Imidazolopyrimidine compound containing a cyclic group, preparation method and use thereof

Abstract

#imgabs0#The present invention relates to imidazopyrimidine compounds containing a paracyclic group, their preparation methods, and uses. Specifically, the present invention relates to compounds of Formula I or pharmaceutically acceptable salts, esters, solvates (e.g., hydrates), stereoisomers, tautomers, polymorphs, metabolites, or prodrugs thereof, pharmaceutical compositions and kits containing the same, their preparation methods, and their use in the preparation of medicaments for preventing or treating diseases or conditions mediated by TGFβR1 (particularly cancer, such as liver cancer).

Description

[0001] This application is a divisional application of application number 201910733001.X, application date 2019-08-09, and invention name “Imidazolopyrimidine compounds containing a cyclic group, preparation method and use thereof”. Technical Field

[0002] The present invention relates to an imidazopyrimidine compound containing a paracyclic group, a pharmaceutical composition and a drug kit containing the same, a preparation method thereof and use thereof in preparing drugs for diseases mediated by TGFβR1 (especially cancer, such as liver cancer). Background Art

[0003] 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, activins, inhibins, and bone morphogenetic proteins. TGF-β signals through two highly conserved single-transmembrane serine / threonine kinases, TGFβR1 and TGFβR2 (ACS Med Chem Lett. 2018, 9, 1117).

[0004] Smads are important intracellular TGF-β signal transducers and regulators, directly transducing TGF-β signals from the cell membrane to the nucleus. The TGF-β / Smads signaling pathway plays a crucial role in tumorigenesis and progression. During TGF-β / Smads signaling, activated TGF-β first binds to TGFβR2 on the cell membrane, forming a heterodimeric complex. TGFβR1 then recognizes and binds to this binary complex. Activated TGFβR1 further phosphorylates Smad2 / Smad3 proteins, which then bind to Smad4 to form a heterotrimeric complex. This complex enters the cell nucleus and synergizes with coactivators / repressors to regulate target gene transcription (Nature. 2003, 425, 577). Alterations in any step of the TGF-β / Smads signaling pathway can lead to abnormalities in the signal transduction pathway (PNAS. 2019, 116, 9166).

[0005] The TGF-β signaling pathway is dysregulated in many diseases, including cancer. TGFβR1 protein levels are significantly elevated in gastric, colorectal, prostate, ovarian, pancreatic, liver, lung, cervical, 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, angiogenesis, and connective tissue hyperplasia. Furthermore, the TGF-β signaling pathway can enhance tumor cell invasiveness, promote epithelial-to-mesenchymal transition, and enhance resistance to tumor epithelial cell therapy (Nat Neurosci. 2014, 17, 943).

[0006] The development of inhibitors targeting TGFβR1, a key target in the TGF-β signaling pathway, has gradually gained attention in the pharmaceutical industry, with published patent applications including WO2002094833A1, WO2009150547A1, WO2017035118A1, and WO2018019106A1. However, there is still an urgent need for new TGFβR1 inhibitors, particularly those with high activity and selectivity. Summary of the Invention

[0007] Through extensive research, the present invention unexpectedly discovered an imidazopyrimidine compound containing a paracyclic group. This compound can significantly inhibit the activity of TGFβR1, has good selectivity between TGFβR1 and TGFβR2, and has good pharmacokinetic properties. As a TGFβR1 inhibitor, it can be used to treat proliferative diseases and cell apoptosis disorders caused by the TGF-β signaling pathway, especially TGFβR1-mediated diseases such as cancer, for example, liver cancer.

[0008] The first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof,

[0009]

[0010] in,

[0011] A is selected from 3-8 membered heterocycloalkyl and a single bond;

[0012] Y and Z are each independently selected from carbon atoms and nitrogen atoms;

[0013] R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 6 replace;

[0014] R6 Each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0015] When ring A is a 3-8 membered heterocycloalkyl group, R 2 Each occurrence is independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a 、-S(O) q NR b R c 、-O-(C 2-6 Alkylene-O) t -R a and-OC 2-6 Alkylene-NR b R c , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0016] When A is a single bond, for R 2 , Z and the carbon atom adjacent to Z together form a carbon atom optionally substituted by one or more R 10 Substituted 5-10 membered heteroaryl or C 6-10 aryl;

