CN114149410B

CN114149410B - Pyridocyclic compounds and preparation methods and uses thereof

Info

Publication number: CN114149410B
Application number: CN202010926863.7A
Authority: CN
Inventors: 田强; 张毅涛; 缪羽; 宋宏梅; 薛彤彤; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2020-09-07
Filing date: 2020-09-07
Publication date: 2025-02-25
Anticipated expiration: 2040-09-07
Also published as: CN114149410A

Description

Pyrido ring compounds, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a pyrido ring compound with TGF beta R1 inhibitory activity, a pharmaceutical composition and a kit containing the pyrido ring compound, a preparation method and application thereof.

Background

Transforming growth factor-beta (transforming growth factor-beta, TGF-beta) is a multifunctional cytokine that regulates a variety of cellular responses, such as cell proliferation, differentiation, migration, and apoptosis. TGF-beta superfamily includes TGF-beta 1, TGF-beta 2, TGF-beta 3, activin, inhibin, bone morphogenic proteins, and the like. TGF- β is signaled by two highly conserved single transmembrane serine/threonine kinases tgfβr1 and tgfβr2 (ACS med. Chem. Lett.,2018,9,1117).

Smads are important TGF- β signaling and regulatory molecules in cells that can transduce TGF- β signaling directly from the cell membrane into the nucleus, TGF- β/Smads signaling pathways play an important role in tumor development and progression. In TGF-beta/Smads signaling, activated TGF-beta first binds to TGF-beta R2 at the surface of the cell membrane, forms a heterodimeric complex, and is further recognized and bound by TGF-beta R1. Activated tgfβr1 further phosphorylates Smad2/Smad3 proteins, which in turn bind further to Smad4 to form a heterotrimeric complex that enters the nucleus to act synergistically with co-activators/inhibitors to regulate transcription of target genes (Nature, 2003,425,577). Any change in any segment of the TGF-beta/Smads signaling pathway results in an abnormality in the signaling pathway (PNAS, 2019,116,9166).

TGF- β signaling pathways are deregulated in many diseases including cancer, gastric, colorectal, prostate, ovarian, pancreatic, liver, lung, cervical and head and neck cancer cell lines and tumor tissues with significantly elevated levels of tgfβr1 protein. Activation of TGF- β signaling pathways causes significant pathological effects in tumor stroma, including immunosuppression, angiogenesis, and connective tissue hyperplasia. In addition, TGF- β signaling pathways can enhance the invasiveness of tumor cells, promote transformation of epithelial cells into the interstitium, and increase the tolerance to treatment by tumor epithelial cells (nat. Neurosci.,2014,17,943).

Currently, the development of inhibitors against the key target tgfβr1 in TGF- β signaling pathways has been gaining attention in the pharmaceutical industry, published patent applications including WO 02/094833A1, WO 2009/150047 A1, WO 2017/035118A1, WO 2018/019106A1, and the like. There remains a need in the art for novel tgfβr1 inhibitors, particularly tgfβr1 inhibitors having high activity and selectivity.

Disclosure of Invention

Through a great deal of research, the invention surprisingly discovers a pyrido ring compound and a corresponding preparation method thereof. The compounds can remarkably inhibit the activity of TGF beta R1, have good selectivity between TGF beta R1 and TGF beta R2, and can be used as TGF beta R1 inhibitors for treating proliferative diseases and apoptosis dysregulated diseases mediated at least in part by TGF-beta signal pathways, especially diseases mediated at least in part by TGF beta R1, such as cancers, e.g. liver cancers.

In a first aspect, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite, or prodrug thereof:

Wherein,

R ¹ is selected from C _6-10 aryl and 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl optionally substituted with one or more R ⁴;

R ² is selected from hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, cyano, -C (=O) NR ^aR^b、-C(＝O)OR^a, 4-8 membered heterocyclyl, and 5-10 membered heteroaryl, said C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with one or more R ⁵;

R ^a and R ^b are each independently at each occurrence selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 4-8 membered heterocyclyl optionally being substituted with one or more R ⁶, or R ^a、R^b together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle, said 4-8 membered heterocycle optionally being substituted with one or more R ⁶;

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

R ^c and R ^d are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, -C (=O) R ^a、C_6-10 aryl, and 5-10 membered heteroaryl, said C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl optionally substituted with one or more R ⁷;

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

R ⁵ is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl, hydroxy, halo, amino, and cyano, said C _1-6 alkyl, C _3-8 cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with one or more groups selected from halo, hydroxy, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-8 cycloalkyl, and 4-8 membered heterocyclyl;

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, said C _1-6 alkyl or C _3-8 cycloalkyl optionally substituted with one or more hydroxy groups;

R ⁷ is independently at each occurrence 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, said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or 4-8 membered heterocyclyl optionally being substituted with one or more groups selected from hydroxy and C _1-6 alkyl;

X is selected from C _1-6 alkylene and-NR ⁸ -;

Y is selected from-CR ⁹R¹⁰-、-NR⁸-、-O-、-S(＝O)_m -and-C (=O) -;

z is selected from-CR ¹¹ -and-N-;

R ⁸ is independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl and-C (=O) R ^a, said C _1-6 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl optionally being substituted with one or more groups selected from halogen, hydroxy, C _1-6 alkoxy, 4-8 membered heterocyclyl, amino and C _1-6 alkylamino;

R ⁹ and R ¹⁰ are each independently at each occurrence selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, hydroxy, amino, cyano, C _1-6 alkoxy, C _1-6 alkylamino, and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, or 4-8 membered heterocyclyl being optionally substituted with one or more groups selected from halogen, hydroxy, C _1-6 alkoxy, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, and 4-8 membered heterocyclyl, or R ⁹、R¹⁰ and the carbon atom to which they are attached form a 3-6 membered ring;

R ¹¹ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl and cyano, and

M is selected from 0, 1 and 2.

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, solvate, nitroxide, isotopic label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

In a third aspect, the present invention provides a kit comprising:

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

b) Optionally 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) Optionally package and/or instructions.

In a fourth aspect, the present invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, for use as a tgfβr1 inhibitor, for use in the prevention and/or treatment of a disease or disorder mediated at least in part by tgfβr1 (in particular cancer, e.g. liver cancer).

In a fifth aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, as a tgfβr1 inhibitor.

In a sixth aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition mediated at least in part by tgfβr1 (in particular cancer, e.g. 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 (particularly cancer, such as liver cancer), comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof or a pharmaceutical composition of the invention.

In an eighth aspect, the present invention provides a process for preparing a compound of the present invention by the following schemes 1, 2 or 3:

Route 1

Wherein,

LG ₁ and LG ₂ are each independently a leaving group, such as methylthio and halogen, preferably chloro or bromo;

w is selected from the group consisting of boric acid groups, 4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl and tri-n-butylstannyl, and

R ¹、R²、R³, X, Y and Z are as defined above;

Route 2

Wherein,

LG ₁ is a leaving group, such as methylthio and halogen, preferably chloro or bromo;

r ² is-C (=O) NR ^aR^b, and

R ¹、R³、X、Y、Z、R^a and R ^b are as defined above;

Route 3

Wherein,

R ² is-C (=O) NR ^aR^b, and

R ¹、R³、X、Y、Z、R^a and R ^b are as defined above.

The compound of the invention can show strong inhibition on TGF beta R1, the IC ₅₀ value can reach below 100nM, and the individual value can reach below 10nM, and meanwhile, the compound can show weak inhibition on TGF beta R2, so the compound can be used as a high-efficiency and high-selectivity TGF beta R1 inhibitor. The compound has anti-tumor activity, has fewer toxic and side effects and drug interactions, is mild in synthesis method, is easy to operate and is suitable for industrial mass production.

