Heterocyclic compounds, pharmaceutical compositions comprising the same, processes for their preparation and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a heterocyclic compound, a pharmaceutical composition containing the same, a preparation method therefor, and use thereof. Specifically, the present application provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically labeled compound, metabolite or prodrug thereof, which exhibits good TGFbetaR1 inhibitory activity, can be used as a highly efficient and highly selective TGFbetaR1 inhibitor, and has antitumor activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to a heterocyclic compound with TGFβR1 inhibitory activity, a pharmaceutical composition comprising the same, a preparation method thereof and uses thereof. BACKGROUND

[0002] Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates various cellular responses, such as cell proliferation, differentiation, migration and apoptosis. The TGF-β superfamily includes TGF-β1, TGF-β2, TGF-β3, activin, inhibin, bone morphogenetic protein, etc. TGF-β signals through two highly conserved single-pass transmembrane serine / threonine kinases, TGFβR1 and TGFβR2 (ACS Med. Chem. Lett., 2018, 9, 1117).

[0003] Smads are important intracellular TGF-β signal transduction and regulation molecules that can directly transduce TGF-β signals from the cell membrane to the nucleus. The TGF-β / Smads signaling pathway plays an important role in the occurrence and development of tumors. In TGF-β / Smads signal transduction, activated TGF-β first binds to TGFβR2 on the surface of the cell membrane to form a heterodimeric complex, which is further recognized and bound by TGFβR1. Activated TGFβR1 further phosphorylates Smad2 / Smad3 protein, which further binds to Smad4 to form a heterotrimeric complex, which enters the nucleus and cooperates with auxiliary activation / inhibition factors to regulate the transcription of target genes (Nature, 2003, 425, 577). Any change in any link of the TGF-β / Smads signaling pathway will lead to abnormal signal transduction pathways (PNAS, 2019, 116, 9166).

[0004] The TGF-β signaling pathway is dysregulated in many diseases, including cancer. The level of TGFβR1 protein is significantly increased in gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, liver cancer, lung cancer, cervical cancer and head and neck cancer cell lines and tumor tissues. Activation of the TGF-β signaling pathway triggers significant pathological effects in the tumor stroma, including immunosuppression, vascular regeneration and connective tissue hyperplasia. In addition, the TGF-β signaling pathway can enhance the invasiveness of tumor cells, promote epithelial-mesenchymal transition and increase the tolerance to treatment of tumor epithelial cells (Nat. Neurosci., 2014, 17, 943).

[0005] Currently, the development of inhibitors against the key target TGFβR1 in the TGF-β signaling pathway has gradually been valued in the pharmaceutical industry, and published patent applications include WO 02 / 094833 A1, WO 2009 / 150547 A1, WO 2017 / 035118 A1, WO 2018 / 019106 A1, etc. However, there is still an urgent need in the art for new TGFβR1 inhibitors, especially TGFβR1 inhibitors with high activity and high selectivity. SUMMARY

[0006] The present application, through a large number of researches, surprisingly found a kind of heterocyclic compound and its corresponding preparation method. The compound can significantly inhibit the activity of TGFβR1, and has good selectivity between TGFβR1 and TGFβR2. As a TGFβR1 inhibitor, it can be used for treating proliferative disorders and apoptosis disorders mediated at least in part by the TGF-β signaling pathway, especially diseases mediated at least in part by TGFβR1, such as cancer, for example, liver cancer.

[0007] In a first aspect, the present application provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite or prodrug thereof:

[0008]

[0009] wherein,

[0010] R 1 is 5-10 membered heteroaryl, optionally substituted with one or more R 4 ;

[0011] R 2 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, cyano, -C(=O)NR a R b and -C(=O)OR a ;

[0012] 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 being optionally substituted with one or more R 5 ; or R a , Rb and the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring, which is optionally substituted with one or more R 5 ;

[0013] R 3 is selected from hydrogen and -NR c ; d

[0014] 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 being optionally substituted with one or more R 6 ;

[0015] R 4 is at each occurrence 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 being optionally substituted with one or more halogen;

[0016] R 5 is at each occurrence independently selected from halogen, hydroxyl, 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 being optionally substituted with one or more hydroxyl;

[0017] R 6 is at each occurrence independently selected from halogen, hydroxyl, 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 being optionally substituted with one or more selected from hydroxyl and C​1-6 alkyl group is substituted;

[0018] Y is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 alkylthio, C 3-8 cycloalkylthio, C 1-6 alkylamino, C 3-8 cycloalkylamino and 4-8 membered heterocyclyl;

[0019] Z is selected from -CR 7 - and -N-; and

[0020] R 7 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl and cyano.

[0021] In a second aspect, the present application provides a pharmaceutical composition comprising at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0022] In a third aspect, the present application provides a kit-of-parts comprising:

[0023] a) at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite or prodrug thereof, as a first therapeutic agent, or a pharmaceutical composition of the present application as a first pharmaceutical composition;

[0024] 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

[0025] c) optionally packaging and / or instructions.

[0026] In a fourth aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite or prodrug thereof, or a pharmaceutical composition of the present application, for use as a TGFpR1 inhibitor for the prevention and / or treatment of a disease or disorder mediated at least in part by TGFpR1, in particular cancer, e.g. liver cancer.

[0027] In a fifth aspect, the present application provides use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso, isotopically-labeled, metabolite or prodrug thereof or a pharmaceutical composition of the present application as a TGFβR1 inhibitor.

[0028] In a sixth aspect, the present application provides use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso, isotopically-labeled, metabolite or prodrug thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing and / or treating a disease or disorder mediated at least in part by TGFβR1, especially cancer, e.g. liver cancer.

[0029] In a seventh aspect, the present application provides a method for preventing and / or treating a disease or disorder mediated at least in part by TGFβR1, especially cancer, e.g. liver cancer, comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso, isotopically-labeled, metabolite or prodrug thereof or a pharmaceutical composition of the present application.

[0030] In an eighth aspect, the present application provides a method for preparing a compound of the present application, comprising:

[0031] Step 1-1: condensation reaction of compound SM1 and N,N-dimethylformamide dimethyl acetal to obtain compound IM1

[0032]

[0033] Step 1-2: cyclization reaction of compound IM1 and compound SM2 to obtain compound IM2

[0034]

[0035] Step 1-3: substitution reaction of compound IM2 to obtain compound IM3

[0036]

[0037] Step 1-4: substitution reaction of compound IM3 and SM3 to obtain a compound of Formula I

[0038]

[0039] wherein LG is a leaving group, such as phenoxy and halogen; and,

[0040] Y, Z, R 1 , R 2 and R 3As defined above.

[0041] The compounds of this invention can serve as highly efficient and selective TGFβR1 inhibitors, exhibiting antitumor activity with fewer toxic side effects and drug interactions. The synthesis method is mild, simple, and easy to perform, making it suitable for large-scale industrial production. Detailed Implementation

[0042] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for description only and not for limiting specific embodiments.

[0043] Definitions

[0044] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0045] As used herein, the terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0046] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. For example, as used herein, the term "C" is... 1-6 "Alkyl" refers to a straight-chain or branched group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogens.

[0047] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated nonaromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, for example 3 to 10, 3 to 8, 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 from 3 to 8 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0048] As used herein, the term "alkoxy" refers to an "alkyl" group as defined above attached to the parent molecular moiety through an oxygen atom, for example, C 1-6 alkoxy, C 1-3 alkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, and the like, which can be optionally substituted with one or more (such as 1 to 3) substituents, which can be the same or different.

