0 mmol) and Intermediate 2 (0.40 g, 1.2 mmol) in DMF (5 mL) eluted with diisopropylethylamine (DIEA, 0.25 mL, 1.5 mmol) Potassium iodide treatment. The mixture was heated in a 5 5 ° C oil bath overnight. The mixture was concentrated at low pressure and purified by automated flash gel chromatography using a 12 g Isco RediSep flash column (dichloromethane / methanol / ammonium hydroxide). The desired fraction was concentrated in vacuo to give title crystall ES/MS theory 値 (C30H37F3N3O4Si + ) : 588.3, experimental 値: w/z = 588.4 (M +Η)+. Intermediate 38: (R)-(5-(4-Aminophenyl)pent-4-yn-yl)(2-((t-butyldimethylmethyl)oxy)-2-(8) -hydroxy-2-keto-I,2,dihydroquinolin-5-yl)ethyl)carbamic acid tert-butyl ester

The intermediate 37 (about 0.35 g, 0.60 mmol) in the solution of dichlorocarbyl (5 mL) -100-201206927 was sequentially treated with triethylamine (0.42 g, 3.0 mmol), dibutyltributate dicarbonate ( 〇_39 g, 1.8 mmol), and #,iV-dimethylaminopyridine (DMAP, 50 mg). After 2 hours, the mixture was concentrated to dryness under reduced pressure and placed in methanol/water (2:1, 5 mL). Tetrahydrofuran was added dropwise until a homogeneous mixture was obtained, followed by treatment with potassium carbonate (about 500 mg). The mixture was stirred at room temperature overnight. Concentrate to an aqueous suspension at low pressure, followed by the addition of a 5 % aqueous potassium hydrogen sulfate solution to adjust to pH 7. The aqueous mixture was extracted three times with dichloromethane. The combined extract was concentrated to a reddish brown foam which was then purified by automated flash gel chromatography using a 12 g Silicycle SiliSep flash column (dichloromethane / methanol / ammonium hydroxide). The desired fraction was concentrated under vacuum to give the title compound (0. g, 30%) as pale brown foam. ES/MS theory 値 (C33H46N305Si + ) : 592.3, experimental 値: m/z = 592.4 (M + H)+. Intermediate 39: (R)-8-Hydroxy-5-(2,2,3,3-tetramethyl-18-(4-nitrophenyl)-4,14-oxax-7-aza -3-矽18焼-5_yl)quinoline_2(1H)-one

The title compound was prepared according to a procedure similar to that described for Intermediate 37, using Intermediate 27 instead of Intermediate 26. ES/MS theory 値(C33H5〇N306Si): 612.4' Experimental 値: w/z = 612.5 (M + H)+o Intermediate 4〇: (R&gt;-(2-(8·((T-butoxy) Carbonyl)oxy)·2·keto-101 - 201206927 Dihydroquinolin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)(6-(4- (4-nitrophenyl)butoxy)hexyl)carbamic acid tert-butyl ester

A solution of the intermediate 3 9 (0.5 3 g, 0.87 mmol) in dichloromethane (5 mL) eluted with di-dibutyldicarbonate (0.57 g, 2.6 mmol), triethylamine (0.61 mL - 4.4 mmol) And; V, #-dimethylaminopyridine (DMAP, 20 mg). The reaction mixture was stirred at room temperature overnight, then concentrated to dryness under reduced pressure. The residue was purified by automated flash gel chromatography using a 25 g SiliSep flash column (hexane/ethyl acetate). The desired fractions are concentrated in vacuo to give the title compound as a clear colourless oil which is converted to a white foam. ES/MS theory 値(C43H66N3O10Si + ): 812.5, experimental 値: w/z = 812.6 (Μ + Η)+» Intermediate 41 : (R)-(2-(2,8-di((3rd butoxide) (carbonyl)oxy)quinolin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)(6-(4-(4-nitrophenyl)butoxy Base hexyl) butyl methacrylate

At room temperature, the intermediate 4 〇 (about 150 mg) in dichloromethane (5 mL) formed a solution of di-tert-butyl dicarbonate and triethylamine (both moderately) and catalyzed -102-201206927 dose Dimethylaminopyridine (DMAP) treatment. The three Bo c protection reactions were analyzed by LC/MS to completeness. The mixture was concentrated to dryness under reduced pressure and the residue was purified by automated flash gel chromatography using a 25 g Si liSep flash column (hexane/ethyl acetate). The desired fractions were concentrated in vacuo to give titled compound (l. ES/MS theory 値 (C48H73N3Na012Si + ) : 934.5, experimental 値: w/z = 934.5 (M + Na) + ο Intermediate 42 : (R)-(6-(4-(4-aminophenyl) butyl Oxy)hexyl)(2-(2,8-bis((t-butoxycarbonyl)oxy)quinolin-5-yl)-2-((t-butyldimethylmethyl)oxy) Ethyl)aminobutyl carbamate

Intermediate 41 (175 mg, 0.19 mmol) was dissolved in MeOH (4 mL) and ethyl acetate (1 mL) and then applied to palladium carbon (10% w/w, wet Degussa-form, catalyst amount). The suspension was stirred for 45 minutes while attached to a hydrogen balloon. The mixture was filtered through a pad of Celite. ES/MS theory 値 (C48H76N301GSi + ): 882·5, experimental 値: w/z = 882.5 (M + H)+. Intermediate 43: 3-[2-[[(2-(2-(3-(dimethyl)methyl)oxy)methyl]-4-hydroxyphenyl]_2-hydroxyethyl Amino] propyldiethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine - 201206927 S-group] Methyl]benzamide

Glacial acetic acid (〇_〇 24 mL, 421.421 mmol) and Intermediate 8 (125 mg, 0.421 mmol) were added to a stirred mixture of intermediate 29 (130 mg, 0.28 mmol) in DMF (3 mL) ) in the solution formed. The resulting solution was stirred for 2 hours. NaBH(OAc)3 (178 mg, 0.84 mmol) was added in portions. The reaction mixture was stirred overnight and then poured into a saturated NaH.sub.3 (40 mL). The precipitate was filtered, EtOAcjjjjjjjjj The compound can be used directly without further purification. ES/MS Theory 値 (C41H61N605 Si + ) : 745.5 ′ Experimental 値 : w / z = 7 4 5.5 ( Μ + Η)+. Intermediate 44: (R)-4-[5-[丨2-[[T-butyldimethylmethyl)oxy]-2-(8-hydroxy-2-keto-1,2-di Hydroquinolin-5-yl)ethyl]amino]pentyl]-N-[[1,6·diethyl-4-[(tetrahydro-2H-pyran-4-yl)amino]- 1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]benzamide

Add NaCNBH3 (1 60 mg, 2.5 5 m mo 1) to intermediate 2 (240 mg, 0.61 mmol), intermediate 36 (250 mg, 0.51 mm), and acetic acid (0.032 mL, 0.561) Methyl) in a solution of THF (5 mL). -104- 201206927 The reaction mixture was stirred at room temperature for 1 hour. Η2Ο (2 mL) was added followed by saturated NaHC03 (20 mL) andEtOAc (EtOAc) The organic layer was separated and dried with MgSO 4 (s), filtered, and concentrated in vacuo. Purify by column chromatography eluting EtOAc EtOAc EtOAc:EtOAc ES/MS theory 値 (C45H64N705Si + ) : 810.5, experimental 値: m/z = 8 1 0.5 (M + H)+. Intermediate 45: (R)-3-丨[[2-(3-[[(t-butyldimethyl)methyl)oxylmethyl-4-hydroxyphenyl]-2-hydroxyethyl] Aminomethyl 】-Ν-Π 1,6-diethyl-4-[(tetrahydro-2H-piperidin-4-yl)aminodi 1H-pyrazoloindole 3,4-b]pyridine -5-yl]methyl]benzamide

The standard II compound was synthesized according to a method similar to that described, using the intermediate 30 instead of the intermediate 29. Es/MS theory 値 (C39H56N6Na05Si + ) • 739.4, experimental 値: Μ /: = 739.4 (M + Na)+. Intermediate 46: (R)-4-丨[[2-(3-[[(t-butyldimethyl)methyl)oxy)methyl]-4-phenylphenyl-2-hydroxyethyl Amino]methyl]_N[丨16_diethyl_ 4-[(tetrahydro-211-piperid-4-yl)amino]_111_pyrazoloindole 3,4_1)]pyridine-5_ Base 1 methyl]benzamide-105- 201206927