Detailed Description

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

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is 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 variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. 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," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended and do not exclude other, unrecited elements or method steps.

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 1to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl) optionally substituted with one or more (such as 1to 3) suitable substituents, such as halogen.

As used herein, the term "alkylene" refers to a straight or branched divalent alkyl radical.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decalinyl, and the like), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15, for example 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-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), optionally substituted with one or more (such as 1 to 3) suitable substituents, e.g., methyl-substituted cyclopropyl.

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

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) same or different halogen atoms. For example, the term "C _1-6 haloalkyl" as used herein refers to haloalkyl groups having from 1 to 6 carbon atoms, including, but not limited to )-CH₂F、-CHF₂、-CF₃、-CH₂CF₃、-CF₂CF₃、-CH₂CH₂CF₃、-CH₂Cl and the like.

As used herein, the term "heterocyclyl" refers to a mono-or polycyclic group having, for example, 2,3, 4,5, 6, 7,8, 9 carbon atoms and one or more (e.g., 1, 2,3, or 4) groups in the ring selected from C (=o), O, S, S (=o), S (=o) ₂, N, and NR (R represents a hydrogen atom or substituent, such as, but not limited to, alkyl or cycloalkyl). The heterocyclyl groups may be saturated or unsaturated. Saturated heterocyclic groups may be referred to as heterocycloalkyl groups, for example 3-8 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl groups, and the like. Unless otherwise specifically indicated in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused ring systems, bridged ring systems or spiro ring systems. In particular, a 3-8 membered heterocyclic 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, 4 to 7,4 to 6, 5 to 8, 5 to 7, and 5 to 6 membered heterocyclic groups, respectively), such as, but not limited to, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, azaGroup, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), and the like, and their benzocyclic derivatives or benzo derivatives or heteroaryl-or spiro derivatives, and the like.

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, anthryl, phenanthryl, acenaphthylenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. For example, the term "C _6-10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂、C_1-6 alkyl, etc.).

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 having 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and additionally may be benzo-fused in each case. 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 which contains at least one heteroatom (which may be the same or different, e.g., 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, and the like, and their benzo derivatives, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives. Heteroaryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, C _1-6 alkyl, etc.).

As used herein, the term "alkylamino" refers to a group on an amino group that is substituted with an alkyl group, e.g., as used herein, the term "C _1-6 alkylamino" refers to a group on an amino group that is substituted with a C _1-6 alkyl group, which may be denoted as C _1-6 alkyl-NH-.

As used herein, the term "hydroxyalkyl" refers to a group on an alkyl group that is substituted with a hydroxyl group, e.g., as used herein, the term "hydroxyc _1-6 alkyl" refers to a group on a C _1-6 alkyl group that is substituted with a hydroxyl group, which may be denoted-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-NH ₂.

The term "substituted" means that one or more (e.g., 1,2,3, or 4) atoms (e.g., hydrogen atoms) or groups of atoms (e.g., triflate groups) on the specified group are replaced with other atoms or groups of atoms, provided that the specified group meets the valence requirements in the current case and forms a stable compound after substitution. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. If a substituent is described as "optionally substituted," the substituent may be unsubstituted or substituted. If a first substituent is described as being optionally substituted with one or more of the second list of substituents, one or more hydrogen atoms in the first substituent may be replaced by one or more of the second list of substituents, either alone (individually) or each Independently (INDEPENDENTLY), or not.

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

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and/or toxicologically compatible with the other components of the formulation and/or the mammal being treated therewith.

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 also being referred to as acid addition salts or base addition salts.

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

The term "isomer" refers to a compound that has the same molecular weight due to the same number and type of atoms, but differs in the spatial arrangement or configuration of the atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular plane of asymmetry due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby enabling rotation of plane polarized light. The present invention also includes stereoisomers and mixtures thereof, due to the presence of asymmetric centers and other chemical structures which may lead to stereoisomers. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, mixtures of enantiomers and diastereomers. In general, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. Gtoreq.98%,. Gtoreq.95%,. Gtoreq.93%,. Gtoreq.90%,. Gtoreq.88%,. Gtoreq.85% or. Gtoreq.80%). As described below, individual stereoisomers of the compounds are prepared synthetically from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds having specific stereochemistry are either commercially available or prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-overlapping mirror images of each other. The term "diastereoisomer" 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 (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal portions of individual enantiomers. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation, amide-imine alcohol isomerisation, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The polymorphs of a molecule can be obtained by a number of known methods by a person skilled in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. In addition, polymorphs can 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, scanning Electron Microscopy (SEM), and the like.

The term "solvate" refers to a substance formed by the association of a compound of the invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule by non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, and the like), ethanolate, acetonates, and the like.

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

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

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

The term "prodrug" refers to a derivative compound that is capable of providing a compound of the invention directly or indirectly after administration to a subject. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to an individual, may increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood) or promote delivery of the parent compound to the site of action (e.g., the lymphatic system). All prodrug forms of the compounds of the invention are within the scope of the invention unless otherwise indicated, and the various prodrug forms are well known in the art.

The term "independently" means that at least two groups (or ring systems) present in the structure that are the same or similar in value range may have the same or different meanings in the particular case. For example, the substituents X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when the substituent X is hydrogen, the substituent Y may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl, and similarly when the substituent Y is hydrogen, the substituent X may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.

The invention also encompasses compounds of the invention containing a protecting group. During 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 of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example 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, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

Compounds of formula (I)

It is an object of the present invention to provide a method for preparing a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof,

Wherein,

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

X is selected from C _1-6 alkylene and-NR ⁸ -;

Y is selected from-CR ⁹R¹⁰-、-NR⁸-、-O-、-S(＝O)_m -and-C (=O) -;

z is selected from-CR ¹¹ -and-N-;

M is selected from 0, 1 and 2.

According to some embodiments of the invention, R ⁴ is each independently at each occurrence selected from deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl.

According to some embodiments of the invention, R ⁴ is each independently at each occurrence selected from halogen, C _1-6 alkyl, and C _1-6 haloalkyl.

According to some embodiments of the invention, R ⁴ is each independently at each occurrence selected from fluorine, chlorine, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

According to some embodiments of the invention, R ¹ is selected from phenyl and 5-6 membered heteroaryl, optionally substituted with one or more R ⁴.

According to some embodiments of the invention, R ¹ is selected from phenyl, pyridinyl, and pyrazolyl, said phenyl, pyridinyl, or pyrazolyl optionally substituted with one or more R ⁴. According to some embodiments of the invention, R ¹ is selected from phenyl and 5-6 membered heteroaryl, optionally substituted with one or more R ⁴, wherein R ⁴ is each independently at each occurrence selected from deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _3-8 cycloalkyl.

In some embodiments of the invention, R ¹ is selected from phenyl, pyridinyl, and pyrazolyl, optionally substituted with one or more R ⁴, wherein R ⁴ is each independently at each occurrence selected from deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl.

In some embodiments of the invention, R ¹ is selected from phenyl, pyridinyl, and pyrazolyl, optionally substituted with one or more (e.g., 1 or 2) R ⁴, wherein R ⁴ is each independently selected at each occurrence from halogen, C _1-6 alkyl, and C _1-6 haloalkyl.

In some embodiments of the invention, R ¹ is selected from phenyl and pyridinyl, optionally substituted with one or more (e.g., 1 or 2) R ⁴, wherein R ⁴ is each independently at each occurrence selected from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl, and monofluoromethyl.