[0049] As used herein, the term "cycloalkoxy" refers to a "cycloalkyl" group as defined above attached to the parent molecular moiety through an oxygen atom, for example, C 3-8 cycloalkoxy, C 3-6 cycloalkoxy. C 3-8 Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like, which can be optionally substituted with one or more (such as 1 to 3) substituents, which can be the same or different.

[0050] As used herein, the term "alkylthio" refers to an "alkyl" group as defined above attached to the parent molecular moiety through a sulfur atom, for example, C 1-6 alkylthio, C 1-3 alkylthio. C 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, t-butylthio, pentoxy, hexyloxy, and the like, which can be optionally substituted with one or more (such as 1 to 3) substituents, which can be the same or different.

[0051] As used herein, the term "cycloalkylthio" refers to a "cycloalkyl" group as defined above attached to the parent molecular moiety through a sulfur atom, for example, C 3-8 cycloalkylthio, C 3-6 cycloalkylthio. C 3-8 Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like, which can be optionally substituted with one or more (such as 1 to 3) substituents, which can be the same or different.

[0052] As used herein, the term "halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0053] 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" refers to a haloalkyl group having 1 to 6 carbon atoms, including, but not limited to, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, and the like. A haloalkyl group herein is optionally substituted with one or more (such as 1 to 3) substituents described herein.

[0054] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) groups selected from C(=0), O, S, S(=0), S(=0)2, N, and NR (R represents a hydrogen atom or a substituent group, such as, but not limited to, alkyl or cycloalkyl). The heterocyclyl group can be saturated or unsaturated. A saturated heterocyclyl group can be referred to as a heterocycloalkyl group, such as a 3-8 membered heterocycloalkyl group, a 5-6 membered heterocycloalkyl group, and the like. Unless otherwise specifically indicated herein, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or more ring ring system, which can include fused ring systems, annulated ring systems, bridged ring systems, or spirocyclic ring systems. In particular, a 3-8 membered heterocyclyl group is a group having 3-8 carbon atoms and heteroatoms in the ring, such as, for example, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 carbon atoms and heteroatoms (referred to as 4 to 8 membered, 4 to 7 membered, 4 to 6 membered, 5 to 8 membered, 5 to 7 membered, and 5 to 6 membered heterocyclyl groups, respectively), such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, azepinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like; as well as annelated derivatives or benzo derivatives or heteroaryl annelated derivatives or spirocyclic derivatives, and the like.

[0055] 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, azulenyl, azuleny, 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. The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, and the like). ​

[0056] 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, particularly having 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and, in each case, may be benzofused. 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 containing at least one heteroatom that may be the same or different (the heteroatom is, for example, N, O, or S). Examples of 5-10 membered heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[a] derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[a] derivatives. The heteroaryl group is optionally substituented with one or more (such as one to three) suitable substituents (e.g., halogen, C). 1-6 Alkyl groups, etc., are substituted.

[0057] As used herein, the term "alkylamino" refers to a group in which one hydrogen atom of an amino group is replaced by an alkyl group; for example, as used herein, the term "C" refers to a group in which one hydrogen atom of an amino group is replaced by an alkyl group. 1-6 "alkylamino" refers to an amino group where one hydrogen atom is separated from the carbon atom by a carbon atom. 1-6 Alkyl-substituted groups can be represented as C0 1-6 Alkyl-NH-.

[0058] As used herein, the term "cycloalkylamino" refers to a group in which one hydrogen atom on an amino group is replaced by a cycloalkyl group; for example, as used herein, the term "C" refers to a group in which one hydrogen atom on an amino group is replaced by a cycloalkyl group. 3-8 "Cycloalkylamino" refers to an amino group where one hydrogen atom is separated from the carbon atom by a carbon atom. 3-8 Cycloalkyl-substituted groups can be represented as C 3-8 Cycloalkyl-NH-.

[0059] As used herein, the term "hydroxyalkyl" refers to a group in which one hydrogen atom on an alkyl group is replaced by a hydroxyl group; for example, as used herein, the term "hydroxyC" refers to a group in which one hydrogen atom on an alkyl group is replaced by a hydroxyl group. 1-6 "alkyl" refers to C 1-6 A group in which one hydrogen atom on an alkyl group is replaced by a hydroxyl group can be represented as -C. 1-6 Alkyl-OH.

[0060] As used in this article, the term "hydroxyl group" refers to -OH.

[0061] As used in this article, the term "cyano" refers to -CN.

[0062] As used in this article, the term "amino" refers to -NH2.

[0063] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) atoms (e.g., hydrogen atoms) or atom groups (e.g., triflate groups) of the designated group are replaced with other atoms or atom groups, provided that the designated group meets the valence requirements in the present context 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," then the substituent can be unsubstituted or substituted. If a first substituent is described as optionally being substituted by one or more of a list of second substituents, then one or more hydrogen atoms of the first substituent can be individually or independently replaced by one or more of the list of second substituents, or not replaced.

[0064] 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.

[0065] Unless specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0066] The term "pharmaceutically acceptable" as used herein means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients of a formulation, and / or the mammal being treated therewith.

[0067] The term "pharmaceutically acceptable salt" generally includes, but is not limited to, salts of the compounds of the application with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases, which are also known as acid or base addition salts.

[0068] The term "pharmaceutically acceptable ester" generally includes, but is not limited to, esters of the compounds of the application with pharmaceutically acceptable carboxylic or sulfonic acids, which are also known as carboxylic or sulfonic acid esters.

[0069] The term "isomer" refers to a compound having the same molecular formula but different structural arrangements of atoms.

[0070] The term "stereoisomers" (or "optical isomers") refers to stable isomers having a fixed orientation of atoms in space, resulting from the presence of at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) that is capable of producing an asymmetry plane perpendicular to which the plane polarized light can be rotated. Since the compounds of the present application can possess asymmetric centers that potentially give rise to stereoisomers and other chemical structures, the present application also includes these stereoisomers and mixtures thereof. Since the compounds of the present application (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in single stereoisomer form, racemates, mixtures of enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in racemic form. However, if desired, pure stereoisomers can be prepared or isolated from such mixtures of compounds, either as single enantiomers or diastereomers, or as single stereoisomer-enriched mixtures (purity > 98%, > 95%, > 93%, > 90%, > 88%, > 85%, or > 80%). As described below, single stereoisomers of the compounds are prepared from optically pure starting materials having the desired chiral centers, or are prepared by resolution of mixtures of enantiomeric products. For example, resolutions of mixtures of enantiomeric products can be effected by standard techniques such as formation of diastereomeric salts or complexes that are separated by fractional crystallization or

[0071] The term "tautomers" (or "tautomeric forms") refers to structural isomers that have different energy states and can interconvert through low energy barriers. If tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (or proton-shift tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0072] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. One skilled in the art can obtain polymorphs of a molecule by a number of known methods. These methods include, but are not limited to, melt-recooling, melt- cooling, solvent-recooling, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. In addition, polymorphs can be detected, classified, and characterized using well-known techniques, including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM), among others.

[0073] The term "solvate" refers to a substance having a compound of the present application (or a pharmaceutically acceptable salt thereof) combined with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemi-hydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetoneates, and the like.

[0074] The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or a nitrogen-containing (hetero)aromatic ring. For example, the nitrogen atom at position 1 in the parent nucleus of a compound of Formula I can form a corresponding nitroxide.

