HK1123303B

HK1123303B - Heterocyclic janus kinase 3 inhibitors

Info

Publication number: HK1123303B
Application number: HK09103134.2A
Authority: HK
Inventors: 井上隆幸; 田中�明; 中井一夫; 佐佐木弘; 高桥史江; 白神升平; 畑中惠子; 中岛丰; 向吉耕一朗; 滨口寿雄; 国川茂辉; 东康之
Original assignee: 安斯泰来制药株式会社
Priority date: 2005-12-28
Filing date: 2006-12-25
Publication date: 2011-12-23

Abstract

The present invention provides a compound of formula having an excellent JAK3 inhibition activity and being useful as an active ingredient of an agent for treating and/or preventing various immune diseases including autoimmune diseases inflammatory diseases, and allergic diseases. The compound according to the present invention has an inhibition activity against JAK3 and is thus useful as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission (e.g., rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, Alzheimer's disease, and atherosclerotic disease), or diseases caused by abnormal cytokine signal transmission (e.g., cancer and leukemia).

Description

Heterocyclic Janus kinase 3 inhibitors

Technical Field

The present invention relates to a novel fused heterocyclic compound and a pharmaceutical agent containing the compound as an active ingredient, and more particularly, to a therapeutic agent for immune diseases.

Background

Janus kinase 3 (hereinafter referred to as JAK3) is a member of the protein kinase family. Although kinases in this family other than JAK3 are expressed in many tissues, JAK3 is expressed only in hematopoietic cells. This is consistent with JAK3 playing an important role in signaling through various receptors such as interleukins (hereinafter referred to as IL) -2, IL-4, IL-7, IL-9, IL-15, and IL-21, through noncovalent binding of the above receptors to a common gamma chain (see non-patent document 1 and non-patent document 2).

It has been found that XSCID (X-linked severe combined immunodeficiency) patient populations have reduced amounts of JAK3 protein or that the common gamma chain of the patient population is genetically defective. This suggests that the above problem is caused by blocking of JAK 3-dependent signaling pathway due to immunosuppressive action (see non-patent document 3 and non-patent document 4). Animal experiments show that JAK3 plays an important role not only in maturation of B lymphocytes and T lymphocytes, but also in maintaining the function of T cells. It would therefore be desirable to be able to control the immune response by this mechanism in order to treat diseases associated with abnormal T cell proliferation (such as rejection in organ and/or tissue transplants and autoimmune diseases).

Meanwhile, pyrrolopyridine derivatives (see patent document 1) or imidazopyridine derivatives (see patent document 2) represented by formula (a) or formula (B) are known compounds having JAK3 inhibitory activity.

(for the symbols in the above formula, see corresponding patent application publication.)

Furthermore, pyrrolopyrimidine derivatives represented by formula (C) (see patent document 3, patent document 4, patent document 5, and patent document 6) are also known compounds having JAK3 inhibitory activity.

In addition, pyrrolopyridine derivatives represented by formula (D) (see patent document 7) are also known compounds having JAK3 inhibitory activity.

However, in all of the above documents, the compounds of the present invention are not specifically disclosed.

[ non-patent document 1] J.J.O' shea et al, Cell, vol.109 (supplement), S121, 2002

[ non-patent document 2] K.Ozaki et al, Science, vol.298, p.1630, 2002

Macchi et al, Nature, vol.377, p.65, 1995 [ non-patent document 3]

[ non-patent document 4] S.M.Russell et al, Science, vol.270, p.797, 1995

[ patent document 1] WO 2004/099205

[ patent document 2] WO 2004/099204

[ patent document 3] WO 99/065908

[ patent document 4] WO 99/065909

[ patent document 5] WO 01/042246

[ patent document 6] WO 02/000661

[ patent document 7] WO 2006/069080

Disclosure of Invention

Problems to be solved by the invention

The present inventors have conducted intensive studies with respect to the above object and found that a novel fused heterocyclic compound has an excellent JAK3 inhibitory activity, thereby completing the present invention.

More specifically, the present invention provides a novel fused heterocyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, and more specifically, a pharmaceutical composition that functions as an agent for treating and/or preventing autoimmune diseases, inflammation, and allergic diseases.

The fused heterocyclic compound is a fused pyridine compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof,

wherein

X is N or CR³，

M is (CH)₂)_m(ii) a m is 0 or 1, and m is,

R¹is-H or lower alkyl which may be substituted,

R²is-H or lower alkyl which may be substituted,

R³is-H, halogen, or lower alkyl which may be substituted,

R⁴¹is-H or a heteroaryl group which may be substituted,

R⁴²is a bridged ring group which may be substituted,

R⁵is selected from the group consisting of halogen, cyano, acyl, acylamino, lower alkyl, lower alkenyl, -O-lower alkyl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heterocycloalkenyl and 5-membered heteroaryl, each of which may be substituted,

when R is assumed⁵When it is a 5-membered heteroaryl group, X is-CR³，

Or R⁴¹And R⁵May be linked by a specific functional group to form a divalent group as shown below:

or

Wherein R is^Ais-H or acyl which may be substituted.

Effects of the invention

The compound of the present invention has JAK3 inhibitory activity and thus it is useful as an active ingredient in medicaments for the treatment and/or prevention of diseases caused by unfavorable cytokine signaling (e.g., rejection at organ/tissue transplantation, autoimmune diseases, asthma, atopic dermatitis, alzheimer's disease and atherosclerotic diseases) or diseases caused by abnormal cytokine signaling (e.g., cancer and leukemia).

Best mode for carrying out the invention

The compounds of the present invention represented by formula (I) are characterized by having the following chemical structure: the compound has a crosslinked amine, and also has a skeleton formed by fusion of a 5-membered heterocyclic ring and a 6-membered heterocyclic ring (such as a skeleton shown in 1H-pyrrolo [2, 3-b ] pyridine, 1H-imidazo [4, 5-b ] pyridine, or pyrazolo [1, 5-a ] pyrimidine); the compound of the present invention is also characterized by having a pharmacological action such as JAK3 inhibitory activity.

The present invention is described in detail below.

The term "alkyl" in this specification is a straight or branched chain monovalent group.

The term "lower alkyl" in the present specification is a straight or branched alkyl group having 1 to 6 carbon atoms, which may include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl and n-hexyl, preferably methyl, ethyl, n-propyl, isopropyl and isobutyl, and particularly preferably methyl and ethyl.

The term "lower alkenyl" in the present specification is a straight or branched chain alkenyl group having 2 to 6 carbon atoms with a double bond at each possible position, and may include, for example, ethylene (vinyl), 1-propenyl, 2-propenyl (allyl), 1-methylethen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl, and 2-methyl-2-propen-1-yl, preferably 1-methyl-2-propen-1-yl.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, preferably fluorine.

The term "cycloalkyl" is a monovalent non-aromatic carbocyclic group having 3 to 8 carbon atoms, and may have an unsaturated bond in part or may be fused with a benzene ring. However, bridged hydrocarbons are not included. Cycloalkyl groups may include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl, indanyl, and tetrahydronaphthyl, preferably cyclohexyl.

The term "heterocycloalkyl" is a five-to six-membered non-aromatic saturated heterocyclic ring, which may have one or more identical or different heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms (which may be oxidized). The heterocycloalkyl group may be partially unsaturated, or may be fused with a benzene ring. However, azabridged hydrocarbons are excluded. The heterocycloalkyl group may include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and benzoxazinyl, with dihydrooxazolyl, oxadiazolyl, oxadizolanyl, and furanyl being preferred.

The term "heterocycloalkenyl" is a partially substituted "heterocycloalkyl".

The term "cyclic amino" is a 3-to 8-membered non-aromatic cyclic amine in the group defined by "heterocycloalkyl", which has at least one nitrogen atom and may have one or more of the same or different heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms (which may be oxidized), wherein at least one nitrogen atom forms a bond. However, azabridged hydrocarbons are not included. The "cyclic amino group" may include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholino, thiomorpholino, and piperazinyl.

The term "aryl" is aromatic and may include phenyl, naphthyl and indenyl, preferably aryl having 6 to 10 carbon atoms, more preferably phenyl.

The term "heteroaryl group" is a monovalent five-or six-membered aromatic heterocyclic group having one or more same or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be condensed with a benzene ring. "heteroaryl" may include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indolyl, indazolyl, quinoxalinyl and quinazolinyl, with pyridazinyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl and thioxyloxazolyl being preferred.

The term "bridged cyclic group" means "bridged cycloalkyl group" and "azabridged cycloalkyl group".

The term "bridged cycloalkyl" is a saturated or unsaturated bicyclic or polycyclic bridged alkyl having two or three cycloalkyl rings of 3 to 10 carbon atoms. Non-bridged cycloalkyl groups are not included. Particularly preferred are bicyclic or polycyclic bridged hydrocarbon groups having 4 to 16 carbon atoms. The bridged cycloalkyl group may include, for example, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [4.3.1] decyl, bicyclo [3.3.1] nonyl, bornyl, norbornyl, norbornenyl, 6-dimethylbicyclo [3.1.1] heptyl, tricyclobutyl and adamantyl, preferably adamantyl or bicyclo [2.2.1] heptyl.

The term "aza-bridged cycloalkyl" is a saturated or unsaturated bicyclic or polycyclic bridged cycloalkyl wherein at least one ring-forming atom is a nitrogen atom. Non-bridged heterocycloalkyl groups are not included. Particularly preferred are bicyclic or polycyclic aza-bridged hydrocarbyl groups having 4 to 16 carbon atoms. The term "azacyclohydrocarbyl" may include, for example, azaboronyl, quinuclidinyl, isoquinuclidinyl, toroalkyl, azabicyclo [3.2.1] octyl, azabicyclo [2.2.1] heptyl, 2-azabicyclo [3.2.1] octyl, azabicyclo [3.2.2] nonyl, azabicyclo [3.3.0] nonyl, and azabicyclo [3.3.1] nonyl, with toroalkyl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl being preferred.

The term "acyl" denotes — C (═ O) -lower alkyl, -C (═ O) -cycloalkyl, -C (═ O) -heterocycloalkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, carbamoyl, lower alkylcarbamoyl, -C (═ O) -NH-lower alkyl, cycloalkylcarbamoyl, heterocycloalkylcarbamoyl, arylcarbamoyl and heteroarylcarbamoyl. The terms "lower alkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl" have the meanings as indicated above.

X in the formula (I) is preferably CH.

R in the formula (I)¹preferably-H. R in the formula (I)²Is preferably-H or CH₃And more preferably-H.

R in the formula (I)⁴¹preferably-H.

Furthermore, R in the formula (I)⁴²Preferred are adamantyl or tropanyl groups, both of which may be substituted with OH.

Furthermore, R in the formula (I)⁵Preferred are carbamoyl (which may be substituted) or-C (═ O) -lower alkyl (which may have OH), R⁵More preferably-CONH₂Or a hydroxyacetyl group. As another embodiment, R⁴¹And R⁵Are linked through specific functional groups to form the above-mentioned cyclic structure, which is preferably of the formula (I-C).

As R which may be used as "may be substituted¹、R²、R³、R⁴¹、R⁴²And/or R⁵A substituent comprising a group described in the following items (a) to (g):

(a) halogen element

(b)-OH、-O-R^Z-O-phenyl, -OCO-R^Z、-OCONH-R^ZOxo (═ O);

(c)-SH、-S-R^Z-S-phenyl, -S-heteroaryl, -SO-R^Z-SO-phenyl, -SO-heteroaryl, -SO₃H、-SO₂-R^Z、-SO₂-phenyl, -SO₂Heteroaryl, optionally substituted by one or two R^ZA substituted sulfonamide group.

(d) Can be substituted by one or two R^ZAmino, -NHCO-R substituted by a group^Z-NHCO-phenyl, -NHCO₂-R^Z、-NHCONH₂、-NHCONH-R^Z、-NHSO₂-R^O、-NHSO₂-phenyl, -NHSO₂NH₂、-NO₂、＝N-O-R^Z；

(e)-CHO、-CO-R^Z、-CO₂H、-CO₂-R^ZMay be substituted by one or two R^ZRadical-substituted carbamoyl, -CO-cycloamino, -COCO-R^ZA cyano group;

(f)R^Z

(g) phenyl, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heteroaryl, 5-or 6-membered heterocycloaryl which may be substituted by one or more groups selected from the groups described in (a) to (f) above.

R in the above-mentioned items (a) to (g)^ZMay include "cyano, -OH and lower alkyl, wherein the lower alkyl may be substituted with one to three groups selected from-O-lower alkyl, -NH-lower alkyl, -CONH-lower alkyl, 5-or 6-membered heterocycloalkyl and 5-or 6-membered heteroaryl".

Depending on the type of structure, the compounds of the present invention may include geometric isomers and tautomers. Furthermore, the compounds of the present invention may have asymmetric carbon atoms. All such isomers, including the isomers obtained after isolation or mixtures of such isomers, are included within the scope of the present invention. Furthermore, labeled compounds (i.e., compounds obtained by substituting one or more atoms of the compounds of the present invention with a radioisotope or a nonradioactive isotope) are also within the scope of the present invention.

In addition, pharmaceutically acceptable prodrugs of the compounds of the present invention are also included within the scope of the present invention. Pharmaceutically acceptable prodrugs are compounds having groups that are convertible by solvolysis or under physiological conditions to amino, hydroxyl, carboxyl, and the like. Examples of the group forming such a prodrug include those described in prog.Med., vol.5, p.2157-2161, 1985 and "Development of medicine", Hirokawa Pub.Co., 1990, vol.7, Molecular Design, p.163-198.

The compounds of formula (I) may form acid addition salts or base addition salts. These salts should be pharmaceutically acceptable only. More specifically, these salts may include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid), and acid addition salts formed with organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid); salts with inorganic bases (e.g., sodium, potassium, magnesium, calcium, and aluminum), and salts with organic bases (e.g., methylamine, ethylamine, ethanolamine, lysine, and ornithine); ammonium salts, and the like.

In addition, various hydrates, solvates, and polymorphic forms of the compound represented by formula (I) and salts thereof are also included in the scope of the present invention.

Preparation method

The compounds of the present invention can be prepared by utilizing the characteristics based on their basic skeleton or on the kind of substituents thereof, and employing various known synthetic methods. Depending on the kind of functional group, this method is sometimes effective in the preparation technique, by protecting the relevant functional group with an appropriate protecting group or replacing the relevant functional group with a group which can be easily converted into a functional group in the stage of the starting material or the intermediate, depending on the kind of functional group. Such functional groups may include, for example, amino, hydroxyl, and carboxyl groups. Protective groups for such functional groups may include protective groups described in, for example, "protective groups in Organic Synthesis (third edition, 1999)" authored by t.w.greene and p.g.wuts, and only one of these protective groups should be selected and used as required by the reaction conditions. In this method, the desired component is obtained by introducing a protecting group, carrying out a reaction, and then removing the protecting group or converting the group into a desired group as necessary.

Further, as in the case of using a protecting group as described above, a prodrug of the compound of the present invention can be prepared by introducing a specific group at a raw material or an intermediate stage, or by using the resulting compound represented by the formula (I) for reaction. Such reactions can be carried out using methods known to those skilled in the art, such as conventional esterification, amidation, and dehydration.

Abbreviations used in this specification are as follows:

pr: the preparation example is numbered; ex: example number; structure: a chemical structure; Rf-Syn: reference to the number of the examples (which indicates that the preparation of the relevant compound is analogous to the preparation of the compound described in the example represented by the number); HPLC: high performance liquid chromatography; TLC: thin layer chromatography; rf: a flow rate; data: NMR data and/or MS data; 1H-NMR:¹h-nuclear magnetic resonance; MS: mass spectrometry; (M + H) +: (M + H)⁺；(M+Na)+：(M+Na)⁺；(M-H)-：(M-H)^-。

< first Process >

[ wherein R¹、R²、R⁴¹、R⁴²、R⁵M and X are as defined above, and Lv is a leaving group]

In this production method, a compound having a leaving group represented by formula (I-a) is reacted with an amine represented by formula (I-b), thereby producing the compound of the present invention represented by formula (I). The leaving group Lv may comprise halogen (e.g. chloro and bromo); sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and trifluoromethanesulfonyloxy) and the like.

In step 1, the leaving group Lv of the compound represented by the formula (I-a) is substituted with an amine. The above reaction is carried out under atmospheric pressure or under a certain pressure in the absence of a solvent or in the presence of a suitable solvent.

The solvent may include, for example, aromatic hydrocarbons (e.g., toluene and xylene); ketones (e.g., acetone and methyl ethyl ketone); ethers (e.g., diethyl ether, Tetrahydrofuran (THF), dioxane, and diethoxyethane); alcohols (e.g., methanol (MeOH), ethanol (EtOH), 2-propanol (i-PrOH), and 1-butanol (n-BuOH)); halogenated hydrocarbons (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, and carbon tetrachloride); acetonitrile; aprotic solvents (e.g., Dimethylformamide (DMF), 1, 3-dimethyl-2-imidazolidinone, N-methylpyrrolidone (NMP), and Dimethylsulfoxide (DMSO)); water; or mixtures of these solvents. Preferably, the above reaction is carried out in the presence of a base, and the base may include, for example, basic carbonates (e.g., sodium carbonate and potassium carbonate); basic bicarbonates (e.g., sodium bicarbonate and potassium bicarbonate); alkoxides (such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide); tertiary amines (e.g., triethylamine, tributylamine, and diisopropylethylamine); organic bases (e.g., 1, 8-diazabicyclo [5.4.0] -undec-7-ene, pyridine, and lutidine). However, an excess of compound (I-b) may also be used. Although the reaction temperature varies depending on the kind of the raw materials and the reaction conditions, the reaction can be generally carried out at a temperature from ambient temperature to the reflux temperature of the solvent. The above reaction can also be carried out in the presence of a base such as sodium hydroxide and sodium carbonate, in an organic solvent inert to the reaction such as N, N-dimethylformamide and N, N-dimethylacetamide under conditions of ambient temperature to heat. In addition, salts of the amines of the formula (I-b) can also be used for this reaction.

In addition, heating may also be performed using microwave radiation. Alternatively, the reaction may be carried out by a coupling reaction using a phosphorus reagent (e.g., 2- (di-t-butylphosphine) biphenyl) and a palladium catalyst (e.g., palladium acetate) in the presence of a base (e.g., cesium carbonate).

For this reaction, the production methods in the present specification and those described in examples can be used, or methods similar thereto can be used. Thus, the compound represented by the formula (I-a) can be produced by using a known method, a method known to those skilled in the art, or a method described in reference examples or examples of the present specification, or a method similar thereto.

< second Process >

[ wherein R¹、R²、R⁴¹、R⁴²、R⁵M and Lv are as defined above]

In this production method, after reacting a nitropyridine compound represented by formula (2-a) with an amine represented by formula (2-b), a leaving group at the 2-position is substituted with the amine, thereby obtaining an aminonitropyridine compound represented by formula (2-c). The obtained compound was used for the preparation of the compound of the present invention represented by the formula (I-2).

The method used in step 1 of the first manufacturing method may be introduced into step 2-1. Salts of the amines represented by the formula (2-b) may also be used in the reaction.

In step 2-2, when-R²When it is-H, the imidazole ring can be constructed by reaction with an orthoformate (e.g., ethyl orthoformate) in the presence of an acidic catalyst. Advantageously, the nitro group should be reduced before the orthoformate is used in the reaction. Further, when-R in the compound represented by the formula (I-2)²When other than-H, the method used to synthesize the compound may include, for example, the following methods: a method of acylating an amino group of the compound represented by the formula (2-c) in advance; a method of replacing orthoformate with tetraalkyl orthocarbonate or alkyl isothiocyanate; and a method of reacting a carboxylic acid or carboxylic acid anhydride with a strong acid such as a sulfonic acid. In a solvent inert to the reaction or notThese reactions are carried out in the presence of a solvent at ambient to heated conditions, or under heated reflux conditions.

< third Process >

[ wherein R¹、R²、R⁴²X and M are as defined above]

In this production method, a compound having a carboxyl group represented by the formula (3-a) is used as a starting material to produce the compound of the present invention represented by the formula (I-3).

In step 3, the carboxyl group of the compound represented by formula (3-a) is reacted with an azidation reagent such as diphenylphosphoryl azide (DPPA) and sodium azide, and the imidazolone ring is constructed according to the so-called Couches rearrangement reaction. Advantageously, the reaction is carried out in the presence of a base.

Triethylamine, pyridine, and the like can be generally used as the base, and the reaction can be carried out under conditions of ambient temperature to heating, or under conditions of heating under reflux.

< fourth Process >

[ wherein R¹、R²、R⁴²M, X and Lv are as defined hereinbefore]

In this production method, a carboxylic acid compound represented by formula (4-a) is reacted with a hydrazine derivative represented by formula (4-b), thereby obtaining a hydrazide represented by formula (4-c). The present compound represented by the formula (I-4) can be obtained from the hydrazide.

Step 4-1 may be performed by a method similar to the reaction in which the compound represented by formula (4-a) and the compound represented by formula (4-b) are fused by amidation. The compound (4-a) may be used in the reaction in the form of a free acid, or may be used in the reaction in the form of a reaction derivative thereof. The reactive derivative of the compound (4-a) may include acid halides (e.g., acid chloride and acid bromide); conventional esters (e.g., methyl, ethyl, and benzyl); acyl azides; active esters with N-hydroxybenzotriazole (HoBt), p-nitrophenyl or N-hydroxysuccinimide; a symmetric anhydride; mixed acid anhydrides formed with halogenated carboxylic acid alkyl esters (e.g., halogenated alkyl carbonates), pivaloyl halides, p-toluenesulfonyl chloride, etc., and mixed acid anhydrides obtained by reacting with diphenyl chlorophosphate or N-methylmorpholine (e.g., phosphoric acid type mixed acid anhydrides), and the like.

When the compound (4-a) is reacted in the form of a free acid or under conditions such that the active ester is not separated, it is preferable to use a thickening agent such as Dicyclohexylcarbodiimide (DCC), 1' -carbonylbis-1H-imidazole (CDI), Diphenylphosphorylazide (DPPA), Diethylcyanophosphate (DEPC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI HCl).

The reaction is generally carried out in an organic solvent inert to the reaction (e.g., halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters (e.g., ethyl acetate), acetonitrile, DMF, and DMSO) under cooling conditions, or under cooling to ambient temperature, or under ambient to heating conditions, but the conditions of the reaction vary depending on the reactive derivative or the fusing agent used.

In order to facilitate the reaction, it is sometimes advantageous to use an excess of the compound (4-b) in the reaction or to carry out the reaction in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, lutidine. Pyridine may also be used as a solvent.

The method used in step 1 of the first recipe may be applied to step 4-2.

< fifth production method >

[ wherein R¹、R²、R⁴¹、R⁴²And M is as previously defined, R' is a suitable substituent. The carboxylic acid represented by the formula (5-f) is a commercially available product, or can be produced using a commercially available product]

In step 5-2, step 5-4 and step 5-6, the reaction is carried out so as to react at R⁵Constructing an oxadiazole ring.

In step 5-1, a reaction for synthesizing an acylhydrazine from a carboxylic acid represented by the formula (5-a) is carried out. Further, an intermediate represented by the formula (5-c) can be synthesized from the carboxylic acid represented by the formula (5-a). The reaction in step 4-1 can be applied to all of these reactions.

In step 5-2, step 5-4 and step 5-6, the reaction for constructing the oxadiazole ring may be performed under ambient to heated conditions. An organic base may be added to facilitate the reaction.

In step 5-5, the aromatic nitrile compound represented by the formula (5-d) is reacted with hydroxylamine to obtain hydroxyamidine represented by the formula (5-e). The obtained hydroxyamidine is reacted with a carboxylic acid represented by the formula (5-f) to obtain the compound of the present invention represented by the formula (I-53).

In step 5-5, a reaction with free hydroxylamine or hydroxylamine hydrochloride is carried out in the presence of a base to produce a hydroxyamidine represented by the formula (5-e).

The reaction may be carried out in a solvent inert to the reaction. The solvent may include, for example, alcohols such as methanol (MeOH), ethanol (EtOH), and 2-propanol (i-PrOH); aromatic hydrocarbons (such as toluene and xylene); ethers (such as diethyl ether, Tetrahydrofuran (THF), dioxane and diethoxyethane); halogenated hydrocarbons (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride); aprotic solvents (e.g., DMF, 1, 3-dimethyl-2-imidazolidinone, and DMSO); water; or mixtures of these solvents. Alcohols can generally be used in the above reaction. In the case where hydroxylamine hydrochloride is used in the above reaction, it is preferable to carry out the reaction in the presence of a base which may include, for example, basic carbonates such as sodium carbonate and potassium carbonate; basic bicarbonates (e.g., sodium bicarbonate and potassium bicarbonate); alkoxides (such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide); tertiary amines (e.g., triethylamine and diisopropylethylamine) and organic bases (e.g., 1, 8-diazabicyclo [5.4.0] undec-7-ene, pyridine, and lutidine). Although the temperature of the reaction varies depending on the kind of the raw material and the reaction conditions, the reaction is generally carried out at a temperature ranging from ambient temperature to the reflux temperature of the solvent. The reaction can be carried out in the presence of a base, such as sodium carbonate, in an organic solvent inert to the reaction, such as methanol, and at ambient to elevated temperatures.

Steps 5-6 include two stages: acylation of hydroxyamidine and subsequent cyclization. The intermediate preparation method in step 4-1 can be applied to the first-stage acylation process. However, the reaction is usually carried out under conditions of ambient temperature to heating, or under conditions of heating under reflux. The second stage of the cyclization reaction can be carried out by isolating and purifying the acylate in the presence or absence of a base, and by heating the acylate in an organic solvent inert to the reaction (e.g., ethanol or dioxane). The base may comprise an inorganic base (such as sodium acetate) or an organic base (such as diisopropylethylamine). The above-described reaction consisting of two stages can be carried out: one such operation of conventional acylation reaction is carried out, and then the reaction mixture is directly heated or subjected to microwave irradiation to carry out the reaction.

The solvent may include, for example, aromatic compounds (e.g., toluene, xylene, and pyridine); ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, and diethoxyethane); halogenated hydrocarbons (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, and carbon tetrachloride); acetonitrile; aprotic solvents (e.g., DMF, N-Dimethylacetamide (DMA), 1, 3-dimethyl-2-imidazolidinone, N-methylpyrrolidone (NMP), and DMSO); water; or mixtures of these solvents. Although the temperature of the reaction varies depending on the kind of the raw material and the reaction conditions, the reaction may be carried out under ambient to heated conditions.

< sixth production method >

[ wherein R¹、R²、R⁴²M and Lv are as defined hereinbefore; r' is a suitable substituent]

In step 6, when the compound represented by formula (6-a) is reacted with the primary amine represented by formula (6-b), the oxadiazole ring is opened after the substitution at the primary position to form an aminopyrazolinone ring. The reaction conditions described in step 1 may be applied here as reaction conditions. The reaction can be carried out at ambient to reflux temperature.

Further, some of the compounds represented by the formula (I) can be prepared from the above-prepared compounds of the present invention by appropriately combining methods generally employed by those skilled in the art, such as known alkylation, acylation, substitution, oxidation, reduction, hydrolysis, deprotection, halogenation and mannich reactions. For example, by wherein R⁵Preparation of-R from a Compound of the invention which is a lower alkoxycarbonyl group⁵is-CO₂H can be prepared by hydrolysis according to the protocol described in "experiments Chemistry in (Courses in Experimental Chemistry) (fifth edition, 2003)". In addition, from the group consisting of³And R⁵Preparation of Compounds of the invention all of which are-H wherein-R⁵The compounds of the present invention, which are halogens, can be prepared by halogenation reaction in accordance with the procedures described in "experiments Chemistry in (Courses in Experimental Chemistry) (fifth edition, 2003)". In addition, from wherein-R³To the compound of the invention which is-H, to prepare a compound in which R is³When the compound of the present invention is a lower alkyl group (the lower alkyl group is substituted with a group selected from the group consisting of a mono (lower alkyl) amino group, a di (lower alkyl) amino group and a cyclic amino group), it can be prepared by a Mannich reaction according to the methods described in the following documents: "Experimental Chemistry (Courses in Experimental Chemistry) (fifth edition, 2003)"; mannich et al, arch. pharm., 1912, volume 250, page 647; brewster et al, org.fact, 1953, volume 7, page 99; blucke, org.fact, 1942, vol 1, page 303; merz et al, Pharmazie, 1956, volume 11, page 505, and so on.

These methods, which are generally used by those skilled in the art, can be used not only for the preparation of the compounds of the present invention, but also for the preparation of intermediates formed during the preparation. These methods may also be continued to the subsequent process.

The compound prepared above may be in a free form, or may be subjected to salt-forming treatment using a conventional method and isolated and purified in a salt form. Separation and purification can be carried out by conventional chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographies.

The various isomers can be separated by using conventional methods, exploiting the differences in physicochemical properties between the isomers. For example, a racemic mixture can be converted into an optically pure isomer using a general racemic resolution method, for example, a salt in which a racemic mixture is converted into diastereoisomers by means of a conventional optically active acid (e.g., tartaric acid), and optically resolved. Furthermore, separation of diastereomeric mixtures can also be carried out, for example, by fractional crystallization or various chromatographic methods. In addition, optically active compounds can also be prepared using suitable optically active substances.

The pharmacological activity of the compounds of the present invention was confirmed by conducting the following tests.

Test example 1: JAK3 inhibition assay

The JAK3 inhibition assay was performed according to the method of Okimoto et al, described below.

(1) Preparation of human JAK3

Purified human JAK3 kinase domain was purchased from Carna Biosciences co. It is obtained by the following method. His-tagged protein (41kDa) was ligated to the N-terminus of the 796-1124 (C-terminal) fragment of human JAK3 protein # NM-000215, expressed using a baculovirus expression system, and then purified by Ni-NTA affinity column chromatography.

(2) Detection of JAK3 Activity

biotin-Lyn-substrate-2 (biotin-XEQED EPEGF YFEWL EPE, X ═ epsilon-Acp (available from PEPTIDE insertion corporation, osaka, japan)) and ATP were used as substrates. 15mM Tris-HCl (pH7.5) containing 0.01% Tween 20 and 2mM DTT was used as a test buffer. Typically, 20. mu.L of substrate solution (containing 627nM biotin-Lyn-substrate-2, 20. mu.M ATP and 25mM MgCl)₂Test buffer of (2), test buffer containing 10. mu.L of the substrate to be tested and 20. mu.L of the enzyme solution were added to the well plate and mixed well.

After incubating the well plate for 1 hour at ambient temperature, the well plate is washed with a wash buffer (50mM Tris-HCl (pH7.5), 150mM NaCl and 0.02% Tween 20) and then a blocking solution (a wash buffer containing 0.1% bovine serum albumin) is added to the well plate. After incubating the resulting well plate at ambient temperature for 30 minutes, the blocking solution was removed and a HRP-PY-20 solution (a solution obtained by diluting HRP-PY-20 with a 500-fold dilution with the blocking solution) was added. After incubation for 30 minutes at ambient temperature, the well plate was washed 4 times and TMB substrate solution (from Sigma) was added to the well plate. After 4 minutes incubation at ambient temperature, 1M sulfuric acid was added to stop the reaction. The absorbance at 450nm was measured as the enzyme activity. With IC₅₀Values represent the efficacy of the test compound as an inhibitor of JAK 3.

The following IC₅₀Has a value ofResults obtained in the above tests.

The results of these tests are shown in table 1.

Table 1: JAK3 inhibitory Activity of Compounds of the invention

Examples	IC₅₀(nM)
		29	2.3
32	1.9
		33	2.1
34	0.17
		121	1.1
122	0.43
		133	4.4

143

0.69

Examples	IC₅₀(nM)
		379	1.2
384	0.28
		405	0.65
426	2.3
		434	0.86
484	0.31
		498	1.3
543	0.33

The compounds of the present invention have been confirmed to have inhibitory activity against JAK3 and are useful as active ingredients in medicaments for the treatment and/or prevention of diseases caused by unfavorable cytokine signaling (e.g., rejection at organ/tissue transplantation, autoimmune diseases, asthma, atopic dermatitis, alzheimer's disease and atherosclerotic diseases) or diseases caused by abnormal cytokine signaling (e.g., cancer and leukemia).

Furthermore, based on the inhibitory activity of JAK3, the compounds of the present invention are useful for the treatment and/or prevention of the following diseases.

The pharmaceutical compositions of the present invention comprising a JAK3 inhibitor (e.g. compound (I)) are useful as medicaments for the treatment or prevention of diseases or conditions caused by adverse cytokine signal transduction, such as rejection in organ/tissue transplantation, autoimmune diseases, asthma, atopic dermatitis, alzheimer's disease, atherosclerosis, tumors, myeloma and leukemia. Wherein the rejection reaction in the organ/tissue transplantation can be listed as follows: rejection reactions caused by transplantation of organs or tissues (e.g., heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, pancreatic islets, small intestine, limbs, muscle, nerve, intervertebral disc, trachea, myoblasts, cartilage, etc.); and graft-versus-host responses following bone marrow transplantation. The autoimmune diseases can be exemplified by: rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes mellitus and complications thereof, and the like.

In addition, pharmaceutical formulations of JAK3 inhibitors (e.g., compound (I)) may be useful in the treatment or prevention of the following diseases.

The diseases are: inflammatory or hyperproliferative skin diseases or clinical manifestations on the skin of diseases mediated by the immune system (e.g. psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, baldness, etc.); autoimmune diseases of the eye (e.g., keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with behcet's disease, keratitis, herpetic keratitis, conoscopitis, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Grave's eye muscle paralysis, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (xerosis), small blisters, iridocyclitis, sarcoidosis, endocrine eye disease, etc.); reversible obstructive airway diseases [ asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, etc.), particularly chronic or intractable asthma (e.g., late asthma, strong airway responsiveness, etc.), bronchitis, etc. ]; mucosal or vascular inflammation (e.g., gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel disease, inflammatory bowel disease, necrotic inflammatory bowel disease, intestinal injury associated with thermal burns, leukotriene B4-mediated disease, etc.); intestinal inflammation/allergy (e.g., celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, etc.); food-related allergic diseases (e.g., migraine, rhinitis, eczema, etc.) with symptomatic manifestations at sites remote from the gastrointestinal tract; autoimmune diseases and inflammatory disorders (e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male infertility, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympathetic ophthalmia, lens-induced uveitis, paroxysmal leukopenia, chronic active hepatitis, sudden cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g., arthritic malformations, etc.), polychondritis, and the like); allergic conjunctivitis.

Therefore, the pharmaceutical composition of the present invention can be used for the treatment and prevention of liver diseases [ for example, immunogenic diseases (for example, chronic autoimmune liver diseases such as autoimmune liver diseases, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial hepatectomy, acute hepatic necrosis (for example, necrosis caused by toxins, viral hepatitis, shock, hypoxia, etc.), hepatitis b, non-a, non-b hepatitis, cirrhosis, liver failure (for example, severe hepatitis, late hepatitis, "chronic plus acute" liver failure (acute liver failure based on chronic liver diseases, etc.)), etc. ], and the like ].

Pharmaceutical formulations of JAK3 inhibitors (e.g., compound (I)) may be used alone or in combination with one or more additional agents, according to standard pharmaceutical practice, and the route of administration of the pharmaceutical formulation of JAK3 inhibitor and the additional agent may be the same or different, and the timing of administration may be the same or different. Such additional agents include, but are not limited to, cyclosporin A, tacrolimus, sirolimus, everolimus, mycophenolate mofetil (e.g.Etc.), azathioprine, brequinar, leflunomide, sphingosine-1-phosphate receptor agonists (e.g., fingolimod, KRP-203, etc.), LEA-29Y, antibodies to the IL-2 receptor (e.g., daclizumab, etc.), anti-CD 3 antibodies (e.g., OKT3, etc.), anti-T cell immunoglobulins (e.g., AtGam, etc.), aspirin, CD28-B7 blocking molecules (e.g., Belatacept, Abatacept, etc.), CD40-CD154 blocking molecules (e.g., anti-CD 40 antibodies, etc.), protein kinase C inhibitors (e.g., AEB-071, etc.), paracetamol, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone).