In some embodiments of the invention, R ¹ is selected from Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

According to some embodiments of the invention, R ⁶ is independently at each occurrence selected from halogen, hydroxy, C _1-6 alkyl, hydroxyc _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-6 cycloalkyl, hydroxyc _3-6 cycloalkyl, and 4-8 membered heterocyclyl.

According to some embodiments of the invention, R ⁶ is independently at each occurrence selected from the group consisting of hydroxy, C _1-6 alkyl, hydroxyc _1-6 alkyl, C _3-6 cycloalkyl, and hydroxyc _3-6 cycloalkyl.

According to some embodiments of the invention, R ⁶ is independently at each occurrence selected from hydroxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, and hydroxy C _3-6 cycloalkyl.

According to some embodiments of the invention, R ^a and R ^b are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _3-8 cycloalkyl, 4-8 membered heterocyclyl optionally being substituted with one or more R ⁶, or

R ^a、R^b together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring.

According to some embodiments of the invention, R ^a and R ^b are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, and 4-6 membered heterocyclyl, said C _1-6 alkyl, C _3-6 cycloalkyl, or 4-6 membered heterocyclyl optionally being substituted with one or more R ⁶.

According to some embodiments of the invention, R ^a and R ^b are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl and piperidinyl, said C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl being optionally substituted with one or more R ⁶.

According to some embodiments of the invention, R ^a and R ^b are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl and piperidinyl, said C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl being optionally substituted with one or more groups independently selected from hydroxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _3-6 cycloalkyl and hydroxy C _3-6 cycloalkyl.

According to some embodiments of the invention, each R ⁵ at each occurrence is independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, 4-8 membered heterocyclyl C _1-6 alkyl, 4-8 membered heterocyclyl, hydroxy and amino.

According to some embodiments of the invention, each occurrence of R ⁵ is independently C _1-6 alkyl.

According to some embodiments of the invention, each occurrence of R ⁵ is independently methyl.

According to some embodiments of the invention, R ² is selected from hydrogen, halogen, cyano, -C (=o) NR ^aR^b, 4-8 membered heterocyclyl and 5-10 membered heteroaryl, said 4-8 membered heterocyclyl or 5-10 membered heteroaryl optionally being substituted with one or more R ⁵.

According to some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b, and 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with one or more R ⁵.

According to some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b, and 5-6 membered heteroaryl optionally substituted with C _1-6 alkyl.

According to some embodiments of the invention, R ² is selected from hydrogen, halogen, cyano, -C (=o) NR ^aR^b, 4-8 membered heterocyclyl and 5-10 membered heteroaryl, said 4-8 membered heterocyclyl or 5-10 membered heteroaryl optionally being substituted by one or more R ⁵, wherein,

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

r ⁵ is independently at each occurrence selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 haloalkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, 4-8 membered heterocyclyl C _1-6 alkyl, 4-8 membered heterocyclyl, hydroxy and amino, and

R ⁶ is independently at each occurrence selected from halogen, hydroxy, C _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkylamino, C _3-6 cycloalkyl, hydroxyC _3-6 cycloalkyl, and 4-8 membered heterocyclyl.

In some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b, and 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with one or more R ⁵, wherein,

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

R ⁵ is, independently at each occurrence, C _1-6 alkyl, and

R ⁶ is independently at each occurrence selected from the group consisting of hydroxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _3-6 cycloalkyl and hydroxy C _3-6 cycloalkyl.

In some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b, and 5-6 membered heteroaryl, optionally substituted with C _1-6 alkyl, wherein,

R ^a and R ^b are each independently at each occurrence selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl and piperidinyl, said C _1-6 alkyl, C _3-6 cycloalkyl, azetidinyl or piperidinyl being optionally substituted by one or more R ⁶, and

In some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b, and thiazolyl optionally substituted with C _1-6 alkyl.

In some embodiments of the invention, R ² is selected from hydrogen, cyano, -C (=o) NH ₂、-C(＝O)N(H)CH₃, Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

According to some embodiments of the invention, R ⁷ at each occurrence is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, or 4-8 membered heterocyclyl optionally being substituted with one or more groups selected from hydroxy and C _1-6 alkyl.

According to some embodiments of the invention, R ⁷ is independently at each occurrence selected from C _1-6 alkyl, C _1-6 alkoxy, and 5-6 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, or 5-6 membered heterocyclyl optionally being substituted with one or more groups selected from hydroxy and C _1-6 alkyl.

According to some embodiments of the invention, R ⁷ at each occurrence is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and piperazinyl, said C _1-6 alkyl, C _1-6 alkoxy, or piperazinyl optionally substituted with a group selected from hydroxy and C _1-6 alkyl.

According to some embodiments of the invention, R ^c and R ^d are each independently at each occurrence selected from hydrogen, C _6-10 aryl, and 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl optionally substituted with one or more R ⁷.

According to some embodiments of the invention, R ^c and R ^d are each independently at each occurrence selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally substituted with one or more R ⁷.

According to some embodiments of the invention, R ^c and R ^d are each independently at each occurrence selected from hydrogen, phenyl and pyridinyl, said phenyl or pyridinyl optionally substituted with one or more R ⁷.

According to some embodiments of the invention, R ^c and R ^d are each independently at each occurrence selected from hydrogen, phenyl and pyridinyl, optionally substituted with one or more groups each independently selected from C _1-6 alkyl, C _1-6 alkoxy and piperazinyl, optionally substituted with a group selected from hydroxy and C _1-6 alkyl.

According to some embodiments of the invention, R ³ is selected from hydrogen and-NR ^cR^d, wherein,

R ^c and R ^d are each independently at each occurrence selected from hydrogen, C _6-10 aryl and 5-to 10-membered heteroaryl, said C _6-10 aryl or 5-to 10-membered heteroaryl optionally substituted with one or more R ⁷, and

R ⁷ is independently at each occurrence selected from C _1-6 alkyl, C _1-6 alkoxy, and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, or 4-8 membered heterocyclyl optionally being substituted with one or more groups selected from hydroxy and C _1-6 alkyl.

In some embodiments of the invention, R ³ is selected from hydrogen and-NR ^cR^d, wherein,

R ^c and R ^d are each independently at each occurrence selected from hydrogen, phenyl and 5-6 membered heteroaryl, optionally substituted with one or more R ⁷, and

R ⁷ is independently at each occurrence selected from C _1-6 alkyl, C _1-6 alkoxy, and 5-6 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, or 5-6 membered heterocyclyl optionally being substituted with one or more groups selected from hydroxy and C _1-6 alkyl.

R ^c and R ^d are each independently at each occurrence selected from hydrogen, phenyl and pyridinyl, said phenyl or pyridinyl optionally substituted with one or more R ⁷, and

R ⁷ is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, and piperazinyl, said C _1-6 alkyl, C _1-6 alkoxy, or piperazinyl optionally substituted with a group selected from the group consisting of hydroxy and C _1-6 alkyl.

In some embodiments of the invention, R ³ is selected from hydrogen,Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

According to some embodiments of the invention, R ⁸ is independently selected at each occurrence from hydrogen, C _1-6 alkyl, and C _3-8 cycloalkyl, said C _1-6 alkyl and C _3-8 cycloalkyl optionally substituted with one or more groups selected from hydroxy, C _1-6 alkoxy, or amino.

According to some embodiments of the invention, R ⁸ is independently selected at each occurrence from hydrogen and C _1-6 alkyl.

According to some embodiments of the invention, R ⁸ is each independently selected from hydrogen, methyl and ethyl at each occurrence.

According to some embodiments of the invention, X is selected from C _1-6 alkylene and-NH-.

In some embodiments of the invention, X is selected from the group consisting of-CH ₂-、-CH₂CH₂ -and-NH-.