[0075] The term "isotopically-labeled" refers to a derivative compound formed by replacing a particular atom in a compound of the present application with an isotopic atom thereof. Unless otherwise indicated, the compounds of the present application include compounds of all isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S, and 37 Cl.

[0076] The term "metabolite" refers to a derivative compound formed by metabolism of a compound of the present application. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th ed.) [M], McGraw-Hill International Editions, 1996.

[0077] The term "prodrug" means a derivative of a compound of the application which, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the application. Particularly preferred derivatives or prodrugs are compounds which enhance the bioavailability of a compound of the application when administered to a subject (e.g., are more readily absorbed into the blood) or facilitate the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise specified, all prodrug forms of a compound of the application are within the scope of the application, and various prodrug forms are well known in the art.

[0078] The term "independently" means that at least two groups (or ring systems) in a structure, which have the same or similar range of values, can have the same or different meaning in a particular instance. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl; and similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl.

[0079] The present application also encompasses compounds of the present application that contain protecting groups. It can be necessary and / or desirable to protect sensitive or reactive groups of the compounds of the present application during the preparations of the compounds of the present application, thus forming protected forms of the compounds of the present application. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0080] Compounds

[0081] It is an object of the present application to provide a compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically-labeled, metabolite, or prodrug thereof,

[0082]

[0083] wherein,

[0084] R 1It is a 5-10 methyl aryl group, wherein the 5-10 methyl aryl group is optionally surrounded by one or more R groups. 4 replace;

[0085] R 2 Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, cyano, -C(=O)NR a R b and -C(=O)OR a ;

[0086] R a and R b Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic groups are optionally surrounded by one or more R 5 Replace; or R a R b Together with the nitrogen atoms attached to them, they form 4-8 membered heterocycles, which are optionally separated by one or more R atoms. 5 replace;

[0087] R 3 Selected from hydrogen and -NR c R d ;

[0088] R c and R d Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, -C(=O)R a C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6 replace;

[0089] R 4 Each time it appears, it is independently selected from deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 The cycloalkyl group may optionally be substituted with one or more halogens;

[0090] R 5 each independently at each occurrence is selected from halogen, hydroxyl, 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 is optionally substituted with one or more hydroxyl groups;

[0091] R 6 each independently at each occurrence is selected from halogen, hydroxyl, 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 is optionally substituted with one or more groups selected from hydroxyl and C 1-6 alkyl;

[0092] Y is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, and cyano. 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 alkylthio, C 3-8 cycloalkylthio, C 1-6 alkylamino, C 3-8 cycloalkylamino, and 4-8 membered heterocyclyl;

[0093] Z is selected from -CR 7 - and -N-; and

[0094] R 7 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, and cyano.

[0095] According to some embodiments of the application, the compound of the application is a compound of formula I-1:

[0096]

[0097] wherein,

[0098] R 1 , R 2 , R 3 , and Y are as defined above.

[0099] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 4 is, at each occurrence, independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-8 cycloalkyl.

[0100] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 4 is, at each occurrence, independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl.

[0101] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 4 is, at each occurrence, independently selected from fluorine, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl.

[0102] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 1 is a 5-6 membered heteroaryl, optionally substituted with one or more R 4 groups.

[0103] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 1 is a 5-6 membered heteroaryl, optionally substituted with one or more groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl.

[0104] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 1 is a 5-6 membered nitrogen-containing heteroaryl, optionally substituted with one or more R 4 groups.

[0105] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 1 is a 5-6 membered nitrogen-containing heteroaryl, optionally substituted with one or more groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl.

[0106] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 1 Selected from pyridyl and pyrazolyl, wherein the pyridyl or pyrazolyl group is optionally surrounded by one or more R groups. 4 replace.

[0107] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 1 Selected from pyridyl and pyrazolyl, wherein the pyridyl or pyrazolyl group is optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl.

[0108] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 1 Selected from Among them, the wavy line This indicates the connection point between the group and the rest of the molecule.

[0109] According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 5 Each time it appears, it is independently selected from halogen, hydroxyl, C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-6 Cycloalkyl, hydroxy C 3-6 Cycloalkyl and 4-8 membered heterocyclic groups.

[0110] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 5 Each time it appears, it is independently selected from hydroxyl and C. 1-6 alkyl.

[0111] According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R a and R b Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6-membered heterocyclic groups are optionally surrounded by one or more R 5 Replace; or R a R band R together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl ring, optionally substituted with one or more R 5 substituted.

[0112] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, 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 is optionally substituted with one or more groups independently selected from hydroxyl and C 1-6 alkyl; or R a , R b and the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl ring, optionally substituted with one or more groups independently selected from hydroxyl and C 1-6 alkyl.

[0113] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, 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 is optionally substituted with one or more R 5 substituted; or R a , R b and the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl ring, optionally substituted with one or more R 5 substituted.

[0114] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, 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 is optionally substituted with one or more groups independently selected from hydroxyl and C 1-6 alkyl; or R a , R b and the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl ring, optionally substituted with one or more groups independently selected from hydroxyl and C 1-6Alkyl groups are substituted.

[0115] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R a and R b Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, azahexacyclic butyl, and piperidinyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, aziridine, or piperidinyl groups are optionally separated by one or more groups independently selected from hydroxyl and C. 1-6 Alkyl group substitution; or R a R b Together with the nitrogen atoms attached to them, they form a nitrogen-containing heterocyclic butyl group, which is optionally separated by one or more atoms independently selected from hydroxyl and C. 1-6 Alkyl groups are substituted.

[0116] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R a and R b Each of the following groups, when appearing independently, is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, aziridine, and piperidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, aziridine, and piperidinyl groups are optionally substituted by one or more groups independently selected from hydroxyl, methyl, and ethyl; or R a R b Together with the nitrogen atoms attached to them, they form a azircyclic butyl group, which is optionally substituted by one or more groups independently selected from hydroxyl and methyl groups.

[0117] According to some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 2 Selected from hydrogen, halogen, cyano, and -C(=O)NR a R b .

[0118] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 2 Selected from hydrogen, cyano, and -C(=O)NR a R b .

[0119] In some embodiments of the present invention, in the compounds of formula I and formula I-1 of the present invention, R 2 Selected from hydrogen, cyano, and -C(=O)NR a R b , where R a and Rb independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, azetidinyl and piperidinyl, said C 1-6 alkyl, C 3-6 cycloalkyl, azetidinyl or piperidinyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxyl and C 1-6 alkyl; or R a , R b and the nitrogen atom to which they are attached together form a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of hydroxyl and C 1-6 alkyl.

[0120] In some embodiments of the present application, in the compounds of formula I and formula I-1 of the present application, R 2 is selected from the group consisting of hydrogen, cyano and -C(=O)NR a R b wherein R a and R b are each independently at each occurrence selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclobutyl, azetidinyl and piperidinyl, said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclobutyl, azetidinyl and piperidinyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, methyl and ethyl; or R a , R b and the nitrogen atom to which they are attached together form azetidinyl, said azetidinyl is optionally substituted with one or more groups independently selected from the group consisting of hydroxyl and methyl.

[0121] In some embodiments of the present application, in the compounds of formula I and formula I-1 of the present application, R 2 is selected from the group consisting of hydrogen, cyano, -C(=O)NH2, -C(=O)N(H)CH3, wherein the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0122] According to some embodiments of the present application, in the compounds of formula I and formula I-1 of the present application, R 6 are each independently at each occurrence selected from the group consisting of 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 is optionally substituted with one or more groups selected from the group consisting of hydroxyl and C 1-6 alkyl.