The title compound was synthesized according to a method similar to that described for Intermediate 43 using Intermediate 31 instead of Intermediate 29. ES/MS theory 値(C39H56N6Na05Si + ): 739.4, experimental 値: w/z = 739.4 (M + Na) + ο Intermediate 47 : (R)-3-[2-[[2-[4-(benzyloxy) Benzyl-3-([(t-butyldimethylmethyl) oxy)methyl]phenyl]-2-[(t-butyldimethylmethyl)oxy]ethyl]amino 】_2·Methylpropyl]methyl benzoate

Intermediate 6 (1.6 g, 2.89 mmol) and intermediate 19 (900 mg, 4.3 mmol) were heated for 3 days at pure and 95 °C. The reaction mixture was cooled with EtOAc EtOAcjjjjjjjj ES/MS theory 値 (C4 〇 H62N 〇 5Si2 + ) : 692.4, Experimental 値: m/z = 692.4 (M + H)+. Intermediate 48: (R)-3-丨2-丨丨2-丨8-(benzyloxy)_2-keto-1,2-dihydroquinolin-5-yl]-2-[(third Butyl dimethyl hydrazinyloxy] ethyl]amino] 2 - methyl propyl] methyl benzoate

-106- 201206927 The title compound is based on a procedure similar to that described for Intermediate 47, using (R)-8-(benzyloxy)-5-[2-bromo-1-[(t-butyl dimethyl hydrazide). Synthesis of ethoxy]ethyl]quinoline-2 (1 Η)-ketone in place of intermediate 6 "ES / MS theory 値 (C36H47N205Si + ): 615.3, experimental 値: w/z := 615.3 (Μ + Η)+. Intermediate 49: (R)-3-丨2-[[2-[4-(Benzyloxy)-3-indole[(t-butyldimethylmethyl)oxy]methyl]phenyl] -2-[(Tertiary butyldimethylhydrazino)oxylethyl]aminopurine 2_methylpropyl]benzoic acid

LiOH (242 mg, lo. i mmol) was added to a stirred solution of intermediate 47 in THF / MeOH / H20 (3:1:1) (10 mL). The resulting mixture was stirred for 3 days, followed by the addition of 1 N HCl (pH &lt; 3) to quench the reaction. The aqueous layer was extracted with EtOAc (3 X 30 mL). The combined organic layer was washed with EtOAc EtOAc (EtOAc) ES/MS theory 値 (C39H6QN〇5Si2 + ): 678.4, experimental 値: m/z = 67 8.5 (M + H)+. Intermediate 50: (R)-3-丨2-[丨2-丨8-(benzyloxy)_2-keto-1,2-dihydroquinoline _5· kib 2_[(t-butyl Dimethylindenyloxy]ethyl 1amino]_2-methylpropyl]benzoic acid

The title compound was synthesized according to a method similar to that described for Intermediate 49, using -107 - 201206927 Intermediate 48 as the substrate. Es/MS theory 値 (C35H45N2〇5Si + ) : 601.3, experimental 値: speak /z = 601.3 (M + H)+. Intermediate 51: (only) _3-[2_丨[2-[4_(benzyloxy)_3_[丨(t-butyldimethyl decyl)oxy]methyl]phenyl phenyl 2_丨( Third butyl dimethyl fluorenyl) oxy] ethyl 1 amino] -2-methyl propyl] diethyl - 4 - [(tetrahydro-2H_pyran-4-yl)amino]- 1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]benzamide

The title compound was synthesized according to a method similar to that described for Intermediate 29, using Intermediate 49 instead of &lt;RTI ID=0.0&gt;&gt; ES/MS theory 値 (C55H83N6 〇 5Si2 + ) : 9 63_6, experimental 値: w/z = 963,6 (M + H)+. Intermediate 52: (R)-3_[2_[[2_[8_(benzyloxybu 2-keto_1)&gt;2_dihydroquinolin-5-ylbu-2-pyrene (t-butyldimethyl) Mercapto)oxylethyl]amino]_2methylpropyl]·Ν-[[ι,6_diethyl_4_[(tetrahydro-211-pyran-4-yl)amino) - shame and [3,4_b丨pyridine_5_yl]methyl]benzamide

E S / M S The title compound was synthesized according to a method similar to that described for Intermediate 29, using Intermediate 50 instead of 3-(2- ketopropyl)benzoic acid. -108- 201206927 On 値(C51H68N7〇5Si + ) : 8 86.5 ' Experimental 値: w/z = 886.5 (M + H) + ο Intermediate 53 : (R)-3-[2-[[2-[4 -(benzyloxy)-3-(hydroxymethyl)phenyl]_2-hydroxyethyll-amino-2-methylpropyl]-N-[[l,6-diethyl_4-[ (tetrahydro-2H-piperazin-4-yl)aminol l·lH-pyrazolo[3,4-b]pyridin-5-yl]methyl]benzamide

The title compound was synthesized by a method similar to that described for Intermediate 3, using intermediate substance 51 as a substrate. ES/MS theory 値 (C43h55N6 〇 5 + ): 735.2, experimental 値: "/z = 735.5 (M + H) +. Intermediate 54 : (R)-3-[2-[[2-[8-(Benzyloxy)-2-keto-dihydroquinolin-5-yl]-2-hydroxyethyl]amino] -2-methylpropyl]-N-[[i,6-diethyl-4-[(tetrahydro-:2H-pyran-4-yl)amino]-1H-pyrazolo[3, 4-b]卩 比 steep-5-yl I methyl 1 benzyl amide

The title compound was synthesized according to a method similar to that described in Intermediate 3, using intermediate compound 52 as a substrate. ES/MS theory 値 (C45h54N7 〇 5 + ) : 772.4, experimental 値: m/z = 772.4 (M + H)+. -109- 201206927 Intermediate S5: (R)-8-[[2·丨(T-butyldimethylmethyl)oxy]_2_(8-hydroxy-2-keto-1,2-dihydroquine啉-5-yl)ethyl]amino]-Ν·[[16_diethyl-4-[(tetrahydro-2Η-piperan-4-yl)amino]]Η-pyrazolo[3, 4 b] 卩 比 steep · 5 _ base] methyl I octamamine

The title compound was prepared according to a method similar to that described for Intermediate 37, using Intermediate 33 instead of Intermediate 26. ES/MS theory 値 (C4lH64N7〇5Si): 762.5, experimental 値: m/z = 762.5 (M + H) + o Intermediate 56 : (R)-1-(4-(5-((2-(( Tert-butyldimethylmercapto)oxy-2-(8-carbyl-2-mercapto-1,2-dioxaquinolin-5-yl)ethyl)amino)pentyl-1-alkyne · 1-yl)phenyl)-3-((1,6-diethyl- 4-((tetrahydro-2H-pentan-4-yl)amino)-1H-pyrazoloindole 3,4 -b]pyridin-5-yl)methyl)urea

The title compound was prepared according to a method similar to that described for Intermediate 37, using Intermediate 35 instead of Intermediate 26. ES/MS theory 値 (C45H61N805Si + ) : 821.5, experimental 値: w/z = 821.6 (Μ + Η)+» -110- 201206927 Intermediate 57 : (R)-(2_(2,8-二((第Tributoxycarbonyl)oxy)quinolin-5-yl)-2-((t-butyldimethylmethyl)oxy)ethyl)(6-(4-(4-(3-) (1,6·Diethyl_4_((tetrahydro-2Η-piperazin-4-yl)amino)-1Η-pyrazolo[3,4-b]pyridyl)methyl)ureido)benzene Butyloxy)hexyl)carbamic acid tert-butyl ester

The title compound was prepared according to a method similar to that described for Intermediate 35, using Intermediate 42 in place of Intermediate 24. ES/MS theory 値 (C65H99N8012Si + ) : 1211.7, experimental 値: w/z = 1211.6 (M + H)+. Intermediate 58: (only)-1-(4-(5-((2-tert-butyldimethylmethyl)oxy)-2-(5-hydroxy-3-keto-3), 4-Dihydro-2H-benzo[b][l,4]oxazol-8-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)-3-((1, 6-Diethyl-4-((tetrahydro-2H-piperidyl)amino)-1Η-pyrazolo[3,4-b]pyridin-5yl)methyl)urea

The title compound was used according to a procedure similar to that described for Intermediate 56, using (R)-8-(2-amino-1-((t-butyldimethylmethyl) oxy)ethyl) -2H-Benzo[b][l,4]oxazine-3 (4H)-one was prepared by substituting Intermediate 2. ES/MS theory 値 (c44H61N806Si + ) ·· 825.5, experimental 値: m/z = 825.6 -111 - 201206927 (M + H)+. Example 1: N-丨[1,6-diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]-1H-B than 哩3,4-b]B ratio Steep-5-yl]methylbu3-[2-[[(R)-2-)-yl-2-(8-c-yl-2-keto-1,2-dihydroquinolin-5-yl) Ethyl]amino]propyl]benzamide