According to some embodiments of the invention, R ⁹ and R ¹⁰ are each independently at each occurrence selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, or 4-8 membered heterocyclyl being optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, C _1-6 alkoxy, hydroxy C _1-6 alkyl, and amino C _1-6 alkyl, or

R ⁹、R¹⁰ together with the carbon atom to which they are attached form a 3-6 membered ring.

According to some embodiments of the invention, R ⁹ and R ¹⁰ are each independently selected from hydrogen and C _1-6 alkyl at each occurrence.

In some embodiments of the invention, R ⁹ and R ¹⁰ are each independently selected from hydrogen, methyl and ethyl at each occurrence.

According to some embodiments of the invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-, -S-and-C (=o) -.

According to some embodiments of the invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-and-C (=o) -.

According to some embodiments of the invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-, -S-and-C (=o) -, wherein,

R ⁹ and R ¹⁰ are each independently at each occurrence selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy and 4-8 membered heterocyclyl, said C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy or 4-8 membered heterocyclyl optionally being substituted with one or more groups selected from halogen, hydroxy, C _1-6 alkoxy, hydroxy C _1-6 alkyl and amino C _1-6 alkyl, or

In some embodiments of the present invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-, -S-and-C (=O) -, wherein,

R ⁸ is independently at each occurrence selected from hydrogen and C _1-6 alkyl;

R ⁹ and R ¹⁰ are each independently at each occurrence selected from hydrogen and C _1-6 alkyl, or

In some embodiments of the present invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-and-C (=O) -, wherein,

r ⁹ and R ¹⁰ are each independently selected from hydrogen and C _1-6 alkyl at each occurrence.

R ⁸ is independently selected at each occurrence from hydrogen, methyl, and ethyl;

R ⁹ and R ¹⁰ are each independently selected from hydrogen, methyl and ethyl at each occurrence.

In some embodiments of the invention, Y is selected from-CH ₂-、-CH(CH₃)-、-N(CH₃) -, -O-, and-C (=o) -.

According to some embodiments of the invention, Z is selected from the group consisting of-CH-and-N-.

The present invention encompasses compounds of formula I resulting from any combination of the above preferred groups.

According to some embodiments of the invention, the compounds of the invention are of formula II-1:

Wherein,

R ¹、R²、R³, X and Y are as defined above.

According to some embodiments of the invention, the compounds of the invention are compounds of formula II-2:

Wherein,

R ¹、R²、R³, X and Y are as defined above.

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

Wherein,

R ¹、R²、R³ and Y are as defined above.

According to some embodiments of the invention, the compound of the invention is a compound of formula III-2:

Wherein,

R ¹、R²、R³ and Y are as defined above.

According to some embodiments of the invention, the compound of the invention is a compound of formula III-3:

Wherein,

R ¹、R²、R³ and X are as defined above.

According to some embodiments of the invention, the compounds of the invention are of formula III-4:

Wherein,

R ¹、R²、R³ and Y are as defined above.

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3, and formula III-4 of the invention, R ¹ is selected from phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted with one or more R ⁴, R ⁴ is each independently at each occurrence selected from deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _3-8 cycloalkyl.

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3, and formula III-4 of the invention, R ¹ is selected from phenyl, pyridinyl, and pyrazolyl, optionally substituted with one or more R ⁴, R ⁴ is each independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl at each occurrence.

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3, and formula III-4 of the invention, R ¹ is selected from phenyl and pyridinyl, optionally substituted with one or more (e.g., 1 or 2) R ⁴, wherein R ⁴ is independently at each occurrence selected from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl, and monofluoromethyl.

In some embodiments of the invention, R ¹ is selected from the group consisting of compounds of formulas II-1, II-2, III-1, III-2, III-3, and III-4 of the inventionWherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3 and formula III-4 of the invention, R ² is selected from hydrogen, halogen, cyano, -C (=O) NR ^aR^b, 4-8 membered heterocyclyl and 5-10 membered heteroaryl, said 4-8 membered heterocyclyl or 5-10 membered heteroaryl being optionally substituted with one or more R ⁵, wherein,

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

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3 and formula III-4 of the invention, R ² is selected from hydrogen, cyano, -C (=O) NR ^aR^b and 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally being substituted with one or more R ⁵, wherein,

R ⁵ is, independently at each occurrence, C _1-6 alkyl, and

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3 and formula III-4 of the invention, R ² is selected from hydrogen, cyano, -C (=O) NR ^aR^b and 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally being substituted with C _1-6 alkyl, wherein,

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3 and formula III-4 of the invention, R ² is selected from hydrogen, cyano, -C (=O) NR ^aR^b and thiazolyl optionally substituted with C _1-6 alkyl.

In some embodiments of the invention, R ² is selected from the group consisting of hydrogen, cyano, -C (=O) NH ₂、-C(＝O)N(H)CH₃, a compound of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3, and formula III-4 of the invention, Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

In some embodiments of the invention, in the compounds of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3 and formula III-4 of the invention, R ³ is selected from hydrogen and-NR ^cR^d, wherein,

In some embodiments of the present invention, R ³ is selected from the group consisting of hydrogen, a compound of formula II-1, formula II-2, formula III-1, formula III-2, formula III-3, and formula III-4 of the present invention,Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

In some embodiments of the present invention, X is selected from the group consisting of C _1-6 alkylene and-NH-in the compounds of formulas II-1, II-2, and III-3 of the present invention.

In some embodiments of the present invention, in the compounds of formula II-1, formula II-2 and formula III-3 of the present invention, X is selected from the group consisting of-CH ₂-、-CH₂CH₂ -and-NH-.

In some embodiments of the present invention, compounds of formula II-1, formula II-2, formula III-1, formula III-2 and formula III-4 of the present invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-, -S-and-C (=O) -.

In some embodiments of the present invention, compounds of formula II-1, formula II-2, formula III-1, formula III-2 and formula III-4 of the present invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-, -S-and-C (=O) -, wherein,

In some embodiments of the present invention, of the compounds of formulas II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-and-C (=O) -, wherein,

In some embodiments of the present invention, of the compounds of formulas II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from-CH ₂-、-CH(CH₃)-、-N(CH₃) -, -O-and-C (=o) -.

In some embodiments of the invention, the compounds of formula III-3 of the invention are those wherein,

R ¹ is selected from phenyl, pyridinyl, and pyrazolyl, optionally substituted with one or more R ⁴, R ⁴ is each independently at each occurrence selected from halogen, C _1-6 alkyl, and C _1-6 haloalkyl;

R ² is selected from hydrogen, cyano, -C (=O) NR ^aR^b, and 5-6 membered heteroaryl, optionally substituted with C _1-6 alkyl, wherein,

R ⁶ is independently at each occurrence selected from the group consisting of hydroxy, C _1-6 alkyl, hydroxyC _1-6 alkyl, C _3-6 cycloalkyl, and hydroxyC _3-6 cycloalkyl;

r ³ is selected from hydrogen and-NR ^cR^d, wherein,

R ⁷ is independently at each occurrence selected from C _1-6 alkyl, C _1-6 alkoxy, and 5-6 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, or 5-6 membered heterocyclyl optionally substituted with one or more groups selected from hydroxy and C _1-6 alkyl;

x is selected from the group consisting of C _1-6 alkylene and-NH-.

R ¹ is selected from phenyl and pyridinyl optionally substituted with one or more (e.g., 1 or 2) R ⁴, wherein R ⁴ is each independently at each occurrence selected from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl;

R ² is selected from hydrogen, cyano, -C (=o) NR ^aR^b and thiazolyl optionally substituted with C _1-6 alkyl;

r ³ is selected from hydrogen and-NR ^cR^d, wherein,

Each occurrence of R ⁷ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and piperazinyl, said C _1-6 alkyl, C _1-6 alkoxy, or piperazinyl optionally substituted with a group selected from hydroxy and C _1-6 alkyl;

x is selected from the group consisting of C _1-6 alkylene and-NH-.