[0123] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 6 each occurrence is independently 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 is optionally substituted with one or more groups selected from hydroxy and C 1-6 alkyl.

[0124] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R 6 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 is optionally substituted with a group selected from hydroxy and C 1-6 alkyl.

[0125] According to some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R c and R d each occurrence is independently selected from hydrogen, C 6-10 aryl and 5-10 membered heteroaryl, said C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 6 substituents.

[0126] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R c and R d each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl is optionally substituted with one or more R 6 substituents.

[0127] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R c and R d each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more R 6 substituents.

[0128] In some embodiments of the application, in the compounds of formula I and formula I-1 of the application, R c and R d each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more groups each independently selected from C1-6 alkyl, C 1-6 alkoxy and piperazinyl, said C 1-6 alkyl or piperazinyl is optionally substituted with a radical selected from the group consisting of hydroxy and C 1-6 alkyl.

[0129] According to some embodiments of the application, in the compounds of formula I and I-1 of the application, R 3 is selected from the group consisting of hydrogen, wherein the wavy line represents the point of attachment of the radical to the rest of the molecule.

[0130] According to some embodiments of the application, in the compounds of formula I and I-1 of the application, Y is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, C 1-6 alkylamino and C 3-8 cycloalkylamino.

[0131] In some embodiments of the application, in the compounds of formula I and I-1 of the application, Y is C 1-6 alkyl.

[0132] In some embodiments of the application, in the compounds of formula I and I-1 of the application, Y is methyl, ethyl and isopropyl.

[0133] According to some embodiments of the application, in the compounds of formula I of the application, R 7 is selected from the group consisting of hydrogen, halogen, C 1-6 haloalkyl and cyano.

[0134] In some embodiments of the application, in the compounds of formula I of the application, R 7 is hydrogen.

[0135] According to some embodiments of the application, in the compounds of formula I of the application, Z is -CR 7 -.

[0136] The present application encompasses the compounds of formula I and I-1 resulting from any combination of the preferred radicals described above. In some embodiments of the application, in the compounds of formula I and I-1 of the application,

[0137] R 1 is selected from the group consisting of pyridyl and pyrazolyl, said pyridyl or pyrazolyl being optionally substituted with one or more radicals independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6haloalkyl and C 3-6 cycloalkyl;

[0138] R 2 selected from the group consisting of hydrogen, cyano and -C(=O)NR a R b wherein R a and R b are each independently at each occurrence selected from the group consisting of 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 being optionally substituted with one or more groups independently selected from hydroxy and C 1-6 alkyl; or R a , R b and the nitrogen atom to which they are attached together form a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring being optionally substituted with one or more groups independently selected from hydroxy and C 1-6 alkyl;

[0139] R 3 selected from the group consisting of hydrogen and -NR c R d ;

[0140] R c and R d are each independently at each occurrence selected from the group consisting of hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted with one or more groups each independently selected from C 1-6 alkyl, C 1-6 alkoxy and piperazinyl, said C 1-6 alkyl or piperazinyl being optionally substituted with a group selected from hydroxy and C 1-6 alkyl; and

[0141] Y is C 1-6 alkyl.

[0142] According to some embodiments of the application, the compound of the application is selected from:

[0143]

[0144]

[0145] Methods of preparation

[0146] It is another object of the present application to provide a process for preparing the compound of the present application, comprising:

[0147] Step 1-1: condensation reaction of compound SM1 and N,N-dimethylformamide dimethyl acetal to give compound IM1

[0148]

[0149] Step 1-2: Compound IM1 and compound SM2 undergo cyclization reaction to obtain compound IM2

[0150]

[0151] Step 1-3: Compound IM2 undergo substitution reaction to obtain compound IM3

[0152]

[0153] Step 1-4: Compound IM3 and SM3 undergo substitution reaction to obtain compound of formula I

[0154]

[0155] wherein, LG is a leaving group, for example phenoxy and halogen; and,

[0156] Y, Z, R 1 , R 2 and R 3 are as defined above.

[0157] Step 1-1: Compound SM1 and N,N-dimethylformamide dimethyl acetal undergo condensation reaction to obtain compound IM1

[0158] In some embodiments of the present application, the reaction is carried out at a suitable temperature in the range of 0-200 °C, preferably 0-100 °C.

[0159] Step 1-2: Compound IM1 and compound SM2 undergo cyclization reaction to obtain compound IM2:

[0160] In some embodiments of the present application, the reaction is carried out in a suitable organic solvent, which can be selected from alcohols (for example MeOH, EtOH, n-BuOH, and the like), THF, AcOH, Diox, and any combination thereof, preferably methanol or ethanol.

[0161] In some embodiments of the present application, the reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base, the organic base can be selected from DIPEA, TEA, t-BuOK, sodium methoxide, sodium ethoxide, and Py, the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably sodium methoxide or sodium ethoxide.

[0162] In some embodiments of the present application, the reaction is carried out at a suitable temperature in the range of 0-200 °C, preferably 100-200 °C.

[0163] Step 1-3: Compound IM2 undergoes substitution reaction to give compound IM3

[0164] In some embodiments of the present application, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, and the like), nitriles (such as AN, and the like), NMP, DMF, DMA, THF, Diox, DMSO, aromatic hydrocarbons (such as TL, XY, and the like), and any combination thereof, preferably DMF, THF, or DCM.

[0165] When LG is halogen:

[0166] In some embodiments of the present application, the reaction is carried out in the presence of a suitable halogenating reagent, which can be selected from SOCl2, POBr3, and POCl3, preferably SOCl2.

[0167] In some embodiments of the present application, the reaction is carried out at a suitable temperature, which is in the range of 0-200 °C, preferably 50-150 °C.

[0168] When LG is phenoxy:

[0169] In some embodiments of the present application, the reaction can occur by sequentially carrying out a halogenation reaction and a further substitution reaction. The halogenation reaction is carried out in the presence of a suitable halogenating reagent, which can be selected from SOCl2, POBr3, and POCl3, preferably SOCl2; the further substitution reaction is carried out in the presence of a suitable substitution reagent, which can be selected from phenol and sodium phenoxide.

[0170] In some embodiments of the present application, the further substitution reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base, the organic base can be selected from DIPEA, TEA, t-BuOK, and Py, the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3, and NaOH, preferably NaH.

[0171] In some embodiments of the present application, the further substitution reaction is carried out at a suitable temperature, which is in the range of 0-200 °C, preferably 0-80 °C.

[0172] Step 1-4: Compound IM3 and SM3 undergo substitution reaction to give a compound of Formula I

[0173] In some embodiments of the present application, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, and the like), nitriles (such as acetonitrile and the like), N-methylpyrrolidinone, DMF, DMA, tetrahydrofuran, dioxane, DMSO, and any combination thereof, preferably DMSO or DMF.

[0174] In some embodiments of the present application, the reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base, the organic base can be selected from DIPEA, triethylamine, potassium tert-butoxide, and pyridine, the inorganic base can be selected from potassium phosphate, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, and sodium hydroxide, preferably potassium carbonate, lithium hydroxide, or sodium hydride.

[0175] In some embodiments of the present application, the reaction is carried out at a suitable temperature, which is 0-200 °C, preferably 50-150 °C.

[0176] Pharmaceutical compositions and kits

[0177] It is another object of the present application to provide a pharmaceutical composition comprising at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso, isotopically-labeled, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0178] It is another object of the present application to provide a pharmaceutical kit comprising:

[0179] a) at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso, isotopically-labeled, metabolite, or prodrug thereof, as a first therapeutic agent, or a pharmaceutical composition of the present application as a first pharmaceutical composition;

[0180] 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

[0181] c) optionally packaging and / or instructions.