A pharmaceutical composition containing one or two or more compounds represented by the formula (I) or pharmaceutically acceptable salts thereof as an active ingredient can be prepared using carriers, excipients and other additives generally used in pharmaceutical preparations.

The therapeutic administration can be carried out by oral administration such as tablets, pills, capsules, granules, powders, and liquid preparations, or by parenteral administration such as intravenous injection, intramuscular injection, suppositories, transdermal agents, nasal agents, and inhalants. The dose of the compound should be appropriately determined in consideration of the symptoms, age, sex, and the like of each patient to be treated. In general, in the case of oral administration, an adult patient takes a compound dose of about 0.001mg/kg to 100mg/kg per day, and the dose is taken once or divided into 2 to 4 times. In the case of intravenous administration as required depending on the symptoms, generally, an adult patient is administered once to several times daily in a dosage range of 0.0001mg/kg to 10mg/kg at a time. In addition, in the case of administration by inhalation, generally, an adult patient is administered once to several times daily in a dosage range of 0.0001mg/kg to 1mg/kg at a time.

In the present invention, the solid composition for oral administration may be in the form of tablets, powders, granules, etc. In such solid compositions, one or more active substances are mixed with at least one inert excipient (e.g., lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminum silicate, etc.). The compositions may also contain inert additives such as lubricants (e.g., magnesium stearate), disintegrants (e.g., sodium carboxymethyl starch) and dissolution aids, in accordance with conventional methods. Tablets or pills may also be coated with a sugar coating or with a gastro-or enteric coating, as desired.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solution preparations, suspensions, syrups, elixirs and the like, and contain inert diluents commonly used (e.g., purified water, ethanol). In addition to the inert diluents, the compositions may also contain adjuvants such as solubilizers, wetting agents, suspending agents, and sweetening, flavoring, perfuming, and preservative agents.

Injections for parenteral administration include sterile aqueous or non-aqueous solution preparations, suspensions, emulsions. Diluents for aqueous solutions can, for example, include distilled water for injection and physiological saline. Diluents for non-aqueous solutions may, for example, include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), alcohols (such as ethanol) and polysorbate 80 (pharmacopoeial name). Such compositions may also contain additives such as isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, solubilizing aids, and the like. The composition may be sterilized by filtration through a bacteria-retaining filter, by addition of a bactericide, or by light irradiation. In addition, these compositions may be prepared as sterile solid compositions, and may be used by dissolving or suspending the compositions in sterile water or a sterile injectable solvent before use.

The transmucosal agents such as inhalants and nasal agents can be used in a solid, liquid or semisolid state, and can be prepared by a conventionally known method. For example, excipients (such as lactose and starch), pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, and the like may be added as needed. Suitable devices for inhalation or insufflation may be used for administration. For example, the compounds can be administered alone or as a powder mixture after formulation using a known device such as a metered dose inhaler or a nebulizer. In addition, the compounds can also be combined with pharmaceutically acceptable carrier, as a solution or suspension to drug delivery. Dry powder inhalers, and the like, may be used for single or multiple administrations, and dry powders or powder-containing capsules may be used. Alternatively, the drug may be administered by using an appropriate propellant (e.g., an appropriate gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide) in the form of a pressurized aerosol spray or the like.

The topical medicine can be ointment, plaster, cream, gel, patch, spray, lotion, eye drop, eye ointment, etc. The external preparation comprises conventional ointment base, lotion base, aqueous or non-aqueous solution, suspension, emulsion, etc. Ointment or lotion bases may include, for example, polyethylene glycol, carbopol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

Examples

Although the present invention is specifically described below by way of examples, the present invention is not limited to these examples. The starting compounds used in the examples include novel compounds, and the methods for producing the starting compounds from known compounds are described in the preparation examples.

Preparation example 1

The compounds in preparation examples 1-1 to 1-25 shown in the following table were prepared according to a method similar to that described in example 1 using the corresponding starting compounds.

TABLE 2

Table 2 (continuation)

TABLE 3

Preparation example	Data of
		1-1	MS：342(M+H)+
1-2	MS：342(M+H)+
		1-3	MS：460(M+H)+
1-4	MS：370(M+H)+
		1-5	MS：370(M+H)+
1-6	MS：358(M+H)+
		1-7	1H-NMR(400MHz，d6-DMSO)δ：1.32(3H，t，J＝7.0Hz)，1.43(9H，s)，1.73-1.87 (2H，m)，1.90-2.08(4H，m)，2.18-2.33(2H，m)，4.08-4.18(2H，m)，4.28(2H，q，J＝ 7.0Hz)，4.37-4.47(1H，m)，6.52-6.57(1H，m)，7.13-7.18(1H，m)，8.56(1H，s)，9. 39(1H，d，J＝7.6Hz)，11.67(1H，s).MS：415(M+H)+

Table 3 (continuation)

Preparation example	Data of
		1-8	1H-NMR(400MHz，d6-DMSO)δ：0.32(3H，t，J＝7.1Hz)，0.48-3.13(14H，m)，4. 26(2H，q，J＝7.1Hz)，4.68(1H，s)，6.71-6.72(1H，m)，7.23-7.24(1H，m)，8.60(1H ，s)，9.34(1H，s)，11.69(1H，s).MS：356(M+H)+

1-9	1H-NMR(400MHz，d6-DMSO)δ：0.32(3H，t，J＝7.1Hz)，0.40-0.47(2H，m)，1.9 5-2.17(11H，m)，0.80-0.83(1H，m)，4.26(2H，q，J＝7.1Hz)，4.73(1H，d，J＝2.9Hz) ，6.76(1H，dd，J＝2.4Hz，3.5Hz)，7.22(1H，dd，J＝2.6Hz，3.3Hz)，8.60(1H，s)，9.33 (1H，s)，11.68(1H，s).MS：356(M+H)+
		1-10	MS：372(M+H)+
1-11	MS：471(M+H)+
		1-12	MS：481(M+H)+
1-13	MS：405(M+H)+
		1-14	MS：484(M+H)+
1-15	MS：484(M+H)+
		1-16	MS：517(M+H)+
1-17	MS：445(M+H)+
		1-18	MS：445(M+H)+
1-19	MS：300(M+H)+
		1-20	MS：342(M+H)+
1-21	MS：354(M+H)+
		1-22	MS：356(M+H)+
1-23	MS：342(M+H)+
		1-24	1H-NMR(400MHz，d6-DMSO)δ：1.35(3H，t，J＝7.1Hz)，1.68-1.77(6H，m)，2.1 0-2.18(9H，m)，4.26(2H，q，J＝7.1Hz)，6.75(1H，d，J＝3.6Hz)，7.22(1H，d，J＝3.4H z)，8.60(1H，s)，9.34(1H，s)，11.67(1H，s).MS：340(M+H)+
1-25	1H-NMR(400MHz，d6-DMSO)δ：1.32(3H，t，J＝7.1Hz)，1.61-2.07(16H，m)，4. 29(2H，q，J＝7.1Hz)，4.48(1H，d，J＝3.5Hz)，7.18(1H，d，J＝3.2Hz)，9.36(1H，d，J＝ 8.0Hz)，11.67(1H，s).MS：340(M+H)+

Preparation example 2

Reacting 3- (4-chloro-1H-pyrrolo [2, 3-b ]]Pyridin-5-yl) -1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester (60mg) in 1-methyl-2-pyrrolidinone (0.6ml) and 1, 8-diazabicyclo [5.4.0]]The resulting solution of undec-7-ene (0.092ml) was added to glycylamine hydrochloride (34mg), and the resulting mixture was stirred at 70 ℃ for 1 hour. After cooling on standing, preparative HPLC (10mM NH)₄HCO₃+NH₃(pH 9.2: 90: 10 to 20: 80) the reaction solution was directly purified. The active fractions were concentrated and dried to dryness to obtain 3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -N-methyl-1, 2, 4-oxadiazole-5-carboxylic acid ester (23mg) as a solid.

The compounds in preparation examples 2-1 to 2-26 shown in the following table were prepared according to a method similar to that described in preparation example 2 using the corresponding starting compounds.

TABLE 4

Table 4 (continuation)

TABLE 5

Preparation example 3

Benzyl 4-chloro-1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (55mg), { [ (4-amino-1-adamantyl) carbonyl ] amino } acetate (54mg) and triethylamine (80. mu.l) were dissolved in N-methyl-2-pyrrolidone (0.55ml), and stirred at 180 ℃ for 1 hour using a microwave reaction system. To the resultant reaction solution were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate), the resulting compound was dissolved in dioxane (1.1ml) and methanol (1.1ml), 10% palladium-carbon (50% wet) was added, and catalytic reduction reaction was performed under ambient temperature and 1 atmosphere for 4 hours. Methanol, dioxane and 1M hydrochloric acid were added and the precipitated solid was dissolved and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to obtain 4- ({5- [ (2-ethoxy-2-oxoethyl) carbamoyl ] adamantan-2-yl } amino) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (18 mg).

TABLE 6

Preparation example 4

Acetyl chloride was carefully added to ethanol (3ml) at 4 ℃. The reaction solution was stirred at 4 ℃ for 30 minutes. A solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (50mg) in chloroform (0.5ml) and a 2M hydrochloric acid/ethanol solution (0.5ml) were added dropwise to the reaction solution. The reaction solution was stirred at ambient temperature for 18 hours. The reaction solution was concentrated under reduced pressure, thereby obtaining ethyl 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboximidamide trihydrochloride (75 mg).

TABLE 7

Preparation example 5

The compounds in preparation examples 5-1 to 5-32 shown in the following table were prepared according to a method similar to that described in example 3 using the corresponding starting compounds.

TABLE 8

Table 8 (continuation)

TABLE 9

Preparation example	Data of
		5-1	MS：272(M+H)+
5-2	MS：272(M+H)+
		5-3	1H-NMR(400MHz，d6-DMSO)δ：1.60-2.06(14H，m)，4.24(1H，d，J＝7.9Hz)，6.46 (1H，dd，J＝1.3Hz，3.3Hz)，7.16(1H，dd，J＝2.4Hz，3.2Hz)，8.52(1H，s)，9.61(1H，s)， 11.59(1H，s)，12.33(1H，br)MS：312(M+H)+
5-4	MS：314(M+H)+
		5-5	1H-NMR(400MHz，d6-DMSO)δ：1.67-1.75(6H，m)，2.09-2.16(9H，m)，6.71(1H ，s)，7.16(1H，s)，8.56(1H，s)，9.76(1H，br)，11.49(1H，s).MS：312(M+H)+
5-6	MS：326(M+H)+
		5-7	MS：410(M+Na)+
5-8	MS：329(M+H)+
		5-9	MS：479(M+H)+
5-10
		5-11	MS：475(M+Na)+
5-12
		5-13	MS：409(M+Na)+
5-14	MS：446(M-H)-

Watch 9 (continuation)

Preparation example	Data of
		5-15	MS：377(M+H)+
5-16	MS：209(M-H)-
		5-17	MS：342(M+H)+

5-18	MS：330(M+H)+
		5-19	1H-NMR(400MHz，d6-DMSO)δ：1.43(9H，s)，1.70-1.88(2H，m)，1.88-2.09(4H， m)，2.14-2.33(2H，m)，4.05-4.20(2H，m)，4.34-4.46(1H，m)，6.48-6.58(1H，m)，7.0 9-7.17(1H，m)，8.52(1H，s)，9.67(1H，d，J＝6.2Hz)，11.62(1H，s)，12.45(1H，br).MS ：387(M+H)+
5-20	MS：463(M+Na)+
		5-21	MS：437(M-H)-
5-22	MS：371(M+Na)+
		5-23	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.46(2H，m)，1.96-2.15(11H，m)，2.44-2. 55(1H，m)，3.82(1H，s)，4.71(1H，s)，6.72-6.75(1H，m)，7.19(1H，t，J＝2.9Hz)，8.56( 1H，s)，9.71(1H，br)，11.57(1H，s).MS：328(M+H)+
5-24	MS：355(M+Na)+
		5-25	MS：314(M+H)+
5-26	MS：437(M-H)-
		5-27	MS：261(M+H)+
5-28	MS：342(M+H)+
		5-29	MS：314(M+H)+
5-30	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.68(6H，m)，1.98(6H，s)，2.26(2H，s)，4.6 6(1H，s)，6.68(1H，dd，J＝5.3Hz，11.4Hz)，7.2(1H，dd，J＝2.5Hz，3.0Hz)，8.57(1H，s) ，9.70(1H，br)，11.58(1H，s).MS：328(M+H)+
		5-31	MS：328(M+H)+
5-32	MS：458(M+H)+

Preparation example 6

To ethyl 7- [ (trans-5-hydroxyadamantan-2-yl) amino ] -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (50mg) was added 47% liquid hydrobromic acid (0.75ml), and the mixture was stirred at 120 ℃ for 1 hour using a microwave reaction system. After the reaction solution was cooled, the pH was adjusted to 5 with a potassium carbonate solution, and the resulting solid was collected by filtration and washed with water to obtain 7- [ (trans-5-bromoadamantan-2-yl) amino ] -3H-imidazo [4, 5-b ] pyridine-6-carboxylic acid (44 mg).

The compounds in preparation example 6-1 shown in the following table were prepared according to a method similar to that described in preparation example 6 using the corresponding starting compounds.

Watch 10

Preparation example 7

A mixture consisting of ethyl 7- [ (3-exo) -8-azabicyclo [3.2.1] oct-3-ylamino ] -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (400mg), di-tert-butyl dicarbonate (203mg), triethylamine (130 μ l), dioxane (4ml) and water (4ml) was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (5ml) and water (20 ml). The resulting precipitate (ethyl 7- { [ (3-Exo) -8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (200mg)) was collected by filtration. The filtrate was diluted with ethyl acetate (50ml), and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated. Recrystallization from ethyl acetate/n-hexane gave ethyl 7- { [ (3-exo) -8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (100mg) as a white solid.

The compounds in preparation example 7-1 shown in the following table were prepared according to a method similar to that described in example 64 using the corresponding starting compounds.

TABLE 11

Preparation example 8

The compounds in preparation examples 8-1 to 8-3 shown in the following table were prepared according to a method similar to that described in example 44 using the corresponding starting compounds.

TABLE 12

Watch 12 (continuation)

Preparation example 9

The compounds in preparation examples 9-1 to 9-2 shown in the following table were prepared according to a method similar to that described in example 10 using the corresponding starting compounds.

Watch 13

Preparation example 10

The compounds in preparation examples 10-1 to 10-18 shown in the following table were prepared according to a method similar to that described in example 4 using the corresponding starting compounds.

TABLE 14

Watch 14 (continue)

Watch 15

Preparation example	Data of
		10-1	MS：332(M+H)+
10-2	MS：246(M+Na)+
		10-3	MS：586(M+H)+
10-4	MS：452(M+H)+
		10-5	MS：370(M+Na)+
10-6	MS：368(M+H)+
		10-7	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.45(2H，m)，1.65-1.86(8H，m)，1.94- 1.97(2H，m)，2.15-2.20(2H，m)，3.08-3.11(1H，m)，5.05-5.08(1H，m)，6.55-6.5 7(1H，m)，7.66-7.68(1H，m)，8.19(1H，s)，9.85(1H，d，J＝6.8Hz)，12.20(1H，brs). MS：367(M+Na)+
10-8	MS：232(M+Na)+
		10-9	MS：427(M+H)+
10-10	MS：415(M+H)+
		10-11	MS：233(M+Na)+
10-12	MS：474(M+Na)+
		10-13	MS：462(M+Na)+
10-14	MS：262(M+Na)+
		10-15	MS：447(M+H)+
10-16
		10-17	MS：232(M+Na)+
10-18	MS：452(M+H)+

Preparation example 11

To a solution of 4-chloro-1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (350mg) in N, N-dimethylformamide (4ml) at ambient temperature was added N, N-carbonyldiimidazole (289mg) and glycine methyl ester hydrochloride (447mg) in that order. The resulting mixture was stirred at ambient temperature for 2 hours. Water was added to the reaction solution. The precipitated solid was filtered, washed with water, and dried to obtain 4-chloro-5- (1H-imidazol-1-ylcarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (325mg) as a white solid.

TABLE 16

Preparation example 12

To a solution of 4-chloro-5- (1H-imidazol-1-ylcarbonyl) -1H-pyrrolo [2, 3-b ] pyridine (300mg) in N, N-dimethylformamide (3ml) at ambient temperature were added N-ethyl-N-isopropylpropan-2-amine (0.64ml) and glycine methyl ester hydrochloride (305 mg). The resulting mixture was rapidly warmed to 60 ℃ and stirred at 60 ℃ for 2 hours. After water was added to the reaction solution, the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to obtain methyl N- [ (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] glycinate (267mg) as a white solid.

TABLE 17

Preparation example 13

To a solution of benzyl REL- [ (1R, 2S, 3S, 5S) -5-hydroxyadamantan-2-yl ] carbamate (1.3g) in dichloroethane (13ml) were added trimethyloxonium tetrafluoroborate (1.28g), 2, 6-di-t-butyl-4-methylpyridine (2.21 g). The reaction solution was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and insoluble matter was filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 19: 1 to 7: 3) to obtain benzyl REL- [ (1R, 2S, 3S, 5S) -5-methoxyadamantan-2-yl ] carbamate (540mg) as a colorless oil.

The compounds in preparation examples 13-1 to 13-2 shown in the following table were prepared according to a method similar to that described in preparation example 13 using the corresponding starting compounds.

Watch 18

Preparation example 14

The compounds in preparation examples 14-1 to 14-6 shown in the following table were prepared according to a method similar to that described in example 12 to example 14 using the corresponding starting compounds.

Watch 19

Watch 20

Preparation example	Data of
		14-1	MS：267(M+H)+

14-2	MS：414(M+H)+
		14-3	MS：443(M+H)+
14-4	MS：467(M+H)+
		14-5	MS：333(M+Na)+
14-6	MS：481(M+H)+

Preparation example 15

To a solution of (3-exo, 7-endo) -7-hydroxybicyclo [3.3.1] nonane-3-carboxylic acid (700mg) in methanol (14ml), concentrated sulfuric acid (2ml) was added dropwise, and the reaction solution was refluxed for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, respectively, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain (3-exo, 7-endo) -7-hydroxybicyclo [3.3.1] nonane-3-carboxylic acid methyl ester (730 mg).

TABLE 21

Preparation example 16

The compounds in preparation examples 16-1 to 16-3 shown in the following table were prepared according to a method similar to that described in example 28 using the corresponding starting compounds.

TABLE 22

TABLE 23

Preparation example	Data of
		16-1	1H-NMR(400MHz，d6-DMSO)δ：1.44(9H，s)，1.77-2.39(8H，m)，2.42(3H， s)，4.09-4.20(2H，m)，4.48-4.57(1H，m)，6.61-6.66(1H，m)，7.21-7.26(1H，m )，8.57(1H，s)，9.16(1H，d，J＝7.5Hz)，11.81(1H，s).MS：425(M+H)+
16-2	MS：315(M+Na)+
		16-3	MS：425(M+H)+

Preparation example 17

The compounds in preparation example 17 shown in the following table were prepared according to a method similar to that described in example 29 using the corresponding starting compounds.

Watch 24

Preparation example 18

The compounds in preparation examples 18-1 to 18-5 shown in the following tables were prepared according to a method similar to that described in example 30 using the corresponding starting compounds.

TABLE 25

Watch 26

Preparation example	Data of
		18-1	MS：315(M+Na)+
18-2	MS：287(M+Na)+
		18-3	MS：424(M+H)+
18-4	MS：291(M+Na)+
		18-5	MS：468(M+H)+

Preparation example 19

To a solution of 4-chloro-N '-hydroxy-1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (4-chloro-N' -hydroxy-1H-pyrolo [2, 3-b ] pyridine-5-carboxyimide) (100mg) in N, N-dimethylformamide (1ml) at 4 ℃ were added pyridine (58. mu.l) and 2-ethylhexyl chloroformate (92. mu.l). The reaction solution was stirred at ambient temperature for 2 hours. To the reaction solution was added water. The precipitate was collected by filtration and dissolved in xylene (2 ml). The reaction solution was stirred at 160 ℃ for 3 hours. To the reaction solution was added water, and the precipitate was collected by filtration to obtain 3- (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazol-5 (4H) -one (63mg) as a white solid.

Watch 27

Preparation example 20

To a solution of methyl N- [ (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] glycinate (167mg) in chloroform (5ml) at ambient temperature was added phosphorus pentoxide (886mg), and the mixture was refluxed for 18 hours. The reaction solution was cooled and added to a saturated aqueous sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 15: 1) to obtain methyl 4-chloro-5- (5-methoxy-1, 3-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridine (45mg) as a yellowish white solid.

Watch 28

Preparation example 21

To a solution of 4- [ 5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (150mg) in tetrahydrofuran (3ml) at-78 deg.C was added 1.01M diisobutylaluminum hydride/toluene solution (1.93 ml). The reaction solution was stirred at ambient temperature for 18 hours. 1M hydrochloric acid was added to the reaction solution under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4- [ (5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carbaldehyde (100mg) as a pale yellow amorphous substance.

The compounds in preparation example 21-1 shown in the following table were prepared according to a method similar to that described in preparation example 21 using the corresponding starting compounds.

Watch 29

Preparation example 22

To a mixture of 6- (benzylamino) -1- (5-hydroxyadamantan-2-yl) -7-nitro-1, 3-dihydro-2H-imidazo [4, 5-c ] pyridin-2-one (68mg) and methanol (1ml) at ambient temperature was added ammonium formate (197mg) and 10% palladium-on-charcoal (50% wet) (33 mg). The mixture was refluxed for 5 hours. After the mixture was cooled, the catalyst was removed by filtration. The mother liquor was concentrated to obtain 6, 7-diamino-1- (5-hydroxyadamantan-2-yl) -1, 3-dihydro-2H-imidazo [4, 5-c ] pyridin-2-one (54 mg).

The compounds in preparation examples 22-1 to 22-3 shown in the following tables were prepared according to a method similar to that described in preparation example 22 using the corresponding starting compounds.

Watch 30

Watch 31

Preparation example	Data of
		22	MS：316(M+H)+
22-1	MS：332(M+H)+
		22-2	MS：320(M+H)+
22-3	MS：332(M+H)+

Preparation example 23

To a suspension of ethyl 6- [ (3, 4-dimethoxybenzyl) amino ] -4- [ (cis-5-hydroxyadamantan-2-yl) amino ] -5-nitronicotinate (2.73g) in ethanol (40ml) was added 10% palladium on charcoal (50% wet) (550 mg). The catalytic reduction reaction was carried out at 80 ℃ for 5 hours under a hydrogen atmosphere. After the reaction solution was cooled to ambient temperature, the catalyst was filtered off and washed with dioxane, and the solvent was evaporated under reduced pressure. Triethyl orthoformate (17ml) and concentrated hydrochloric acid (864 μ l) were added to the residue and the mixture was stirred at ambient temperature overnight. The reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby ethyl 3- (3, 4-dimethoxybenzyl) -7- [ (cis-5-hydroxyadamantan-2-yl) amino ] -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (2.17g) was obtained.

The compounds in preparation example 23-1 shown in the following table were prepared according to a method similar to that described in preparation example 23 using the corresponding starting compounds.

Watch 32

Preparation example 24

The compounds in preparation examples 24-1 to 24-3 shown in the following tables were prepared according to a method similar to that described in example 35 using the corresponding starting compounds.

Watch 33

Preparation example 25

To a solution of N-tert-butoxycarbonyl-nortropinone (N-Boc-nortropinone) (1.38g), benzylamine (0.803ml) and acetic acid (0.35ml) in dichloromethane (10ml) and 1, 2-dichloroethane (32ml) was added sodium triacetoxyborohydride (1.95 g). The mixture was stirred at ambient temperature for 2 hours. Benzylamine (0.201ml) and sodium triacetoxyborohydride (649mg) were added to the reaction mixture, and the mixture was stirred at 50 ℃ for 3.5 hours. Further, sodium triacetoxyborohydride (649mg) was added to the reaction mixture, and stirred at 50 ℃ for 3 hours. The reaction solvent was evaporated under reduced pressure. To the residue were added saturated aqueous sodium bicarbonate and 1M aqueous sodium hydroxide solution to basify the residue. The residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water and saturated brine, respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby tert-butyl 3- (benzylamino) -8-azabicyclo [3.2.1] oct-8-carbamate (1.78g) was obtained as a white solid.

The compounds in preparation examples 25-1 to 25-8 shown in the following tables were prepared according to a method similar to that described in preparation example 25 using the corresponding starting compounds.

Watch 34

Watch 34 (continuation)

Watch 35

Preparation example	Data of
		25	1H-NMR(400MHz，CDCl₃)δ：1.35-1.66(3H，m)，1.45(9H，s)，1.86-2.22(6H ，m)，3.00(1H，dd，J＝6.0，6.0Hz)，3.78(2H，s)，4.04-4.28(2H，m)，7.20-7.38(5 H，m)
25-1	MS：423，425(M+H)+
		25-2	MS：383(M+Na)+
25-3	MS：357(M+H)+
		25-4	MS：311(M+H)+
25-5	MS：320，322(M+H)+
		25-6	MS：327(M+Na)+
25-7	MS：258(M+H)+
		25-8	MS：423，425(M+H)+

Preparation example 26

The compounds in preparation examples 26-1 to 26-2 shown in the following tables were prepared according to a method similar to that described in example 50 using the corresponding starting compounds.

Watch 36

Preparation example 27

To a solution of REL- (1 ' R, 3 ' S, 5 ' S, 7 ' S) -5 ' H-spiro [1, 3-dioxolane-2, 2 ' -tricyclo [ 3.3.1.1-3, 7- ] decane ] -5 ' -carboxylic acid (100mg) in toluene (1ml) were added diphenyl azide phosphate (99. mu.l) and triethylamine (64. mu.l). The mixture was stirred at 110 ℃ for 2 hours. After the reaction solution was cooled to ambient temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylacetamide (1ml), and potassium tert-butoxide (49mg) was added thereto. The mixture was stirred at ambient temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate), whereby tert-butyl REL- (1 ' R, 3 ' S, 5 ' S, 7 ' S) -5 ' H-spiro [1, 3-dioxolane-2, 2 ' -tricyclo [3.3.1.1 to 3, 7- ] decane ] -5 ' -ylcarbamate (40mg) was obtained.

The compounds in preparation examples 27-1 to 27-3 shown in the following tables were prepared according to a method similar to that described in preparation example 27 using the corresponding starting compounds.

Watch 37

Preparation example 28

70% nitric acid (20ml) was added dropwise to concentrated sulfuric acid (175ml) under ice-cooling, and 2-amantadine hydrochloride (25g) was slowly added at 10 ℃ or lower. The mixture was warmed to ambient temperature and stirred for 2 hours. The reaction solution was poured into ice water, and the mixture was neutralized with a 6M aqueous solution of sodium hydroxide and extracted four times with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4-aminoadamantan-1-ol (17.7 g).

Watch 38

Preparation example 29

A mixture consisting of ethyl 4- { [ 3-exo (hydroxymethyl) bicyclo [2.2.1] heptyl-2-exo ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (54mg), triisopropylchlorosilane (52. mu.l), imidazole (17mg), and N, N-dimethylformamide (0.3ml) was stirred at ambient temperature for 2 hours. The reaction solution was diluted with ethyl acetate (20ml), and it was poured into a saturated aqueous sodium hydrogencarbonate solution (15 ml). The mixture was extracted 2 times with ethyl acetate (15ml), and the extract was washed with brine (20ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to give ethyl 4- { [ 3-exo (triisopropylsilyl) oxy ] methyl } bicyclo [2.2.1] heptyl-2-exo ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (76mg) as a pale brown solid.

Watch 39

Preparation example 30

To a solution of 4-chloro-2-methyl-1H-pyrrolo [2, 3-b ] pyridine (0.85g) in N, N-dimethylformamide (8.5ml) was added 60% NaH (245mg) suspended in oil under a nitrogen atmosphere while cooling with an ice-water bath. The reaction solution was stirred at ambient temperature for 1 hour and cooled again in an ice-water bath. Triisopropylchlorosilane (1.3ml) was slowly added dropwise to the reaction solution, and the addition was completed over 10 minutes or more. The reaction solution was stirred at ambient temperature for 3 hours and diluted with ethyl acetate (30 ml). The solution was washed with saturated aqueous sodium bicarbonate (30ml) and brine (20ml), respectively. The solution was dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain a colorless transparent liquid of 4-chloro-2-methyl-1- (triisopropylsilyl) -pyrrolo [2, 3-b ] pyridine (1.45 g).

Watch 40

Preparation example 31

The compounds in preparation examples 31-1 to 31-2 shown in the following tables were prepared according to a method similar to that described in example 19 using the corresponding starting compounds.

Table 41

Preparation example 32

A mixture consisting of 4-chloro-2-methyl-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b ] pyridine (4.73g), potassium carbonate (6.4g), methanol (45ml) and water (15ml) was stirred at 90 ℃ for 2 hours. After the mixture was cooled, the resulting needle-shaped crystals were filtered off and washed with water, thereby obtaining 4-chloro-2-methyl-1H-pyrrolo [2, 3-b ] pyridine (1.85 g).

Watch 42

Preparation example 33

To a solution of benzyl REL- [ (1R, 2S, 3S, 5S) -5-hydroxyadamantan-2-yl ] carbamate (5.5g) in methanol (55ml) was added 10% palladium on charcoal (50% wet) (1.1g) and the mixture was stirred under a hydrogen atmosphere at ambient temperature for 3 hours. After 10% of the palladium-charcoal was removed with celite, the filtrate was concentrated under reduced pressure to obtain REL- (1S, 3R, 4S, 5S) -4-adamantanamine-1-ol (3.8 g).

The compounds in production examples 33-1 to 33-11 shown in the following table were prepared according to a method similar to that described in production example 33 using the corresponding starting compounds.

Watch 43

Watch 43 (continuation)

Watch 44

Preparation example	Data of	Preparation example	Data of
				33	MS：168(M+H)+	33-1	MS：281(M+H)+
33-2	MS：168(M+H)+	33-3	MS：234(M+H)+
				33-4	MS：182(M+H)+	33-5	MS：182(M+H)+
33-6	MS：170(M+H)+	33-7	MS：170(M+H)+
				33-8	MS：196(M+H)+	33-9	MS：281(M+H)+
33-10	MS：170(M+H)+	33-11	MS：234(M+H)+

Preparation example 34

The compounds in preparation examples 34-1 to 34-3 shown in the following table were prepared according to a method similar to that described in example 21 using the corresponding starting compounds.

TABLE 45

Preparation example 35

To a solution of ethyl 5- (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-3-carboxylate (350mg) in ethanol (3.5ml) was added 1M aqueous sodium hydroxide solution (1.79ml), and the reaction solution was stirred at 50 ℃ for 3 hours. The reaction solution was cooled to 4 ℃, and 1M hydrochloric acid was added to acidify the solution. The mixture was extracted with a mixture of chloroform and methanol (4: 1) and washed with water. The organic layer was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 4-chloro-5- (1, 2, 4-oxadiazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridine (215mg) as a white solid.

TABLE 46

Preparation example 36

Tert-butyl REL- (1 ' R, 3 ' S, 5 ' S, 7 ' S) -5 ' H-spiro [1, 3-dioxolane-2, 2 ' -tricyclo [ 3.3.1.1-3, 7- ] decan ] -5 ' -ylcarbamate (420mg) was dissolved in tetrahydrofuran (4.2ml) and water (4.2ml), p-toluenesulfonic acid monohydrate (516mg) was added, and the mixture was stirred at 60 ℃ for 4 hours. The reaction solution was evaporated under reduced pressure and saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate), whereby tert-butyl (cis-4-oxoadamantan-1-yl) carbamate (120mg) was obtained.

The compounds in preparation 36-1 shown in the following table were prepared according to a method similar to that described in preparation 36, using the corresponding starting compounds.

Watch 47

Preparation example 37

To a reaction solution of 2- [ (1R, 2R, 4S) -bicyclo [2.2.1] hept-2-yl ] -1H-isoindole-1, 3(2H) -dione (1.4g) in tetrahydrofuran (28ml) and ethanol (28ml) was added 80% aqueous hydrazine monohydrate solution (1.1ml), and the mixture was refluxed for 3 hours. After the reaction solution was cooled to ambient temperature, insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to reduce the content of the solvent. Methylene chloride was added to the residue, and the mixture was washed with a 1M aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To the residue was added methanol, and the mixture was converted to the hydrochloride salt by adding 4M hydrochloric acid/dioxane solution, concentrated under reduced pressure, and dried to dryness to obtain (1R, 2R, 4S) -bicyclo [2.2.1] heptane-2-amine hydrochloride (0.6 g).

The compounds in preparation example 37-1 shown in the following table were prepared according to a method similar to that described in preparation example 37, using the corresponding starting compounds.

Watch 48

Preparation example 38

To a suspension of methyl (2- { [ 4-chloro-6- (methylamino) -5-vinylpyridin-3-yl ] carbonyl } hydrazino) (oxo) acetate (450mg) in tetrahydrofuran (7ml) and dioxane (7ml) was added phosphorus pentasulfide (383mg) with ice bath cooling. After stirring the mixture at ambient temperature for 5 hours, tetrahydrofuran (10ml) and phosphorus pentasulfide (190mg) were added to the reaction mixture. After stirring the mixture at ambient temperature for 2 hours, water was added to the reaction solution and the pH was adjusted to about 10 with aqueous sodium hydroxide solution and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby methyl 5- (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 3, 4-thiadiazole-2-carboxylate (90mg) was obtained.

Watch 49

Preparation example 39

The compounds in preparation examples 39-1 to 39-4 shown in the following table were prepared according to a method similar to that described in example 45 using the corresponding starting compounds.

Watch 50

Watch 50 (continuation)

Preparation example 40

To a reaction solution of 4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridine (2.26g) in tetrahydrofuran (16ml) at-78 ℃ under a nitrogen atmosphere, sec-butyllithium (14.6ml) was added dropwise. After the mixture was stirred at the same temperature for 30 minutes, a solution of benzyl chloroformate (2.1ml) in tetrahydrofuran (16ml) was added dropwise to the above reaction mixture at-78 ℃. Further, the reaction solution was stirred at-78 ℃ for 15 minutes, neutralized with a saturated aqueous ammonium chloride solution (12ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (17ml), a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (16.9ml) was added, and the mixture was stirred at ambient temperature for 3 hours. To the reaction solution were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate), whereby benzyl 4-chloro-1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (690mg) was obtained.

The compounds in preparation examples 40-1 to 40-3 shown in the following table were prepared according to a method similar to that described in preparation example 40 using the corresponding starting compounds.

Watch 51

Table 52

Preparation example	Data of
		40	1H-NMR(d6-DMSO)δ：5.40(2H，s)，6.6(1H，d，J＝1.8Hz)，7.35-7.39(3 H，m)，7.41-7.45(2H，m)，7.71(1H，d，J＝3.5Hz)，8.75(1H，s)，12.42(1H，b r).MS：(+)：297
40-1	MS：279(M+Na)+
		40-2	MS：247(M+H)+
40-3	MS：285(M-H)-

Preparation example 41

To a 100ml metal sealed tube were added a stir bar, ethyl 4- { [ (3-Exo) -8-benzyl-8-azabicyclo [3.2.1] oct-3-yl ] amino } -6-chloro-5-nicotinate (1.5g), 28% aqueous ammonia solution (4.6ml) and ethanol (7.5 ml). The tube was sealed and stirred at 90 ℃ for 2 hours. After the reaction solution was cooled, it was diluted with methanol (20ml) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to obtain ethyl 6-amino-4- { [ (3-exo) -8-benzyl-8-azabicyclo [3.2.1] oct-3-yl ] amino } -5-nicotinate (1.3g) as a yellow solid.

The compounds in preparation example 41-1 shown in the following table were prepared according to a method similar to that described in preparation example 41, using the corresponding starting compounds.

Watch 53

Preparation example 42

The compounds in preparation examples 42-1 to 42-26 shown in the following table were prepared according to a method similar to that described in example 7 using the corresponding starting compounds.