R ¹ is selected fromWherein the wavy lineRepresents the point of attachment of the group to the remainder of the molecule;

R ² is selected from hydrogen, cyano, -C (=O) NH ₂、-C(＝O)N(H)CH₃, Wherein the wavy lineRepresents the point of attachment of the group to the remainder of the molecule;

R ³ is selected from hydrogen, Wherein the wavy lineRepresents the point of attachment of the group to the remainder of the molecule;

X is selected from the group consisting of-CH ₂-、-CH₂CH₂ -and-NH-.

In some embodiments of the invention, compounds of the formulae III-1, III-2 and III-4 according to the invention, wherein,

r ³ is selected from hydrogen and-NR ^cR^d, wherein,

Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-and-C (=O) -, wherein,

r ³ is selected from hydrogen and-NR ^cR^d, wherein,

Y is selected from-CR ⁹R¹⁰-、-NR⁸ -, -O-and-C (=O) -, wherein,

In some embodiments of the invention, of the III-1, III-2 and III-4 compounds of the invention, wherein,

Y is selected from-CH ₂-、-CH(CH₃)-、-N(CH₃) -, -O-and-C (=o) -.

The present invention encompasses compounds of formulas II-1, II-2, III-1, III-2, III-3 and III-4, obtained by any combination of the above preferred groups.

According to some embodiments of the invention, the compound of the invention is selected from:

preparation method it is a further object of the present invention to provide a method for preparing a compound of the present invention by the following schemes 1,2 or 3:

Route 1

Wherein,

W is selected from the group consisting of boric acid groups, 4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl and tri-n-butylstannyl, and R ¹、R²、R³, X, Y and Z are as defined above.

Step 1-1 coupling reaction of compound SM1 and compound SM2 to obtain compound IM1

In some embodiments of the invention, the reaction is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water, which may be selected from the group consisting of halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), meOH, etOH, t-BuOH, DMF, AN, ethers (e.g., DME, THF, diox), aromatic hydrocarbons (e.g., TL, XY), and any combination thereof, preferably TL or Diox.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable catalyst, preferably a palladium catalyst, such as Pd(PPh₃)₄、Pd(OAc)₂、Pd₂(dba)₃、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₂Cl₂ dichloromethane complex, pdCl ₂(Amphos)₂ and Pd (dppf) Cl ₂, preferably Pd (dppf) Cl ₂ or Pd (PPh ₃)₄.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable ligand, which may be selected from PPh ₃、BINAP、P(o-tol)₃, TCHP and X-PHOS, preferably PPh ₃ or X-PHOS.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable base, including an organic base, which may be selected from DIPEA, TEA, t-BuOK and Py, or an inorganic base, which may be selected from K ₃PO₄、NaH、K₂CO₃、Na₂CO₃、Cs₂CO₃ and NaOH, preferably K ₂CO₃ or Cs ₂CO₃.

In some embodiments of the invention, the reaction is carried out at a suitable temperature, which is in the range of 0 to 200 ℃, preferably 50 to 150 ℃.

Step 1-2 Buchwald reaction of Compound IM1 and Compound SM3 to give Compound of formula I

In some embodiments of the invention, the reaction is carried out in a suitable organic solvent or a mixture of organic solvents and water, which may be selected from the group consisting of halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), meOH, etOH, t-BuOH, DMF, AN, ethers (e.g., DME, THF, diox), aromatic hydrocarbons (e.g., TL, XY), and any combination thereof, preferably TL or Diox.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable catalyst, preferably a palladium catalyst, such as Pd (PPh ₃)₄、Pd(OAc)₂ and Pd ₂(dba)₃, preferably Pd (OAc) ₂ and Pd ₂(dba)₃).

In some embodiments of the invention, the reaction is carried out in the presence of a suitable ligand, which may be selected from PPh ₃、BINAP、P(o-tol)₃, TCHP, xant-PHOS and X-PHOS, preferably Xant-PHOS or BINAP.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable base, including an organic base, which may be selected from DIPEA, TEA, t-BuOK and Py, or an inorganic base, which may be selected from K ₃PO₄、NaH、K₂CO₃、Na₂CO₃、Cs₂CO₃ and NaOH, preferably K ₃PO₄ or Cs ₂CO₃.

Route 2

Wherein,

r ² is-C (=O) NR ^aR^b, and

R ¹、R³、X、Y、Z、R^a and R ^b are as defined above.

Step 2-1 Buchwald reaction of the compound IM1 and the compound SM4 to obtain a compound IM2

Step 2-2, performing amine transesterification on the compound IM2 and the compound SM5 to obtain a compound of the formula I

In some embodiments of the invention, the reaction is carried out in a suitable organic solvent or a mixture of organic solvents and water, which may be selected from the group consisting of halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), DMSO, NMP, DMF, ethers (e.g., DME, THF, diox), and any combination thereof, preferably DMSO or DMF.

Route 3

Wherein,

R ² is-C (=O) NR ^aR^b, and

R ¹、R³、X、Y、Z、R^a and R ^b are as defined above.

Step 3-1, obtaining a compound IM3 through hydrolysis reaction of the compound IM2

In some embodiments of the invention, the reaction is carried out in a suitable organic solvent or a mixture of organic solvents and water, which may be selected from alcohols (e.g., meOH, etOH, n-BuOH, etc.), THF, acOH, diox, and any combination thereof, preferably THF, etOH, or a mixture thereof with water.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable base, which may be selected from NaOH, KOH and LiOH, preferably NaOH.

In some embodiments of the invention, the reaction is carried out at a suitable temperature, said temperature being in the range of 0-100 ℃, preferably 25-100 ℃.

Step 3-2, condensation reaction of the compound IM3 and the compound SM5 to obtain the compound of the formula I

In some embodiments of the invention, the reaction is carried out in the presence of a suitable condensing agent, which may be selected from SOCl₂、(COCl)₂、POCl₃、PCl₃、PCl₅、ECF、IPCF、HATU、HBTU、EEDQ、DEPC、DCC、DIC、EDC、T3P、BOP、PyAOP and PyBOP, preferably HATU.

In some embodiments of the invention, the reaction is carried out in the presence of a suitable base, including an organic base, which may be selected from DIPEA, TEA, t-BuOK and Py, or an inorganic base, which may be selected from K ₃PO₄、NaH、K₂CO₃、Na₂CO₃、Cs₂CO₃ and NaOH, preferably DIPEA, K ₂CO₃ or t-BuOK.

In some embodiments of the invention, the reaction is carried out at a suitable temperature, which is in the range of 0 to 200 ℃, preferably 25 to 120 ℃.

Pharmaceutical composition and kit

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

It is another object of the present invention to provide a kit comprising:

C) Optionally package and/or instructions.

The term "pharmaceutically acceptable carrier" refers to an adjuvant that is administered with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

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

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

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

The pharmaceutical compositions of the present invention may also be administered in the form of sterile injectable preparations.

The pharmaceutical composition of the present invention may comprise 0.01mg to 1000mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite or prodrug thereof.

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

The kit of the invention may comprise 0.01mg to 1000mg of at least one compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite or prodrug thereof.

In some embodiments, the invention provides a method of preparing a kit of the invention comprising combining at least one compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, with optionally at least one other therapeutic agent, or a pharmaceutical composition comprising the other therapeutic agent, packaging, and/or instructions.