[0182] The term "pharmaceutically acceptable carrier" means a pharmaceutically-acceptable agent that is adrninistered in conjunction with a therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, commensurate with a reasonable benefit / risk ratio, as is determined by a person skilled in the art.

[0183] The pharmaceutical compositions of the present application can act systemically and / or locally. To this end, they can be administered by appropriate routes, such as parenterally, topically, intravenously, orally, subcutaneously, intra-arterially, intra-dermally, transdermally, rectally, intracranially, intraperitoneally, intranasally, intramuscularly or as an inhalant.

[0184] For these routes of administration, the pharmaceutical compositions of the present application can be administered in a suitable dosage form. Dosage forms that can be used in the present application include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

[0185] When administered orally, the pharmaceutical compositions of the present application can be formulated in any orally acceptable dosage form including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like. In such tablets, the carrier generally includes lactose and corn starch. Lubricating agents, such as magnesium stearate, also can be added. In such capsules, the carrier generally includes lactose and dried corn starch. The aqueous suspensions can be formulated by dispersing the API in the appropriate aqueous base that contains the appropriate emulsifying agent, suspending agent and / or sweetening, flavoring or coloring agent.

[0186] The pharmaceutical compositions of the present application also can be administered in the form of sterile injectable solutions, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable aqueous or oleaginous solutions. The carrier that can be used includes, but is not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils can be employed as a solvent or suspending medium, such as, for example, synthetic mono- or diglycerides.

[0187] The pharmaceutical compositions of the present application can comprise 0.01 mg to 1000 mg of at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof.

[0188] In some embodiments, the present application provides a method of making a pharmaceutical composition or pharmaceutical formulation of the present application, the method comprising combining at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0189] The kits of the present application can comprise 0.01 mg to 1000 mg of at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof.

[0190] In some embodiments, the present application provides a method of preparing a kit of the present application, the method comprising combining at least one compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application, with optionally at least one other therapeutic agent or a pharmaceutical composition comprising the other therapeutic agent, packaging, and / or instructions.

[0191] Methods of treatment and uses

[0192] The compounds of the present application can exhibit strong inhibitory effect on TGFβR1, IC 50 values can reach below 100 nM, and even below 10 nM for individual compounds, while exhibiting weak inhibitory effect on TGFβR2, and can be used as TGFβR1 inhibitors (especially TGFβR1 selective inhibitors).

[0193] It is another object of the present application to provide a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application for use as a TGFβR1 inhibitor for preventing and / or treating a disease or condition mediated at least in part by TGFβR1 (especially cancer, such as liver cancer).

[0194] It is another object of the present application to provide the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application as a TGFβR1 inhibitor.

[0195] It is another object of the present application to provide the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing and / or treating a disease or condition mediated at least in part by TGFβR1 (especially cancer, such as liver cancer).

[0196] It is another object of the present application to provide a method for preventing and / or treating a disease or condition mediated at least in part by TGFβR1 (especially 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 present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application.

[0197] The term "disease or disorder mediated at least in part by TGFβR1" refers to a disease in which at least a portion of the pathogenesis involves TGFβR1, including but not limited to cancer or fibrotic diseases.

[0198] The term "effective amount" refers to an amount that is capable of eliciting a biological or medical response of cells, tissues, organs, or organisms (e.g., individuals), and sufficient to achieve the desired prophylactic and / or therapeutic effect.

[0199] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single dose can be administered, doses can be administered at intervals, or the dose can be proportionally reduced or increased as actual conditions require. It will be appreciated that the specific dose level and frequency of dosage for any particular individual can be adjusted by the attending physician in accordance with the dosage teaching identified above and the individual's circumstances and response to the drug.

[0200] The amount of a compound of the present application that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, the severity of the disorder or condition, the route of administration, and the judgment of the prescribing physician. In general, an effective amount is in the range of about 0.001 to 10000 mg / kg of body weight per day. In some cases, an effective amount is in the range of about 0.01 to 1000 mg / kg of body weight per day. An effective amount can be administered in single or multiple doses, e.g., about 0.01 to 1000 mg / kg of body weight, typically about 0.1 to 500 mg / kg of body weight, per day. An exemplary dosage regimen is one or more times per day, or one or more times per week, or one or more times per month. When multiple doses are used, the intervals between single dosages can be daily, weekly, monthly or yearly. Alternatively, a sustained release formulation can be used where lower frequency dosing is required. The dosing and frequency of administration can vary depending on the half-life of the drug in the subject, and whether prophylactic or therapeutic applications are involved. In prophylactic applications, a relatively low dosage taken at extended intervals (e.g., weekly or monthly) can be appropriate, whereas in therapeutic applications, a relatively high dosage taken at relatively short intervals (e.g., daily) can be indicated. In some cases, a single dose can be administered.

[0201] The term "treatment" refers to the reduction or elimination of the disease or condition being targeted. A subject has been successfully "treated" if, after receiving a therapeutic amount of a compound of the application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the application, at least one indicia and symptom of the subject exhibits an observable and / or detectable reduction and / or improvement. It is understood that treatment includes, but is not limited to, complete treatment. Specifically, "treatment" means that a compound of the application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroso derivative, isotopically-labeled, metabolite, or prodrug thereof, or a pharmaceutical composition of the application can achieve at least one of the following effects, for example: (1) preventing the disease from occurring in an animal that can be predisposed to the disease but does not yet experience or display any disease pathology or symptomatology; (2) inhibiting the disease (i.e., arresting further progression of the pathology and / or symptomatology) in an animal that is experiencing or displaying the pathology or symptomatology of the disease; (3) ameliorating the disease (i.e., reversing the pathology and / or symptomatology) in an animal that is experiencing or displaying the pathology or symptomatology of the disease.

[0202] The term "prevention" refers to the prophylactic administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or condition. One of ordinary skill in the medical arts recognizes that the term "prevention" is not an absolute term. In the medical arts, it is understood that a drug is administered prophylactically to substantially reduce the likelihood or severity of a condition or symptoms of a condition, which is the intended meaning in the present disclosure. As used therein, the term "prevention" with respect to a condition or disease refers to avoiding the cause, effects, symptoms, or progression of the disease or condition prior to full manifestation of the disease or condition.

[0203] The term "administration" or "administering" means the process of applying a pharmaceutically active ingredient, such as a compound of the application, or a pharmaceutical composition comprising a pharmaceutically active ingredient, such as a pharmaceutical composition of the application, to an individual or a cell, tissue, organ, biological fluid, etc., of the individual, in order to contact the pharmaceutically active ingredient or the pharmaceutical composition with the individual or a cell, tissue, organ, biological fluid, etc., of the individual. 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, etc.

[0204] The term "in need thereof means the judgment of a physician or other care provider that an individual needs or will benefit from a prophylactic and / or therapeutic process, which judgment is based on various factors in the physician's or other care provider's area of expertise.

[0205] The term "individual" (or subject) includes humans or non-human animals. Individuals in this invention include individuals suffering from diseases and / or conditions (patients) and healthy individuals. Non-human animals in this invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc.; and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0206] Examples

[0207] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention.

[0208] All reagents and instruments used in the examples are commercially available conventional products. Unless otherwise specified, all conditions were performed under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" as used in this invention refers to 20℃ ± 5℃. When used to modify a numerical value or range, the term "about" as used in this invention refers to the value or range and a range of errors acceptable to those skilled in the art, such as ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0209] The meanings of the abbreviations in the conventional synthesis methods and in the examples and intermediate synthesis examples are shown in the table below.