Watch 54

Watch 54 (continuation)

Watch 55

Preparation example	Data of
		42-1	MS：348(M+H)+
42-2	MS：377(M+H)+
		42-3	MS：316(M+Na)+
42-4	MS：370(M+H)+
		42-5	MS：384(M+Na)+
42-6	MS：335(M+H)+
		42-7	MS：375(M+H)+
42-8	MS：322(M+H)+
		42-9	MS：308(M+H)+
42-10	MS：314(M+Na)+
		42-11	MS：384(M+Na)+
42-12	MS：286(M+Na)+
		42-13	MS：384(M+Na)+
42-14	MS：358(M+Na)+
		42-15	MS：358(M+Na)+
42-16	MS：398(M+Na)+
		42-17	MS：404(M+Na)+
42-18	MS：412(M+Na)+
		42-19	MS：398(M+Na)+
42-20	MS：286(M+Na)+
		42-21	MS：418(M+Na)+，394(M-H)-
42-22	MS：300(M+Na)+
		42-23	MS：369(M+Na)+
42-24	MS：286(M+Na)+
		42-25	MS：346(M+H)+
42-26	MS：322(M+H)+，344(M+Na)+，320(M-H)-

Preparation example 43

The compounds in preparation 43 shown in the following table were prepared according to a method similar to that described in example 41, using the corresponding starting compounds.

Watch 56

Preparation example 44

To a solution of 4-aminoadamantan-1-ol (8.9g) in tetrahydrofuran (89ml) were added dropwise benzyloxycarbonyl chloride (7.6ml) and a 1M aqueous solution (53.4ml) of sodium hydroxide successively under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. The reaction solution was poured into an aqueous potassium hydrogensulfate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 1: 1 to 1: 3), whereby benzyl REL- [ (1R, 2S, 3S, 5S) -5-hydroxyadamantan-2-yl ] carbamate (6.2g) and benzyl REL- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] carbamate (5.3g) were obtained.

Watch 57

Preparation example 45

To a solution of (1R, 2S, 4S) -bicyclo [2.2.1] heptan-2-ol (1.0g) in tetrahydrofuran (10ml) were added phthalimide (1.4g) and triphenylphosphine (12.6g) and diethyl azodicarboxylate (1.5ml) dropwise under ice-cooling. The mixture was warmed to ambient temperature and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 100: 0 to 95: 5), whereby 2- [ (1R, 2R, 4S) -bicyclo [2.2.1] hept-2-yl ] -1H-isoindole-1, 3(2H) -dione (1.4g) was obtained as a colorless solid.

The compounds in preparation example 45-1 shown in the following table were prepared according to a method similar to that described in preparation example 45 using the corresponding starting compounds.

Watch 58

Preparation example 46

A mixture consisting of 6-chloro-4- { [ 5-methoxyadamantan-2-yl ] amino } -5-nicotinic acid ethyl ester (635mg), benzylamine (253. mu.l), diisopropylethylamine (270. mu.l) and 2-propanol (3ml) was subjected to microwave irradiation under a nitrogen atmosphere and heated at 90 ℃ for 30 minutes. After the reaction solution was cooled, the reaction solution was diluted with ethyl acetate (20ml) and poured into 1/2 saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted twice with ethyl acetate (20ml), washed with brine (30ml), dehydrated over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain ethyl 6-benzylamino-4- { [ 5-methoxyadamantan-2-yl ] amino } -5-nicotinate (550mg) as an orange solid.

The compounds in preparation example 46-1 to preparation example 46-2 shown in the following tables were prepared according to a method similar to that described in preparation example 46 using the corresponding starting compounds.

Watch 59

Preparation example 47

A solution of 4-chloro-2-methyl-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridine (525mg) in tetrahydrofuran (10ml) was cooled to-78 ℃ under a nitrogen atmosphere, and a 0.99M sec-butyllithium/cyclohexane solution (4.1ml) was added dropwise to the reaction mixture. After the mixture was stirred at-78 ℃, ethyl chloroformate (389 μ l) was added dropwise. The reaction solution was stirred at-78 ℃ for 30 minutes, saturated aqueous ammonium chloride (20ml) was added, and the temperature was allowed to rise back to ambient temperature. The reaction solution was transferred to a separatory funnel and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain ethyl 4-chloro-2-methyl-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (645mg) as a colorless viscous liquid.

The compounds of preparation 47-1 shown in the following table were prepared according to a method similar to that described in preparation 47 using the corresponding starting compounds.

Watch 60

Preparation example 48

A mixture composed of ethyl 4, 6-dichloro-5-nitronicotinate (1g), 2-amantadine hydrochloride (708mg), diisopropylethylamine (1.3ml) and 2-propanol (4ml) was subjected to microwave irradiation under a nitrogen atmosphere and heated at 90 ℃ for 10 minutes. After the reaction solution was cooled, the reaction solution was diluted with ethyl acetate (20ml) and poured into 1/2 saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted twice with ethyl acetate (20ml), washed with brine (30ml), dehydrated over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate) to obtain ethyl 4- (2-adamantylamino) -6-chloro-5-nicotinate (1.23g) as an orange solid.

The compounds in preparation examples 48-1 to 48-5 shown in the following tables were prepared according to a method similar to that described in preparation example 48 using the corresponding starting compounds.

Watch 61

Watch 61 (continuation)

Watch 62

Preparation example	Data of
		48	MS：380(M+H)+
48-1	MS：396(M+H)+
		48-2	MS：410(M+H)+
48-3	MS：445(M+H)+
		48-4	MS：377(M+H)+
48-5	MS：410(M+H)+

Preparation example 49

A mixture composed of ethyl 4, 6-dichloro-5-nitronicotinate (333mg), 4-amino-1-adamantanol (200mg), diisopropylethylamine (219. mu.l) and isopropanol (1ml) was subjected to microwave irradiation under a nitrogen atmosphere, and heated at 90 ℃ for 10 minutes. After the reaction solution was cooled, benzylamine (157. mu.l) was added to the reaction solution, and the mixture was subjected to microwave irradiation again and heated at 90 ℃ for 10 minutes. After the reaction solution was cooled, the reaction solution was diluted with ethyl acetate (20ml), and it was poured into 1/2 saturated aqueous ammonium chloride solution (20ml), extracted twice with ethyl acetate (20ml), washed with brine (30ml), dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby 6- (benzylamino) -4- [ (5-hydroxy-2-adamantyl) amino ] -nicotinic acid ethyl ester (515mg) was obtained as an orange solid.

The compounds in preparation examples 49-1 to 49-5 shown in the following tables were prepared according to a method similar to that described in preparation example 49, using the corresponding starting compounds.

Table 63

Watch 63 (continuation)

Table 64

Preparation example	Data of
		49	MS：467(M+H)+
49-1	MS：469(M+H)+
		49-2	MS：476(M+H)+
49-3	MS：467(M+H)+
		49-4
49-5	MS：527(M+H)+

Preparation example 50

The compounds in preparation example 50 shown in the following table were prepared according to a method similar to that described in example 10 using the corresponding starting compounds.

Table 65

Preparation example 51

The compound in preparation example 51 shown in the following table was prepared according to a method similar to that described in example 28 using the corresponding starting compound.

TABLE 66

Preparation example 52

To a solution of benzyl 4- [ (5-carbamoyladamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (183mg) in methanol (5ml) and 1, 4-dioxane (5ml) was added 10% palladium on charcoal (50% wet) (40mg) and hydrogenated under a hydrogen atmosphere for 5 hours. The resulting precipitate was dissolved in tetrahydrofuran and the catalyst was filtered off. The filtrate was evaporated in vacuo to give 4- [ (5-carbamoyladamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (117 mg).

The compounds in preparation example 52-1 to preparation example 52-17 shown in the following tables were prepared according to a method similar to that described in preparation example 52 using the corresponding starting compounds.

Watch 67

Watch 67 (continuation)

Table 68

Preparation example	Data of
		52-1	MS：355(M+H)+
52-2	MS：370(M+H)+
		52-3	MS：168(M+H)+.
52-4	MS：267(M+H)+
		52-5	MS：316(M+H)+
52-6	MS：313(M-H)-

Watch 68 (continuation)

Preparation example	Data of
		52-7	MS：390，392(M+H)+
52-8	MS：230，232(M+H)+
		52-9	MS：381(M+H)+

52-10	MS：221(M+H)+
		52-11	MS：284(M+H)+
52-12	MS：394(M+H)+
		52-13	MS：427(M+H)+
52-14	MS：355(M+H)+
		52-15	MS：168(M+H)+.
52-16	1H-NMR(400MHz，CDCl₃)δ：1.46(9H，s)，1.61-2.29(10H，m)，3 .33(1H，dd，J＝6.2，6.2Hz)，4.06-4.29(2H，m)MS：227(M+H)+
		52-17	MS：394(M+H)+

Preparation example 53

The compounds in preparation examples 53-1 to 53-4 shown in the following tables were prepared according to a method similar to that described in example 16 using the corresponding starting compounds.

Watch 69

Watch 70

Preparation example	Structure of the product
		53-1	MS：143(M-H)-
53-2	MS：430(M+Na)+
		53-3	MS：176(M-H)-
53-4	MS：372，374(M+H)+

Example 1

To a solution of 5- (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N-methyl-1, 3, 4-oxadiazole-2-carboxamide (18mg) in 1-methyl-2-pyrrolidone (0.18ml) at ambient temperature were added N, N-dibutyl-1-butanamine (0.046ml) and cis- (1S, 3R, 4R, 5S) -4-aminoadamantan-1-ol (32.5 mg). The mixture was rapidly heated to 150 ℃ and stirred for 2 hours. After confirming that the starting compound had been consumed, the residue was purified by silica gel column chromatography (chloroform: methanol ═ 97: 3 to 85: 15) to obtain cis-5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N-methyl-1, 3, 4-oxadiazole-2-carboxamide (19.8mg) as a white solid.

Example 2

Reacting 4-chloro-1H-pyrrolo [2, 3-b ]]A solution of pyridine-5-carboxamide (39mg) in 1-methyl-2-pyrrolidone (0.6ml), triethylamine (0.056ml) and sodium iodide (3mg) were added to 1- [ (1S, 2R, 5S) -6, 6-dimethylbicyclo [3.1.1]Hept-2-yl]Methylamine (61mg), and the mixture was stirred at 130 ℃ for 17 hours. After the reaction mixture was left to cool, N-dimethylformamide (0.3ml) and water (0.1ml) were added to the reaction mixture, and the reaction mixture was dissolved. Preparative HPLC (10mM NH) was used₄HCO₃+NH₃(pH＝9.2)∶CH₃CN 98: 2 to 30: 70) was directly purified. The active fraction was concentrated and dried to dryness, thereby obtaining 4- ({ [ (1S, 2R, 5S) -6, 6-dimethylbicyclo [3.1.1]Hept-2-yl]Methyl } amino) -1H-pyrrolo [2, 3-b]Pyridine-5-carboxamide (33.5mg) as a solid.

Example 3

To a suspension of methyl 4- (2-oxo-3, 6-dihydropyrazolo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantane-1-carboxylate (40mg) in methanol (0.4ml) and dioxane (0.4mg) was added 1M aqueous sodium hydroxide solution (0.22ml), and the suspension was refluxed for 2 hours. The temperature of the reaction solution was lowered to ambient temperature, and the pH was adjusted to 5 with 1M aqueous hydrochloric acid and a buffer solution of pH 4, and the reaction solution was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with water to give 4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantane-1-carboxylic acid (32 mg).

Example 4

4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantane-1-carboxylic acid (50mg) was suspended in N, N-dimethylformamide (1 ml). To this suspension was added successively aminoacetonitrile hydrochloride (17mg), 1-hydroxybenzotriazole (28mg), diisopropylethylamine (62 μ l) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (41mg) and the mixture was stirred at ambient temperature overnight. To the reaction solution were added ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby N- (cyanomethyl) -4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) adamantane-1-carboxamide (23mg) was obtained.

Example 5

To a solution of 3-methylbenzoic acid (22.4mg) in 1-methyl-2-pyrrolidone (0.6ml) was added 4- [ (3-exo-8-azabicyclo [3.2.1] z]Oct-3-yl) amino]-1H-pyrrolo [2, 3-b]Pyridine-5-carboxamide (42.8mg) and 1-hydroxybenzotriazole (22.3 mg). A1M solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide/1-methyl-2-pyrrolidone (0.225ml) was additionally added, and the mixture was stirred at 50 ℃ for 4 hours. After the reaction solution was cooled, it was passed through a preparative HPLC system (10mM NH)₄HCO₃ +NH₃(pH＝9.2)∶CH₃CN 98: 2 to 30: 70) directly purifying the reactionAnd (3) solution. The active fractions were concentrated and dried to dryness to obtain 4- { [ (3-exo) -8- (3-methylbenzoyl) -8-azabicyclo [3.2.1]Oct-3-yl) amino]} -1H-pyrrolo [2, 3-b]Pyridine-5-carboxamide (34.8mg) as a solid.

Example 6

To a solution of 2-aminoethanol (18.6mg) in 1-methyl-2-pyrrolidone (0.6ml) was added cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl]Amino } -1H-pyrrolo [2, 3-b)]Pyridine-5-carboxylic acid (41mg) and 1-hydroxybenzotriazole (18.6 mg). Further, a solution of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide/1-methyl-2-pyrrolidone (0.188ml) was added, and the mixture was stirred at 60 ℃ for 6 hours. After the reaction solution was cooled, it was purified by preparative HPLC (10mM NH)₄HCO₃+NH₃ (pH＝9.2)∶CH₃CN 98: 2 to 30: 70) the reaction solution was directly purified. The active fractions were concentrated and dried to dryness to obtain 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl]Amino } -N- (2-hydroxyethyl) -1H-pyrrolo [2, 3-b]Pyridine-5-carboxamide (22.9mg) as a solid.

Example 7

To a solution of ethyl 3- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-5-carboxylate (25mg) in 1-methyl-2-pyrrolidone (0.25ml) at ambient temperature was added 2-piperazin-1-ylethanol (8.5 mg). The mixture was rapidly warmed to 50 ℃ and stirred for 0.5 hour. After confirming that the starting compound had been consumed, the residue was purified by silica gel column chromatography (chloroform: methanol ═ 96: 4 to 87: 13) to obtain a yellowish white solid of cis- (1S, 3R, 4R, 5S) -4- { [5- (5- [4- (2-hydroxyethyl) piperazin-1-yl ] carbonyl } -1, 2, 4-oxadiazol-3-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (22.6 mg).

Example 8

To methylamine hydrochloride (4.7mg) in 1-methyl-2-pyrineTo a solution of pyrrolidone (0.3ml) was added cis-5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl]Amino } -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -1, 2, 4-oxadiazole-5-carboxylic acid ethyl ester (14.8mg) and diisopropylamine (0.0183ml), and the mixture was stirred at 90 ℃ for 6 hours. After the reaction solution was cooled, it was passed through a preparative HPLC system (10mM NH)₄HCO₃+NH₃ (pH＝9.2)∶CH₃CN 90: 10 to 20: 80) the reaction solution was directly purified. The active fractions were concentrated and dried to dryness to obtain 5- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl)]Amino } -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -N-methyl-1, 2, 4-oxadiazole-3-carboxamide (6.74mg) as a solid.

Example 9

To a solution of cis-5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N-piperidin-4-yl-1, 2, 4-oxadiazole-3-carboxamide dihydrochloride (20mg) in 1-methyl-2-pyrrolidone (0.25ml) at ambient temperature was added N-ethyl-N-isopropylpropan-2-amine (0.025ml) and acetic anhydride (0.043ml), and the mixture was stirred for 1 hour. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 99: 1 to 89: 11) to give cis-N- (1-acetylpiperidin-4-yl) -5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-3-carboxamide as a yellowish white solid (7.8 mg).

Example 10

To 1- (5-aminoadamantan-2-yl) -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one dihydrochloride (15mg) was added methylene chloride-methanol and a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was extracted. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was suspended in dichloromethane (7.5ml) and triethylamine (13. mu.l) and propionyl chloride (4. mu.l) were added. The mixture was stirred at ambient temperature overnight. The reaction solution was purified by NH silica gel column chromatography (chloroform: methanol) to obtain N- [4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantan-1-yl ] propionamide (2 mg).

Example 11

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (30mg) in N, N-dimethylformamide (0.21ml) was added N, N' -carbonyldiimidazole (22.3ml) and 2M dimethylamine/methanol solution (0.183ml) in this order at ambient temperature. The mixture was stirred at ambient temperature for 18 hours. To the reaction solution was added water, and the reaction solution was filtered. The solid residue was washed with water and dried. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 10: 1) to give methyl cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylate (18mg) as a pale yellow white solid.

Example 12

To a suspension of REL-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (25mg) in N, N-dimethylformamide (0.4ml) were added potassium carbonate (15.8mg) and 1-chloropropanone (0.0073ml), and the mixture was stirred at ambient temperature for 5 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol) to obtain REL-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid-2-oxopropyl ester (25mg) as a white solid.

Example 13

To a suspension of REL-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (45mg), acetamido-oxime (25.5mg), and 1-hydroxybenzotriazole (27.9mg) in N, N-dimethylformamide (1.08ml), triethylamine (0.077ml) and N- [3- (dimethylamino) propyl ] -N' -ethylcarbodiimide hydrochloride (39.5mg) were added. The mixture was stirred at 60 ℃ for 2 hours. The reaction solution was diluted with chloroform and ethanol, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol) to obtain REL- (1Z) -N' - { [ (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] oxy } ethanamidine (38.9mg) as a white powder.

Example 14

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (30mg) in N, N-dimethylformamide (0.9ml) was added N, N' -carbonyldiimidazole (83mg), N-ethyl-N-isopropylpropan-2-amine (0.018ml) and guanidine carbonate (1: 2) (82.5mg) successively at ambient temperature. Further, after adding 1-methyl-2-pyrrolidone (0.3ml), the mixture was rapidly warmed to 60 ℃ and stirred for 5 hours. The mixture was evaporated under reduced pressure and dried. The residue was purified by basic thin layer silica gel column chromatography (chloroform: methanol ═ 6: 1) to give cis-N- (diaminomethylene) -4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (18.1mg) as a pale yellow white solid.

Example 15

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (80mg) in 1-methyl-2-pyrrolidinone (0.8ml) was added (O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate) (HATU) (139mg), N-ethyl-N-isopropylpropan-2-amine (0.17ml) and semicarbazide hydrochloride (32.7mg) sequentially at ambient temperature. The mixture was stirred at ambient temperature for 3 hours. To the reaction mixture were added ethyl acetate and diisopropyl ether, and the mixture was filtered. The solid residue was washed with ethyl acetate-diisopropyl ether and dried to obtain cis-2- [ (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] semicarbazide (90mg) as a yellow-white solid.

Example 16

4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantane-1-carboxamide (70mg) was suspended in N, N-dimethylformamide (1ml), and 2, 4, 6-trichloro-1, 3, 5-triazine (37mg) was added to the resulting suspension under ice-cooling. The mixture was stirred at ambient temperature for 4 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, and the resulting solid was collected by filtration, washed with water and ethyl acetate, to give 4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantane-1-carbonitrile (30 mg).

Example 17

To a solution of 5- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-3-carboxamide (30mg) in tetrahydrofuran (1ml) was added pyridine (37. mu.l) and trifluoroacetic anhydride (64. mu.l) while cooling with ice, and the reaction mixture was stirred at ambient temperature for 30 minutes. Water was added to the reaction solution, and the precipitate was collected by filtration and dissolved in tetrahydrofuran (1 ml). To the reaction solution was added a 1M aqueous solution (0.114ml) of sodium hydroxide under ice-cooling, and the reaction solution was stirred at ambient temperature for 1 hour. The reaction solution was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10) to obtain 5- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-3-carbonitrile (5mg) as a white solid.

Example 18

Tert-butyl [4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -adamantan-1-yl ] carbamate (118mg) was suspended in dioxane (1.2 ml). 4M hydrochloric acid/dioxane (0.7ml) was added and the mixture was stirred at ambient temperature overnight. Ethyl acetate was added to the reaction solution, and the resulting solid was collected by filtration and washed with ethyl acetate, thereby obtaining 1- (5-adamantan-2-yl) -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one dihydrochloride (108 mg).

Example 19

To 3- (3, 4-dimethoxybenzyl) -N- (4-fluorobenzyl) -7- { (5-hydroxyadamantan-2-yl) amino } -3H-imidazo [4, 5-b ] pyridine-6-carboxamide (170mg) was added trifluoroacetic acid (1.7ml), and the mixture was stirred at ambient temperature overnight. The reaction solution was neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby N- (4-fluorobenzyl) -7- { (5-hydroxyadamantan-2-yl) amino } -3H-imidazo [4, 5-b ] pyridine-6-carboxamide (31mg) was obtained.

Example 20

To a solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -N- (tetrahydro-2H-pyran-2-yloxy) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (35mg) in ethanol (0.525ml) at ambient temperature was added 2M hydrochloric acid/ethanol solution (0.205 ml). The reaction solution was stirred at ambient temperature for 2 hours. To the reaction solution was added ethyl acetate, and the precipitate was collected by filtration to obtain N-hydroxy-4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide hydrochloride (18mg) as a white solid.

Example 21

To a solution of 3- { [ (triisopropylsilyl) oxy ] methyl } bicyclo [2.2.1] hept-2-yl ] -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (45mg) in tetrahydrofuran (0.15ml) was added 1M tetrabutylammonium fluoride/tetrahydrofuran solution (297. mu.l), and the mixture was stirred at ambient temperature overnight. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol) to thereby obtain 1- [3- (hydroxymethyl) bicyclo [2.2.1] hept-2-yl ] -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (14.8mg) as a white solid. To a solution of REL-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbohydrazide in 1-methyl-2-pyrrolidone (1ml) were added triethyl orthoformate (340. mu.l) and p-toluenesulfonic acid monohydrate (5.6 mg). After stirring at 120 ℃ for 30 minutes, triethyl orthoformate (340. mu.l) and p-toluenesulfonic acid monohydrate (5.6mg) were added. After the mixture was stirred at 120 ℃ for 40 minutes, the reaction solution was extracted with 20% chloroform/methanol solution and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby REL- (1S, 3R, 4S, 5S) -4- { [1- (diethoxymethyl) -5- (1, 3, 4-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (28mg) and REL- (1S, 3R, 4S, 5S) -4- { [5- (1, 3, 4-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (70mg) were obtained.

Example 22

By HPLC ((NH)₄)HCO₃Isolation of N- (cyanomethyl) -4- (2-oxo-3, 6-dihydropyrazolo [4, 5-d) from aqueous solution-aqueous ammonia solution (pH 9.2) acetonitrile)]Pyrrolo [2, 3-b]A mixture of cis and trans isomers of pyridin-1 (2H) -yl) adamantane-1-carboxylate to obtain a fraction with a shorter peak retention time (8mg) and a fraction with a longer peak retention time (15 mg).

Example 23

4- (Adamantan-1-ylamino) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (17mg) and triethylamine (15. mu.l) were dissolved in dioxane (0.5 ml). To the mixture was added diphenyl azide phosphate (DPPA) (18. mu.l) with stirring at 120 ℃. The mixture was stirred at the same temperature for 2 hours and cooled to ambient temperature. The obtained solid was collected by filtration and washed with acetonitrile to obtain (adamantan-1-yl) -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (11 mg).

Example 24

To a mixture consisting of 5, 6-diamino-4- { cis-5-hydroxy-2-adamantyl ] amino } -N-methylnicotinamide (9mg) and triethyl orthoformate (0.15ml) was added concentrated hydrochloric acid (5. mu.l), and the mixture was heated at 90 ℃ for 3 hours. After the reaction solution was cooled, the reaction solution was diluted with ethyl acetate (10ml), and a saturated aqueous sodium hydrogencarbonate solution (10ml) was added. The organic layer was extracted, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol) to give 7- { [ cis-5-hydroxyadamantan-2-yl ] amino } -N-methyl-3H-imidazo [4, 5-d ] pyridine-6-carboxamide (0.5mg) as a pale yellow solid.

Example 25

A mixture of acetic anhydride (897. mu.l) and formic acid (342. mu.l) was stirred at 60 ℃ for 2 hours. After the mixture was cooled, a solution of 4- (2-adamantylamino) -6-amino-5-nicotinamide (200mg) in dichloromethane (1ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour and at 50 ℃ for 2 hours. After the reaction mixture was cooled, it was evaporated under reduced pressure. To the residue were added ethanol (2ml), tetrahydrofuran (1ml) and water (1 ml). Subsequently, iron powder (169mg) and ammonium chloride (16mg) were added to the reaction mass. The mixture was stirred at 120 ℃ for 6 hours. After the mixture was cooled, it was evaporated under reduced pressure. To the residue was added saturated aqueous sodium hydroxide solution (10ml), and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby 7- (2-adamantylamino) -3H-imidazo [4, 5-d ] pyridine-6-carboxamide (110mg) was obtained as a white solid.

Example 26

To a mixture consisting of 6- (benzylamino) -4- { [ cis-5-hydroxyadamantan-2-yl ] amino } -5-nicotinic acid isopropyl ester (90mg), ammonium formate (236mg) and methanol was added 10% palladium-on-charcoal (50% wet) (40mg), and the mixture was stirred under reflux for 5 hours. After the reaction mixture was cooled, it was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. Triethyl orthoformate (0.6ml) and concentrated hydrochloric acid (31 μ l) were added to the residue and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (20ml), and saturated aqueous sodium hydrogencarbonate solution (20ml) was added. The organic layer was extracted, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby isopropyl REL-7- { [ (1R, 2S, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -3H-imidazo [4, 5-b ] pyridine-6-carboxylate (45mg) was obtained as a white solid.

Example 27

To a solution of 4- [ (5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (100mg) in methanol (3ml) were added hydroxylamine hydrochloride (34mg) and sodium hydrogencarbonate (82mg), and the reaction solution was stirred at 90 ℃ for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10), whereby a white solid of N '-hydroxy-4- { [ (2r, 5s) -hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (32mg) was obtained, and a white solid of N' -hydroxy-4- { [ (2s, 5r) -hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (35mg) was obtained.

Example 28

A solution of REL- (1Z) -N' - { [ (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] oxy } ethanamidine (16.2mg) in N, N-dimethylformamide (0.4mL) was stirred at 160 ℃ for 3 hours, followed by 165 ℃ for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium chloride solution, water (3 times) and brine, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 15: 1), whereby REL- (1S, 3R, 4R, 5S) -4- { [5- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (6.0mg) was obtained as orange crystals.

Example 29

To a solution of REL-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbohydrazide in 1-methyl-2-pyrrolidone (1ml) were added triethyl orthoformate (340. mu.l) and p-toluenesulfonic acid monohydrate (5.6 mg). After the mixture was stirred at 120 ℃ for 30 minutes, triethyl orthoformate (340. mu.l) and p-toluenesulfonic acid monohydrate (5.6mg) were added. After the mixture was stirred at 120 ℃ for 40 minutes, the reaction solution was extracted with 20% chloroform/methanol solution and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol) to thereby obtain REL- (1S, 3R, 4R, 5S) -4- { [1- (diethoxymethyl) -5- (1, 3, 4-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (28mg) and REL- (1S, 3R, 4R, 5S) -4- { [5- (1, 3, 4-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (70 mg).

Example 30

To a solution of N' -hydroxy-4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (45mg) in dichloromethane (0.45ml) were added pyridine (32. mu.l) and acetic anhydride (19. mu.l). The reaction solution was stirred at ambient temperature for 2 hours. Pyridine (32. mu.l) and acetic anhydride (19. mu.l) were further added to the reaction solution, and the reaction solution was stirred at 60 ℃ for 2 hours. Pyridine (0.5ml) was further added to the reaction solution, and the reaction mixture was stirred at 90 ℃ for 16 hours. The reaction solution was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10) to obtain (1s, 4r) -4- { [5- (5-methyl-1, 2, 4-oxadiazol-3-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (10mg) as a white solid.

Example 31

To a solution of N' -hydroxy-4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (25mg) in N, N-dimethylformamide (0.5ml) were added pyridine (9. mu.l) and 2-ethylhexyl chloroformate (14. mu.l) while cooling with ice. The reaction solution was stirred at ambient temperature for 2 hours. To the reaction solution was added water. The mixture was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (0.5ml) and xylene (0.5ml), and the reaction solution was stirred at 150 ℃ for 2 hours. After the reaction solution was cooled to ambient temperature, the precipitate was collected by filtration and washed with a small amount of ethyl acetate to obtain (1s, 4r) -4- (3-aminopyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-1 (6H) -yl) adamantan-1-ol (8mg) as a white solid.

Example 32

To a solution of 3- (4-chloro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N- (2-methoxyethyl) -1, 2, 4-oxadiazole-5-carboxamide (35mg) in 1-methyl-2-pyrrolidone (0.35ml) at ambient temperature were added N, N-dibutyl-1-butylamine (0.078ml) and cis- (1S, 3R, 4R, 5S) -4-aminoadamantan-1-ol (36 mg). The mixture was rapidly warmed to 190 ℃ and stirred for 1 hour. After confirming that the starting compound had been consumed, water was added to the reaction solution, and the solution was filtered. The solid residue was washed with water and dried. The solid residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 12: 1) to give cis-N- {1- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] -1, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-3-yl } -N' - (2-methoxyethyl) ethanediamide (18.1mg) as a yellowish white solid.

Example 33

To 3- (4-chloro-1H-pyrrolo [2, 3-b)]To a solution of pyridin-5-yl) -N-methyl-1, 2, 4-oxadiazole-5-carboxamide (14.2mg) in 1-methyl-2-pyrrolidone (0.142ml) were added N, N-dibutyl-1-butylamine (0.0487ml) and cis- (1S, 3R, 4R, 5S) -4-aminoadamantan-1-ol (25.7 mg). The mixture was stirred at 200 ℃ for 100 minutes using a microwave reaction system. After the reaction solution was cooled, a preparative HPLC system (10mM NH) was used₄HCO₃+NH₃(pH＝9.2)∶CH₃CN 95: 5 to 20: 80) was directly purified. The active fractions were concentrated to obtain cis-N- {1- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl]-1, 6-dihydropyrazolo [3, 4-d]Pyrrolo [2, 3-b]Pyridin-3-yl } -oxalamide (11.1mg) as a solid.

Example 34

To a suspension of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (60mg) in toluene (0.6ml) were added thiosemicarbazide (35.5mg) and trifluoroacetic acid (0.15ml), and the mixture was stirred at 70 ℃ for 6 hours. Thiosemicarbazide (35.5mg) and trifluoroacetic acid (0.15ml) were again added to the mixture, and the mixture was stirred at 90 ℃ for 51 hours. More thiosemicarbazide (17.8mg) was added, and the mixture was stirred at 90 ℃ for 48 hours. The reaction solution was basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol) to obtain (1s, 4r) -4- { [5- (5-amino-1, 3, 4-thiadiazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (8.3mg) as a white solid.

Example 35

To a solution of ethyl 5- [4- (2-oxo-3, 6-dihydroimidazo [2, 3-b ] pyridin-1 (2H) -yl) -adamantan-1-yl ] -1, 2, 4-oxadiazole-3-carboxylate (30mg) in tetrahydrofuran (1ml) was added lithium aluminum hydride (10mg) while cooling with ice, and the mixture was stirred at ambient temperature for 1 hour. To the reaction solution was added a 1M aqueous solution of sodium hydroxide. The mixture was stirred at ambient temperature for 30 minutes and extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby 1- {5- [3- (hydroxymethyl) -1, 2, 4-oxadiazol-5-yl ] adamantan-2-yl } -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (3mg) was obtained.

Example 36

To a solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (27mg) in ethanol (0.5ml) were added 10% palladium on charcoal (30mg) and 2M hydrochloric acid/ethanol solution (0.5 ml). The reaction solution was stirred at 60 ℃ for 3 hours under a hydrogen atmosphere. The catalyst was filtered off with celite, and the filtrate was concentrated under reduced pressure to give (1s, 4r) -4- { [5- (aminomethyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol trihydrochloride (37mg) as a white solid.

Example 37

To a solution of 1- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) ethanone (20mg) in tetrahydrofuran (2.5ml) at ambient temperature was added lithium aluminum hydride (19.4 mg). Further, the mixture was stirred at ambient temperature for 2 hours. After confirming that the starting compound had been consumed, water (19. mu.l), a 2M aqueous solution of sodium hydroxide (19. mu.l) and water (57. mu.l) were added to the reaction solution one after the other. The precipitated solid was removed by filtration with celite and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 4: 1), whereby (1s, 4r) -4- { [5- (1-hydroxyethyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (9.1mg) was obtained.

Example 38

To a solution of 4- { [ (3-Exo) -8- (5-nitropyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (25mg) in methanol (0.5ml) were added ammonium formate (38.6mg) and palladium on charcoal (50% wet) (1.3mg), and the mixture was heated under reflux for 5 hours. After the mixture was cooled to ambient temperature, the insoluble material was removed by celite filtration and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 4: 1), whereby 4- { [ (3-exo) -8- (5-aminopyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (12mg) was obtained.

Example 39

To a solution of N' - (5-bromoadamantan-2-yl) -4-chloro-1H-pyrrolo [2, 3-b ] pyridine-5-carbohydrazide (200mg) in 1-methyl-2-pyrrolidone (1.5ml), triethylamine (0.2ml) was added, and the reaction solution was stirred at 200 ℃ for 2 hours using a microwave reaction system. After the reaction solution was cooled, water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol), whereby 1- (5-bromoadamantan-2-yl) -1, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-3 (2H) -one (91mg) was obtained.

Example 40

To a solution of 4- { [ (2R, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (50mg) in a mixture of toluene (1.5ml) and N, N' -dimethylformamide (1.5ml) were added sodium azide (105mg) and triethylamine hydrochloride (223mg), and the mixture was stirred at 100 ℃ for 3 hours. To the reaction mixture were added sodium azide (210mg) and triethylamine hydrochloride (446mg), and the mixture was stirred at 100 ℃ for 3.5 hours. The reaction solution was diluted with a mixed solvent of dichloromethane and methanol (10: 1), and the organic layer was separated. In addition, the aqueous layer was extracted three times with a mixture of dichloromethane: methanol (═ 10: 1). The obtained organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methanol ═ 10: 1) to give REL- (1S, 3R, 4R, 5S) -4- { [5- (2H-tetrazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (35mg) as a solid.

EXAMPLE 41

To 4- [ (5-bromoadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (52mg) were added cyanoethanol (250. mu.l) and triethylamine (56. mu.l), and the mixture was stirred at 150 ℃ for 20 minutes using a microwave reaction system. The reaction solution was cooled and purified by silica gel column chromatography (chloroform: methanol). The resulting fractions were concentrated under reduced pressure and water was added. The resulting solid was collected by filtration to give 4- { [5- (2-cyanoethoxy) adamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (16 mg).

Example 42

To a solution of 4- ({5- [5- (trichloromethyl) -1, 2, 4-oxadiazol-3-yl ] -1H-pyrrolo [2, 3-b ] pyridin-4-yl } amino) adamantan-1-ol (80mg) in 1-methyl-2-pyrrolidone (1.6ml) was added an ethylamine/methanol solution (2.0M) (1.7ml) under ice-cooling. The reaction solution was stirred at ambient temperature for 5 hours. To the reaction solution were added ethyl acetate, tetrahydrofuran and water. The mixture was extracted with a mixed solvent composed of tetrahydrofuran and ethyl acetate, and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel (NH silica gel) column chromatography (chloroform: methanol ═ 100: 0 to 91: 9) to obtain 4- ({5- [5- (ethylamino) -1, 2, 4-oxadiazol-3-yl ] -1H-pyrrolo [2, 3-b ] pyridin-4-yl } amino) adamantan-1-ol (50mg) as a yellow solid.

Example 43

4- [ (5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (100mg) was dissolved in 45% aqueous HBr (0.5ml), and the mixture was refluxed for 1.5 hours. The reaction solution was cooled, and the obtained solid was collected by filtration and washed with water. The obtained solid was dissolved in methylene chloride and methanol, and purified by silica gel column chromatography (chloroform: methanol), thereby obtaining 4- [ (5-bromoadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (85 mg).

