CN114369083A - Heterocyclic compound, pharmaceutical composition containing same, preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a heterocyclic compound, a medicinal composition containing the heterocyclic compound, a preparation method of the heterocyclic compound and application of the heterocyclic compound. Specifically, the invention provides a compound with a structure shown in formula I or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic marker, metabolite or prodrug thereof, which shows better TGF beta R1 inhibition activity, can be used as a high-efficiency and high-selectivity TGF beta R1 inhibitor and has antitumor activity.

Description

Heterocyclic compound, pharmaceutical composition containing same, preparation method and use thereof

technical field

The invention belongs to the field of medicinal chemistry, and relates to a heterocyclic compound with TGFβR1 inhibitory activity, a pharmaceutical composition comprising the same, a preparation method and use thereof.

Background technique

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates various cellular responses such as cell proliferation, differentiation, migration and apoptosis. The TGF-β superfamily includes TGF-β1, TGF-β2, TGF-β3, activin, inhibin, bone morphogenetic protein, and the like. TGF-β signals through two highly conserved single-transmembrane serine/threonine kinases, TGFβR1 and TGFβR2 (ACS Med. Chem. Lett., 2018, 9, 1117).

Smads are important TGF-β signal transduction and regulation molecules in cells, which can directly transduce TGF-β signals from the cell membrane to the nucleus. The TGF-β/Smads signaling pathway plays an important role in the occurrence and development of tumors . In TGF-β/Smads signal transduction, activated TGF-β first binds to TGFβR2 on the cell membrane surface to form a heterodimeric complex, which is further recognized and bound by TGFβR1. Activated TGFβR1 further phosphorylates Smad2/Smad3 protein, which further binds to Smad4 to form a heterotrimeric complex, which enters the nucleus and cooperates with co-activators/repressors to regulate the transcription of target genes (Nature, 2003, 425, 577). As long as any part of the TGF-β/Smads signaling pathway is altered, it will lead to abnormalities in the signal transduction pathway (PNAS, 2019, 116, 9166).

The TGF-β signaling pathway is dysregulated in many diseases including cancer, TGFβR1 in gastric, colorectal, prostate, ovarian, pancreatic, liver, lung, cervical and head and neck cancer cell lines and tumor tissues Protein levels were significantly elevated. Activation of the TGF-β signaling pathway triggers pronounced pathological effects in the tumor stroma, including immunosuppression, angiogenesis, and connective tissue hyperplasia. In addition, the TGF-β signaling pathway can enhance the invasiveness of tumor cells, promote the transition of epithelial cells to mesenchyme, and improve the tolerance of tumor epithelial cells (Nat. Neurosci., 2014, 17, 943).

At present, the development of inhibitors targeting TGFβR1, a key target in the TGF-β signaling pathway, has gradually attracted attention in the pharmaceutical industry, and published patent applications include WO 02/094833 A1, WO 2009/150547 A1, and WO 2017/035118 A1 , WO 2018/019106 A1, etc. However, there is still an urgent need in the art for new TGFβR1 inhibitors, especially TGFβR1 inhibitors with high activity and selectivity.

SUMMARY OF THE INVENTION

The present invention surprisingly finds a heterocyclic compound and its corresponding preparation method through a large number of researches. The compounds can significantly inhibit the activity of TGFβR1 and have good selectivity between TGFβR1 and TGFβR2, and can be used as TGFβR1 inhibitors for the treatment of proliferative disorders and dysregulation of apoptosis mediated at least in part by TGF-β signaling pathway Sexual disorders, especially diseases mediated at least in part by TGF[beta]Rl, such as cancer, eg liver cancer.

In the first aspect, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide thereof , isotopic labels, metabolites or prodrugs:

in,

R ¹ is a 5-10-membered heteroaryl group optionally substituted with one or more R ⁴ ;

R ² is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, cyano, -C(=O)NR ^a R ^b and -C(=O) OR ^a ;

R ^a and R ^b are each independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl and 4-8 membered heterocyclyl, the C _1-6 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl optionally substituted with one or more R ⁵ ; or R ^a , R ^b and the nitrogen atom to which they are attached together form a 4-8 membered heterocycle, the ^The 4-8 membered heterocycle is optionally substituted with one or more R5;

R ³ is selected from hydrogen and -NR ^c R ^d ;

R ^c and R ^d at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, -C(=O)R ^a , C _6-10 -membered aryl and 5-10-membered heteroaryl, the C _1-6 alkyl, C _3-8 cycloalkyl, 4-8-membered heterocyclyl, C _6-10 -membered aryl or 5-10-membered Heteroaryl is optionally substituted with one or more R ^;

R ⁴ at each occurrence is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, the C _1-6 alkyl, C _1-6 alkyl _-6 alkoxy or C _3-8 cycloalkyl optionally substituted with one or more halogens;

R ⁵ at each occurrence is independently selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-8 cycloalkyl and 4 -8-membered heterocyclyl, the C _1-6 alkyl or C _3-8 cycloalkyl is optionally substituted with one or more hydroxyl groups;

R ⁶ at each occurrence is independently selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-8 cycloalkyl and 4 -8-membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted with one or more groups selected from hydroxy and C _1-6 alkyl;

Y is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylthio base, C _3-8 cycloalkylthio, C _1-6 alkylamino, C _3-8 cycloalkylamino and 4-8 membered heterocyclyl;

Z is selected from ^-CR7- and -N-; and

R ⁷ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl and cyano.

In a second aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, A solvate, nitrogen oxide, isotopic label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

A third aspect, the present invention provides a kind of medicine box, it comprises:

a) at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, an isotopic label, metabolite or prodrug, or a pharmaceutical composition of the invention as the first pharmaceutical composition;

b) optionally present at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising the other therapeutic agent as a second pharmaceutical composition; and

c) Optional packaging and/or instructions.

In a fourth aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels thereof , metabolites or prodrugs or pharmaceutical compositions of the invention for use as TGFβR1 inhibitors for the prevention and/or treatment of diseases or disorders (especially cancers, eg liver cancer) mediated at least in part by TGFβR1.

In a fifth aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels thereof Use of a , metabolite or prodrug or a pharmaceutical composition of the invention as an inhibitor of TGFβR1.

In a sixth aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels thereof , metabolite or prodrug or use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder mediated at least in part by TGFβR1, especially cancer, eg liver cancer.

In a seventh aspect, the present invention provides a method for the prevention and/or treatment of a disease or disorder mediated at least in part by TGFβR1, in particular cancer, such as liver cancer, comprising administering to an individual in need thereof the prophylactic and A therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite drug or prodrug or pharmaceutical composition of the present invention.

In an eighth aspect, the present invention provides a method for preparing the compound of the present invention, comprising:

Step 1-1: Compound SM1 and N,N-dimethylformamide dimethyl acetal undergo condensation reaction to obtain compound IM1

Step 1-2: Compound IM1 and compound SM2 undergo cyclization reaction to obtain compound IM2

Step 1-3: Compound IM2 undergoes substitution reaction to obtain compound IM3

Step 1-4: Substitution reaction of compound IM3 and SM3 to obtain compound of formula I

where LG is a leaving group such as phenoxy and halogen; and,

Y, Z, R ¹ , R ² and R ³ are as defined above.

The compound of the present invention can be used as an efficient and highly selective TGFβR1 inhibitor, has antitumor activity, less toxic side effects and drug interactions, mild synthesis method, simple and easy operation, and is suitable for industrial scale-up production.

Detailed ways

Before the present invention is further described, it is to be understood that this invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing and not limiting the specific embodiments.

definition

Unless otherwise defined below, all technical and scientific terms used herein are intended to 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 commonly understood in the art, including those variations or substitutions of equivalent techniques that would be apparent 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 present invention.

As used herein, the terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended, and do not Other unlisted elements or method steps are excluded.

As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C _1-6 alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl) , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spirocyclic, 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]nonyl, decalinyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, eg, 3 to 10 carbon atoms, 3 to 8 carbon atoms, or 3 to 6 carbon atoms. For example, as used herein, the term "C _3-8 cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 8 ring carbon atoms (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally substituted with one or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl .

As used herein, the term "alkoxy" refers to an "alkyl" as defined above attached to the parent molecular moiety through an oxygen atom, eg, C _1-6 alkoxy, C _1-3 alkoxy. Representative examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy alkoxy groups, hexyloxy groups, etc., the alkoxy groups may be optionally substituted with one or more (such as 1 to 3) substituents which may be the same or different.

