WO2014187262A1 - Bruton's tyrosine kinase inhibitor - Google Patents

Abstract

Provided are a 2-phenyl-isoquinoline-1-ketone derivative having a structure of formula (I), and uses thereof. The compound has good inhibitory effect on Bruton's tyrosine kinase activity, and the median inhibition concentration of the compound is generally below 10^-7 mol.L^-1. The compound having the structure of formula (I) and prepared in an embodiment of the present invention has clear anti-inflammatory activity on different animal models.

Description

 Description book, a class of Bruton technical field

 The present invention relates to novel derivatives for inhibiting Bruton's kinase (Btk) and for treating autoimmune diseases and inflammatory diseases caused by abnormal B cell activation. The novel derivative 2-phenyl-isoquinolin-1-one derivatives described herein can be used to treat arthritis.

Background technique

 Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by the addition of phosphate groups to proteins (T. Hunter, Cell 1987 50:823-829). In particular, tyrosine kinase phosphorylates proteins in the phenolic portion of tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in many human diseases, including cancer, autoimmune diseases and inflammatory diseases. Because protein kinases are key regulators of cell signaling, they provide the goal of regulating cell function with small molecule kinase inhibitors and are therefore good drug design targets. In addition to the treatment of kinase-mediated disease processes, selective and potent inhibitors of kinase activity can be used to study cellular signaling processes and to identify other therapeutically significant cellular targets.

 There is good evidence that B cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics that deplete B cells, such as Rituxan, are effective against autoantibody-induced inflammatory diseases such as rheumatoid arthritis (Rastetter et al, Annu Rev Med 2004 55:477). Therefore, an inhibitor of protein kinase that plays a role in B cell activation should be a therapeutic agent for B cell-mediated disease pathology such as autoantibody production.

 Signaling through the B cell receptor (BCR) controls a range of B cell responses, including proliferation and differentiation into mature antibody-producing cells. BCR is a key regulatory point for B cell activity and abnormal signaling can lead to dysregulated B cell proliferation and the formation of pathogenic autoantibodies that result in a variety of autoimmune and/or inflammatory diseases. Bruton's tyrosine acid kinase (Btk) is a non-BCR-associated kinase proximal to and downstream of the BCR membrane. The lack of Btk has been shown to block BCR signaling, and thus inhibition of Btk can be an effective treatment for blocking B-cell mediated disease processes.

Btk is a member of the Tec family of tyrosine kinases and shows early B cell formation as well as mature B cell activity. Key regulators of chemistry and survival (Khan et al, Immuni ty 1995 3: 283; Ellmeier et al, J. Exp. Med. 2000 192: 1611). Human Btk mutations lead to disease X-linked agammaglobulin deficiency (XLA) (reviewed in Rosen et al., New Eng J. Med. 1995 333: 431, P Li ndvall et al., Immunol. Rev. 2005 203:200). These patients are immunocompromised and show impaired B cell maturation, reduced immunoglobulin and topical B cell levels, reduced T cell-independent immune responses, and reduced calcium motility after BCR stimulation.

 Evidence for the role of Btk in autoimmune diseases and inflammatory diseases has been provided via the Btk-deficient mouse model. Btk-deficient mice showed a significant improvement in disease progression in a preclinical mouse model of systemic lupus erythematosus (SLE). Furthermore, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson Wo P Holmda Clin. Exp. Immunol. 1993 94:459). The dose-dependent efficacy of selective Btk inhibitors in the mouse arthritis model has been demonstrated (z. Pan et al, Chem. Med Chem. 2007 2: 58-61).

 Btk is also expressed by cells that may be involved in disease processes in addition to B cells. For example, Btk is expressed by mast cells and Btk-deficient bone marrow-derived mast cells show impaired antigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280: 40261). This shows that Btk can be used to treat pathological mast cell responses such as allergies and asthma. Furthermore, monocytes from XLA patients lacking Btk activity show reduced TNFa production following stimuli (Horwood et al J Exp Med 197: 1603, 2003). Thus, TNFa-mediated inflammation can be modulated by small molecule Btk inhibitors. In addition, Btk has been reported to play a role in apoptosis in Oslam and Smith Immunol. Rev. 2000178:49), and thus Btk inhibitors will be effective in the treatment of certain B cell lymphomas and leukemias (Feldha n et al J) Exp. Med. 2005 201: 183 7).

 A class of 2-phenyl-isoquinoline 1-one derivatives as Bruton kinase inhibitors is disclosed by Roche in WO2010100070. According to data from Thomson Pharma, according to reports in the literature, the representative compound is RN486 and has entered the clinical research stage. However, we believe that the methyl group on the piperazine ring at the end of the molecule may be easily metabolized, which will result in faster clearance of the compound in the body, and the exposure is not high. The reports in the literature have also verified our speculation (Xu et al. Pharmacol. Exp. Ther. 2012 341: 1 90). Therefore, in order to obtain compounds with excellent pharmacokinetic properties and in vivo efficacy and excellent effects, we conducted a more systematic study on the terminal piperazine ring and obtained the expected compounds.

RN486 Summary of the invention

 The present application provides a Btk inhibitor compound having the structure shown in formula (I), and its use method, as provided herein below, provides a formula (I)

 among them,

R ¹ is -R ⁶ - R ⁷ - R ⁸ ;

R ^{2 is} selected from hydrogen or -C ₆ fluorenyl;

R ^{3 is} selected from the group consisting of hydrogen, dC ₆ fluorenyl or hydroxy CC ₆ fluorenyl;

R ^{4 is} selected from the group consisting of hydrogen, C _r C ₆ fluorenyl or 3⁄4 ₈ cyclodecyl;

R ^{5 is} selected from hydrogen or halogen;

 X, Y, Ζ are independently selected from CH or Ν;

 Q is selected from CH or Ν, provided that when Ζ is Ν, Q is CH;

 D, G are independently selected from CH or N, but D and G are not N at the same time;

R ^{6 is} selected from C ₆ -C _1Q aryl, C ₅ -C _1Q heteroaryl, C ₃ -C ₈ cyclodecyl or C ₄ -C ₈ heterocycloalkyl, each of which is optionally one or more R ^1Q substitution;

R ^{7 is} selected from C ₃ -C ₈ cyclodecyl or C ₄ -C ₈ heterocycloalkyl, each of which is optionally substituted by one or more R ¹¹ ;

R ^{8 is} selected from the group consisting of C ₄ -C ₈ heterocyclic fluorenyl, C ₃ -C ₈ cyclodecyl-C ₆ fluorenylene, C ₄ -C ₈ heterocycloalkyl C _r C ₆ fluorenylene, dC ₆ fluorenyl , -COR ⁹ or -(S0 ₂ )R ⁹ , C ₄ -C ₈ heterocycloalkyl is optionally substituted by one or more R ¹² ;

R ^{9 is} selected from the group consisting of -C ₆ fluorenyl, 3⁄4 ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₆ -C ₁₍₎ aryl, C ₅ -. Heteroaryl, C ₃ -C ₈ cyclodecyl dC ₆ -fluorenylene, C ₅ -C ₈ heterocyclic fluorenyl CC ₆ fluorenylene, C ₆ -C _1Q aryl CC ₆ fluorenylene, C ₅ -C ₁₀ wide heteroaryl _{TJ Ci- e ¾υ¾ Ci-C 6} ¾¾¾ ¾S¾ C C 6 ¾¾ C wide C ₆ ¾¾, wide _{C C 6 ¾¾, C 3 -C} 8 cycloalkyl group embankment, C ₅ -C ₈ heterocyclic group optionally embankment The ground is replaced by one or more halogen, hydroxy, dC ₆ methoxy, C ₆ -C ₁₀ aryl, C ₅ -C _1Q heteroaryl optionally substituted by one or more halogens, C _r C ₆ fluorenyl, ₁ -0 ₎ decyloxy, halo-C ₆ fluorenyl substituted;

R ^{1Q is} selected from the group consisting of hydrogen, dC ₆ fluorenyl, hydroxy, hydroxy dC ₆ fluorenylene, CC ₆ decyloxy, halogen, nitro, amino, acylamino, cyano, oxo or 3⁄4 generation-C _r C ₆ Substituent substitution R ^{11 is} selected from the group consisting of hydrogen, -C ₆ fluorenyl, C _r C ₆ decylamino, C _r C ₆ fluorenyl-C ₆ decylamino, hydroxy, hydroxy dC ₆ fluorenyl, CC ₆ decyloxy, halogen, nitrate Base, amino, acylamino, acyl, cyano, oxo, decyl, hydroxyamino, carboxy, carbamoyl, carbamate, ^H CH^ decyloxy, ^H d-Cs decyl or hydroxy Substituting dC ₆ thiol substitution;

R ^{12 is} selected from the group consisting of hydrogen, C _r C ₆ fluorenyl, ^-^cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl C _r C ₆ fluorenylene or C ₄ -C ₈ heterocyclic fluorenyl CC ₆ anthracenyl.

When R ^{3 is} selected from hydroxy-C ₆ fluorenyl, X, Y, D, G are selected from CH, R ⁸ , R ^{11 are} not selected from hydrogen or C _r C ₆ fluorenyl; when R ^{3 is} selected from C -Co 垸Or a hydroxy dC ₆ fluorenyl group, X, Y, D, G are selected from CH, and when Q is selected from N, R ^{8 is} not selected from hydrogen, -C ₆ fluorenyl or -COR ⁹ , and R ^{11 is} not selected from hydrogen, - C ₆ thiol or acyl.

 Further, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

Wherein R ^{1 is} selected from

;

R' is selected from -R ⁷ R ⁸ ;

R ^{7 is} selected from C ₄ -C ₈ heterocycloalkyl, and C ₄ -C ₈ heterocycloalkyl is optionally substituted by one or more R ¹¹ ;

R ^{8 is} selected from the group consisting of C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl-C ₆ -fluorenylene, C ₄ -C ₈ heterocycloalkyl-C ₆ -fluorenylene, dC ₆ fluorenyl, -COR ⁹ or -(S0 ₂ )R ⁹ , C ₄ -C ₈ heterocyclic fluorenyl is optionally substituted by one or more R ¹² ;

R ^{9 is} selected from the group consisting of -C ₆ fluorenyl, 3⁄4 ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₆ -C ₁₍₎ aryl, C ₅ -. Heteroaryl, C ₃ -C ₈ cyclodecyl dC ₆ -fluorenylene, C ₅ -C ₈ heterocyclic fluorenyl CC ₆ fluorenylene, C ₆ -C _1Q aryl CC ₆ fluorenylene, C ₅ -C ₁₀ heteroaryl _{Ci-C 6 ¾υ¾ Ci-C} 6 ¾¾¾ wide ¾S¾ C C ₆ ¾¾ C wide C ₆ ¾¾, wide _{C C 6 ¾¾, C 3 -C} 8 cycloalkyl group embankment, C ₅ -C ₈ heterocyclic group optionally embankment The ground is replaced by one or more halogen, hydroxy, dC ₆ methoxy, C ₆ -C ₁₀ aryl, C ₅ -C _1Q heteroaryl optionally substituted by one or more halogens, C _r C ₆ fluorenyl, ₁ -0 ₎ decyloxy, halo-C ₆ fluorenyl substituted;

R ¹¹ is selected from hydrogen, alkyl with dC _6, cyano, hydroxyl or optionally substituted by one or more halo, hydroxy substituted firing dC _6-yl;

R ^{12 is} selected from the group consisting of hydrogen, dC ₆ fluorenyl, C ₃ -C ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl CC ₆ fluorenylene, C ₄ -C ₈ Cyclodecyl-C ₆ anthracenyl.

 In the compound of the formula (I) or a pharmaceutically acceptable salt thereof,

R' is preferably

m is selected from 0-2, more preferably 0 or 1.