Example 44

(5-hydroxyadamantan-2-yl) -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (92mg) was suspended in dichloromethane, and diethylaminosulfur trifluoride (DAST) was added thereto. The mixture was stirred at ambient temperature for 1 hour. To this was added saturated aqueous sodium bicarbonate and ethyl acetate. The obtained solid was collected by filtration and washed with diisopropylethyl ether to obtain (5-fluoroadamantan-2-yl) -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (34 mg).

Example 45

To a solution of cis- (1S, 3R, 4R, 5S) -4- { [5- (2H-tetrazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (55mg) in 1-methyl-2-pyrrolidone (0.65ml) were added N-ethyl-N-isopropylpropan-2-amine (0.11ml) and iodomethane (0.015ml) at ambient temperature and the mixture was stirred for 4 hours at ambient temperature. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 99: 1 to 90: 10) to obtain cis- (1S, 3R, 4R, 5S) -4- { [5- (2-methyl-2H-tetrazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (19.5mg) (the Rf value obtained when TLC (chloroform-methanol ═ 10: 1) was used was large) as a main product, and cis- (1S, 3R, 4R, 5S) -4- { [5- (1-methyl-1H-tetrazol-5-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (4.5mg) as a sub-product was obtained (the Rf values obtained with TLC (10: 1 in chloroform-methanol) were small) and both the major and minor products were obtained as yellowish white solids.

Example 46

To 2-chloronicotinonitrile (56.7mg) and 4- [ (3-exo) -8-azabicyclo [3.2.1] z]Oct-3-ylamino]-1H-pyrrolo [2, 3-b]To a solution of pyridine-5-carboxamide (58.4mg) in 1-methyl-2-pyrrolidone (0.6ml) were added triethylamine (0.057ml) and sodium iodide (3mg), and the mixture was stirred at 130 ℃ for 10 hours. After the reaction mixture was allowed to cool, 1-methyl-2-pyrrolidone (0.3ml) was added to the reaction mixture, thereby dissolving the reaction mixture. By preparative HPLC (10mM NH)₄HCO₃+NH₃ (pH＝9.2)∶CH₃CN 98: 2 to 60: 40) the mixture was directly purified. The active fractions were concentrated and dried to dryness to obtain 4- { [ (3-Exo) -8- (3-cyanopyridin-2-yl) -8-azabicyclo [3.2.1 [ ] -]Oct-3-yl]Amino } -1H-pyrrolo [2, 3-b)]Pyridine-5-carboxamide (10.1mg) as a solid.

Example 47

To a solution of 4- { [ (3-exo-8- (5-aminopyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (11mg) in methanol/dichloromethane was added aqueous formalin (0.022ml), and the mixture was stirred at ambient temperature for 0.5 hour, sodium triacetoxyborohydride (30.9mg) was further added, and the mixture was stirred at ambient temperature for 16 hours, to the reaction solution was added saturated aqueous sodium bicarbonate solution, and the mixture was stirred at ambient temperature for 30 minutes, followed by extraction with chloroform-methanol, the extract was concentrated, and the obtained yellow oily substance was purified with a thin-layer chromatography (chloroform: methanol ═ 7: 1) silica gel column, thus, 4- { [ (3-Exo) -8- (5- (dimethylamino) pyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (5.2mg) was obtained as a slightly yellowish white solid.

Example 48

To a solution of 4- [ (3-endo) -8-azabicyclo [3.2.1] oct-3-ylamino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide dihydrochloride (25mg) in 1, 3-dimethyl-2-imidazolidinone (0.5ml) was added triethylamine (0.029 ml). Further, methanesulfonyl chloride (0.0059ml) was added while cooling with ice. After stirring the mixture at ambient temperature for 1 hour, dilute aqueous sodium bicarbonate solution was added and the mixture was stirred. The precipitated white solid was collected by filtration, washed with water, and dried to obtain 4- { [ (3-endo) -8- (methanesulfonyl) -8-azabicyclo [3.2.1] oct-3-yl ] amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (14.1mg) as a white solid.

Example 49

To a solution of 1- [ (3-exo) -8-azabicyclo [3.2.1] oct-3-yl ] -3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-2 (1H) -one (12mg) in N, N-dimethylacetamide (0.48ml) and N, N-dimethylformamide (0.24ml) were added N-ethyl-N-isopropylpropan-2-amine (0.015ml) and 6-chloronicotinonitrile (11.7 mg). The mixture was rapidly heated to 90 ℃ and stirred for 12 hours. After confirming that the starting compound had been consumed, the reaction solution was evaporated under reduced pressure and dried. The solid residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 8: 1) to give 6- [ (3-exo) -3- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) -8-azabicyclo [3.2.1] oct-8-yl ] nicotinonitrile (5.2mg) as a yellowish white solid.

Example 50

To a solution of ethyl 3- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 2, 4-oxadiazole-5-carboxylate (80mg) in tetrahydrofuran (3.2ml) was added a 3M solution of magnesium methyliodide/diethyl ether (0.315ml) under ice-cooling, and the reaction solution was stirred at ambient temperature for 16 hours. To the reaction solution was further added a 3M solution of methyl magnesium iodide/diethyl ether (0.189ml) under ice-cooling. The reaction solution was stirred at ambient temperature for 16 hours. Water was added to the reaction solution under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To the reaction solution were added chloroform and a saturated aqueous ammonium chloride solution. The mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10) to obtain REL- [ (1S, 3R, 4R, 5S) -4- ({5- [5- (1-hydroxy-1-methylethyl) -1, 2, 4-oxadiazol-3-yl ] -1H-pyrrolo [2, 3-b ] pyridin-4-yl } amino) adamantan-1-ol (15mg) as a white solid.

Example 51

To a solution of 4- { [ (3-Exo) -8- (5-bromopyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (22.2mg) in N, N-dimethylformamide (0.67ml) and 1, 3-dimethyl-2-imidazolidinone (0.67ml) was added tetrakis (triphenylphosphine) palladium (O) (5.8mg) and dicyano zinc (17.7 mg). The reaction was carried out at 160 ℃ for 1 hour using a microwave reaction system. Dichloromethane was added to the reaction solution, and the mixture was filtered. The solid residue was washed with dichloromethane and dried. The solid residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 8: 1) to give 4- { [ (3-exo) -8- (5-cyanopyrimidin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (15mg) as a slightly yellowish white solid.

Example 52

To a solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (30mg) in tetrahydrofuran (0.6ml) was added diisobutylaluminum hydride (0.99M in toluene) (0.49ml) at 5 deg.C. The mixture was stirred at 5 ℃ for 2 hours and continued to stir at ambient temperature for 3 hours. To the reaction solution was added 6M aqueous hydrochloric acid (0.09ml) at 5 ℃. The mixture was stirred at ambient temperature for 0.5 h. Solid sodium hydroxide (23.3mg) and magnesium sulfate were added and the mixture was stirred at ambient temperature for 0.5 h. Insoluble material was removed by celite filtration and washed with tetrahydrofuran. The filtrate was evaporated under reduced pressure and purified by thin layer silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbaldehyde (18mg) as a yellowish white solid.

Example 53

To a solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbaldehyde (20mg) in ethanol (0.6ml) were added pyridine (0.052ml) and O-methylhydroxylamine hydrochloride (32.1mg), and the mixture was heated under reflux conditions for 6 hours. After the reaction solution was cooled to room temperature, it was evaporated under reduced pressure, dried, and purified by thin layer silica gel column chromatography (chloroform: methanol ═ 10: 1), to obtain a yellowish white solid of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbaldehyde O-methyloxime (11 mg).

Example 54

To acetic acid (0.8ml) were added pyrrolidine (0.013ml) and paraformaldehyde (5.72mg), and the mixture was stirred at 60 ℃ for 5 minutes. To the reaction solution was added cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (40.0mg) at 60 deg.C, and the mixture was stirred at 60 deg.C for 2 hours. The reaction solution was evaporated under reduced pressure, and toluene and N-ethyl-N-isopropylpropan-2-amine were added to make the mixture azeotropic. The solid residue was purified by NH thin layer silica gel column chromatography (chloroform: methanol ═ 10: 1) to obtain a yellowish white solid of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -3- (pyrrolidin-1-ylmethyl) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (10.8 mg).

Example 55

To a solution of 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carbaldehyde (40mg) in tetrahydrofuran (1ml) was added methyl (triphenylphosphine) acetate (56mg), and the reaction solution was stirred at 80 ℃ for 16 hours. Methyl (triphenylphosphine) acetate (43mg) was further added to the reaction solution, and the reaction solution was stirred at 90 ℃ for 3 hours. Methyl (triphenylphosphine) acetate (129mg) was added again to the reaction solution, and the reaction solution was stirred at 90 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10) to obtain methyl (2E) -3- (4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) acrylate (7mg) as a yellow solid.

Example 56

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (50mg) in N, N-dimethylformamide (0.6ml) at ambient temperature was added 1-chloro-2, 5-pyrrolidinedione (18.4 mg). After stirring the mixture at ambient temperature for 2 hours, water was added to the reaction solution, and the solution was filtered. The solid residue was washed with water and dried. The solid residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 4: 1) to obtain a slightly yellowish white solid of cis-3-chloro-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (5 mg).

Example 57

To a solution of N' -hydroxy-4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamidine (30mg) in acetic acid (0.5ml) was added acetic anhydride (11. mu.l), and the reaction solution was stirred at ambient temperature for 30 minutes. To the reaction solution was added 10% palladium-charcoal (10mg), and the mixture was stirred under a hydrogen atmosphere at 50 ℃ for 3 hours. After the reaction solution was cooled to room temperature, the catalyst was removed by celite filtration. The filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile with stirring. The precipitate was collected by filtration to give 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxyamidine acetate (20mg) as a yellow solid.

Example 58

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (30mg) in 1-methyl-2-pyrrolidone (0.18ml) at ambient temperature was added pyridine hydrochloride (10.6 mg). The reaction was allowed to proceed at 200 ℃ for 1 hour using a microwave reaction system. To the reaction solution was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, followed by washing with water. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 10: 1) to give cis- { [ (1S, 3R, 4R, 5S) -4- (1H-pyrrolo [2, 3-b ] pyridin-4-ylamino) adamantan-1-ol (14.1mg) as a yellowish white solid.

Example 59

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxylic acid (30mg) in N, N-dimethylformamide (0.1ml), N' -carbonyldiimidazole (29.7mg) was added, and the mixture was stirred at 60 ℃ for 0.5 hour. To the reaction mixture was added methanesulfonamide (17.4mg) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.027 ml). After the reaction solution was stirred at 60 ℃ for 3 hours again, it was concentrated under reduced pressure. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 4: 1) to obtain a slightly yellowish white solid of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -N- (methylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (7.8 mg).

Example 60

To a solution of cis-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (75mg) in tetrahydrofuran (0.5ml) and methanol (0.375ml) at ambient temperature was added 1, 1-dimethoxy-N, N-dimethylmethylamine (1.54 ml). After stirring the mixture under heating at reflux for 1 hour, the reaction mixture was cooled to ambient temperature and stirred for 1 hour. The precipitated solid was collected by filtration, washed and dried to obtain cis-N- [ (dimethylamino) methylene ] -4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide (70mg) as a white solid.

Example 61

A solution of cis-2- [ (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) carbonyl ] semicarbazide (30mg) in a mixture of xylene (0.45ml) and acetic acid (0.45ml) was stirred at 120 ℃ for 3 hours. Further, 1-methyl-2-pyrrolidone (0.45ml) was added, and the mixture was stirred at 150 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure and dried. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 10: 1), whereby cis-5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (5.6mg) (Rf value obtained when TLC (chloroform-methanol ═ 10: 1) was used was large) was obtained as a product, and cis-5- (4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -1, 3, 4-oxadiazol-2 (3H) -one (8.9mg) (lower Rf values obtained by TLC (chloroform-methanol 10: 1) and these products were obtained as yellowish white solids.

Example 62

To a solution of ethyl 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxyiminocarboxylate trihydrochloride (75mg) in ethanol (1ml) was added 1, 2-ethylenediamine (0.11ml), and the reaction solution was stirred at 120 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (chloroform: methanol ═ 100: 0 to 95: 5), whereby (1s, 4r) -4- { [5- (4, 5-dihydro-1H-imidazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (17mg) was obtained as a white solid.

Example 63

To a solution of ethyl 4- { [ (2r, 5s) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxyimidate trihydrochloride (150mg) in ethanol (1.5ml) were added 2-aminoethanol (78. mu.l) and triethylamine (0.225ml), and the reaction solution was stirred at 110 ℃ for 2 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol 100: 0 to 90: 10). The obtained solid was washed with ethyl acetate under stirring and collected by filtration to obtain (1s, 4r) -4- { [5- (4, 5-dihydro-1, 3-oxazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol (5mg) as a white solid.

Example 64

4- [ (5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carbonitrile (200mg) and Raney's nickel were added to ethanol (5ml), and the reaction solution was stirred under a hydrogen atmosphere at 60 ℃ for 8 hours. The catalyst was filtered off with celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (3ml) and 1M aqueous sodium hydroxide solution (0.65ml) was added. Di-tert-butyl dicarbonate (0.22ml) was added to the reaction solution at ambient temperature, and the mixture was stirred for 16 hours. The reaction solution was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 100: 0 to 90: 10) to give tert-butyl ({4- [ (5-hydroxyadamantan-2-yl) amino ] -1H-pyrrolo [2, 3-b ] pyridin-5-yl } methyl) carbamate (40mg) as a pale yellow solid.

The compounds shown in table 71 below were prepared according to the methods of preparation described above, methods well known to those skilled in the art, or variations of these methods. Tables 71 and 72 show the structure and physicochemical data for the compounds described in the above examples, and also show the methods of making these compounds.

Watch 71

Watch 71 (continuation)

Watch 72

Examples	Reference to the examples	Data of
			1	-	1H-NMR(400MHz，d6-DMSO)δ：1.44-2.38(10H，m)，2.85(3 H，d，J＝4.8Hz)，4.23(1H，m)，4.53(1H，s)，6.58(1H，m)，7.27(1H ，m)，8.58(1H，s)，8.78(1H，m)，9.25(1H，m)，11.79(1H，s).MS：4 09(M+H)+
2	-	MS：313(M+H)+
			3	-	1H-NMR(400MHz，d6-DMSO)δ：1.52-2.46(11H，m)，2.63-2 .72(2H，m)，4.49-4.53(1H，m)，6.31-6.35(1H，m)，7.42-7.45(1 H，m)，7.89-7.90(1H，m)，10.75-10.77(1H，m)，11.55-11.58(1 H，m)，12.10(1H，br).MS：353(M+H)+
4	-	1H-NMR(400MHz，d6-DMSO)δ：1.51-2.13(8H，m)，2.18-2. 47(3H，m)，2.65-2.76(2H，m)，4.02-4.13(2H，m)，4.50-4.55(1 H，m)，6.34-6.39(1H，m)，7.44-7.46(1H，m)，7.90(1H，s)，8.14- 8.39(1H，m)，10.77-10.78(1H，m)，11.58(1H，s).MS：391(M+ H)+
			5	-	MS：404(M+H)+
6	-	MS：371(M+H)+
			7	-	MS：508(M+H)+
8	-	MS：409(M+H)+
			9	-	MS：542(M+Na)+
10	-	1H-NMR(400MHz，d6-DMSO)δ：1.38-2.77(18H，m)，4.38-4 .54(1H，m)，6.29-6.35(1H，m)，7.25-7.37(1H，m)，7.42-7.45(1 H，m)，7.89-7.90(1H，m)，10.75(1H，br)，11.57(1H，s).MS：380( M+H)+
			11	-	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.29(9H，m)，3.83(3 H，s)，4.10(1H，m)，4.56(1H，s)，6.50(1H，m)，7.18(1H，m)，8.55( 1H，s)，9.27(1H，m)，11.68(1H，s).MS：342(M+H)+
12	-	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.54(2H，m)，1.58-1. 73(4H，m)，1.73-1.86(4H，m)，2.05-2.12(1H，m)，2.17(3H，s)，2 .21-2.29(2H，m)，4.08-4.16(1H，m)，4.56(1H，s)，4.99(2H，s)，6. 48-6.55(1H，m)，7.18-7.24(1H，m)，8.63(1H，s)，9.12(1H，d，J＝ 7.8Hz)，11.74(1H，s).MS：384(M+H)+
			13	-	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.53(2H，m)，1.57-1. 74(4H，m)，1.74-1.90(4H，m)，1.80(3H，s)，2.04-2.12(1H，m)，2 .20-2.29(2H，m)，4.06-4.14(1H，m)，4.56(1H，s)，6.45(2H，brs) ，6.47-6.52(1H，m)，7.14-7.19(1H，m)，8.76(1H，s)，9.41(1H，d， J＝8.0Hz)，11.64(1H，s).MS：384(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			14	-	MS：369(M+H)+
15	-	MS：383(M-H)-
			16	-	1H-NMR(400MHz，d6-DMSO)δ：1.57-1.63(2H，m)，1.95-2. 09(3H，m)，2.17-2.24(2H，m)，3.31-3.71(6H，m)，4.62(1H，s)，6 .38-6.40(1H，m)，7.44(1H，t，J＝3.0Hz)，7.90(1H，s)，10.80(1H， s)，11.58(1H，s).MS：334(M+H)+
17	-	1H-NMR(400MHz，d6-DMSO)δ：1.51-1.56(2H，m)，1.63-1. 74(4H，m)，1.83-1.91(4H，m)，2.09-2.13(1H，m)，2.30-2.34(2 H，m)，4.22-4.25(1H，m)，4.58(1H，s)，6.62(1H，d，J＝3.6Hz)，7.3 1(1H，d，J＝3.6Hz)，8.50(1H，d，J＝7.6Hz)，8.66(1H，s)，12.00(1 H，brs).MS：399(M+Na)+
			18	-	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.48(10H，m)，2.72-2 .85(2H，m)，4.61(1H，s)，6.44-6.61(1H，m)，7.64-7.71(1H，m)， 8.02-8.35(4H，m)，11.59-11.64(1H，m)，12.51-12.53(1H，m). MS：324(M+H)+
19	-	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.48(2H，m)，1.59-1. 74(6H，m)，1.79-1.85(2H，m)，2.02-2.07(1H，m)，2.16-2.20(2 H，m)，4.45-4.48(3H，m)，4.97(1H，d，J＝7.4Hz)，7.13-7.19(2H， m)，7.36-7.40(2H，m)，8.06(1H，s)，8.48(1H，s)，8.89(1H，t，J＝5. 9Hz)，9.62.MS：436(M+H)+
			20	-	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.56(2H，m)，1.62-1. 72(4H，m)，1.77-1.88(4H，m)，2.08-2.11(1H，m)，2.24-2.28(2 H，m)，3.56(1H，m)，4.15-4.20(1H，m)，6.67-6.69(1H，m)，7.36- 7.38(1H，m)，8.28(1H，s)，9.40(1H，br)，10.36-10.41(1H，m)，1 1.55(1H，s)，12.53(1H，brs)，14.29(1H，br).MS：343(M-HCl+ H)+
21	-	1H-NMR(400MHz，d6-DMSO)δ：0.86-1.37(3H，m)，1.58-1. 69(2H，m)，2.20-2.24(1H，m)，2.41-2.51(2H，m)，2.77-2.80(1 H，m)，2.90(1H，s)，3.03-3.05(1H，m)，4.29-4.35(2H，m)，6.63( 1H，s)，7.43(1H，s)，7.87(1H，s)，10.7(1H，s)，11.6(1H，s).MS：29 9(M+H)+
			22	-	1H-NMR(400MHz，d6-DMSO)δ：1.68-1.93(6H，m)，2.02-2. 13(3H，m)，2.40-2.47(2H，m)，2.71-2.75(2H，m)，4.04(2H，d，J ＝5.5Hz)，4.50(1H，s)，6.34-6.36(1H，m)，7.45(1H，t，J＝3.0Hz)， 7.90(1H，s)，8.16(1H，t，J＝5.6Hz)，10.77(1H，s)，11.59(1H，s). MS：391(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			23	-	1H-NMR(400MHz，d6-DMSO)δ：1.71-1.89(6H，m)，2.21-2. 25(3H，m)，2.53-2.56(6H，m)，6.63(1H，s)，7.46(1H，t，J＝3.2Hz )，7.90(1H，s)，10.77(1H，s)，11.61(1H，s).MS：309(M+H)+
24	-	MS：342(M+H)+
			25	-	MS：312(M+H)+
26	-	1H-NMR(400MHz，d6-DMSO)δ：1.33(6H，d，J＝6.2Hz)，1.46 -1.86(10H，m)，2.06(1H，brs)，2.22(2H，brs)，4.54(1H，s)，5.05( 1H，d，J＝8.8Hz)，5.18-5.15(1H，m)，8.12(1H，s)，8.63(1H，s)，9. 16(1H，d，J＝8.8Hz)，13.0(1H，brs).MS：371(M+H)+
			27	-	1H-NMR(400MHz，d6-DMSO)δ：1.41-1.45(2H，m)，1.59-1. 62(2H，m)，1.65-1.70(2H，m)，1.74-1.79(2H，m)，1.88-1.92(2 H，m)，2.05-2.09(1H，m)，2.18-2.21(2H，m)，4.02-4.05(1H，m)， 4.32(1H，s)，5.82(2H，brs)，6.41-6.42(1H，m)，7.09-7.11(1H，m )，8.13(1H，s)，8.96(1H，d，J＝8.1Hz)，9.50(1H，s)，11.23(1H，brs ).MS：342(M+H)+
28	-	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.57(2H，m)，1.57-1. 78(4H，m)，1.78-1.97(4H，m)，2.05-2.14(1H，m)，2.26-2.34(2 H，m)，2.44(3H，s)，4.17-4.24(1H，m)，4.53(1H，s)，6.56-6.61(1 H，m)，7.24-7.28(1H，m)，8.58(1H，s)，9.10(1H，d，J＝7.8Hz)，11. 82(1H，brs).MS：366(M+H)+
			29	-	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.32(13H，m)，4.20-4 .22(1H，m)，4.55(1H，s)，6.55-6.57(1H，m)，7.25-7.27(1H，m)， 8.49(1H，s)，8.79(1H，d，J＝8.0Hz)，9.27(1H，s)，11.73(1H，brs). MS：374(M+Na)+
30	-	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.52(2H，m)，1.62-1. 64(2H，m)，1.68-1.73(2H，m)，1.81-1.91(4H，m)，2.09-2.11(1 H，m)，2.28-2.31(2H，m)，2.67(3H，s)，4.19-4.22(1H，m)，4.53( 1H，s)，6.53-6.54(1H，m)，7.22-7.24(1H，m)，7.88(1H，d，J＝7.8 Hz)，8.69(1H，s)，11.61(1H，brs).MS：366(M+H)+
			31	-	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.49(2H，m)，1.62-1. 64(2H，m)，1.74-1.79(2H，m)，1.98-2.03(4H，m)，2.15-2.18(1 H，m)，3.00-3.03(2H，m)，4.45(1H，brs)，4.61(1H，brs)，5.77(2H ，s)，6.35-6.37(1H，m)，7.33-7.35(1H，m)，8.14(1H，s)，11.44(1 H，brs).MS：324(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			32	-	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.60(13H，m)，3.27(3 H，s)，3.37-3.49(4H，m)，4.44(1H，m)，4.77(1H，s)，6.66(1H，m)， 7.46(1H，m)，8.71(1H，s)，8.98(1H，m)，10.92(1H，s)，12.08(1H ，s).MS：453(M+H)+
33	-	MS：409(M+H)+
			34	-	1H-NMR(400MHz，d6-DMSO)δ：1.42-1.51(2H，m)，1.58-1. 75(4H，m)，1.76-1.95(4H，m)，2.05-2.13(1H，m)，2.25-2.32(2 H，m)，4.11-4.19(1H，m)，4.50(1H，brs)，6.49-6.54(1H，m)，7.1 7-7.22(1H，m)，7.24(2H，s)，8.06(1H，s)，9.70(1H，d，J＝7.6Hz)， 11.57(1H，s).MS：383(M+H)+
35	-	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.49(10H，m)，2.72-2 .80(2H，m)，4.49-4.56(2H，m)，4.60-4.67(1H，m)，5.64-5.71(1 H，m)，6.34-6.39(1H，m)，7.42-7.47(1H，m)，7.89-7.92(1H，m)， 8.62(1H，s)，10.77-10.83(1H，m)，11.55-11.61(1H，m).MS：40 7(M+H)+
			36	-	1H-NMR(400MHz，d6-DMSO)δ：1.32-1.87(12H，m)，2.09(1 H，m)，2.08(2H，m)，4.18-4.22(1H，m)，4.68(1H，m)，6.70-6.71( 1H，m)，7.09(1H，s)，7.25(1H，s)，7.37-7.39(1H，m)，8.32(1H，s) ，10.32(1H，m)，12.68(1H，brs).MS：313(M-3HCl+H)+
37	-	MS：328(M+H)+
			38	-	MS：378(M+H)+
39	-	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.63(2H，m)，1.86-2. 56(10H，m)，2.77-2.85(1H，m)，4.91(1H，s)，6.64-6.66(1H，m)， 7.36-7.38(1H，m)，8.50(1H，s)，10.82(1H，s)，11.93-11.95(1H， m).MS：387，389(M+H)+
			40	-	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.53(2H，m)，1.64-2. 01(8H，m)，2.11(1H，s)，2.32(2H，s)，4.21(1H，d，J＝7.5Hz)，4.56 (2H，s)，6.58(1H，s)，7.26(1H，s)，8.61(1H，s)，9.86(1H，brs)，11. 77(1H，s) .MS：350(M-H)-
41	-	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.60(2H，m)，1.68-1. 77(4H，m)，1.78-1.86(2H，m)，1.90-1.98(2H，m)，2.12-2.16(1 H，m)，2.25-2.30(2H，m)，2.68(2H，t，J＝6.0Hz)，3.57(2H，t，J＝6. 0Hz)，4.08(1H，d，J＝7.8Hz)，6.46(1H，dd，J＝2.0，3.6Hz)，7.04(1 H，br)，7.13(1H，dd，J＝2.6，3.6Hz)，7.80(1H，br)，8.38(1H，s)，10 .17(1H，d，J＝8.2Hz)，11.47(1H，s).MS：380(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			42	-	1H-NMR(400MHz，d6-DMSO)δ：1.21(3H，t，J＝7.2Hz)，1.41- 2.34(13H，m)，3.33-3.42(2H，m)，4.12-4.18(1H，m)，4.50(1H，s )，6.48-6.51(1H，m)，7.17-7.21(1H，m)，8.02(1H，brd，J＝7.6Hz )，8.42(1H，brt，J＝5.6Hz)，8.58(1H，s)，11.51(1H，brs).MS：395 (M+H)+
43	-	1H-NMR(400MHz，d6-DMSO)δ：1.58-1.69(2H，m)，1.86-1. 96(2H，m)，2.04-2.11(1H，m)，2.14-2.23(2H，m)，2.34-2.44(4 H，m)，2.61-2.71(2H，m)，4.38-4.42(1H，m)，6.63-6.67(1H，m)， 7.25(1H，s)，7.35(1H，br)，8.05(1H，br)，10.58(1H，s)，10.58(1H ，s)，11.94(1H，s).MS：389，391(M+H)+
			44	-	1H-NMR(400MHz，d6-DMSO)δ：1.72-2.04(9H，m)，2.29-2. 91(4H，m)，4.42-4.45(1H，m)，6.37(1H，d，J＝3.5Hz)，7.44(1H， d，J＝3.5Hz)，7.90(1H，s)，10.80(1H，br，s)，11.58(1H，s).MS：32 7(M+H)+
45	-	MS：366(M+H)+
			46	-	MS：388(M+H)+
47	-	MS：406(M+H)+
			48	-	1H-NMR(400MHz，d6-DMSO)δ：1.84-1.97(2H，m)，1.97-2. 17(4H，m)，2.19-2.34(2H，m)，2.96(3H，s)，4.12-4.24(2H，m)，4 .30-4.40(1H，m)，6.44-6.51(1H，m)，7.04(1H，br)，7.08-7.15(1 H，m)，7.81(1H，br)，8.38(1H，s)，10.22(1H，d，J＝7.6Hz)，11.47( 1H，s).MS：364(M+H)+
49	-	MS：386(M+H)+
			50	-	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.53(2H，m)，1.62-1. 65(2H，m)，1.64(6H，s)，1.69-1.74(2H，m)，1.81-1.93(4H，m)，2 .08-2.12(1H，m)，2.29-2.32(2H，m)，4.19-4.23(1H，m)，4.53(1 H，s)，6.07(1H，s)，6.53-6.55(1H，m)，7.22-7.24(1H，m)，7.87-7. 90(1H，m)，8.72(1H，s)，11.62(1H，brs).MS：410(M+H)+

51	-	MS：389(M+H)+
			52	-	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.47(9H，m)，3.17(1 H，m)，4.10(1H，m)，4.58(1H，s)，6.51(1H，m)，7.21(1H，m)，8.22 (1H，s)，9.79(1H，s)，9.90(1H，m)，11.84(1H，s) .MS：312(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			53	-	1H-NMR(400MHz，d6-DMSO)δ：1.48-2.33(8H，m)，3.90(3 H，s)，4.15(1H，m)，4.51(1H，s)，6.48(1H，m)，7.17(1H，m)，7.90( 1H，s)，8.43(1H，s)，8.46(1H，m)，11.50(1H，s) .MS：341(M+H)+
54	-	MS：410(M+H)+
			55	-	1H-NMR(400MHz，d6-DMSO)δ：1.37-1.48(2H，m)，1.57-1. 91(8H，m)，2.04-2.08(1H，m)，2.24-2.33(2H，m)，3.71(3H，s)，3 .99-4.02(1H，m)，4.50(1H，s)，5.85-5.87(1H，m)，6.34-6.38(1 H，m)，6.43-6.46(1H，m)，7.14-7.17(1H，m)，7.93-7.98(1H，m)， 8.20(1H，s)，11.49(1H，brs) .MS：368(M+H)+
56	-	MS：361(M+H)+
			57	-	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.45(2H，m)，1.59-1. 61(2H，m)，1.64-1.70(2H，m)，1.73-1.79(2H，m)，1.85-1.91(5 H，m)，2.05-2.08(1H，m)，2.20-2.23(2H，m)，4.01-4.04(1H，m)， 4.42-4.52(1H，m)，6.44(1H，d，J＝3.6Hz)，7.12(1H，d，J＝3.6Hz) ，8.15(1H，s)，10.05(1H，br)，11.38(1H，brs).MS：326(M-AcO H+H)+
58	-	MS：284(M+H)+
			59	-	MS：427(M+Na)+，403(M-H)-
60	-	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.27(7H，m)，3.12(3 H，s)，3.18(3H，s)，4.07(1H，m)，4.46(1H，s)，6.44(1H，m)，7.09( 1H，m)，8.58(1H，s)，9.08(1H，s)，10.56(1H，m)，11.45(1H，s).M S：382.3(M+H)+
			61	-	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.69(13H，m)，4.19(1 H，m)，4.53(1H，s)，6.54(1H，m)，7.25(1H，m)，8.43(1H，s)，8.75( 1H，m)，11.68(1H，s).MS：367.3(M+H)，365.0(M-H)-
62	-	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.45(2H，m)，1.59-1. 70(4H，m)，1.75-1.81(2H，m)，1.90-1.95(2H，m)，2.06-2.09(1 H，m)，2.20-2.23(2H，m)，3.35(2H，m)，3.89(2H，t，J＝9.6Hz)，4. 04-4.08(1H，m)，4.43(1H，br)，6.44(1H，d，J＝3.6Hz)，6.87(1H， brs)，7.10(1H，d，J＝3.5Hz)，8.21(1H，s)，10.97(1H，d，J＝7.8Hz)， 11.34(1H，brs).MS：352(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			63	-	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.48(2H，m)，1.60-1. 63(2H，m)，1.66-1.72(2H，m)，1.77-1.83(2H，m)，1.87-1.92(2 H，m)，2.06-2.10(1H，m)，2.22-2.26(2H，m)，4.05(2H，t，J＝9.0H z)，4.09-4.13(1H，m)，4.32(2H，t，J＝9.0Hz)，4.47(1H，s)，6.47-6 .49(1H，m)，7.15-7.17(1H，m)，8.34(1H，s)，9.98(1H，d，J＝7.8H z)，11.49(1H，brs).MS：353(M+H)+
64	-	1H-NMR(400MHz，d6-DMSO)δ：1.02-1.05(4H，m)，1.37-1. 41(9H，m)，1.53-1.67(5H，m)，1.74-1.85(2H，m)，2.01-2.23(5 H，m)，4.11-4.18(2H，m)，6.29-6.36(1H，m)，7.09-7.13(1H，m)， 7.28-7.32(1H，m)，7.64-7.65(1H，m)，11.11(1H，brs).MS：413 (M+H)+
			65	1	MS：431(M+H)+
66	1	MS：341(M+H)+
			67	1	1H-NMR(400MHz，d6-DMSO)δ：1.81-2.02(8H，m)，2.09-2. 62(5H，m)，4.15-4.20(1H，m)，6.43-6.46(1H，m)，7.09(1H，br)， 7.14-7.16(1H，m)，7.86(1H，br)，8.40(1H，s)，10.25(1H，d，J＝8. 2Hz)，11.50(1H，s).MS：336(M+H)+
68	1	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.60(2H，m)，1.86-1. 97(3H，m)，1.99-2.03(2H，m)，2.08-2.15(4H，m)，2.27-2.35(2 H，m)，4.27(1H，d，J＝7.6Hz)，6.50-6.52(1H，m)，6.99(1H，br)，7. 14(1H，t)，7.81(1H，s)，8.38(1H，s)，10.17(1H，d，J＝8.3Hz)，11.4 8(1H，s).MS：336(M+H)+
			69	1	MS：534(M+H)+，532(M-H)-
70	1	MS：376(M+H)+
			71	1	MS：402(M+H)+
72	1	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.43(2H，m)，1.62-1. 72(4H，m)，1.79-1.89(4H，m)，2.02-2.09(1H，m)，2.11-2.17(2 H，m)，2.75(3H，d，J＝4.3Hz)，4.09-4.16(1H，m)，4.49(1H，brs)， 6.39-6.41(1H，m)，7.11-7.15(1H，m)，8.18-8.25(1H，m)，8.30( 1H，s)，9.87(1H，d，J＝8.3Hz)，11.42(1H，brs).MS：341(M+H)+
			73	1	MS：341(M+H)+
74	1	MS：355(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			75	1	1H-NMR(400MHz，d6-DMSO)δ：1.44-2.27(9H，m)，2.76(3 H，d，J＝4.4Hz)，4.23(1H，m)，6.48(1H，m)，7.14(1H，m)，8.25(1 H，m)，8.32(1H，s)，9.87(1H，m)，11.45(1H，s).MS：343(M+H)+
76	1	MS：355(M+H)+
			77	1	MS：440(M+H)+
78	1	1H-NMR(400MHz，d6-DMSO)δ：1.43-2.36(8H，m)，1.63(6 H，s)，4.22(1H，m)，4.54(1H，s)，5.90(1H，s)，6.55(1H，m)，7.25( 1H，m)，8.50(1H，s)，8.80(1H，m)，11.72(1H，s).MS：410(M+H) +
			79	1	MS：382(M+H)+，380(M-H)-
80	1	MS：417(M+Na)+，395(M+H)+
			81	1	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.48(2H，m)，1.60-1. 68(4H，m)，1.76-1.85(4H，m)，2.06-2.08(1H，m)，2.29-2.31(2 H，m)，4.13-4.15(1H，m)，4.53-4.54(1H，m)，5.99(1H，d，J＝7.0 Hz)，6.68(1H，d，J＝3.6Hz)，7.28(1H，d，J＝3.6Hz)，8.11(1H，s)，1 1.86(1H，brs).MS：331(M+Na)+
82	1	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.43(2H，m)，1.64-1. 69(4H，m)，1.83-1.88(4H，m)，2.05-2.07(1H，m)，2.21-2.23(2 H，m)，4.25-4.27(1H，m)，4.52(1H，brs)，6.04(1H，d，J＝7.2Hz)， 6.68(1H，d，J＝3.5Hz)，7.28(1H，d，J＝3.4Hz)，8.10(1H，s)，11.85 (1H，brs).MS：309(M+H)+
			83	1	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.55(2H，m)，1.62-1. 73(4H，m)，1.79-1.89(4H，m)，2.08-2.12(1H，m)，2.28-2.32(2 H，m)，4.24-4.28(1H，m)，6.68-6.71(1H，m)，7.39-7.41(1H，m)， 8.42(1H，s)，8.44-8.48(1H，m)，12.48(1H，brs).MS：368(M+H )+
84	1	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.57(2H，m)，1.81-1. 87(2H，m)，1.92-2.00(5H，m)，2.04-2.09(2H，m)，2.18-2.24(2 H，m)，3.62(3H，s)，4.30-4.33(1H，m)，6.16(1H，d，J＝7.1Hz)，6.7 2(1H，d，J＝3.4Hz)，7.28(1H，d，J＝3.3Hz)，8.11(1H，s)，11.85(1 H，brs).MS：373(M+Na)+
			85	1	1H-NMR(400MHz，d6-DMSO)δ：1.70-1.75(2H，m)，1.78-1. 91(5H，m)，1.94-2.02(2H，m)，2.04-2.12(2H，m)，2.19-2.26(2 H，m)，3.60(3H，s)，4.25-4.28(1H，m)，6.19(1H，d，J＝7.1Hz)，6.7 0-6.72(1H，m)，7.27-7.29(1H，m)，8.10(1H，s)，11.85(1H，brs). MS：373(M+Na)+
86	1	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.53(2H，m)，1.63-1. 74(4H，m)，1.81-1.91(4H，m)，2.08-2.11(1H，m)，2.21(3H，s)，2 .29-2.36(4H，m)，2.39-2.42(2H，m)，3.49-3.53(2H，m)，3.66-3. 70(2H，m)，4.19-4.23(1H，m)，4.49(1H，s)，6.57-6.59(1H，m)，7 .27-7.29(1H，m)，8.64(1H，s)，8.83-8.86(1H，m)，11.86(1H，brs ).MS：478(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			87	1	1H-NMR(400MHz，d6-DMSO)δ：1.46-1.52(2H，m)，1.61-1. 81(8H，m)，2.05-2.08(1H，m)，2.20-2.24(2H，m)，4.09-4.12(1 H，m)，4.53(1H，s)，6.63-6.65(1H，m)，6.82-6.86(1H，m)，7.30- 7.32(1H，m)，8.65(1H，s)，10.52-10.56(1H，m)，11.80(1H，brs). MS：352(M+H)+
88	1	1H-NMR(400MHz，d6-DMSO)δ：0.85-0.93(1H，m)，1.34，1. 40(9H，s)，1.47-1.53(1H，m)，1.67-1.79(1H，m)，1.85-1.92(3H ，m)，1.99-2.06(3H，m)，2.13-2.34(4H，m)，4.21-4.25，4.30-4.3 4(1H，m)，6.37-6.41，6.54-6.56(1H，m)，6.51-6.63，6.57-6.59( 1H，m)，7.28-7.29(1H，m)，8.06-8.32(2H，m)，8.63，8.64(1H，s)， 8.87-8.89，8.99-9.01(1H，m)，11.88(1H，brs).MS：516(M+Na )+
			89	1	1H-NMR(400MHz，d6-DMSO)δ：1.31-1.36(1H，m)，1.47-1. 53(3H，m)，1.59-1.64(1H，m)，1.67-1.80(2H，m)，1.89-2.00(3 H，m)，2.06-2.11(1H，m)，2.16-2.20(2H，m)，3.02-3.09(2H，m)， 4.27-4.44(2H，m)，6.52-6.54，6.61-6.63(1H，m)，7.26-7.29(1 H，m)，8.10-8.31(2H，m)，8.63(1H，s)，8.92-8.95，9.04-9.07(1H ，m)，11.86(1H，brs).MS：431(M+Na)+
90	1	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.53(2H，m)，1.62-1. 73(4H，m)，1.81-1.92(4H，m)，2.09-2.12(1H，m)，2.29-2.32(2 H，m)，3.46(3H，s)，4.20-4.24(1H，m)，4.54(1H，s)，4.86(2H，s)， 6.54-6.56(1H，m)，7.24-7.25(1H，m)，7.84-7.86(1H，m)，8.72( 1H，s)，11.65(1H，s).MS：396(M+H)+
			91	1	1H-NMR(400MHz，d6-DMSO)δ：0.74-0.88(1H，m)，1.13-1. 75(7H，m)，2.10-2.30(2H，m)，4.27-4.44(1H，m)，6.55(1H，brs) ，6.56(1H，d，J＝3.4Hz)，7.11(1H，m)，7.65(1H，d，J＝3.4Hz)，8.3 5(1H，s)，9.86(1H，d，J＝7.9Hz)，11.43(1H，brs).MS：271(M+H )+