As used herein, the term "cycloalkoxy" refers to a "cycloalkyl" as defined above attached to the parent molecular moiety through an oxygen atom, eg, _C3-8 cycloalkoxy, _C3-6 ring alkoxy. Representative examples of C _3-8 cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc., said cycloalkoxy may be optionally or multiple (such as 1 to 3) of the same or different substituents are substituted.

As used herein, the term "alkylthio" refers to an "alkyl group" as defined above attached to the parent molecular moiety through a sulfur atom, eg, _C1-6 alkylthio, _C1-3 alkylthio. Representative examples of C _1-6 alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, pentylthio The alkylthio group may be optionally substituted with one or more, such as 1 to 3, the same or different substituents.

As used herein, the term "cycloalkylthio" refers to a "cycloalkyl" as defined above attached to the parent molecular moiety through a sulfur atom, eg, _C3-8 cycloalkylthio, _C3-6 ring Alkylthio. Representative examples of C _3-8 cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc., and the cycloalkylthio can be optionally or multiple (such as 1 to 3) of the same or different substituents are substituted.

As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more, such as 1 to 3, the same or different halogen atoms. For example, the term "C _1-6 haloalkyl" as used herein refers to a haloalkyl having 1 to 6 carbon atoms, including but not limited to -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ Cl and the like. The haloalkyl groups herein are optionally substituted with one or more (such as 1 to 3) substituents described herein.

基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基、三噻烷基(trithianyl)等；以及它们的并环衍生物或苯并衍生物或杂芳基并衍生物或螺环衍生物等。As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more carbon atoms in the ring (eg 1, 2, 3 or 4) selected from C(=O), O, S, S(=O), S(=O) ₂ , N and NR (R represents a hydrogen atom or a substituent , such as, but not limited to, alkyl or cycloalkyl). Heterocyclyl groups can be saturated or unsaturated. Saturated heterocyclyl groups may be referred to as heterocycloalkyl groups, such as 3-8 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, and the like. Unless specifically stated otherwise in this specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a paracyclic ring system, a bridged ring system or a spiro ring system. In particular, a 3-8 membered heterocyclyl group is a group having 3-8 carbon atoms and heteroatoms in the ring, for example, it has 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 or 5 to 6 carbon atoms and heteroatoms (referred to as 4 to 8 membered, 4 to 7 membered, 4 to 6 membered, 5 to 8 membered, 5 to 7 membered and 5 to 6 membered heterocyclyl, respectively), for example Without limitation , tetrahydropyranyl, aza

group, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, etc.; and their cyclic derivatives or benzo derivatives or hetero derivatives Aryl derivatives or spiro derivatives, etc.

As used herein, the term "aryl" refers to an all carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi electron system. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. For example, the term " _C6-10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl groups are optionally substituted with one or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, _-NO2 , _C1-6 alkyl, etc.).

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 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, in addition, in each case may be benzo-fused of. For example, as used herein, the term "5-10 membered heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring system having 5-10 ring atoms and comprising at least one which may be the same or different Heteroatoms (the heteroatoms are eg N, O or S). Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives. Heteroaryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, _C1-6 alkyl, etc.).

As used herein, the term "alkylamino" refers to a group in which one hydrogen on an amino group is replaced by an alkyl group, eg, as used herein, the term " _C1-6 alkylamino" refers to a group on an amino group A group in which hydrogen is replaced by a C _1-6 alkyl group can be represented as C _1-6 alkyl-NH-.

As used herein, the term "cycloalkylamino" refers to a group in which one hydrogen on an amino group is replaced by a cycloalkyl group, eg, as used herein, the term " _{C3-8cycloalkylamino} " refers to an amino group A group in which one hydrogen is replaced by a C _3-8 cycloalkyl group can be represented as C _3-8 cycloalkyl-NH-.

As used herein, the term "hydroxyalkyl" refers to a group in which one hydrogen on an alkyl group is replaced by a hydroxy group, eg, as used herein, the term "hydroxyC _1-6 alkyl" refers to C _1- A group in which one hydrogen on the ₆ alkyl group is replaced by a hydroxyl group can be represented as -C _1-6 alkyl-OH.

As used herein, the term "hydroxy" refers to -OH.

As used herein, the term "cyano" refers to -CN.

As used herein, the term "amino" refers to _-NH2 .

The term "substituted" means that one or more (eg, 1, 2, 3, or 4) atoms (eg, hydrogen atoms) or radicals (eg, triflate) of the specified group are replaced by other atoms or Atomic group substitution, provided that the specified group satisfies the valence requirements in the present case and forms a stable compound after substitution. 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 can be unsubstituted or substituted. If the first substituent is described as being optionally substituted with one or more of the list of second substituents, one or more hydrogen atoms in the first substituent may be individually or independently ) is replaced by one or more of the second list of substituents, or is not replaced.

As used herein, the term "one or more" means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

The term "pharmaceutically acceptable" as used herein means that a substance or composition must be chemically and/or toxicologically compatible with the other components that make up the formulation and/or the mammal to be treated with it.

The term "pharmaceutically acceptable salts" generally includes, but is not limited to, salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases, such salts are also known as acid additions. Salt or base addition salt.

The term "pharmaceutically acceptable ester" generally includes, but is not limited to, esters of compounds of the present invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters also known as carboxylate or sulfonate.

The term "isomers" refers to compounds that have the same molecular weight due to the same number and type of atoms, but differ in the spatial arrangement or configuration of the atoms.

The term "stereoisomer" (or "optical isomer") refers to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) resulting in a vertical asymmetric plane, Thus, a stable isomer capable of rotating plane-polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can be in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers form exists. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e. single enantiomers or diastereomers, or enriched for single stereoisomers (purity ≥ 98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%). Single stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral centers, as described hereinafter, or by preparation of mixtures of enantiomeric products followed by separation or resolution The resulting mixture is, for example, converted to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on a chiral chromatography column. Starting compounds with specific stereochemistry are either commercially available or can be prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (ie, an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" (or "tautomeric form") refers to structural isomers of different energies that can be interconverted through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversion by proton transfer, such as keto-enol isomerization, imine-enamine isomerization isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of the molecule can be obtained by one of skill in the art by a number of known methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor phase diffusion, and sublimation. Additionally, polymorphs may be detected, classified and identified using well known techniques including, but not limited to, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-ray Powder Diffraction (XRPD) , Single Crystal X-ray Diffraction (SCXRD), Solid State Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), Raman Spectroscopy and Scanning Electron Microscopy (SEM), etc.

The term "solvate" refers to a substance formed by the association of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, and the like), ethanolates, acetonates, and the like.

The term "nitrogen oxide" refers to compounds formed by oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds. For example, a nitrogen atom in position 1 in the parent nucleus of a compound of formula I can form the corresponding nitrogen oxide.

The term "isotopic label" refers to a derivative compound formed by substituting a particular atom in a compound of the present invention for its isotopic atom. Unless otherwise indicated, compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as ² H(D), ³ H(T), ¹³ C, ¹⁴ C, ¹⁵ N , ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ S and ³⁷ Cl.

The term "metabolite" refers to a derivative compound formed upon metabolism of a compound of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9th ^ed .) [M], McGraw-Hill International Editions, 1996.

The term "prodrug" refers to a derivative compound capable of providing, directly or indirectly, a compound of the present invention upon administration to an individual. Particularly preferred derivative compounds or prodrugs are those that, when administered to an individual, increase the bioavailability of the compounds of the invention (eg, more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (eg, the lymphatic system) compound of. Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of this invention, and various prodrug forms are well known in the art.

The term "each independently" means that at least two groups (or ring systems) present in the structure with the same or similar value ranges may have the same or different meanings under certain circumstances. For example, Substituent X and Substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when Substituent X is hydrogen, Substituent Y can be either hydrogen or halogen, Hydroxyl, cyano, alkyl or aryl; the same is true; when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.