The title compound was prepared by substituting Intermediate 4 for Intermediate 8 according to a procedure similar to that described for Intermediate 43. *H NMR (400 MHz &gt; DMSO-d6) δ 10.51 (brs « 1Η) · 9.15 (brs &gt; 1H) &gt; 8.86 (brs, 1H), 8.73 (brs, 1H), 8.34 (brs, 1H) &gt ; 8.15 (dd &gt; 1H &gt; / = 4.5 &gt; 9.9 Hz) » 7.77 (m &gt; 2H) &gt; 7.47 (m &gt; 2H) - 7.19 (dd - 1H &gt; / = 6.6 - 8.0 Hz) » 7.00 (d &gt; 1H » J = 8.0 Hz) &gt; 6.60 (d &gt; 1H &gt; 7 = 10.0 Hz) - 6.23

(brs, 1H), 5.3 5 (m, 1H), 4.57 (m, 2H), 4.44 (dd, 2H &gt; J = 7.1 &gt; 14.3 Hz) * 4.29 (m &gt; 2H) &gt; 3.9-2.64 ( m &gt; 11H) , 1.95 (m, 2H), 1.65 (m, 2H), 1.37 (t, 3H, J = 7_2

Hz) &gt; 1.30 (t &gt; 3H &gt; 7 = 6.8 Hz) &gt; 1.10 (dd &gt; 3H &gt; V = 6.5 &gt; 10.7 Hz); ES/MS Theory 値 (C37H46N705 + ): 668.4, Experiment 値: mlz = 668.3 (M + H) + 〇 Example 2: N-[[l,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino]-1H-pyrazole And [3,4-b]pyridin-5-yl]methyl]-3-[2-[[(R)-2-hydroxy-2- [4-hydroxy-112- 201206927 -3- (hydroxyl) Phenyl]ethyl]amino]propyl]benzamide

The title compound was synthesized according to a method similar to that described in Intermediate 3, using Intermediate 43 as a substrate. 'H NMR (400 MHz &gt; DMSO-d6) δ 9.44 (brs &gt; 1H) &gt; 9.17 (brs, 1H), 8.80 (brs, 1H), 8.64 (brs, 1H), 8.34 (s, 1H), 7.74 (m, 2H), 7.46 (m, 2H), 7.36 (s, 1H), 7.09 (dd &gt; 1H &gt; J = 1.5 &gt; 8.9 Hz) &gt; 6.77 (d &gt; 1H &gt; J = 8.2 Hz)-6.06 (m,1H),4.82 (m,1H),4.57 (d,2H,J = 6.5 Hz), 4.50 (s,1H), 4.45 (dd,2H,/ = 6.2,13.5 Hz) &gt ; 4.30 (m, 1H), 3.88 (m - 3H) &gt; 3.61 (t, 2H, / = 11.5 Hz) &gt; 3.48 (m, 2H), 3.30 (m, 1H), 3.09 (m, 4H), 2.70 (m, 1H)&gt; 1.95 (m&gt;2H)&gt; 1.66 (m&gt;2H)&gt; 1.37 (t&gt;3H&gt; J = 7.1 Hz), 1.30 (t, 3H, J = 7.5 Hz), 1.09 ( m,3H) ; ES/MS theory 値(C35H47N6〇5 + ): 631_4, experimental 値:m/z = 631.3 (M + H) + Example 3 : (R)-N-[[l,6-二乙4-[(tetrahydro-2H-pyran-4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[ [2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]_2-methylpropyl]benzamide-113- 201206927

The title compound was synthesized according to a method similar to that described in Intermediate 2, using Intermediate 53 as a substrate. NMR (400 MHz, DMSO-d6) δ 9.44 (brs, iH), g ^ · 1 0 (brs, 1H), 8.66 (brs, 1H), 8.53 (brs, 1H), 8.3 〇 (brs 1H), 7.80 (d, 1H, ·/ = 7.7 Hz), 7.73 (s, 1H), 7 47 H 7 (m , 2H), 7.39 (d &gt; 1H &gt; J = 1.9 Hz) &gt; 7.13 (dd * ih, r J 2.0 H) , 8.1 Hz), 6.79 (d, 1H, · / = 8.2 Hz), 6.08 (m 4.7 9 (m, 1H), 4.5 8 (d, 1H, / = 6.0 Hz), 4 (s ' 1H) &gt; 4.42 (m &gt; 2H) &gt; 4.28 (m &gt; 1H) &gt; 3.89 (m &gt; 2H) » 》 ^ ·1 % . 2.78 (m,11H), 1.95 (m,2H) , 1.63 (m, 2H), l 37 3H, · / = 7.1 Hz), 1.30 (t, 3H, · / = 7.4 Hz), i 2〇 ( 6H) ; ES/MS theory 値 (C36H49N605 + ) : 645.4 , Experimental 値: 645.4 (M + H)+. Example 4: (R)-N-[[l,6-Diethyl·4-[(tetrahydro-2H-piperidin-4-yl)amino] 1H-pyrazolo[3,4-b] Pyridin-5-yl]methyl]_3-[2-[[2-(2,2-dihydroquinolin-5-yl)ethyl]amino) 2-methylpropyl]benzamide

The title compound was synthesized according to a method similar to that described in Intermediate 2, using the intermediate material 54 as the substrate. 'H NMR (400 MHz &gt; DMSO-d6) δ 10.31 (brs ' 1H). &gt;1H&gt; J = 6.1 Hz)&gt; 8.19 (d&gt;1H&gt; J = 10.0 Hz)&gt;, 1H), 7.67 ( m &gt; 2H) 7.30 (m &gt; 2H) &gt; 7.07 (t &gt; 23⁄4 , 7.6 Hz), 6.90 (d, 1H, ·/ = 8.1 Hz), 6.50 (d, 1H, 9.9 Hz), 5.2 9 (m,1H), 4.94 (m,1H), 4.5 5 (d,23⁄4, 6.2 Hz), 4.32 (q,2H,·/ = 7.2 Hz), 4.11 (m,1H), (m,2H,/ = 7.9 Hz), 3_54 (t, 2H, "/ = 11.3 Hz), (m, 2 H), 3. 16 (m, 1 H), 2 · 9 5 (m, 2 H), 2 · 8 6 - 2.5 4 3H), 1.91 (d, 2H, ·/ = 1 5.5 Hz), 1.54 (m, 3H), }, 3H, "/ = 7.0 Hz), 1.24 (t, 3H, "/ = 7.3 Hz) ), 0.92 , '(m, 6H - 7 = 5.7 Hz) ; ES/MS theory 値 (C38H48N7〇5 + ) : 6 8 2.3, test: w/z = 682.4 (M + H)+. 8〇 .0 (t (s

J 3-85 3-32 (m . 34 (t Example 5: (11)-]^-[[1,6-Diethyl-4-[(tetrahydro-211-pyran-4-yl)) Amino] 1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[[[2-hydroxy-2-(8-)-yl 2-keto-1,2- Dihydroquinoline _5_yl)ethyl 1amino benzyl]benzamide

J〇°

The title compound was synthesized by substituting the intermediate 4 for the intermediate 8 and the intermediate 3 s for the intermediate 29, according to a method similar to that described for the intermediate 43. *H NMR (400 MHz &gt; DMSO-d6) δ 8.88 (t » 1H &gt; 7 = 5.9 Hz) -115- 201206927 ,8 .1 0 (d ,1H &gt; J = :10.0 Hz),8 .0 1 (s &gt; 1 H) , 7.82 (s &gt; 1H), 7. 71 (d, 1H, J = 9.1 Hz) ' '7. 47 (d ,1 H,〇r = i '.6 Hz) , 7. 39 (t, 1H, J = 7.6 Hz), 7. 10 (d , 1 H,j ” = 7. 7 Hz), 7. 04 (d, 1H, J = 8.2 Hz), 6. 88 (d , 1 H, jr = 8 :.1 Hz), 6. 44 (d, 1H, J = 9.9 Hz) , 5.32 (brs , 1H), 5. 05 (dd, 1H,. /=4 • 5, 8.2 Hz) &gt; 4.55 (d , 2H, J = 6.1 Hz) i 4.32 (q , 2H, J = 7 • 2 Hz), 4.10 (m &gt; 1 H) , 3 .86 (s, 2H ) 78 (s ' 2H) ' 3.55 (m ' 2H) ' 3.32 (m, 3H), 2.98 (q, J - 7.4 Hz) . 2.65 (m - 2H) - 1.91 (m - 2H) &gt; 1.54 (m ' 2H) ' 1.34 (t ' 3H '// = 7.2 Hz), 1.26 (t, 3H, "/ = 7.5