R ⁸ is preferably C ₃ -C ₆ cyclodecylmethylene, C ₄ -C ₆ heterocycloalkyl, C ₄ -C ₆ heterocycloalkylmethylene, dC ₆ fluorenyl,

-COR ^y sK-(S0 ₂ )R ^y , C ₄ -C ₆ heterocyclic fluorenyl is optionally substituted by one or more R ¹² , wherein C ₄ -C ₆ heterocyclic ring

W is selected from 0, S or NR ¹² ; R ^{12 is} as defined above.

R ⁹ is preferably CC ₄ fluorenyl, C ₃ -C ₆ cyclodecyl, C ₄ -C ₆ heterocycloalkyl, phenyl, C ₅ -C _{1 ()} heteroaryl, C ₃ -C ₆ cyclodecyl Methylene, C ₄ -C ₆ heterocyclodeclyl methylene, benzyl, methylamino, dimethylamino, ethylamino, diethylamino, dC ₄ fluorenyl, C ₃ -C ₆ cyclodecyl, The C ₄ -C ₆ heterocyclic fluorenyl group is optionally substituted by one or more halogen, hydroxy, dC ₄ decyloxy groups, and the phenyl group, the phenyl group on the benzyl group, and the C ₅ -C _1Q heteroaryl group are selectively One or more halogen, -C ₄ fluorenyl, CC ₄ decyloxy, halogenated dC ₄ fluorenyl, wherein C ₅ -C _1Q heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, triazolyl , furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole.

R ¹¹ is preferably hydrogen, methyl, ethyl, cyano, hydroxy, -CH ₂ F, CHF ₂ , CF ₃ or CH ₂ OH.

 Further, the above structure is a salt of the formula (I) or a drug thereof,

Wherein -R ⁶ - R ⁷ consists of -R ⁶ - R - R'

The composition of R ^{1 is} as follows:

M is selected from CH or N;

R ^{8 is} selected from C ₄ -C ₈ heterocycloalkyl, C _r C ₆ fluorenyl, -COR ⁹ , C ₄ -C ₈ heterocyclic fluorenyl is optionally substituted by R ¹² ; R ^{9 is} selected from C ₃ -C _8- ring sulfhydryl;

R ^{12 is} selected from the group consisting of hydrogen and -C ₆ fluorenyl

Further, R ^{8 is} selected from Y ⁰ CT

Or methyl, ethyl, propyl.

R ^{2 is} selected from the group consisting of methylethyl and propyl.

R ^{3 is} selected from the group consisting of hydrogen, methyl, hydroxymethyl

R ^{4 is} selected from cyclopropyl. R ^{5 is} selected from hydrogen or fluorine.

 X, Y, Ζ, Q are independently selected from CH.

 D, G are independently selected from CH or N, but D and G are different at the same time? .

The invention further relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of formula (I) in free form or in a pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier materials and/or diluents. The compound of the formula (I) of the present invention and a pharmaceutically acceptable carrier, excipient or diluent may also be included. The invention further relates to a combined pharmaceutical composition comprising an effective amount of a compound of the formula (I) in free form or in a pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier materials and/or diluents.

 The application provides a method for treating an inflammatory and/or autoimmune disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.

 The application provides a method for treating arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formula I.

 The application provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of the above formulas or variants thereof.

 The application provides a method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.

 The application provides a method of inhibiting B cell proliferation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.

 The application provides a method for treating an inflammatory condition, the method comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound and a Btk inhibitor compound of any of Formulas I.

 The application provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound and a Btk inhibitor compound of any of Formulas I.

 The application provides a pharmaceutical composition comprising a Btk inhibitor compound of any of Formula I in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

 To test the level of action of the compounds provided herein for protein kinases, biochemical level enzyme activity assays and cell level enzyme activity assays were employed to determine the level of activity and effect of various compounds of the invention on one or more PKs. Similar experiments can be designed in the same manner for any kinase using methods well known in the art.

In the biochemical level enzyme activity test, HTRF technology is used to detect the activity of tyrosine kinase. HTRF is a time-resolved fluorescence resonance ability transfer technique, which can be carried out according to known specifications or literature methods. See Kolb et al., "Tyrosine kinase assays". Adapted to homogenous time-resolved fluorescence". Drug Discovery Today. Volume 3: pp 333-342. HTRF (Homogeneous Time-Resolved Fluorescence) is one of the most commonly used methods for detecting analytes in homogeneous systems. This technique combines fluorescence resonance energy transfer (FRET) and time-resolved (TR) techniques and has been widely used. It is applied to different stages of drug development based on cell experiments and biochemical experiments. According to the measurement principle of HTRF method, after incubation of pure enzyme Btk with biotinylated substrate and ATP, avidin-labeled XL-665 and Eu-labeled antibody which recognizes substrate phosphorylation are added as substrate. After phosphorylation by Btk, Eu-labeled antibodies are recognized This phosphorylated product forms a time-resolved fluorescence resonance energy transfer (FRET) with avidin-labeled XL665, whereas the unphosphorylated substrate cannot form a FRET signal due to the inability to recognize the antibody, by measuring 665 nm and 620 nm. The fluorescence signal difference is used to determine the inhibitory activity of the test substance on Btk tyrosine kinase at different concentrations. Thus, the activity of the compounds of the invention against the biochemical levels of Btk tyrosine kinase can be determined by this method, and similar assays can be used for other protein kinases using methods well known in the art.

 The determination of enzyme activity at the cellular level is achieved by measuring calcium flux. The experiment used the Fluo-4 DirectTM Calcium Assay Kits kit. The main dye used in the kit is Fluo 4-AM. Fluo 4-AM is a acetyl methyl ester derivative of Fluo 4 that can be easily introduced into cells by culture. When AM enters the cell, it is hydrolyzed by intracellular esterase, and the resulting Fluo 4 then binds to calcium ions and fluoresces. The concentration of intracellular calcium can be measured using a laser confocal microscope or flow cytometry.

 The pharmacodynamic properties of the compounds in rats can also be examined by using a general test method for pharmacological experiments in rats. The in vivo efficacy of the compound in mice or rats can be examined using a generic mouse Arthus Reaction model or a rat collagen-induced arthritis (rCIA) model.

Good inhibition of formula (I) having the compound represented by the structure of the kinase activity of Bruton prepared in the present invention, 50% inhibitory concentration (IC _5Q) common in 10- ⁷ mol / L or less. At the same time, the compounds of the formula I prepared in the examples of the present invention have good oral pharmacokinetic properties and exhibit clear in vivo efficacy in the Arthus Reaction model or the rat collagen-induced arthritis (rCIA) model. It is inferred that the compounds of the present invention having the structure of formula (I) are useful for the preparation of a medicament for the treatment of Bruton's kinase-associated inflammatory and/or autoimmune disorders in an organism.

 Detailed description of the invention

 Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Mercapto" refers to a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. Preference is given to medium-sized mercapto groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The fluorenyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C ₂ -C ₆ alkenyl, C ₆ -C _1Q aryl, C ₅ -C _1Q heteroaryl, halogen a -C ₆ fluorenyl group, a 4 to 8 membered heteroalicyclic group, a hydroxy group, a CC ₆ decyloxy group, a C ₆ -C _1Q aryloxy group.

"Indenylene" means a divalent saturated direct hydrocarbon group of 1 to 10 carbon atoms (for example, (CH ₂ ) _n ) or a branched saturated divalent hydrocarbon group of 2 to 10 carbon atoms (for example, -CHMe), unless otherwise . Except in the case of methylene groups, the open state of the fluorene group is not attached to the same atom. Examples of the fluorenylene group include, but are not limited to, methylene, ethylene, Propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

 "Cyclopentyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring ("thick" ring means each in the system The ring shares an adjacent pair of carbon atoms in the ring with the other ring in the system, wherein one or more of the rings have a fully connected pi-electron system, and examples of the ring thiol group are not limited to cyclopropene, cyclobutan , cyclopentanyl, cyclopentene, cyclohexanthene, adamantane, cyclohexadiene, cycloheptadene and cycloheptatriene. The cycloalkyl group is a substitutable and substituted. When substituted, the substituent is preferably one or more groups each selected from the group consisting of: hydrogen, hydroxy, decyl, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic Base, lower halogenated methoxy, sulfonyl, 3⁄4, lower 3⁄4 decyl, lower hydroxydecyl, lower cyclodecyl fluorenyl, lower heterocyclic fluorenylene, aryl, heteroaryl, Alkoxycarbonyl, amino, decylamino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, decylaminocarbonyl, Arylaminocarbonyl, fluorenylcarbonylamino, arylcarbonylamino.

 "Aryl" means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated π-electron system. "Aryl" includes:

 a six-membered carbon aromatic ring, such as benzene;

 The bicyclic ring, wherein at least one of the rings is a carbon aromatic ring, such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring, at least one of which is a carbon aromatic ring, such as hydrazine.

 For example, an aryl group includes a six-membered carbon aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring. However, the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbon aromatic rings are entangled with a heteroaromatic ring, the resulting ring system is a heteroaryl group rather than an aryl group. Non-limiting examples of aryl groups are phenyl, naphthyl. The aryl group can be substituted or unsubstituted. When substituted, preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocycloalkyl, lower halodecyloxy , thiol, halogen, lower 3⁄4 decyl, lower hydroxydecyl, lower cyclodecyl fluorenylene, lower heterocyclic fluorenylene, aryl, heteroaryl, decyloxycarbonyl, amino, fluorenyl Amino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, fluorenylaminocarbonyl, arylaminocarbonyl, decylcarbonylamino , arylcarbonylamino.

"Heteroaryl" means a monocyclic or fused ring radical of 5 to 14 ring atoms containing one, two, three or four ring heteroatoms selected from fluorene, 0 or S, the remaining ring atoms being C In addition, it has a fully conjugated π-electron system. Heteroaryl refers to: a 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, 0 and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring. Is a carbon atom;

 An 8-12 membered bicyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, 0 and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, the other atoms on the ring are a carbon atom; at least one of which is an aromatic ring;

 A 11-14 membered tricyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, 0 and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring It is a carbon atom; at least one of the rings is an aromatic ring.

 For example, a heteroaryl group includes a 5-6 membered heteroaromatic ring and a 5-6 membered ring fluorenyl group. For such a heterocyclic ring in which the bicyclic rings are combined, only one of the rings contains one or more hetero atoms, and the linking site is on the heteroaromatic ring.

 When the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur atoms and oxygen atoms in the heteroaryl group does not exceed one.

 Examples of heteroaryl groups, including but not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, pyridine, pyrazine, pyridazine, anthracene, Azaindene, benzimidazole, benzotriazole, porphyrin, anthrone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole. One or all of the hydrogen atoms in the heteroaryl group may be substituted by hydrogen, hydroxy, nitro, cyano, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic fluorenyl, Lower halogenated decyloxy, sulfonylthio, 3⁄4, lower 3⁄4 thiol, lower hydroxydecyl, lower cyclodecyl fluorenylene, lower heterocyclic fluorenylene, aryl, heteroaryl, oxime Carbocarbonyl, amino, decylamino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, decylaminocarbonyl, aryl Aminocarbonyl, decylcarbonylamino, arylcarbonylamino.

