WO2018149284A1 - Kinase inhibitor and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to an apoptosis signal regulating kinase 1 (ASK1) inhibitor, a pharmaceutical composition comprising same, a preparation method therefor and an intermediate thereof, and the use thereof for preventing or treating ASK1-mediated diseases.

Description

Kinase inhibitor and preparation method and use thereof Field of invention

The present invention relates to an inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a pharmaceutical composition comprising the same, a process for the preparation thereof and an intermediate thereof, and the use thereof for preventing or treating ASK1-mediated diseases.

Background of the invention

The mitogen-activated protein kinase (MAPK) signaling cascade combines different extracellular and intracellular cohorts with appropriate cellular stress responses including cell growth, differentiation, inflammation, and cell dying. Death (Kumar, S., Boehm, J. and Lee., JC (2003) Nat. Rev. Drug Dis. 2: 717-726; Pimienta, G. and Pascual, J. (2007) Cell Cycle, 6: 2826 -2632). MAPK exists in the form of MAP3K, MAP2K, and MAPK, which are sequentially activated. MAPK3 responds directly to environmental signals and phosphorylates MAP2K, which in turn phosphorylates specific MAPKs. MAPK then mediates an appropriate cellular response by phosphorylating a cellular matrix comprising a transcription factor that regulates gene expression.

Apoptosis signal-regulated kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase ("MAP3K") family that activates c-Jun N-terminal protein kinase ("JNK") and p38 MAP kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, PT, Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K. and Gotoh, Y. (1997) Science, 275, 90-94). Activation of ASK1 can be achieved by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-α, FasL, ER stress, and increased intracellular calcium concentration (Hattori, K., Naguro, I., Runchel, C. and Ichijo, H. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I. and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27). In response to these stimulation signals, ASK1 is activated via autophosphorylation at Thr838 and, in turn, phosphorylates MAP2K (eg, MKK3/6 and MKK4/7), which subsequently phosphorylates and activates p38 and JNK MAPK, respectively.

Phosphorylation of the ASK1 protein can lead to apoptosis or other cellular responses. ASK1 activation and signaling are reported to include conditions and diseases caused by chronic fatty and fibrotic degeneration (eg, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)), neurodegenerative diseases, cardiovascular Disease, diabetes (including diabetic nephropathy and other complications of diabetes), inflammatory diseases, autoimmune diseases, respiratory diseases (including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and acute lung injury) And play an important role in a variety of diseases of metabolic disorders. In addition, ASK1 is involved in organ damage following ischemia and reperfusion in the heart, brain, and kidney (Watanabe et al., (2005) BBRC 333, 562-567; Zhang et al., (2003) Life Sci 74-37-43; Terada Et al. (2007) BBRC 364: 1043-49). Thus, ASK1 inhibitors can remedy or improve the lives of patients with such diseases.

Summary of invention

The present invention provides a compound for use as an ASK1 inhibitor having good inhibitory activity against ASK1, good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., good organisms) Excellent properties such as availability, suitable blood concentration, half-life and duration of action), good safety (lower toxicity and/or fewer side effects, wider therapeutic window).

One aspect of the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):

among them:

表示单键或双键，条件是Y和Z各自至多与一个双键连接；

Represents a single bond or a double bond, provided that Y and Z are each connected to at most one double bond;

R ^{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _6-10 aryl, a 5-14 membered heteroaryl group and a C _6-12 aralkyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, and aralkyl group are each optionally one or more independent Substituted with a substituent selected from the group consisting of halogen, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, phenoxy, cyano, nitro, -OR ⁶ , -C(=O)R ⁶ , -OC(=O)R ⁶ , -C(=O)OR ⁶ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ C(=O)R ⁷ , -N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)N(R ⁶ )(R ⁷ ), -C(=O)N(R ⁶ ) (R ⁷ ), -S(=O) _m R ⁶ and -S(=O) _m N(R ⁶ )(R ⁷ ), wherein the alkyl group, cycloalkyl group, heterocyclic group, phenyl group And the phenoxy group are each optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _3-10 cycloalkyl and -OC _1-6 alkyl;

R ^{2 is} selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, and -OC _1-6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R ^{3 is} selected from 3-10 membered heterocyclic groups optionally fused to another C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl a C _6-10 aryl group and a 5-14 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is each optionally one or more substituents independently selected from the group consisting of Substitution: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _6-12 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, halogen, oxo, cyano, -OR ⁶ , -OC(=O)R ⁶ , -OC(=O)N(R ⁶ ) (R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ ) (R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ )C(=O)N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally further substituted by one or more substituents independently selected from halogen: hydroxy , oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl Base, 3-10 membered heterocyclic group and -OR ⁶ ;

Q is selected from C, C(R ⁴ ) and N;

W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are each independently selected from C(R ⁴ ) and N;

When both W ⁵ and W ⁶ are C(R ⁴ ), the two R ^{4 ,} together with the carbon atom to which they are attached, are optionally taken together to form a 5 member, optionally substituted by C _1-6 alkyl, hydroxy or halogen. a 6-membered cycloalkyl, heterocyclic, aryl or heteroaryl;

X, Y and Z are each independently selected from a direct bond, C(R ⁴ ), C(R ⁴ )(R ⁵ ), N, N(R ⁴ ) and O;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, oxo, halogen, nitro, cyano, C _1-6 alkyl, -OC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _3-10 cycloalkyl, C _6-10 aryl, C _6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic, -OR ⁶ , -OC (=O R ⁶ , -OC(=O)N(R ⁶ )(R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ ) C(=O)N(R ⁶ )(R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) And -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally Further substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, -N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -OR ⁶ ;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-8 cycloalkyl; or when R ⁶ and R ^{7 are} bonded to the same nitrogen atom, R ⁶ and R ^{7 are} attached thereto The nitrogen atom optionally together form a 3-10 membered heterocyclic group;

m is 0, 1, or 2.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for use as an ASK1 inhibitor.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A pharmaceutical or a pharmaceutical composition of the invention for use as an ASK1 inhibitor.

Another aspect of the invention provides a method of preventing or treating an ASK1-mediated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof , polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

Another aspect of the invention provides a process for the preparation of the compounds of the invention and intermediates used in the process.

Detailed description of the invention

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

The terms "including", "comprising", "having", "containing", or "comprising", as used herein, and other variants thereof, are inclusive or open, and not Exclude other unlisted elements or method steps.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms. For example, as used herein, the term " _C1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl") (eg CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl) Or -CH ₂ CH ₂ CF _{3 ,} etc.). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).

As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having from 2 to 6 carbon atoms ("C _2-6 alkenyl"). The alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the invention contain alkenyl groups, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, which preferably has 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

The term "cycloalkyl" as used herein refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). , cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbons Atom. For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl). Or cyclohexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring. An atom and one or more (eg one, two, three or four) heteroatoms selected from C(=O), O, S, S(=O), S(=O) ₂ and NR ^a a group wherein R ^a represents a hydrogen atom or a C _1-6 alkyl group or a halo-C _1-6 alkyl group; the heterocyclic group may pass through any one of the carbon atoms or a nitrogen atom (if present) ) is connected to the rest of the molecule. In particular, the 3-10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, such as, but not limited to, an oxiranyl group, an aziridine group, an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term " _C6-14 aryl" means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

The term "aralkyl" as used herein preferably denotes an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

The term "heteroaryl" as used herein refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), and additionally In each case it may be benzofused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia A oxazolyl group or the like, and a benzo derivative thereof; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a benzo derivative thereof.

The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

As used herein, the term "substituted" means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the The atomic valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted," the substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

The substituents of the substituents, as used herein, may be derived from any suitable position of the substituent, unless otherwise indicated.

When a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium ⁽² H), tritium ⁽³ H)); isotopes of carbon (e.g. ¹¹ C, ¹³ C and ¹⁴ C) Chlorine isotope (eg ³⁶ Cl); fluorine isotopes (eg ¹⁸ F); iodine isotopes (eg ¹²³ I and ¹²⁵ I); nitrogen isotopes (eg ¹³ N and ¹⁵ N); oxygen isotopes (eg ¹⁵ O) , ¹⁷ O and ¹⁸ O); phosphorus isotope (eg ³² P); and sulfur isotope (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotope ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, one, two, three or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

、实楔形

或虚楔形

描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。 Solid lines can be used in this article

Solid wedge

Virtual wedge

The carbon-carbon bonds of the compounds of the invention are depicted. The use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof The compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, glucoheptonate, gluconate, orotate, palmitate, and other similar salts.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound). The compounds of the invention may also be esters per se.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. The synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups. Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; ARKatritzky and AJ Boulton, Eds., Academic Press And GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJ Boulton, Eds., Academic Press.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

Compound and preparation method thereof

In one embodiment, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (I):

among them:

表示单键或双键，条件是Y和Z各自至多与一个双键连接；

Represents a single bond or a double bond, provided that Y and Z are each connected to at most one double bond;

R ^{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _6-10 aryl, a 5-14 membered heteroaryl group and a C _6-12 aralkyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, and aralkyl group are each optionally one or more independent Substituted with a substituent selected from the group consisting of halogen, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, phenoxy, cyano, nitro, -OR ⁶ , -C(=O)R ⁶ , -OC(=O)R ⁶ , -C(=O)OR ⁶ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ C(=O)R ⁷ , -N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)N(R ⁶ )(R ⁷ ), -C(=O)N(R ⁶ ) (R ⁷ ), -S(=O) _m R ⁶ and -S(=O) _m N(R ⁶ )(R ⁷ ), wherein the alkyl group, cycloalkyl group, heterocyclic group, phenyl group And the phenoxy group are each optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _3-10 cycloalkyl and -OC _1-6 alkyl;

R ^{2 is} selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, and -OC _1-6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R ^{3 is} selected from 3-10 membered heterocyclic groups optionally fused to another C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl a C _6-10 aryl group and a 5-14 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is each optionally one or more substituents independently selected from the group consisting of Substitution: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _6-12 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, halogen, oxo, cyano, -OR ⁶ , -OC(=O)R ⁶ , -OC(=O)N(R ⁶ ) (R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ ) (R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ )C(=O)N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally further substituted by one or more substituents independently selected from halogen: hydroxy , oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl Base, 3-10 membered heterocyclic group and -OR ⁶ ;

Q is selected from C, C(R ⁴ ) and N;

W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are each independently selected from C(R ⁴ ) and N;

When both W ⁵ and W ⁶ are C(R ⁴ ), the two R ^{4 ,} together with the carbon atom to which they are attached, are optionally taken together to form a 5 member, optionally substituted by C _1-6 alkyl, hydroxy or halogen. a 6-membered cycloalkyl, heterocyclic, aryl or heteroaryl;

X, Y and Z are each independently selected from a direct bond, C(R ⁴ ), C(R ⁴ )(R ⁵ ), N, N(R ⁴ ) and O;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, oxo, halogen, nitro, cyano, C _1-6 alkyl, -OC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _3-10 cycloalkyl, C _6-10 aryl, C _6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic, -OR ⁶ , -OC (=O R ⁶ , -OC(=O)N(R ⁶ )(R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ ) C(=O)N(R ⁶ )(R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) And -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally Further substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, -N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -OR ⁶ ;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-8 cycloalkyl; or when R ⁶ and R ^{7 are} bonded to the same nitrogen atom, R ⁶ and R ^{7 are} attached thereto The nitrogen atom optionally together form a 3-10 membered heterocyclic group;

m is 0, 1, or 2.