Hz); ES/MS theory 値 (C35H42N7〇5 + ): M〇3, experimental 値: = 640.3 (M + H)+. Example 6: (R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-piperidin-4-yl)amino) 1H-pyridinium [3,4-b] IJ ratio steep-5-yl]methyl I-4-[[丨2-carbo-2-(8-hydroxy-2-keto·l,2-dihydroquinolin-5-ylhydrazineethyl] Aminomethyl methionine

The title compound was synthesized according to a method similar to that described for the intermediate, using Intermediate 4 in place of Intermediate 8 and Intermediate 31 in place of Intermediate 29. 'H NMR (400 MHz &gt; , 8 · 1 1 (d, 1 Η, · / = DMSO-d6) δ 8_85 (t,1Η ’ = 乂y

10.0 Hz), 8.01 (s ' 1H) ' 7·80 (d ' 2H -116- 201206927 - 8.3 Η z), 7.4 0 (d, 2 Η, / = 8 · 4 Η z), 7 · 1 2 ( d,1 Η, J = 7.9 Hz) &gt; 7.04 (d - 1H . y = 8.2 Hz) - 6.88 (d &gt; 1H &gt; 7 = 8.1 Hz), 6.44 (d, 1H, / = 9.9 Hz), 5.33 (brs , 1H), 5.05 (dd ' 1H ' J = 4.1 ' 8 ] Hz), 4.54 (d ' 2H, J = 5.9 H z) ' 4 · 3 2 (q, 2 H , J = 7.2 H z ), 4. ii (m, 1 H), 3 8 7 (m ' 2H), 3.78 (s, 2H), 3.55 (td, 2H' · 7 = 2 · 1, 11.4 Hz), 3. 3 3 ( m ' 3 H ) ' 2.9 7 (q, 2 H, _/ = 7.4 H z ), 2.6 5 (m ' 2 H ) , 1.91 (m, 2 Η), 1 · 5 3 (m, 2 η), 1 · 3 4 (t , 3 h, / = 7 · 2

Hz), 1·26 (t, 3H, "/ = 7.5 Hz); £S/MS theory 値 (C35H42N7〇5) · 640.3 ′ Experimental 値: w/z = 640.3 (m + H)+. Example 7: (R)-N-[[l,6-Diethyl-4-[(tetrahydro-2H-pyranyl)amino]_1H-pyrazolo[3,4_b]pyridine_5 _ base] methyl b [[[[hhydroxy-2_[4.hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]benzamide

The title compound was synthesized according to a method similar to that described in Intermediate 3, using HF. shame-staple-substituted TBAF and using intermediates &amp; as the substrate to give 9.24 (brs, 1H), 8 9l " 7.85 (s, 1H), 7.74 (8), 7.6)» 7.42 (t&gt; j • 10 (d,1H ' J = 7 8), *H NMR (400 MHz &gt; DMSO-d6) δ , 1Η, J = 6_0), 8.01 (s, 1Η) ), 1H, J = 7.8), 7.52 (d, 1H, j = 7.7), 7.24 (d, 1H, J = 2.0), 7 -117- 201206927 6.97 (dd,1 η 2.2 » 8.21 » 6.68 rd » 1 Oh,

Example 8: (R)-N-[[l,6·Diethyl-4-[(tetrahydro-2Η-piperidin-4-yl))amino-1Η-pyrazolo[3,4-b]pyridine _5_基】methyl b 4·丨[[2_hydroxy·2_[4hydroxy 3-(transmethyl)phenyl]ethyl]amino]methyl]benzamide

The title compound was synthesized according to a method similar to that described for Intermediate 3, &lt;&lt;&gt;&gt; using HF·pyridine instead of TBAF and using intermediate 46 as a substrate to obtain 〇*H NMR (400 MHz &gt; DMSO-d6) δ 9.19 ( Brs &gt; 1Η) ' 8.87 (t &gt;1H&gt; J = 5.8)&gt; 8.01 (s ' 1H), 7.82 (d, 2H, J = 8.4) ' 7.44 (d, 2H, J = 8.3), 7.24 ( d,1H,J = 2.0),7.&quot; (d, 1H, J = 7.7), 6_96 (dd, 1H, J = 2.2, 8.2), 6.68 (d ' 1H , J = 8.2), 4.91 (m , 1H), 4.54 (m, 3H, J = 6.0), 4.44 (s, 2H), 4.32 (q, 2H, J = 7.2), 4.11 (m, 1H), 3.84 (s -118- 201206927, 3H) , 3.56 (td, 2H, J = 1.9, 11.2), 3.34 (m, 3H), 2.97 (q ' 2H, J = 7 5), 2 6 〇 (s, 2H), 1.91 (s, 2H), 1.53 (m ' 2H) ' 1.34 (t ' 3H, J = 7.2), 1.26 (t, 3H, J = 7.5); ES/MS theory 値 (c33h43n6〇5 + ): 603.3, experimental time: m/z = 603.3 (M + H) + 〇 Example 9: (R)-N-[[i,6-diethyl-4_[(tetrahydro-211-pyran-4-yl)amino)j·1H-pyrazole [3,4-b]pyridin-5-yl]methyl]-4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto-I,2- Dihydroquinoline-yl) ethyl] amino I pentyl] benzoyl amine

The title compound was synthesized according to a method similar to that described in Intermediate 3, using Intermediate 44 as a substrate. *H NMR (400 MHz, DMSO-d6) δ 1 0.5 8- 1 0-39 (m - 2Η)-9.19-8.95 (m, 2Η), 8.6 8- 8.45 (m, 2Η), 8.42-8.25 (s , 1H) &gt; 8.14 (d - y = 9.99 Hz &gt; 1H) · 7.81 (d ' J = 8.28 Hz &gt; 2H), 7.33 (d, J = 8.24 Hz, 2H), 7.14 (d 1 / = 8.21 Hz &gt; 1H) - 6.98 (d, / = 8.17 Hz, 1H) &gt; 6.65-6.51 (m, 1H), 6.29-6.04 (s, 1H), 5.41-5.21 (m, 1H), 4.56 (d, J = 6.14 Hz, 2H), 4.49-4.36 (m, 2H), 4.36-4.19 (m, 1H), 3.99-3.82 (m, 2H), 3.7 2 - 3.5 3 (m, 2H), 3.19-2.86 ( m, 6H), 2.64 (m, 2H), 2.07- 1.86 (m, 2H), 1.79-1.51 (m, 6H), 1.34 (m &gt; / = 3 0.5 0 - 7.3 9 Hz, 7H) ; ES/ MS Theory 値-119- 201206927 (C39H50N7O5 + ) : 696.4 ' Experimental 値: m/z = 696.4 (M + H)+. Example 10: (R)-N-[[l,6-Diethyl-4-indole (tetrahydro-2H-pyran-4-yl)amino)J-1H-pyrazoloindole 3,4-b Pyridine-5-yl]methyl]-8-丨丨2-hydroxy_2_(8-hydroxy-2-keto-I,2-dihydroquinoline-S-yl)ethyl]amine 1 xin Guanamine

The title compound was synthesized according to a method similar to that described in Intermediate 3, using Intermediate 5 5 as a substrate to give ° 'H NMR (400 MHz 'DMSO-dg) δ 10.65 (brs» 2 Η) &gt; 8.65 (brs, 1 Η) &gt; 8 · 5 9 (brs ' 2 Η) ' 8.33 (brs ' 1H) ' 8.15 (d &gt; 1 H &gt; / = 10 Hz)' 7.14 (d&gt; 1Η» J = 8 Hz)* 6.98 (d&gt; 1H' J = 8 Hz) &gt; 6.20 (brs » 1H) &gt; 5.30 (d &gt; 1H &gt; 7 = 8.8 Hz) &gt; 4.42 (m,3 H) &gt; 4.35 (d » 2H &gt; J = 6 Hz) ' 4.25 (brs ' 1H) » 3.9 (m &gt; 3H) &gt; 3.60 (t &gt; 2H &gt; 7 = 11.2 Hz) » 3.18-2.9 (m &gt; 6H) , 2 · 1 5 (t,2 H ' ·/ = 7.2 H z),1 . 9 5 (m ' 2 H) ' 1.6 -1 . 5 (m ' 6H), 1.35 (t &gt; 3H &gt; 7 = 7.2Hz ) ' 1.22 (Μ ' 8H) ; ES/MS theory 値 (C35H50N7〇5 + ): 648.4, experimental 値: m/z = 649.0 (M + H) + Example 11 : (R)-l-((l, 6-Diethyl- 4-((tetraki- 2H-indol-4-yl)amine-based oxime [3,4-1)]-deep-5-yl)methyl)-3-(4- (5-((2-Amino-2-keto)-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1--120 - 20120692 7-phenyl)urea