"Heterocyclic fluorenyl" means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings, including a spiro ring system, each ring having 3 to 8 atoms in combination with one or a plurality of ring heteroatoms (selected from hydrazine, 0 or S(0) _Q _ ₂ ), and which may be optionally substituted independently by one or more, preferably one or two substituents, said substituents being selected From: hydrogen, hydroxy, decyl, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic fluorenyl, lower halodecyloxy, sulfonylthio, halogen, lower halogenated fluorenyl, Lower hydroxymethyl, lower cyclodecyl fluorenyl, lower heterocyclic fluorenyl fluorene, aryl, heteroaryl, decyloxycarbonyl, amino, decylamino, decylsulfonyl, arylsulfonyl, hydrazine Aminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, decylaminocarbonyl, arylamine Alkylcarbonyl, fluorenylcarbonylamino, arylcarbonylamino. Unless otherwise stated. Examples of heterocyclic fluorenyl groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroaza, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl , oxazolyl, thiazolyl, isoxazolyl, tetrahydropyranyl, thio-allinyl,

And W is selected from 0, S or NR ¹² , and each group is as described above, and the example may also be bicyclic, such as, for example, 3, 8-diaza-bicyclo[3.2.1]octane, 2, 5 - diazabicyclo[2. 2. 2] octyl or octahydro-pyrazino[2, 1-c] [1, 4] oxazine. Its heterocyclic thiol group (and derivatives) include its ionic form.

 "Alkoxy" means -0- (unsubstituted fluorenyl) and -0 (unsubstituted fluorenyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

 "Aryloxy" means -0-aryl and -0-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

"Arylhydrazone" means a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by an aryl group as described above, for example -CH ₂ phenyl, -(CH ₂ ) ₂ phenyl, -(CH _{2 3} phenyl, CH ₃ CH (CH ₃ ) CH ₂ phenyl and its derivatives.

"Heteroaryl fluorenyl" means a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by a heteroaryl group as described above, for example 3⁄4 pyridyl, -(03⁄4) ₂ pyrimidinyl, -(CH ₂ ) )|Czolyl and the like and derivatives thereof.

 "Hydroxy" means a -0H group.

 "Hydroxycarbonyl" means - fluorenyl - 0H.

 "Mercapto" means a -SH group.

 "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Haloalkyl" denotes a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by one or more of the same or different halogen atoms, for example -CH ₂ C1, -CF ₃ , -CC1 ₃ , -CH ₂ CF ₃ , -CH ₂ CC1 _3, and the like.

 "Cyano" means a -CN group.

"Amino" means a -NH ₂ group.

"Nitro" means a -N0 ₂ group. "Acyl" means a radical of the formula -C (=0) R, wherein R is hydrogen or C _r C ₆ fluorenyl, -C ₆ decyloxy, C ₆ -C ₁₍₎ aryl, C ₆ -C _1Q aryl An oxy group or a C ₅ -C _1Q heteroaryl group or the like.

"Acylamino" means a -(CO)NH ₂ group.

 By "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description may or may not occur, and that the description includes or does not occur. Two situations.

 In some embodiments, "substituted with one or more groups" means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.

 A wavy line indicates a connection site;

 "Pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) salt formation with an acid, obtained by the reaction of a free base of a parent compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc. , organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .

 (2) a salt formed by replacing an acidic proton in a parent compound with a metal ion or by complexing with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, Ν-methyl glucosamine, and the like.

 "Pharmaceutical composition" means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is mixed with another chemical component, such as a pharmaceutically acceptable carrier. . The purpose of the pharmaceutical composition is to facilitate the administration to the animal.

 "Pharmaceutically acceptable carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, each Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, Ethylene glycol, castor oil or hydrogenated castor oil or polyethoxy hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.

The aforementioned pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant commonly used in medicine, for example: an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, a tone. Toners, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, Sweeteners, colors, flavors or combinations thereof.

Concrete implementation

 The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. Example h Preparation of Compound 1

 Compound 1

Preparation of tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazine-1-carboxylate intermediate (1 a)

5-Bromo-2-nitropyridine (1.7 lg, 84.7 mmol) and dimethyl sulfoxide (DMSO) (550 mL) were weighed into a 1 L three-necked flask, and N-tert-butoxycarbonylpiperazine was added. 15.8g, 84.7mmol) and potassium carbonate (K ₂ C0 ₃ ) (35.4g, 254.1 mmol), add, heat to 65 ° C overnight, cool to room temperature, slowly pour the reaction into 2L ice water mixture After stirring for 30 minutes, a large amount of solid precipitated, which was filtered and dried in vacuo to give a yellow product (14 g, 53.8%). MS (ESI) m/z: [M+H] ⁺ = 309.2. 1H-NMR (CDCI3, 400 MHz): δ 8.18(d, 1H), 8.13 (s, 1H), 7.16(d, 1H), 3.64(t, 4H), 3.45(t, 4H), 1.49(s, 9H) ppm.

Preparation of tert-butyl 4-(6-amino-3-pyridyl)-1-piperazine-1-carboxylate intermediate (1 b)

Weigh tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazine-1-carboxylate (1.6 g, 5.19 mmol), add Pd/C (10%, 0.32 g) and no Water, methanol (45 mL), sealed, and then replaced with hydrogen three times, and then reacted at room temperature for 3 hours. After the reaction was stopped, Pd/C was filtered off, methanol was removed under reduced pressure, and dried in vacuo to give brown product (0.91 g, 63.2 %). MS (ESI) m/z: [M+H] + = 279.2. 1H-NMR (CDC1 ₃ , 400 MHz): δ 7.78 (s, 1H), 7.18 (d, H), 6.49 (d, H), 4.21 (bs, 2H), 3.57 (t, 4H), 2.97 (t , 4H) 1.48 (s, 9H) ppm.

tert-Butyl 4-(6-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl)piperazine-1-carboxylate Preparation of acid ester intermediate (1 c)

Weigh 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos) (410 mg, 0.709 mmol), Pd ₂ (dba) ₃ (160 mg, 0.177 mmol), mix, in argon Under the protection, add 50 mL of dioxane, continue nitrogen protection, stir for 20 min, continue to add cesium carbonate (Cs ₂ C0 ₃ ) ( 3.47 g, 10.7 mol), tert-butyl 4-(6-amino-3-pyridyl) 1-piperazine-1-carboxylate (1.0 g, 3.5 mmol), 3,5-dibromo-1-methylpyridine-2(1H)-one, heated to 100 ° C under nitrogen After the reaction was stopped for 2.5 h, the reaction was cooled to room temperature, celite was filtered, and the mixture was extracted with ethyl acetate (40mL*3), and then washed once with saturated NaCl (30mL), and the ester layer was dried over anhydrous Na ₂ S04 The solid was filtered and concentrated in vacuo to give a yellow solid (q. MS (ESI) m/z: [M+H] + = 466.2.

Preparation of 5-bromo-1-methyl-3-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyridine-2(1H)-one intermediate (1 d )

Weighing tert-butyl 4-(6-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl)piperazine-1 - Carboxylic ester (470 mg, 1 mmol) was placed in a 50 mL round bottom flask, 20 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid were added and allowed to react at room temperature overnight. After completion of the reaction, saturated NaHC0 ₃ was added. solution until the PH value 7-8, then DCM (40mL * 3). the organic layer was dried over anhydrous ₂ S04 Na, filtered the solvent removed under reduced pressure to give a yellow solid (270mg, 72.9% MS (ESI ) m / z : [M+H] ⁺ = 364.1. ¹ H-NMR (CDC1 ₃ , 400 MHz) : δ 8.57 (s, 1H), 7.99 (s, 1H), 7.41 (s, 1H), 7.24 (d, 1H) , 6.93 (s, 1H), 6.75 (d, 1H), 3.59 (s, 3H), 3.06 (bs, 8H) ppm.

 5-bromo-1-methyl-3-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridine-2(1H)- Preparation of ketone intermediate (1 e )

5-Bromo-small methyl-3-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyridine-2 (1H> ketone (1.4 g, 38 mmol), 3-oxocyclohexane Butanone (0.8 g, 144 mmol), anhydrous zinc chloride (1.5 g, 144 mmol), anhydrous methanol (45 mL) were placed in a 100 mL round bottom flask and stirred for 3 min, and sodium cyanoborohydride was slowly added at room temperature ( 2.3g, 144mmol), after the addition, the temperature was raised to 50 ° C for 3 hours, and the reaction was stopped by adding 2 mL of water to room temperature. The reaction solution was extracted with ethyl acetate (60 mL * 3 ), and then saturated sodium chloride (NaCl) was used. (30 mL) After washing once, the ester layer was dried over anhydrous Na ₂ EtOAc. EtOAc (EtOAc) m. ⁺ = 420.1. iH-NMR (DMSO-^, 400 MHz): δ 8.56 (d, 1H), 8.48 (s, 1H), 7.93 (d, 1H), 7.42 (d, 1H), 7. 38 (dd , H), 7.21 (d, H), 4.56 (t, 2H), 4.46 (t, 2H), 3.46(s, 3H), 3.43(t, 1H), 3.09 (t, 4H), 2.39 (t, 4H) ppm.

 5-bromo-1-methyl-3-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5- (4,4 Of 5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)pyridine-2(1H)-one intermediate (1 f )

Weigh out 2-dicyclohexylphos-2',4',6'-triisopropylbiphenyl (X-phos) (0.678g, 1.4mmol), Pd(OAC) ₂ (0.16g, 0.7mmol) In a 100 mL three-necked flask, 1,4-dioxane (3 mL) was added, protected with nitrogen, stirred for 20 min, and added 5-bromo-1-methyl-3-((5-(4-) But-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridine-2 (1H>ketone (1.5 g, 0.35 mmol), boronic acid pinacol ester (B ₂ Pin ₂ ) ( 1.8 g, 1.5mmol), potassium acetate (KOAc) (1.05g, 4.2mmol), dioxane 52mL, nitrogen protection, heating at 100 ° C for 2.5h, pad diatomaceous earth suction filtration, The filtrate was added water, ethyl acetate (60mL * 3) was extracted, washed once with saturated NaCl (30mL), and finally the ester layer was dried over anhydrous Na ₂ S04 and the organic phase was dried and concentrated to a large amount of solid precipitated was filtered and vacuum dried to give (0.78 g, 46.6%). MS (ESI) m/z: [M+H] + = 468.3, ¹ H-NMR (OMSO-d6, 400 MHz): δ 8.44 (s, IH), 8.19 (s, IH), 7.88 (d, IH) ), 7.48(s,lH), 7.36(dd, H), 7.15 (d, IH), 4.57(t, 2H), 4.48-4.45 (t, 2H), 3.54(s, 3H), 3.44(t, IH), 3.09(t, 4H), 2.40(t, 4H), 1.28 (s, 12H) ppm.

 6-Cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(l-methyl-5-((5-(4-(oxetan-3-yl)piperazine) -1-yl)-pyridin-2-yl)amino)-6-oxa-1,6-dihydro-pyridin-3-yl)-phenyl)-isoquinoline-1(2H)-one (compound) 1) Preparation

Weigh out 5-bromo-1-methyl-3-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5- (4 ,4,5,5-tetramethyl- 1,3,2 dioxaborolan-2-yl)pyridine-2 (1H>ketone (246 mg, 0.478 mmol), 2-(3-chloro-2- (hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2Η)-one (185 mg, 0.478 mmol), [Ι, Γ-bis(diphenylphosphino)ferrocene Palladium dichloromethane ruthenium complex (Pd (dppf) ₂ C1 ₂ *CH ₂ C1 ₂ ) (175 mg, 0.19 mmol) was placed in a 50 mL three-necked flask, replaced with argon three times and then added to 1, 4-Dioxane (15 mL), stirring for 5 minutes, adding 2M NaHC0 ₃ (0.7 mL, 1.43 mmol), replacing with argon three times, then heating to 100 ° C for 2 hours, stopping the reaction and cooling to room temperature, pad celite filtration, the filtrate was added water and ethyl acetate (30mL * 3) was extracted, washed once with saturated NaCl GOmL), and finally the ester layer was dried over anhydrous Na ₂ S04 column chromatography to give the product (163mg, 48.1 %) , MS (ESI) m/z: [M+H]+=649.4, ¹ H-NMR (DMSO-d6, 400 MHz): δ 8.57 (s, IH), 8.38 (s, IH), 7.86 ( d, IH), 7.50-7.54(m, 2H), 7.43(d, IH), 7.33-7.38(m, 4H), 7.26(s, IH), 6.99(d, IH) , 6.59(d, IH), 5.80(t, IH), 4.55 (t, 2H), 4.47 (t, 2H) 4.35-4.15 (m, 2H), 3.58(s, 3H), 3.45(s, IH) , 3.06(t, 4H), 2.46(t, 4H), 2.1(m, IH), 1.08-1.07(m, 2H), 0.87-0.8 l(m, 2H) ppm.