92

1

1H-NMR(400MHz，d6-DMSO)δ：1.75-2.33(5H，m)，2.97-3. 36(5H，m)，3.73-3.88(1H，m)，4.38-4.64(1H，m)，6.63(1H，d，J ＝3.4Hz)，7.17(1H，brs)，7.23(1H，d，J＝3.4Hz)，7.92(1H，brs)，8. 44(1H，s)，10.25(1H，d，J＝7.8Hz)，11.68(1H，s).MS：286(M+H )+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			93	1	1H-NMR(400MHz，d6-DMSO)δ：1.29-2.02(5H，m)，2.41(1 H，dd，J＝3.8，13.8Hz)，2.65-2.83(4H，m)，4.05-4.20(1H，m)，4. 36(1H，t，J＝5.1Hz)，6.51-6.58(1H，m)，6.88-7.94(3H，m)，8.37( 1H，s)，9.99(1H，d，J＝7.9Hz)，11.46(1H，brs).MS：286(M+H)+
94	1	1H-NMR(400MHz，d6-DMSO)δ：1.12-1.65(7H，m)，1.82-1. 97(1H，m)，2.25-2.34(2H，m)，3.85-3.96(1H，m)，6.57(1H，d，J ＝3.3Hz)，7.12(1H，d，J＝2.4Hz)，6.78-7.92(2H，brs)，8.35(1H，s )，9.57(1H，d，J＝7.1Hz)，11.5(1H，brs).MS：271(M+H)+
			95	1	1H-NMR(400MHz，d6-DMSO)δ：1.17-1.64(10H，m)2.0-2.0 7(1H，m)，2.18-2.22(1H，m)，2.38-2.40(1H，m)，3.18-3.23(1H， m)，4.14(1H，t，J＝7.8Hz)，4.25(2H，q，J＝7.0Hz)，4.46(1H，t，J＝4 .8Hz)，7.17(1H，s)，6.70(1H，s)，8.51(1H，s)，8.78(1H，d，J＝8.0H z)，11.7(1H，s).MS：330(M+H)+
96	1	1HNMR(400MHz，d6-DMSO)δ：1.38-1.86(10H，m)，2.07(1 H，brs)，2.19(2H，brs)，2.29(3H，s)，3.97(1H，d，J＝8.0Hz)，4.49( 1H，s)，6.14(1H，s)，6.98(1H，brs)，7.78(1H，brs)，8.28(1H，s)，9. 99(1H，d，J＝8.0Hz)，11.3(1H，s).MS：341(M+H)+
			97	1	1HNMR(400MHz，CDCl3)δ：1.35-2.67(13H，m)，3.75(1H，br s)，4.05-4.20(1H，m)，5.00-5.12(1H，brs)，6.45-6.48(1H，m)，7. 15-7.16(1H，m)，7.95(1H，d，J＝4.7Hz)，10.0(1H，brs)..MS：302 (M+H)+
98	1	1HNMR(400MHz，d6-DMSO)δ：1.40-2.30(13H，m)，3.92-3. 96(1H，m)，4.44(1H，s)，5.27-5.29(1H，m)，6.51(1H，dd，J＝2.0， 3.2Hz)，7.21(1H，dd，J＝2.8，3.2Hz)，7.88(1H，d，J＝4.8Hz)，11.3 (1H，s).MS：302(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			99	1	1H-NMR(400MHz，d6-DMSO)δ：1.13-1.40(3H，m)，1.48-1. 63(3H，m)，1.93-2.00(1H，m)，2.14-2.18(1H，m)，2.35-2.38(1 H，m)，3.12-3.20(1H，m)，3.41-3.47(1H，m)，4.04-4.10(1H，m)， 4.38-4.41(1H，m)，6.61-6.65(1H，m)，6.81-7.03(1H，br)，7.09- 7.13(1H，m)，7.61-7.86(1H，br)，8.33(1H，s)，9.64(1H，d，J＝8.0 Hz)，11.45(1H，brs).MS：301(M+H)+.
100	1	1H-NMR(400MHz，d6-DMSO)δ：1.38-2.28(12H，m)，2.87-2 .98(1H，m)，3.63(3H，s)，4.45-4.57(1H，m)，6.42-6.45(1H，m)， 6.80-7.13(1H，br)，7.18-7.22(1H，m)，7.51-7.93(1H，br)，8.34( 1H，s)，9.44(1H，d，J＝8.0Hz)，11.49(1H，brs).MS：357(M+H)+
			101	1	1H-NMR(400MHz，d6-DMSO)δ：1.33(3H，t，J＝8.0Hz)，1.47- 1.51(2H，m)，1.61-1.72(4H，m)，1.78-1.85(4H，m)，2.07-2.10( 1H，m)，2.23-2.27(2H，m)，4.09-4.12(1H，m)，4.30(2H，q，J＝8.0 Hz)，4.56(1H，brs)，6.48-6.50(1H，m)，7.17-7.19(1H，m)，8.56( 1H，s)，9.28(1H，d，J＝7.6Hz)，11.69(1H，brs).MS：356(M+H)+
102	1	1H-NMR(400MHz，d6-DMSO)δ：1.32(3H，t，J＝6.8Hz)，1.43- 1.50(2H，m)，1.65-1.73(4H，m)，1.78-1.90(4H，m)，2.06-2.10( 1H，m)，2.16-2.21(2H，m)，4.19-4.23(1H，m)，4.29(2H，q，J＝6.8 Hz)，4.54(1H，brs)，6.45-6.46(1H，m)，7.18-7.20(1H，m)，8.56( 1H，s)，9.26(1H，d，J＝8.0Hz)，11.68(1H，brs).MS：356(M+H)+
			103	1	1H-NMR(400MHz，d6-DMSO)δ：1.38-1.48(2H，m)，1.59-1. 70(4H，m)，1.73-1.86(4H，m)，2.03-2.09(1H，m)，2.11-2.16(1 H，m)，2.18-2.23(1H，m)，3.258(1.5H，s)，3.263(1.5H，s)，3.53( 1.5H，s)，3.54(1.5H，s)，4.00-4.05(0.5H，m)，4.10-4.15(0.5H， m)，4.50(0.5H，brs)，4.52(0.5H，brs)，6.42-6.45(0.5H，m)，6.46 -6.48(0.5H，m)，7.16-7.19(1H，m)，7.89(0.5H，d，J＝8.4Hz)，7.9 4(0.5H，d，J＝8.4Hz)，8.15-8.16(1H，m)，11.52(1H，brs).MS：37 1(M+H)+.
104	1	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.24(13H，m)，4.31-4 .33(1H，m)，4.52(1H，s)，6.52-6.53(1H，m)，7.25-7.27(1H，m)， 8.49(1H，s)，8.76(1H，d，J＝8.0Hz)，9.25(1H，s)，11.72(1H，s).M S：352(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			105	1	1H-NMR(400MHz，d6-DMSO)δ：1.51-2.17(13H，m)，3.07-3 .08(2H，m)，4.31-4.32(1H，m)，4.40-4.42(1H，m)，6.50-6.51(1 H，m)，7.24-7.25(1H，m)，8.49(1H，s)，8.84(1H，d，J＝8.0Hz)，9.2 5(1H，s)，11.71(1H，s).MS：366.3(M+H)+
106	1	1H-NMR(400MHz，d6-DMSO)δ：1.13-2.19(13H，m)，2.97-3 .00(2H，m)，3.82-3.83(1H，m)，4.31-4.40(1H，m)，6.57-6.58(1 H，m)，7.26-7.27(1H，m)，8.48(1H，s)，8.78(1H，d，J＝8.0Hz)，9.2 4-9.25(1H，m)，11.70(1H，s).MS：366(M+H)+
			107	1	1H-NMR(400MHz，d6-DMSO)δ：1.51-2.31(13H，m)，4.17-4 .18(1H，m)，4.58(1H，brs)，6.56(1H，d，J＝3.4Hz)，7.22(1H，d，J＝ 2.7Hz，7.50-7.57(5H，m)，8.06(1H，s)，10.58(1H，d，J＝7.9Hz)， 11.82(1H，brs).MS：388(M+H)+.
108	1	1H-NMR(400MHz，d6-DMSO)δ：0.88-2.26(13H，m)，4.10-4 .11(1H，m)，4.58(1H，brs)，4.60(2H，s)，4.82(2H，s)，6.51-6.52( 1H，s)，7.17-7.18(1H，s)，7.30-7.38(5H，m)，10.52(1H，d，J＝7.9 Hz)，11.76(1H，brs).MS：432(M+H)+
			109	1	1H-NMR(400MHz，d6-DMSO)δ：1.48-2.25(13H，m)，3.36(3 H，s)，4.10-4.12(1H，m)，4.57(1H，s)，4.69(2H，s)，6.51-6.52(1 H，m)，7.16-7.18(1H，m)，8.49(1H，s)，10.51(1H，d，J＝8.0Hz)，1 1.76(1H，brs).MS：356(M+H)+
110	1	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.25(14H，m)，4.10(1 H，d，J＝7.9Hz)，5.48(2H，s)，6.51-6.53(1H，m)，6.92-6.99(3H， m)，7.18(1H，brs)，7，28-7.30(2H，m)，8.65(1H，s)，10.44(1H，d， J＝7.9Hz)，11.8(1H，s).MS：418(M+H)+
			111	1	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.19(13H，m)，4.21-4 .23(1H，m)，4.51(1H，s)，4.59(2H，s)，4.80(2H，s)，6.46-6.48(1 H，m)，7.17-7.18(1H，m)，7.29-7.37(6H，m)，10.45(1H，d，J＝8.0 Hz)，11.73(1H，s).MS：432(M+H)+
112	1	1H-NMR(400MHz，d6-DMSO)δ：1.23-2.33(13H，m)，2.99-3 .11(2H，m)，4.21(1H，brs)，4.40-4.41(1H，m)，4.59(2H，s)，4.79 (2H，s)，6.51(1H，brs)，7.16-7.37(6H，m)，8.51(1H，s)，10.50(1 H，d，J＝8.0Hz)，11.72(1H，s).MS：446(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			113	1	1H-NMR(400MHz，d6-DMSO)δ：1.47-2.33(13H，m)，3.53-3 .75(2H，m)，4.16-4.17(1H，m)，4.40(1H，s)，4.87(1H，s)，6.19-6. 20(1H，m)，6.82(1H，s)，7.21-7.22(1H，m)，9.80(1H，d，J＝8.0Hz )，11.64(1H，s).MS：398(M+H)+
114	1	1H-NMR(400MHz，d6-DMSO)δ：1.49-1.52(2H，m)，1.62(6 H，s)，1.64-2.31(11H，m)，4.19-4.20(1H，m)，4.54(1H，s)，6.27( 1H，s)，6.53(1H，brs)，7.20-7.22(1H，m)，8.30(1H，s)，9.80(1H， d，J＝8.0Hz)，11.64(1H，brs).MS：426(M+H)+
			115	1	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.32(13H，m)，2.82(3 H，d，J＝4.8Hz)，4.27-4.28(1H，m)，4.52(1H，s)，6.55-6.57(1H， m)，7.22-7.23(1H，m)，8.83(1H，m)，9.31-9.32(1H，m)，9.82-9. 83(1H，m)，11.76(1H，s).MS：424.9(M-H)-
116	1	1H-NMR(400MHz，d6-DMSO)δ：1.27-2.77(24H，m)，3.75-3 .77(1H，m)，4.24-4.25(1H，m)，4.53(1H，s)，6.55-6.56(1H，m)， 7.23-7.24(1H，m)，8.38(1H，s)，9.24(1H，d，J＝8.0Hz)，9.80(1H， d，J＝7.6Hz)，11.77(1H，brs).MS：508(M+H)+
			117	1	1H-NMR(400MHz，d6-DMSO)δ：1.55-1.61(2H，m)，1.71-1. 75(2H，m)，1.81-2.05(10H，m)，4.16-4.21(1H，m)，6.40-6.43(1 H，m)，6.81-7.06(1H，br)，7.10-7.13(1H，m)，7.53-7.91(1H，br) ，8.37(1H，s)，10.17(1H，d，J＝8.0Hz)，11.44(1H，brs).MS：311( M+H)+.
118	1	1H-NMR(400MHz，d6-DMSO)δ：1.64-1.74(6H，m)，2.02-2. 15(9H，m)，6.66-6.69(1H，m)，6.96-7.13(1H，br)，7.15-7.18(1 H，m)，7.66-7.93(1H，br)，8.33(1H，s)，9.70(1H，brs)，11.45(1H， brs).MS：311(M+H)+.
			119	1	1H-NMR(400MHz，d6-DMSO)δ：1.37-1.43(2H，m)，1.91-2. 10(11H，m)，3.77-3.81(1H，m)，4.68-4.70(1H，m)，6.67-6.70(1 H，m)，6.92-7.14(1H，br)，7.16-7.19(1H，m)，7.66-7.91(1H，br) ，8.33(1H，s)，9.68(1H，brs)，11.45(1H，brs).MS：349(M+Na)+.

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			120	1	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.66(6H，m)，1.88-1.95( 6H，m)，2.21-2.26(2H，m)，4.63(1H，brs)，6.63-6.66(1H，m)，6.93- 7.15(1H，br)，7.17-7.20(1H，m)，7.70-7.91(1H，br)，8.34(1H，s)，9. 70(1H，brs)，11.46(1H，brs).MS：349(M+Na)+.
121	1	1H-NMR(400MHz，d6-DMSO)δ：1.38-1.44(2H，m)，1.63-1.71( 4H，m)，1.80-1.87(4H，m)，2.02-2.07(1H，m)，2.12-2.16(2H，m)，4 .11-4.15(1H，m)，4.50(1H，brs)，6.39-6.41(1H，m)，6.90-7.05(1H ，br)，7.11-7.14(1H，m)，7.70-7.83(1H，br)，8.37(1H，s)，10.09(1H， d，J＝8.0Hz)，11.45(1H，brs).MS：327(M+H)+
			122	1	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.50(2H，m)，1.58-1.71( 4H，m)，1.76-1.86(4H，m)，2.06-2.10(1H，m)，2.21-2.25(2H，m)，4 .05-4.10(1H，m)，4.54(1H，brs)，6.51-6.53(1H，m)，7.08-7.26(2H ，m)，7.88-8.03(1H，br)，8.42(1H，s)，10.43-10.51(1H，m)，11.80(1 H，s).MS：327(M+H)+.
123	1	1H-NMR(400MHz，d6-DMSO)δ：1.41-1.48(0.8H，m)，1.49-1.5 6(1.2H，m)，1.65-1.97(8H，m)，2.08-2.16(1H，m)，2.17-2.23(0.8 H，m)，2.23-2.28(1.2H，m)，4.05-4.11(0.6H，m)，4.15-4.20(0.4H， m)，6.44-6.48(1H，m)，6.87-7.11(1H，br)，7.11-7.15(1H，m)，7.66 -7.91(1H，br)，8.37(0.4H，s)，8.38(0.6H，s)，10.12(0.4H，d，J＝8.4H z)，10.14(0.6H，d，J＝8.4Hz)，11.45(1H，brs).MS：341(M+H)+.
			124	1	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.51(1H，m)，1.68-1.96( 8H，m)，2.01-2.31(3H，m)，2.33-2.40(1H，m)，4.06-4.12(0.5H，m) ，4.21-4.28(0.5H，m)，6.45-6.53(1H，m)，6.88-7.20(2H，m)，7.65- 7.95(1H，br)，8.38(0.5H，s)，8.39(0.5H，s)，10.10(0.5H，d，J＝8.4H z)，10.18(0.5H，d，J＝8.4Hz)，11.48(1H，brs).MS：329(M+H)+.
125	1	1H-NMR(400MHz，d6-DMSO)δ：1.41-1.48(2H，m)，1.69-1.78( 4H，m)，1.82-1.98(4H，m)，2.08-2.13(1H，m)，2.17-2.23(2H，m)，3 .15(3H，s)，4.15-4.20(1H，m)，6.44-6.47(1H，m)，6.86-7.10(1H，b r)，7.11-7.15(1H，m)，7.62-7.91(1H，br)，8.37(1H，s)，10.12(1H，d， J＝8.4Hz)，11.45(1H，brs).MS：341(M+H)+.

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			126	1	1H-NMR(400MHz，d6-DMSO)δ：1.49-1.56(2H，m)，1.64-1.75( 4H，m)，1.77-1.95(4H，m)，2.10-2.15(1H，m)，2.23-2.28(2H，m)，3 .12(3H，s)，4.05-4.11(1H，m)，6.44-6.48(1H，m)，6.89-7.10(1H，b r)，7.11-7.15(1H，m)，7.61-7.93(1H，br)，8.38(1H，s)，10.14(1H，d )，11.45(1H，brs).MS：341(M+H)+.
127	1	1H-NMR(400MHz，d6-DMSO)δ：1.68-1.76(4H，m)，1.79-1.89( 4H，m)，2.01-2.09(2H，m)，2.19-2.25(1H，m)，2.32-2.38(2H，m)，4 .06-4.12(1H，m)，6.45-.6.49(1H，m)，6.91-7.18(2H，m)，7.65-7.9 2(1H，br)，8.39(1H，s)，10.18(1H，d，J＝8.4Hz)，11.48(1H，brs).MS ：351(M+Na)+.
			128	1	1H-NMR(400MHz，d6-DMSO)δ：1.06(3H，t，J＝8.0Hz)，1.53-1. 59(2H，m)，1.68-1.75(4H，m)，1.80-1.94(4H，m)，2.10-2.14(1H， m)，2.24-2.28(2H，m)，3.42(2H，q，J＝8.0Hz)，4.08-4.13(1H，m)，6. 51-6.53(1H，m)，7.12-7.31(2H，m)，7.83-8.03(1H，br)，8.42(1H，s )，10.43(1H，d，J＝8.0Hz)，11.74(1H，brs).MS：355(M+H)+.
129	1	1H-NMR(400MHz，d6-DMSO)δ：1.53-2.20(13H，m)，3.58-3.6 4(3H，m)，4.19-4.29(1H，m)，6.54-6.58(1H，m)，7.19-7.47(2H，m )，7.96-8.16(1H，br)，8.46(1H，s)，10.65-10.72(1H，m)，11.98(1H， brs).MS：369(M+H)+.
			130	1	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.49(2H，m)，1.82-1.94( 6H，m)，2.12-2.29(5H，m)，4.22-4.26(1H，m)，6.47-.6.50(1H，m)， 6.86-7.17(2H，m)，7.66-7.93(1H，br)，8.38(1H，s)，10.10(1H，d，J＝ 8.0Hz)，11.47(1H，brs).MS：329(M+H)+.
131	1	1H-NMR(400MHz，d6-DMSO)δ：1.32-1.39(1H，m)，1.63-1.90( 8H，m)，1.98-2.14(2H，m)，2.30-2.37(1H，m)，3.76-3.80(1H，m)，4 .18-4.23(1H，m)，4.96-5.00(1H，m)，6.34-.6.38(1H，m)，6.61-7.0 9(2H，m)，7.21-7.72(1H，br)，8.23(1H，s)，10.03(1H，d，J＝8.0Hz)， 11.33(1H，brs).MS：327(M+H)+.