In another embodiment, when Q is C, which is connected with a double bond; when Q is C (R ⁴⁾ or N, which is not connected to the double bond.

In another embodiment, when X, Y or Z is C(R ⁴ ) or N, it is bonded to a double bond; when X, Y or Z is C(R ⁴ )(R ⁵ ), N(R ^{When 4} ) or O, it is not connected to the double bond.

In another embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or a prodrug wherein the compound has the structure of formula (II):

In another embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicament wherein the compound has the structure of formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX):

In a preferred embodiment, the compound of formula (IV) is a compound of formula (IV)-1 or a compound of formula (IV)-2:

In a preferred embodiment, the compound of formula (V) is a compound of formula (V)-1 or a compound of formula (V)-2:

In a preferred embodiment, the compound of formula (VIII) is a compound of formula (VIII)-1 or a compound of formula (VIII)-2:

In a preferred embodiment, the compound of formula (IX) is a compound of formula (IX)-1 or a compound of formula (IX)-2:

In another embodiment, the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein R ^{1 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl and pyrrolidinyl groups, said group optionally substituted with 1, 2 or 3 substituents independently selected from the following substituents: F, Cl, Br, I , -OH, -CF 3, -OCH 3 , and -C (= O) CH _3. In a preferred embodiment, R ^{1 is} selected from the group consisting of isopropyl, cyclopropyl,

In another embodiment, the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein R ^{3 is} selected from the group consisting of:

The above group is attached to the remainder of the molecule through any ring atom;

The above groups are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-Butyl, sec-butyl, tert-butyl, cyclopropyl and -CF ₃ .

In a preferred embodiment, R ^{3 is} selected from

In a preferred embodiment, R ^{3 is} selected from

In another embodiment, the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein R ^{4 is} selected from the group consisting of H, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, Cyclopropyl,

In a preferred embodiment, R ^{4 is} selected from the group consisting of F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and cyclopropyl.

In another embodiment, the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug, wherein W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are each independently selected from the group consisting of CH, CF, C-CH ₃ , N,

In a preferred embodiment, W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are each independently selected from the group consisting of CF, C-CH ₃ and N.

In another embodiment, the present invention provides a compound of any of the above formulas or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug, wherein W ¹ , W ^{2 are} selected from N; W ³ , W ⁴ , W ⁵ and W ^{7 are} selected from CH; and W ^{6 is} selected from CH,

The present invention encompasses compounds obtained by any combination of the various embodiments.

In another embodiment, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicament wherein the compound is selected from the group consisting of

In another embodiment, the invention provides a compound of formula (IN-8):

among them:

Hal ¹ is a halogen such as F, Cl, Br or I;

The remaining groups are as defined above;

The compound of the formula (IN-8) is preferably:

In another embodiment, the invention provides a method of preparing a compound of formula (IN-8) comprising the steps of:

among them:

Hal ¹ , Hal ² and Hal ³ are the same or different halogens, such as F, Cl, Br or I;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

First step: IN-1 is obtained by halogenation to give IN-2, a halogenating reagent such as Cl ₂ , Br ₂ , I ₂ or N-bromosuccinimide (NBS), preferably in an aprotic solvent (for example) In carbon tetrachloride);

The second step: reacting IN-3 with DMF-DMA to obtain IN-4, and the reaction is preferably carried out under heating;

The third step: cyclization of IN-4 with R ¹ -NH ₂ to obtain IN-5, the reaction is preferably carried out in the presence of an acid such as acetic acid in an aprotic solvent such as acetonitrile;

Step 4: IN-5 is first subjected to a diazotization reaction (preferably in the presence of an acid (preferably a mineral acid such as hydrobromic acid) with a nitrite (such as sodium nitrite), followed by a halogenation reaction (halogenation reagent) For example, Cl ₂ , Br ₂ or I ₂ ), to obtain IN-6;

Step 5: IN-6 is reacted with hydrazine to obtain IN-7, and the reaction is preferably carried out in a protic solvent such as ethanol;

Sixth step: IN-7 is reacted with IN-2 to give IN-8, and the reaction is preferably carried out under heating.

In another embodiment, the invention provides a method of preparing a compound of formula (IV)-1, comprising the steps of:

among them:

Hal ¹ , Hal ² and Hal ³ are the same or different halogens, such as F, Cl, Br or I;

PG is a hydroxy protecting group including, but not limited to, benzyl, triphenylmethyl, tetrahydropyranyl, formyl, acetyl, benzoyl, and silyl groups (eg, trimethylsilyl, triethyl) Silyl group, tert-butyldimethylsilyl group, etc.);

LG is selected from H and halogen;

)； R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence; or R ^a and R ^a' together with the group to which they are attached form a 5-10 membered ring system (eg, common Composition

);

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

First step: the hydroxyl group in the compound of formula (IV)-1-a is treated with a suitable hydroxy protecting group (for example benzyl) under the corresponding conditions (for example in the presence of an organic base or an inorganic base such as potassium carbonate). Protected in a polar solvent (eg DMF) to give a compound of formula (IV)-1-b;

Second step: the cation of the formula (IV)-1-b and R ³ -LG under the catalysis of a metal or metal salt such as a copper salt catalyst such as CuO, Cu ₂ O or CuI in an organic or inorganic base (for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (IV)-1-c is obtained;

The third step: the compound of the formula (IV)-1-c is subjected to conditions for removing the PG group (for example, when PG is a benzyl group, the conditions are hydrogenation in a hydrogen atmosphere under palladium/carbon catalysis). The removal is carried out to obtain a compound of the formula (IV)-1-d;

Step 4: reacting a compound of formula (IV)-1-d with a formamide such as DMF (the reaction is preferably carried out in an aprotic solvent such as toluene under heating (for example at 90-150 ° C) To carry out a compound of formula (IV)-1-e;

Step 5: The compound of the formula (IV)-1-e is reacted in the presence of an organic base (for example, pyridine) or an inorganic base, and a halogen (for example, Br ₂ or I ₂ ) to give the formula (IV)-1- a compound of f;

The sixth step: the compound of the formula (IV)-1-f is catalyzed by a palladium catalyst (for example Pd(dppf)Cl ₂ ) with a boric acid or a boric acid ester (for example, a pinacol borate), preferably in an organic base. Or reacting in the presence of an inorganic base such as potassium acetate to provide a compound of formula (IV)-1-g;

Step 7: Catalyzing the compound of the formula (IV)-1-g with the compound Int-3-E under the catalysis of a palladium catalyst (for example Pd(dppf)Cl ₂ ), preferably in an organic or inorganic base (for example potassium carbonate) The reaction is carried out in the presence of a compound of formula (IV)-1.

In another embodiment, the invention provides a method of preparing a compound of formula (V)-1, comprising the steps of:

among them:

Hal ¹ is halogen, such as F, Cl, Br or I;

R' is selected from the group consisting of -OH, -OC _1-6 alkyl and halogen;

LG is selected from H and halogen;

R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

First step: Optionally, the compound of formula (V)-1-a is firstly present in the presence of an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl ₂ or oxalyl chloride. Forming an acid halide compound (for example, an acid chloride compound or an acid bromide compound), and then reacting it with Int-3-D in the presence of an organic base (for example, pyridine) or an inorganic base to obtain a compound of the formula (V)-1-b;

Second step: reacting a compound of formula (V)-1-b with a formamide such as DMF (the reaction is preferably carried out in an aprotic solvent such as toluene under heating (for example at 90-150 ° C) To carry out a compound of formula (V)-1-c;

The third step: the compound of the formula (V)-1-c is reacted in an aprotic solvent (for example, toluene) under heating (for example, at 90 to 150 ° C) to obtain a compound of the formula (V)-1-d. ;as well as

The fourth step: catalyzing the formula (V)-1-d and R ³ -LG in a metal or metal salt (for example, a copper salt catalyst such as CuO, Cu ₂ O or CuI) in an organic or inorganic base (for example The reaction of the metal ligand (for example, 8-hydroxyquinoline) is optionally carried out in the presence of potassium carbonate) to give a compound of formula (V)-1.

In another embodiment, the invention provides a method of preparing a compound of formula (V)-2, comprising the steps of:

Wherein each group is as defined above; and the reaction is carried out under hydrogenation conditions (for example hydrogenation in a hydrogen atmosphere under palladium on carbon catalysis).

In another embodiment, the invention provides a method of preparing a compound of formula (VIII)-2, comprising the steps of:

among them:

Hal ¹ and Hal ³ are the same or different halogens, such as F, Cl, Br or I;

LG is selected from H and halogen;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

The first step: the cation of the formula (VIII)-2-a and R ³ -LG under the catalysis of a metal or metal salt (for example a copper salt catalyst such as CuO, Cu ₂ O or CuI) in an organic or inorganic base (for example In the presence of potassium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (VIII)-2-b is obtained;

Second step: reacting a compound of formula (VIII)-2-b with an azide salt (for example sodium azide) in the presence of a strong acid such as a strong mineral acid such as concentrated sulfuric acid to give formula (VIII)-2 a compound of -c;

Third step: catalyzing the compound of formula (VIII)-2-c with the compound Int-3-E under the catalysis of a palladium catalyst such as Pd(dppf)Cl ₂ or Pd ₂ (dba) ₃ , preferably in an organic base or Reaction of the inorganic base (e.g., potassium carbonate or cesium carbonate), optionally in the presence of a ligand (e.g., Xantphos), provides a compound of formula (VIII)-2.

In another embodiment, the invention provides a method of preparing a compound of formula (VII), comprising the steps of:

among them:

Hal ¹ is halogen, such as F, Cl, Br or I;

R' is selected from the group consisting of -OH, -OC _1-6 alkyl and halogen;

LG is selected from H and halogen;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

First step: Optionally, the compound of formula (VII)-a is first formed into an acyl group in the presence of an acid halide reagent such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl ₂ or oxalyl chloride. a halogen compound (such as an acid chloride compound or an acid bromide compound), which is then reacted with Int-3-D in the presence of an organic base such as pyridine or an inorganic base to give a compound of formula (VII)-b;

a second step: reacting a compound of the formula (VII)-b with a nitrite such as sodium nitrite in the presence of a strong acid such as a strong mineral acid such as concentrated hydrochloric acid to give a compound of (VII)-c;

The third step: catalyzing the formula (VII)-c and R ³ -LG in a metal or metal salt (for example, a copper salt catalyst such as CuO, Cu ₂ O or CuI) in an organic or inorganic base (for example, potassium carbonate). The reaction of the metal ligand (for example, 8-hydroxyquinoline) is optionally carried out in the presence of a metal ligand to give a compound of the formula (VII).