Real

Preparation of tert-butyl-6-nitro-5',6'-dihydro-[3,4'-bipyridyl]-l'(2'H)-carboxylate

5-Bromo-2-nitropyridine (250 mg, 1.23 mmol), N-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (456 mg, 1.47 mmol), Pd (dppf) ₂ C1 ₂ *CH ₂ C1 ₂ (30 mg, 0.37 mmol) was placed in a 50 mL three-necked flask, replaced with argon three times, then added with 1,4-dioxane (15 mL) and stirred for 5 minutes. Join 2M NaHC0 ₃ (1.85 mL, 3.7 mmol) was replaced with argon three times and then warmed to 100 ° C for 2 hours. The reaction was stopped and cooled to room temperature. The padded celite was filtered and filtered, and ethyl acetate (20mL*3) ) extraction, followed by saturated NaCl

(10 mL) wash, and finally the ester layer was dried over anhydrous Na ₂ S04 column chromatography to give the product (270mg, 71%), MS (ESI) m / z: [M + H] + = 306.2 1 H. - NMR (CDC1 ₃ , 400 MHz): δ 8.65 (s, IH), 8.24 (d, IH), 7.94 (d, IH), 6.32 (bs, IH), 4.16 (t, 2H), 3.70 (m, 2H), 2.57(t, 2H), 1.50(s, 9H) ppm.

Preparation of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate

Weigh tert-butyl-6-nitro-5',6'-dihydro-[3,4'-bipyridine H'(2'H> carboxylate (250 mg, 0.82 mmol), add Pd/C ( 10%, 0.05 g) and anhydrous methanol (45 mL). After sealing, the mixture was replaced with hydrogen three times and then reacted at room temperature for 3 hours. After stopping the reaction, the Pd/C was filtered off, the methanol was removed under reduced pressure, and dried in vacuo to give a brown product (0.147 g). MS (ESI) m/z: [Μ+Η] + = 278.2. ¹ H-NMR (CDC1 ₃ , 400 MHz): δ 7.92 (s, lH), 7.27 (d, lH), 6.47 (d,lH), 4.34(t, 2H), 4.20(bs, 2H), 2.79(t, 2H), 2.55(m, IH), 2.04(t, IH), 1.85(m, 2H), 1.67( m, IH) 1.47 (s, 9H) ppm.

tert-Butyl 4-(6-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl)piperidine-1-carboxylate Preparation of acid ester

Xantphos (436 mg, 0.752 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) (80.52 mg, 0.188 mmol) were weighed and mixed, and 50 mL of dioxane was added under argon atmosphere. Continue nitrogen purge, stir for 20 min, continue to add Cs ₂ C0 ₃ (1.83 g, 5.64 mol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (0.52 g, 1.88 mmol) , 3,5-dibromo-1-methylpyridine-2(1H)-one (0.5g, 1.88mmol), heated to 100 ° C under nitrogen atmosphere for 2.5 h, stop the reaction and cool to room temperature, diatom The mixture was extracted with EtOAc (40 mL*3), and then washed with saturated NaCI (30mL). The final ester layer was dried over anhydrous Na ₂ SO ₄ and concentrated to a small A yellow solid (0.53 g, 60.9%) was obtained. MS (ESI) m/z: [M+H] ⁺ = 463.2.1H-NMR (DMSO-^, 400 MHz): δ 8.68 (s, 1H), 8.65 (s, IH), 8.15 (s, IH) , 7.50-7.55(m, 2H), 7.28(d, IH), 4.06 (d, 2H), 3.51(s, 3H), 2.79(bs, 2H), 2.63(m, IH), 1.73(d, 2H ), 1.50-1.47 (m, 2H), 1.46 (s, 9H) ppm.

 Preparation of 5-bromo-1-methyl-3-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridine-2(1H)-one

Weighing tert-butyl 4-(6-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-3-yl)piperidine-1 - Carboxylic acid ester (379 mg, 0.82 mmol) was placed in a 50 mL round bottom flask, 20 mL of DCM and 1 mL of trifluoroacetic acid were added and allowed to react at room temperature overnight. After completion of the reaction, saturated NaHC0 ₃ was added to adjust the pH of the solution to 7 Until -8, (20mL * 3) and extracted with DCM, dried organic layer over anhydrous Na ₂ S0 _4, filtered solvent was removed under reduced pressure to give a yellow solid (210mg, 70.9% MS (ESI) m/z: [M+H] ⁺ = 363.1. 1H-NMR DMSO-d6, 400 MHz) : (5 8.73(s, 1H), 8.66(s, 1H), 8.15 (s, 1H), 7.49-7.53 (m, 2H), 7.31 (d, 1H), 5.75 (s, H), 3.51 (s, 3H), 3.19 (d, 1H), 2.96-2.90 (m, 2H) ), 2.76-2.73 (m, 1H), 1.91-1.88 (m, 2H), 1.79-1.73 (m, 2H) ppm.

 Preparation of bromomethyl(oxetanyl)piperidinyl)pyridyl)amino)pyridine H)-one

5-Bromo-1-methyl-3-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridine-2 (1H>ketone (225m, 0.62mmol), 3-oxo Heterocyclic butanone (44.6 mg, 1.86 mmol), anhydrous zinc chloride (256 mg, 1.86 mmol), anhydrous methanol (15 mL) were placed in a 50 mL round bottom flask and stirred for 3 min. Sodium hydride (40 mg, 1.86 mmol) was added, and the mixture was heated to 50 ° C for 5 hours. After cooling to room temperature, 2 mL of water was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate (20 mL*3) and then saturated NaCI (10 mL) ) wash, and finally the ester layer was dried over anhydrous Na ₂ S0 _4, the organic layer was concentrated to give a pale yellow solid by column chromatography (160mg, 61.7%) MS ( ESI) m / z:. [Μ + Η] + = 419.1. ¹ H-NMR (DMSO-ίΜ, 400 MHz) : δ 8.67 (s, 1H), 8.65 (s, 1H), 8.15 (s, 1H), 7.56 (dd, 1H), 7.50 (d, 1H) , 7.28 (d, 1H), 4.55-4.54(t, 2H), 4.45-4.42 (t, 2H), 3.51(s, 3H), 3.41(t, 1H), 2.80-2.78(d, 2H), 1.87 -1.81 (m, 2H), 1.74- 1.63 (m, 4H) ppm.

 Preparation of bromomethyl (oxetanyl) piperidinyl) pyridyl)amino),,, tetramethyl, dioxaborolanylpyridine H)-one

Weigh X-phos (68mg, 0.14mmol), Pd(OAc) ₂ (16mg, 0.07mmol) in a 25mL three-necked flask, add 1,4-dioxane (1mL), protect with nitrogen, stir for 20min Add 5-bromo-1-methyl-3-((5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyridine-2 (1H) > Ketone (150mg, 0.35mmol), B ₂ Pin ₂ (180mg, 0.71mmol), KOAc (105g, 1.07mmol), dioxane 5mL, nitrogen protection, heating at 100 ° C for 2.5h, pad diatomaceous earth pumping Filtration, the filtrate was added with water, ethyl acetate (15 mL*3), and then washed once with saturated NaCI (10 mL). The ester layer was dried over anhydrous Na ₂ SO ₄ , and the organic phase was dried and concentrated to a large amount of solids.得(70mg, 41.9% MS (ESI) m/z: [Μ+Η] ⁺ = 467.3, ¹ H-NMR (DMSO- (5, 400 MHz): δ 8.52 (s, 1H), 8.37 (s, 1H) ), 8.10(d, 1H), 7.52-7.49(m,2H), 7.17(d, H), 4.57t, 2H), 4.55 (t, 2H), 4.45(s, 2H), 3.56(s, 3H) ), 2.80 (d, 2H), 1.87-1.81 (m, 2H), 1.74- 1.63 (m, 4H), 1.28 (s, 12H) ppm.

 Cyclopropylfluoro(hydroxymethyl)methyl(oxetanyl)piperidinyl)-pyridyl)amino)oxalate, dihydro-pyridyl)-phenyl)-isoquinoline H)-one ( Preparation of compounds

Weigh out 5-bromo-1-methyl-3-((5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)-5- (4 ,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)pyridine-2(1H)-one (37 mg, 0.085 mmol), 2-(3-chloro-2 -(Hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinoline-l(2H)-one (40 mg, 0.085 mmol), Pd (dppf) ₂ C1 ₂ *CH ₂ C1 ₂ ( 23.4 Mg , 0.0225 mmol) was placed in a 25 mL three-necked flask, replaced with argon three times, then added with 1,4-dioxane (1 mL), stirred for 5 minutes, and then added with 2M NaHC0 ₃ (27 mg, 0.255 mmol). After replacing three times, the temperature was raised to 10 CTC for 2 hours. The reaction was stopped and cooled to room temperature. The padded diatomaceous earth was filtered, and the filtrate was extracted with water, ethyl acetate (10 mL*3), and then washed once with saturated NaCl (5 mL). dried over anhydrous NaS0 ₄ after drying column chromatography to give product (30.9mg, 50%), MS (ESI) m / z: [m + H] + = 648.4, 1H-NMR (DMSO-d6, 400 MHz) : δ 8.66(s, 1H), 8.52(s, lH), 8.05(d, 1H), 7.56-7.52(m, 4H), 7.35-7.3 l(m, 3H), 7.26-7.22(m, 2H) , 6.98(d 1H), 6.59(d, 1H), 4.76 (t, 1H), 4.53 (t, 2H) 4.43 (t, 2H), 4.38-4.15(m, 2H), 3.59(s, 3H), 3.41(t, 1H), 2.78(t, 2H), 2.08(t, 1H), 1.80- 1.65(m, 6H), 1.17- 1.10(m, 2H), 0.87-0.86(m, 2H) ppm.

 3: Preparation of compound 3

Preparation of tert-butyl 3-(4-(6-nitropyridin-3-yl)piperazine-1-yl)azetidin-1-carboxylate

The tert-butyl 3-(4-(6-nitropyridin-3-yl)piperazine-1-yl)azetidinium-1 can be obtained by a similar method to the preparation of the compound intermediate (1e). - Carboxylic ester (1.5 g, 79%). [M+H]+=364.2 ; ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.27 (d, = 2.64 Hz, 1H), 8.16 (d, J = 9.16 Hz, 1H), 8.50 (dd, J = 2.68Hz, 9.24Hz, 1H), 3.92-3.83(m, 2H), 3.78-3.67(m, 2H), 3.57-3.49(m, 4H), 3.13-3.06(m, 1H), 2.47-2.40 (m, 4H), 1.39 (s, 12H).

Preparation of 1-(azetidin-3-yl)-4-(6-nitropyridin-3-yl)piperazine

 1-(Azeticyclyl-3-yl)-4-(6-nitropyridin-3-yl)piperazine (0.93 g, 88.6) can be obtained by a similar method to the compound compound intermediate (Id). %) [M+H]+=264.2.