The present invention also encompasses compounds of the present invention that contain protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 basis, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

compound

An object provided by the present invention is to provide a compound represented by formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide compounds, isotopic labels, metabolites or prodrugs,

in,

R ¹ is a 5-10-membered heteroaryl group optionally substituted with one or more R ⁴ ;

R ² is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, cyano, -C(=O)NR ^a R ^b and -C(=O) OR ^a ;

R ^a and R ^b are each independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl and 4-8 membered heterocyclyl, the C _1-6 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl optionally substituted with one or more R ⁵ ; or R ^a , R ^b and the nitrogen atom to which they are attached together form a 4-8 membered heterocycle, the ^The 4-8 membered heterocycle is optionally substituted with one or more R5;

R ³ is selected from hydrogen and -NR ^c R ^d ;

R ^c and R ^d at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, -C(=O)R ^a , C _6-10 -membered aryl and 5-10-membered heteroaryl, the C _1-6 alkyl, C _3-8 cycloalkyl, 4-8-membered heterocyclyl, C _6-10 -membered aryl or 5-10-membered Heteroaryl is optionally substituted with one or more R ^;

R ⁴ at each occurrence is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, the C _1-6 alkyl, C _1-6 alkyl _-6 alkoxy or C _3-8 cycloalkyl optionally substituted with one or more halogens;

R ⁵ at each occurrence is independently selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-8 cycloalkyl and 4 -8-membered heterocyclyl, the C _1-6 alkyl or C _3-8 cycloalkyl is optionally substituted with one or more hydroxyl groups;

R ⁶ at each occurrence is independently selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-8 cycloalkyl and 4 -8-membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 4-8 membered heterocyclyl are optionally substituted with one or more groups selected from hydroxy and C _1-6 alkyl;

Y is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylthio base, C _3-8 cycloalkylthio, C _1-6 alkylamino, C _3-8 cycloalkylamino and 4-8 membered heterocyclyl;

Z is selected from ^-CR7- and -N-; and

R ⁷ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl and cyano.

According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-1:

in,

R ¹ , R ² , R ³ and Y are as defined above.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, each occurrence of R ⁴ is independently selected from deuterium, halogen, C _1-6 alkyl, C _1-6 Haloalkyl and C _3-8 cycloalkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, each occurrence of R ⁴ is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkane group and C _3-6 cycloalkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ⁴ at each occurrence is independently selected from fluoro, methyl, trifluoromethyl, difluoromethyl , monofluoromethyl, isopropyl and cyclopropyl.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is a 5-6 membered heteroaryl group optionally formed by one or more R ⁴ is substituted.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is a 5-6 membered heteroaryl, optionally substituted by a or A plurality of groups independently selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl, and _C3-6 cycloalkyl are substituted.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is a 5-6 membered nitrogen-containing heteroaryl, and the 5-6 membered nitrogen-containing heteroaryl is optionally is substituted with one or more R ⁴ .

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is a 5-6 membered nitrogen-containing heteroaryl, and the 5-6 membered nitrogen-containing heteroaryl is optionally is substituted with one or more groups independently selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl, and _C3-6 cycloalkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is selected from pyridyl and pyrazolyl, said pyridyl or pyrazolyl optionally being replaced by one or more R ⁴ is substituted.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is selected from pyridyl and pyrazolyl, said pyridyl or pyrazolyl optionally being replaced by one or more substituted with groups independently selected from the group consisting of halogen, _C1-6 alkyl, _C1-6 haloalkyl, and _C3-6 cycloalkyl.

其中波浪线

表示该基团与分子其余部分的连接点。In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ¹ is selected from

where the wavy line

Indicates the point of attachment of this group to the rest of the molecule.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, each occurrence of R ⁵ is independently selected from halogen, hydroxy, C _1-6 alkyl, hydroxy C _{1- 6} alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-6 cycloalkyl, hydroxy C _3-6 cycloalkyl and 4-8 membered heterocyclic group.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, each occurrence of R ⁵ is independently selected from hydroxy and C _1-6 alkyl at each occurrence.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _{3- 6} -cycloalkyl and 4-6 membered heterocyclyl, the _C1-6 alkyl, _C3-6 cycloalkyl or 4-6 membered heterocyclyl optionally substituted with one or more R5 ^; or ^Ra , ^Rb and the nitrogen atom to which they are attached together form a 4-6 membered heterocycle optionally substituted with one or more ^R5 .

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _{3 -6} cycloalkyl and 4-6 membered heterocyclyl, the C _1-6 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl optionally being independently selected from one or more hydroxy and C _1-6 alkyl groups; or R ^a , R ^b and the nitrogen atom to which they are attached together form a 4-6 membered heterocycle optionally substituted by one or more substituted with groups independently selected from hydroxy and C _1-6 alkyl.

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _{3 -6} cycloalkyl, azetidinyl and piperidinyl, the C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl optionally being replaced by one or more R5 is substituted ^; or ^Ra , ^Rb and the nitrogen atom to which they are attached together form a 4-6 membered heterocycle optionally substituted with one or more ^R5 .

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _{3 -6} cycloalkyl, azetidinyl and piperidinyl, the C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl optionally being replaced by one or more substituted with groups independently selected from hydroxy and C _1-6 alkyl; or R ^a , R ^b and the nitrogen atom to which they are attached together form a 4-6 membered heterocycle optionally Substituted with one or more groups independently selected from hydroxy and C _1-6 alkyl.

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _{3 -6} cycloalkyl, azetidinyl and piperidinyl, the C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl optionally being replaced by one or more substituted with groups independently selected from hydroxy and C _1-6 alkyl; or R ^a , R ^b and the nitrogen atom to which they are attached together form an azetidine optionally substituted by a substituted with more than one group independently selected from hydroxy and C _1-6 alkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ^a and R ^b at each occurrence are each independently selected from hydrogen, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, azetidinyl and piperidinyl, the methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, azetidinyl, and piperidinyl optionally surrounded by one or more groups independently selected from hydroxy, methyl, and ethyl or R ^a , R ^b and the nitrogen atom to which they are attached together form an azetidine group optionally with one or more groups independently selected from hydroxy and methyl replace.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ² is selected from hydrogen, halogen, cyano and -C(=O)NR ^a R ^b .

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ² is selected from hydrogen, cyano and -C(=O)NR ^a R ^b .

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ² is selected from hydrogen, cyano and -C(=O)NR ^a R ^b , wherein R ^a and R ^b Each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl, and piperidinyl, the C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl optionally substituted with one or more groups independently selected from hydroxy and _C1-6 alkyl; or R ^a , R ^b and the nitrogen to which they are attached The atoms together form a 4-6 membered heterocycle optionally substituted with one or more groups independently selected from hydroxy and _C1-6 alkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ² is selected from hydrogen, cyano and -C(=O)NR ^a R ^b , wherein R ^a and R ^b Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, azetidine and piperidinyl, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, azetidinyl and piperidine radicals are optionally substituted with one or more groups independently selected from hydroxy, methyl and ethyl; or R ^a , R ^b and the nitrogen atom to which they are attached together form an azetidine, the azacyclo The butyl group is optionally substituted with one or more groups independently selected from hydroxy and methyl.

其中波浪线

表示该基团与分子其余部分的连接点。In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ² is selected from hydrogen, cyano, -C(=O)NH ₂ , -C(=O)N( H)CH ₃ ,

where the wavy line

Indicates the point of attachment of this group to the rest of the molecule.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ⁶ at each occurrence is each independently selected from C _1-6 alkyl, C _1-6 alkoxy and 4-8-membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy or 4-8-membered heterocyclyl is optionally by one or more selected from hydroxyl and C _1-6 alkyl group substitution.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ⁶ at each occurrence is independently selected from C _1-6 alkyl, C _1-6 alkoxy and 5-6 membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy or 5-6 membered heterocyclyl is optionally replaced by one or more selected from hydroxyl and C _1-6 alkane radical group substitution.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ⁶ at each occurrence is independently selected from C _1-6 alkyl, C _1-6 alkoxy and piperazinyl, the C _1-6 alkyl, C _1-6 alkoxy or piperazinyl is optionally substituted with a group selected from hydroxy and C _1-6 alkyl.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R ^c and R ^d at each occurrence are each independently selected from hydrogen, C _6-10 aryl and 5-10 Membered heteroaryl, the C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted with one or more R ⁶ .

In some embodiments of the invention, in the compounds of formula I and formula I-1 of the invention, R ^c and R ^d at each occurrence are each independently selected from hydrogen, phenyl and 5-6 membered heteroaryl group, the phenyl or 5-6 membered heteroaryl is optionally substituted with one or more R ⁶ .

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, ^Rc and ^Rd are each independently selected at each occurrence from hydrogen, phenyl, and pyridyl, the benzene or pyridyl is optionally substituted with one or more R ⁶ .

In some embodiments of the present invention, in the compounds of Formula I and Formula I-1 of the present invention, ^Rc and ^Rd are each independently selected at each occurrence from hydrogen, phenyl, and pyridyl, the benzene or pyridyl optionally substituted with one or more groups each independently selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and piperazinyl, the C _1-6 alkyl Or piperazinyl is optionally substituted with a group selected from hydroxy and C _1-6 alkyl.