Therapeutic methods and uses

It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a tgfβr1 inhibitor (especially a tgfβr1 selective inhibitor) for the prevention and/or treatment of a disease or disorder (especially cancer, e.g. liver cancer) mediated at least in part by tgfβr1.

It is another object of the present invention to provide the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof or a pharmaceutical composition of the present invention as a tgfβr1 inhibitor.

It is a further object of the present invention to provide the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for the manufacture of a medicament for the prevention and/or treatment of a disease or disorder mediated at least in part by tgfβr1 (in particular cancer, e.g. liver cancer).

It is another object of the present invention to provide a method for preventing and/or treating a disease or disorder (particularly cancer, such as liver cancer) mediated at least in part by tgfβr1, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite or prodrug thereof or a pharmaceutical composition of the present invention.

The term "disease or disorder mediated at least in part by tgfβr1" refers to a disease in which pathogenesis includes at least a portion of the factors associated with tgfβr1, including, but not limited to, cancers such as lung cancer, colorectal cancer, multiple Myeloma (MM), acute Myelogenous Leukemia (AML), acute Lymphoblastic Leukemia (ALL), pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors, or other hematological cancers.

The term "effective amount" refers to a dose capable of eliciting a biological or medical response from a cell, tissue, organ or organism (e.g., an individual) and sufficient to achieve a desired prophylactic and/or therapeutic effect.

The dosing regimen may be adjusted to provide the best desired response. For example, it may be administered in a single dose, it may be administered in divided doses over time, or it may be administered after a proportional decrease or increase in dose depending on the actual situation. It will be appreciated that the particular dosage regimen for any particular individual will be adjusted according to the needs and the discretion of the attendant administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the individual condition, the severity of the disease or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, the effective amount is about 0.001-10000mg/kg body weight of the subject per day. In suitable cases, the effective amount is about 0.01-1000mg/kg body weight of the subject per day. About 0.01-1000mg/kg of subject body weight, typically about 0.1-500mg/kg of subject body weight, may be administered daily, every two days, or every three days. Exemplary dosing regimens are one or more times per day, or one or more times per week, or one or more times per month. The interval between individual doses may typically be daily, weekly, monthly or yearly when administered multiple times. Or may be administered in the form of a slow release formulation, in which case a lower frequency of administration is required. The dosage and frequency of administration may vary depending on the half-life of the drug in the subject, and may also vary depending on whether it is for prophylactic or therapeutic use. In prophylactic applications, relatively low doses are administered at relatively low frequency intervals over a long period of time, while in therapeutic applications, it is sometimes desirable to administer relatively high doses at shorter intervals until the progression of the disease is delayed or stopped, preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which prophylactic applications may be employed.

The term "treatment" refers to the alleviation or elimination of a disease or condition for which it is intended. A subject is indicated to have been successfully "treated" if the subject has received a therapeutic amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, at least one indicator and symptom of the subject exhibits observable and/or detectable relief and/or improvement. It is understood that treatment includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant results. In particular, "treating" means that the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopic label, metabolite, or prodrug thereof, or the pharmaceutical composition of the invention, can achieve at least one of (1) preventing disease onset in an animal that may be predisposed to the disease but has not undergone or exhibited disease pathology or symptomology, (2) inhibiting disease (i.e., preventing further development of pathology and/or symptomology) in an animal that is undergoing or exhibiting disease pathology or symptomology, and (3) ameliorating disease (i.e., reversing pathology and/or symptomology) in an animal that is undergoing or exhibiting disease pathology or symptomology.

The term "administering" or "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a subject or a cell, tissue, organ, biological fluid, etc. thereof, such that the pharmaceutically active ingredient or pharmaceutical composition is brought into contact with the subject or a cell, tissue, organ, biological fluid, etc. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof" refers to a judgment of a physician or other caregiver that the individual needs or is about to benefit from the prevention and/or treatment process based on various factors of the physician or other caregiver in their expertise.

The term "individual" (or subject) includes humans or non-human animals. The subject of the present invention includes subjects (patients) suffering from diseases and/or disorders and normal subjects. Non-human animals in the present invention include all vertebrates, such as non-mammals, e.g., birds, amphibians, reptiles, etc., and mammals, e.g., non-human primates, domestic animals, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Examples

In order to make the objects and technical solutions of the present invention more apparent, embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention.

The reagents or apparatus used in the examples are all conventional products commercially available. Those not specifying the specific conditions were carried out according to the conventional conditions or the conditions recommended by the manufacturer. The term "room temperature" as used in the present invention means 20.+ -. 5 ℃. As used herein, the term "about" when used in reference to a particular value or range of values is intended to encompass the value or range of values as well as ranges of errors that are acceptable to those skilled in the art of the value or range of values, such as, for example, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

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

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

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

Abbreviations in Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:

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

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

The Mass Spectrum (MS) measuring instrument uses an Agilent 6120B mass spectrometer, and the ion source is an electrospray ion source (ESI).

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

Method A:

chromatographic column SunFire Prep C ₁₈ OBD (5 μm 19mm 150 mm)

Mobile phase A acetonitrile, mobile phase B water (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 B:

chromatographic column SunFire Prep C ₁₈ OBD (5 μm 19mm 150 mm)

Mobile phase A acetonitrile, mobile phase B water (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
				20.00	90	10	28

Method C:

Chromatographic column SunFire Prep C18 OBD (5 μm 19mm 150 mm)

Mobile phase A acetonitrile, mobile phase B water (0.05% ammonium bicarbonate)

Preparation of the Compounds

Example 1 Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) -N- (1, 3-dihydroxypropan-2-yl) nicotinamide (Compound 4)

Step one Synthesis of 4-chloro-2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridine (Compound 4-2)

2, 4-Dichloro-6, 7-dihydro-5H-cyclopenta [ b ] pyridine (compound 4-1,300mg,1.60 mmol) and (5-chloro-2-fluorophenyl) boric acid (278.16 mg,1.60 mmol) were weighed out in a mixed solvent of 1, 4-dioxane (10 mL) and water (3 mL), then Pd (dppf) Cl ₂ (116.73 mg, 159.53. Mu. Mol) and potassium carbonate (660.45 mg,4.79 mmol) were added, the reaction system was replaced 3 times with nitrogen and heated to 100℃under nitrogen protection, and reacted for 8 hours. The reaction solution was cooled to room temperature, diluted with 50mL of dichloromethane, washed once with 20mL of clear water and 20mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate=9:1) to give the title compound (358 mg, yield 79.53%).

MS(ESI):m/z 282.0[M+H]⁺

Step two Synthesis of methyl 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinic acid ester (Compound 4-3)

4-Chloro-2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridine (compound 4-2,110mg, 389.88. Mu. Mol) and methyl 4-aminonicotinate (71.18 mg, 467.85. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), palladium acetate (8.75 mg, 38.99. Mu. Mol), BINAP (48.55 mg, 77.98. Mu. Mol) and cesium carbonate (317.57 mg, 974.69. Mu. Mol) were added, the reaction system was replaced with nitrogen 3 times, and the reaction was carried out under a microwave of 120℃for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give the title compound (100 mg, yield 64.47%).

MS(ESI):m/z 398.1[M+H]⁺

Step three Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) -N- (1, 3-dihydroxypropan-2-yl) nicotinamide (Compound 4)

Methyl 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinate (compound 4-3,21mg, 52.79. Mu. Mol) and 2-aminopropane-1, 3-diol (24.05 mg, 263.93. Mu. Mol) were weighed into N, N-dimethylformamide (1 mL), heated to 100℃and reacted for 15 hours. After cooling the reaction to room temperature, it was directly purified by preparative high performance liquid chromatography (method a) and the preparation was lyophilized to give the title compound (6.55 mg, yield 27.15%).