Preparation of 1 (1-methylazetidin-3-yl)-4-(6-nitro-3-yl)piperazine

Add 1-(azetidin-3-yl)-4-(6-nitropyridin-3-yl)piperazine (0.93 g, 3.53 mmol), paraformaldehyde (954 mg, 10.6 mmol) to 100 ml In a round bottom flask, 25 ml of formic acid was added as a solvent, and the reaction was carried out at 10 CTC overnight. After the reaction is completed, at least the formic acid is concentrated under reduced pressure, and the pH is adjusted to 8-9 with concentrated aqueous ammonia. The mixture was extracted with EtOAc (EtOAc m.) [M+H] ⁺ =278.2; ¹ H-NMR (400MHz, CDC1 ₃ ) δ: 8.18 (d, = 9.12Hz, 1H), 8.14 (d, J = 2.84Hz, 1H), 7.22 (dd, =2.8 Hz, 9.16Hz, 1H), 4.23 (t, = 8.2Hz, 2H), 3.60 (t, = 8.08Hz, 2H), 3.51-3.45(m, 4H), 3.42-3.37(m, 1H), 2.79( s, 3H), 2.57-2.43 (m, 4H).

Preparation of 5-(4-(l-methylazetidin-3-yl)piperazine-1-yl)pyridine-2-amine

 5-(4-(1-methylazetidin-3-yl)piperazine-1-yl)pyridin-2-amine can be obtained by a similar method to the preparation of the compound intermediate (1b). 354mg, 78%). [M + H] + = 248.2.

 5-bromo-1-methyl-3-((5-(4-(1-methylazetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amine)pyridine- Preparation of 2(1H)-ketoamine

5-Bromo-1-methyl-3-((5-(4-(1-methylazetidin-3-yl))piperidyl can be prepared by a similar method to the preparation of compound intermediate (1 e ) Pyrazin-1-yl)pyridin-2-yl)amine)pyridine-2(1H)-one amine (550 mg, 63%). [M+H] ⁺ =433.1 ; ¹ H-NMR (400MHz, CDC1 ₃ ) δ: 8.57 (d, J = 2.0Hz, 1H), 7.98 (d, J = 2.8Hz, 1H), 7.74 (s, 1H ), 7.23 (dd, J = 2.76Hz, 9.2Hz, 1H), 6.93 (d, J = 2.04Hz, 1H), 6.75 (d, J = 8.88Hz, 1H), 3.59 (s, 3H), 3.55 ( m, 2H), 3.14 (t, = 4.68Hz, 4H), 3.07-3.0 (m, 1H), 2.95 (m, 2H), 2.50 (t, = 4.76Hz, 4H), 2.37(s, 3H).

 1-methyl-3-((5-(4-(l-methylazetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amine)-5-(4, Preparation of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one

 1-methyl-3-((5-(4-(1-methylazetidin-3-yl)piperazine-1-) can be obtained by a similar method to the preparation of compound intermediate (1f). -pyridin-2-yl)amine) -5-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)pyridine-2(1H)- Ketone (245 mg, 48%) [M+H]+ = 481.3.

 6-Cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-(methylazetidin-3-yl)) Preparation of piperazin-1-yl)pyridin-2-yl)amine-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-1(2H)-one compound 3

Compound 3 (51 mg, 50.2%) was obtained in a similar manner to the preparation of compound 1. Mp: 230.4-232 ° C; MS ( ESI) m / z 662.3 [M + H] +; 1H NMR (400 MHz, DMSO- 6): δ 8.56 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.53 (t, = 7.64 Hz, 1H), 7.43 (d, = 7.24 Hz, 1H), 7.40-7.28 (m, 4H), 7.26 (s, 1H), 7.21 (d, = 9.12) Hz, 1H), 6.98 (d, J = 13.08 Hz, 1H), 6.60 (d, J = 7.00 Hz, 1H), 4.77 (s, 1H), 4.37-4.29 (m, 1H), 4.25-4.15 (m , 1H), 3.59 (s, 4H), 3.35 (m, 1H), 3.03 (s, 4H), 2.88 (s, 3H), 2.35 (s, 4H), 2.27 (s, 3H), 2.12-2.03 ( m, 1H), 1.15-1.03 (m, 2H), 0.93-0.82 (m, 2H); ¹³ C NMR (100 MHz, DMSO- ₆ ): δ 163.25, 161.13, 158.88, 157.08, 152.10, 149.08, 142.03, 141.39, 140.91, 140.71, 136.39, 135.71, 134.43, 131.21, 131.01, 129.22, 128.35, 127.53, 127.14, 118.82, 118.60, 117.10, 113.39, 111.08, 104.56, 60.54, 57.45, 54.90, 49.59, 49.12, 46.02, 37.90, 15.89, 11.13; HPLC 97.7%; HRMS (ESI) m/z calcd for C ₃₈ H ₄₀ FN ₇ O ₃ [M+H] ⁺ 662.3177, found 662.3252.

Example 4: Preparation of Compound 4

 Compound 4

 Preparation of 5-bromo-3-((5-(4-(cyclopropylmethyl)piperazine-1-yl)pyridin-2-yl)amine)-1methylpyridine-2(1H)-one

The compound intermediate (Id) (247 mg, 0.68 mmol), Et ₃ N (137 mg, 1.36 mmol) was dissolved in 20 ml of CH ₂ C1 ₂ and the reaction solution was cooled to 0 ° C and the cyclopropyl group was slowly added dropwise. Formyl chloride (77. 8 rr3⁄4, 0.75 ΓΤΤΤΌΙ), after the addition was completed, the temperature was raised to room temperature and the reaction was continued for 2 hours. After completion of the reaction, saturated NaHC0 ₃ , ethyl acetate (15 mL*3) was added, and then washed with saturated NaCl (10 mL). Once again, the final ester layer was dried over anhydrous Na ₂ SO ₄ and then purified by column chromatography to yield white solid (250 mg, 58.1 %) as a gray solid. MS (ESI) m/z 432.1 [M + H]+; 1H NMR (400 MHz, DMSO- ₆ ): δ 8.59-8.58 (d, J = 2.44 Hz, IH), 8.00-7.99 (d, J = 2.84 Hz, IH), 7.77 (s, IH), 7.28-7.27 ( d, J = 2.86 Hz, IH), 6.95-6.94 (d, J = 2.44 Hz, IH), 6.78-6.76 (d, J = 8.88 Hz, IH), 3.86-3.81 (d, J = 20.2 Hz, 4H ), 3.60 (s, 3H), 3.14-3.08 (d, J = 22.4 Hz, 4H), 1.58 (m, IH), 1.04-1.01 (m, 2H), 0.83-0.79 (m, 2H).

 3-((5-(4-(cyclopropanoyl)piperazin-1-yl)pyridin-2-yl)amine)-1-methyl-5-(4,4,5,5-tetramethyl Preparation of -1,3,2-dioxaborolan-2-yl-2-yl)pyridine-2(1H)-one

3-((5-(4-(cyclopropanoyl)piperazin-1-yl)pyridin-2-yl)amine)-1-methyl can be obtained by a similar method to the preparation of the compound intermediate (If) -5-(4,4,5,5-tetramethyl-1,3,2-dioxapentain-2-yl-2-yl)pyridine-2(1H)-one (96 mg, 48.2 %)o MS (ESI) m/z 480.3 [M + H]+; 1H NMR (400 MHz, CDC1 ₃ ): δ 8.48-8.47 (d, J = 2.42 Hz, IH), 8.03 (d, J = 2.84 Hz, IH), 7.64 (s, IH), 7.34-7.33 (d, J = 2.43 Hz, IH), 7.24-7.23 (d, J Γ 'Ρ)89·9 '(Ηΐ 'ζΗε·8 = 'Ρ) LL \ΥίΖ 'Ρ) 0VL-6VL '(Ηΐ 'ΖΗ0·8 = 'Ρ) L '(Ηΐ'ζΗ 8 ' ^Ζ Η6·Δ = 'ΡΡ' ZLL '(Ηΐ 'ζΗΐ·8 = 'Ρ) Z6'L '(Ηΐ '3⁄4£'8 = 'Ρ) 90' 8 '(Ηΐ 's) Gang: g ( ⁹ P-OSWa ' z匪0017) PA NH _T ^: r89 £= ₊ [H+W] :(IS3)SW %LV ' 8Ό) W^ '1⁄21ί3⁄4

' Jim '-翻'wozi ^A ^: Α)Μώ/^ώΜ^Υ ^mw ^im

Soil: οει ^ 'dwa ^ wi yarr '固#^^士3⁄4呦^ 3⁄4 簟 簟

' 9 0) ^ε Ο ¥(Ι ^0ΧΠΧΠ 8179Ό ' ΠΌ) hang Φ ' ^s 'l)fli 3⁄4^ "93⁄4 '(\omm _V '§χ) wake up - (ΗΖ)ΐ-foot fti 3⁄4Mir9琳

 Mother circle s啄 : s painting

'8£6 'I99 Punoj '££6 'I99 +[H+W] 3⁄4 ⁹ Nd ^i£ H ^8£ DP z/ui (isa) SW3⁄4H ·% L£6 DldH ■WL '6ΐΌΐ '69Όΐ '017' SI 'WLi 'ΖΥ6 L6 '68.9S '66'£0ΐ '^ό'ΐΐΐ 'ξ&ΖΙΙ '8Δ·9ΐΐ '66·Δΐΐ Όε·8ΐΐ L9Z\ '99·ΔΠ '98·ΔΠ '89'8Π '8 Όεΐ ' 85Ό£ΐ '9 '1⁄21 iil 'Δ8Ήΐ 'ΔΐΌΗ

'9ε·(Μ 3⁄49Όΐ7ΐ ''ςο·6 ΐ

Ό9Ό9ΐ O m 'IO' I δ -( ⁹ P-osna

'ZHW 00I)3⁄4WN D _£l '(Η17 ΟΔΌ^ΔΌ \Ήί £8'0"£6'0 \Ήί 80·ΐ-ΐΐ·ΐ \Ήί 00'-80''(Η17's)L0'£'(Η£'s)8S'£'(Η's) 6 £ '(Ηΐ 9L = Γ ' ^Ζ Η ZL = Γ 'ΡΡ) IV -\Z''(Ηΐ'ZH 9V£ = f ' ^Z HZ ' = f 'PP) 6Z'-££''(Ηΐ 8 ·8 = 'ϊ) '(Ηΐ WL

= f 'Ρ) 8S'9"09'9 '(Ηΐ 'ZH 9LZ\ = f 'Ρ) Δ6·9-00·Δ \Ήί L6'9-£Z'L '(Η£ 'l£'L-6£'L \Ήί 'm) WL-WL '(Ηΐ 'ZH 88'Δ = 'ϊ) τ · LW L '(Ηΐ %9'Z = f 'Ρ) 88·Δ-68·Δ '( Ηΐ 's) ZVS '(Ηΐ ' ^Ζ Η ΖΥΖ = Γ 'Ρ) 8S'8"6S'82 :( ⁹ P-OSWa '^HW 0017) 3⁄4WN H _T +[H + W] £'199 z/ui (isa) SW •Do Γΐ6ΐ-ε·68ΐ : dw ·(% Ζ Ρ L\) XI ^W^

 ^ m ^ ^ιι-(Ηζ)ι-#ιΐι 3⁄4-83⁄4 4ί-9-(3⁄4*(3⁄4ώ3⁄4)-ζ-(3⁄4

-ε-3⁄43⁄4ϋ霄二-9'ι-^3⁄4-9-3⁄4ώ -i-(3⁄4f(3⁄4-z-3⁄43⁄4d(3⁄4-i-*i3⁄46(3⁄43⁄4li 4iH)-s))-s)-e)- z

6ΔΌ-Ε8Ό XUZ ΐΟ'ΐ-ΚΠ '(ΗΠ 's) 8 ΐ '(Ηΐ 9Δ·ΐ-6Δ·ΐ ΧΐίΡ '^Η ΖΎΖ = f 'Ρ) L0-£-£V£ '(Η£ 's ) £9'£ '(Η17 '^Η ΐ\Ζ = Γ 'Ρ) 08'£"58'£ '(Ηΐ 88·8 = 'Ρ) 9Δ·9—6Δ·9 '(Ηΐ ZVZ = = 7.4 Hz, IH), 2.2-2.15 (m, IH), 1.15-1.0 (m, 2H), 0.92-0.8 (m, 2H).