In another embodiment, the invention provides a method of preparing a compound of formula (VI), comprising the steps of:

among them:

Hal ¹ and Hal ² are the same or different halogens, such as F, Cl, Br or I;

LG is selected from H and halogen;

R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

First step: the presence of a compound of formula (VI)-a with an acid halide such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, SOCl ₂ or oxalyl chloride in the presence of formamide (eg DMF) The reaction is carried out to obtain a compound of the formula (VI)-b;

a second step: reacting a compound of formula (VI)-b with Int-3-D in the presence of an organic base such as pyridine or an inorganic base to provide a compound of formula (VI)-c;

The third step: the compound of the formula (VI)-c and the R ³ -LG are catalyzed by a metal or a metal salt (for example, a copper salt catalyst such as CuO, Cu ₂ O or CuI) in an organic or inorganic base (for example The reaction of the metal ligand (for example, 8-hydroxyquinoline) is optionally carried out in the presence of potassium carbonate) to give a compound of formula (VI).

In another embodiment, the invention provides a method of preparing a compound of formula (IX)-1 comprising the steps of:

among them:

Hal ¹ and Hal ³ are the same or different halogens, such as F, Cl, Br or I;

LG is selected from H and halogen;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

The first step: the cation of the formula (IX)-1-a and R ³ -LG under the catalysis of a metal or metal salt such as a copper salt catalyst such as CuO, Cu ₂ O or CuI, in an organic or inorganic base (for example In the presence of potassium carbonate or cesium carbonate, optionally in the presence of a metal ligand such as 8-hydroxyquinoline, a compound of formula (IX)-1-b is obtained;

Second step: catalyzing the compound of formula (IX)-1-b with the compound Int-3-E under the catalysis of a palladium catalyst such as Pd(dppf)Cl ₂ or Pd ₂ (dba) ₃ , preferably in an organic base or In the presence of an inorganic base such as potassium carbonate, cesium carbonate or sodium t-butoxide, optionally in the presence of a ligand such as Xantphos, to give a compound of formula (IX)-1-c;

Third step: a compound of formula (IX)-1-c with a formic acid ester (such as methyl formate) or DMF-DMA, optionally in the presence of an organic or inorganic base such as potassium carbonate or sodium hydride The reaction gives a compound of the formula (IX)-1.

Pharmaceutical compositions and methods of treatment

In another embodiment, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, or a pharmaceutically acceptable salt thereof An N-oxide, an isotopically-labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation. In another embodiment, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

In another embodiment, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolism thereof Use of a prodrug or prodrug or a pharmaceutical composition of the invention in the manufacture of a medicament for use as an ASK1 inhibitor.

In another embodiment, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolism thereof Or a prodrug or a pharmaceutical composition of the invention for use as an ASK1 inhibitor.

In another embodiment, the invention provides a method of preventing or treating an ASK1-mediated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester thereof, Stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

In another embodiment, the compounds of the invention are used for the prevention or treatment of ASK1-mediated diseases, including conditions and diseases caused by chronic fatty and fibrotic degeneration (eg, nonalcoholic fatty liver disease (NAFLD) or non-alcoholic Fatty hepatitis (NASH), primary sclerosing cholangitis, extrahepatic cholestasis; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis; cirrhosis caused by alcohol or viral infection Forms of hepatitis-related cholestasis and fibrotic lesions; autoimmune diseases; respiratory diseases (including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute lung injury); inflammatory diseases Chronic kidney disease; cardiovascular disease; diabetes (including diabetic nephropathy and other complications of diabetes); metabolic disorders; organ damage after ischemia and reperfusion of the heart, brain and kidneys, and neurodegenerative diseases.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration. Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form.

The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

The amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

In another embodiment, the pharmaceutical compositions of the invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, PPAR alpha/delta agonists (GFT505), type 2 and type 5 chemotaxis Factor receptor antagonist (cenicriviroc [CVC]), fatty acid-bile acid conjugate (aramchol), FXR agonist (Obecholic acid, GS-9674, LJN-452, EDP-305).

Example

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectrometry (MS).

The chemical shift (δ) is given in parts per million (ppm). ^{The 1} H NMR measurement was performed on a JEOL Eclipse 400 nuclear magnetic instrument. The test solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or hexamethyl dimethyl sulfoxide (DMSO-d ₆ ). It is tetramethylsilane (TMS).

The measurement of MS was carried out on an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6120B).

The preparative high performance liquid chromatography was carried out using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mm column).

Thin layer chromatography (TLC) was carried out using an aluminum plate (20 x 20 cm) manufactured by Merck, and thin layer preparative chromatography was carried out using a silica gel plate of GF254 (0.4 to 0.5 nm) having a specification of Yantai.

The reaction is detected by thin layer chromatography (TLC) or LC-MS using a developing solvent system including a dichloromethane and methanol system, a n-hexane and ethyl acetate system, and a petroleum ether and ethyl acetate system depending on the compound to be separated. The developing agent system is adjusted by the difference in polarity (by adjusting the volume ratio of the solvent or adding triethylamine or the like).

The microwave reaction was carried out using a Biotage Initiator + (400 W, RT ~ 300 ° C) microwave reactor.

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. The system of the eluent includes a dichloromethane and methanol system and a n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) get on).

As specified in the examples, the reaction temperature is room temperature (20 ° C ~ 30 ° C)

The reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.

The abbreviations in the present invention have the following meanings:

abbreviation meaning Br ₂ bromine CCl ₄ Carbon tetrachloride (COCl) ₂ Oxalyl chloride CuBr Cuprous bromide CuI Cuprous iodide

Cu ₂ O Cuprous oxide DCM Dichloromethane DMF dimethylformamide DMF-DMA N,N-dimethylformamide dimethyl acetal DMSO Dimethyl sulfoxide EA Ethyl acetate EtOH Ethanol HBr Hydrogen bromide HPLC High performance liquid chromatography K ₂ CO ₃ Potassium carbonate LC-MS Liquid chromatography-mass spectrometry MeOH Methanol N ₂ Nitrogen NaN ₃ Sodium azide NaNO ₂ Sodium nitrite NaOH Sodium hydroxide Pd/C Palladium/carbon Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Xantphos 4,5-bisdiphenylphosphino-9,9-dimethyloxazepine

Preparation of intermediates

Intermediate Preparation Example 1: Preparation of 3,6-dibromoisobenzofuran-1(3H)-one (Int-1)

First step: Preparation of 6-aminoisobenzofuran-1(3H)-one (Int-1-b)

6-Nitroisobenzofuran-1(3H)-one (Int-1-a) (1.79 g, 10 mmol) was dissolved in MeOH (30 mL), Pd / C (179 mg) Stir overnight. Then, the reaction liquid was suction filtered and concentrated to give Compound (Int-1-b) (1.4 g, yield: 94.0%).

Step 2: Preparation of 6-bromoisobenzofuran-1(3H)-one (Int-1-c)

Compound (Int-1-b) ( 1.4g, 9.39mmol) was dissolved in aqueous HBr (20mL) was added dropwise an aqueous solution of NaNO ₂ (648mg, 9.39mmol) under ice-cooling, and stirred at this temperature for 0.5 hours. Then, the reaction liquid was poured into a mixed solution of CuBr (4.32 g, 30 mmol) and HBr aqueous solution (10 mL), and stirred for 1 hour. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc).

The third step: preparation of 3,6-dibromoisobenzofuran-1(3H)-one (Int-1)

The compound (Int-1-c) (870 mg, 4.1 mmol) was dissolved in CCl ₄ (10 mL), Br ₂ (985 mg, 6.1 mmol) was diluted with CCl ₄ and then added dropwise to the reaction system. After 5 hours, the reaction was completed by TLC, the solvent was removed by rotary evaporation, and the residue was purified by EtOAc (EtOAc)

Intermediate Preparation Example 2: Preparation of 4-cyclopropyl-1H-imidazole (Int-2)

2-Bromo-1-cyclopropylethanone (Int-2-a) (8.2 g, 50 mmol), formazan acetate (26 g, 250 mmol) was added to ethylene glycol (60 mL) and stirred at 135 ° C overnight. The reaction mixture was poured into water, extracted with EtOAc EtOAc (EtOAc)

Intermediate Preparation Example 3: Preparation of 2-mercapto-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Int-3)

First step: Preparation of 6-aminopicolinyl hydrazide (Int-3-b)

Methyl 6-aminopicolinate (Int-3-a) (50 g, 329 mmol) and hydrazine hydrate (32.9 g, 658 mmol) were added to methanol (500 mL) and stirred for 3 hr. Then, the reaction liquid was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate to give Compound (Int-3-b) (42 g, yield: 84.0%).

The second step: (E)-N'-(6-((E)-2-((dimethylamino)methylene) fluorenylcarbonyl)pyridin-2-yl)-N,N-dimethylmethyl Preparation of cerium (Int-3-c)

The compound (Int-3-b) (42 g, 275 mmol) was dissolved in EtOAc (EtOAc) The reaction solution was then cooled and concentrated. Ethyl acetate was added, and the reaction mixture was heated to 50 ° C for 20 minutes, cooled, and filtered to give Compound (Int-3-c) (60 g, yield: 72%).

Third step: Preparation of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (Int-3-d)

The compound (Int-3-c) (10 g, 38.2 mmol) was dissolved in a mixed solvent of acetonitrile and acetic acid (4:1, 100 mL), isopropylamine (11.3 g, 191 mmol) was added, and the mixture was heated to reflux for 24 hours. Then, the reaction liquid was cooled, concentrated, and water was added thereto, and the reaction liquid was adjusted to be weakly basic with a 1N NaOH solution, and the solid was precipitated, filtered, and dried to give Compound (Int-3-d) (3.0 g, yield: 39 %).

Fourth step: Preparation of 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Int-3-e)

The compound (Int-3-d) (3.0 g, 14.8 mmol) was dissolved in aqueous solution of hydrobromic acid (30 mL), cooled to 0 ° C, and then aqueous NaNO ₂ (1.0 g, 14.8 mmol) was added dropwise at this temperature. Stirring was continued for 0.5 hours, then Br ₂ (2.37 g, 14.8 mmol) was added dropwise and stirred at room temperature for 2 hr. The reaction mixture was made to a weak basic with 2N NaOH solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium thiosulfate, dried, filtered, concentrated and purified to give compound (Int-3-e) ( 2.8 g, yield: 72%).