A solution of intermediate 56 (0_16 g, 0.19 mmol) in tetrahydrofuran (2 mL) was then taken up in EtOAc (EtOAc (EtOAc) The mixture was stirred at room temperature overnight and then concentrated to dryness under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc. 'H NMR (400 MHz, DMSO-heart) δ 11.44 (bs, 1H), 10.49 (s ' 1 Η) ' 9.26 (s, 1 Η), 8.90 (bs, 1 Η), 8.67 (s, 1 Η), 8.35 (s &gt; 1H) &gt; 8.17 (d &gt; J = l〇.〇Hz · 1H) &gt; 7.42 (d &gt; 7 = 8.8 Hz &gt; 2H) &gt; 7.30 (d &gt; J = 8.4 Hz &gt; 2H &gt; 7.16 (d » 7 = 8.4 Hz ' 1H) ' 6.99 (d,&gt;/ = 8.0 Hz, 1H), 6.58 (d, J = 10.0 Hz ' 1H) ' 6.65-6.51 (m,1H), 6.24-6.09 (bs, 1H), 5_31 (m'lH), 4.41 (m, 2H), 4.37-4.22 (m, lH), 3.93-3.85 (m, 2H), 3.83 - 3.75 (m, 2H), 3.68-3.57 (m,2H), 3.55-3.48 (m ' 2H) ' 3.10-2.96 (m,6H),2.07- 1.8 2 (m, 2H) » 1.75-1.61 (m ' 4H) ' 1 · 3 8 (t, J = 7.2 H z, 3 H), 1.3 0 (t ' · / = 7.6 Hz, 3H) ; ES/MS theory 値 (C39H47N8〇5 + ): 707.4, experimental 値·· m/z = 707.5 (M + H)+. -121 - 201206927 Example 12: (R)-l-((l,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1Η-pyrazolo[3 ,4-b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(8-hydroxy-2-keto)-I,2·dihydroquinoline- 5-yl)ethyl)amino)pentyl)phenyl)

A solution of the trifluoroacetic acid salt of Example 11 (60 mg) in methanol (4 mL) and ethyl acetate (1 mL) was then applied to palladium carbon (10% w/w, 10 mg) In the case of a balloon, it was stirred for 1 hour. The mixture was filtered through a pad of Celite, and then filtered, and then evaporated to dryness to give the title compound as a tri-acetic acid salt as a pale yellow glass, which was scraped to powder (27 mg) 1H NMR (400 MHz &gt; DMSO- Rfe) δ 1 0.5 5 - 1 0.48 (m, 2H), 9.83 (s, 1H), 8.82-8.74 (m ' 2H) ' 8.54 (s, 1H), 8.29 (bs, 1H), 8.15 (d, / = 10.0 Hz, 1H), 7.32 (d, "/ = 8.4

Hz - 2H) &gt; 7.14 (d &gt; J = 8.0 Hz » 1H) &gt; 7.08 (d &gt; J = 8.4

Hz, 2H), 6.98 (d &gt; 7 = 8.0 Hz, 1H), 6.65-6.51 (d - 7 = 9.6 Hz, 1H), 6.19-6.10 (bs ' 1H), 5.29 (m, 1H), 4.56 ( d 1 7 = 6.14 Hz &gt; 2H) &gt; 4.48-4.3 3 (m ' 2 H), 4.3 2-4 · 2 0 (m , 1H), 3.93 -3.83 (m, 2 H ), 3 · 6 5 - 3 · 5 5 (m, 2 H), 3.4 7- 3.42 (m, 2H), 3. 1 8 -2 · 86 (m ' 6H), 2.64 (m, 2H), 2.05- 1.92 (m, 2H ) '1.74-1.51 (m '6H), 1.34 (m,7H); ES/MS theory 値(C39H51N805 + ) : 7 1 1.4, experimental time: m/z = 711.4 -122- 201206927 (M + H)+ . Example 13: (11)-3-(((1,6-diethyl_4_((tetrahydro-21)[_pyran-4-yl)amino)-11-pyrazolo[3,4- 1&gt;]pyridine-5-yl)methyl)amino)_4_((4-(5-((2-hydroxy-2-(8-hydroxy-2-one-)-dihydrosin-5乙基)ethyl)amino)pentyl)phenyl)amino)cyclobutane-3-ene-1,2-dione

A mixture of intermediate 38 (0_11 g' 019 mmol) and intermediate 28 (0.15 g, 0.36 mmol) in ethanol (2 mL) (: heating in an oil bath for 3 days. The mixture was concentrated at low pressure and then purified by automated rapid gel chromatography using '12 g SiliCyCie SiHSep flash column (dichloromethane/methanol)' to obtain an impure intermediate (R)- 2-(Third butyl dimethyl decyloxy)-2-( 8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl (5_(4_(2- ((1,6-Diethyl-4-(tetrahydro-2H-piperazin-4-ylamino)-1Η-pyrazolo[3,4-b]pyridine-5-yl)methylamino -3,4-dionecyclobutan-indole-alkenylamino)phenyl)pent-4-ynyl) tert-butyl carbamic acid. This material is then subjected to reverse phase high performance liquid chromatography (RP). -HPLC 'acetonitrile/water/0.1% TFA), after concentration to give intermediate (R)-5-(4-(2-((1,6-diethyl-4-(tetrahydro-2H-pyran)- 4-Aminoamino)-1Η-pyrazolo[3,4-b]pyridin-5-yl)methylamino)-3,4-dionecyclobut-1-enylamino)phenyl) Pent-4-ynyl (t-butyl 2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)carbamate. This intermediate Dissolved in methanol (5 mL), treated with palladium on carbon (10% w/w, wet Degussa-type, catalyst amount). Suspension-123- 2012069 27 The float was stirred while connected to a hydrogen balloon until LC/MS analysis showed complete reduction of the spheroids. The mixture was then filtered through a pad of Celite, and the filtrate was concentrated to dryness under reduced pressure. Methanol (1:1,5 mL) was treated with a solution of hydrochloric acid in dioxane (4 N, 2 mL).. LC/MS analysis indicated that the Boc-protecting group was completely removed and the mixture was concentrated to dryness. Purification of the reverse phase high performance liquid chromatography (RP-HPLC, acetonitrile / water / 0.1% TFA) eluted to afford the title compound of trifluoroacetate as pale yellow powder (28 mg). *H NMR (400 MHz, DMSO-c/6) δ 1 0.50- 1 0.46 (m &gt; 2Η) &gt; 9.8 1 (s,1 Η), 8.53 (m,2Η), 8.28 (bs,1 Η),8 · 15 (d, "/ =9.6 Hz&gt; 1H)· 7.85 (m&gt;1H)&gt; 7.36 (d&gt; J = 8.4 Hz* 2H) &gt; 7.13-7.17 (m &gt; 3H) &gt; 6.98 (d &gt; J = 8.0 Hz &gt; 1H) ' 6.58 (d , J = 10.0 Hz, 1H), 6.24-6.04 (bs, 1H), 5.29 (m, 1H), 4.94 (d &gt; 7 = 5.2 Hz' 2H), 4.42 (m, 2H), 4.30-4.18 (m, 1H), 3.92-3.85 (m, 2H), 3.59 (m, 2H), 3.18-2.86 (m, 6H) 2.54 (m, 2H), 2.06- 1.88 (m, 2H), 1.79-1.51 (m ' 6H) ' 1.33 (m ' 7H) ; ES/MS theory 値 (c42H51N806 + ): 763.4, experimental number: zn/2 = 763.3 (M + H)+« Example 14: (R)-l-((l,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1Η- Pyridoxin 3,4-b]pyridin-5-yl)methyl)-3-(4-(4-((6-(2-)-yl-2-(8-hydroxy-2-one) - I,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)butyl)phenyl)urea-124-201206927