其中波浪线

表示该基团与分子其余部分的连接点。According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, ^R is selected from hydrogen,

where the wavy line

Indicates the point of attachment of this group to the rest of the molecule.

According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, Y is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylamino and C _3-8 cycloalkylamino.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, Y is _C1-6 alkyl.

In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, Y is methyl, ethyl and isopropyl.

According to some embodiments of the present invention, in the compounds of formula I of the present invention, R ⁷ is selected from hydrogen, halogen, C _1-6 haloalkyl and cyano.

In some embodiments of the present invention, in the compounds of formula I of the present invention, ^R7 is hydrogen.

According to some embodiments of the present invention, in the compounds of formula I of the present invention, Z is ^-CR7- .

The present invention encompasses compounds of formulae I and I-1 resulting from any combination of the above preferred groups. In some embodiments of the invention, in the compounds of formula I and I-1 of the invention,

R ¹ is selected from pyridyl and pyrazolyl optionally substituted with one or more groups independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R ² is selected from hydrogen, cyano and -C(=O)NR ^a R ^b , wherein R ^a and R ^b at each occurrence are each independently selected from hydrogen, C _1-6 alkyl, C _3-6 ring Alkyl and 4-6 membered heterocyclyl, the C _1-6 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl optionally being one or more independently selected from hydroxy and C _1-6 alkyl group substitution; alternatively R ^a , R ^b and the nitrogen atom to which they are attached together form a 4-6 membered heterocycle optionally substituted by one or more independently substituted with a group selected from hydroxy and C _1-6 alkyl;

R ³ is selected from hydrogen and -NR ^c R ^d ;

R ^c and R ^d are each independently selected at each occurrence from hydrogen, phenyl and pyridyl optionally substituted with one or more groups each independently selected from: C _1-6 alkyl, C _1-6 alkoxy and piperazinyl, the C _1-6 alkyl or piperazinyl optionally substituted with a group selected from hydroxy and C _1-6 alkyl; and

Y is C _1-6 alkyl.

According to some embodiments of the present invention, the compounds of the present invention are selected from:

Preparation

Another object of the present invention is to provide a method for preparing the compound of the present invention, comprising:

Step 1-1: Compound SM1 and N,N-dimethylformamide dimethyl acetal undergo condensation reaction to obtain compound IM1

Step 1-2: Compound IM1 and compound SM2 undergo cyclization reaction to obtain compound IM2

Step 1-3: Compound IM2 undergoes substitution reaction to obtain compound IM3

Step 1-4: Substitution reaction of compound IM3 and SM3 to obtain compound of formula I

where LG is a leaving group such as phenoxy and halogen; and,

Y, Z, R ¹ , R ² and R ³ are as defined above.

Step 1-1: Compound SM1 and N,N-dimethylformamide dimethyl acetal undergo condensation reaction to obtain compound IM1

In some embodiments of the invention, the reaction is carried out at a suitable temperature, said temperature being 0-200°C, preferably 0-100°C.

Step 1-2: Compound IM1 and compound SM2 undergo cyclization reaction to obtain compound IM2:

In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent, which may be selected from alcohols (eg, MeOH, EtOH, n-BuOH, etc.), THF, AcOH, Diox, and any combination thereof, Methanol or ethanol is preferred.

In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, the organic base may be selected from DIPEA, TEA, t-BuOK, sodium methoxide, sodium ethoxide and Py, the inorganic base can be selected from K ₃ PO ₄ , NaH, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ and NaOH, preferably sodium methoxide or sodium ethoxide.

In some embodiments of the present invention, the reaction is carried out at a suitable temperature, said temperature being 0-200°C, preferably 100-200°C.

Step 1-3: Compound IM2 undergoes substitution reaction to obtain compound IM3

In some embodiments of the invention, the reaction is carried out in a suitable organic solvent, which may be selected from halogenated hydrocarbons (eg, DCM, TCM, 1,2-DCE, etc.), nitriles (eg, AN, etc.) ), NMP, DMF, DMA, THF, Diox, DMSO, aromatics (eg TL, XY) and any combination thereof, preferably DMF, THF or DCM.

When LG is halogen:

In some embodiments of the invention, the reaction is carried out in the presence of a suitable halogenating reagent, which may be selected from SOCl ₂ , POBr ₃ and POCl ₃ , preferably SOCl ₂ .

In some embodiments of the present invention, the reaction is carried out at a suitable temperature, said temperature being 0-200°C, preferably 50-150°C.

When LG is phenoxy:

In some embodiments of the present invention, this reaction may occur by performing a halogenation reaction followed by a further substitution reaction. The halogenation reaction is carried out in the presence of a suitable halogenating reagent, which can be selected from SOCl ₂ , POBr ₃ and POCl ₃ , preferably SOCl ₂ ; the further substitution reaction is carried out in the presence of a suitable substitution reagent carried out, the substitution reagent may be selected from phenol and sodium phenate.

In some embodiments of the present invention, the further substitution reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, the organic base may be selected from DIPEA, TEA, t-BuOK and Py, _The inorganic base may be selected from _K3PO4 , _NaH , _K2CO3 , _Na2CO3 , _Cs2CO3 and _NaOH , preferably _NaH .

In some embodiments of the present invention, the further substitution reaction is carried out at a suitable temperature, the temperature being 0-200°C, preferably 0-80°C.

Step 1-4: Substitution reaction of compound IM3 and SM3 to obtain compound of formula I

In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent, which may be selected from halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitrile (eg acetonitrile, etc.), N-methylpyrrolidone, DMF, DMA, tetrahydrofuran, dioxane, DMSO and any combination thereof, preferably DMSO or DMF.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, the organic base may be selected from DIPEA, triethylamine, potassium tert-butoxide, and pyridine, The inorganic base may be selected from potassium phosphate, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide and sodium hydroxide, preferably potassium carbonate, lithium hydroxide or sodium hydride.

In some embodiments of the present invention, the reaction is carried out at a suitable temperature, the reaction temperature being 0-200°C, preferably 50-150°C.

Pharmaceutical compositions and kits

Another object of the present invention is to provide a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, A solvate, nitrogen oxide, isotopic label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide a kind of medicine kit, it comprises:

a) at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, an isotopic label, metabolite or prodrug, or a pharmaceutical composition of the invention as the first pharmaceutical composition;

b) optionally present at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising the other therapeutic agent as a second pharmaceutical composition; and

c) Optional packaging and/or instructions.

The term "pharmaceutically acceptable carrier" refers to an excipient with which a therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with human and/or other animal tissue without undue toxicity, irritation, Allergic reactions or other problems or complications with a reasonable benefit/risk ratio.

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose they can be administered by suitable routes, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as an inhalant.

For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms. Dosage forms that can be used in the present invention include, but are not limited to: tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions , ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

When administered orally, the pharmaceutical compositions of the present invention can be formulated into any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions, and the like. Among them, the carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Carriers used in capsules typically include lactose and dried cornstarch. Aqueous suspensions are usually prepared by mixing the API with suitable emulsifying and suspending agents. Optionally, some sweetening agents, flavoring agents, coloring agents, etc. may also be added to the above oral formulations.

The pharmaceutical compositions of the present invention can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions, or sterile injectable aqueous or oily solutions. Among them, the carriers that can be used include (but are not limited to): water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can also be employed as a solvent or suspending medium, such as mono- or diglycerides.

The pharmaceutical compositions of the present invention may contain from 0.01 mg to 1000 mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof , nitrogen oxides, isotopic labels, metabolites or prodrugs.

In some embodiments, the present invention provides a method of preparing a pharmaceutical composition or pharmaceutical formulation of the present invention, the method comprising combining at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof , tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite or prodrug in combination with one or more pharmaceutically acceptable carriers.

The kits of the present invention may contain from 0.01 mg to 1000 mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, Nitrogen oxides, isotopic labels, metabolites or prodrugs.

In some embodiments, the present invention provides a method of making a kit of the present invention, the method comprising combining at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conforms, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs or pharmaceutical compositions of the invention with optionally at least one other therapeutic agent or a drug comprising other therapeutic agent Composition, Packaging and/or Instructions Combination.

Treatment methods and uses

The compounds of the present invention can show a strong inhibitory effect on TGFβR1, the IC ₅₀ value can reach below 100nM, some even below 10nM, and at the same time show a weak inhibitory effect on TGFβR2, and can be used as TGFβR1 inhibitors (especially TGFβR1 selective inhibitor).

Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels , metabolites or prodrugs or pharmaceutical compositions of the invention for use as TGFβR1 inhibitors for the prevention and/or treatment of diseases or disorders (especially cancers, eg liver cancer) mediated at least in part by TGFβR1.

Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels Use of a , metabolite or prodrug or a pharmaceutical composition of the invention as an inhibitor of TGFβR1.

Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels , metabolite or prodrug or use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder mediated at least in part by TGFβR1, especially cancer, eg liver cancer.

Another object of the present invention is to provide a method for the prevention and/or treatment of a disease or disorder mediated at least in part by TGFβR1, in particular cancer, such as liver cancer, comprising administering to an individual in need thereof prophylactic and A therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite drug or prodrug or pharmaceutical composition of the present invention.

The term "disease or disorder mediated at least in part by TGF[beta]Rl" refers to diseases in which at least a portion of the pathogenesis of TGF[beta]Rl is involved, including but not limited to cancer or fibrotic diseases.

The term "effective amount" refers to an amount sufficient to induce a biological or medical response in a cell, tissue, organ or organism (eg, an individual) and which is sufficient to achieve the desired prophylactic and/or therapeutic effect.

Dosage regimens can be adjusted to provide the optimal desired response. For example, it may be administered in a single dose, may be administered in divided doses over time, or may be administered in proportionately reduced or increased doses as appropriate. It will be appreciated that, for any particular individual, the specific dosing regimen should be adjusted as needed and according to the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the present invention administered will depend on the individual circumstances, the severity of the disease or disorder, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, an effective amount is about 0.001-10000 mg/kg subject body weight/day. Where appropriate, an effective amount is about 0.01-1000 mg/kg subject body weight/day. About 0.01-1000 mg/kg of the subject's body weight can be administered daily, every two days, or every three days, usually about 0.1-500 mg/kg of the subject's body weight. Exemplary dosing regimens are one or more times per day, or one or more times per week, or one or more times per month. In the case of multiple administrations, the interval between single doses can generally be daily, weekly, monthly or yearly. Alternatively, it may be administered in a sustained release formulation, in which case less frequent dosing is required. The dose and frequency of administration can vary depending on the half-life of the drug in the subject, as well as whether it is for prophylactic or therapeutic use. In prophylactic applications, relatively low doses are administered chronically at relatively infrequent intervals; in therapeutic applications, it is sometimes necessary to administer relatively high doses at shorter intervals until progression of the disease is delayed or stopped, preferably until the individual Shows partial or complete improvement in disease symptoms, after which prophylactic applications can be employed.

The term "treating" refers to alleviating or eliminating the targeted disease or condition. If the subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label A substance, metabolite or prodrug or a pharmaceutical composition of the present invention, the subject exhibits observable and/or detectable alleviation and/or improvement in at least one indicator and symptom, indicating that the subject have been successfully "treated". It is understood that treatment includes not only complete treatment, but also incomplete treatment, but the achievement of some biologically or medically relevant result. In particular, "treatment" means a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label thereof , metabolites or prodrugs, or pharmaceutical compositions of the present invention may achieve at least one of the following effects, for example: (1) prevention of disease in animals that may be predisposed to disease but have not experienced or displayed disease pathology or symptomatology Occurs; (2) inhibits disease (i.e. prevents further progression of the pathology and/or symptomology) in an animal that is experiencing or exhibits disease pathology or symptomology; (3) occurs in animals experiencing or showing disease pathology or symptomology improved disease (ie, reversal of pathology and/or symptomatology) in animals.

The term "prevention" refers to the pre-administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or disorder. One of ordinary skill in the medical arts recognizes that the term "prevention" is not an absolute term. In the medical arts, prophylactic administration of a drug to substantially reduce the likelihood or severity of a disorder or symptoms of a disorder is understood in the intended sense of this disclosure. As used herein, the term "preventing" with respect to a condition or disorder refers to avoiding the cause, effect, symptom, or progression of the disease or disorder until the disease or disorder is fully manifested.

The term "administration" or "administration" refers to the application of a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (eg, a pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs , biological fluids, etc., in order to make a pharmaceutical active ingredient or pharmaceutical composition come into contact with an individual or its cells, tissues, organs, biological fluids, etc. Common modes of administration include, but are not limited to, oral, subcutaneous, intramuscular, subperitoneal, ocular, nasal, sublingual, rectal, vaginal, and the like.

The term "needs" refers to a physician or other caregiver's judgment that an individual needs or will benefit from a prophylactic and/or therapeutic procedure based on the physician's or other caregiver's various areas of expertise. factor.

The term "individual" (or subject) includes humans or non-human animals. Individuals of the present invention include individuals (patients) with a disease and/or disorder and normal individuals. Non-human animals in the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc.; and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, etc.) , cats, cows, pigs, etc.).

Example

In order to make the objectives and technical solutions of the present invention clearer, the embodiments of the present invention are described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

The reagents or instruments used in the examples are conventional products that can be obtained commercially. If the specific conditions are not specified, it is carried out in accordance with the conventional conditions or the conditions suggested by the manufacturer. The term "room temperature" used in the present invention refers to 20°C ± 5°C. When used to modify a value or range of values, the term "about" as used herein is meant to include the value or range of values and the range of errors acceptable to those skilled in the art for the value or range of values, such as the error The range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

In the conventional synthesis methods, examples and intermediate synthesis examples, the meanings of each abbreviation are shown in the following table.

The structures of the compounds described in the following examples were determined by nuclear magnetic resonance ( ¹ H-NMR) and/or mass spectrometry (MS).

The measuring instrument of nuclear magnetic resonance ( ¹ H-NMR) was a Bruker 400 MHz nuclear magnetic resonance apparatus, and the measuring solvents were deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), hexadeuterated dimethyl sulfoxide (DMSO-d) ₆ ), the internal standard substance is tetramethylsilane (TMS).

The meanings of the abbreviations in the nuclear magnetic resonance (NMR) data in the following examples are as follows:

s: singlet (singlet), d: doublet (doublet), t: triplet (triplet), q: quartet (quartet), dd: double doublet (double doublet), qd: quadruplet quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet , br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

All chemical shift (δ) values are given in parts per million (ppm).

An Agilent 6120B mass spectrometer was used as the measuring instrument for mass spectrometry (MS), and the ion source was an electrospray ion source (ESI).

Examples of the present invention were purified by preparative high performance liquid chromatography (Prep-HPLC) using the method shown below.

Method A:

Chromatographic column: YMC (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% trifluoroacetic acid)

time [min] Mobile phase A[%] Mobile phase B [%] Flow rate [mL/min] 0.00 7 93 28 2.00 7 93 28 18.00 90 10 28

Method B:

Column: Sunfire C ₁₈ OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid)

Method C:

Chromatographic column: Sunfire C18 OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% ammonium bicarbonate)

time [min] Mobile phase A[%] Mobile phase B [%] Flow rate [mL/min] 0.00 10 90 28 16.00 70 30 28

Method D:

Column: Sunfire C ₁₈ OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid)

time [min] Mobile phase A[%] Mobile phase B [%] Flow rate [mL/min] 0.00 10 90 28 2.00 10 90 28 16.00 90 10 28

Method E:

Column: Waters XBridge Prep C18 OBD 5μm 19x 150mm

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% ammonium bicarbonate)

time [min] Mobile phase A[%] Mobile phase B [%] Flow rate [mL/min] 0.00 10.0 90.0 28 16.00 90.0 10.0 28

Method F:

Column: Sunfire C ₁₈ OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid)

time [min] Mobile phase A[%] Mobile phase B [%] Flow rate [mL/min] 0.00 10 90 28 2.00 10 90 28 16.00 90 10 28

Method G:

Column: Sunfire C ₁₈ OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% sodium bicarbonate)

Method H:

Chromatographic column: C ₁₈ OBD (5μm*19mm*150mm)

Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% sodium bicarbonate)

Preparation of compounds

Example 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinonitrile (Compound 1)

Step 1: Synthesis of 5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-ol (Compound 1-2)

At 25°C, ethyl 2-formyl 3-methylbutanoate (compound 1-1, 6 g, 37.93 mmol) and 6-methylpyridine-2-carboxamide (1.85 g, 13.69 mmol) were dissolved in methanol ( 5 mL), sodium methoxide methanol solution (5 mol/L, 5 mL) was added, and the reaction was carried out at 120° C. for 16 hours. The reaction solution was extracted with dichloromethane (10 mL*3), washed with saturated brine (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (eluting solvent: petroleum ether/ethyl acetate = 2/1 (v/v))) to obtain the title compound (810 mg).