[0210]

[0211]

[0212] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (NMR). 1 Determined by 1H-NMR and / or mass spectrometry (MS).

[0213] Nuclear magnetic resonance (NMR) 1 The H-NMR analysis was performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS).

[0214] The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings:

[0215] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, dd t: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: hertz, δ: chemical shift.

[0216] All chemical shift (δ) values are given in parts per million (ppm).

[0217] The instrument for the determination of mass spectrometry (MS) uses Agilent 6120B mass spectrometer, and the ion source is electrospray ion source (ESI).

[0218] Embodiments of the present application are prepared by preparative high performance liquid chromatography (Prep-HPLC) purification using the method shown below.

[0219] Method A:

[0220] Column: YMC (5 pm*19 mm*150 mm)

[0221] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0222] Time [min] Mobile phase A [%] Mobile phase B [%] Flow rate [mL / min] 0.00 7 93 28 2.00 7 93 28 18.00 90 10 28

[0223] Method B:

[0224] Column: Sunfire C 18 OBD (5 pm*19 mm*150 mm)

[0225] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid)

[0226]

[0227]

[0228] Method C:

[0229] Column: Sunfire C18 OBD (5 pm*19 mm*150 mm)

[0230] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Ammonium bicarbonate)

[0231] Time [min] Mobile phase A [%] Mobile phase B [%] Flow rate [mL / min] 0.00 10 90 28 16.00 70 30 28

[0232] Method D:

[0233] Column: Sunfire C 18 OBD (5 pm * 19 mm * 150 mm)

[0234] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Formic acid)

[0235] 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

[0236] Method E:

[0237] Column: Waters XBridge Prep C18 OBD 5 pm 19 x 150 mm

[0238] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Ammonium bicarbonate)

[0239] Time [min] Mobile phase A [%] Mobile phase B [%] Flow rate [mL / min] 0.00 10.0 90.0 28 16.00 90.0 10.0 28

[0240] Method F:

[0241] Column: Sunfire C 18 OBD (5 pm * 19 mm * 150 mm)

[0242] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Formic acid)

[0243] 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

[0244] Method G:

[0245] Column: Sunfire C 18 OBD (5 pm * 19 mm * 150 mm)

[0246] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Sodium bicarbonate)

[0247]

[0248] Method H:

[0249] Column: C 18 OBD (5 pm * 19 mm * 150 mm)

[0250] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (with 0.05% Sodium bicarbonate)

[0251]

[0252]

[0253] Preparation of compounds

[0254] Example 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinonitrile (Compound 1)

[0255]

[0256] Step 1: Synthesis of 5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-ol (Compound 1-2)

[0257] Ethyl 2-formyl 3-methylbutanoate (Compound 1-1, 6 g, 37.93 mmol) and 6- methylpyridine-2-carboxamide (1.85 g, 13.69 mmol) were dissolved in methanol (5 mL) at 25 °C, sodium methoxide methanol solution (5 mol / L, 5 mL) was added, and the reaction was carried out at 120 °C for 16 h. The reaction solution was extracted with dichloromethane (10 mL*3), washed with saturated brine (10 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound (810 mg).

[0258] ESI-MS (m / z): 230.1 [M+H] + .

[0259] Step 2: Synthesis of 4-chloro-5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidine (Compound 1-3)

[0260] 5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-ol (Compound 1-2, 800 mg, 3.49 mmol) was dissolved in dichlorosulfoxide (10 mL) at 25 °C, and two drops of N,N- dimethylformamide were added dropwise to catalyze the reaction, and the reaction was carried out at 90 °C for 0.5 h. The reaction solution was concentrated, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10 mL) three times, and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give the title compound (850 mg).

[0261] ESI-MS (m / z): 248.1 [M+H] + .

[0262] Step 3: Synthesis of 5-isopropyl-2-(6-methylpyridin-2-yl)-4- phenoxy pyrimidine (Compound 1-4)

[0263] At 25 °C, 4-chloro-5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidine (Compound 1-4, 850 mg, 3.43 mmol) and sodium phenolate (796.69 mg, 6.86 mmol) were dissolved in THF (5 mL) and reacted at 120 °C for 2 hours. The reaction solution was concentrated, extracted with ethyl acetate (10 mL) for 3 times, the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1 / 1 (v / v)) to give the title compound (880 mg).

[0264] ESI-MS (m / z): 306.1 [M+H] + .

[0265] Step 4: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinonitrile (Compound 1)

[0266] At 25 °C, 5-isopropyl-2-(6-methylpyridin-2-yl)-4-phenoxy pyrimidine (Compound 1-4, 30 mg, 98.24 umol) and 1H-pyrazolo[4,3-c]pyridine (23.41 mg, 196.48 umol) were dissolved in DMSO (3 mL), and LiOH (8.06 mg, 196.48 umol) was added, and reacted at 80 °C for 2 hours. The reaction solution was extracted with ethyl acetate (10 mL) for 3 times, the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography preparation (Method A) to give the title compound (22 mg).

[0267] ESI-MS (m / z): 331.1 [M+H] + .

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 8.08-8.04 (m, 2H), 7.84 (d, J = 6.1 Hz, 1H), 7.66-7.62 (m, 1H), 3.30 (p, J = 6.8 Hz, 1H), 2.68 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H).

[0269] Example Two: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinamide (Compound 2)

[0270]

[0271] To a solution of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinonitrile (20 mg, 60.54 umol) in tetrahydrofuran (3 mL) was added sodium hydroxide (4.84 mg, 121.07 umol) and then hydrogen peroxide (2 mL) was added slowly. The reaction was stirred at 25 °C for 1 h. The reaction was extracted with ethyl acetate (10 mL*3), washed with saturated aqueous sodium sulfite solution (10 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to give the crude product, which was purified by preparative high performance liquid chromatography (Method B) to give the title compound (4 mg).

[0272] The structure was characterized as follows:

[0273] 1 H NMR (400 MHz, DMSO-d6) d 12.39 (s, 1H), 9.44 (d, J = 5.9 Hz, 1H), 8.97 (s, 1H), 8.66 - 8.52 (m, 3H), 8.17 (d, J = 7.7 Hz, 1H), 8.00 (s, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 3.13 (p, J = 6.8 Hz, 1H), 2.62 (s, 3H), 1.36 (d, J = 6.8 Hz, 6H).

[0274] ESI-MS (m / z): 349.1 [M+H] + .

[0275] Example Three: Synthesis of N-(1,3-dihydroxypropan-2-yl)-4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (Compound 5)

[0276]

[0277] Step one: synthesis of methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinate (compound 5-1)

[0278] ESI-MS (m / z): 364.2 [M+H] + .

[0279] Step two: synthesis of N-(1,3-dihydroxypropan-2-yl)-4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (compound 5)

[0280] Methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (compound 5-1, 22 mg, 0.06 mmol) and 2-aminopropane-1,3-diol (55 mg, 0.6 mmol) were dissolved with DMSO (0.6 mL) and reacted at 100 °C for 3 h. The reaction solution was cooled to room temperature and directly purified by preparative high performance liquid chromatography (Method C). The title compound (16 mg) was obtained after lyophilization of the preparation solution. Its structure was characterized as follows:

[0281] 1 H NMR (400 MHz, DMSO-d6) d 11.8 (s, 1H), 9.36 (d, J = 6.0 Hz, 1H), 8.96 (s, 1H), 8.70 - 8.57 (m, 3H), 8.16 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 4.74 (t, J = 6.0 Hz, 2H), 4.15 - 4.00 (m, 1H), 3.67 - 3.45 (m, 4H), 3.17 - 3.04 (m, 1H), 2.62 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H).