MS(ESI):m/z 457.1[M+H]⁺

The structural characterization is as follows:

¹H NMR(400MHz,DMSO-d₆):δ10.56(s,1H),8.86(s,1H),8.49(d,J＝8.1Hz,1H),8.41(d,J＝5.8Hz,1H),7.96(dd,J＝6.7,2.8Hz,1H),7.61(s,1H),7.53(ddd,J＝8.8,4.2,2.8Hz,1H),7.44–7.34(m,2H),4.72(t,J＝5.7Hz,2H),4.00(dq,J＝8.0,5.8Hz,1H),3.52(q,J＝5.3Hz,4H),3.01(t,J＝7.7Hz,2H),2.88(t,J＝7.4Hz,2H),2.15(p,J＝7.6Hz,2H).

EXAMPLE two Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinamide (Compound 2)

Step one Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinic acid (Compound 2-1)

Methyl 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinate (compound 4-3,100mg, 251.36. Mu. Mol) was dissolved in methanol (6 mL), sodium hydroxide (30.16 mg, 754.09. Mu. Mol) and water (2 mL) were added, and after the addition, the temperature was raised to 80℃and reacted for 1 hour with stirring. The reaction mixture was distilled off under reduced pressure to give ethanol, which was then adjusted to pH 5 with 1mol/L aqueous hydrochloric acid, directly filtered, and the filtrate was washed with 50mL of clear water, followed by drying to give the title compound (89 mg, yield 92.25%).

MS(ESI):m/z 384.1[M+H]⁺

Step two Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinamide (Compound 2)

4- ((2- (5-Chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinic acid (compound 2-1,35mg, 91.19. Mu. Mol) and ammonium chloride (9.76 mg, 182.39. Mu. Mol) were weighed into N, N-dimethylformamide (3 mL), then N, N-diisopropylethylamine (47.14 mg, 364.77. Mu. Mol) and HATU (41.61 mg, 109.43. Mu. Mol) were added, and the reaction was carried out with stirring at room temperature for 1 hour. The reaction solution was slowly poured into 20mL of water, and after filtration, the filtrate was washed with 30mL of clear water and 50mL of acetonitrile, and then dried to obtain the title compound (21 mg, yield 60.15%).

MS(ESI):m/z 383.1[M+H]⁺

The structural characterization is as follows:

¹H NMR(400MHz,DMSO-d₆):δ10.98(s,1H),8.86(s,1H),8.41(d,J＝5.9Hz,2H),7.96(dd,J＝6.7,2.8Hz,1H),7.85(s,1H),7.65–7.60(m,1H),7.53(ddd,J＝8.8,4.2,2.8Hz,1H),7.43–7.35(m,2H),3.01(t,J＝7.7Hz,2H),2.87(t,J＝7.4Hz,2H),2.15(p,J＝7.6Hz,2H).

EXAMPLE three Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinonitrile (Compound 1)

4- ((2- (5-Chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) nicotinamide (compound 2,18mg, 47.02. Mu. Mol) was dissolved in phosphorus oxychloride (2 mL), warmed to 90℃and reacted for 5 hours. After the reaction solution was concentrated to dryness under reduced pressure to give an oil, 10mL of a saturated aqueous sodium hydrogencarbonate solution and 10mL of methylene chloride were added, then the organic phase was separated, washed with 5mL of clear water, dried over anhydrous sodium sulfate, then filtered, and the filtrate was evaporated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (method B) and the preparation was lyophilized to give the title compound (1.91 mg, yield 8.48%).

MS(ESI):m/z 365.0[M+H]⁺

The structural characterization is as follows:

¹H NMR(400MHz,DMSO-d₆):δ10.02(s,1H),8.90(s,1H),8.54(s,1H),7.95(dd,J＝6.6,2.8Hz,1H),7.60(ddd,J＝8.8,4.2,2.8Hz,1H),7.52–7.37(m,2H),7.07(s,1H),3.08(t,J＝7.6Hz,2H),2.78(t,J＝7.3Hz,2H),2.14(p,J＝7.5Hz,2H).

Example four Synthesis of 4- ((2- (5-chloro-2-fluorophenyl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-4-yl) amino) -N- (2-hydroxyethyl) nicotinamide (Compound 43)

Compound 4-3 (20 mg,0.05 mmol) and 2-aminoethanol (92 mg,1.50 mmol) were dissolved in DMSO (1.5 mL) and reacted at 100℃for 15 hours. The reaction solution was cooled to room temperature and purified directly by high performance liquid chromatography (method C), and the preparation was lyophilized to give the title compound (15 mg, yield 69.20%).

MS(ESI):m/z 427.0[M+H]+。

The structural characterization is as follows:

¹H NMR(400MHz,DMSO-d₆)δ10.6(s,1H),8.89(t,J＝5.2Hz,1H),8.83(s,1H),8.41(d,J＝6.0Hz,1H),7.95(dd,J＝6.8,2.8Hz,1H),7.61(s,1H),7.56–7.49(m,1H),7.43–7.34(m,2H),4.78(t,J＝5.6Hz,1H),3.54(q,J＝6.0Hz,2H),3.35(q,J＝6.0Hz,2H),3.01(t,J＝7.6Hz,2H),2.88(t,J＝7.2Hz,2H),2.20–2.09(m,2H).

referring to the synthetic methods of examples one to four, the following compounds were synthesized similarly:

Pharmacological Activity test

Test example one in vitro enzymatic Activity inhibition test (TGF beta R1)

The inhibition of TGF-beta R1 enzyme activity by the compounds of the present invention was determined according to the ADP-Glo ^TM kinase assay kit (Promega) protocol, as follows:

After preincubation of tgfβr1 enzyme with test compounds (1000 nM, 100nM, 10 nM) at different concentrations, respectively, for 30min at 30 ℃, tgfβr1 peptide and Adenosine Triphosphate (ATP) were added to initiate a reaction. ADP-Glo ^TM reagent was added after incubation at 30℃for 3h, and kinase detection reagent was added after incubation at room temperature for 90 min. After incubation for 30min at room temperature, chemiluminescent signal values were detected. The percent inhibition of compounds at different concentrations was calculated using the solvent set (DMSO) as a negative control, the buffer set (without tgfβr1enzyme) as a blank according to the following formula:

Percentage inhibition = (1- (chemiluminescent signal value of compound at different concentration-chemiluminescent signal value of blank)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank)) × 100%;

When the percent inhibition is between 30-80%, the half inhibition concentration (IC ₅₀) or range of compounds is calculated according to the following formula:

IC ₅₀ = X (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 the Compounds of the invention against TGF-beta R1

Examples numbering	IC ₅₀ (nM) for TGF beta R1
		Example 1	69.19±28.56
Example two	3.01±1.05
		Example III	70.43±11.68
Example IV	30.42±7.93

As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on TGF-beta R1.

Test example two in vitro enzymatic Activity inhibition test (TGF beta R2)

The inhibition of TGF-beta R2 enzyme activity by the compounds of the present invention was determined according to the ADP-Glo ^TM kinase assay kit (Promega) protocol, as follows:

After preincubation of tgfβr2 enzyme with test compounds (1000 nM, 100nM, 10 nM) at different concentrations, respectively, for 30min at 30 ℃, myelin Basic Protein (MBP) and Adenosine Triphosphate (ATP) were added to initiate the reaction. ADP-Glo ^TM reagent was added after incubation at 30℃for 3h, and kinase detection reagent was added after incubation at room temperature for 90 min. After incubation for 30min at room temperature, the chemiluminescent signal value was measured. The percent inhibition of compounds at different concentrations was calculated using the solvent set (DMSO) as a negative control, the buffer set (without tgfβr2enzyme) as a blank according to the following formula:

The experimental results are shown in table 2 below:

TABLE 2 inhibition of TGF-beta R2 enzyme Activity by Compounds of the invention

Examples numbering	IC ₅₀ (nM) for TGF beta R2
		Example 1	>1000

As can be seen from Table 2, the compounds of the present invention have a weak inhibitory activity against TGF-beta R2.