Step 5: Preparation of 2-mercapto-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Int-3)

(Int-3-e) (2.8 g, 10.5 mmol) was dissolved in ethanol (30 mL), hydrazine hydrate (1.1 g, 21.0 mmol) was added, and refluxed for 5 hr, and concentrated to give compound (Int-3) (2.26 g) , yield: 99%).

Intermediate Preparation Example 4: Preparation of 2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-mercaptopyridine (Int-4)

Compound (Int-4) (300 mg) was prepared by a method similar to that in Intermediate Preparation Example 3, except that isopropylamine (2.0 g, 35.1 mmol) was used instead of isopropylamine in the third step.

Intermediate Preparation Example 5: 2-Mercapto-6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine (Int -5) preparation

A compound (Int-) was prepared by a method similar to that in Intermediate Preparation Example 3 except that 1,1,1-trifluoropropan-2-amine (2.0 g, 17.7 mmol) was used instead of isopropylamine in the third step. 5) (150 mg).

Intermediate Preparation Example 6: 2-Bromo-6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine (Int- 6) Preparation

A compound (Int-) was prepared by a method similar to that in Intermediate Preparation Example 3 except that 1,1,1-trifluoropropan-2-amine (4.0 g, 35.4 mmol) was used instead of isopropylamine in the third step. 6) (450 mg).

Intermediate Preparation Example 7: 6-(4-(1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-4H-1,2,4-triazol-3-yl) Preparation of pyridin-2-amine (Int-7)

First step: Preparation of 6-aminopicolinyl hydrazide (Int-7-b)

Methyl 6-aminopicolinate (Int-7-a) (5 g, 32.9 mmol) and hydrazine hydrate (3.3 g, 65.8 mmol) were added to methanol (50 mL), and stirred under reflux for 3 hr. Then, the reaction liquid was cooled to room temperature, filtered, and the cake was washed with ethyl acetate to give Compound (Int-7-b) (4.0 g, yield: 80.0%).

The second step: (E)-N'-(6-(2-((E)-(dimethylamino)methylene)fluoren-1-yl)pyridin-2-yl)-N,N-di Preparation of methylformamidine (Int-7-c)

The compound (Int-7-b) (4 g, 27 mmol) was dissolved in EtOAc (EtOAc) The reaction solution was then cooled and concentrated. Ethyl acetate was added, and the reaction mixture was heated to 50 ° C for 20 minutes, cooled, and filtered to give Compound (Int-7-c) (6.0 g, yield: 86.9%).

Third step: Preparation of 2-(3-(6-aminopyridin-2-yl)-4H-1,2,4-triazol-4-yl)propan-1-ol (Int-7-d)

The compound (Int-7-c) (6.0 g, 22.9 mmol) was dissolved in a mixed solvent of acetonitrile and acetic acid (4:1, 100 mL), 2-aminopropan-1-ol (8.6 g, 114 mmol) was added and heated Reflux for 24 hours. Then, the reaction liquid was cooled, concentrated, and water was added thereto, the reaction liquid was adjusted to be weakly basic with a 1N aqueous sodium hydroxide solution, solids were precipitated, filtered, dried, and purified by preparative high-performance liquid chromatography (Int-7) -d) (3.0 g, yield: 59.9%).

Fourth step: 6-(4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-Amine (Int-7)

The compound (Int-7-d) (1.3 g, 5.93 mmol) and imidazole (1.6 g, 23.72 mmol) were dissolved in DMF (25.0 mL) and tert-butyldimethylchlorosilane (2.7 g, 17.79 mmol). After the completion of the addition, the mixture was stirred at room temperature for 6 hours, and the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjj

Intermediate Preparation Example 8: (R)-2-indolyl-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine ( Preparation of Int-8)

A compound was prepared by a method similar to that in Intermediate Preparation Example 3 except that (R)-1-methoxypropan-2-amine hydrochloride (4.8 g, 38 mmol) was used instead of isopropylamine in the third step. (Int-8) (1.2g).

Example 1: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)pyridazine-1(2H)-one (1)

First step: 7-bromo-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one Preparation of (1-b)

Compound (Int-4) (216 mg, 1 mmol) was dissolved in ethanol (10 mL), and Compound (Int-1) (292 mg, 1 mmol) was added. After the mixture was heated to reflux for 2 h, LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 409 [M+H] ⁺ .

Second step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)pyridazine-1(2H)-one (1)

Compound (1-b) (89 mg, 0.22 mmol) was dissolved in DMSO (1 mL). Compound (Int-2) (25.8 mg, 0.24 mmol), Cu ₂ O (32 mg, 0.22 mmol) and K ₂ CO ₃ (45 mg, 0.32 mmol). The mixture was heated at 110-120 °C overnight. The reaction was concentrated under reduced vacuo.

MS m/z (ESI): 437 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.91 (s, 1H), 8.63 (s, 1H), 8.44 (m, 2H), 8.34 - 8.31 (m, 1H), 8.26-8.18 (m, 3H) , 7.85-7.81 (m, 2H), 5.21-5.18 (m, 1H), 1.89-1.85 (m, 1H), 0.92-0.90 (m, 2H), 0.85-0.81 (m, 4H), 0.75-0.72 ( m, 2H).

Example 2: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)pyridazine-1(2H)-one (2)

First step: 7-bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one Preparation of (2-b)

Compound (Int-3) (218 mg, 1 mmol) was dissolved in ethanol (10 mL), and compound (Int-1) (292 mg, 1 mmol) was added. After the mixture was heated to reflux for 3 h, LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 411 [M+H] ⁺ .

Second step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)pyridazine-1(2H)-one (2)

Compound (2-b) (112 mg, 0.27 mmol) was dissolved in DMSO (1 mL), and compound (Int-2) (32.4 mg, 0.3 mmol), Cu ₂ O (39 mg, 0.27 mmol) and K ₂ CO _{3 were added.} (55 mg, 0.4 mmol). The mixture was heated at 110-120 °C overnight. The reaction was concentrated under reduced vacuo. EtOAc m.

MS m/z (ESI): 437 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.91 (s, 1H), 8.63 (s, 1H), 8.44 (m, 2H), 8.34 - 8.31 (m, 1H), 8.26-8.18 (m, 3H) , 7.85-7.81 (m, 2H), 5.41-5.37 (m, 1H), 1.89-1.85 (m, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 0.85-0.81 (m, 2H) , 0.75-0.72 (m, 2H).

Example 3: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1,1,1-trifluoroprop-2-yl)-4H-1, Preparation of 2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one (3)

First step: 7-bromo-2-(6-(4-(1,1,1-trifluoroprop-2-yl)-4H-1,2,4-triazol-3-yl)pyridine-2 -base) Preparation of pyridazine-1(2H)-one (3-b)

Compound (Int-5) (272 mg, 1 mmol) was dissolved in ethanol (10 mL), and compound (Int-1) (292 mg, 1 mmol) was added. After the mixture was heated to reflux for 1.5-2 h, LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 465 [M+H] ⁺ .

Second step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1, Preparation of 2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one (3)

Compound (3-b) (159 mg, 0.34 mmol) was dissolved in DMSO (2 mL), and compound (Int-2) (40 mg, 0.37 mmol), Cu ₂ O (49 mg, 0.34 mmol) and K ₂ CO ₃ ( 70 mg, 0.51 mmol). The mixture was heated at 120 °C overnight. The reaction was concentrated under reduced vacuo.

MS m/z (ESI): 495 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO-d} 6) δ: 9.18 (s, 1H), 8.66 (s, 1H), 8.44-8.43 (m, 2H), 8.34-8.31 (m, 1H), 8.28-8.25 (m, 2H), 8.21-8.19 (m, 1H), 7.94-7.92 (m, 1H), 7.81 (s, 1H), 6.85-6.82 (m, 1H), 1.89-1.86 (m, 1H), 1.81 (m, 3H), 0.86-0.81 (m, 2H), 0.76-0.72 (m, 2H).

Example 4: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-4H-chromen-4-one (4)

First step: Preparation of 1-(2-(benzyloxy)-5-bromophenyl)ethanone (4-b)

1-(5-Bromo-2-hydroxyphenyl)ethanone (4-a) (1.0 g, 4.6 mmol) was dissolved in DMF (10 mL). 0.87 g, 5.1 mmol). After the mixture was stirred at room temperature for 5-6 h, LC-MS showed the reaction was completed. The reactant was added dropwise to water to precipitate a solid, which was filtered, dried and concentrated to give compound (4-b) (1.0 g, yield: 70.4%).

MS m/z (ESI): 305 [M+H] ⁺ .

Second step: Preparation of 1-(2-(benzyloxy)-5-(4-cyclopropyl-1H-imidazol-1-yl)phenyl)ethanone (4-c)

Compound (4-b) (1.0 g, 3.3 mmol) was dissolved in DMSO (10 mL), and compound (Int-2) (396 mg, 3.3 mmol), CuI (94 mg, 0.50 mmol), 8-hydroxyquinoline ( 72 mg, 0.50 mmol) and K ₂ CO ₃ (912 mg, 6.6 mmol). The mixture was heated at 120-125 ° C overnight. The reaction mixture was concentrated under reduced vacuo. m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

MS m/z (ESI): 333 [M+H] ⁺ .

Third step: Preparation of 1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-hydroxyphenyl)ethanone (4-d)

Compound (4-c) (350 mg, 1.1 mmol) was dissolved in methanol (10 mL), and palladium/carbon (50 mg) was added and hydrogen was passed. The mixture was stirred at room temperature overnight and LC-MS showed the reaction was completed. The reactant was filtered, dried and concentrated to give compound (4-d) (230 mg, yield: 90.1%).

MS m/z (ESI): 243 [M+H] ⁺ .

Fourth step: (E)-1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-hydroxyphenyl)-3-(dimethylamino)prop-2-ene- Preparation of 1-ketone (4-e)

Compound (4-d) (230 mg, 0.95 mmol) was dissolved in EtOAc (5 mL). The mixture was stirred at 105-110 °C for 4-4.5 h and LC-MS showed the reaction was completed. The reactant was concentrated to give the compound (4-e) (270 mg, yield: 96%).

MS m/z (ESI): 298 [M+H] ⁺ .

Step 5: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-3-iodo-4H-chromen-4-one (4-f)

Compound (4-e) (270 mg, 0.91 mmol) was dissolved in chloroform (5 mL), pyridine (79 mg, 1.0 mmol) and iodine (462 mg, 1.8 mmol). The mixture was stirred at room temperature overnight and LC-MS showed the reaction was completed. The reaction mixture was poured into an aqueous solution of sodium thiosulfate, stirred for 10 min, extracted with ethyl acetate, dried and concentrated to afford compound (4-f) (208 mg, yield: 61%).

MS m/z (ESI): 379 [M+H] ⁺ .