ESI-MS (m/z): 230.1 [M+H] ⁺ .

Step 2: Synthesis of 4-chloro-5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidine (Compound 1-3)

5-Isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-ol (compound 1-2, 800 mg, 3.49 mmol) was dissolved in thionyl chloride (10 mL) at 25°C , drop two drops of N,N-dimethylformamide to catalyze the reaction, and react at 90°C for 0.5 hours. The reaction solution was concentrated, neutralized with aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1 (v/v)) to obtain the title compound (850 mg).

ESI-MS (m/z): 248.1 [M+H] ⁺ .

Step 3: Synthesis of 5-isopropyl-2-(6-methylpyridin-2-yl)-4-phenoxypyrimidine (Compound 1-4)

4-Chloro-5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidine (compound 1-4, 850 mg, 3.43 mmol) and sodium phenolate (796.69 mg, 6.86 mmol) were combined at 25°C It was dissolved in THF (5 mL) and reacted at 120°C for 2 hours. The reaction solution was concentrated, extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1 (v/v)) to obtain the title compound (880 mg).

ESI-MS (m/z): 306.1 [M+H] ⁺ .

Step 4: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinonitrile (Compound 1)

At 25 °C, 5-isopropyl-2-(6-methylpyridin-2-yl)-4-phenoxypyrimidine (compound 1-4, 30 mg, 98.24 umol) and 1H-pyrazolo[4 ,3-c]pyridine (23.41 mg, 196.48 umol) was dissolved in DMSO (3 mL), LiOH (8.06 mg, 196.48 umol) was added, and the reaction was carried out at 80° C. for 2 hours. The reaction solution was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was preparatively purified by high performance liquid chromatography (Method A) to give the title compound (22 mg).

ESI-MS (m/z): 331.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.01(s,1H), 8.69(s,1H), 8.34(s,1H), 8.08-8.04(m,2H), 7.84(d, J=6.1 Hz, 1H), 7.66–7.62 (m, 1H), 3.30 (p, J=6.8Hz, 1H), 2.68 (s, 3H), 1.35 (d, J=6.8Hz, 6H).

Example 2: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (compound 2)

4-((5-Isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinonitrile (20 mg, 60.54 umol) was dissolved in tetrahydrofuran (3 mL), hydrogen was added Sodium oxide (4.84 mg, 121.07 umol) was slowly added with hydrogen peroxide (2 mL), and the reaction was carried out at 25° C. for 1 hour. The reaction solution was extracted with ethyl acetate (10 mL*3), washed with saturated aqueous sodium sulfite solution (10 mL), and the organic phases were combined. It was dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure to obtain the crude product, which was preparatively purified by high performance liquid chromatography (Method B) to obtain the title compound (4 mg).

Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),9.44(d,J=5.9Hz,1H),8.97(s,1H),8.66-8.52(m,3H),8.17( d, J＝7.7Hz, 1H), 8.00(s, 1H), 7.87(t, J＝7.7Hz, 1H), 7.40(d, J＝7.6Hz, 1H), 3.13(p, J＝6.8Hz, 1H), 2.62(s, 3H), 1.36(d, J=6.8Hz, 6H).

ESI-MS (m/z): 349.1 [M+H] ⁺ .

Example three: N-(1,3-dihydroxypropan-2-yl)-4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino ) Synthesis of Nicotinamide (Compound 5)

Step 1: Synthesis of methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (compound 5-1) (5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinonitrile (compound 1, 1 g, 1.82 mmol) was dissolved in MeOH (10 mL) and H was added slowly ₂ SO ₄ (1.82 mmol, 5 mL), the addition was completed, the temperature was raised to 100° C., and the reaction was carried out for 15 hours. The reaction solution was cooled to room temperature, adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, then extracted with EA (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. , the filtrate was evaporated to dryness under reduced pressure to obtain the title compound (589 mg).

ESI-MS (m/z): 364.2 [M+H] ⁺ .

Step 2: N-(1,3-Dihydroxypropan-2-yl)-4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino) Synthesis of Nicotinamide (Compound 5)

Methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (compound 5-1, 22 mg, 0.06 mmol) and 2- Aminopropane-1,3-diol (55 mg, 0.6 mmol) was dissolved in DMSO (0.6 mL) and reacted at 100°C for 3 hours. The reaction solution was cooled to room temperature, and directly purified by high performance liquid chromatography (Method C). The title compound (16 mg) was obtained after the preparation solution was lyophilized. Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ11.8(s, 1H), 9.36(d, J=6.0Hz, 1H), 8.96(s, 1H), 8.70-8.57(m, 3H), 8.16( d, J＝8.0Hz, 1H), 7.87(t, J＝8.0Hz, 1H), 7.39(d, J＝7.6Hz, 1H), 4.74(t, J＝6.0Hz, 2H), 4.15–4.00( m, 1H), 3.67–3.45 (m, 4H), 3.17–3.04 (m, 1H), 2.62 (s, 3H), 1.37 (d, J=6.8Hz, 6H).

ESI-MS (m/z): 423.2 [M+H] ⁺ .

Example 4: (S)-N-(2-hydroxypropyl)-4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinum Synthesis of Amide (Compound 6)

At 25°C, methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (compound 5-1, 20mg, 55.03umol ) and (S)-1-aminopropan-2-ol (41.34 mg, 550.34 μmol) were dissolved in dimethyl sulfoxide (1 mL), and the temperature was raised to 100° C. and reacted for 3 hours. The reaction solution was directly purified by high performance liquid chromatography (Method D) to give the title compound (8.5 mg).

Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 9.38 (d, J=5.9Hz, 1H), 9.00 (t, J=5.8Hz, 1H), 8.93 (s, 1H) , 8.63–8.56 (m, 2H), 8.20–8.13 (m, 1H), 7.87 (t, J=7.7Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 4.84 (d, J=4.8 Hz, 1H), 3.85(dd, J＝6.4, 5.0Hz, 1H), 3.27(t, J＝5.9Hz, 2H), 3.17–3.05(m, 1H), 2.62(s, 3H), 1.36(dd , J=6.8, 1.5Hz, 6H), 1.10(d, J=6.2Hz, 3H).

ESI-MS (m/z): 407.1 [M+H] ⁺ .

Embodiment 5: (R)-N-(2-hydroxypropyl)-4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide Synthesis of Amide (Compound 7)

Methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (compound 5-1, 20 mg, 0.055 mmol) and (R )-1-aminopropan-2-ol (41 mg, 0.55 mmol) was dissolved in DMSO (0.5 mL), the temperature was raised to 100 °C, and the reaction was carried out for 2 h. After cooling the reaction solution to room temperature, it was separated and purified by preparative high performance liquid chromatography (Method E), and the preparative solution was lyophilized to obtain the title compound (12 mg).

Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.85(s, 1H), 9.37(d, J=5.9Hz, 1H), 9.00(t, J=5.7Hz, 1H), 8.93(s, 1H) ,8.63-8.57(m,2H),8.16(d,J=7.7Hz,1H),7.86(t,J=7.7Hz,1H),7.39(d,J=7.6Hz,1H),4.84(d, J=4.8Hz, 1H), 3.85(dt, J=11.1, 6.1Hz, 1H), 3.26(t, J=6.0Hz, 2H), 3.14-3.07(m, 1H), 2.62(s, 3H), 1.42-1.30(m, 6H), 1.10(d, J=6.2Hz, 3H).

ESI-MS (m/z): 407.2 [M+H]+.

Embodiment 6: (3-hydroxyazetidin-1-yl)(4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)pyridine Synthesis of -3-yl)methanone (Compound 14)

Step 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (Compound 14-1)

At 25°C, sulfuric acid (1 mL) was dissolved in water (1 mL), followed by 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino) Nicotinonitrile (compound 1, 100 mg, 302.68 umol) was added to the reaction solution, and the reaction was carried out at 98° C. for 16 h. The reaction solution was cooled, adjusted to pH 6-7 with 1N NaOH aqueous solution under ice bath, extracted with dichloromethane (10ml), the aqueous phase was adjusted to pH 3-4 with hydrochloric acid, extracted with n-butanol, and the The organic phases were combined, concentrated, and purified by preparative high performance liquid chromatography (Method F) to give the title compound (60 mg).

ESI-MS (m/z): 350.1 [M+H] ⁺ .