The crude concentrated reaction mixture containing intermediate 5 7 was taken in methanol (~0.5 mL) and was taken in a dioxane aqueous solution (4 EtOAc, 2 mL). The mixture was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high-purity liquid chromatography ( EtOAc (EtOAc/EtOAc/EtOAc) 'H NMR (400 MHz &gt; DMSO-^6) δ 10.48 (m &gt; 2H) &gt; 8.82 (s , 1H), 8.54 (m, 2H), 8.32 (s, 1H), 8.15 (d, J = 10.0 Hz &gt;1H)&gt; 7.31 (d* J = 8.4 Hz &gt;2H)&gt; 7.14 (d&gt; J = 8.4 Hz, 1 H), 7.0 7 (d, / = 8 · 4 H z, 2 H), 6 · 9 8 (d, "/ = 8.4 H z, 1 H), 6.5 8 (d, / = 9 · 9 Η z, 1 H), 6 · 1 5 (s, 1 H), 5.3 0 (d , J = 8.1 Hz, 1H), 4.44 - 4.22 (m, 6H), 3.91 (m, 2H), 3.60 (m, 3H), 3.33 (m, 4H), 3.14 - 2.88 (m &gt; 8H) &gt; 2.02-1.91 (m,2H), 1.78 - 1.42 (m,8H), 1.40- 1.34 (m,4H), 1.32- 1.24 (m,8H); ES/MS theory 値(C44H61N806 + ): 797.5, experimental 値:m/z = 797.4 (M + H)+. Example 15: (R)-l-((l,6-Diethyl-4-((tetrahydro-2H-piperidin-4-yl)amino)-1 Η-pyrazoloindole 3,4- b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(5-hydroxy-3-yl)-3,4·dihydro-2H-benzo[ b][l,4]oxazin-8·yl)ethyl)amino)pent-1-yn-1-yl)phenyl)urea-125- 201206927

The title compound was prepared according to a method similar to that described in Example 1 1 using the φ inter-substrate 58 as a substrate. NMR (400 MHz, DMSO-rf6) δ 1 0.05-9.96 (m, 2η) 9.19-8.70 (bs, 2Η), 8.63-8.56 (m, 2Η) ' 8.48-8.25 (bs 1H), 7.4 1 (d, · / = 8.4 Hz, 2H), 7_3 〇 (d, "/ = 8 9 Hz, 2 H), 6.9 2 (d, · / = 8.0 Η z, 1 H), 6.5 6 (d ' &lt;/ = 8.8 H z , 1H), 5.94 (s, 1H), 5.07 (d, J = 9.3 Hz, 2H), 5·94 (s, 1H), 5.06 (d &gt; 7 = 9.2 Hz, 1H), 4.5 8 - 4.4 9 (m , 4 H), 4.49-4.32 (m, 2H), 4.32-4.19 (m, 1H), 3.91-3.88 (m, 2H), 3.63 - 3.53 (m, 2H), 3.14 - 2.86 ( m,6H), 2.68 (m , 2H), 2.07- 1.86 (m &gt; 2H) &gt; 1.72-1.56 (m &gt; 2H) &gt; 1.37 (t » J = 7.2 Hz, 3H), 1.29 (t - 7 = 7.6 Hz » 3H) ; ES/MS theory 値 (C38H47N806+) : 71 1.4, experimental 値: m/z = 71 1.3 (M + H)+. Examples 16-2 0 can be prepared using the general methods described above. Example 16: (R)-l-Ethyl-indole-[4'-indole[2-(3.carbamoyl-4-hydroxyphenyl)2-hydroxyethyl]amino]methyl]biphenyl _4·[(tetrahydro-2Η-piperidin-4-yl)amino]-lH-pyrazolo[3,4-b]pyridin-5-formamide-126- 201206927

CHO OH

Example 17: (R)-8-[2-[2-[4-[l-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Η-pyrazolo[3, 4-b]pyridine-5-carbonyl-1 piperazin-1-yl Iethylamino]-1-hydroxyethyl]-5-hydroxy-2H-benzo[b][l,4]oxazin-3 (4H)-ketone

Example 18: (foot)-]\-[[1,6-diethyl-4-(tetrahydro-211-pyran-4-ylamino)-1H-pyrazolo[3,4-b] Pyridin-5-yl]methyl]-6-[4-[2-hydroxy-2-(8-hydroxy-2-keto-I,2-dihydroquinoline-S-yl)ethylamino] Butoxyl nicotinamide

Example 19: (R)-N-((l,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1Η-pyrazolo[3,4-b Pyridine-5-yl)methyl)-4-(5-((2-hydroxy-2-(4-hydroxy-3-(methylsulfonylamino)phenyl)ethyl)amino)amino)pentyl) Benzylamine-127- 201206927

Example 20: ((1,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-lH-pyrazolo[3,4-b]pyridin-5-yl )methyl)aminocarbamic acid (R)-6-((2.hydroxy-2-(8-hydroxy-2-keto-l,2-dihydroquinolin-5-yl)ethyl)amino) Hexyl ester

Biological Examples Inhibition of PDE4B4 Enzyme Activity The inhibitory activity of the test compound was determined using the PDE Glo assay (Promega, V1361). A PDE-Glo reaction buffer (1 mL of 5X buffer + 4 mL of water) and 150 nM of the test compound dissolved in the reaction buffer were prepared, followed by serial dilutions of 1··3 in the reaction buffer. The final concentration used in the assay did not exceed 0.1% DMSO using D M S 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. Enzyme and test. Compounds were pre-incubated for a few minutes at room temperature. Then add 50 nM enzyme-accepting cAMP to initiate the enzyme reaction, and terminate the reaction after 1 hour. Add Stop Buffer-128-201206927 to each reaction tank (1 mL 5X Stop Buffer + 3.9 mL Water + 100 μΐ^ 100) mM IBMX (ICN Chemicals in DM SO) was used to terminate the reaction. Add detection buffer (1 mL 5X PDE-Glo Detection Buffer + 3.96 mL Water + 40 pL PKA (supplied in kit)) to the cAMP-enzyme-test compound mixture 'this secondary reaction in the chamber Warm for 20 minutes. An equal volume of Kinase Glo reagent was then added to the reaction mixture, and after 1 minute, luminescence was measured using a luminometer (EnVision, reading luminosity every 0.1 seconds). The luminescent enthalpy is directly related to the cAMP concentration in the reaction mixture. Data were plotted against relative light units (RLU) versus test compound concentration, and IC50 was determined using a non-linear curve fitting method using a single point binding mode using GraphPad Prism 5.0. The ic 5Q measurement of the above compounds is shown in column 1 (PDE4 IC50) of Table 1 below. P-2 Adrenergic Receptor Binding Assay The test compound was incubated with Chinese hamster oocytes (CHO) expressing human recombinant P-2 adrenergic receptor for 120 minutes. The binding of the test compound to the β-2 adrenergic receptor was measured by measuring the amount of radiolabeled ligand [3H](-)CGP-12177 (0.3 ηΜ) displaced by the receptor by a scintillation counter. The concentration response curve of the test compound was prepared and the IC5Q (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 Joseph ei α/·, (2004) iVaM/i.-ScA. JrcA. _PAar/n.; 369:525-532. The IC5Q measurement of the above compounds is shown in column 2 of Table 1 below (β2 IC5〇) -129- 201206927 Functional agonistic receptors of human recombinant p-2 adrenergic receptors expressed in Chinese hamster oocytes (CHO) Compounds were incubated with CHO cells expressing human recombinant P-2 adrenergic receptor for 30 minutes. Receptor agonism 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). The concentration response curve of the test compound was prepared, and the EC5 〇 (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. (2〇〇5) /. PAarmaco/., 144:317-322. The EC5G measurement of the above compounds is shown in column 3 of Table 1 below (P2 EC50) inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF-«) 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 (P BMC) were purified using standard Ficoll gradient purification techniques and placed in 96-well microplates at a concentration of 100,000 cells/well. p-2 adrenergic receptor agonists for some immune cells expressing the receptor It also has an anti-inflammatory effect, which inhibits the production of tumor necrosis factor α-130-201206927 (TNF-α) in this assay. Therefore, PBMC is involved in the β-2 adrenergic receptor antagonist ICI-118551 [3-(isopropylamino)-1-[(7-methyl-4-dihydroindenyl)oxy]butyl-2 - Pre-incubation for 30 minutes in the presence of alcohol] (10 μM) to determine PD Ε 4 -directed activity of the test compound and pre-incubation in the absence of IC I - 1 1 85 51 The conjugate activity guided by PDE4 and beta-2 receptors. The test compound was dissolved in D M S , and diluted in buffer (final d M S Ο concentration 0.1% ν/ν), then added to the cell suspension and pre-incubated for 1 hour at 37 °C. The LPS solution (0.4 ng/mL) was then added and the sputum cells were incubated for an additional 6 hours. Cell culture supernatants were collected at the end of the incubation, and TNF-α was measured using a Procarta Cytokine Assay Kit (Affymetrix, Santa Clara, CA) according to the manufacturer's instructions. The data was analyzed using MiraiBio Masterplex QT ν4·0 software (MasterPlex Version 1.0.1.18 Copyright 2008, Hitachi Software Engineering Co., Ltd), the average fluorescence intensity (MFI) was extrapolated to the TNF-α concentration, and the measurement of the re-groove Average 値. Using the software GraphPad Prism 5 for Windows (version 5.02) (GraphPad Software, San Diego CA), using a non-linear curve fitting method in a single point binding mode, plot each test compound with or without ICI- 1 1 8 5 5 1 The inhibition curve in the presence of 1C50. The EC 5G measurement of the above compounds is shown in column 4 (P BMC TNF EC50) of Table 1 below. Lipopolysaccharide (LPS)-induced neutrophil aggregation into the lungs of Lewis rats The rats were anesthetized with 4% isofluurane's placed at a supine 30° angle -131 - 201206927, opening the mouth Exposed the trachea. A 22-gauge needle with a syringe was introduced into the trachea, and a suspension of the test compound (200 μΐ volume / 400 g) was delivered to the lung about 1 cm above the tracheal protuberance. The rats were allowed to return to awake, and 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 2 minutes. Rats were euthanized 4 hours after LPS exposure by intraperitoneal injection of excess 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 to stain with trypan blue blue dye. 1 〇μΐ Resuspend the cell sample as a baseline to measure the total number of cells, counted using a Countess® cell counter (Invitrogen). Differential cell counts were performed on cytosolic cells stained with May-Grunwald and Giemsa solution 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 by one-way variation analysis (ANOVA) using software GraphPad Prism 5 for Windows (version 5.02) (GraphPad Software, San Diego CA). • 132- 201206927 The compounds of Examples 1 and 9 were tested in this assay, both showing greater than 40% neutrophil inhibition at a dose of 300 Hg/kg. Inhibition of acetylcholine-induced bronchoconstriction in D unkin-Hartley guinea pigs Dunkin-Hartley (available from Charles River Laboratories 'male, 500 to 800 g) was anesthetized with 4% isoflurane At the position of 30 degrees on the back, open the mouth to expose the trachea. A 22-gauge needle with a syringe was introduced into the trachea, and a suspension of the test compound (2 〇 0 μm volume) was delivered to the lung about 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), PAUSE (Penh) has been widely used for scientific research and preclinical drug screening as an alternative to measuring lung tolerance in conscious animals. (Chong et al., J. Pharmnacol. Toxicol. Methods 1 998; 39: 163-168. Pennock et al., J. Appl. Physiol. 1979; 46: 399-406). The guinea pig was placed in the WBP system chamber and exposed to an aerosol of 0.9% saline solution or ACh solution (4 mg/mL) for 1 minute. Pulmonary function measurements were continuously recorded immediately after saline or Ach challenge for 20 minutes (expressed by Penh and at maximum expiratory flow rate/maximum inspiratory flow rate X pause time). The results are expressed as the area under the curve (AUC) of the airway reaction (Penh) versus the reaction time (20 minutes). The airway response of guinea pigs was measured to determine the base reaction of the compound before treatment, starting from 24 hours -133 to 201206927, when the test compound was initially evaluated. Thus, each animal can be used as a control group for itself when assessing the bronchial protective effect 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 challenging 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 P of PenH for each group was measured. Statistical analysis used to measure significant differences between groups was performed using the single factor factor analysis (ANOVA) software GraphPad Prism 5 for Windows (version 5.0 2) (G r ap h P ad S oftware, S an D iego CA ) proceed. Table 1 Example # PDE4 IC5〇32 IC5〇β2 EC50 PBMC TNF EC50 1 + + + + ++ + + 2 ++ ++ ++ 3 ++ + + ++ 4 + + + + ++ + + 5 + + + ++ ++ 6 + + • ++ ++ 7 ++ • - 8 ++ • _ + 9 ++ + + ++ ++ 10 + + • ++ ++ 11 + + + + ++ + + 12 ++ + + ++ + + 13 books + + ++ ++ 14 Umbrella + + ++ + + 15 丰氺 + + ++ ++ -134- 201206927