Step 6: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan Preparation of alk-2-yl)-4H-chromen-4-one (4-g)

The compound (4-f) (208 mg, 0.55 mmol) was dissolved in dioxane (5 mL), then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ) Cl ₂ (40 mg, 0.06 mmol). The mixture was stirred at 50-55 ° C for 3.5-4 h and LC-MS showed the reaction was completed. The mixture was concentrated and purified to give the compound (4-g) (120 mg, yield: 58%).

MS m/z (ESI): 379 [M+H] ⁺ .

Step 7: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-4H-chromen-4-one (4)

Compound (4-g) (120mg, 0.32mmol) was dissolved in DMF (5mL), was added Int-3-e (85mg, 0.32mmol), potassium carbonate (88mg, 0.64mmol) and Pd (dppf) Cl ₂ ( 22 mg, 0.03 mmol). The mixture was stirred at 75-80 °C for 4-5 h and LC-MS showed the reaction was completed. The mixture was concentrated and purified by preparative HPLC to afford compound (4) (6mg, yield: 4.3%).

MS m/z (ESI): 437 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO-d} 6) δ: 9.15 (s, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 8.25 (m, 1H), 7.73-7.50 (m, 4H), 7.52 (s, 1H), 7.12 (s, 1H), 5.41-5.36 (m, 1H), 1.87-1.84 (m, 1H), 1.42 (s, 3H), 1.41 (s, 3H), 0.84-0.80 (m , 2H), 0.73-0.71 (m, 2H).

Example 5: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)isoquinoline-1(2H)-one (5)

First step: 5-iodo-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-methylbenzamide ( Preparation of 5-b)

5-Iodo-2-methylbenzoic acid (5-a) (1.0 g, 3.9 mmol) was dissolved in DCM (10 mL). DMF (1 drop) and oxalyl chloride (0.73 g, 5.7 mmol). After the mixture was stirred at room temperature for 2-3 h, LC-MS showed the reaction was completed. The mixture was concentrated, and a mixture of EtOAc (EtOAc, EtOAc. The organic compound (5-b) (1.6 g, yield: 94%) was obtained.

MS m/z (ESI): 448 [M+H] ⁺ .

The second step: (Z)-2-(2-(dimethylamino)vinyl)-5-iodo-N-(6-(4-isopropyl-4H-1,2,4-triazole- Preparation of 3-yl)pyridin-2-yl)benzamide (5-c)

Compound (5-b) (1.6 g, 3.6 mmol) was dissolved in toluene (20 mL). After the mixture was stirred at 120-130 ° C for 3-4 h, LC-MS showed the reaction was completed. The crude product (2.0 g) of Compound (5-c) was obtained.

MS m/z (ESI): 503 [M+H] ⁺ .

The third step: 7-iodo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoquinoline-1(2H)- Preparation of ketone (5-d)

Compound (5-c) (2.0 g, 4.0 mmol) was dissolved in toluene (20 mL). After the mixture was stirred at 130 ° C for 6 h in a sealed tube, LC-MS showed that the reaction was completed. The mixture was concentrated and purified to give Compound (5-d) (600 m, yield: 33%).

MS m/z (ESI): 458 [M+H] ⁺ .

Fourth step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)isoquinoline-1(2H)-one (5)

Compound (5-d) (300 mg, 0.66 mmol) was dissolved in DMSO (10 mL), Compound (Int-2) (84 mg, 0.72 mmol), CuI (18 mg, 0.09 mmol), 8-hydroxyquinoline (12 mg) , 0.09 mmol) and K ₂ CO ₃ (180 mg, 1.3 mmol). The mixture was heated at 120 °C overnight. The reactant was concentrated under reduced pressure in vacuo and purified by preparative HPLC to afford compound (5) (35 mg, yield: 12%).

MS m/z (ESI): 438 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.76 (s, 1H), 8.60 (s, 1H), 7.84-7.81 (m, 1H), 7.60-7.56 (m, 2H), 7.45 (s, 1H) , 7.42 - 7.39 (m, 3H), 7.12 (s, 1H), 6.13 - 6.11 (m, 1H), 5.22-5.18 (m, 1H), 1.87-1.84 (m, 1H), 1.43 (s, 3H) , 1.42 (s, 3H), 0.84 - 0.79 (m, 2H), 0.74 - 0.71 (m, 2H).

Example 6: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-3,4-dihydroisoquinolin-1(2H)-one (6)

Compound (5) (25 mg, 0.06 mmol) was dissolved in methanol (5 mL), and palladium/carbon (10 mg) was added and then hydrogen was passed. The mixture was stirred at room temperature overnight. The reactant was filtered, concentrated under reduced vacuum and purified by preparative HPLC to afford compound (6) (3mg, yield: 12%).

MS m/z (ESI): 440 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.76 (s, 1H), 8.59 (s, 1H), 7.62-7.60 (m, 2H), 7.47-7.42 (m, 3H), 7.13 (s, 1H) , 6.67-6.65 (m, 1H), 5.21-5.18 (m, 1H), 3.52-3.50 (m, 2H), 3.14 - 3.12 (m, 2H), 1.89-1.86 (m, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 0.84-0.80 (m, 2H), 0.73-0.71 (m, 2H).

-5(2H)-酮(7)的制备 Example 7: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydrobenzo[f][1,4]oxaza

Preparation of -5(2H)-one (7)

First step: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)chroman-4-one (7-b)

6-Bromochroman-4-one (7-a) (1.0 g, 4.4 mmol) was dissolved in DMSO (10 mL). Compound (Int-2) (528 mg, 4.8 mmol), CuI (125 mg, 0.66 mmol) ), 8-hydroxyquinoline (96 mg, 0.66 mmol) and K ₂ CO ₃ (1.22 g, 8.8 mmol). The mixture was heated at 110-120 °C overnight. The reactant was concentrated under reduced pressure in vacuo and purified by preparative HPLC to afford compound (7-b) (302 mg, yield: 27%).

MS m/z (ESI): 254 [M+H] ⁺ .

-5(2H)-酮(7-c)的制备 Second step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-3,4-dihydrobenzo[f][1,4]oxazepine

Preparation of -5(2H)-one (7-c)

Compound (7-b) (302 mg, 1.19 mmol) was dissolved in toluene (5 mL), NaN ₃ (309 mg, 4.8 mmol) was added, the mixture was cooled to 0 ° C, concentrated sulfuric acid (1 mL) was added dropwise Always maintained below about 5 °C. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. The reactant was added dropwise to water, extracted with ethyl acetate, dried, and concentrated to give Compound (7-c) (103 mg, yield: 32%).

MS m/z (ESI): 269 [M+H] ⁺ .

-5(2H)-酮(7)的制备 The third step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-4-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-3,4-dihydrobenzo[f][1,4]oxaza

Preparation of -5(2H)-one (7)

Compound (7-c) (103 mg, 0.38 mmol) was dissolved in dioxane (5 mL), EtOAc (EtOAc, <RTI ID=0.0> The mixture was protected with nitrogen, Pd ₂ (dba) ₃ (18 mg, 0.02 mmol) was added, and the mixture was stirred at 97-100 ° C overnight. The reactant was filtered, concentrated and purified by preparative HPLC to afford compound (7) (15 mg, yield: 8.6%).

MS m/z (ESI): 456 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.70 (s, 1H), 8.61 (s, 1H), 7.74-7.71 (m, 1H), 7.61-7.41 (m, 4H), 7.12 (s, 1H) , 6.69-6.67 (m, 1H), 5.21-5.19 (m, 1H), 4.32-4.29 (m, 2H), 3.63-3.59 (m, 2H), 1.90-1.87 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 0.84-0.81 (m, 2H), 0.74-0.73 (m, 2H).

Example 8: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-1-methylquinolin-4(1H)-one (43)

First step: Preparation of 1-(5-bromo-2-(methylamino)phenyl)ethan-1-one (43-b)

Add 1-(5-bromo-2-fluorophenyl)ethan-1-one (43-a) (1.0 g, 4.6 mmol) and potassium carbonate (1.2 g, 9.1 mmol) to DMF (30 mL) Aqueous methylamine (20 mL) was reacted at 99 ° C overnight. The reaction liquid was concentrated to dryness to give Compound (43-b) (0.8 g, yield: 81.0%).

Second step: Preparation of 1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-(methylamino)phenyl)ethan-1-one (43-c)

Compound (43-b) (300 mg, 1.4 mmol), 4-cyclopropyl-1H-imidazole (Int-2) (150 mg, 1.4 mmol), 8-hydroxyquinoline (29 mg, 0.2 mmol), 515 mg, 1.6 mmol) and cuprous iodide (38 mg, 0.2 mmol) were added to dimethyl sulfoxide (10 mL) and allowed to react overnight at 120 ° C under nitrogen atmosphere. Then, the mixture was extracted with ethyl acetate, washed with brine, and dried and evaporated to give Compound (43-c) (130 mg, yield: 43.3%).

The third step: 1-(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-(methylamino)phenyl)-2-(6-(4-isopropyl-4H- Preparation of 1,2,4-triazol-3-yl)pyridin-2-yl)ethan-1-one (43-d)

The compound obtained in the second step (300 mg, 1.2 mmol) and 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Compound Int-3-e) (400 mg, 1.5 mmol) dissolved in dioxane solution (10 mL), Xantphos (340 mg, 0.6 mmol), Pd ₂ (dba) ₃ (538 mg, 0.6 mmol) and sodium tert-butoxide (160 mg, 1.6 mmol) Under microwave protection, the reaction was carried out at 90 ° C for 4 hours. Then, the reaction liquid was filtered, and the filtrate was collected, concentrated, and purified by preparative high-performance liquid chromatography to give Compound (43-d) (20 mg, yield: 3.8%).

Fourth step: 6-(4-cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-1-methylquino-4(1H)-one (43)

The compound obtained in the third step (20 mg, 0.05 mmol) was dissolved in DMF-DMA (10 mL) and reacted at 96 ° C for 4 hours. Then, it was extracted with ethyl acetate, and the organic phase was concentrated, and purified by preparative thin layer chromatography to give compound (43) (10 mg, yield: 50.4%).

MS m/z (ESI): 452 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.81-8.83 (m, 1H), 8.67-8.71 (m, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.04-8.40 (m, 1H), 7.89-7.93 (m, 2H), 7.73-7.76 (m, 1H), 7.58-7.61 (d, J = 6.8 Hz, 1H), 7.17 (s, 1H), 5.47-5.50 (m, 1H) , 3.99 (s, 3H), 1.91-2.05 (m, 1H), 1.59-1.61 (d, J = 6.8 Hz, 6H), 1.25-1.43 (m, 4H).

Example 9: 6-(4-Isopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)quinazoline-4(3H)-one (9)

First step: Preparation of (E)-5-bromo-2-(((dimethylamino)methylene)amino)benzoyl chloride (9-b)

2-Amino-5-bromobenzoic acid (9-a) (1.0 g, 4.6 mmol) was dissolved in DCM (10 mL). DMF (335 mg, 4.6 mmol) and oxalyl chloride (1.17 g, 9.2 mmol). After the mixture was stirred at room temperature for 2.5-3 h, LC-MS showed the reaction was completed. The mixture was concentrated to give a crude compound (9-b).