Preparation of 2-(3-bromo-2-(hydroxymethyl)phenyl)-6-cyclopropylisoquinoline-1(2H)-one

 2-Bromo 6-(6-cyclopropyl-1 -oxoisoquinolin-2(1 H)-yl)benzaldehyde (368 mg, 1 mmol) was dissolved in 500 ml of methanol, and boron was slowly added in an ice bath. Sodium hydride (5.5 mg, 1.5 mmol) was added and stirring was continued for 15 min. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc:EtOAc. [M+H]+=372.1 ; 1H NMR (400MHz, DMSO-d6) δ: 8.10 (d, J = 8.4Hz, IH), 7.78 (d, J = 7.9Hz, IH), 7.5-7.4 (m, 2H), 7.36 (d, J = 7.8Hz, IH), 7.33-7.28 (m, 2H), 6.64 (, d, = 7.4Hz, IH), 4.91 (d, = 4.0Hz, IH), 4.47 (dd , = 3.9Hz, 11.5Hz, IH), 4.27 (dd, J = 3.8Hz, 11.6Hz, IH), 2.20-2.05 (m, IH), 1.15-1.0 (m, 2H), 0.92-0.78 (m, 2H).

 6-Cyclopropyl-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amine) Preparation of -6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-1 (2H)-one compound 5

Compound 5 (63 mg, 57.1%) was obtained in a similar manner to the compound. Mp: 170.4 - 173.2 ° C; MS (ESI) m/z 589.2 [M + H]+; 1H NMR (400 MHz, DMSO- ₆ ): δ 8.58 (s, IH), 8.36 (s, IH), 8.12 (d, = 8.40 Hz, IH), 7.86 (s, IH), 7.54 (dd, J = 7.70 Hz, 7.80 Hz, IH), 7.49-7.40 (d, 2H), 7.41-7.31 (m, 4H), 7.28 (d, J = 8.40 Hz, IH), 7.22 (d, J = 9.00 Hz, IH), 6.64 (d, J = 7.40 Hz, IH), 4.74 (s, IH), 4.39-4.35 (m, IH), 4.25-4.15 (m, IH), 3.60 (s, 3H), 3.04 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 2.18-2.03 (m, IH), 1.15-1.01 (m, 2H), 0.92-0.78 (m, 2H); ¹³ C NMR (100 MHz, DMSO- ₆ ): δ 161.80, 157.07, 149.93, 149.02, 142.29, 141.35, 140.93, 138.00, 136.32, 134.63, 134.39, 131.15, 130.96, 129.19, 128.20, 127.82, 127.46, 127.15, 125.09, 123.73, 122.58, 118.56, 117.06, 113.33, 105.19, 57.41, 54.92, 49.22, 46.13, 37.87, 15.93, 10.86, 10.82; HPLC 97.5 %; HRMS (ESI) m/z calcd for C ₃₅ H ₃₆ N ₆ 0 ₃ [M+H] ⁺ 589.2849, found 589.2919.

 Preparation of 2-bromo-6-(2-cyclopropyl-5-oxo-1,6-naphthyridin-6(5Η)-yl)benzaldehyde

The compound 2-bromo-6-(2-cyclopropyl-5-oxo-1,6-naphthyridin-6(5H)-yl)benzaldehyde can be obtained by a similar method to the preparation of the compound intermediate (5a). (218 mg, 77.1%). MS (ESI) m/z 369.1 [M + H]+. Preparation of 6-(3-bromo-2-(hydroxymethyl)phenyl)-2-cyclopropyl-1,6-naphthyridin-5(6H)-one

 The compound 6-(3-bromo-2-(hydroxymethyl)phenyl)-2-cyclopropyl-1,6-naphthyridin-5 (6H) can be obtained by a similar method to the preparation of compound intermediate (5b). )-ketone (100 mg, 83.0%). MS (ESI) m/z 371.1 [M + H]+.

2-cyclopropyl-6-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-methylpiperazin-1 -yyl)pyridin-2-yl)) Preparation of amine-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-1,6-naphthyridin-5(6H)-one compound 6

Compound 6 (33 mg, 65 %) was obtained in a similar manner to the compound. Mp: 167.3-170.8 ° C; MS (ESI) m/z 590.2 [M + H]+; 1H NMR (400 MHz, DMSO- ₆ ): δ 8.59 (S, 1H), 8.41 (s, 1H), 8.38 (d, = 3.10 Hz, 1H), 7.86 (d, J = 2.80 Hz, 1H), 7.65-7.50 (m, 2H) ), 7.51-7.42 (m, 2H), 7.41-7.31 (m, 3H), 7.22 (d, J = 9.00 Hz, 1H), 6.64 (d, J = 7.60 Hz, 1H), 4.81 (dd, = 4.10) Hz, 4.40 Hz, 1H), 4.33 (dd, J = 3.60 Hz, 11.10 Hz, 1H), 4.20 (dd, J = 4.60 Hz, 11.30 Hz, 1H), 3.60 (s, 3H), 3.05 (s, 4H) ), 2.45 (s, 4H), 2.40-2.27 (m, 1H), 2.22 (s, 3H), 1.20-1.05 (m, 4H); ¹³ C NMR (100 MHz, DMSO- ₆ ): δ 168.41, 161.40 , 156.52, 150.25, 153.51, 148.56, 141.32, 140.81, 140.36, 137.82, 135.70, 135.44, 133.75, 130.62, 128.71, 127.76, 127.02, 126.64, 120.41, 119.02, 117.94 116.52, 112.84, 106.11, 56.82, 54.41, 48.81, 45.64, 37.46, 17.52, 11.31, 11.22; HPLC 95.5%; HRMS (ESI) m / z calcd for C 33 H 36 N 8 0 3 [m + H] + 590.2801, found 590.2877.

 Preparation of 2-bromo-6-(6-cyclopropyl-1,3-oxo-2,7-naphthyridine-2(1 H)-yl)benzaldehyde

 The compound 2-bromo-6-(6-cyclopropyl-1 -oxo-2,7-naphthyridin-2(1 H)-yl)benzene can be obtained by a similar method to the preparation of the compound intermediate (5a). Formaldehyde (103 mg, 52.2%). MS (ESI) m/z 369.1 [M + H]+.

Preparation of 2-(3-bromo-2-(hydroxymethyl)phenyl)-6-cyclopropyl-2,7-naphthyridine-1 (2H)-one

 The compound 2-(3-bromo-2-(hydroxymethyl)phenyl)-6-cyclopropyl-2,7-naphthyridin-1 (2H) can be obtained by a similar method to the preparation of compound intermediate (5b). - ketone MS (ESI) m/z 371.1 [M + H]+.

 6-Cyclopropyl-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amine) Preparation of -6-oxo-1,6-dihydropyridin-3-yl)phenyl)-2,7-naphthyridin-1 (2H)-one Compound 7

Compound 7 (63 mg, 58.0%) was obtained in a similar manner to the preparation of compound 1. Mp: 149.6-151.3 ° C; MS ( ESI) m / z 590.2 [M + H] +; 1H NMR (400 MHz, DMSO- 6): δ 9.20 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 7.84 (d, J = 2.20 Hz, 1H), 7.61-7.50 (m, 3H), 7.46 (d, J = 7.30 Hz, 1H), 7.37 (m, 2H), 7.32 (s, IH), 7.22 (d, J = 9.00 Hz, IH), 6.18 (d, J = 7.60 Hz, IH), 4.85 (s, IH), 4.41-4.10 (m , 2H), 3.59 (s, 3H), 3.04 (s, 4H), 2.45 (s, 4H), 2.22 (s, 4H), 1.01-0.92 (m, 4H). ¹³ C NMR (100 MHz, DMSO- ₆ ): δ 164.69, 160.89, 156.55, 150.21, 148.62, 142.76, 141.18, 140.82, 140.36, 139.08, 135.81, 133.82, 130.66, 128.68, 128.40, 127.77, 127.04, 126.65, 118.41, 117.93, 116.53, 115.75, 112.91, 102.70, 74.32, 58.44, 56.90, 48.89, 48.63, 37.39, 17.09, 10.34, 10.26; HPLC 99.0%; HRMS (ESI) m / z calcd for C 34 H 35 N 7 0 3 [m + H] + 590.2801, found 590.2877.

 8: Preparation of compound 8

 Preparation of 2-(3-bromophenyl)-6-cyclopropyl-8-fluoroquinoline-1 (2H)-one

The compound 2-(3-bromophenyl)-6-cyclopropyl-8-fluoroquinolin-1 (2H)-one (93 mg, 53.1 %) was obtained by a similar method to the compound intermediate (5a). As a white solid ₀ MS (ESI) m/z 358.1 [M + H]+; 1H NMR (400 MHz, DMSO- ₆ ): δ 7.73 (s, IH), 7.66 (s, IH), 7.48 (s, 3H), 7.26 (s, IH), 6.99 (d, J = 10.80 Hz, IH), 6.60 (d, = 5.20 Hz, IH), 2.2-2.01 (m, IH), 1.2-1.01 (m, 2H) , 0.95-0.81 (m, 2H).

6-Cyclopropyl-8-fluoro-2-(3-(1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amine)-6- Preparation of oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinoline-1 (2H)-one compound 8

Compound 8 (114 mg, 79.1%) was prepared in a similar manner to the preparation of compound 1. Mp: 200.8-202.1 ° C; MS (ESI) m/z 577.2 [M + H]+; 1H NMR (400 MHz, DMSO- ₆ ): δ 8.87 (d, J = 2.40 Hz, IH), 8.43 (s , IH), 7.90 (d, = 2.80 Hz, IH), 7.67 (d, = 2.40 Hz, IH), 7.66-7.55 (m, 3H), 7.51 (d, J = 6.60 Hz, IH), 7.43-7.35 (m, 2H), 7.30-7.21 (m, 2H), 7.01 (d, J = 12.80 Hz, IH), 6.63 (d, J = 6.50 Hz, IH), 3.61 (s, 3H), 3.06 (s, 4H), 2.44 (s, 4H), 2.21 (s, 3H), 2.15-2.01 (m, IH), 1.21-1.09 (m, 2H), 0.90-0.79 (m, 2H); ¹³ C NMR (100 MHz , DMSO- ₆ ): δ 162.10, 160.38, 158.34, 156.66, 152.20, 150.35, 149.40, 141.50, 140.93, 139.81, 138.52, 134.26, 133.67, 131.42, 129.63, 127.06, 125.48, 124.89, 124.13, 118.40, 117.63, 113.30 , 113.06, 110.38, 104.75, 54.49, 48.77, 45.73, 37.37, 15.41, 10.76; HPLC 97.8 %; HRMS (ESI) m/z calcd for C ₃₄ H ₃₃ FN ₆ 0 ₂ [M+H] ⁺ 577.2649, found 577.2724 .

Example 9: Preparation of Compound 9

 Preparation of 2-(3-bromo-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinoline-1 (2H)-one

The compound 2-(3-bromo-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1 (2H)-one (72) can be obtained by a similar method to the preparation of compound intermediate (5a). Mg, 38.7 %). MS (ESI) m / z 372.1 [M + H] +; 1H NMR (400 MHz, DMSO- 6): δ 7.76 (d, J = 7.48 Hz, IH), 7.40-7.25 (m, 4H), 7.01 ( d, J = 13.56 Hz, IH), 6.64 (d, = 5.20 Hz, IH), 2.21-2.01 (m, 4H), 1.13-1.01 (m, 2H), 0.91-0.77 (m, 2H).