Dry powder blends Dry powder blends for inhalation administration of one or more of the compounds of the invention can be prepared as follows: The particles of the compound of the invention (AP I) are micronized using conventional methods including, but not limited to, jet honing, The distribution of the mass median aerodynamic particle size (MMAD) is about 2 and 030 &lt; about 2.5. The micronized particles are then mixed with conventional dry powder excipients 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. The bulk blend can be filled to a multi-dose DPI, such as the Valois Prohaler, which is designed to deliver the desired dose. -135-

Claims (1)

201206927 VII. Scope of application: 1. A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of: 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 ruthenium, osmium and S and the rest The ring atom is C, wherein 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; R3 is selected from (: 4.12 alkylene) Base, C4-12 extended alkenyl group, 〇4-12 stretching alkynyl group, R4-〇-R4, r4_N(R8)-R4, C3.6 stretching ring base, R4_C3-6 extension ring base, C3-6 extension Cycloalkyl-R4, R4-C3.6 cycloalkyl-R4, C6_1G extended aryl, R4-C6.1G extended aryl, c6 1Q extended aryl _R4, R4-C6·, aryl- R4, R4-c6-10 extended aryl-O-R4, R4-C6.|Q-exoaryl-Νί118)-114, R4-C6·10 extension-136- 201206927 aryl-Cn◦ aryl, Het , R4-Het, R4-Het-C6.1G extended aryl, R4-C6.1Q aryl, C6 1 aryl, Het-R4, R4-Het-R4, R4-0-Het, R4- C6.1q extended aryl _〇_Het, R4_C6 丨. Aryl, and R4-C6-1() aryl-N(R8)_Het; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl group is optionally 2 or 3 substituents selected from a halogen group, a ketone group, and a hydrazine R8; H et is a 5-6 membered saturated or unsaturated extended heterocyclic group, wherein 1 or 2 ring atoms are selected from N, Ο And S, and wherein the heterocyclic group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo, alkyl, alkoxy, keto and oxime H; R is Ci_1Q stretching, C2 a -1Q stretching group, or a C2-10 stretching group, wherein each R4 is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR8; the prerequisite is any definition of R3 The two R4 groups have a C^oalkyl group, a C2_1Q-alkenyl group, or a (2.10 alkynyl chain having a total number of carbon atoms of not more than 1 2; Y is c(o), c(o)n ( R8)ch2, n(r8)c(o), oc(o)n(r8)ch2, n(r8)c(o)n(r8)ch2, or so2n(r8)ch2; R5 is an alkyl group; R6 Is H or an alkyl group; R7 is selected from the group consisting of unsubstituted C3-6 cycloalkyl, substituted c3.6 cycloalkyl, and heterocyclic group selected from the following formulas (1), (ii), and (iii) : 201206927 wherein Z is 0, S, S(0)2, NH or N-R7a, and R7a is selected from the group consisting of alkyl, C(O)alkyl, C(0)NH2, C(0)N(H) alkane And C(0)N(alkyl h; and R8 are a fluorene or a hospital base. 2. A compound according to claim 1 wherein R3 is selected from the group consisting of C4-l2 alkylene, (: 4.12) Base, 0:4.12 alkynyl, R4-〇-R4, R4-N(R8)-R4, (:3·6 cycloalkyl, R4-C3.6 cycloalkyl, C3-6 cycloalkane -R4, R4-C3.6-cycloalkyl-R4, phenylene, R4-phenylene, phenyl-R4, R4-phenylene-R4, R4-phenylene-O-R4, R4-phenylene-N(R8)-R4, R4·phenylene-phenylene, Het, R4-Het, R4-Het-phenylene, Het-R4, R4-Het-R4, R4-0 -Het, R4-phenyl-indole-Het, R4-phenylene-C(0)-Het, and R4-phenylene-N(R8)-Het; wherein the alkyl group, the alkenyl group, An alkynyl, cycloalkyl, or aryl group is optionally substituted with 1, 2 or 3 substituents selected from halo, keto, and OR8; or a pharmaceutically acceptable salt thereof. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is CH2OH' and R2 is H. 4. The compound of claim 1, wherein R1 and R2 together with the attached phenyl form a bicyclic fused heterocyclic ring having 9 or 10 ring atoms, wherein 1 or 2 ring atoms Is selected from the group consisting of N, hydrazine and S, and the bicyclic fused heterocyclic ring is optionally substituted with an additional substituent selected from the group consisting of alkyl, keto and 0H. 5. The compound of claim 1 The pharmaceutically acceptable salt-138-201206927 is subjected to a salt in which R1 and R2 are formed together with the attached phenyl group. The compound of any one of claims 1 to 5, wherein R3 is selected from the group consisting of 2 alkylene, Ci 12 alkenyl, 〇4.12, alkynyl, R4, or a pharmaceutically acceptable salt thereof. -0-R4, and R4-N(R8)-R4, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by 1, 2 or 3, respectively, from the country g, the keto group, and the OR8 Substituted by the base. 7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of Cs-8 alkylene, Cs-8 extended alkenyl, C5-8 extended block, R4- 0-R4, and R4-N(R8)-R4, wherein each R4 is a Ci-4 stretching group, a Cm stretching alkenyl group, or a Cm stretching alkynyl group, and each alkyl group, a stretching group, and an alkynyl group are optionally Substituted by 1 or 2 substituents selected from halo, keto, and OR8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R3 is an unsubstituted C5.8 alkylene group. 9. The compound of any one of claims 1 to 5, wherein R3 is selected from the group consisting of C6-1G exoaryl, r, c6.1(), aryl, or a pharmaceutically acceptable salt thereof, R4-C6·,. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R3 is selected, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of R3, Het, R4-Het, and R4-Het-R4. from! ^_€6_1() aryl, Het, R4-Het, and R4-Het-R4. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of R4-phenylene, R4-phenylene-R4, Het, R4-Het' And R4-Het-R4. 12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of R4-phenylene, Het, and R4-Het. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is C(0)N(R8)CH2. 14. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R5 is -CH2CH3. 15. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R6 is -CH2CH3. 