Second step: 6-bromo-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)quinazoline-4(3H)- Preparation of ketone (9-c)

The compound (Int-3-d) (0.9 g, 4.6 mmol) was dissolved in pyridine, and the compound (9-b) (1.33 g, 4.6 mmol) was added, and the mixture was stirred at 60 ° C for 5 h, and the reaction was dropped. The mixture was extracted with chloroform, dried, concentrated and purified to afford compound (9-c) (200 mg, yield: 11%).

MS m/z (ESI): 409 [M+H] ⁺ .

The third step: 6-(4-isopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)quinazoline-4(3H)-one (9)

Compound (9-c) (200 mg, 0.48 mmol) was dissolved in DMSO (4 mL), Compound (Int-2) (59 mg, 0.54 mmol), CuI (14 mg, 0.07 mmol), 8-hydroxyquinoline (10 mg) , 0.07 mmol) and K ₂ CO ₃ (132 mg, 0.96 mmol). The mixture was heated at 120 °C overnight. The reactant was concentrated under reduced pressure in vacuo and purified by preparative HPLC to afford compound (9) (3mg, yield: 1.3%).

MS m/z (ESI): 437 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.86 (s, 1H), 8.63 (s, 1H), 7.68-7.61 (m, 2H), 7.53-7.42 (m, 4H), 7.14 (s, 1H) , 6.72-6.70 (m, 1H), 5.19-5.17 (m, 1H), 1.92-1.89 (m, 1H), 1.40-1.39 (m, 6H), 0.81-0.78 (m, 2H), 0.73-0.71 ( m, 2H).

Example 10: 7-(3-Hydroxypiperidin-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl Preparation of pyridazine-1(2H)-one (21)

The title compound (11 mg) was obtained by the procedure mjjjjjjjjjjj

MS m/z (ESI): 422 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.85 (s, 1H), 8.43 (s, 1H), 8.01 (m, 1H), 7.99-7.54 (m, 4H), 7.43 (m, 1H) , 5.41-5.37 (m, 1H), 3.21 (s, 1H), 3.15-3.10 (m, 1H), 3.05-2.95 (m, 4H), 1.75-1.60 (m, 4H), 1.45 (s, 3H) , 1.43 (s, 3H).

Example 11: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-(1,1,1-trifluoroprop-2-yl)-4H-1, Preparation of 2,4-triazol-3-yl)pyridin-2-yl)-4H-chromen-4-one (22)

The title compound (5 mg) was obtained by the procedure mjjjjjjjj

MS m/z (ESI): 495 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.19 (s, 1H), 8.96 (s, 1H), 8.33 - 8.26 (m, 3H), 8.22 - 8.13 (m, 3H), 7.97 - 7.95 ( m, 1H), 7.68 (s, 1H), 6.74 (s, 1H), 1.87-1.83 (m, 4H), 0.84-0.80 (m, 2H), 0.75-0.72 (m, 2H).

Example 12: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (37)

First step: Preparation of 5-bromo-6-nitro-2,3-dihydro-1H-inden-1-one (37-b)

5-Bromo-2,3-dihydro-1H-inden-1-one (37-a) (30.0 g, 142 mmol) was added portionwise to an ice salt bath cooled fuming nitric acid (200 mL), -10 ° C. After stirring at -15 ° C for 4.5 hours, the reaction mixture was poured into ice water and stirred for 30 minutes, then filtered, and the filter cake was dissolved with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated, (37-b) (19.0 g, yield: 52.2%).

Second step: Preparation of 6-amino-5-bromo-2,3-dihydro-1H-inden-1-one (37-c)

Compound (37-b) (19.0 g, 74.2 mmol) was dissolved in ethanol (180 mL) and water (60 mL), and reduced iron powder (20.8 g, 371.0 mmol) and ammonium chloride (2.0 g, 37.1 mmol). The mixture was warmed to reflux and stirred for 4 hours. The reaction mixture was filtered hot, and then filtered and washed twice with hot ethyl ether. The filtrate was evaporated and evaporated to dryness. The aqueous solution was washed twice, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness to give compound (37-c) (11.2 g, yield: 66.8%).

Third step: Preparation of 5-bromo-6-((2-cyclopropyl-2-oxoethyl)amino)-2,3-dihydro-1H-inden-1-one (37-d)

Compound (37-c) (7.0 g, 31.0 mmol), potassium iodide (4.7 g, 28.2 mmol) and potassium carbonate (5.1 g, 37.2 mmol) were dissolved in DMF (100 mL), and stirred under nitrogen for 10 min. Bromo-1-cyclopropylethanone (10.1 g, 62.0 mmol), added, warmed to 60 ° C, stirred overnight, and the reaction mixture was evaporated to dryness vacuo. (7.3 g, yield: 76.8%).

The fourth step: 5-bromo-6-(4-cyclopropyl-2-indolyl-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-1-one (37-e) preparation

The compound (37-d) (6.6 g, 21.4 mmol) was dissolved in acetic acid (80 mL), and potassium thiocyanate (4.2 g, 42.8 mmol) was added thereto, and the mixture was heated to 110 ° C for 8 hours, and the reaction solution was depressurized. The acetic acid was evaporated, and water (100 mL) was added, and ethyl acetate was evaporated. (6.8 g of a brown solid, used directly in the next step).

Step 5: Preparation of 5-bromo-6-(4-cyclopropyl-1H-imidazol-1-yl)-2,3-dihydro-1H-inden-1-one (37-f)

Hydrogen peroxide (9 mL), acetic acid (80 mL) and water (16 mL) were placed in a three-necked flask, and the temperature was raised to 45 ° C, and the compound (37-e) (6.8 g, 19.5 mmol) was added in portions. After stirring for 2 hours, 20 was added. % sodium sulfide (30 mL), after stirring for 1 hour, the pH was adjusted to 10 with aqueous ammonia, extracted with dichloromethane, and the organic phase was concentrated and purified by silica gel column chromatography to yield compound (37-f) (4.0 g, yield: 64.7%) ).

Step 6: Preparation of 6-bromo-7-(4-cyclopropyl-1H-imidazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (37-g)

The compound (37-f) (4.0 g, 12.6 mmol) was dissolved in chloroform (80 mL), methanesulfonic acid (12.1 g, 126 mmol) was added, and the mixture was cooled to 0 ° C in an ice bath, then sodium azide (2.5 g) was added in portions. , 37.8 mmol), after adding, slowly returning to room temperature and stirring overnight, the reaction solution was quenched with 1N aqueous sodium The organic compound (37-g) (3.6 g, yield: 85.9%) was evaporated to dryness.

Step 7: 4-(7-(4-Cyclopropyl-1H-imidazol-1-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3 Of 6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (37-h)

Compound (37-g) (500 mg, 1.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 , 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (702 mg, 2.3 mmol) and potassium carbonate (626 mg, 4.5 mmol) dissolved in 1,4-dioxane (20 mL) and water (0.5 mL) Pd(dppf)Cl ₂ (100 mg) was added under a nitrogen atmosphere, and the mixture was heated to 100 ° C overnight, and the reaction mixture was evaporated to dryness. 600 mg, yield: 92.0%).

Step 8: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquine Preparation of porphyrin-1(2H)-one hydrochloride (37-i)

The compound (37-h) (600 mg, 1.4 mmol) was dissolved in methanol (5 mL), THF (5 mL) (0.6 g, crude) was used directly in the next reaction.

Step 9: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4 -Preparation of dihydroisoquinoline-1(2H)-one (37-j)

Compound (37-i) (0.6 g, crude) was dissolved in acetic acid-methanol buffer (20 mL), pH 4, and aqueous sodium hydroxide (30%, 3mL) and sodium borohydride (890mg, 4.2mmol) Stir for 4 hours. The reaction mixture was adjusted to pH 9 with potassium carbonate and evaporated to dryness. The residue was evaporated, evaporated, evaporated. Compound (37-j) (410 mg, two-step yield: 84.0%) was obtained.

Step 10: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinoline-1 (2H Preparation of -ketone (37-k)

The compound (37-j) (410 mg, 1.2 mmol) was dissolved in anhydrous ethanol (20 mL), and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Compound (37-k) (400 mg, yield: 97.1%).

Eleventh step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Preparation of pyridin-2-yl)-6-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (37)

Compound (37-k) (400 mg, 1.1 mmol), compound (Int-3-e) (454 mg, 1.7 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (171 mg) , 1.2 mmol) and anhydrous potassium phosphate (318 mg, 1.5 mmol) were dissolved in 1,4-dioxane (30 mL), and cuprous iodide (209 mg, 1.1 mmol) was added under nitrogen. Stir at reflux for two days. The reaction liquid was filtered, and the filtrate was evaporated to dryness.

MS m/z (ESI): 537 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.91 (s, 1H), 8.91 (s, 1H), 8.08-8.00 (m, 1H), 7.99-7.92 (m, 2H), 7.79 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.38-5.35 (m, 1H), 4.25 (t, J = 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.51-2.41 (m, 4H), 2.24 (s, 3H), 1.92-1.87 (m, 4H), 1.85-1.84 (m, 1H) , 1.50 (d, J = 6.8 Hz, 6H), 0.85 - 0.77 (m, 2H), 0.76 - 0.68 (m, 2H).

Example 13: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-(3-morpholinoprop-1-yn-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (38)

First step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-6-(3-morpholinoprop-1-yn-1-yl)-3,4-dihydroisoquinoline Preparation of -1(2H)-one (38-a)

Compound (37-g) (140 mg, 0.42 mmol), 4-(prop-2-yn-1-yl)morpholine (210 mg, 1.68 mmol) and potassium carbonate (116 mg, 0.84 mmol) were dissolved in acetonitrile (5 mL) Pd ₂ (dba) ₃ (20 mg) and Xantphos (20 mg) were added to DMF (2 mL), and the mixture was heated to 85 ° C overnight, and the reaction mixture was evaporated to dryness. Compound (38-a) (130 mg, yield: 82.3%).

Second step: 7-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)-6-(3-morpholinoprop-1-yn-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (38)

Compound (38-a) (130 mg, 0.35 mmol), compound (Int-3-e) (142 mg, 0.53 mmol), trans-N,N-dimethyl-1,2-cyclohexanediamine (55 mg) , 0.39 mmol) and anhydrous potassium phosphate (104 mg, 0.49 mmol) were dissolved in 1,4-dioxane (30 mL), and cuprous iodide (67 mg, 0.35 mmol) was added under nitrogen. The mixture was stirred under reflux overnight, and the reaction mixture was filtered, evaporated, evaporated, evaporated,

MS m/z (ESI): 564 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.92 (s, 1H), 8.08-8.01 (m, 1H), 8.00-7.94 (m, 2H), 7.91 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.29 (d, J = 1.2 Hz, 1H), 5.38-5.36 (m, 1H), 4.26 (s, 2H), 3.65-3.52 (m, 4H) ), 3.51 (s, 2H), 3.20 (t, J = 6.0 Hz, 2H), 2.41-2.39 (m, 4H), 1.91-1.81 (m, 1H), 1.50 (d, J = 6.8 Hz, 6H) , 0.84-0.76 (m, 2H), 0.74-0.66 (m, 2H).