6-Cyclopropyl-8-fluoro-2-(2-methyl-3-(1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)) Preparation of amine-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinoline-1 (2H)-one compound 9

Compound 9 (28 mg, 57.3%) was prepared in a similar manner to the preparation of compound 1. Mp: 204.3-206.7 ° C; MS ( ESI) m / z 591.3 [M + H] +; 1H NMR (400 MHz, DMSO- 6): δ 8.51 (d, J = 1.32 Hz, IH), 8.39 (s , IH), 7.86-7.85 (d, = 2.52 Hz, IH), 7.47-7.28 (m, 6H), 7.23-7.17 (m, 2H), 7.01 (d, = 13.32 Hz, IH), 6.64 (d, J = 7.28 Hz, IH), 3.60 (s, 3H), 3.05 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 2.15-2.05 (m, IH), 2.02 (m, 3H) ), 1.13-1.02 (m, 2H), 0.90-0.80 (m, 2H); ¹³ C NMR (100 MHz, DMSO- ₆ ): δ 163.22, 160.63, 157.70, 156.53, 151.70, 148.60, 140.89, 140.86, 139.98 , 139.67, 134.18, 133.75, 133.29, 130.72, 129.98, 127.20, 127.00, 126.69, 126.48, 118.73, 118.44, 116.20, 113.01, 110.76, 104.85, 54.43, 48.71, 45.64, 37.22, 15.39, 15.04, 10.64; HPLC 97.1 % HRMS (ESI) m/z calcd for C ₃₅ H ₃₅ FN ₆ 0 ₂ [M+H] ⁺ 591.2878, found 591.2881.

Real

 Compound 10 (40 mg, 53.1%) was obtained in a similar manner to the preparation of compound 1. Mp: 198.3-200.4; MS

(ESI) m/z 633.3 [M + H]+; NMR (400 MHz, DMSO- ₆ ): δ 8.53 (s, IH), 8.43 (s, IH), 7.86 -7.85 (d, = 2.52 Hz, IH), 7.43-7.32 (m, 4H), 7.30 (s, IH), 7.23 -7.22 (m, 2H), 7.01-6.98 (d, J = 13.10 Hz, IH), 6.63 -6.62 (d, = 8.40 Hz, IH), 4.57-4.55 (m, = 12.10 Hz, 2H), 4.46-4.37 (m, = 12.20 Hz, 2H), 3.59 (s, 3H), 3.38 (m, IH), 3.06 (s, 4H) ), 2.37 (s, 4H), 2.02 (m, 3H), 1.99 (s, 2H), 1.13-1.02 (m, 2H), 0.90-0.80 (m, 2H); "C NMR (400 MHz, DMSO- ₆ ): δ 163.20, 160.61, 157.75, 156.47, 151.80, 148.71, 140.87 , 140.81, 139.97, 139.66, 134.20, 133.72, 133.28, 130.70, 129.99, 127.21, 127.07, 126.70, 126.51, 118.69, 118.42, 116.23, 113.05, 110.85, 104.84, 74.32, 58.43, 48.89, 48.60, 37.25, 15.39, 15.05 HPLC 7.76; HRMS (ESI) m/z calcd for C ₃₇ H ₃₇ FN ₆ 0 ₃ [M+H] ⁺ 633.2983, found 633.2987.

Example 11: In vitro biochemical level inhibition of protein kinase (PK) activity assay

 Materials and Methods: BTK kinase from Invitrogen; HTRF KinEASE; TK kit (Cisbio);

384-well plate (Greiner); ATP (sigma), MgCl ₂ (sigma); PHERAstar FS multi-function microplate reader (BMG); low-speed centrifuge (StaiteXiangyi); incubator (Binder). The selected positive drug is RN486, which can be prepared by the existing literature (WO2010100070). The structure is as follows:

 RN486

 Dissolution and storage of the compound: Depending on the solubility, the test compound was formulated into a mother liquor of 0.5-10 mmol/L in DMSO, and stored at -20 ° C after dispensing;

 Preparation of the compound working solution: The compound to be dispensed is taken out from the refrigerator before the test, diluted with pure DMSO to the desired concentration of 50 Torr; then the compound is diluted to the desired concentration with 4 Torr in deionized water;

 1.33><Enzymatic buffer preparation: 5><Enzymatic buffer derived from HTRF kit) diluted to 1.33 x with deionized water, and added the corresponding composition of 1.33 x final concentration: 1.33 mmol / L DTT and 1.33 mmol / L MgC12; Preparation of the kinase working solution: Dilute the Btk to 2 用 with a 1.33 x Enzymatic buffer to a final concentration of 0.2 ng/μί; Preparation of the substrate working solution: substrate-biotin (derived from HTRF kit) and ATP (lO) with 1.33 x Enzymatic buffer mM) a mixture of the final concentration required to be diluted to 4 Torr;

 Preparation of the test solution: Dilute 16.67 μηιοΙ/L of Streptavidin-XL665 to a final concentration of 4 用 with HTRF detection buffer, then mix with an equal volume of Antibody-Cryptate (both from the HTRF kit).

Enzyme reaction step: 4 μL μl of kinase working solution was added to each well of a low volume 384 microplate, and 4 1.33x Enzymatic buffer was added as a negative control (Negative); 2 μΐ of the compound working solution was added to the well while adding 2% DMSO aqueous solution as a zero compound concentration control (ie positive control, Positive); incubate at 25 V (or 30 V) for 5-10 min; add 2 μL of substrate working solution to the well to start the enzymatic reaction at 25 ° C (or 30 ° C) Oscillating reaction for 15-60 min.

 HTRF reagent detection step: 8 μL of test solution is added to the well to terminate the reaction; 25 ° C reaction for 1 h;

 Reading of HTRF signal: Using PHERAstar FS reading detection signal, the instrument is set as follows:

 Optic module HTRF®

 Integration delay (lag time) 50

 Integration time 400

 Number of flashes 200

 For raw data read per well, the ratio = 665 nm / 620 nm;

 Calculation of inhibition rate: ratio of test group to ratio of negative control group

 Inhibition rate % = ( 1- ) 100 %

 ^ Positive control ratio - negative control ratio -

Calculation of the IC ₅ o value: The logarithm of the compound concentration is plotted on the abscissa and the inhibition rate is plotted on the ordinate. In GmphPad Pri _S m 5 , the nonlinear curve is fitted: log (inhibitor) vs. response - Variable slope, The concentration of the test compound at the enzyme inhibition rate of 50% is IC ₅ o.

Experimental results: BTK kinase activity half inhibitory concentration (IC _5Q , nM)

The present invention provides a half-inhibitory concentration (IC _5Q ) of a compound of formula I as shown in Formula I for BTK kinase activity.

 Conclusion: Some of the compounds of the present invention have better inhibitory activity against the biochemical level of BTK kinase than the positive drug RN486.

 Example : 12: In vitro cell water, protein kinase (PK) activity assay

 Materials and Methods: Fluo-4 DirectTM Calcium Assay Kits [J Box, Invitrogen; RPMI1640 Medium: GIBCO; 96-well Blackboard: CORNING; PHERAstar FS Multi-Function Labeler (BMG); Low-Speed Centrifuge ( StaiteXiangyi);. The positive drug selected was RN486.

 Cell treatment: Wash cells with serum-free medium and remove serum.

Dye preparation: The 2 Å dye was then diluted to lx with serum free medium. Resuspension of the cells: The washed cells were resuspended with the lx dye prepared above.

 Cell seeding: 200,000/well, 40 μl/well, 96-well plate, black wall plate required.

 Incubation of the dye: Place in the incubator and incubate for 40 min.

 Dosing: Then add a series of prepared compounds, ΙΟμΙ/well, and continue to act for 20 min.

 Room temperature equilibration: Take out the test plate and equilibrate for 5 min at room temperature.

 Baseline determination: Baseline was first tested with a PHERStar plate reader before the agonist was added.

 Add agonist: Add IgM, ΙΟμΙ/well at a final concentration of l (^g/ml).

Determination: Immediately after the addition of the agonist, the test was performed using a PHERStar microplate reader, and every 10 seconds, a total of 8 min was detected. Data processing: OD (highest value) - OD (baseline), then IC50 values were calculated using GraphPad Prism 5 software. Experimental results: BTK cell calcium flow half inhibitory concentration (IC _5Q , nM)

The present invention provides a half-inhibitory concentration (IC _5Q ) of a compound of the formula I for calcium flux in BTK cells.

 Conclusion: The inhibitory activity of some compounds of the present invention on calcium flux in BTK cells is superior to that of positive drug RN486.

 Example 13: Method for determining pharmacokinetic properties in rats

 1, abstract

 SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration of the compound of Example 1 was measured by LC/MS/MS. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

 2. Test plan:

 2.1 Test drugs

 Example 1 Compound and positive control drug RN486.

 2.2 Test animals

 Category: SD Rats Quantities: 12

Sex: Male weight: 190-210g Food, water supply: Words, free intake of water during drug administration, 12 hours before blood withdrawal, source of fasting: Shanghai Slack Laboratory Animal Co., Ltd.

 2.3 Administration design of the drug: 12 rats were divided into 4 groups, 3 in each group.

 2.4 Dispensing and administration:

 Compound RN486 Prescription: Compound RN486 is dissolved in 5% DMA and 5% solute solution, and the formulated solution is clear and transparent.

 Compound 1 Prescription: Compound 1 was dissolved in 5% DMA and 5% solute solution, and the formulated solution was clear and transparent.

 2.5 Sample collection and treatment: Rats in the gavage group were collected blood samples at 0 min, 10 min, 20 min, 40 min, 1, 2, 4, 6, 8, 10, 24 h after administration. The intravenous injection group was administered 5 min, 10 min after the administration. 20min, 40min, 1, 2, 4, 6, 8, 10, 24h, respectively, take about 0.3ml of blood to the heparinized Eppendorf tube, temporarily stored in the ice bath, whole blood was collected by centrifugation, and the plasma was transferred to 96 wells. In the plate, store at -20 °C until LC-MS/MS detection.

 3, pharmacokinetic parameters results

 The pharmacokinetic parameters of the compounds of the invention are as follows:

The pharmacopoeetic property of RN486 was superior to that of compound RN486.

Example 14: In vivo efficacy determination of mouse Arthus Reaction molding

 1, abstract

 Balb/c mice were used as test animals, and the in vivo efficacy of the compounds of the present invention and positive control drugs was evaluated using the Arthus Reaction model.

 2. Material:

 Test drug: Dexamethasone: 100701, Jinling Pharmaceutical Co., Ltd.

 Compound 1 and RN486: 3 mL each, at a concentration of 3 mg/mL, placed in an Eppendorf tube,

Store at 4 ° C. Solvent: Anesthetic: 1% sodium pentobarbital

 OVA: batch number SLBB5992V, sigma; rabbit anti-OVA: 099K4830, sigma; rabbit IgG: SLBD1647V, sigma; Evans blue, 72496LJ, sigma; all reagents were prepared using cold physiological saline (4 ° C) before use. The reagents are stored in an ice bath and are now ready for use.

 Experimental animals: Balb/c mice, SPF grade; C57/BL6, SPF grade;

 3. Test protocol: Grouping: Animals are randomly grouped.

 The drug was administered after grouping, and it was set to time point 0 at the time of administration.

 Anesthetized animals (i.p. 1% sodium pentobarbital, dose 70 mg/kg) were anesthetized about half an hour after administration, and the animals were depilated on the back and the intradermal injection site was marked.

 The animal was injected with 0.2 mL of OVA+Evans blue in the tail vein.

 One hour after the administration, IgG and antibody (anti-OVA) were injected intradermally, 30 μί per point, and 3 points per skin injection.

After 4 hours of intradermal injection, the animals were anesthetized with C0 ₂ anesthesia, and the back skin of the isolated animals was peeled off and photographed; the skin of the injection site was drilled with a 0.9 cm rubber stopper puncher. After the tissue was cut, a certain amount of formamide was added, and after ultrasonication for 30 minutes, it was extracted overnight at 37 ° C in a water bath.

Detection Indicator:

 Injection site tissue formamide extraction solution OD value determination at 620 nm (96-well plate).