16. A compound as claimed in any one of claims 1 to 5, or A pharmaceutically acceptable salt thereof, wherein R7 is a compound of the formula: which is selected from the group consisting of N-[[l,6-diethyl-4-[(tetraki-2H-indol-4-yl) Amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[[(R)-2-hydroxy-2-[4-hydroxy·3 -(hydroxymethyl)phenyl]ethyl]amino]propyl]benzamide; (R)-N-[[l,6-diethyl-4-[(tetrahydro-2H-pyran) 4-yl)amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-3-[2-[[2-hydroxy-2- [4-hydroxy-3] -(hydroxymethyl)phenyl]ethyl]amino]methylpropyl]benzamide; (11)-&gt;1-[[1,6-diethyl-4-[(tetrahydro-) 2}1-piperidin-4-yl)amino]-111_ 卩 哩 [ [3,4-b] 卩 陡 steep-5-yl] methyl]-3-[2-[[ 2 - - 2-(8-Pyryl-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]-2-methylpropyl]benzamide-140- 201206927 ( 11)-Heart [[1,6-diethyl-4-[(tetrahydro-21^-piperidin-4-yl)amino]-1^1-pyrazolo[3,4-b]pyridine -5-yl]methyl]-3-[[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl]amino]] Benzoguanamine; (R)-N-[[l,6-diethyl-4-[(tetraz- 2H-indol-4-yl)amino] -1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[[[2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydro) Quinoline-5-yl]ethyl]amino]methyl]benzamide; (R)-N-[[l,6-diethyl-4-[(tetrahydro-2H-pyran-4) -yl)amino]-1H-pyrazolo[3,4-1&gt;]pyridin-5-yl]methyl]-3-[[[2-hydroxy-2-[4-hydroxy-3-(hydroxyl) Methyl)phenyl]ethyl]amino]methyl]benzamide: (11)-1^-[[1,6-diethyl-4-[(tetrahydro-211-pyran-4) -yl)amino]-111-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[[[2-hydroxy-2-[4-hydroxy-3-(hydroxyl) ()Phenyl]ethyl]amino]methyl]benzamide; (R)-N-[[l,6-diethyl-4-[(tetrahydro-2H-pyran-4-yl) Amino]-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-4-[5-[[2-hydroxy-2-(8-hydroxy-2-keto)- 1,2-dihydroquinolin-5-yl)ethyl]amino]pentyl]benzamide; (anaphnea)-:^-[[1,6-diethyl-4-[(tetrahydro) -211-piperidin-4-yl)amino]-1^ 哩 哩[3,4-b] 陡-5-yl]methyl]-8-[[2-carbo-2-( 8-(transyl-2-mercapto-1,2-dihydroquinolin-5-yl)ethyl]amino]octylamine; (R)-l-((l,6-diethyl- 4 -((tetrahydro-2H-piperazin-4-yl)amine )-1Η-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(5-((2-hydroxy-2-(8-hydroxy-2-keto)-) 1,2-dihydroquinolin-5-yl)ethyl)amino)pentan-indole-alkyne-indenyl)phenyl)urea; (R)-l-((l,6-diethyl- 4-((tetrahydro-2H-pyran-4-yl)amino)_1Η· -141 - 201206927 pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4- (5-((2-hydroxy-2-(8-hydroxy-2-keto-1,2·dihydroquinolin-5-yl)ethyl)amino)pentyl)phenyl)urea; (R -3(((1,6-diethyl-4-((tetrahydro-2Η-piperidin-4-yl)amino)-1Η-pyrazolo[3,4-b]pyridine-5 -yl)methyl)amino)-4-((4-(5-((2-hydroxy-2-(8-hydroxy-2-keto)-l,2-dihydroquinolin-5-yl)) Ethyl)amino)pentyl)phenyl)amino)cyclobut-3-ene-1,2-dione; (11)-1-((1,6-diethyl-4-((4) Hydrogen-211-piperidin-4-yl)amino)-111-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-(4-(4-((6-( (2-hydroxy-2-(8-hydroxy-2-keto-I,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)butyl)phenyl)urea; R)-l-((l,6-Diethyl-4-((tetrahydro-2H-pyran-4-yl)amino)-1 -pyrido[3,4-b]P than steep-5-yl)methyl)-3-(4-(5-((2-carbo-2-(5-hydroxy-3-keto)- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)urea; (R) -l-ethyl-N-[4'-[[[2-(3-carbamido-4-hydroxyphenyl)-2-hydroxyethyl]amino]methyl]biphenyl-4-yl ]-4-[(tetrahydro-2H-pyran-4-yl)amino]-1Η-pyrazolo[3,4-b]pyridine-5-carboxamide; (R)-8-[2 -[2-[4-[l-ethyl-4-(tetrahydro-2H-piperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carbonyl]piperidin Pyrazin-1-yl]ethylamino]perylethyl]-5-hydroxy-2H-benzo[b][l,4]oxazine-3(4H)-one: (R)-N-[ [l,6-Diethyl-4-(tetrahydro-2H-piperazin-4-ylamino)-iH-pyrazolo[3,4-b]pyridin-5-yl]methyl]-6 -[4-[2-hydroxy·2·(8_carbyl-2-keto-1,2-dihydroquinolin-5-yl)ethylamino]butoxy]nicotinamide; (R )-N-((l,6-Diethyl- 4-((tetrahydro-2Η-pyran-4-yl)amino)-ΐΗ--142- 201206927 pyrazolo[3,4-b] Pyridin-5-yl)methyl)-4-(5-((2-hydroxy-2-(4-hydroxy-3-(methylsulfonylamino)phenyl)ethyl)amino)amino)pentyl) benzene Indoleamine; (1,6-diethyl-4-((tetrahydro-2H-piperidin-4-yl)amino)-1Η-pyrazolo[3,4-b]pyridin-5-yl )methyl)aminocarbamic acid (R)_6-((2-hydroxy-2-(8-hydroxy-2-keto-1,2-dihydroquinolin-5-yl)ethyl)amine) An ester; or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in a method for treating inflammation or bronchial contraction in a human lung. A compound according to any one of claims 1 to 5, 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 (C 〇p D), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, 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. A compound according to any one of claims 1 to 5, 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 The method. 22. The use of a compound of any one of claims 1 to 17 or any pharmaceutically acceptable salt thereof, for use in the manufacture of an inflamed or bronchoconstrictor for treating a human lung Drug. A use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in human therapy and reversible or irreversible Sexual airway obstruction-related diseases, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis (including bronchiectasis due to conditions other than cystic fibrosis), acute bronchitis, chronic bronchitis, viral infection Cough, cystic fibrosis, emphysema, pneumonia, bronchiolitis, bronchiolitis associated with transplantation, nasal inflammatory disease, and tracheobronchitis associated with respirators, or prevention of pneumonia associated with respirators Or treat sinusitis. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 2 5. The pharmaceutical composition of claim 24, which is suitable for inhalation. 26. The pharmaceutical composition of claim 24, further comprising a therapeutically active agent selected from the group consisting of an anti-inflammatory agent, an anticholinergic agent, a peroxisome proliferator-activated receptor agonist Agents, epithelial sodium channel blockers, kinase inhibitors, protease inhibitors, anti-infectives, and antihistamines. A pharmaceutical composition comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating inflammation or bronchoconstriction in the lungs of a human. . 144 · 201206927 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the manufacture of a medicament Treatment of humans 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, panbronchiolitis, bronchiolitis associated with transplantation, sinusitis, and tracheobronchitis associated with respirators, or prevention Respirator-related pneumonia, or treatment of sinusitis. -145- 201206927 Four designated representatives: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 201206927 If there is a chemical formula in the case, please disclose the chemical formula that best shows the characteristics of the invention: Formula I I HIST, R7 -4-