Example 14: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-6-(3-hydroxyprop-1-yn-1-yl)-2-(6-(4-isopropyl) Of -4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (39)

By the same method as in Example 13, except that propan-2-yn-1-ol (300 mg, 5.3 mmol) was used instead of 4-(prop-2-yn-1-yl)morpholine in the first step. The title compound (6 mg) was obtained.

MS m/z (ESI): 494 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.39 (s, 1H), 8.12-8.10 (m, 2H), 8.03-8.00 (m, 1H), 7.96-7.89 (m, 2H), 7.51 ( s, 1H), 7.00 (s, 1H), 5.49-5.46 (m, 1H), 4.46 (s, 2H), 4.30-4.27 (m, 2H), 3.18 (t, J = 6.4 Hz, 2H), 1.93 - 1.91 (m, 1H), 1.50 (d, J = 6.8 Hz, 6H), 0.91 - 0.88 (m, 2H), 0.83 - 0.81 (m, 2H).

Example 15: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-tri Preparation of oxazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (40)

Steps 1 to 5: 2-(6-(4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4H-1,2,4-tri Zyrid-3-yl)pyridin-2-yl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-one (40- Preparation of f)

In addition to 6-(4-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine-2 Compound (40-f) (60 mg) was obtained by a method similar to that of Example 5 and Example 6 except that the compound (Int-7) (500 mg, 2.28 mmol) was used instead of the compound (Int-3-d).

Step 6: 7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-tri Preparation of oxazol-3-yl)pyridin-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (40)

The compound (40-f) (60 mg, 0.1 mmol) was placed in a vial, and a solution of 4N hydrochloric acid in 1,4-dioxane (15.0 mL) was added, and the mixture was stirred at room temperature overnight. Purification by preparative high performance liquid chromatography gave Compound (40) (30 mg).

MS m/z (ESI): 456 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.78 (s, 1H), 8.61 (s, 1H), 7.62-7.59 (m, 2H), 7.44-7.40 (m, 3H), 7.15 (s, 1H), 6.67-6.65 (m, 1H), 4.10-3.85 (m, 3H), 3.66 (br, 1H), 3.28-3.22 (m, 2H), 3.10-3.3.08 (m, 2H), 1.89- 1.86 (m, 1H), 1.53 (m, 3H), 0.89-0.85 (m, 2H), 0.73-0.70 (m, 2H).

Example 16: 6-(4-Cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)quinoline-4(1H)-one (41)

First step: Preparation of 1-(2-amino-5-(4-cyclopropyl-1H-imidazol-1-yl)phenyl)ethan-1-one (41-b)

4-Cyclopropyl-1H-imidazole (Int-2) (1.08 g, 10 mmol), 1-(2-amino-5-bromophenyl)ethan-1-one (41-a) (2.14 g, 10 mmol , 8-hydroxyquinoline (290 mg, 2 mmol) and potassium carbonate (1.51 g, 11 mmol) were dissolved in dimethyl sulfoxide (30 mL), and cuprous iodide (382 mg, 2 mmol) was added under nitrogen. The mixture was replaced with nitrogen three times, and the mixture was heated to 125 ° C and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. EtOAcjjjjjjjjjjjjj 53.9%).

MS m/z (ESI): 242 [M+H] ⁺ .

The second step: 1-(2-amino-5-(4-cyclopropyl-1H-imidazol-1-yl)phenyl)-2-(6-(4-isopropyl-4H-1,2, Preparation of 4-triazol-3-yl)pyridin-2-yl)ethan-1-one (41-c)

Compound (41-b) (1.3 g, 5.4 mmol), 2-bromo-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (Int-3-e (1.44 g, 5.4 mmol), sodium tert-butoxide (623 mg, 6.5 mmol) and Xantphos (50 mg) were dissolved in tetrahydrofuran (20 mL), replaced with nitrogen three times, and then Pd ₂ (dba) ₃ (150 mg) was added. The solution was stirred at 80 ° C overnight. The reactant was concentrated under reduced pressure in vacuo, and the residue was purified by preparative high-purity chromatography to afford compound (41-c) (460 mg, yield: 20%).

MS m/z (ESI): 428 [M+H] ⁺ .

The third step: 6-(4-cyclopropyl-1H-imidazol-1-yl)-3-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl)quinoline-4(1H)-one (41)

The compound (41-c) (460 mg, 1.08 mmol) was dissolved in EtOAc (EtOAc) The reaction solution was further stirred at 40 ° C overnight, and then the reaction solution was poured into ice water and extracted with dichloromethane. The mixture was concentrated under reduced vacuo.

MS m/z (ESI): 438 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.64 (s, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.63-7.55 (m, 2H), 7.45 (s, 1H) , 7.39-7.22 (m, 3H), 6.99-6.85 (m, 1H), 5.31-5.29 (m, 1H), 1.89-1.86 (m, 1H), 1.55-1.51 (m, 6H), 0.83-0.80 ( m, 2H), 0.72-0.70 (m, 2H).

Example 17: (R)-7-(4-Cyclopropyl-1H-imidazol-1-yl)-2-(6-(4-(1-methoxypropan-2-yl)-4H-1 Of 2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one (17)

In addition to the (R)-2-mercapto-6-(4-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridine in the first step (Int-8) (234 mg, 1.0 mmol) Compound Compound Compound Compound Compound Compound

MS m/z (ESI): 469 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.93 (s, 1H), 8.66 (s, 1H), 8.41-8.39 (m, 2H), 8.30-8.28 (m, 1H), 8.13-8.08 ( m,3H), 7.90-7.86 (m, 2H), 4.47-4.38 (m, 1H), 3.94-3.89 (m, 2H), 3.26 (s, 3H), 1.88-1.86 (m, 1H), 1.77- 1.73 (m, 3H), 0.85-0.81 (m, 2H), 0.75-0.72 (m, 2H).

Example 18: 7-(6-Cyclopropylpyridin-3-yl)-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Preparation of pyridazine-1(2H)-one (42)

7-Bromo-2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)pyridazine-1(2H)-one (Compound 2) -b) (88 mg, 0.21 mmol) was dissolved in DMF (1 mL), (6-cyclopropylpyridin-3-yl)boronic acid (49 mg, 0.3 mmol) Pd(dppf)Cl ₂ (16 mg, 0.02 mmol) was added and the mixture was heated at 80 ° C overnight. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 450 [M+H] ⁺ .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 8.87 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.34-8.29 (m, 3H), 8.18-8.10 (m, 1H), 7.60-7.55 (m, 2H), 7.33-7.28 (m, 1H), 6.89-6.86 (m, 1H), 5.33-5.30 (m, 1H), 1.88-1.86 (m, 1H), 1.40- 1.39 (m, 6H), 0.83-0.80 (m, 2H), 0.77-0.73 (m, 2H).

The following compounds were prepared by a method similar to that in Example 1-18:

Biological experiment

1. ASK1 inhibition test

1.1 Test method

The inhibitory effect of the compound on the ASK1 enzyme was determined using the HTRF KinEZSE-STK (Cisbio) kit. The ASK1 enzyme was pre-incubated with different concentrations of test compound for 30 min at room temperature, and then the substrate and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation for 120 min at room temperature, TK antibody-cryptate and streptavidin-XL665 were added and assayed. The vehicle control group (DMSO) was used as the negative control, and the buffer group (excluding the ASK1 enzyme) was used as the blank control. The relative inhibitory activity percentage of the test compounds at different concentrations was calculated by the following formula:

Relative inhibitory activity percentage = 1 - (different concentrations of test compound group - buffer group) / (solvent group - buffer group) * 100%

The relative inhibitory activity percentages of the different concentrations of the compound group were plotted against the compound concentration, and the curve was fitted according to the four-parameter model, and the IC ₅₀ value was calculated by the following formula:

y=min+(max-min)/(1+(x/IC ₅₀ )^(-Hillslope))

Where y is the relative inhibitory activity percentage, max and min are the maximum and minimum values of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

1.2 test results

The inhibitory effect of the compound on ASK1 activity was determined according to the above method, and the results were as follows:

Compound number IC ₅₀ (nM) 1 15.54±5.48 2 0.90±0.10 3 1.25±0.12 4 1.14±0.15 5 0.91±0.12 6 1.21±0.13 7 4.26±0.45 9 11.09±1.19 twenty two 2.39±0.31 37 1.08±0.09 38 0.98±0.12 39 1.35±0.13 40 1.18±0.10

17 11.00±1.63 42 2.66±0.35 43 1.37±0.14

From the above results, it was found that the compounds of the respective examples had strong inhibitory activity against the ASK1 enzyme.

2. ASK1 cell reporter gene test

2.1 Test methods

The pcDNA3.1-ASK1 expression vector was constructed and co-transfected into HEK293 cells with pGL4.44[luc2P/AP1RE/Hygro] vector, plated at 3×10 ⁴ cells/well, and incubated with different concentrations of test compounds for 24 h, then Bright was used. -Glo ^TM luciferase assay system (Promega), luciferase activity in cells according to the instructions of the detection method. Using the vehicle group (DMSO) as a negative control, the percentage of relative inhibitory activity of the test compounds at different concentrations was calculated by the following formula:

Percentage of relative inhibitory activity = 1 - (test compound group at different concentrations) / (solvent group) * 100%

The relative inhibitory activity percentages of the test compound groups at different concentrations were plotted against the compound concentration, the curve was fitted according to a four-parameter model, and the IC ₅₀ values were calculated by the following formula:

y=min+(max-min)/(1+(x/IC ₅₀ )^(-Hillslope))

Where y is the relative inhibitory activity percentage, max and min are the maximum and minimum values of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

2.2 Test results

The inhibitory effect of the compound on the activity of ASK1 in cells was determined according to the above method, and the results were as follows:

Compound number IC ₅₀ (nM) 2 108.31±28.24 3 27.68±12.40

From the above results, it was found that the compounds of the respective examples inhibited the ASK1 enzyme of the cells.

Further, in the anti-inflammatory test, the compounds of the examples of the present invention exhibited a good swelling inhibition rate; the compounds of the examples of the present invention have a good effect on the improvement of fatty liver, inflammation, and fibrosis.