Step 2: (3-Hydroxyazetidin-1-yl)(4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)pyridine- Synthesis of 3-yl)methanone (Compound 14)

At 25°C, 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (compound 14-1, 20 mg, 57.24 μmol) and Azetidine-3-ol (4.60mg, 62.97μmol) was dissolved in DMF (2mL), then TBTU (17.58mg, 68.69μmol) and DIPEA (22.19mg, 171.73μmol) were added in sequence, and the reaction was carried out at 25°C After 1 hour, the reaction solution was directly purified by high performance liquid chromatography (Method G) to give the title compound (1.51 mg).

Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ11.23(s, 1H), 9.28(d, J=5.9Hz, 1H), 8.64(s, 1H), 8.61(s, 1H), 8.58(d, J=5.9Hz, 1H), 8.16 (d, J=7.7Hz, 1H), 7.87 (t, J=7.7Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 5.82 (d, J= 6.1Hz,1H),4.60(d,J=8.6Hz,1H),4.50(q,J=5.9,5.3Hz,1H),4.36(d,J=10.0Hz,1H),4.23(s,1H) ,3.87(d,J＝10.8Hz,1H),3.07(p,J＝6.8Hz,1H),2.61(s,3H),1.37(d,J＝6.8Hz,6H).

ESI-MS (m/z): 405.1 [M+H] ⁺ .

Embodiment 7: N-(3-hydroxycyclobutyl)-4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (compound 15) Synthesis

At 25°C, 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (compound 14-1, 20 mg, 57.24 μmol) and 3-Aminocyclobutan-1-ol (5.49 mg, 62.97 μmol) was dissolved in DMF (2 mL), followed by adding TBTU (14.65 mg, 57.24 μmol) and DIPEA (22.19 mg, 171.73 μmol), at 25°C After reacting for 1 hour, the reaction solution was directly purified by high performance liquid chromatography (Method H) to obtain the title compound (1.35 mg).

Its structure is characterized as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.90-11.80 (m, 1H), 9.37 (d, J=5.9Hz, 1H), 9.15 (t, J=7.6Hz, 1H), 8.93 (s, 1H), 8.59(d, J＝8.4Hz, 2H), 8.16(d, J＝7.8Hz, 1H), 7.87(t, J＝7.7Hz, 1H), 7.40(d, J＝7.6Hz, 1H) , 5.20–5.10 (m, 1H), 4.53–3.68 (m, 2H), 3.10 (p, J=6.7Hz, 1H), 2.65–2.55 (m, 5H), 2.32–2.16 (m, 1H), 1.99 –1.95(m,2H),1.40–1.30(m,6H).

ESI-MS (m/z): 419.1 [M+H] ⁺ .

Pharmacological activity test

Test Example 1: In vitro enzymatic activity inhibition test (TGFβR1).

Experimental method: The inhibitory effect of the compounds of the present invention on the enzymatic activity of TGFβR1 was determined according to the instructions of ADP-Glo ^™ Kinase Detection Kit (Promega). The steps are as follows:

After pre-incubating TGFβR1 enzyme with different concentrations of test compounds (1000 nM, 100 nM, 10 nM) at 30°C for 30 min, TGFβR1 peptide and adenosine triphosphate (ATP) were added to initiate the reaction. ADP-Glo ^TM reagent was added after incubation at 30°C for 3 h, and kinase detection reagent was added after incubation at room temperature for 90 min. Chemiluminescence signal value was detected after 30min incubation at room temperature. Taking the solvent group (DMSO) as the negative control and the buffer group (without TGFβR1 enzyme) as the blank control, the percentage inhibition rate of different concentrations of compounds was calculated according to the following formula:

Percent inhibition rate=(1-(chemiluminescence signal value of compounds with different concentrations-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))×100%;

When the percent inhibition was between 30-80%, the median inhibitory concentration ( _IC50 ) or range of the compound was calculated according to the following formula:

_IC50 =XX(1-percent inhibition (%))/percent inhibition (%), where: X is the test concentration of the compound.

The experimental results are shown in Table 1 below:

Table 1. Inhibitory activity of compounds of the invention on TGFβR1

Example number IC₅₀(nM) against TGFβR1 Example 1 16.42±3.3 Embodiment 2 1.12±0.31 Embodiment 3 12.2±2.25 Embodiment 4 2.47±0.75 Embodiment 5 3.05±0.54 Embodiment 7 3.92±0.92

It can be seen from Table 1 that the compounds of the present invention have obvious inhibitory effect on TGFβR1.

Test Example 2: In vitro cell activity inhibition test.

Experimental method: The inhibitory effect of the compounds of the present invention on the TGFβ/Smad signaling pathway in HEK293-SBE cells was determined according to the instructions of Bright-Glo ^TM luciferase detection kit (Promega). The steps are as follows:

HEK293-SBE cells (Bps bioscience) were added to a 96-well plate (MEM medium containing 10% FBS), 30,000/well, and cultured overnight at 37° C., 5% CO ₂ . The medium was changed to 0.5% FBS medium, and the test compound diluted in 0.5% FBS medium was added. The highest final concentration of the test compound was 10 μM, and the compound was diluted 4 times, with a total of 8 concentration gradients. After 4-5 hours of incubation, 10 [mu]l of TGF[beta] was added. The final concentration of TGFβ was 0.5 ng/ml. 10 μl of medium was added in place of TGFβ as a negative control. In the blank control, no test compound was added, and TGFβ was added. Bright Glo reagent was added to each well, and the chemiluminescence signal value was read on a microplate reader.

The percent inhibition of different concentrations of compounds was calculated according to the following formula:

Percent inhibition rate=(1-(chemiluminescence signal value of test compound-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))×100%;

The percent inhibition rates of different concentrations of compounds were plotted against compound concentrations, the curves were fitted according to a four-parameter model, and the _IC50 values were calculated by the following formula:

y=Min+(Max-Min)/(1+(x/IC ₅₀ )^(-Hillslope)), where: y is the percentage inhibition rate; Max and Min are the maximum and minimum values of the fitted curve, respectively; x is The logarithmic concentration of the compound; and Hillslope is the slope of the curve.

The experimental results are shown in Table 2 below:

Table 2. Inhibitory effect of compounds of the present invention on TGFβ/Smad signaling pathway in HEK293-SBE cells

Example number IC₅₀(nM) Example 1 28.17±0.89 Embodiment 2 3.65±0.13 Embodiment 3 71.02±4.05 Embodiment 4 16.85±3.29 Embodiment 5 16.26±2.72 Embodiment 6 29.63±1.19 Embodiment 7 36.36±1.79

It can be seen from Table 2 that the compounds of the present invention have a significant inhibitory effect on the TGFβ/Smad signaling pathway in HEK293-SBE cells.

Test Example 3: CYP enzyme (cytochrome P450) inhibition test.

1. Test system:

P450-Glo ^™ CYP1A2 Screening System (Promega);

P450-Glo ^™ CYP2D6 Screening System (Promega);

P450-Glo ^™ CYP3A4 Screening System (Promega).

2. Test equipment:

BMG PHERAstar FS Luminescent.

3. Test method:

Test according to the kit instructions, the steps are as follows:

3.1. Inhibition of CYP1A2:

Test group: different concentrations of test compounds were added to the microplate, Luciferin-ME (100 μM), K ₃ PO ₄ (100 mM) and CYP1A2 (0.01 pmol/μL) were added to each well, and pre-incubated at room temperature 10min, then add NADPH regeneration system, react at room temperature for 30min, finally add an equal volume of detection buffer, incubate at room temperature for 20min, and then perform chemiluminescence detection.

Negative control group: the experimental method is the same as that of the test group, but the compound to be tested is not added.

Blank control group: the experimental method is the same as that of the test group, but no test compound is added, and CYP1A2 Membrance (0.01pmol/μL) is used instead of CYP1A2.

3.2. Inhibition of CYP2D6:

Test group: different concentrations of test compounds were added to the microplate, Luciferin-MEEGE (3 μM), K ₃ PO ₄ (100 mM) and CYP2D6 (5 nM) were added to each well, pre-incubated at room temperature for 10 min, and then The NADPH regeneration system was added, and the reaction was carried out at 37 °C for 30 min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min, followed by chemiluminescence detection.

Negative control group: the experimental method is the same as that of the test group, but the compound to be tested is not added.

Blank control group: the experimental method is the same as that of the test group, but no test compound is added, and CYP2D6 Membrance (5nM) is used instead of CYP2D6.

3.3. Inhibition of CYP3A4:

Test group: different concentrations of test compounds were added to the microplate, Luciferin-IPA (3 μM), K ₃ PO ₄ (100 mM) and CYP3A4 (2 nM) were added to each well, pre-incubated at room temperature for 10 min, and then Add the NADPH regeneration system, react at room temperature for 30 minutes, and finally add an equal volume of detection buffer, incubate at room temperature for 20 minutes, and then perform chemiluminescence detection.