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			132	1	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.83(7H，m)，1.87-2.09( 4H，m)，2.19-2.25(1H，m)，3.88-3.92(1H，m)，4.53-4.58(1H，m)，4 .97-5.00(1H，m)，6.75-6.78(1H，m)，6.80-7.14(2H，m)，7.59-7.89 (1H，br)，8.35(1H，s)，10.17(1H，d，J＝8.0Hz)，11.39(1H，brs).MS： 327(M+H)+.
133	1	1H-NMR(400MHz，d6-DMSO)δ：1.17-1.57(7H，m)，1.87-1.91( 1H，m)，2.27-2.30(2H，m)，3.90(1H，m)，6.57-6.58(1H，m)，6.88-7 .15(1H，brs)，7.11-7.13(1H，m)，7.60-7.90(1H，brs)，8.35(1H，s)，9 .57(1H，d，J＝3.6Hz)，11.45(1H，s).MS：271(M+H)+
			134	1	1H-NMR(400MHz，d6-DMSO)δ：0.12-0.15(2H，m)，0.40-0.44( 2H，m)，0.89-0.92(2H，m)，1.49-1.72(8H，m)，1.81-1.91(4H，m)，2 .10(1H，s)，2.30(1H，s)，4.12(1H，s)，4.21(1H，d，J＝7.5Hz)，4.54(1 H，s)，6.53-6.57(2H，brs)，6.55(1H，s)，7.24(1H，m)，7.89(1H，d，J＝ 7.7Hz)，8.72(1H，s)，11.63(1H，s).MS：435(M+H)+
135	1	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.91(15H，m)，2.10(1H， s)，2.30(2H，s)，2.70(2H，d，J＝5.7Hz)，3.58-3.63(1H，m)，3.72-3.7 7(1H，m)，3.88-3.91(1H，m)，4.12(2H，s)，4.21(1H，d，J＝7.6Hz)，4. 54(1H，s)，6.54(1H，d，J＝1.7Hz)，7.23-7.24(1H，m)，7.89(1H，d，J＝ 7.6Hz)，8.72(1H，s)，11.62(1H，s).MS：465(M+H)+，487(M+Na) +
			136	1	1H-NMR(400MHz，d6-DMSO)δ：1.24-1.33(2H，m)，1.48-1.51( 2H，m)，1.64-1.72(4H，m)，1.79-1.91(6H，m)，2.10(1H，s)，2.30(2 H，s)，2.66(1H，brs)，2.72-2.77(1H，m)，3.26-3.33(2H，m)，3.81-3. 85(2H，m)，4.13(2H，s)，4.21(1H，d，J＝7.5Hz)，4.54(1H，s)，6.54-6. 55(1H，m)，7.23-7.24(1H，m)，7.90(1H，d，J＝7.8Hz)，8.71(1H，s)， 11.63(1H，s).MS：465(M+H)+
137	1	1H-NMR(400MHz，d6-DMSO)δ：0.90(1H，m)，1.48-1.51(2H， m)，1.63(2H，s)，1.69-1.72(2H，m)，1.82-1.91(4H，m)，2.10(1H，s) ，2.30(2H，s)，2.79-2.82(2H，m)，3.25(3H，s)，3.41-3.44(2H，m)，4. 11(2H，s)，4.20(1H，d，J＝7.5Hz)，4.54(1H，s)，6.54(1H，m)，7.23-7. 24(1H，m)，7.89(1H，d，J＝7.8Hz)，8.71(1H，s)，11.63(1H，s).MS：4 39(M+H)+，461(M+Na)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			138	1	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.52(2H，m)，1.63(2H，s )，1.69-1.72(2H，m)，1.82-1.92(4H，m)，2.10(1H，s)，2.30(2H，s)，2 .70-2.73(2H，m)，3.49-3.50(2H，m)，4.12(2H，s)，4.22(1H，d，J＝7. 5Hz)，4.55(2H，s)，6.55(1H，s)，7.24(1H，s)，7.89(2H，d，J＝7.8Hz)， 8.72(1H，s)，11.63(1H，s).MS：425(M+H)+，447(M+Na)+
139	2	MS：343(M+H)+
			140	2	MS：343(M+H)+
141	2	MS：364(M+H)+
			142	2	MS：300(M+H)+
143	2	MS：388(M+H)+
			144	3	1H-NMR(400MHz，d6-DMSO)δ：1.47-2.46(11H，m)，2.64-2.8 2(2H，m)，4.47-4.69(1H，m)，6.33-6.39(1H，m)，7.41-7.50(1H，m )，7.89-7.94(1H，m)，10.77-10.83(1H，m)，11.59(1H，s).MS：421( M+H)+
145	3	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.46(2H，m)，1.58-1.68( 4H，m)，1.72-1.78(2H，m)，1.83-1.89(2H，m)，2.04-2.09(1H，m)，2 .29-2.33(2H，m)，3.99-4.03(1H，m)，4.52(1H，brs)，5.74-5.77(1H ，m)，6.26(1H，d，J＝15.7Hz)，6.43-6.45(1H，m)，7.16-7.18(1H，m)， 7.87(1H，d，J＝15.7Hz)，8.16(1H，s)，11.47(1H，brs)，12.12(1H，br) .MS：354(M+H)+
			146	3	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.62(4H，m)，1.69-1.78( 2H，m)，1.90-1.99(2H，m)，2.09-2.14(2H，m)，2.19-2.26(2H，m)，2 .77-2.88(1H，m)，4.47-4.59(1H，m)，6.43-6.47(1H，m)，6.85-7.10 (1H，br)，7.20-7.23(1H，m)，7.57-7.90(1H，br)，8.34(1H，s)，9.45( 1H，d，J＝8.0Hz)，11.49(1H，brs)，12.12(1H，brs).MS：343(M+H) +.
147	3	MS：328(M+H)+
			148	3	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.55(2H，m)，1.58-1.75( 4H，m)，1.77-1.93(4H，m)，2.05-2.13(1H，m)，2.22-2.29(2H，m)，4 .09-4.16(1H，m)，4.60(1H，s)，6.61(1H，d，J＝3.5Hz)，7.27(1H，d，J ＝3.5Hz)，8.63(1H，s)，11.83-12.00(1H，m)，12.08(1H，brs)，13.43 (1H，br).MS：396(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			149	3	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.50(2H，m)，1.61-1.71( 4H，m)，1.77-1.86(4H，m)，2.06-2.10(1H，m)，2.23-2.27(2H，m)，4 .06-4.11(1H，m)，4.54(1H，brs)，6.46-6.50(1H，m)，7.15-7.18(1H ，m)，8.52(1H，s)，9.50(1H，brs)，11.61(1H，brs)，12.36(1H，brs).M S：350(M+Na)+.
150	3	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.49(2H，m)，1.65-1.73( 4H，m)，1.78-1.91(4H，m)，2.05-2.10(1H，m)，2.16-2.21(2H，m)，4 .18-4.24(1H，m)，4.54(1H，brs)，6.47-6.50(1H，m)，7.20-7.22(1H ，m)，8.54(1H，s)，9.65(1H，d，J＝8.0Hz)，11.76(1H，brs)，12.69(1H， brs).MS：328(M+H)+.
			151	3	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.15(13H，m)，4.12-4.2 0(1H，m)，6.42-6.46(1H，m)，6.87-7.15(2H，m)，7.63-7.91(1H，br )，8.37(1H，s)，10.14-10.23(1H，m)，11.45(1H，brs)，12.13(1H，brs ).MS：355(M+H)+.
152	4	1H-NMR(400MHz，d6-DMSO)δ：1.50-2.75(15H，m)，3.21-3.7 2(2H，m)，4.48-4.54(1H，m)，6.33-6.39(1H，m)，7.43-7.46(1H，m )，7.75-8.01(2H，m)，10.76-10.78(1H，m)，11.58(1H，s).MS：405( M+H)+
			153	4	1H-NMR(400MHz，d6-DMSO)δ：1.69-1.77(2H，m)，1.83-1.92( 4H，m)，2.03-2.12(3H，m)，2.39-2.48(2H，m)，2.70-2.75(2H，m)，3 .59(2H，d，J＝5.6Hz)，4.49(1H，s)，6.34-6.36(1H，m)，6.99(1H，s)，7 .12(1H，s)，7.42-7.45(2H，m)，7.90(1H，s)，10.76(1H，s)，11.57(1 H，s).MS：409(M+H)+
154	4	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.57(2H，m)，1.83-1.89( 2H，m)，1.95-2.03(3H，m)，2.20-2.28(2H，m)，2.38-2.46(2H，m)，2 .63-2.70(2H，m)，3.63(2H，d，J＝5.8Hz)，4.54(1H，s)，6.39-6.40(1 H，m)，6.95-7.25(3H，m)，7.45(1H，t，J＝3.0Hz)，7.90(1H，s)，10.77 (1H，br)，11.57(1H，s).MS：409(M+H)+
			155	4	1H-NMR(400MHz，d6-DMSO)δ：1.57-2.73(13H，m)，3.20-3.2 8(3H，m)，4.36-4.39(2H，m)，4.51-4.59(1H，m)，6.30-6.38(1H，m )，7.41-7.46(1H，m)，7.89-7.90(1H，m)，10.72-10.87(1H，m)，11.5 3-11.61(1H，m).MS：405(M+H)+
156	4	1H-NMR(400MHz，d6-DMSO)δ：1.20-1.56(2H，m)，1.80-2.16( 7H，m)，2.31-2.45(2H，m)，2.65-2.78(2H，m)，3.54-3.60(2H，m)，4 .45-4.54(1H，m)，6.27-6.37(1H，m)，7.43-7.46(1H，m)，7.83-7.94 (2H，m)，10.78(1H，s)，11.58(1H，s).MS：391(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			157	4	1H-NMR(400MHz，d6-DMSO)δ：1.51-2.70(17H，m)，3.71-3.8 4(1H，m)，4.46-4.56(1H，m)，6.29-6.39(1H，m)，7.42-7.44(1H，m )，7.89-7.91(1H，m)，10.77-10.81(1H，m)，11.55-11.59(1H，m). MS：417(M+H)+
158	4	1H-NMR(400MHz，d6-DMSO)δ：1.40-2.87(13H，m)，4.41-4.7 2(1H，m)，6.28-6.42(1H，m)，7.40-7.48(1H，m)，7.86-7.93(1H，m )，8.01-8.11(1H，m)，8.20-8.32(1H，m)，10.71-10.82(1H，m)，11.5 4-11.63(1H，m).MS：420(M+H)+
			159	4	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.22(9H，m)，2.36-2.44( 2H，m)，2.63-2.74(2H，m)，3.06-3.18(2H，m)，3.36-3.44(2H，m)，4 .46-4.54(1H，m)，4.61-4.68(1H，m)，6.35-6.38(1H，m)，7.24-7.55 (2H，m)，7.90(1H，s)，10.74-10.76(1H，m)，11.57(1H，s).MS：396( M+H)+
160	4	1H-NMR(400MHz，d6-DMSO)δ：1.35-1.99(9H，m)，1.50-2.45( 11H，m)，2.63-2.74(2H，m)，2.92-3.14(4H，m)，4.46-4.53(1H，m)， 6.32-6.39(1H，m)，6.78-9.86(1H，m)，7.32-7.60(2H，m)，7.90(1H ，s)，10.73-10.79(1H，m)，11.57(1H，s).MS：495(M+H)+
			161	4	1H-NMR(400MHz，d6-DMSO)δ：1.59-1.65(2H，m)，1.85-1.95( 2H，m)，2.05-2.11(1H，m)，2.13-2.21(2H，m)，2.35-2.47(6H，m)，5 .16(1H，d，J＝8.7Hz)，7.13(1H，br)，7.91(1H，br)，8.08(1H，s)，8.47( 1H，s)，9.98(1H，d，J＝8.7Hz)，12.81(1H，br).MS：390，392(M+H) +
162	4	MS：479(M+H)+
			163	4	MS：465(M+H)+
164	4	MS：508(M+H)+
			165	4	MS：492(M+H)+
166	4	MS：508(M+H)+
			167	4	MS：488(M+H)+
168	4	MS：513(M+H)+
			169	4	1H-NMR(400MHz，d6-DMSO)δ：1.78-1.89(4H，m)，2.04-2.11( 1H，m)，2.22-2.25(4H，m)，2.30-2.35(2H，m)，2.51-2.56(2H，m)，5 .05(1H，d，J＝8.7Hz)，7.20(1H，br)，7.95(1H，br)，8.07(1H，s)，8.49( 1H，s)，10.17(1H，d，J＝8.7Hz)，12.81(1H，br).MS：390，392(M+H )+
170	4	MS：353(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			171	4	MS：390(M+H)+
172	4	MS：434(M+H)+
			173	4	MS：417(M+H)+
174	4	MS：369(M+H)+
			175	4	MS：369(M+H)+
176	4	MS：355(M+H)+
			177	4	MS：433(M+H)+
178	4	MS：423(M+H)+
			179	4	MS：433(M+H)+
180	4	MS：419(M+H)+
			181	4	MS：558(M+Na)+
182	4	1H-NMR(400MHz，d6-DMSO)δ：1.39-2.34(12H，m)，3.09(3 H，s)，4.08(2H，s)，4.44(1H，s)，4.50(1H，m)，5.00(1H，m)，8.04( 1H，s)，9.11(1H，s)，10.18(1H，m)，11.11(1H，m)，12.80(1H，s). MS：424(M+H)+
			183	4	MS：434(M+H)+.MS：432(M-H)-
184	4	1H-NMR(400MHz，d6-DMSO)δ：1.43(9H，s)，1.68-1.84(2H， m)，1.84-2.13(4H，m)，2.13-2.31(2H，m)，4.04-4.17(2H，m)，4. 30-4.39(1H，m)，6.44-6.49(1H，m)，7.01(1H，br)，7.06-7.12(1 H，m)，7.77(1H，br)，8.37(1H，s)，10.24(1H，d，J＝7.6Hz)，11.43( 1H，s).MS：386(M+H)+
			185	4	1H-NMR(400MHz，d6-DMSO)δ：1.76-2.40(8H，m)，3.95(1 H，d，J＝18.8Hz)，4.05(1H，d，J＝18.8Hz)，4.13-4.24(1H，m)，4.2 9-4.41(1H，m)，4.44-4.55(1H，m)，6.39-6.47(1H，m)，7.04(1H， br)，7.08-7.15(1H，m)，7.80(1H，br)，8.38(1H，s)，10.28(1H，d，J ＝7.6Hz)，11.46(1H，s).MS：353(M+H)+
186	4	1H-NMR(400MHz，d6-DMSO)δ：1.72-2.52(8H，m)，3.94-4. 09(1H，m)，4.37-4.48(1H，m)，4.58-4.73(1H，m)，6.45-6.51(1 H，m)，7.02(1H，br)，7.07-7.14(1H，m)，7.42-7.56(5H，m)，7.79 (1H，br)，8.37(1H，s)，10.29(1H，d，J＝7.7Hz)，11.45(1H，s).MS： 390(M+H)+
			187	4	1H-NMR(400MHz，d6-DMSO)δ：1.30-1.50(11H，m)，1.67-2 .22(6H，m)，4.12(2H，brs)，5.40-5.55(1H，m)，7.10(1H，brs)，7. 82(1H，brs)，8.10(1H，s)，8.43(1H，s)，9.28(1H，d，J＝8.6Hz)，12. 8(1H，brs).MS：387(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			188	4	1H-NMR(400MHz，d6-DMSO)δ：0.96-2.19(13H，m)，4.09-4 .19(1H，m)，6.42-6.43(1H，m)，6.55-6.57(1H，m)，7.11-7.14(1 H，m)，7.63-7.65(1H，m)，7.86-7.89(1H，m)，7.86-7.89(1H，m)， 8.20(1H，s)，8.37(1H，d，J＝2.8Hz)，10.11-10.23(1H，m)，11.47( 1H，s)，12.16(1H，s)..MS：393(M+H)+
189	4	1H-NMR(400MHz，d6-DMSO)δ：1.42-1.60(4H，m)，1.70-1. 83(4H，m)，2.05-2.11(2H，m)，2.19-2.26(2H，m)，2.76-2.87(1 H，m)，4.54-4.66(1H，m)，6.53-6.56(1H，m)，6.71(1H，brs)，6.8 8-7.10(1H，br)，7.19-7.22(1H，m)，7.35(1H，brs)，7.60-7.85(1 H，br)，8.34(1H，s)，9.45(1H，d，J＝8.0Hz)，11.46(1H，brs).MS：3 64(M+Na)+.
			190	4	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.13(13H，m)，4.10-4 .21(1H，m)，6.43-6.46(1H，m)，6.73-6.78(1H，m)，6.92-7.14(3 H，m)，7.61-7.95(1H，br)，8.37-8.39(1H，m)，10.11-10.18(1H， m)，11.46(1H，brs).MS：354(M+H)+
191	4	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.53(2H，m)，1.78-1. 96(7H，m)，2.00-2.10(4H，m)，4.16-4.21(1H，m)，6.44-6.46(1 H，m)，6.76(1H，brs)，6.88-7.13(3H，m)，7.62-7.90(1H，br)，8.3 7(1H，s)，10.17(1H，d，J＝8.0Hz)，11.45(1H，brs).MS：376(M+ Na)+.
			192	4	1H-NMR(400MHz，d6-DMSO)δ：1.69-1.98(11H，m)，2.10-2 .15(2H，m)，4.10-4.15(1H，m)，6.43-6.46(1H，m)，6.75(1H，brs )，6.90-7.09(2H，m)，7.11-7.15(1H，m)，7.66-7.93(1H，br)，8.3 7(1H，s)，10.13(1H，d，J＝8.0Hz)，11.46(1H，brs).MS：354.2(M +H)+.
193	4	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.86(10H，m)，2.05(1 H，brs)，2.19(2H，brs)，4.48(1H，s)，4.94(1H，d，J＝8.7Hz)，7.09( 1H，brs)，7.83(1H，brs)，8.04(1H，s)，8.45(1H，s)，9.97(1H，d，J＝ 8.7Hz)，12.8(1H，brs).MS：328(M+H)+
			194	4	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.89(10H，m)，2.11(1 H，brs)，2.18(2H，brs)，3.15(3H，s)，5.04(1H，d，J＝8.8Hz)，7.10( 1H，brs)，7.82(1H，brs)，8.06(1H，s)，8.46(1H，s)，9.98(1H，d，J＝ 8.8Hz)，12.7(1H，brs).MS：342(M+H)+
195	4	1HNMR(400MHz，d6-DMSO)δ：1.40-1.65(2H，m)，1.80-2.1 5(6H，m)，3.90-4.10(2H，m)，4.20(1H，brs)，4.55(1H，brs)，5.45 -5.55(1H，m)，7.18(1H，brs)，7.81(1H，brs)，8.11(1H，s)，8.25(1 H，s)，9.25(1H，d，J＝9.1Hz)，12.8(1H，brs).MS：376(M+Na)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			196	4	1H-NMR(400MHz，d6-DMSO)δ：1.2-2.1(14H，m)，2.73(1H，s)， 2.89(1H，s)，3.7-4.6(4H，m)，6.4-6.5(1H，m)，7.1-7.5(1H，m)，7.9- 8.0(1H，m)，8.3-8.4(1H，m)，10.1-10.2(1H，m)，11.46(1H，s).MS： 497.2(M+H)+.
197	4	MS：385(M+H)+
			198	4	1H-NMR(400MHz，d6-DMSO)δ：1.52-2.23(13H，m)，3.23-3.3 4(3H，m)，4.12-4.47(3H，m)，6.47-6.58(1H，m)，6.94-7.14(2H，m )，7.81(1H，brs)，8.34-8.47(1H，m)，10.12-10.27(1H，m，J＝11.44 Hz)，11.44(1H，s) .MS：393(M+H)+.
199	4	1H-NMR(400MHz，d6-DMSO)δ：1.56-2.31(14H，m)，2.77(3H， d，J＝4.4Hz)，4.16-4.18(1H，m)，6.43(1H，s)，7.14-7.16(1H，s)，8.3 1-8.40(1H，s)，9.96-9.98(1H，s)，11.48(1H，s).MS：350(M+H)+
			200	4	1H-NMR(400MHz，d6-DMSO)δ：1.51-2.34(14H，m)，2.74(3H， d，J＝4.0Hz)，4.2-4.3(1H，m)，6.50-6.52(1H，m)，7.13-7.15(1H，m )，8.25-8.26(1H，m)，9.92-9.95(1H，m)，11.46(1H，s).MS：350(M +H)+
201	4	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.54(2H，m)，1.62-1.74( 4H，m)，1.81-1.92(4H，m)，2.08-2.11(1H，m)，2.28-2.31(2H，m)，3 .36-3.44(2H，m)，3.48-3.76(6H，m)，4.04，4.12(2H，s)，4.20-4.24( 1H，m)，4.40，4.50(1H，s)，6.58-6.61(1H，m)，7.27-7.30(1H，m)，8. 65(1H，s)，8.83-8.86(1H，m)，11.90(1H，brs).MS：531(M+H)+
			202	4	1H-NMR(400MHz，d6-DMSO)δ：1.57-2.20(8H，m)，2.42(3H，s )，4.05-4.06(2H，m)，4.26-4.27(1H，m)，4.58(2H，s)，6.66-6.67(1 H，m)，7.31-7.32(1H，m)，8.43(1H，d，J＝8.0Hz)，8.57(1H，s)，11.88 (1H，brs).MS：392.2(M+H)+
203	4	1H-NMR(400MHz，d6-DMSO)δ：1.31-1.50(4H，m)，1.54-1.72( 8H，m)，1.72-1.89(4H，m)，2.03-2.11(1H，m)，2.16-2.25(2H，m)，2 .75-2.87(4H，m)，3.98-4.06(1H，m)，4.53(1H，s)，6.41-6.47(1H， m)，7.10-7.15(1H，m)，8.27(1H，s)，9.09(1H，brs)，9.52(1H，d，J＝6. 8Hz)，11.46(1H，brs).MS：410(M+H)+
			204	4	1H-NMR(400MHz，d6-DMSO)δ：1.38-1.81(16H，m)，2.02-2.1 0(1H，m)，2.14-2.22(2H，m)，3.45-3.56(4H，m)，3.93-4.01(1H，m )，4.50(1H，s)，6.44-6.48(1H，m)，6.97(1H，d，J＝8.4Hz)，7.16-7.21 (1H，m)，7.80(1H，s)，11.46(1H，brs).MS：395(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			205	4	1H-NMR(400MHz，d6-DMSO)δ：0.93-1.88(20H，m)，2.01-2.0 9(1H，m)，2.12-2.22(2H，m)，3.85-4.03(2H，m)，4.48(1H，s)，4.59( 2H，s)，6.42-6.47(1H，m)，7.11(1H，d，J＝8.0Hz)，7.13-7.18(1H，m )，7.94(1H，s)，11.40(1H，brs).MS：424(M+H)+
206	4	1H-NMR(400MHz，d6-DMSO)δ：1.04-1.92(20H，m)，2.03-2.1 2(1H，m)，2.15-2.27(2H，m)，2.65-2.77(1H，m)，3.98-4.08(1H，m )，4.51(1H，s)，4.90-5.01(1H，m)，6.40-6.47(1H，m)，7.10-7.16(1 H，m)，8.27(1H，s)，9.47(1H，d，J＝8.1Hz)，9.66-9.74(1H，m)，11.47 (1H，s).MS：424(M+H)+
			207	4	1H-NMR(400MHz，d6-DMSO)δ：1.42-1.49(2H，m)，1.58-1.72( 4H，m)，1.75-1.88(4H，m)，1.92(3H，s)，2.04-2.10(1H，m)，2.18-2. 25(2H，m)，4.03-4.08(1H，m)，4.52(1H，s)，6.44-6.48(1H，m)，7.1 4-7.17(1H，m)，8.42(1H，s)，9.65(1H，d，J＝8.0Hz)，9.76(1H，s)，9.9 9(1H，brs)，11.52(1H，brs).MS：384(M+H)+
208	4	1H-NMR(400MHz，d6-DMSO)δ：1.88-2.47(8H，m)，2.42(3H，s )，3.98(1H，d，J＝18.9Hz)，4.08(1H，d，J＝18.9Hz)，4.20-4.26(1H， m)，4.48-4.57(2H，m)，6.56-6.61(1H，m)，7.23-7.28(1H，m)，8.58 (1H，s)，9.17(1H，d，J＝7.6Hz)，11.83(1H，s).MS：392(M+H)+
			209	4	1H-NMR(400MHz，d6-DMSO)δ：1.81-1.94(4H，m)，2.11(1H， m)，2.46-2.51(3H，m)，4.13(2H，s)，4.39(1H，s)，4.71(1H，s)，4.97( 1H，m)，6.26(1H，s)，7.36-7.44(1H，m)，7.94(1H，s)，11.02(1H，brs )，11.65(1H，s).MS：373(M+Na)+
210	4	MS：439(M+H)+
			211	4	MS：493(M+H)+
212	4	MS：404(M+H)+
			213	4	MS：404(M+H)+
214	4	MS：415(M+H)+
			215	4	MS：415(M+H)+
216	4	MS：415(M+H)+
			217	4	MS：408(M+H)+
218	4	MS：420(M+H)+
			219	4	MS：420(M+H)+
220	4	MS：432(M+H)+
			221	4	MS：448(M+H)+
222	4	MS：328(M+H)+
			223	4	MS：342(M+H)+
224	4	MS：344(M+H)+
			225	4	MS：354(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			226	4	MS：356(M+H)+
227	4	MS：358(M+H)+
			228	4	MS：370(M+H)+
229	4	MS：371(M+H)+
			230	4	MS：391(M+H)+
231	4	MS：391(M+H)+
			232	4	MS：391(M+H)+
233	4	MS：396(M+H)+
			234	4	MS：397(M+H)+
235	4	MS：405(M+H)+
			236	4	MS：422(M+H)+
237	4	MS：434(M+H)+
			238	4	MS：468(M+H)+
239	4	MS：483(M+H)+
			240	4	MS：385(M+H)+
241	4	MS：398(M+H)+
			242	4	MS：413(M+H)+
243	4	MS：384(M+H)+
			244	4	MS：399(M+H)+
245	4	MS：425(M+H)+
			246	4	MS：424(M+H)+
247	4	MS：450(M+H)+
			248	4	MS：411(M+H)+
249	4	MS：415(M+H)+
			250	4	MS：425(M+H)+
251	4	MS：411(M+H)+
			252	4	MS：438(M+H)+
253	4	1H-NMR(400MHz，d6-DMSO)δ：0.81(3H，s)，0.91(3H，s)，0. 99(3H，s)，0.87-1.31(3H，m)，1.34-1.52(3H，m)，2.33-2.49(1H ，m)，4.13-4.28(1H，m)，6.42(1H，d，J＝2.6Hz)，6.72-7.94(3H，m )，8.36(1H，s)，10.09(1H，d，J＝8.4Hz)，11.46(1H，brs).MS：313( M+H)+
			254	4	MS：440(M+H)+
255	4	MS：398(M+H)+
			256	4	MS：435(M+H)+
257	4	MS：435(M+H)+
			258	4	MS：435(M+H)+
259	4	MS：442(M+H)+
			260	4	MS：407(M+H)+
261	4	MS：403(M+H)+

Watch 72 (continuation)

Examples	Examples of reference	Data of
			262	4	MS：410(M+H)+
263	4	MS：411(M+H)+
			264	4	MS：447(M+H)+
265	4	MS：432(M+H)+
			266	4	MS：447(M+H)+
267	4	MS：432(M+H)+
			268	7	MS：469(M+H)+
269	7	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.35(10H，m)，3.39 (2H，m)，3.76-4.13(5H，m)，4.23(1H，m)，4.54(1H，s)，6.56(1 H，m)，7.26(1H，m)，7.74(1H，m)，8.80(1H，s)，9.41(1H，m)，1 1.69(1H，s).MS：479(M+H)+
			270	7	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.48(14H，m)，3.41 (2H，m)，4.23(1H，m)，4.55(1H，s)，6.57(1H，m)，7.26(1H，m) ，7.72(1H，m)，8.78(1H，s)，9.30(1H，m)，11.69(1H，s) .MS：466(M+H)+
271	7	1H-NMR(400MHz，d6-DMSO)δ：1.39-2.32(12H，m)，3.45 (2H，m)，3.85(2H，m)，4.01(1H，m)，4.23(1H，m)，4.56(1H，s) ，4.87(1H，m)，6.56(1H，m)，7.26(1H，m)，7.72(1H，m)，8.71( 1H，s)，11.71(1H，s).MS：479(M+H)+
			272	7	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.47(14H，m)，3.67 -3.78(4H，m)，4.24(1H，m)，4.56(1H，s)，6.56(1H，m)，7.25(1 H，m)，7.71(1H，m)，8.71(1H，s)，11.71(1H，s).MS：478(M+ H)+
273	7	MS：550(M+H)+
			274	7	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.38(13H，m)，3.55 (4H，m)，3.99(1H，m)，4.23(1H，m)，4.51(1H，s)，4.82(2H，m) ，6.60(1H，m)，7.27(1H，m)，8.17(1H，m)，8.65(1H，m)，8.84( 1H，m)，11.88(1H，s).MS：469(M+H)+
275	7	MS：469(M+H)+
			276	7	MS：556(M+H)+
277	7	MS：505(M+Na)+
			278	7	MS：491(M+Na)+
279	7	1H-NMR(400MHz，d6-DMSO)δ：1.42(9H，s)，1.44-2.38(7 H，m)，2.85(2H，m)，3.89-4.05(4H，m)，4.22(1H，m)，4.38(1 H，s)，6.60(1H，m)，7.27(1H，m)，8.31(1H，m)，8.73(1H，m)，8. 89(1H，m)，11.87(1H，s).MS：600(M+Na)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			280	7	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.51(2H，m)，1.61-1.64( 2H，m)，1.67-1.73(2H，m)，1.81-1.87(2H，m)，1.93-1.99(2H，m)，2 .08-2.12(1H，m)，2.32-2.36(2H，m)，4.19-4.23(1H，m)，4.46(1H， s)，6.60(1H，d，J＝3.6Hz)，7.28(1H，d，J＝3.6Hz)，8.17-8.21(2H，m) ，8.64(1H，s)，8.88(1H，d，J＝7.5Hz)，11.88(1H，brs).MS：395(M+ H)+
281	7	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.53(2H，m)，1.62-1.65( 2H，m)，1.67-1.74(2H，m)，1.81-1.92(4H，m)，2.08-2.12(1H，m)，2 .28-2.32(2H，m)，3.06(3H，s)，3.11(3H，s)，4.19-4.23(1H，m)，4.50 (1H，s)，6.59(1H，d，J＝3.6Hz)，7.28(1H，d，J＝3.6Hz)，8.65(1H，s)，8 .88(1H，d，J＝7.6Hz)，11.89(1H，brs).MS：423(M+H)+
			282	7	1H-NMR(400MHz，d6-DMSO)δ：1.5-2.2(14H，m)，2.98(3H，s)， 3.00(3H，s)，4.11-4.18(1H，m)，6.44-6.48(1H，m)，7.11-7.12(1H， m)，7.39-7.56(1H，m)，7.70-7.73(1H，m)，8.31(1H，s)，8.37-8.38( 1H，m)，10.16-10.18(1H，m)，11.46(1H，brs).MS：382.3(M+H)+.
283	7	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.54(2H，m)，1.61-1.65( 2H，m)，1.68-1.74(2H，m)，1.82-1.93(4H，m)，2.08-2.12(1H，m)，2 .29-2.33(2H，m)，3.56-3.63(4H，m)，3.68-3.70(4H，m)，4.20-4.24 (1H，m)，4.52(1H，s)，6.59(1H，d，J＝3.6Hz)，7.29(1H，d，J＝3.6Hz)， 8.64(1H，s)，8.84(1H，d，J＝7.8Hz)，11.89(1H，brs).MS：487(M+N a)+
			284	7	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.53(2H，m)，1.62-1.65( 2H，m)，1.68-1.73(2H，m)，1.81-1.92(4H，m)，2.08-2.12(1H，m)，2 .28-2.33(2H，m)，2.68-2.72(2H，m)，2.75-2.79(2H，m)，3.40-3.43 (2H，m)，3.59-3.62(2H，m)，4.19-4.22(1H，m)，4.51(1H，brs)，6.57 -6.60(1H，m)，7.27-7.29(1H，m)，8.64(1H，s)，8.83-8.86(1H，m)，1 1.89(1H，brs).MS：464(M+H)+
285	7	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.54(2H，m)，1.63-1.65( 2H，m)，1.69-1.74(2H，m)，1.82-1.92(4H，m)，2.09-2.12(1H，m)，2 .30-2.33(2H，m)，2.86(3H，s)，4.22-4.25(1H，m)，4.55(1H，brs)，6. 57(1H，d，J＝3.6Hz)，7.27(1H，d，J＝3.6Hz)，7.71-7.74(1H，m)，8.7 8(1H，s)，9.38(1H，brs)，11.68(1H，brs).MS：409(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			286	7	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.51(2H，m)，1.61-1.64( 2H，m)，1.67-1.73(2H，m)，1.81-1.87(2H，m)，1.93-1.99(2H，m)，2 .08-2.12(1H，m)，2.32-2.36(2H，m)，4.19-4.23(1H，m)，4.46(1H， s)，6.60(1H，d，J＝3.6Hz)，7.28(1H，d，J＝3.6Hz)，8.17-8.21(2H，m) ，8.64(1H，s)，8.88(1H，d，J＝7.5Hz)，11.88(1H，brs).MS：395(M+ H)+
287	7	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.53(2H，m)，1.63-1.80( 8H，m)，1.82-1.99(6H，m)，2.09-2.12(1H，m)，2.17(3H，s)，2.30-2. 33(2H，m)，2.76-2.81(2H，m)，3.73-3.79(1H，m)，4.22-4.25(1H， m)，4.53(1H，s)，6.56-6.57(1H，m)，7.25-7.27(1H，m)，7.74-7.76( 1H，m)，8.80(1H，s)，9.33-9.36(1H，m)，11.68(1H，brs).MS：492( M+H)+
			288	7	1H-NMR(400MHz，d6-DMSO)δ：1.49-1.55(2H，m)，1.63-1.66( 2H，m)，1.69-1.75(2H，m)，1.82-1.93(4H，m)，2.09-2.12(1H，m)，2 .30-2.33(2H，m)，3.67-3.73(6H，m)，3.83-3.86(2H，m)，4.22-4.26 (1H，m)，4.52(1H，s)，6.55-6.57(1H，m)，7.24-7.26(1H，m)，7.70-7 .73(1H，m)，8.72(1H，s)，11.68(1H，brs).MS：465(M+H)+
289	7	1H-NMR(400MHz，d6-DMSO)δ：1.49-1.54(2H，m)，1.63-1.65( 2H，m)，1.69-1.75(2H，m)，1.82-1.93(4H，m)，2.09-2.12(1H，m)，2 .30-2.33(2H，m)，3.10(3H，s)，3.25(3H，s)，4.22-4.26(1H，m)，4.52 (1H，s)，6.55-6.57(1H，m)，7.24-7.26(1H，m)，7.71-7.73(1H，m)，8 .72(1H，s)，11.67(1H，brs).MS：423(M+H)+
			290	7	1H-NMR(400MHz，d6-DMSO)δ：1-41-1.42(9H，m)，1.48-1.57( 4H，m)，1.63-1.74(4H，m)，1.78-1.92(6H，m)，2.09-2.12(1H，m)，2 .30-2.32(2H，m)，2.79-2.90(1H，m)，3.33-3.39(2H，m)，3.93-4.02 (2H，m)，4.22-4.26(1H，m)，4.53(1H，s)，6.56-6.58(1H，m)，7.25-7 .27(1H，m)，7.73-7.76(1H，m)，8.79(1H，s)，9.37-9.40(1H，m)，11. 68(1H，brs).MS：578(M+H)+
291	7	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.54(2H，m)，1.63-1.65( 2H，m)，1.69-1.74(2H，m)，1.82-2.00(6H，m)，2.09-2.12(1H，m)，2 .30-2.33(2H，m)，3.33-3.62(2H，m)，3.79-4.01(2H，m)，4.22-4.25 (1H，m)，4.54，4.55(1H，m)，4.72-4.73(1H，m)，5.00-5.01，5.55-5. 56(1H，m)，6.55-6.57(1H，m)，7.25-7.26(1H，m)，7.71-7.74(1H， m)，8.73，8.74(1H，s)，11.72(1H，m).MS：477(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			292	7	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.52(2H，m)，1.67-1.75( 4H，m)，1.87-1.93(4H，m)，2.08-2.12(1H，m)，2.23-2.26(2H，m)，2 .85(3H，d，J＝4.7Hz)，3.17(1H，s)，4.33-4.37(1H，m)，6.53-6.55(1 H，m)，7.27-7.29(1H，m)，7.74-7.77(1H，m)，8.78(1H，s)，9.37-9.4 1(1H，m)，11.72(1H，brs).MS：409(M+H)+
293	7	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.31(13H，m)，3.28(3H， s)，3.47-3.52(4H，m)，4.22-4.23(1H，m)，4.52(1H，brs)，6.55-6.57 (1H，m)，7.25-7.26(1H，m)，7.71-7.73(1H，m)，8.78(1H，s)，9.42(1 H，brs)，11.66(1H，brs).MS：453(M+H)+
			294	7	1H-NMR(400MHz，d6-DMSO)δ：1.08(3H，d，J＝6.0Hz)，1.49-2. 32(13H，m)，3.16-3.27(2H，m)，3.84-3.86(1H，m)，4.23-4.24(1H， m)，4.52(1H，s)，4.82(1H，d，J＝4.8Hz)，6.55-6.57(1H，m)，7.25-7. 27(1H，m)，7.72-7.74(1H，m)，8.78(1H，s)，9.26-9.27(1H，m)，11. 66(1H，brs)..MS：453(M+H)+
295	7	1H-NMR(400MHz，d6-DMSO)δ：1.02-2.31(18H，m)，3.20-3.2 4(4H，m)，3.83-3.84(2H，m)，4.23-4.24(1H，m)，4.52(1H，brs)，6.5 6-6.57(1H，m)，7.24-7.26(1H，m)，7.72-7.74(1H，m)，8.78(1H，s)， 9.45-9.46(1H，m)，11.66(1H，brs).MS：493(M+H)+
			296	8	MS：439(M+H)+
297	8	MS：453(M+H)+
			298	8	MS：453(M+H)+
299	8	MS：466(M+H)+
			300	8	MS：452(M+H)+
301	8	MS：463(M+H)+
			302	8	MS：479(M+H)+
303	8	MS：488(M+H)+
			304	8	MS：460(M+H)+
305	8	MS：465(M+H)+
			306	8	MS：479(M+H)+
307	8	MS：506(M+H)+
			308	8	MS：506(M+H)+
309	8	MS：478(M+H)+
			310	8	MS：477(M+H)+
311	8	MS：493(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			312	8	MS：479(M+H)+
313	8	MS：492(M+H)+
			314	8	MS：479(M+H)+
315	8	MS：493(M+H)+
			316	8	MS：506(M+H)+
317	8	MS：508(M+H)+
			318	8	MS：541(M+H)+
319	8	MS：546(M+H)+
			320	8	MS：434(M+H)+
321	8	MS：499(M+H)+
			322	8	MS：423(M+H)+
323	8	MS：352(M+H)+
			324	8	MS：452(M+H)+
325	8	MS：467(M+H)+
			326	8	MS：483(M+H)+
327	8	MS：475(M+H)+
			328	8	MS：486(M+H)+
329	8	MS：486(M+H)+
			330	8	MS：486(M+H)+
331	8	MS：492(M+H)+
			332	8	MS：493(M+H)+
333	8	MS：506(M+H)+
			334	8	MS：509(M+H)+
335	8	MS：477(M+H)+
			336	8	MS：556(M+H)+
337	8	MS：513(M+H)+

338	8	MS：527(M+H)+
			339	8	MS：508(M+H)+
340	8	MS：479(M+H)+
			341	8	MS：504(M+H)+
342	8	MS：449(M+H)+
			343	8	1H-NMR(400MHz，d6-DMSO)δ：1.92-2.32(8H，m)， 2.49(3H，s)，3.58-4.57(5H，m)，6.76-6.77(1H，m)，7.39 -7.40(1H，m)，8.69(1H，s)，8.79-9.05(3H，m)，12.20(1 H，brs).MS：325(M+H)+
344	10	MS：542(M+H)+
			345	10	1H-NMR(400MHz，d6-DMSO)δ：1.43-2.39(9H，m)， 2.79(6H，s)，2.81(2H，m)，3.57(2H，m)，3.99(1H，m)，4. 21(1H，m)，4.40(1H，s)，6.59(1H，m)，7.27(1H，m)，8.64 (1H，s)，8.76(1H，m)，8.90(1H，m)，11.89(1H，s).MS：57 1(M+Na)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			346	10	MS：585(M+H)+
347	10	MS：535(M+H)+
			348	13	1H-NMR(400MHz，d6-DMSO)δ：1.30(3H，t，J＝7.1Hz)，1.45-1. 54(2H，m)，1.58-1.75(4H，m)，1.77-1.89(4H，m)，2.06-2.12(1H， m)，2.23-2.29(2H，m)，4.09-4.15(1H，m)，4.30(2H，q，J＝7.1Hz)，4. 58(1H，s)，6.49-9.53(1H，m)，7.10(2H，brs)，7.17-7.21(1H，m)，8. 90(1H，s)，9.33(1H，d，J＝7.8Hz)，11.72(1H，brs).MS：442(M+H) +
349	13	1H-NMR(400MHz，d6-DMSO)δ：1.43(9H，s)，1.71-1.85(2H，m )，1.80(3H，s)，1.90-2.09(4H，m)，2.17-2.32(2H，m)，4.08-4.17(2 H，m)，4.38-4.46(1H，m)，6.45(2H，brs)，6.50-6.56(1H，m)，7.12-7 .17(1H，m)，8.77(1H，s)，9.51(1H，d，J＝7.6Hz)，11.64(1H，s).MS： 443(M+H)+
			350	14	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.55(2H，m)，1.79-1.82( 2H，m)，1.86-1.99(5H，m)，2.02-3.15(4H，m)，4.09(2H，d，J＝5.5H z)，4.17-4.23(1H，m)，6.44-6.47(1H，m)，7.00(1H，br)，7.11-7.14( 1H，m)，7.78(1H，br)，8.28(1H，t，J＝5.4Hz)，8.38(1H，s)，10.18(1H ，d，J＝8.2Hz)，11.46(1H，s).MS：393(M+H)+
351	14	1H-NMR(400MHz，d6-DMSO)δ：1.71-2.03(11H，m)，2.13-2.1 7(2H，m)，4.06(2H，d，J＝5.5Hz)，4.12-4.16(1H，m)，6.43-6.46(1H ，m)，6.99(1H，br)，7.11-7.15(1H，m)，7.77(1H，br)，8.21(1H，d，J＝5 .5Hz)，8.37(1H，s)，10.18(1H，d)，11.46(1H，s).MS：393(M+H)+
			352	14	1H-NMR(400MHz，d6-DMSO)δ：1.37-1.39(9H，m)，1.43-1.48( 2H，m)，1.68-2.03(8H，m)，2.05-2.19(3H，m)，4.04-4.17(1H，m)，6 .36-6.56(2H，m)，6.87-7.16(2H，m)，7.76(1H，br)，8.36-8.38(1H， m)，10.11-10.15(1H，m)，11.44(1H，m).MS：426(M+H)+
353	14	1H-NMR(400MHz，d6-DMSO)δ：1.14-2.21(13H，m)，4.02-4.0 4(1H，m)，4.36(2H，brs)，4.48(1H，s)，6.43-6.33(1H，m)，7.12-7.1 3(1H，m)，8.28(1H，s)，9.48(1H，s)，9.67(1H，d，J＝8.0Hz)，11.42(1 H，brs).MS：342(M+H)+
			354	14	MS：366(M+H)+
355	14	MS：418(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			356	14	MS：418(M+H)+
357	14	MS：418(M+H)+
			358	14	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.22(8H，m)，3.70(3 H，s)，4.04(1H，m)，4.53(1H，s)，6.45(1H，m)，7.15(1H，m)，8.16( 1H，s)，9.41(1H，s)，11.41(1H，s)，11.51(1H，s).MS：357(M+H) +
359	14	MS：355(M+H)+，353(M-H)-
			360	14	1H-NMR(400MHz，d6-DMSO)δ：1.09-2.23(16H，m)，3.28(2 H，m)，4.48(1H，s)，4.96(1H，m)，8.05(1H，s)，8.31(1H，m)，8.40( 1H，s)，9.73(1H，m)，12.73(1H，s).MS：356(M+H)+
361	14	1H-NMR(400MHz，d6-DMSO)δ：1.22-2.34(13H，m)，4.29(2 H，m)，4.51(1H，s)，5.01(1H，m)，8.08(1H，s)，8.43(1H，s)，8.99( 1H，m)，9.65(1H，m)，12.86(1H，s).MS：367(M+H)+
			362	14	MS：377(M-H)-
363	15	MS：408(M+Na)+，384(M-H)-
			364	16	1H-NMR(400MHz，d6-DMSO)δ：0.80-2.84(13H，m)，4.60-4 .69(1H，m)，7.43-7.47(1H，m)，7.90-7.92(1H，m)，8.91-8.94(1 H，m)，10.78-10.85(1H，m)，11.55-11.65(1H，m).MS：402(M+ H)+
365	16	1H-NMR(400MHz，d6-DMSO)δ：1.90-1.97(4H，m)，2.03-2. 12(5H，m)，2.62-2.67(2H，m)，2.74-2.79(2H，m)，4.54(1H，s)，6 .34-6.35(1H，m)，7.45(1H，t，J＝3.1Hz)，7.91(1H，s)，10.86(1H， s)，11.61(1H，s).MS：334(M+H)+
			366	17	1H-NMR(400MHz，d6-DMSO)δ：1.46-1.83(10H，m)，2.07(1 H，brs)，2.29(2H，brs)，4.57(1H，s)，4.67-4.77(1H，m)，5.95-6.0 2(1H，m)，8.245(1H，s)，8.249(1H，s)，13.1(1H，brs).MS：332( M+Na)+
367	18	1H-NMR(400MHz，d6-DMSO)δ：1.52-1.61(2H，m)，1.72-1. 92(3H，m)，1.99-2.13(4H，m)，2.22-2.41(3H，m)，2.64-2.74(2 H，m)，2.80-2.93(2H，m)，3.26-3.38(2H，m)，4.57-4.64(1H，m)， 6.52-6.59(1H，m)，7.58-7.63(1H，m)，7.82-7.91(2H，m)，7.96. MS：395(M+H)+
			368	18	1H-NMR(400MHz，d6-DMSO)δ：1.50-1.59(2H，m)，1.72-1. 99(6H，m)，2.05-2.17(2H，m)，2.24-2.36(2H，m)，4.21-4.30(1 H，m)，6.52-6.66(1H，m)，7.31-7.39(1H，m)，7.62(1H，br)，7.70 -7.71(1H，m)，8.00-8.39(4H，m)，8.53-8.56(1H，m)，9.10(1H，s )，11.08(1H，br)，12.44(1H，br)，14.38(1H，br).MS：326(M+H) +

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			369	18	MS：340(M+H)+
370	18	MS：478(M+H)+
			371	18	1H-NMR(400MHz，d6-DMSO)δ：1.51-1.57(1H，m)，1.71-1.7 9(2H，m)，1.83-1.90(2H，m)，1.96-2.02(2H，m)，2.06-2.20(4H， m)，2.33-2.46(2H，m)，4.38-4.42(1H，m)，6.60-6.62，6.73-6.75( 1H，m)，7.41-7.45(1H，m)，8.11-8.29(3H，m)，8.44，8.56(1H，brs )，8.80(1H，s)，9.31-9.34，9.45-9.50(1H，m)，12.45(1H，brs).MS ：394(M-3HCl+H)+
372	18	1H-NMR(400MHz，d6-DMSO)δ：1.52-1.57(2H，m)，1.65-1.7 5(4H，m)，1.84-1.92(6H，m)，1.97-2.02(2H，m)，2.10-2.14(1H， m)，2.32-2.36(2H，m)，2.99-3.09(2H，m)，3.30-3.36(2H，m)，4.0 9-4.16(1H，m)，4.32-4.35(1H，m)，6.72-6.75(1H，m)，7.40-7.42 (1H，m)，8.29-8.41(1H，m)，8.56-8.65(1H，m)，8.74-8.79(1H，m )，8.82(1H，s)，9.66-9.68(1H，m)，12.37(1H，brs).MS：478(M-2 HCl+H)+
			373	18	1H-NMR(400MHz，d6-DMSO)δ：1.93-2.24(6H，m)，2.46-2.6 1(2H，m)，3.95-4.09(2H，m)，4.42-4.54(1H，m)，6.68-6.76(1H， m)，7.34-7.41(1H，m)，7.78(1H，brs)，8.51(1H，brs)，8.63(1H，s)， 9.11-9.51(2H，m)，11.25(1H，d，J＝7.3Hz)，12.69(1H，s)，14.76( 1H，br).MS：286(M+H-2HCl)+
374	18	1H-NMR(400MHz，d6-DMSO)δ：2.02-2.20(4H，m)，2.24-2.3 6(2H，m)，2.43-2.61(2H，m)，2.47(3H，s)，4.01-4.11(2H，m)，4.5 3-4.62(1H，m)，6.67-6.73(1H，m)，7.37-7.42(1H，m)，8.74(1H，s )，9.00-9.10(1H，m)，9.18-9.29(1H，m)，9.45(1H，d，J＝7.6Hz)，1 2.34(1H，brs).MS：325(M+H-2HCl)+
			375	18	1H-NMR(400MHz，d6-DMSO)δ：1.34-2.15(15H，m)，4.02-4. 11(1H，m)，6.43(1H，d，J＝2.9Hz)，6.56(1H，d，J＝2.9Hz)，7.11-7. 12(1H，m)，7.63-7.65(1H，m)，8.37(1H，s)，10.11(1H，d，J＝8.0H z)，11.43(1H，brs).MS：326(M+H)+.
376	18	1H-NMR(400MHz，d6-DMSO)δ：1.38-2.08(15H，m)，4.09-4. 11(1H，m)，6.39(1H，d，J＝3.5Hz)，6.56(1H，d，J＝3.5Hz)，7.11-7. 12(1H，m)，7.64-7.65(1H，m)，8.35(1H，s)，10.09(1H，d，J＝8.2H z)，11.44(1H，brs).MS：326(M+H)+.