[0282] ESI-MS (m / z): 423.2 [M+H] + .

[0283] Example Four: Synthesis of (S)-N-(2-hydroxypropyl)-4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (Compound 6)

[0284]

[0285] Methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinate (Compound 5-1, 20 mg, 55.03 umol) and (S)-1-aminopropan-2-ol (41.34 mg, 550.34 umol) were dissolved in dimethyl sulfoxide (1 mL) at 25 °C, and the temperature was raised to 100 °C for 3 hours. The reaction was directly purified by preparative high performance liquid chromatography (Method D) to give the title compound (8.5 mg).

[0286] Its structure was characterized as follows:

[0287] 1 H NMR (400 MHz, DMSO-d6) d 11.86 (s, 1H), 9.38 (d, J = 5.9 Hz, 1H), 9.00 (t, J = 5.8 Hz, 1H), 8.93 (s, 1H), 8.63 - 8.56 (m, 2H), 8.20 - 8.13 (m, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 4.84 (d, J = 4.8 Hz, 1H), 3.85 (dd, J = 6.4, 5.0 Hz, 1H), 3.27 (t, J = 5.9 Hz, 2H), 3.17 - 3.05 (m, 1H), 2.62 (s, 3H), 1.36 (dd, J = 6.8, 1.5 Hz, 6H), 1.10 (d, J = 6.2 Hz, 3H).

[0288] ESI-MS (m / z): 407.1 [M+H] + .

[0289] Example Five: Synthesis of (R)-N-(2-hydroxypropyl)-4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (Compound 7)

[0290]

[0291] Methyl 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (compound 5-1, 20 mg, 0.055 mmol) and (R)-1-aminopropane-2-ol (41 mg, 0.55 mmol) were dissolved in DMSO (0.5 mL), heated to 100 °C, and reacted for 2 h. After cooling to room temperature, the reaction solution was purified by preparative high-performance liquid chromatography (method E), and the preparative solution was freeze-dried to obtain the title compound (12 mg).

[0292] Its structural characterization is as follows:

[0293] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),9.37(d,J=5.9Hz,1H),9.00(t,J=5.7Hz,1H) ,8.93(s,1H),8.63-8.57(m,2H),8.16(d,J=7.7Hz,1H),7.86(t,J=7.7Hz,1H),7.39 (d,J=7.6Hz,1H),4.84(d,J=4.8Hz,1H),3.85(dt,J=11.1,6.1Hz,1H),3.26(t,J=6. 0Hz,2H),3.14-3.07(m,1H),2.62(s,3H),1.42-1.30(m,6H),1.10(d,J=6.2Hz,3H).

[0294] ESI-MS(m / z): 407.2[M+H]+.

[0295] Example 6: Synthesis of (3-hydroxyazacyclobut-1-yl)(4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)methyl ketone (compound 14)

[0296]

[0297] Step 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (compound 14-1)

[0298] Step 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinic acid (Compound 14-1)

[0299] ESI-MS (m / z): 350.1 [M+H] + .

[0300] Step two: Synthesis of (3-hydroxyazetidin-l-yl)(4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)pyridin-3-yl)methanone (Compound 14)

[0301] Step 1: Synthesis of 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4- yl)amino)nicotinic acid (Compound 14-1)

[0302] The structure thereof is characterized as follows:

[0303] 1 H NMR (400 MHz, DMSO-d6) d 11.23 (s, 1H), 9.28 (d, J = 5.9 Hz, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.58 (d, J = 5.9 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 6.1 Hz, 1H), 4.60 (d, J = 8.6 Hz, 1H), 4.50 (q, J = 5.9, 5.3 Hz, 1H), 4.36 (d, J = 10.0 Hz, 1H), 4.23 (s, 1H), 3.87 (d, J = 10.8 Hz, 1H), 3.07 (p, J = 6.8 Hz, 1H), 2.61 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H).

[0304] ESI-MS (m / z): 405.1 [M+H] + .

[0305] Example Seven: Synthesis of N-(3-hydroxycyclobutyl)-4-((5-isopropyl-2-(6- methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinamide (Compound 15)

[0306]

[0307] At 25 °C, 4-((5-isopropyl-2-(6-methylpyridin-2-yl)pyrimidin-4-yl)amino)nicotinic acid (Compound 14-1, 20 mg, 57.24 μmol) and 3-aminocyclobutan-1-ol (5.49 mg, 62.97 μmol) were dissolved in DMF (2 mL), then TBTU (14.65 mg, 57.24 μmol) and DIPEA (22.19 mg, 171.73 μmol) were added successively, and the reaction was carried out at 25 °C for 1 h. The reaction mixture was directly purified by high performance liquid chromatography preparation (Method H) to obtain the title compound (1.35 mg).

[0308] The structure was characterized as follows:

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 - 11.80 (m, 1H), 9.37 (d, J = 5.9 Hz, 1H), 9.15 (t, J = 7.6 Hz, 1H), 8.93 (s, 1H), 8.59 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 5.20 - 5.10 (m, 1H), 4.53 - 3.68 (m, 2H), 3.10 (p, J = 6.7 Hz, 1H), 2.65 - 2.55 (m, 5H), 2.32 - 2.16 (m, 1H), 1.99 - 1.95 (m, 2H), 1.40 - 1.30 (m, 6H).

[0310] ESI-MS (m / z): 419.1 [M+H] + .

[0311] Pharmacological activity testing

[0312] Test Example One: In vitro enzymatic activity inhibition test (TGFβR1).

[0313] Experimental method: according to ADP-Glo TMThe inhibition of TGFβR1 enzyme activity by the compounds of the present application was determined according to the instruction of the Kinase Assay Kit (Promega) as follows:

[0314] After pre-incubation of TGFβR1 enzyme with different concentrations of test compounds (1000 nM, 100 nM, 10 nM) at 30°C for 30 min, the reaction was initiated by adding TGFβR1 peptide and adenosine triphosphate (ATP). After incubation at 30°C for 3 h, ADP-Glo TM reagent was added and incubated at room temperature for 90 min. After incubation at room temperature for 30 min, the chemiluminescence signal value was detected. The solvent group (DMSO) was used as negative control and the buffer group (without TGFβR1 enzyme) was used as blank control. The percentage inhibition of different concentrations of compounds was calculated according to the following formula:

[0315] Percentage inhibition = (1 - (chemiluminescence signal value of different concentrations of compounds - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) x 100%;

[0316] When the percentage inhibition was between 30-80%, the half maximal inhibitory concentration (IC 50 ) or range of the compound was calculated according to the following formula:

[0317] IC 50 = X x (1 - percentage inhibition (%)) / percentage inhibition (%), wherein: X is the test concentration of the compound.

[0318] The experimental results are shown in Table 1 below:

[0319] Table 1. Inhibitory activity of compounds of the present application on TGFβR1

[0320] Example number IC for TGFβR1 50 (nM) Example 1 16.42±3.3 Example 2 1.12±0.31 Example 3 12.2±2.25 Example 4 2.47±0.75 Example 5 3.05±0.54 Example 7 3.92±0.92

[0321] As can be seen from Table 1, the compounds of the present application have obvious inhibitory effect on TGFβR1.

[0322] Test Example Two: In vitro cell activity inhibition test.