4. Test results: OD value at 620 nm of the injection site tissue formamide extraction solution

 Conclusion: Compound 1 is superior to the positive control drug RN486 in the in vivo efficacy of the Arthus Reaction model.

Example 15: In vivo pharmacodynamic assay on rat collagen-induced arthritis (rCIA) model

 1. Experimental animals: strains and sources: Wistar rats, SPF grade, Shanghai Slack

 Weight: 170-190 g

 Gender: Female

 2. Test plan:

Modeling: DAY0, take 10 ml of incomplete Freund's adjuvant IFA and 10 ml of collagen, emulsified with a homogenizer on ice, Until the emulsion is dripped into the water. Multiple injections were made in the tail of the rat, and each rat was injected with 0.3 ml of emulsion to form a local bulge on the skin surface.

 Grouping: Observe the onset of the model, after the onset (about Dayl4), measure the volume of the hind limbs of each rat, and randomly group the disease model rats according to the volume.

 Dosing and measurement: According to the above group, it lasted for 14 days. The body weight of the rats was weighed twice a week during the administration, and the foot volume of the hind limbs of the rats was measured with an ankle tester and scored.

 Gross anatomy: In addition to the blood-collecting animals, the other animals were grossly dissected and the immune organs (spleen, thymus, lymph nodes) were observed.

Measurement indicators and methods: Animal weight: twice a week weighing records;

 Animal hindlimb volume: measured and recorded twice a week with an ankle tester;

 Rating: The indicator is as follows

 Grading

 3. Test results

 18 19 20 21

Tr eat merit ci ays Conclusion: Compound 1 can significantly inhibit the symptoms of arthritis induced by bovine type II collagen, and the effect is better than the positive control drug RN486. The above invention has been described in more detail by way of illustration and example of the embodiments of the invention. It will be apparent to those skilled in the art that changes and modifications may be made within the scope of the appended claims. Therefore, the above description is intended to be illustrative, and not restrictive. Therefore, the scope of the invention should be construed as being limited by the claims of the appended claims

Claims

Claims

A compound of the formula (I) or a pharmaceutically acceptable salt thereof:

among them,

R ¹ is -R ⁶ - R ⁷ - R ⁸ ;

R ^{2 is} selected from hydrogen or dC ₆ fluorenyl;

R ^{3 is} selected from the group consisting of hydrogen, C _r C ₆ fluorenyl or hydroxy-C ₆ fluorenyl;

R ^{4 is} selected from hydrogen, dC ₆ fluorenyl or C ₃ -C ₈ cyclodecyl;

R ^{5 is} selected from hydrogen or halogen;

 X, Y, Ζ are independently selected from CH or Ν;

 Q is selected from CH or Ν, provided that when Ζ is Ν, Q is CH;

 D, G are independently selected from CH or N, but D and G are not N at the same time;

R ^{6 is} selected from C ₆ -C _1Q aryl, C ₅ -C _1Q heteroaryl, 3⁄4-cyclodecyl or C ₄ -C ₈ heterocycloalkyl, each of which is optionally substituted by one or more R ^1Q ;

R ^{7 is} selected from 3⁄4 ₈ cyclodecyl or C ₄ -C ₈ heterocycloalkyl, each of which is optionally substituted by one or more R ¹¹ ;

R ^{8 is} selected from C ₄ -C ₈ heterocyclic fluorenyl, C ₃ -C ₈ cyclodecyl CC ₆ fluorenylene, C ₄ -C ₈ heterocycloalkyl- >indenylene, -C ₆ fluorenyl, - COR ⁹ or -(S0 ₂ )R ⁹ , C ₄ -C ₈ heterocyclic fluorenyl is optionally substituted by one or more R ¹² ;

R ^{9 is} selected from the group consisting of dC ₆ fluorenyl, C ₃ -C ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -d. Heteroaryl, C ₃ -C ₈ cyclodecyl-C ₆ -fluorenylene, C ₅ -C ₈ heterocycloalkyl-C ₆ -indenyl, C ₆ -C ₁₍₎ aryl-C ₆ -indenyl , C ₅ -C ₁₀ miscellaneous TJ Ci-Ce 3⁄4υ3⁄4 Ci-C ₆ 3⁄43⁄43⁄4 3⁄4S3⁄4 Ci-C ₆ 3⁄4υ3⁄4 Ci-C ₆ 3⁄4υ3⁄4 3⁄4» Ci-C ₆ 3⁄4υ3⁄4 C ₃ -C ₈ ring 垸 base, C ₅ -C ₈ The cycloalkyl group is optionally substituted by one or more halogen, hydroxy, dC ₆ decyloxy groups, and the C ₆ -C ₁₀ aryl group, C ₅ -C _1Q heteroaryl group is optionally substituted by one or more halogens, CC ₆ Mercapto group, CC ₆ methoxy group, halogenated CC ₆ fluorenyl group;

R ^{1Q is} selected from the group consisting of hydrogen, -C ₆ fluorenyl, hydroxy, hydroxy-C ₆ -fluorenylene, C _r C ₆ decyloxy, halogen, nitro, amino, acylamino, cyano, oxo or 3⁄4 - dC ₆ thiol substitution;

R ^{11 is} selected from the group consisting of hydrogen, -C ₆ fluorenyl, C _r C ₆ decylamino, C _r C ₆ fluorenyl-C ₆ decylamino, hydroxy, hydroxy dC ₆ fluorenyl, CC ₆ decyloxy, halogen, nitrate Base, amino, amido, acyl, cyano, oxo, decyl, hydroxy a base amino group, a carboxyl group, a carbamoyl group, a carbamate, a ^H CH^ decyloxy group, a ^H d-Cs fluorenyl group or a hydroxy-substituted dC ₆ fluorenyl group;

R ^{12 is} selected from the group consisting of hydrogen, C _r C ₆ fluorenyl, ^-^cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl C _r C ₆ fluorenylene or C ₄ -C ₈ heterocyclic fluorenyl CC ₆ anthracenyl;

When R ^{3 is} selected from hydroxy-C ₆ fluorenyl, X, Y, D, G are selected from CH, R ⁸ , R ^{11 are} not selected from hydrogen or C _r C ₆ fluorenyl; when R ^{3 is} selected from C -Co 垸Or a hydroxy dC ₆ fluorenyl group, X, Y, D, G are selected from CH, and when Q is selected from N, R ^{8 is} not selected from hydrogen, -C ₆ fluorenyl or -COR ⁹ , and R ^{11 is} not selected from hydrogen, - C ₆ thiol or acyl.

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from

R' is selected from -R ⁷ R ⁸ ;

R ^{7 is} selected from C ₄ -C ₈ heterocycloalkyl, and C ₄ -C ₈ heterocycloalkyl is optionally substituted by one or more R ¹¹ ;

R ^{8 is} selected from the group consisting of C ₄ -C ₈ heterocyclic fluorenyl, C ₃ -C ₈ cyclodecyl CC ₆ fluorenylene, C ₄ -C ₈ heterocycloalkyl CC ₆ fluorenylene, -C ₆ fluorenyl, - COR ⁹ or -(S0 ₂ )R ⁹ , C ₄ -C ₈ heterocyclic fluorenyl is optionally substituted by one or more R ¹² ;

R ^{9 is} selected from the group consisting of dC ₆ fluorenyl, C ₃ -C ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -d. Heteroaryl, C ₃ -C ₈ cyclodecyl-C ₆ -fluorenylene, C ₅ -C ₈ heterocycloalkyl-C ₆ -indenyl, C ₆ -C ₁₍₎ aryl-C ₆ -indenyl , C ₅ -C ₁₀ hetero-Ci-C ₆ 3⁄4υ3⁄4 Ci-C ₆ 3⁄43⁄43⁄4 3⁄4S3⁄4 Ci-C ₆ 3⁄4υ3⁄4 Ci-C ₆ 3⁄4υ3⁄4 3⁄4» Ci-C ₆ 3⁄4υ3⁄4 C ₃ -C ₈ ring 垸 base, C ₅ -C ₈ The cycloalkyl group is optionally substituted by one or more halogen, hydroxy, dC ₆ decyloxy groups, and the C ₆ -C ₁₀ aryl group, C ₅ -C _1Q heteroaryl group is optionally substituted by one or more halogens, CC ₆ Mercapto group, CC ₆ methoxy group, halogenated CC ₆ fluorenyl group;

R ^{11 is} selected from the group consisting of hydrogen, -C ₆ fluorenyl, cyano, hydroxy or dC ₆ fluorenyl optionally substituted with one or more halogens, hydroxy groups;

R ^{12 is} selected from the group consisting of hydrogen, -C ₆ fluorenyl, 3⁄4 ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl CC ₆ fluorenylene, C ₄ -C ₈ heterocyclic fluorene Base CC ₆ fluorene.

 The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein

R' is selected from

 m is selected from 0-2.

 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein

R ^{8 is} selected from the group consisting of C ₃ -C ₆ cyclodecylmethylene, C ₄ -C ₆ heterocycloalkyl, C ₄ -C ₆ heterocycloalkylmethylene, dC ₆ fluorenyl, -COR ⁹ or -(S0 ₂ )R ⁹ , C ₄ -C ₆ heterocycle substituted by one or more R ¹² , wherein C ₄ -C ₆ heterocycloalkyl and C ₄ -C ₆ heterocycloalkyl Base

X

W is selected from 0, S or NR ¹² ;

R ^{12 is} selected from the group consisting of hydrogen, dC ₆ fluorenyl, C ₃ -C ₈ cyclodecyl, C ₄ -C ₈ heterocycloalkyl, C ₃ -C ₈ cyclodecyl CC ₆ fluorenylene C ₄ -C ₈ heterocycle Mercapto-C ₆ alkylene group.

 The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein

R ^{9 is} selected from the group consisting of C _r C ₄ fluorenyl, C ₃ -C ₆ cyclodecyl, C ₄ -C ₆ heterocycloalkyl, phenyl, C ₅ -C _{1 ()} heteroaryl, C ₃ -C ₆ ring Mercaptomethylene, C ₄ -C ₆ heterocycloalkylidene methylene, benzyl, methylamino, dimethylamino, ethylamino, diethylamino, dC ₄ fluorenyl, 3⁄4-0>cyclodecyl a C ₄ -C ₆ heterocyclic fluorenyl group is optionally substituted by one or more halogen, hydroxy, dC ₄ decyloxy groups, phenyl, phenyl group on benzyl, C ₅ -C _1Q heteroaryl group, optionally Substituted by one or more halogen, dC ₄ fluorenyl, dC ₄ decyloxy, halo-C ₄ fluorenyl, wherein the C ₅ -C _1Q heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, triazole Base, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole.

 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein

R ^{11 is} selected from the group consisting of hydrogen, methyl, ethyl, cyano, hydroxy, -CH ₂ F, CHF ₂ , CF ₃ or CH ₂ OH.

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

 M is selected from CH or N;

R ^{8 is} selected from C ₄ -C ₈ heterocycloalkyl, dC ₆ fluorenyl, -COR ⁹ , C ₄ -C ₈ heterocycloalkyl, optionally substituted by R ¹² ; R ^{9 is} selected from C ₃ -C ₈ Cyclic sulfhydryl group;

R ^{12 is} selected from the group consisting of hydrogen and dC ₆ fluorenyl.

 0

The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R ^{8 is} selected from

 The compound according to any one of claims 1, 2, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein

R ^{2 is} selected from a methyl group; R ^{3 is} selected from the group consisting of hydrogen, methyl, hydroxymethyl;

R ^{4 is} selected from cyclopropyl;

R ^{5 is} selected from hydrogen or fluorine;

 X, Y, Z, Q are independently selected from CH;

 D, G are independently selected from CH or N, but D and G are different at the same time? .

 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent.

 Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an inflammatory and/or autoimmune disorder.

 13. The use of claim 12, wherein the inflammatory condition is rheumatoid arthritis.