377

18

1H-NMR(400MHz，d6-DMSO)δ：1.15-2.51(15H，m)，4.28-4. 33(1H，m)，6.53-6.59(1H，m)，6.75-6.79(1H，m)，7.32-7.34(1H ，m)，8.06-8.12(3H，m)，8.24-8.25(1H，m)，12.09-12.14(1H，m). MS：308(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			378	19	MS：286(M+H)+
379	19	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.51(2H，m)，1.63(1 H，brs)，1.68-1.71(2H，m)，1.80-1.89(4H，m)，2.09(1H，brs)，2. 25(1H，brs)，4.10-4.13(1H，m)，4.56(1H，m)，4.75(2H，d，J＝5.6 Hz)，4.87(1H，t，J＝5.6Hz)，6.50-6.52(1H，m)，7.11-7.18(1H，m )，8.47(1H，s)，10.50(1H，d，J＝8.0Hz)，11.77(1H，brs).MS：342( M+H)+
			380	19	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.19(13H，m)，4.21-4 .23(1H，m)，4.51(1H，s)，4.74-4.76(2H，d，J＝6.0Hz)，4.83(1H，t ，J＝6.9Hz)，6.46-6.48(1H，m)，7.17-7.19(1H，m)，8.47(1H，s)，1 0.46(1H，d，J＝8.0Hz)，11.74(1H，s) .MS：342(M+H)+
381	19	1H-NMR(400MHz，d6-DMSO)δ：1.23-2.32(13H，m)，3.00-3 .07(2H，m)，4.21(1H，brs)，4.43(1H，brs)，4.75(2H，brs)，6.46-6. 49(1H，m)，6.55(1H，s)，7.16-7.17(1H，m)，8.46(1H，s)，10.54(1 H，d，J＝8.0Hz)，11.75(1H，brs).MS：356(M+H)+
			382	22	MS：391(M+H)+
383	22	1H-NMR(400MHz，d6-DMSO)δ：1.77-1.87(2H，m)，1.92-2. 08(6H，m)，2.10-2.15(1H，m)，2.65-2.73(4H，m)，3.21(3H，s)，4 .36(2H，s)，4.51(1H，s)，6.35-6.38(1H，m)，7.45(1H，t，J＝2.9Hz) ，7.91(1H，s)，10.84(1H，s)，11.60(1H，s).MS：405(M+H)+
			384	22	1H-NMR(400MHz，d6-DMSO)δ：1.59-1.67(2H，m)，1.82-2. 07(3H，m)，2.16-2.30(4H，m)，2.35-2.43(2H，m)，2.69-2.73(2 H，m)，3.28(3H，s)，4.39(2H，s)，4.59(1H，s)，6.31-6.35(1H，m)， 7.43(1H，t，J＝3.0Hz)，7.90(1H，s)，10.77(1H，br)，11.56(1H，s). MS：406(M+H)+
385	22	MS：340(M+H)+
			386	22	MS：340(M+H)+
387	22	1H-NMR(400MHz，d6-DMSO)δ：1.48-1.53(4H，m)，1.58-1. 64(2H，m)，1.70-1.75(2H，m)，1.93-1.96(1H，m)，2.05-2.11(2 H，m)，2.16-2.20(2H，m)，3.06-3.08(2H，m)，4.27-4.30(1H，m)， 4.41-4.45(1H，m)，6.52-6.54(1H，m)，7.26-7.28(1H，m)，8.11- 8.12(1H，m)，8.29-8.31(1H，m)，8.63(1H，s)，9.03-9.06(1H，m) ，11.86(1H，brs).MS：409(M+H)+
			388	22	1H-NMR(400MHz，d6-DMSO)δ：1.31-1.35(2H，m)，1.47-1. 49(2H，m)，1.75-1.80(2H，m)，1.85-2.00(5H，m)，2.16-2.19(2 H，m)，3.01-3.03(2H，m)，4.33-4.41(2H，m)，6.61-6.63(1H，m)， 7.27-7.28(1H，m)，8.14-8.16(1H，m)，8.19-8.20(1H，m)，8.63( 1H，s)，8.92-8.95(1H，m)，11.87(1H，brs).MS：409(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			389	22	1H-NMR(400MHz，d6-DMSO)δ：1.41-1.46(2H，m)，1.69-1.79( 4H，m)，1.96-2.08(3H，m)，2.31-2.37(2H，m)，2.67-2.70(2H，m)，4 .48(1H，s)，4.57(1H，s)，6.3(1H，d，J＝3.4Hz)，7.45-7.45(1H，m)，7. 89(1H，s)，10.75(1H，s)，11.57(1H，s).MS：325(M+H)+
390	22	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.49(2H，m)，1.63-1.79( 4H，m)，1.92-1.98(2H，m)，2.14-2.34(3H，m)，2.78-2.81(1H，m)，4 .37(1H，s)，4.39(1H，s)，6.33-6.35(1H，m)，6.55(1H，s)，7.43(1H，t， J＝2.9Hz)，7.89(1H，s)，10.75(1H，s)，11.56(1H，s).MS：325(M+H )+
			391	23	1H-NMR(400MHz，d6-DMSO)δ：1.57-1.63(2H，m)，1.75-2.11( 8H，m)，2.44-2.59(4H，m)，4.55(1H，s)，6.34(1H，dd，J＝1.4Hz，3.3 Hz)，7.43(1H，t，J＝2.9Hz)，7.89(1H，s)，10.74(1H，s)，11.56(1H，s) .MS：309(M+H)+
392	23	1H-NMR(400MHz，d6-DMSO)δ：1.42-3.57(13H，m)，4.37-4.6 1(2H，m)，3.29-3.36(1H，m)，7.42-7.46(1H，m)，7.90(1H，s)，10.7 5-10.77(1H，m)，11.56(1H，s).MS：325(M+H)+
			393	23	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.68(12H，m)，1.86-1.9 1(3H，m)，3.71(2H，s)，6.65(1H，dd，J＝1.8Hz，3.5Hz)，7.39(1H，t，J ＝3.1Hz)，7.91(1H，s)，10.86(1H，s)，11.52(1H，s).MS：323(M+H) +
394	23	1H-NMR(400MHz，d6-DMSO)δ：1.51-1.59(2H，m)，2.03-2.14( 5H，m)，2.33-2.52(4H，m)，2.63-2.68(2H，m)，3.90(1H，s)，4.76(1 H，d，J＝3.1Hz)，6.64-6.65(1H，m)，7.47(1H，t，J＝3.1Hz)，7.90(1H， s)，10.78(1H，s)，11.61(1H，s.MS：325(M+H)+
			395	23	1H-NMR(400MHz，d6-DMSO)δ：1.56-1.79(5H，m)，2.31-2.55( 9H，m)，4.75(1H，s)，6.61(1H，s)，7.48(1H，t，J＝3.1Hz)，7.91(1H，s) ，10.78(1H，s)，11.61(1H，s).MS：325(M+H)+
396	23	1H-NMR(400MHz，d6-DMSO)δ：1.51-1.60(2H，m)，1.71-1.84( 4H，m)，1.95-2.02(2H，m)，2.20-2.25(1H，m)，2.39-2.45(2H，m)，2 .79-2.84(2H，m)，3.11(3H，s)，4.42(1H，s)，6.35-6.38(1H，m)，7.44 (1H，t，J＝3.1Hz)，7.90(1H，s)，10.76(1H，s)，11.57(1H，s).MS：338 (M+H)+
			397	23	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.50(2H，m)，1.74-1.77( 2H，m)，1.83-1.88(2H，m)，2.02-2.15(3H，m)，2.72-2.37(2H，m)，2 .75-2.79(2H，m)，3.19(3H，s)，4.50(1H，s)，6.34(1H，dd，J＝1.7Hz， 3.6Hz)，7.44(1H，t，J＝3.0Hz)，7.90(1H，s)，10.77(1H，s)，11.56(1 H，s).MS：339(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			398	23	1H-NMR(400MHz，d6-DMSO)δ：1.53-1.60(2H，m)，1.85-1. 92(2H，m)，1.97-2.09(3H，m)，2.18-2.26(2H，m)，2.38-2.45(2 H，m)，2.65-2.71(2H，m)，3.64(3H，s)，4.54(1H，s)，6.30-6.31(1 H，m)，7.43(1H，t，J＝3.0Hz)，7.90(1H，s)，10.78(1H，s)，11.57(1 H，s).MS：367(M+H)+
399	23	1H-NMR(400MHz，d6-DMSO)δ：1.17(3H，t，J＝7.1Hz)，1.69- 1.93(6H，m)，2.03-2.11(2H，m)，2.37-2.47(2H，m)，2.71-2.75( 2H，m)，3.73(2H，d，J＝5.8Hz)，4.06(2H，q，J＝7.1Hz)，4.49(1H，s )，6.34-6.36(1H，m)，7.44(1H，t，J＝3.0Hz)，7.81(1H，t，J＝5.8Hz )，7.90(1H，s)，10.75(1H，s)，11.57(1H，s).MS：438(M+H)+
			400	23	1H-NMR(400MHz，d6-DMSO)δ：1.2(3H，t，J＝7.1Hz)，1.50-1 .58(2H，m)，1.84-1.88(2H，m)，1.95-2.03(3H，m)，2.18-2.26(2 H，m)，2.38-2.46(2H，m)，2.63-2.70(2H，m)，3.8(2H，d，J＝5.8H z)，4.09(2H，q，J＝7.1Hz)，4.55(1H，s)，6.36-6.38(1H，m)，7.45( 1H，t，J＝3.0Hz)，7.90(1H，s)，8.07(1H，t，J＝6.1Hz)，10.78(1H，s) ，11.58(1H，s).MS：438(M+H)+
401	23	1H-NMR(400MHz，d6-DMSO)δ：1.67-1.73(2H，m)，1.78-1. 82(2H，m)，1.84-1.91(2H，m)，2.00-2.10(3H，m)，2.37-2.44(2 H，m)，2.68-2.72(2H，m)，4.48(1H，s)，6.34-6.35(1H，m)，6.70( 1H，s)，6.91(1H，s)，7.44(1H，t，J＝3.0Hz)，7.90(1H，s)，10.75(1H ，s)，11.56(1H，s).MS：352(M+H)+
			402	23	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.55(2H，m)，1.81-1. 85(2H，m)，1.93-2.00(3H，m)，2.16-2.21(2H，m)，2.38-2.45(2 H，m)，2.61-2.66(2H，m)，4.53(1H，s)，6.38-6.39(1H，m)，6.80( 1H，s)，7.15(1H，s)，7.44(1H，t，J＝3.0Hz)，7.90(1H，s)，10.76(1H ，s)，11.56(1H，s).MS：352(M+H)+
403	23	1H-NMR(400MHz，d6-DMSO)δ：1.35-1.40(9H，m)，1.45-2. 13(7H，m)，2.25-2.40(4H，m)，2.64-2.77(2H，m)，4.41-4.49(1 H，m)，6.27-6..34(1H，m)，6.39-6.58(1H，m)，7.42-7.47(1H，m) ，7.89(1H，s)，10.75-10.76(1H，m)，11.54-11.59(1H，m).MS：4 24(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			404	23	1H-NMR(400MHz，d6-DMSO)δ：1.57-1.63(2H，m)，1.74-1.85( 4H，m)，1.95-2.02(2H，m)，2.21-2.26(1H，m)，2.42-2.48(2H，m)，2 .65(2H，t，J＝6.0Hz)，2.79-2.83(2H，m)，3.55(2H，t，J＝6.0Hz)，4.44 (1H，s)，6.38-6.40(1H，m)，7.46(1H，t，J＝3.0Hz)，7.92(1H，s)，10.8 3(1H，s)，11.65(1H，s).MS：378(M+H)+
405	23	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.52(2H，m)，1.75-1.81( 2H，m)，1.86-1.92(2H，m)，2.08-2.17(3H，m)，2.31-2.37(2H，m)，2 .71(2H，t，J＝6.0Hz)，2.75-2.79(2H，m)，3.65(2H，t，J＝6.0Hz)，4.53 (1H，s)，6.38(1H，s)，7.45(1H，t，J＝3.0Hz)，7.91(1H，s)，10.82(1H，s )，11.62(1H，s).MS：378(M+H)+
			406	23	1H-NMR(400MHz，d6-DMSO)δ：1.58-1.67(2H，m)，2.06-2.11( 1H，m)，2.30-2.59(6H，m)，2.66-2.78(4H，m)，4.68(1H，s)，6.34-6. 36(1H，m)，7.44(1H，t，J＝3.1Hz)，7.90(1H，s)，10.79(1H，s)，11.58( 1H，s).MS：387，389(M+H)+
407	23	1H-NMR(400MHz，d6-DMSO)δ：1.59-1.69(2H，m)，2.07-2.14( 1H，m)，2.36-2.47(6H，m)，2.65-2.72(2H，m)，2.86-2.92(2H，m)，4 .98(1H，s)，7.99(1H，s)，8.35(1H，s)，10.98(1H，s)，13.00(1H，s).M S：388，390(M+H)+
			408	23	1H-NMR(400MHz，d6-DMSO)δ：1.17-2.47(9H，m)，2.93-3.00( 1H，m)，4.36-4.42(1H，m)，6.54-6.57(1H，m)，7.42-7.44(1H，m)，7 .88(1H，s)，10.77(1H，brs)，11.58(1H，brs).MS：269(M+H)+
409	23	1H-NMR(400MHz，d6-DMSO)δ：1.20-1.86(7H，m)，2.32-2.42( 1H，m)，3.05-3.17(1H，m)，4.71-4.84(1H，m)，6.49-6.55(1H，m)，6 .91(1H，s)，7.40-7.46(1H，m)，7.90(1H，s)，10.77(1H，brs)，11.56( 1H，brs).MS：269(M+H)+
			410	23	1H-NMR(400MHz，d6-DMSO)δ：1.01(3H，d，J＝7.2Hz)，1.24(3 H，s)，1.30(3H，s)，1.88-2.09(3H，m)，2.29-2.52(4H，m)，4.81-4.92 (1H，m)，6.44-6.49(1H，m)，7.43-7.47(1H，m)，7.92(1H，s)，10.92( 1H，brs)，11.64(1H，brs).MS：311(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			411	23	1H-NMR(400MHz，d6-DMSO)δ：0.78(3H，s)，0.91(3H，s)，1.14( 3H，s)，1.21-1.31(1H，m)，1.63-1.73(1H，m)，1.80-1.88(2H，m)，1. 97-2.11(2H，m)，2.75(1H，dd，J＝5.3，12.5Hz)，4.80(1H，ddd，J＝2. 4，5.3，12.0Hz)，6.45(1H，dd，J＝1.7，3.6Hz)，7.40-7.43(1H，m)，7.9 1(1H，s)，10.89(1H，brs)，11.58(1H，brs).MS：311(M+H)+
412	23	1H-NMR(400MHz，d6-DMSO)δ：1.15-3.14(13H，m)，4.41-4.6 0(1H，m)，6.35-6.40(1H，m)，7.43-7.47(1H，m)，7.90-7.92(1H，m )，10.80-10.87(1H，m)，11.62(1H，brs).MS：327(M+H)+
			413	24	MS：330(M+H)+
414	24	1H-NMR(400MHz，d6-DMSO)δ：1.46(2H，d，J＝12.3Hz)，1.63( 2H，s)，1.72(2H，d，J＝12.1Hz)，1.92(2H，d，J＝12.1Hz)，1.99(1H，s) ，2.39(2H，d，J＝12.3Hz)，2.96(2H，s)，4.34(1H，s)，4.67(1H，s)，7.97 (1H，s)，8.31(1H，s)，10.9(1H，s)，13.0(1H，s).MS：348(M+Na)+
			415	24	1H-NMR(400MHz，d6-DMSO)δ：1.42(2H，d，J＝12.5Hz)，1.68( 2H，s)，1.72(2H，d，J＝12.0Hz)，2.00(2H，d，J＝12.0Hz)，2.08(1H，s) ，2.39(2H，d，J＝12.5Hz)，2.79(2H，s)，4.49(1H，s)，4.88(1H，s)，7.97 (1H，s)，8.32(1H，s)，10.9(1H，brs)，13.0(1H，brs).MS：348(M+Na )+
416	25	1HNMR(400MHz，d6-DMSO)δ：1.38-2.18(11H，m)，3.33-3.40 (1H，m)，4.47(1H，s)，4.92-5.05(1H，m)，7.05(1H，br)，7.82(1H，br )，8.05(1H，s)，8.45(1H，s)，9.97(1H，d，J＝9.2Hz)，11.5(1H，s)，12.8 (1H，br).MS：328(M+H)+
			417	25	1HNMR(400MHz，d6-DMSO)δ：1.32(3H，t，J＝7.1Hz)，1.56(2H ，t，J＝10.7Hz)，1.80-1.83(2H，m)，1.92-2.08(4H，m)，3.20(2H，brs) ，3.57(2H，s)，4.28(2H，q，J＝7.1Hz)，5.30-5.45(1H，brs)，7.20-7.24 (1H，m)，7.32(2H，dd，J＝7.2，7.8Hz)，7.39(2H，d，J＝7.2Hz)，8.14(1 H，s)，8.48(1H，d，J＝8.8Hz)，8.60(1H，s)，13.0(1H，brs).MS：406( M+H)+
418	25	1HNMR(400MHz，d6-DMSO)δ：1.11(6H，t，J＝6.8Hz)，1.50-2.3 1(13H，m)，3.46-3.68(4H，m)，4.11-4.12(1H，m)，4.57(1H，s)，6.6 5-6.66(1H，m)，6.74(1H，s)，7.38-7.39(1H，m)，8.54(1H，s)，8.88( 1H，d，J＝8.0Hz)，9.30(1H，s).MS：454(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			419	26	1H-NMR(400MHz，d6-DMSO)δ：1.46-1.52(2H，m)，1.64-1.66( 2H，m)，1.78-1.84(2H，m)，2.01-2.06(2H，m)，2.18-2.27(3H，m)，3 .10-3.12(2H，m)，4.40(1H，s)，4.76(1H，br)，6.53-6.55(1H，m)，7.6 1-7.63(1H，m)，8.56-8.59(1H，s)，12.09(1H，brs)，13.14(1H，brs). MS：442(M+Na)+
420	26	1H-NMR(400MHz，d6-DMSO)δ：1.39(3H，t，J＝7.1Hz)，1.48-1. 53(2H，m)，1.62-1.65(2H，m)，1.69-1.74(2H，m)，1.81-1.93(4H， m)，2.09-2.12(1H，m)，2.29-2.33(2H，m)，4.22-4.26(1H，m)，4.47 (2H，q，J＝7.1Hz)，4.54(1H，brs)，6.56-6.58(1H，m)，7.26-7.27(1H ，m)，7.80-7.83(1H，m)，8.71(1H，s)，11.71(1H，brs).MS：424(M+ H)+
			421	26	1H-NMR(400MHz，d6-DMSO)δ：1.48-2.31(13H，m)，4.24(1H， m)，4.52(1H，s)，6.55(1H，m)，7.23(1H，m)，7.86(1H，m)，8.75(1H， s)，9.67(1H，s)，11.63(1H，s).MS：352(M+H)+
422	26	1HNMR(400MHz，d6-DMSO)δ：1.34(3H，t，J＝7.1Hz)，1.45-1.8 4(10H，m)，2.06(1H，brs)，2.22(2H，brs)，4.31(2H，q，J＝7.1Hz)，4. 53(1H，s)，5.04(1H，d，J＝8.7Hz)，8.12(1H，s)，8.64(1H，s)，9.16(1 H，d，J＝8.7Hz)，12.8(1H，brs).MS：357(M+H)+
			423	26	1HNMR(400MHz，d6-DMSO)δ：1.32(3H，t，J＝7.1Hz)，1.42- 1.90(10H，m)，2.15(1H，brs)，2.22(2H，brs)，3.15(3H，s)，4.31(2H， q，J＝7.1Hz)，5.12(1H，d，J＝8.7Hz)，8.14(1H，s)，8.64(1H，s)，9.14( 1H，d，J＝8.7Hz)，13.0(1H，brs).MS：371(M+H)+
424	26	1H-NMR(400MHz，d6-DMSO)δ：1.40-1.67(10H，m)，1.88- 1.94(1H，m)，2.02(2H，brs)，3..03(2H，d，J＝5.5Hz)，4.37(1H，t，J＝5 .5Hz)，5.05(1H，d，J＝8.9Hz)，7.04(1H，brs)，7.82(1H，brs)，8.03(1 H，s)，8.45(1H，s)，10.0(1H，d，J＝8..9Hz)，12.7(1H，brs).MS：342( M+H)+
			425	26	1H-NMR(400MHz，d6-DMSO)δ：1.22-1.84(10H，m)，1.94( 1H，brs)，2.06(2H，brs)，2.98(2H，d，J＝5.7Hz)，4.36(1H，t，J＝5.7Hz )，5.06(1H，d，J＝8.7Hz)，7.10(1H，brs)，7.82(1H，brs)，8.04(1H，s)， 8.45(1H，s)，10.0(1H，d，J＝8.7Hz)，12.7(1H，brs).MS：342(M+H) +
426	26	MS：337(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			427	27	1H-NMR(400MHz，d6-DMSO)δ：1.36-1.41(2H，m)，1.64-1. 70(4H，m)，1.80-1.93(4H，m)，2.04-2.07(1H，m)，2.11-2.14(2 H，m)，4.13-4.16(1H，m)，4.44(1H，s)，5.82(2H，brs)，6.37-6.38 (1H，m)，7.09-7.11(1H，m)，8.13(1H，s)，8.97(1H，d，J＝8.2Hz)， 9.54(1H，s)，11.23(1H，brs).MS：342(M+H)+
428	28	1H-NMR(400MHz，d6-DMSO)δ：1.39(3H，t，J＝7.2Hz)，1.46- 1.54(2H，m)，1.58-1.77(4H，m)，1.80-1.90(2H，m)，1.97-2.14( 3H，m)，2.28-2.35(2H，m)，4.18-4.25(1H，m)，4.42(1H，s)，4.43 (2H，q，J＝7.2Hz)，6.60(1H，d，J＝3.5Hz)，7.29(1H，d，J＝3.5Hz)， 8.65(1H，s)，9.04(1H，d，J＝7.7Hz)，11.91(1H，brs).MS：424(M +H)+
			429	28	1H-NMR(400MHz，d6-DMSO)δ：1.30-1.36(3H，m)，1.63-1. 72(2H，m)，1.93-2.04(2H，m)，2.07-2.49(6H，m)，2.75-2.84(3 H，m)，4.37-4.45(2H，m)，4.61-4.68(1H，m)，6.36-6.41(1H，m)， 7.43-7.47(1H，m)，7.91(1H，s)，10.82(1H，s)，11.58-11.61(1H， m).MS：449(M+H)+
430	28	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.29(13H，m)，3.42(3 H，s)，4.21-4.22(1H，m)，4.46(1H，s)，4.65(2H，s)，6.58-6.59(1 H，m)，7.26-7.27(1H，m)，8.60(1H，s)，9.04(1H，d，J＝8.0Hz)，11. 84(1H，s).MS：396.3(M+H)+
			431	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.39(20H，m)，2.60(1 H，s)，2.69(1H，m)，3.22(3H，s)，3.69(1H，m)，4.44(1H，m)，4.77( 1H，s)，6.64(1H，m)，7.45(1H，m)，8.74(1H，m)，8.78(1H，m)，10. 83(1H，s)，12.05(1H，s).MS：507(M+H)+
432	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.67(18H，m)，3.12(2 H，m)，4.02(2H，m)，4.44(1H，m)，4.77(1H，s)，6.66(1H，m)，7.46 (1H，m)，8.73(1H，s)，9.21(1H，m)，10.94(1H，m)，12.07(1H，m) .MS：549(M+Na)+
			433	32	MS：543(M+Na)+
434	32	MS：505(M-H)-
			435	32	MS：467(M+H)+
436	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.69(21H，m)，3.89(1 H，m)，4.42(1H，m)，4.76(1H，s)，6.65(1H，m)，7.45(1H，m)，8.74 (1H，s)，9.02(1H，m)，10.88(1H，s)，12.05(1H，s).MS：513(M+ H)+
			437	32	1H-NMR(400MHz，d6-DMSO)δ：0.85-2.61(21H，m)，3.63-3 .79(2H，m)，4.35(1H，m)，4.44(1H，m)，4.76(1H，s)，6.65(1H，m )，7.46(1H，m)，8.72(1H，s)，8.74(1H，s)，10.86(1H，s)，12.07(1 H，s).MS：493(M+H)+
438	32	MS：464(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			439	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.50(2H，m)，1.65-1.68( 2H，m)，1.77-2.04(6H，m)，2.17-2.21(1H，m)，2.33-2.40(2H，m)，2 .59-2.64(2H，m)，3.35-3.48(1H，m)，3.77-3.88(3H，m)，4.46-4.48 (1H，m)，4.67-4.69(1H，m)，4.75-4.77(1H，m)，4.89，5.18(1H，m)， 6.64-6.65(1H，m)，7.44-7.46(1H，m)，8.74，8.78(1H，m)，11.03-1 1.19(1H，m)，12.10(1H，brs).MS：499(M+N)+
440	32	1H-NMR(400MHz，d6-DMSO)δ：1.44-1.49(2H，m)，1.65-1.68( 2H，m)，1.77-1.83(2H，m)，1.99-2.05(2H，m)，2.17-2.21(1H，m)，2 .35-2.40(2H，m)，2.58-2.62(2H，m)，4.45(1H，s)，4.75-4.77(1H， m)，6.65-6.67(1H，m)，7.45-7.47(1H，m)，8.03(1H，brs)，8.39(1H， brs)，8.74(1H，s)，10.82(1H，brs)，12.08(1H，brs).MS：417(M+Na )+
			441	32	1H-NMR(400MHz，d6-DMSO)δ：0.77-3.54(22H，m)，4.84(1H， brs)，6.82-6.86(1H，m)，7.49-7.53(1H，m)，8.64(1H，s)，8.87-8.93 (1H，m)，12.12(1H，brs).MS：453(M+H)+
442	32	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.44(2H，m)，1.71-1.73( 2H，m)，1.78-1.83(2H，m)，2.04-2.09(2H，m)，2.11-2.15(1H，m)，2 .38-2.44(2H，m)，2.49-2.51(2H，m)，4.56(1H，s)，4.88-4.89(1H， m)，6.60-6..62(1H，m)，7.45-7.47(1H，m)，8.01(1H，brs)，8.36(1H ，brs)，8.74(1H，s)，10.85-10.90(1H，m)，12.07(1H，brs).MS：417( M+Na)+
			443	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.39(13H，m)，3.16(2H， d，J＝5.2Hz)，3.50(2H，q，J＝5.6Hz)，4.07(1H，q，J＝5.6Hz)，4.76(1 H，brs)，4.78(1H，t，J＝5.2Hz)，6.65-6.66(1H，m)，7.45-7.47(1H，m )，8.71(1H，s)，8.88-8.90(1H，m)，10.89(1H，s)，12.07(1H，brs).M S：439(M+H)+
444	32	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.37(13H，m)，2.94(3H， s)，3.12(3H，s)，4.46-4.47(1H，m)，4.75(1H，brs)，6.63-6.64(1H，m )，7.45-7.46(1H，m)，8.78(1H，s)，11.36(1H，s)，12.16(1H，s).MS： 423.3(M+H)+
			445	32	1H-NMR(400MHz，d6-DMSO)δ：1.15-2.45(13H，m)，2.49-2.5 1(6H，m)，4.21(4H，brs)，4.76(1H，brs)，6.55-6.55(1H，m)，7.45-7. 46(1H，m)，8.56(1H，s)，8.72(1H，s)，8.83-8.87(1H，m)，11.44(1H， s)，12.07(1H，brs).MS：466.3(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			446	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.39(11H，m)，2.49-2.4 5(m，3H)，2.60(2H，brs)，3.16-3.20(2H，m)，3.81-3.82(1H，m)，4.4 5(1H，s)，4.76(1H，brs)，4.85(1H，d，J＝4.8Hz)，6.65-6.67(1H，m)， 7.45-7.46(1H，m)，8.72(1H，s)，8.82-8.82(1H，m)，10.90(1H，s)，1 2.07(1H，brs).MS：453(M+Na)+
447	32	1H-NMR(400MHz，d6-DMSO)δ：1.04-2.38(17H，m)，3.46-3.7 0(5H，m)，4.35-4.36(1H，m)，4.45(1H，q)，4.57-4.59(1H，m)，4.76( 1H，brs)，6.65-6.66(1H，m)，7.45-7.46(1H，m)，8.72(1H，s)，8.82( 1H，d，J＝8.0Hz)，10.88(1H，s)，12.06(1H，brs).MS：515(M+H)+
			448	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.60(17H，m)，3.45-4.0 0(6H，m)，4.47(1H，s)，4.76(1H，brs)，6.56-6.57(1H，m)，7.45-7.4 6(1H，m)，8.71(1H，s)，10.93(1H，brs)，12.07(1H，brs).MS477(M -H)-
449	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.39(17H，m)，3.43-3.9 9(5H，m)，4.34-4.54(1H，m)，4.76(1H，brs)，6.65-6.66(1H，m)，7.4 5-7.46(1H，m)，8.73(1H，s)，9.02(1H，d，J＝8.0Hz)，10.91(1H，brs) ，12.07(1H，brs).MS：477(M-H)-
			450	32	1H-NMR(400MHz，d6-DMSO)δ：1.56-1.59(2H，m)，2.03-2.08( 3H，m)，2.22-2.25(2H，m)，2.46-2.57(6H，m)，3.28(3H，s)，3.39-3. 40(2H，m)，3.48-3.49(2H，m)，5.04(1H，s)，6.78(1H，s)，7.46(1H，s )，8.73(1H，s)，8.95(1H，m)，10.99(1H，s)，12.05(1H，s).MS：462( M+H)+，484(M+Na)+
451	32	1H-NMR(400MHz，d6-DMSO)δ：1.36-2.37(17H，m)，3.43-3.6 0(7H，m)，4.48(1H，brs)，4.75(1H，brs)，6.64(1H，brs)，7.45(1h，brs )，8.81-8.83(1H，m)，11.45(1H，brs)，12.11(1H，brs).MS：506(M+ H)+
			452	32	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.39(18H，m)，3.42-4.0 1(6H，m)，4.47(1H，s)，4.76(1H，brs)，6.56-6.57(1H，m)，7.45-7.4 6(1H，m)，8.71(1H，s)，8.95-8.96(1H，m)，10.93(1H，brs)，12.07(1 H，brs).MS：515(M+Na)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			453	32	1H-NMR(400MHz，d6-DMSO)δ：1.56(2H，m)，1.75-1.77(1H， m)，1.88-1.95(4H，m)，2.04-2.12(4H，m)，2.29-2.33(2H，m)，3.28 (3H，s)，3.38-3.42(2H，m)，3.47-3.49(2H，m)，3.59and3.65(total3 H，eachs)，4.90and4.96(total1H，eachs)，6.66-6.77(1H，m)，7.44- 7.47(1H，m)，8.71and8.72(total1H，eachs)，8.97(1H，m)，11.00(1 H，s)，12.07(1H，s).MS：517(M+Na)+
454	32	1H-NMR(400MHz，d6-DMSO)δ：52-1.55(3H，m)，1.74-1.84(5 H，m)，2.04-2.07(2H，m)，2.25(1H，s)，2.64(2H，s)，3.13(3H，s)，3.2 8(3H，s)，3.39-3.42(2H，m)，3.47-3.50(2H，m)，4.81(1H，s)，6.68( 1H，dd，J＝1.9，3.3Hz)，7.40(1H，t，J＝3.0Hz)，8.71(1H，s)，8.94(1H， t，J＝5.8Hz)，11.02(1H，s)，12.06(1H，s).MS：467(M+H)+，489(M +Na)+
			455	32	1H-NMR(400MHz，d6-DMSO)δ：1.27-1.32(2H，m)，1.45-1.55( 4H，m)，1.68-1.71(2H，m)，1.84-1.91(2H，m)，2.00(1H，s)，2.09-2. 17(2H，m)，3.03and3.13(total2H，eachd，J＝5.5and5.5Hz)，3.28( 3H，s)，3.39-3.42(2H，m)，3.47-3.50(2H，m)，4.30and4.47(total1 H，eacht，J＝5.5and5.5Hz)，4.85and4.87(total1H，eachs)，6.60an d6.65(total1H，eachm)，7.46(1H，t，J＝3.0Hz)，8.71and8.72(total 1H，s)，8.97(1H，m)，10.96and10.97(total1H，s)，12.07(1H，s).MS ：467(M+H)+，489(M+Na)+
456	33	MS：646(M+H)+
			457	33	MS：506(M+H)+
458	33	1H-NMR(400MHz，d6-DMSO)δ：1.01(3H，d，J＝7.6Hz)，1.24(3 H，s)，1.30(3H，s)，1.88-2.83(7H，m)，4.80-4.90(1H，m)，6.45-6.48 (1H，m)，7.43-7.46(1H，m)，7.92(1H，s)，10.91(1H，brs)，11.63(1H ，brs).MS：311(M+H)+
			459	33	MS：465(M+H)+
460	33	MS：497(M+H)+
			461	33	MS：509(M+H)+
462	33	MS：509(M+H)+
			463	33	MS：478(M+H)+
464	33	MS：465(M+H)+
			465	33	MS：463(M+H)+
466	33	MS：434(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			467	33	MS：499(M+H)+
468	33	MS：541(M+H)+
			469	33	MS：477(M+H)+
470	33	MS：449(M+H)+
			471	33	MS：546(M+H)+
472	33	MS：506(M+H)+
			473	33	MS：453(M+H)+
474	33	MS：504(M+H)+
			475	33	MS：453(M+H)+
476	34	1H-NMR(400MHz，d6-DMSO)δ：1.75-1.90(4H，m)，2.00-2. 10(2H，m)，2.14-2.28(3H，m)，2.37-2.54(4H，m)，4.21-4.27(1 H，m)，6.36(1H，d，J＝6.8Hz)，6.73-6.78(1H，m)，7.27-7.31(1H， m)，8.11(1H，s)，11.86(1H，brs).MS：427(M+Na)+
			477	35	MS：314(M+H)+
478	35	MS：393(M+H)+
			479	35	MS：382(M+H)+
480	35	1H-NMR(400MHz，d6-DMSO)δ：1.39-1.46(2H，m)，1.56-1. 87(8H，m)，2.07(1H，m)，2.18(3H，s)，2.25(2H，m)，4.03(1H，m) ，4.47(1H，s)，4.77(1H，d，J＝7.2Hz)，6.38(1H，d，J＝3.6Hz)，7.13 (1H，d，J＝3.6Hz)，7.71(1H，s)，8.32(1H，s)，11.156(1H，s).MS：2 98(M+H)+
			481	35	MS：378(M+Na)+
482	35	MS：420(M+Na)+
			483	35	1H-NMR(400MHz，d6-DMSO)δ：1.22-2.24(13H，m)，3.20-3 .40(2H，m)，4.42-4.65(2H，m)，6.44-6.48(1H，m)，6.82-7.09(1 H，br)，7.16-7.19(1H，m)，7.56-7.84(1H，br)，8.34(1H，s)，9.45( 1H，d，J＝8.0Hz)，11.48(1H，brs).MS：329(M+H)+.
484	35	1H-NMR(400MHz，d6-DMSO)δ：1.47-1.51(2H，m)，1.61-1. 63(2H，m)，1.68-1.73(2H，m)，1.81-1.87(2H，m)，1.91-1.96(2 H，m)，2.08-2.12(1H，m)，2.28-2.31(2H，m)，4.19-4.23(1H，m)， 4.46(1H，brs)，4.66-4.68(2H，m)，5.68-5.71(1H，m)，6.58-6.60 (1H，m)，7.25-7.26(1H，m)，8.60(1H，s)，9.07(1H，d，J＝7.8Hz)， 11.83(1H，brs).MS：382(M+H)+
			485	35	1H-NMR(400MHz，d6-DMSO)δ：1.31-1.35(2H，m)，1.47-1. 50(2H，m)，1.61-1.98(7H，m)，2.07-2.12(2H，m)，2.96-2.99(2 H，m)，4.11-4.16(1H，m)，4.35-4.39(1H，m)，6.42-6.46(1H，m)， 6.80-7.09(1H，br)，7.10-7.13(1H，m)，7.52-7.88(1H，br)，8.36( 1H，s)，10.13(1H，d，J＝8.0Hz)，11.43(1H，brs).MS：(M+H)+.