Negative control group: the experimental method is the same as that of the test group, but the compound to be tested is not added.

Blank control group: the experimental method is the same as that of the test group, but no test compound is added, and CYP3A4 Membrance (2nM) is used instead of CYP3A4.

4. Data processing:

Percent inhibition rate (%)=(1-(chemiluminescence signal value of test compound-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))×100% ;

According to the inhibition rate of CYP enzymes by different concentrations of compounds, the median inhibitory concentration (IC ₅₀ ) or range of the compounds was estimated:

_IC50 =XX(1-percent inhibition (%))/percent inhibition (%), where: X is the test concentration of the compound.

5. Experimental results:

Inhibition of the three CYPs by the compounds of the present invention was determined as described above and the results are shown in Table 3 below.

Table 3. Results of CYPs inhibition test

Claims (18)

1. A compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite or prodrug thereof,

wherein,

R¹is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with one or more R⁴Substitution;

R²selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl, cyano, -C (═ O) NR^aR^band-C (═ O) OR^a；

R^aAnd R^bEach occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl and 4-8 membered heterocyclyl, said C_1-6Alkyl radical, C_3-8Cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with one or more R⁵Substitution; or R^a、R^bAnd together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring, said 4-8 membered heterocyclic ring optionally substituted with one or more R⁵Substitution;

R³selected from hydrogen and-NR^cR^d；

R^cAnd R^dEach occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-8 membered heterocyclyl, -C (═ O) R^a、C_6-10Aryl and 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_3-8Cycloalkyl, 4-8 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with one or more R⁶Substitution;

R⁴each occurrence independently selected from deuterium, halogen, C_1-6Alkyl radical, C_1-6Alkoxy and C_3-8Cycloalkyl radical, said C_1-6Alkyl radical, C_1-6Alkoxy or C_3-8Cycloalkyl is optionally substituted with one or more halo;

R⁵each occurrence is independently selected from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 4-8 membered heterocyclyl, said C_1-6Alkyl or C_3-8Cycloalkyl is optionally substituted with one or more hydroxy groups;

R⁶each occurrence is independently selected from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 4-8 membered heterocyclyl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more groups selected from hydroxy and C_1-6Radical substitution of alkyl;

y is selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, C_1-6Alkylthio radical, C_3-8Cycloalkylthio radical, C_1-6Alkylamino radical, C_3-8Cycloalkylamino and 4-8 membered heterocyclyl;

z is selected from-CR⁷-and-N-; and is

R⁷Selected from hydrogen, halogen, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl and cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof,

R⁴each occurrence independently selected from deuterium, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-8A cycloalkyl group;

preferably, R⁴Independently at each occurrence, is selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-6A cycloalkyl group;

more preferably, R⁴Each occurrence is independently selected from the group consisting of fluoro, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl, and cyclopropyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R¹is a 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with one or more R⁴Substitution;

preferably, R¹Is a 5-6 membered nitrogen containing heteroaryl group, said 5-6 membered nitrogen containing heteroaryl group optionally substituted with one or more R⁴Substitution;

more preferably, R¹Selected from pyridyl and pyrazolyl optionally substituted by one or more R⁴Substitution;

more preferably, R¹Selected from pyridyl and pyrazolyl, said pyridyl or pyrazolyl being optionally substituted by one or more groups independently selected from: halogen, C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-6A cycloalkyl group;

more preferably, R¹Is selected from

Wherein the wavy line

Indicates the point of attachment of the group to the rest of the molecule.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R⁵each occurrence is independently selected from halogen, hydroxy, C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_3-6Cycloalkyl, hydroxy C_3-6Cycloalkyl and 4-8 membered heterocyclyl;

preferably, R⁵Each independently at each occurrence is selected from hydroxy and C_1-6An alkyl group.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R^aand R^bEach occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl and 4-6 membered heterocyclylSaid C is_1-6Alkyl radical, C_3-6Cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more R⁵Substitution; or R^a、R^bAnd together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring optionally substituted with one or more R⁵Substitution;

more preferably, R^aAnd R^bEach occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, azetidinyl and piperidinyl, said C_1-6Alkyl radical, C_3-6Cycloalkyl, azetidinyl or piperidinyl optionally substituted by one or more R⁵Substitution; or R^a、R^bAnd together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring optionally substituted with one or more R⁵Substitution;

more preferably, R^aAnd R^bEach occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, azetidinyl and piperidinyl, said C_1-6Alkyl radical, C_3-6Cycloalkyl, azetidinyl or piperidinyl optionally substituted with one or more substituents independently selected from hydroxy and C_1-6Radical substitution of alkyl; or R^a、R^bAnd together with the nitrogen atom to which they are attached form an azetidinyl group optionally substituted with one or more substituents independently selected from hydroxy and C_1-6Alkyl groups.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R²selected from hydrogen, halogen, cyano and-C (═ O) NR^aR^b；

Preferably, R²Selected from hydrogen, cyano and-C (═ O) NR^aR^b；

More preferably, R²Selected from hydrogen, cyano, -C (═ O) NH₂、-C(＝O)N(H)CH₃、

Wherein the wavy line

Indicates the point of attachment of the group to the rest of the molecule.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R⁶each occurrence of which is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy and 4-8 membered heterocyclic group, said C_1-6Alkyl radical, C_1-6Alkoxy or 4-8 membered heterocyclyl is optionally substituted by one or more groups selected from hydroxy and C_1-6Radical substitution of alkyl;

preferably, R⁶Each occurrence of which is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy and 5-6 membered heterocyclic group, said C_1-6Alkyl radical, C_1-6Alkoxy or 5-6 membered heterocyclyl is optionally substituted by one or more groups selected from hydroxy and C_1-6Radical substitution of alkyl;

more preferably, R⁶Each occurrence of which is independently selected from C_1-6Alkyl radical, C_1-6Alkoxy and piperazinyl, said C_1-6Alkyl radical, C_1-6Alkoxy or piperazinyl optionally substituted by a group selected from hydroxy and C_1-6Alkyl groups.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R^cand R^dEach occurrence independently selected from hydrogen, C_6-10Aryl and 5-to 10-membered heteroaryl, said C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with one or more R⁶Substitution;

preferably, R^cAnd R^dEach independently at each occurrence is selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally substituted with one or more R⁶Substitution;

more preferably, R^cAnd R^dEach occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted with one or more R⁶Substitution;

more preferably, R^cAnd R^dEach independently at each occurrence is selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted with one or more groups each independently selected from: c_1-6Alkyl radical, C_1-6Alkoxy and piperazinyl, said C_1-6Alkyl or piperazinyl optionally substituted by a group selected from hydroxy and C_1-6Alkyl groups.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R³selected from hydrogen,

Wherein the wavy line

Indicates the point of attachment of the group to the rest of the molecule.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

y is selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, C_1-6Alkylamino and C_3-8A cycloalkylamino group;

preferably, Y is C_1-6An alkyl group;

preferably, Y is methyl, ethyl and isopropyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

R⁷selected from hydrogen, halogen, C_1-6Haloalkyl and cyano;

preferably, R⁷Is hydrogen.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein,

z is-CR⁷-；

Preferably, Z is-CH-.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein the compound is a compound of formula I-1:

14. the compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:

15. a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

16. A kit, comprising:

a) at least one compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, as a first therapeutic agent, or a pharmaceutical composition of claim 15 as a first pharmaceutical composition;

b) optionally at least one further therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising a further therapeutic agent as a second pharmaceutical composition; and

c) optionally packaging and/or instructions.

17. Use of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 15, in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder mediated at least in part by TGF β R1 (particularly cancer, e.g., liver cancer).

18. A process for preparing a compound as claimed in any one of claims 1 to 14, which comprises:

step 1-1: the compound SM1 and N, N-dimethylformamide dimethyl acetal are subjected to condensation reaction to obtain a compound IM1

Step 1-2: the compound IM1 and the compound SM2 are subjected to cyclization reaction to obtain a compound IM2

Step 1-3: the compound IM2 is subjected to substitution reaction to obtain a compound IM3

Step 1-4: the compound IM3 and the compound SM3 are subjected to substitution reaction to obtain the compound shown in the formula I

Wherein LG is a leaving group, such as phenoxy and halogen; and,

Y、Z、R¹、R²and R³As defined in any one of claims 1 to 13.