[0323] Experimental method: According to the instruction of Bright-Glo TM Luciferase Assay Kit (Promega), the inhibitory effect of the compounds of the present application on the TGFβ / Smad signaling pathway of HEK293-SBE cells was determined as follows:

[0324] HEK293-SBE cells (Bps bioscience) were added to 96-well plates (MEM medium containing 10% FBS) at 30,000 cells / well and incubated at 37°C, 5% CO2overnight. The medium was replaced with 0.5% FBS medium, and test compounds diluted with 0.5% FBS medium were added. The final concentration of test compounds was 10 μM, and the compounds were diluted 4-fold, with a total of 8 concentration gradients. After incubation for 4-5 hours, 10 μl of TGFβ was added. The final concentration of TGFβ was 0.5 ng / ml. 10 μl of medium was added instead of TGFβ as a negative control group. No test compound was added in the blank control group, and TGFβ was added. Bright Glo reagent was added to each well, and the chemiluminescence signal value was read on a microplate reader.

[0325] The percentage inhibition of different concentrations of compounds was calculated according to the following formula:

[0326] Percentage inhibition = (1 - (chemiluminescence signal value of test compound - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) x 100%;

[0327] The percentage inhibition of different concentrations of compounds was plotted against the concentration of the compound, and the curve was fitted according to a four-parameter model. The IC value was calculated by the following formula: 50

[0328] y = Min + (Max - Min) / (1 + (x / IC 50 )^ (-Hillslope)), where y is the percentage inhibition, Max and Min are the maximum and minimum values of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0329] The experimental results are shown in Table 2 below:

[0330] Table 2. Inhibition of TGFβ / Smad signaling pathway in HEK293-SBE cells by compounds of the present application

[0331] Example number IC 50 (nM) <!-- 27 -->]]> Example 1 28.17±0.89 Example 2 3.65±0.13 Example 3 71.02±4.05 Example 4 16.85±3.29 Example 5 16.26±2.72 Example 6 29.63±1.19 Example 7 36.36±1.79

[0332] As can be seen from Table 2, the compounds of the present application have a significant inhibitory effect on the TGFβ / Smad signaling pathway in HEK293-SBE cells.

[0333] Test Example Three: CYP enzyme (cytochrome P450) inhibition test

[0334] 1. Test system:

[0335] P450-Glo TM ​CYP1A2 screening system (Promega);

[0336] P450-Glo TM CYP2D6 screening system (Promega);

[0337] P450-Glo TM CYP3A4 screening system (Promega).

[0338] 2. Test instrument:

[0339] BMG PHERAstar FS Luminescent.

[0340] 3. Test method:

[0341] According to the kit instructions, the steps are as follows:

[0342] 3.1. Inhibition of CYP1A2:

[0343] Test group: Different concentrations of test compounds were added to the microplate, and Luciferin-ME (100 μM), K3PO4 (100 mM) and CYP1A2 (0.01 pmol / μL) were added to each well. Incubate at room temperature for 10 min, then add NADPH regeneration system, react at room temperature for 30 min, finally add equal volume of detection buffer, incubate at room temperature for 20 min, then perform chemiluminescence detection.

[0344] Negative control group: The experimental method is the same as the test group, but no test compound is added.

[0345] Blank control group: The experimental method is the same as the test group, but no test compound is added, and CYP1A2 Membrance (0.01 pmol / μL) is used instead of CYP1A2.

[0346] 3.2. Inhibition of CYP2D6:

[0347] Test group: Different concentrations of test compounds were added to the microplate, and Luciferin-MEEGE (3 μM), K3PO4 (100 mM) and CYP2D6 (5 nM) were added to each well. Incubate at room temperature for 10 min, then add NADPH regeneration system, react at 37°C for 30 min, finally add equal volume of detection buffer, incubate at room temperature for 20 min, then perform chemiluminescence detection.

[0348] Negative control group: The experimental method is the same as the test group, but no test compound is added.

[0349] Blank control group: the experimental method is the same as the test group, but no test compound is added, and CYP2D6 Membrance (5 nM) is used instead of CYP2D6.

[0350] 3.3. Inhibition of CYP3A4:

[0351] Test group: different concentrations of test compounds are added to the microplate, Luciferin-IPA (3 μM), K3PO4 (100 mM) and CYP3A4 (2 nM) are added to each well, pre-incubated at room temperature for 10 min, then the NADPH regeneration system is added, reacted at room temperature for 30 min, finally an equal volume of detection buffer is added, incubated at room temperature for 20 min, and then chemiluminescence detection is performed.

[0352] Negative control group: the experimental method is the same as the test group, but no test compound is added.

[0353] Blank control group: the experimental method is the same as the test group, but no test compound is added, and CYP3A4 Membrance (2 nM) is used instead of CYP3A4.

[0354] 4. Data processing:

[0355] Percent inhibition (%) = (1 - (chemiluminescence signal value of test compound - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) x 100%;

[0356] According to the inhibition rate of different concentrations of compounds on CYP enzymes, the half-inhibitory concentration (IC 50 ) or range of the compound is estimated:

[0357] IC 50 = X x (1 - percent inhibition (%)) / percent inhibition (%), wherein X is the test concentration of the compound.

[0358] 5. Experimental results:

[0359] The inhibition of the compounds of the present application on three CYPs is determined according to the above method, and the results are shown in Table 3 below.

[0360] Table 3. Results of CYPs inhibition test

[0361]

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from R 2 selected from -C(=O)NR a R b ; R a and R b are each, independently at each occurrence, selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl being optionally substituted with one or more R 5 ; or R a , R b and the nitrogen atom to which they are attached together form a 4-8 membered heterocyclic ring, said 4-8 membered heterocyclic ring being optionally substituted with one or more R 5 ; R 3 selected from hydrogen; R 5 each independently at each occurrence is selected from the group consisting of hydroxyl and C 1-6 alkyl; Y is selected from C 1-6 alkyl; Z is -CH-.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 5 selected from hydroxyl.

3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, R a and R b are each, at each occurrence, independently selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl being optionally substituted with one or more groups independently selected from hydroxy and C 1-6 alkyl; or R a , R b and the nitrogen atom to which they are attached together form an azetidinyl group, said azetidinyl group being optionally substituted with one or more groups independently selected from hydroxy and C 1-6 alkyl.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, R 2 selected from -C(=O)NH2, wherein the wavy line represents the point of attachment of the group to the rest of the molecule.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, Y is methyl, ethyl and isopropyl.

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

7. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers.

8. A kit comprising: a) at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as a first therapeutic agent, or a pharmaceutical composition according to claim 7 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 packaging and / or instructions.

9. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder mediated at least in part by TGFpRl.

10. The use according to claim 9, wherein the disease or disorder mediated by TGFpRl is selected from cancer.

11. The use according to claim 10, wherein the disease or disorder mediated by TGFpRl is selected from liver cancer.

12. A process for preparing a compound according to any one of claims 1 to 6, comprising: Step 1-1: condensation of compound SM1 and N,N-dimethylformamide dimethyl acetal to give compound IM1 Step 1-2: cyclization of compound IM1 and compound SM2 to give compound IM2 Step 1-3: substitution of compound IM2 to give compound IM3 Step 1-4: substitution of compound IM3 and compound SM3 to give a compound of Formula I wherein, LG is a leaving group; and, Y, Z, R 1 , R 2 and R 3 as defined in any one of claims 1-6.

13. The process according to claim 12, wherein LG is selected from phenoxy and halogen.

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