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			486	35	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.70(8H，m)，1.89-1. 96(3H，m)，2.05-2.10(2H，m)，3.03-3.08(2H，m)，4.08-4.15(1 H，m)，4.39-4.44(1H，m)，6.40-6.44(1H，m)，6.95-7.19(2H，m)， 7.68-7.96(1H，br)，8.38(1H，s)，10.27(1H，d，J＝8.0Hz)，11.55( 1H，brs).MS：341(M+H)+.
487	35	1H-NMR(400MHz，d6-DMSO)δ：1.34-1.44(2H，m)，1.58-1. 72(4H，m)，1.80-1.90(2H，m)，2.00-2.11(3H，m)，2.33-2.44(2 H，m)，4.18-4.28(3H，m)，6.59-6.60，(1H，m)，6.90-6.98(1H，m) ，7.20(1H，brs)，7.33(1H，brs)，7.38-7.39(1H，m)，7.46(1H，brs)， 8.19(1H，s)，8.61(3H，br)，12.63(1H，brs).MS：313(M-3HCl+ H)+
			488	39	1H-NMR(400MHz，d6-DMSO)δ：1.85-2.25(8H，m)，2.37-2. 41(1H，m)，2.53-2.57(2H，m)，2.91-2.96(1H，m)，3.11-3.18(1 H，m)，4.74(1H，s)，6.55-6.59(1H，m)，7.37(1H，t，J＝2.7Hz)，8.5 1-8.52(1H，m)，10.89(1H，s)，11.94(1H，s).MS：387，389(M+H )+
489	39	1H-NMR(400MHz，d6-DMSO)δ：1.10-1.28(2H，m)，1.36-2. 38(7H，m)，2.54(1H，brs)，5.02-5.08(1H，m)，6.72-6.74(1H，m) ，7.35-7.37(1H，m)，8.47(1H，s)，10.9(1H，brs)，12.0(1H，s).MS ：269(M+H)+
			490	39	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.64(2H，m)，2.10-2. 63(9H，m)，2.75-2.83(2H，m)，4.91(1H，s)，6.64-6.66(1H，m)，7 .37(1H，t，J＝3.0Hz)，8.50(1H，s)，10.81(1H，s)，11.93(1H，s).M S：387，389(M+H)+
491	39	1H-NMR(400MHz，d6-DMSO)δ：1.55-1.60(2H，m)，1.77-1. 80(2H，m)，1.90-2.02(4H，m)，2.06-2.13(2H，m)，2.32-2.36(2 H，m)，2.52-2.57(2H，m)，4.75-4.77(1H，m)，6.53-6.56(1H，m)， 7.35-7.38(1H，m)，8.50(1H，s)，10.78(1H，brs)，11.92(1H，brs). MS：309(M+H)+.
			492	40	1H-NMR(400MHz，d6-DMSO)δ：1.38-1.48(2H，m)，1.64-1. 81(4H，m)，1.93-2.05(2H，m)，2.11-2.19(1H，m)，2.37-2.57(4 H，m)，4.44(0.34H，brs)，4.56-4.59(1H，m)，4.70(0.66H，brs)，6. 50-6.52(0.66H，m)，6.54-6.56(0.34H，m)，7.36-7.38(1H，m)，8 .50(0.66H，s)，8.51(0.34H，s)，10.78(1H，brs)，11.92(1H，brs). MS：325(M+H)+.
493	40	MS：325(M+H)+.

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			494	40	1HNMR(400MHz，d6-DMSO)δ：0.88(3H，d，J＝6.9Hz)，1.72- 1.92(2H，m)，2.15-2.26(1H，m)，3.55-3.70(4H，m)，5.30-5.40( 1H，m)，7.01(1H，d，J＝9.2Hz)，7.15(1H，brs)，7.76(1H，d，J＝9.2 Hz)，7.90(1H，brs)，8.09(1H，s)，8.39(1H，s)，8.48(1H，s)，9.89(1 H，d，J＝9.0Hz)，12.9(1H，brs).MS：420(M+H)+
495	41	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.52(2H，m)，1.76-1. 91(6H，m)，2.10-2.16(1H，m)，2.27-2.33(3H，m)，2.68(2H，t，J＝ 6Hz)，3.59(2H，t，J＝6Hz)，4.76-4.85(1H，m)，6.09(1H，d，J＝7.3 Hz)，8.25-8.27(3H，m)，13.21(1H，br).MS：363(M+H)+
			496	41	1H-NMR(400MHz，d6-DMSO)δ：1.00-1.59(13H，m)，2.64-2 .75(2H，m)，3.54-3.69(2H，m)，4.63-4.76(1H，m)，6.55-6.64(1 H，m)，7.35-7.39(1H，m)，8.50(1H，s)，10.79-10.83(1H，m)，11. 91(1H，s).MS：378(M+H)+
497	41	1H-NMR(400MHz，d6-DMSO)δ：1.54-1.62(2H，m)，1.73-1. 86(4H，m)，1.96-2.27(4H，m)，2.54-2.61(3H，m)，2.67(2H，t，J＝ 6.0Hz)，3.57(2H，t，J＝6.0Hz)，4.63(1H，s)，6.56-6.59(1H，m)，7. 36-7.39(1H，m)，8.49-8.51(1H，m)，10.83(1H，s)，11.93(1H，s). MS：378(M+H)+
			498	41	1H-NMR(400MHz，d6-DMSO)δ：1.41-1.49(2H，m)，1.77-1. 82(2H，m)，1.84-1.89(2H，m)，2.15-2.22(4H，m)，2.41-2.48(3 H，m)，2.71(2H，t，J＝6.0Hz)，3.66(2H，t，J＝6.0Hz)，4.76(1H，s)， 6.61-6.63(1H，m)，7.36-7.37(1H，m)，8.50(1H，s)，10.79(1H，s) ，11.92(1H，s).MS：378(M+H)+
499	41	1H-NMR(400MHz，d6-DMSO)δ：1.42-1.49(2H，m)，1.73-1. 80(4H，m)，1.83-1.89(2H，m)，1.97-2.03(2H，m)，2.09-2.13(1 H，m)，2.18-2.23(2H，m)，2.68(2H，t，J＝6.0Hz)，3.61(2H，t，J＝6. 0Hz)，4.17-4.21(1H，m)，6.48(1H，dd，J＝1.9，3.5Hz)，6.99(1H， br)，7.12(1H，dd，J＝2.5，3.5Hz)，7.79(1H，br)，8.37(1H，s)，10.1 1(1H，d，J＝8.3Hz)，11.46(1H，s).MS：390(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			500	41	1H-NMR(400MHz，d6-DMSO)δ：1.42-1.48(2H，m)，1.71-1.90( 7H，m)，2.10-2.20(4H，m)，2.68(2H，t，J＝5.9Hz)，3.59(2H，t，J＝5.9 Hz)，5.07(1H，d，J＝8.7Hz)，7.12(1H，br)，7.86(1H，br)，8.05(1H，s) ，8.45(1H，s)，9.97(1H，d，J＝8.7Hz)，12.78(1H，br).MS：381(M+H )+
501	41	1H-NMR(400MHz，d6-DMSO)δ：1.53-1.60(2H，m)，1.70-1.79( 6H，m)，1.87-1.95(2H，m)，2.08-2.15(1H，m)，2.21-2.27(2H，m)，2 .69(2H，t，J＝6Hz)，3.58(2H，t，J＝6Hz)，4.99(1H，d，J＝8.6Hz)，7.18 (1H，br)，7.89(1H，br)，8.06(1H，s)，8.46(1H，s)，10.05(1H，d，J＝8.6 Hz)，12.79(1H，br).MS：381(M+H)+
			502	41	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.51(2H，m)，1.77-1.80( 2H，m)，1.83-1.90(2H，m)，2.03-2.09(2H，m)，2.12-2.17(1H，m)，2 .33-2.40(3H，m)，2.70(2H，t，J＝6.0Hz)，2.89-2.93(2H，m)，3.61(2 H，t，J＝6.0Hz)，4.87(1H，s)，7.98(1H，s)，10.94(1H，s)，12.95(1H，b r).MS：379(M+H)+
503	41	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.52(2H，m)，1.79-1.84( 2H，m)，1.87-1.95(2H，m)，2.06-2.10(2H，m)，2.14-2.19(1H，m)，2 .28-2.38(2H，m)，2.95-3.02(2H，m)，4.48(2H，s)，4.82(1H，s)，7.98 (1H，s)，8.33(1H，s)，10.95(1H，s)，12.99(1H，br).MS：356(M+H) +
			504	43	1H-NMR(400MHz，d6-DMSO)δ：1.83-1.90(2H，m)，1.93-1.99( 2H，m)，2.08-2.13(1H，m)，2.23-2.29(5H，m)，2.32-2.36(3H，m)，4 .27(1H，d，J＝7.8Hz)，6.6(1H，d，J＝1.9Hz)，7.3(1H，t，J＝2.3Hz)，7.5 3(1H，br)，8.16(1H，br)，8.47(1H，s)，10.94(1H，s)，12.11(1H，s).M S：389，391(M+H)+
505	43	1H-NMR(400MHz，d6-DMSO)δ：1.22-2.33(10H，m)，4.12(1H， m)，6.44(1H，m)，7.03(1H，m)，7.14(1H，m)，7.64(1H，m)，8.39(1H ，s)，10.25(1H，m)，11.48(1H，s).MS：345(M+H)+
			506	43	1H-NMR(400MHz，d6-DMSO)δ：1.68-2.38(13H，m)，4.98-5.0 2(1H，m)，7.08(1H，brs)，7.90(1H，brs)，8.06(1H，s)，8.47(1H，s)，1 0.4(1H，d，J＝8.6Hz)，12.7(1H，brs).MS：330(M+H)+
507	45	MS：366(M+H)+
			508	46	MS：388(M+H)+
509	46	MS：387(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			510	46	MS：397(M+H)+
511	46	MS：363(M+H)+
			512	46	MS：405(M+H)+
513	46	MS：749(M+H)+
			514	46	MS：381(M+H)+
515	46	MS：314(M+H)+
			516	46	MS：328(M+H)+
517	46	MS：356(M+H)+
			518	46	MS：368(M+H)+
519	46	MS：370(M+H)+
			520	46	MS：377(M+H)+
521	46	MS：379(M+H)+
			522	46	MS：382(M+H)+
523	46	MS：394(M+H)+
			524	46	MS：378(M+H)+
525	46	MS：378(M+H)+
			526	46	MS：393(M+H)+
527	46	MS：426(M+H)+
			528	46	MS：342(M+H)+
529	46	MS：384(M+H)+
			530	47	MS：368(M+H)+
531	47	MS：354(M+H)+
			532	47	MS：354(M+H)+
533	47	MS：354(M+H)+
			534	47	MS：368(M+H)+
535	47	1H-NMR(400MHz，d6-DMSO)δ：1.13-1.27(1H，m)，1.43-1. 52(2H，m)，1.62-1.73(4H，m)，1.78-1.91(5H，m)，2.07-2.42(6 H，m)，3.54-3.67(5H，m)，4.00-4.13(1H，m)，4.53(1H，brs)，6.3 5-6.43(1H，m)，7.18-7.20(1H，m)，7.70(1H，s)，7.82(1H，m)，11 .64(1H，brs).MS：383(M+H)+
			536	49	MS：440(M+H)+
537	47	1H-NMR(400MHz，d6-DMSO)δ：1.58-2.42(8H，m)，3.04-3. 66(4H，m)，4.19-4.38(1H，m)，6.37-6.54(1H，m)，6.87-7.96(8 H，m)，8.36(1H，s)，10.08-10.26(1H，m)，11.42(1H，brs).MS：3 76(M+H)+
			538	49	MS：421(M+H)+
539	49	MS：408(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			540	49	1H-NMR(400MHz，d6-DMSO)δ：1.47-2.22(9H，m)，4.59(1H， m)，4.83(2H，m)，6.59(1H，m)，6.98(1H，m)，7.20(1H，m)，7.73(1H ，m)，8.33(1H，m)，8.37(1H，m)，9.34(1H，m)，11.53(1H，s).MS：38 9(M+H)+
541	49	1H-NMR(400MHz，d6-DMSO)δ：1.49-2.36(7H，m)，4.63(1H， m)，4.91(2H，m)，6.61(1H，m)，6.98(1H，m)，7.21(1H，m)，7.77(1H ，m)，8.32(1H，m)，9.15(2H，m)，9.39(1H，m)，11.54(1H，s).MS：40 9(M+H)+
			542	49	MS：442，444
543	49	1H-NMR(400MHz，d6-DMSO)δ：1.41-2.33(8H，m)，4.61(1H， m)，4.86(2H，m)，6.60(1H，m)，6.95(1H，m)，7.21(1H，m)，7.32(1H ，m)，7.74(1H，m)，7.88(1H，m)，8.32(1H，m)，9.34(1H，m)，11.53(1 H，s).MS：389(M+H)+
			544	49	MS：394(M+H)+
545	49	MS：389(M+H)+
			546	49	1H-NMR(400MHz，d6-DMSO)δ：1.45-1.51(2H，m)，1.59-1.62( 2H，m)，1.66-1.71(2H，m)，1.81-1.92(4H，m)，2.07-2.10(1H，m)，2 .28-2.31(2H，m)，3.69-3.87(8H，m)，4.20-4.24(1H，m)，4.47(1H， s)，6.59-6.61(1H，m)，6.96(1H，d，J＝9.0Hz)，7.28-7.29(1H，m)，7. 91(1H，dd，J＝2.4，9.1Hz)，8.52-8.53(1H，m)，8.66(1H，s)，8.86-8. 89(1H，m)，11.90(1H，brs).MS：566(M+H)+
547	49	MS：405(M+H)+
			548	49	1H-NMR(400MHz，d6-DMSO)δ：1.75-1.87(2H，m)，1.98-2.14( 2H，m)，2.14-2.33(4H，m)，4.25-4.35(1H，m)，4.50-4.83(2H，m)，6 .38-6.45(1H，m)，6.85(1H，d，J＝9.0Hz)，7.03-7.10(1H，m)，7.05(1 H，br)，7.83(1H，br)，7.85(1H，dd，J＝9.0，2.2Hz)，8.38(1H，s)，8.51( 1H，d，J＝2.2Hz)，10.36(1H，d，J＝7.7Hz)，11.43(1H，s) MS：388(M+H)+
549	49	1H-NMR(400MHz，d6-DMSO)δ：1.75-1.87(2H，m)，1.98-2.14( 2H，m)，2.14-2.33(4H，m)，4.25-4.35(1H，m)，4.50-4.83(2H，m)，6 .38-6.45(1H，m)，6.85(1H，d，J＝9.0Hz)，7.03-7.10(1H，m)，7.05(1 H，br)，7.83(1H，br)，7.85(1H，dd，J＝9.0，2.2Hz)，8.38(1H，s)，8.51( 1H，d，J＝2.2Hz)，10.36(1H，d，J＝7.7Hz)，11.43(1H，s).MS：388(M +H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			550	49	1H-NMR(400MHz，d6-DMSO)δ：1.83-1.94(2H，m)，2.01-2. 18(2H，m)，2.18-2.36(4H，m)，4.27-4.38(1H，m)，4.46-5.09(2 H，m)，6.38-6.45(1H，m)，6.87(1H，d，J＝9.5Hz)，7.04-7.11(1H， m)，7.05(1H，br)，7.83(1H，br)，8.24(1H，dd，J＝9.5，2.8Hz)，8.39 (1H，s)，9.01(1H，d，J＝2.8Hz)，10.38(1H，d，J＝7.7Hz)，11.45(1 H，s).MS：408(M+H)+
551	49	1H-NMR(400MHz，d6-DMSO)δ：1.69-1.84(2H，m)，1.99-2. 14(2H，m)，2.14-2.36(4H，m)，4.24-4.34(1H，m)，4.54-4.75(2 H，m)，6.38-6.44(1H，m)，6.88(1H，d，J＝8.9Hz)，7.02-7.07(1H， m)，7.06(1H，br)，7.79(1H，dd，J＝8.9，2.5Hz)，7.80(1H，br)，8.38 (1H，s)，8.42-8.45(1H，m)，10.35(1H，d，J＝7.7Hz)，11.42(1H，s) .MS：431(M+H)+
			552	49	1H-NMR(400MHz，d6-DMSO)δ：1.83-1.95(2H，m)，2.05-2. 21(2H，m)，2.21-2.41(4H，m)，2.45(3H，s)，4.42-4.52(1H，m)，4 .58-4.85(2H，m)，6.54-6.60(1H，m)，6.89(1H，d，J＝8.9Hz)，7.1 7-7.22(1H，m)，7.87(1H，dd，J＝8.9，2.4Hz)，8.53(1H，dd，J＝2.4， 0.4Hz)，8.59(1H，s)，9.26(1H，d，J＝7.6Hz)，11.79(1H，s).MS：4 27(M+H)+
553	49	1H-NMR(400MHz，d6-DMSO)δ：1.80-2.00(4H，m)，2.11-2. 22(2H，m)，2.29-2.42(2H，m)，4.28-4.40(3H，m)，6.42-6.48(1 H，m)，6.89(1H，dd，J＝8.0，4.6Hz)，7.04(1H，br)，7.05-7.10(1H， m)，7.74(1H，br)，8.21(1H，dd，J＝8.0，1.7Hz)，8.37(1H，s)，8.42( 1H，dd，J＝4.6，1.7Hz)，10.27(1H，d，J＝7.7Hz)，11.41(1H，s).M S：408(M+H)+
			554	49	1H-NMR(400MHz，d6-DMSO)δ：1.55-1.65(2H，m)，2.02-2. 25(6H，m)，4.38-4.44(2H，m)，5.55-5.65(1H，m)，7.10(1H，brs) ，7.82(1H，brs)，8.05(1H，s)，8.11(1H，s)，8.42(1H，s)，9.18(1H，d ，J＝8.5Hz)，12.9(1H，brs).MS：395(M+H)+
555	49	1H-NMR(400MHz，d6-DMSO)δ：1.60-1.67(2H，m)，1.96-2. 06(4H，m)，2.16-2.21(2H，m)，4.50-4.60(2H，m)，4.99(1H，brs) ，6.59(1H，s)，7.00(1H，brs)，7.20(1H，s)，7.80(1H，brs)，8.22(1H ，d，J＝1.9Hz)，8.34(1H，s)，8.55(1H，d，J＝1.9Hz)，9.43(1H，d，J＝ 8.5Hz)，11.5(1H，s).MS：422(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			556	49	1H-NMR(400MHz，d6-DMSO)δ：1.22-2.03(8H，m)，4.58-4. 67(5H，m)，5.38(1H，brs)，6.58-6.59(1H，m)，6.97(1H，brs)，7.1 9-7.25(2H，m)，7.44-7.46(1H，m)，7.75(1H，brs)，8.31(1H，s)，9 .30(1H，d，J＝8.0Hz)，11.54(1H，s).MS：394(M+H)+
557	49	1H-NMR(400MHz，d6-DMSO)δ：1.30-2.15(8H，m)，4.34(2 H，brs)，4.55-4.56(1H，m)，6.57-6.58(1H，m)，6.95(1H，brs)，7. 18-7.20(1H，m)，7.86(1H，brs)，8.00(1H，s)，8.34(1H，s)，9.39(1 H，d，J＝8.0Hz)，11.55(1H，brs).MS：394(M+H)+
			558	49	1H-NMR(400MHz，d6-DMSO)δ：1.56-2.56(8H，m)，3.69(3 H，s)，4.66-4.85(3H，m)，6.66(1H，s)，7.25-7.35(2H，m)，7.85-7. 94(1H，m)，8.35-8.43(1H，m)，9.33-9.45(1H，m)，11.53(1H，m) .MS：422(M+H)+
559	49	1H-NMR(400MHz，d6-DMSO)δ：1.23-2.32(8H，m)，4.60-4. 80(3H，m)，6.61(1H，s)，7.24-7.36(2H，m)，7.85-8.40(6H，m)，9 .27-9.37(1H，m)，11.53(1H，brs).MS：405(M-H)-
			560	49	1H-NMR(400MHz，d6-DMSO)δ：1.96-1.98(2H，m)，2.15-2. 20(2H，m)，2.31-2.37(2H，m)，2.51-2.58(2H，m)，4.33(1H，m)， 5.00(2H，s)，5.96(1H，s)，6.94-6.97(1H，m)，7.37(1H，t，J＝3.0H z)，7.90(1H，s)，8.14(1H，dd，J＝1.8，7.7Hz)，8.47(1H，dd，J＝2.0， 4.8Hz)，10.95(1H，s)，11.60(1H，s).MS：386(M+H)+
561	49	1H-NMR(400MHz，d6-DMSO)δ：1.71-1.73(2H，m)，1.98-1. 99(2H，m)，2.13(2H，m)，2.43-2.54(4H，m)，4.81(2H，s)，5.10(1 H，brs)，7.07(1H，d，J＝4.9Hz)，7.44(1H，s)，7.90(1H，s)，8.41(1 H，d，J＝5.1Hz)，10.97(1H，s)，11.52(1H，s).MS：386(M+H)+，4 08(M+Na)+
			562	49	1H-NMR(400MHz，d6-DMSO)δ：1.94-1.96(2H，m)，2.15(2 H，m)，2.26-2.32(2H，m)，2.47-2.54(2H，m)，4.04(1H，m)，4.77( 1H，s)，5.59(1H，brs)，7.06(1H，d，J＝5.2Hz)，7.32(1H，brs)，7.48 (1H，s)，7.88(1H，s)，8.39(1H，d，J＝5.0Hz)，10.92(1H，s)，11.58( 1H，s).MS：386(M+H)+

Watch 72 (continuation)

Examples	Reference to the examples	Data of
			563	49	1H-NMR(400MHz，d6-DMSO)δ：1.97-1.99(2H，m)，2.16(2H，b rs)，2.28-2.35(2H，m)，2.46-2.54(2H，m)，4.03(1H，m)，4.83(2H，s )，5.70(1H，s)，7.70(1H，d，J＝9.0Hz)，7.33(1H，s)，7.88(1H，s)，7.98 (1H，dd，J＝2.4，9.0Hz)，8.60(1H，d，J＝2.4Hz)，10.94(1H，s)，11.60 (1H，s).MS：386(M+H)+
564	50	MS：394(M+H)-
			565	50	1H-NMR(400MHz，d6-DMSO)δ：1.46-2.22(13H，m)，2.59(3H， s)，4.09(1H，m)，4.55(1H，s)，6.49(1H，m)，7.16(1H，m)，8.58(1H，s )，10.67(1H，m)，11.71(1H，s).MS：326.2(M+H)+
566	50	MS：410(M+H)+
			567	50	1H-NMR(400MHz，d6-DMSO)δ：1.43-1.50(4H，m)，1.63(6H，s )，1.65-1.74(3H，m)，1.87-1.94(3H，m)，2.03-2.11(1H，m)，2.21-2 .24(2H，m)，4.30-4.34(1H，m)，4.53(1H，s)，6.06(1H，s)，6.49-6.51 (1H，m)，7.23-7.25(1H，m)，7.84-7.87(1H，m)，8.71(1H，s)，11.63( 1H，brs).MS：410(M+H)+
568	53	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.33(7H，m)，3.80(3H，s )，4.07(1H，m)，4.46(1H，m)，6.07(2H，s)，6.43(1H，m)，7.11(1H，m )，8.13(1H，s)，8.84(1H，m)，11.31(1H，s).MS：356(M+H)+
			569	53	1H-NMR(400MHz，d6-DMSO)δ：1.40-2.45(13H，m)，4.11(1H， m)，4.44(1H，s)，6.45(1H，m)，7.14(1H，m)，7.86(1H，s)，8.32(1H，s )，8.60(1H，m)，10.77(1H，s)，11.41(1H，s).MS：327(M+H)+
570	53	1H-NMR(400MHz，d6-DMSO)δ：1.47-2.25(7H，m)，2.31(3H，s )，3.96(3H，s)，4.10(1H，m)，4.50(1H，s)，6.46(1H，m)，7.13(1H，m) ，8.16(1H，s)，9.12(1H，m)，11.39(1H，s).MS：328(M+H)+
			571	53	1H-NMR(400MHz，d6-DMSO)δ：1.29-2.27(12H，m)，2.31(3H， s)，4.09(1H，m)，4.32-4.37(2H，m)，6.44(1H，m)，7.12(1H，m)，8.1 1(1H，s)，9.33(1H，m)，10.88(1H，s)，11.32(1H，s).MS：341(M+H) +
572	54	MS：398(M+H)+
			573	54	MS：366(M+H)+
574	54	MS：439(M-H)+
			575	54	MS：384(M+H)+

Watch 72 (continuation)

Examples	Examples of reference	Data of
			576	54	MS：440(M-H)-
577	54	MS：384(M+H)+
			578	55	1H-NMR(400MHz，d6-DMSO)δ：1.36-1.42(2H，m)，1.57- 1.69(4H，m)，1.73-1.79(2H，m)，1.93-1.99(2H，m)，2.05-2.0 9(1H，m)，2.27-2.31(2H，m)，4.00-4.04(1H，m)，4.48(1H，s)， 6.11(1H，d，J＝16.1Hz)，6.10-6.13(1H，m)，6.42-6.44(1H，m )，7.16-7.18(1H，m)，7.91(1H，d，J＝16.1Hz)，8.21(1H，s)，11. 53(1H，brs).MS：335(M+H)+
579	61	1H-NMR(400MHz，d6-DMSO)δ：1.45-2.69(13H，m)，4.19 (1H，m)，4.53(1H，s)，6.54(1H，m)，7.25(1H，m)，8.43(1H，s)， 8.75(1H，m)，11.68(1H，s)，MS：367(M+H)+，365(M-H)-

Claims

1. A fused pyridine compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

x is N or CR³，

M is (CH)₂)_m(ii) a m is 0 or 1, and m is,

R¹is-H or is C₁-C₆Alkyl radical, C₁-C₆The alkyl group may be selected from mono C₁-C₆Alkylamino or di-C₁-C₆Alkylamino and-O-C₁-C₆The substitution of the groups in the alkyl group,

R²is-H or C₁-C₆An alkyl group, a carboxyl group,

R³is-H or C₁-C₆Alkyl radical, C₁-C₆The alkyl group may be selected from halogen, mono-C₁-C₆Alkylamino or di-C₁-C₆Substituted by groups in alkylamino and cycloamino groups,

R⁴¹is-H or pyridyl which may be substituted by cyano,

R⁴²is bicyclic or polycyclic C₄-C₁₆Bridged hydrocarbyl radicals, or bicyclic or polycyclic C₄-C₁₆An azabridged cycloalkyl group, both of which may be substituted,

R⁵is selected from the group consisting of fluoro, cyano, acetyl, methoxycarbonyl, formyl, amidinooxycarbonyl, guanidooxycarbonyl, carbamoyl,Methyl, vinyl,Groups in the oxadiazolyl and thiadiazolyl radicals, which are each optionally substituted,

with the proviso that when R⁵Is composed ofWhen the oxadiazolyl or thiadiazolyl group is present, X is-CR³，

wherein R is^AIs a group of the formula-H or acyl,

provided that R is⁴²And/or R⁵The term "substituted" in the definition of (a) means substituted with one or more substituents selected from the group consisting of:

(a) halogen element

(b)-OH、-O-R^Z-O-phenyl, -OCO-R^Z、-OCONH-R^ZOxo (═ O);

(c)-SH、-S-R^Z-S-phenyl, -S-heteroaryl, -SO-R^Z-SO-phenyl, -SO-heteroaryl, -SO₃H、-SO₂-R^Z、-SO₂-phenyl, -SO₂Heteroaryl, optionally substituted by one or two R^ZA substituted sulfonamide group;

(d) can be substituted by one or two R^ZAmino, -NHCO-R substituted by a group^Z-NHCO-phenyl, -NHCO₂-R^Z、-NHCONH₂、-NHCONH-R^Z、-NHSO₂-R^O、-NHSO₂-phenyl, -NHSO₂NH₂、-NO₂、＝N-O-R^Z

(f)R^Z

(g) phenyl which may be substituted by one or more groups selected from the groups described in (a) to (f) above, 5-or 6-membered heterocycloalkyl, 5-or 6-membered heteroaryl, 5-or 6-membered heterocycloaryl,

r in the above-mentioned items (a) to (g)^ZMay include "cyano, -OH and C₁-C₆Alkyl radical, wherein said C₁-C₆The alkyl group may be selected from-O-C₁-C₆Alkyl, -NH-C₁-C₆Alkyl, -CONH-C₁-C₆One to three groups of alkyl, 5-or 6-membered heterocycloalkyl and 5-or 6-membered heteroaryl, wherein said heteroaryl is pyridyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, furyl or pyrrolyl,the heterocycloalkyl is morpholinyl, piperidinyl, homopiperidinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl or tetrahydrofuranyl, and the cycloalkyl is cyclopropyl or cyclohexyl.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴²Is adamantyl, bicyclo [2.2.1]Heptyl or tropanyl, each of which may be substituted, wherein R⁴²The term "substituted" in the definition of (1) is as defined in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R⁵Is a carbamoyl group,Oxadiazolyl, thiadiazolyl, acetyl, these radicals being optionally substituted by NH₂A hydroxymethyl group or an OH group, or a salt thereof,

or R⁴¹And R⁵Can be linked through specific functional groups to form the formula (I-A),

or R⁴¹And R⁵Can be linked through specific functional groups to form the formula (I-B),

or R⁴¹And R⁵May be linked through specific functional groups to form formula (I-C), wherein R^ACan be covered with C₁-C₆alkyloxy-substituted-C (═ O) NH-C₁-C₆An alkyl group.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R⁵Is composed ofDiazoles or thiadiazoles, both of which may be substituted, in which R is⁵The term "substituted" in the definition of (1) is as defined in claim 1.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

X is a group of a CH,

R¹is a hydrogen atom, and is,

R²is hydrogen or CH₃，

R⁴¹Is a hydrogen atom, and is,

R⁴²is an adamantyl group, which may be substituted with OH,

R⁵is carbamoyl which may be substituted, or-C (═ O) -C which may have OH₁-C₆An alkyl group, a carboxyl group,

wherein R may be substituted⁵The substituent of the carbamoyl group in (A) is as defined in claim 1.

6. A compound selected from the following compounds:

1)4- [ (1R, 2R, 4S) -bicyclo [2.2.1] hept-2-ylamino ] -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

2)4- { [ (3-Exo) -8- (5-cyanopyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

3) rel-4- { [ (1R, 2S, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

4) rel-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

5)4- { [ (3-Exo) -8- (5-nitropyridin-2-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

6) rel- (1S, 3R, 4R, 5S) -4- { [5- (5-amino-1, 3, 4-thiadiazol-2-yl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] amino } adamantan-1-ol,

7)4- { [ (3-Exo) -8- (6-cyanopyridazin-3-yl) -8-azabicyclo [3.2.1] oct-3-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridine-5-carboxamide,

8) rel- (1S, 3R, 4R, 5S) -4- ({5- [3- (hydroxymethyl) -1, 2, 4-Diazol-5-yl]-1H-pyrrolo [2, 3-b]Pyridin-4-yl } amino) adamantan-1-ol,

9) n- (cyanomethyl) -N-methyl-4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) adamantane-1-carboxamide,

10)7- [ (5-cyanoadamantan-2-yl) amino ] -3H-imidazo [4, 5-b ] pyridine-6-carboxamide,

11)rel-(1s，3R，4R，5S)-4-{[5-(1，3，4-oxadiazol-2-yl) -1H-pyrrolo [2, 3-b]Pyridin-4-yl]Amino group, adamantan-1-ol,

12) 2-hydroxy-1- (rel-4- { [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2, 3-b ] pyridin-5-yl) ethanone,

13)3- { [4- (3-oxo-3, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) adamantan-1-yl ] oxy } propionitrile,

14) rel-N- {1- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] -1, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-3-yl } -N' - (2-methoxyethyl) ethanediamide,

15) rel-N- {1- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] -1, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-3-yl } -oxalamide,

16) rel-N- {1- [ (1R, 2R, 3S, 5S) -5-hydroxyadamantan-2-yl ] -1, 6-dihydropyrazolo [3, 4-d ] pyrrolo [2, 3-b ] pyridin-3-yl } -N' - (trans-4-methoxycyclohexyl) ethanediamide,

17)3- { [4- (2-oxo-3, 6-dihydroimidazo [4, 5-d ] pyrrolo [2, 3-b ] pyridin-1 (2H) -yl) adamantan-1-yl ] oxy } propionitrile.

7. A compound according to any one of claims 1 to 6, which is an optically active substance and/or is an endo-exo isomer, or a pharmaceutically acceptable salt thereof.

8. A process for producing a compound represented by the following formula (II) or a salt thereof by reacting a compound represented by the following formula (III) with R⁴²-M-NH₂Wherein said primary amine is represented by formula (II):

wherein R is¹、R²、R⁴²And M is as defined in claim 1; x is a group of a CH,

r' is-C (═ O) NHCH₂CH₂OCH₃，

The formula (III) is as follows:

wherein R is¹、R²And R' is as defined above, and Lv is a leaving group.

9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a medicament.

10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of diseases in humans or animals, including rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, alzheimer's disease, tumours, plasma cell myeloma and leukaemia.

11. A medicament containing a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. A medicament containing a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

13. A Janus kinase 3(JAK3) inhibitor comprising a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases in humans or animals, comprising: rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, alzheimer's disease, tumors, plasma cell myeloma and leukemia.

15. A product comprising a pharmaceutical composition comprising a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and written instructions for the pharmaceutical composition that specify: compound (I) may or should be used for the treatment or prevention of diseases in humans or animals, including: rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, alzheimer's disease, tumors, plasma cell myeloma and leukemia.