The compounds of the examples of the invention have both good pharmacokinetic properties, pharmacodynamic properties and excellent safety.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims (12)

a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the formula (I) )Structure:

among them:

Represents a single bond or a double bond, provided that Y and Z are each connected to at most one double bond; R ^{1 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _6-10 aryl, a 5-14 membered heteroaryl group and a C _6-12 aralkyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, and aralkyl group are each optionally one or more independent Substituted with a substituent selected from the group consisting of halogen, oxo, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, phenoxy, cyano, nitro, -OR ⁶ , -C(=O)R ⁶ , -OC(=O)R ⁶ , -C(=O)OR ⁶ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ C(=O)R ⁷ , -N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)N(R ⁶ )(R ⁷ ), -C(=O)N(R ⁶ ) (R ⁷ ), -S(=O) _m R ⁶ and -S(=O) _m N(R ⁶ )(R ⁷ ), wherein the alkyl group, cycloalkyl group, heterocyclic group, phenyl group And the phenoxy group are each optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _3-10 cycloalkyl and -OC _1-6 alkyl; R ^{2 is} selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, and -OC _1-6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens; R ^{3 is} selected from 3-10 membered heterocyclic groups optionally fused to another C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl a C _6-10 aryl group and a 5-14 membered heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is each optionally one or more substituents independently selected from the group consisting of Substitution: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, C _6-12 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, halogen, oxo, cyano, -OR ⁶ , -OC(=O)R ⁶ , -OC(=O)N(R ⁶ ) (R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ ) (R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ )C(=O)N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally further substituted by one or more substituents independently selected from halogen: hydroxy , oxo, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl Base, 3-10 membered heterocyclic group and -OR ⁶ ; Q is selected from C, C(R ⁴ ) and N; W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are each independently selected from C(R ⁴ ) and N; When both W ⁵ and W ⁶ are C(R ⁴ ), the two R ^{4 ,} together with the carbon atom to which they are attached, are optionally taken together to form a 5 member, optionally substituted by C _1-6 alkyl, hydroxy or halogen. a 6-membered cycloalkyl, heterocyclic, aryl or heteroaryl; X, Y and Z are each independently selected from a direct bond, C(R ⁴ ), C(R ⁴ )(R ⁵ ), N, N(R ⁴ ) and O; R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, oxo, halogen, nitro, cyano, C _1-6 alkyl, -OC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _3-10 cycloalkyl, C _6-10 aryl, C _6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic, -OR ⁶ , -OC (=O R ⁶ , -OC(=O)N(R ⁶ )(R ⁷ ), -N(R ⁶ )(R ⁷ ), -S(=O) _m R ⁶ , -S(=O) _m OR ⁶ , -S(=O) _m N(R ⁶ )(R ⁷ ), -N(R ⁶ )C(=O)R ⁷ , -N(R ⁶ )C(=O)OR ⁷ , -N(R ⁶ ) C(=O)N(R ⁶ )(R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) And -N(R ⁶ )S(=O) _m R ⁷ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally Further substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, -N(R ⁶ )( R ⁷ ), -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )(R ⁷ ) and -OR ⁶ ; R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-8 cycloalkyl; or when R ⁶ and R ^{7 are} bonded to the same nitrogen atom, R ⁶ and R ^{7 are} attached thereto The nitrogen atom optionally together form a 3-10 membered heterocyclic group; m is 0, 1, or 2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein said compound Structure with formula (II):

The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein said compound A structure having the formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX):

A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein R ^{1 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl and pyrrolidinyl, said group optionally being 1 And 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -CF ₃ , -OCH ₃ and -C(=O)CH ₃ . A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein R ^{3 is} selected from the group consisting of:

The above group is attached to the remainder of the molecule through any ring atom; The above groups are optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, methyl, ethyl, n-propyl, isopropyl, n-Butyl, sec-butyl, tert-butyl, cyclopropyl and -CF ₃ . A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein R ^{4 is} selected from the group consisting of F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl,

R ⁴ is preferably F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or cyclopropyl. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein the compound is selected from the group consisting of

A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or a prodrug, and a pharmaceutically acceptable carrier, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Use of a medicament or a pharmaceutical composition of claim 8 for the manufacture of a medicament for use as an ASK1 inhibitor. The use according to claim 9, wherein the medicament is for preventing or treating an ASK1-mediated disease, which includes conditions and diseases caused by chronic fatty and fibrotic degeneration (for example, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic fat Hepatitis (NASH), primary sclerosing cholangitis, extrahepatic cholestasis; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis; cirrhosis caused by alcohol or viral infectious forms Hepatitis-related cholestasis and fibrotic lesions; autoimmune diseases; respiratory diseases (including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and acute lung injury); inflammatory diseases; Chronic kidney disease; cardiovascular disease; diabetes (including diabetic nephropathy and other complications of diabetes); metabolic disorders; organ damage after ischemia and reperfusion of the heart, brain and kidneys, and neurodegenerative diseases. Compound of formula (IN-8):

among them: Hal ¹ is a halogen such as F, Cl, Br or I; The remaining groups are as defined in any one of claims 1-7; The compound is preferably:

Preparation, The preparation method is a method for preparing a compound of the formula (IN-8), the method comprising the steps of:

among them: Hal ¹ , Hal ² and Hal ³ are the same or different halogens, such as F, Cl, Br or I; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: The first step: obtaining IN-1 by halogenation reaction; The second step: reacting IN-3 with DMF-DMA to obtain IN-4; The third step: cyclization reaction of IN-4 with R ¹ -NH ₂ to obtain IN-5; The fourth step: IN-5 first diazotization reaction, followed by halogenation reaction to obtain IN-6; Step 5: IN-6 reacts with hydrazine to obtain IN-7; Step 6: IN-7 reacts with IN-2 to obtain IN-8. Alternatively, the preparation method is a method of preparing a compound of formula (IV)-1, which comprises the steps of:

among them: Hal ¹ , Hal ² and Hal ³ are the same or different halogens, such as F, Cl, Br or I; PG is a hydroxy protecting group; LG is selected from H and halogen; R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence; or R ^a and R ^{a '} together with the group to which they are attached form a 5-10 membered ring system; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: First step: protecting the hydroxyl group of the compound of formula (IV)-1-a with a suitable hydroxy protecting group to give a compound of formula (IV)-1-b; The second step: reacting the formula (IV)-1-b with R ³ -LG to obtain a compound of the formula (IV)-1-c; Third step: removing the hydroxy protecting group of the compound of formula (IV)-1-c to give a compound of formula (IV)-1-d; The fourth step: reacting a compound of the formula (IV)-1-d with a formamide to obtain a compound of the formula (IV)-1-e; Step 5: reacting a compound of the formula (IV)-1-e in the presence of an organic base or an inorganic base and a halogen to obtain a compound of the formula (IV)-1-f; Step 6: reacting a compound of the formula (IV)-1-f with a boronic acid or a boronic acid ester under the catalysis of a palladium catalyst to obtain a compound of the formula (IV)-1-g; Step 7: reacting a compound of the formula (IV)-1-g with a compound Int-3-E under the catalysis of a palladium catalyst to obtain a compound of the formula (IV)-1; Alternatively, the preparation method is a method of preparing a compound of formula (V)-1, which comprises the steps of:

among them: Hal ¹ is halogen, such as F, Cl, Br or I; R' is selected from the group consisting of -OH, -OC _1-6 alkyl and halogen; LG is selected from H and halogen; R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: First step: optionally, the compound of formula (V)-1-a is first formed into an acid halide compound, which is then reacted with Int-3-D to give a compound of formula (V)-1-b; The second step: reacting a compound of the formula (V)-1-b with a formamide to obtain a compound of the formula (V)-1-c; Third step: reacting a compound of the formula (V)-1-c in an aprotic solvent under heating to obtain a compound of the formula (V)-1-d; The fourth step: reacting the formula (V)-1-d with R ³ -LG to obtain a compound of the formula (V)-1; Alternatively, the method is a method of preparing a compound of formula (V)-2, which comprises the steps of:

Wherein each group is as defined in any one of claims 1 to 7; and the reaction is carried out under hydrogenation conditions (for example, hydrogenation in a hydrogen atmosphere under palladium on carbon catalysis); Alternatively, the method is a method of preparing a compound of formula (VIII)-2, which comprises the steps of:

among them: Hal ¹ and Hal ³ are the same or different halogens, such as F, Cl, Br or I; LG is selected from H and halogen; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: First step: reacting the formula (VIII)-2-a with R ³ -LG to give a compound of the formula (VIII)-2-b; a second step: reacting a compound of formula (VIII)-2-b with an azide salt in the presence of a strong acid to provide a compound of formula (VIII)-2-c; The third step: reacting a compound of the formula (VIII)-2-c with the compound Int-3-E to obtain a compound of the formula (VIII)-2; Alternatively, the method is a method of preparing a compound of formula (VII), which comprises the steps of:

among them: Hal ¹ is halogen, such as F, Cl, Br or I; R' is selected from the group consisting of -OH, -OC _1-6 alkyl and halogen; LG is selected from H and halogen; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: First step: optionally, the compound of formula (VII)-a is first formed into an acid halide compound, which is then reacted with Int-3-D to give a compound of formula (VII)-b; Step 2: reacting a compound of the formula (VII)-b with a nitrite in the presence of a strong acid to obtain a compound of (VII)-c; The third step: reacting the formula (VII)-c with R ³ -LG to obtain a compound of the formula (VII); Alternatively, the method is a method of preparing a compound of formula (VI), which comprises the steps of:

among them: Hal ¹ and Hal ² are the same or different halogens, such as F, Cl, Br or I; LG is selected from H and halogen; R ^a and R ^{a '} are each independently selected from H and C _1-6 alkyl at each occurrence; The remaining groups are as defined in any one of claims 1-7; The reaction conditions of each step are as follows: The first step: reacting a compound of the formula (VI)-a with an acid halide reagent in the presence of formamide to obtain a compound of the formula (VI)-b; Second step: reacting a compound of formula (VI)-b with Int-3-D to provide a compound of formula (VI)-c; The third step: reacting a compound of the formula (VI)-c with R ³ -LG to give a compound of the formula (VI). Alternatively, the method is a method of preparing a compound of formula (IX)-1, which comprises the steps of:

among them: Hal ¹ and Hal ³ are the same or different halogens, such as F, Cl, Br or I; LG is selected from H and halogen; The remaining groups are as defined above; The reaction conditions of each step are as follows: The first step: reacting the formula (IX)-1-a and R ³ -LG under the catalysis of a metal or a metal salt in the presence of an organic base or an inorganic base, optionally in the presence of a metal ligand, to obtain a compound of formula (IX)-1-b; Second step: reacting a compound of formula (IX)-1-b with a compound Int-3-E under the catalysis of a palladium catalyst, preferably in the presence of an organic or inorganic base, optionally in the presence of a ligand To obtain a compound of formula (IX)-1-c; Third step: The compound of the formula (IX)-1-c is reacted with a formate or DMF-DMA, optionally in the presence of an organic base or an inorganic base to give a compound of the formula (IX)-1.