As can be seen from tables 1 and 2, the compounds of the present invention have selective inhibition of TGF-beta R1.

Test example III in vitro cell Activity inhibition test

Experimental methods the inhibition of HEK293-SBE cells by the compounds of the invention was determined according to the instructions of the Bright-Glo ^TM luciferase assay kit (Promega) as follows:

HEK293-SBE cells (Bps bioscience) were added to 96-well plates (10% FBS medium MEM medium), 3 ten thousand per well, 37℃and 5% CO ₂ were cultured overnight. The medium was changed to 0.5% fbs in MEM and 0.5% fbs in MEM medium diluted test compound was added at a final test compound concentration of 10 μm, 4-fold dilution of compound, 9 concentration gradients total. After 4-5 hours of incubation, 10. Mu.l TGF-beta-1 was added. The final concentration of TGF-1 was 0.5ng/ml. Mu.l of medium was added instead of TGF beta as negative control. No test compound was added to the blank and tgfβ -1 was added. Bright Glo reagent was added to each well and chemiluminescent signal values were read on a microplate reader.

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

percentage inhibition = (1- (chemiluminescent signal value of test compound-chemiluminescent signal value of blank)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank)) ×100%;

the percent inhibition of compounds at different concentrations was plotted against compound concentration, and IC ₅₀ values were calculated by fitting a curve according to a four parameter model by the following formula:

y=min+ (Max-Min)/(1+ (x/IC ₅₀)/(Hillslope)), where y is the percent inhibition, max and Min are the maximum and minimum values, respectively, of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

The experimental results are shown in table 3 below:

TABLE 3 inhibition of HEK293-SBE cell luciferase reporter by the compounds of the invention

Examples numbering	IC₅₀(nM)
		Example 1	20.87±2.56
Example two	8.61±0.77
		Example IV	20.91±2.25

As can be seen from Table 3, the compounds of the present invention have significant inhibitory effects on the TGF beta/Smad signaling pathway of HEK293-SBE cells.

Test example IV Biochemical hERG inhibition assay.

1. Test system:

Kit Predictor ^TM hERG fluorescence polarization detection kit (ThermoFisher), which contains positive control compound hERG potassium channel blocker E4031, hERG cell membrane, affinity Tracer tracker, and hERG buffer.

2. Test parameters:

hERG concentration 1X, tracker concentration 1nM, incubation time 2h;BMG PHERAstar FS FP.

3. The test method comprises the following steps:

The test was performed according to the kit instructions, the steps were as follows:

test group 10. Mu.M and 1. Mu.M of the test compound was added to a microplate containing hERG cell membranes, a Tracer having high hERG affinity was added to each well, and after incubating the microplate at room temperature for 2 hours, the change in fluorescence polarization (excitation wavelength: 540nm; emission wavelength: 590 nm) was detected using a multifunctional microplate reader.

Positive control group 30. Mu.M positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.

Blank control group, hERG buffer was used instead of test compound, and hERG cell membrane was not added, and the experimental method was the same as that of test group.

4. And (3) data processing:

Based on the data ratios, the percent inhibition (%) of the compounds of the invention against hERG at various concentrations was calculated and the range of half inhibition concentrations (IC ₅₀) of the compounds was judged.

Percentage inhibition (%) = (1- (fluorescence polarization value of test compound-fluorescence polarization value of positive control)/(fluorescence polarization value of blank control-fluorescence polarization value of positive control)) ×100%;

5. Experimental results:

Inhibition of hERG by compounds was determined using the methods described above and the results are shown in table 4 below.

TABLE 4 results of hERG inhibition assay of the compounds of the invention

Examples numbering	IC₅₀(μM)
		Example 1	>10

The test results show that the compounds of the invention have low affinity for hERG and have a competition for the affinity Tracer with an IC ₅₀ of greater than 10 μm, demonstrating that the compounds of the invention have a lower risk of cardiotoxicity associated with hERG ion channels.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

in,

R ¹ is selected from C _6-10 aryl and 5-10 membered heteroaryl, wherein the C _6-10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more R ⁴ ;

^R2 is selected from cyano and -C(=O)NR ^a R ^b ;

^Ra and ^Rb are each independently selected at each occurrence from hydrogen and _C1-6 alkyl, said _C1-6 alkyl being optionally substituted with one or more ^R6 ;

^R3 is selected from hydrogen;

R ⁴ is independently selected at each occurrence from deuterium, halogen and C _1-6 alkyl, said C _1-6 alkyl being optionally substituted with one or more halogens;

^R6 at each occurrence is independently selected from halogen, hydroxy, _C1-6 alkyl and amino;

X is selected from -CH ₂ ;

Y is selected from -CH ₂ -;

Z is selected from -CH-.

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

R ⁴ at each occurrence is independently selected from deuterium, halogen, C _1-6 alkyl and C _1-6 haloalkyl.

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

R ⁴ at each occurrence is independently selected from halogen.

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

^R4 at each occurrence is independently selected from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from phenyl and 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R ⁴ .

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from phenyl, which is optionally substituted with one or more R ⁴ .

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from phenyl, pyridinyl and pyrazolyl, and the phenyl, pyridinyl or pyrazolyl is optionally substituted with one or more R ⁴ .

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted with one or more groups independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from phenyl, which is optionally substituted with one or more halogens.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from

12. The compound according to any one of claims 1 to 4 or 6 to 11 or a pharmaceutically acceptable salt thereof, wherein:

^R6 at each occurrence is independently selected from hydroxy.

13. The compound according to any one of claims 1 to 4 or 6 to 11 or a pharmaceutically acceptable salt thereof, wherein:

^R2 is selected from cyano, -C(=O) _NH2 , -C(=O)N(H) _CH3 , The wavy line Indicates the point of attachment of the group to the rest of the molecule.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

16. A kit comprising:

a) at least one compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as a first therapeutic agent, or a pharmaceutical composition according to claim 15 as a first pharmaceutical composition;

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

c) optional packaging and/or instructions.

17. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and/or treating a disease or condition mediated at least in part by TGFβR1.

18. The use of claim 17, wherein the disease or condition mediated at least in part by TGF[beta]R1 is selected from cancer.

19. The use according to claim 18, wherein the disease or condition mediated at least in part by TGFβR1 is selected from liver cancer.

20. A method for preparing a compound according to any one of claims 1 to 14, which is carried out by the following reaction scheme 1, 2 or 3:

Route 1

LG ₁ and LG ₂ are each independently a leaving group;

W is selected from boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and tri-n-butyltin; and R ¹ , R ² , R ³ , X, Y and Z are as defined in any one of claims 1 to 14;

Route 2

in,

LG ₁ is a leaving group;

^R2 is -C(= ^O ) ^NRaRb ; and

R ¹ , R ³ , X, Y, Z, Ra and ^{R b} ^are as defined in any one of claims 1 to 14;

Route 3

in,

^R2 is -C(= ^O ) ^NRaRb ; and

R ¹ , R ³ , X, Y, Z, Ra and ^{R b} ^are as defined in any one of claims 1-14.

21. The method of claim 20, wherein _LG1 and _LG2 are each independently methylthio and halogen.

22. The method of claim 20, wherein _LG1 and _LG2 are each independently chlorine or bromine.