[0017] R 10 Each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0018] R3 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a and -C(O)NR b R c , the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0019] R 7 is independently selected at each occurrence from deuterium, halogen, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a and -S(O) q NR b R c ;

[0020] R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0021] R 5 Selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0022] R a is independently selected at each occurrence from hydrogen, deuterium, -C(O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of deuterium, C 1-6 Alkyl, halogen, hydroxyl, -NR d R e 、-C(O) w R 9 and -S(O) w R 9 ;

[0023] R b 、R c is independently selected at each occurrence from hydrogen, deuterium, -C(O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of deuterium, C 1-6 Alkyl, halogen, hydroxyl, -NR d R e 、-C(O) w R 9 and -S(O) w R 9 ;or

[0024] R b 、R c Together with the atoms to which it is attached, it forms a 3-7 membered ring;

[0025] R 8 and R 9 Each occurrence is independently selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0026] Rd 、R e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl; or

[0027] R d 、R e Together with the atoms to which it is attached, it forms a 3-7 membered ring;

[0028] q and w are each independently selected from 1 and 2 at each occurrence;

[0029] t is independently selected at each occurrence from 1, 2, 3, and 4; and

[0030] m and n are each independently selected from 0, 1, 2 and 3.

[0031] On the other hand, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0032] In another aspect, the present invention provides a kit comprising:

[0033] a) a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention as a first pharmaceutical composition;

[0034] and b) optional packaging and / or instructions.

[0035] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a kit of the present invention for use in treating a disease or condition mediated by TGFβR1 (particularly cancer, such as liver cancer).

[0036] On the other hand, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention for the preparation of a medicament for treating a disease or condition mediated by TGFβR1 (especially cancer, such as liver cancer).

[0037] On the other hand, the present invention provides a method for preventing or treating a disease or condition mediated by TGFβR1 (especially cancer, such as liver cancer), which comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention.

[0038] In another aspect, the present invention provides a method for preparing the compound of the present invention, comprising the steps shown in the following reaction scheme 1:

[0039] Reaction Scheme 1

[0040]

[0041] in,

[0042] R 1 、R 2 、R 3 、R 4 , A, Y, Z, m, n are as defined above;

[0043] R5 is hydrogen;

[0044] PG is a protecting group for an amino group; and

[0045] LG is a leaving group.

[0046] The compound of formula e can be prepared by reaction route 2, route 3 or the method in patent WO2017035118:

[0047] Reaction Scheme 2

[0048]

[0049] or

[0050] Reaction Scheme 3

[0051]

[0052] in,

[0053] R 1 、R 4 , LG, PG are as defined above, X is halogen; and

[0054] M is selected from -SnBu3, -SnMe3, -B(OH)2 and

[0055] definition

[0056] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0057] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0058] As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 8, such as 1 to 4, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogen.

[0059] As used herein, the term "alkylene" refers to a straight-chain or branched divalent alkyl group.

[0060] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15, for example 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. For example, as used herein, the term "C 3-8 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 8 ring carbon atoms (for example, 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.

[0061] As used herein, the term "alkoxy" refers to an "alkyl" group, as defined above, attached to the parent molecular moiety through an oxygen atom, such as C 1-6 Alkoxy, C 1-3Alkoxy or C 3-8 Cycloalkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, which may be optionally substituted with one or more (e.g., 1 to 3) identical or different substituents.

[0062] As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkyl" refers to a halogenated alkyl group having 1 to 6 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0064] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms, for example, -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl or -OCH2CH2CF3.

[0065] As used herein, the term "heterocycloalkyl" refers to a saturated monocyclic or bicyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, N, S(=O), S(=O)2 in the ring. The heterocycloalkyl group may be attached to the rest of the molecule via any one of the carbon atoms or heteroatoms (if valence permits) in the ring. Representative examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0066] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 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 by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0067] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in each case, may additionally be benzo-fused. For example, as used herein, the term "5-10 membered heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 10 ring atoms and comprising at least one heteroatom which may be identical or different (the heteroatom being, for example, N, O or S). Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. The heteroaryl group is optionally substituted with one or more (such as one to three) suitable substituents (e.g., halogen, C 1-6 alkyl, etc.) substituted.

[0068] As used herein, the term "alkenyl" refers to a hydrocarbon group containing at least one C=C double bond. An alkenyl group can be a straight chain or branched alkenyl group and contain 2 to 15 carbon atoms. For example, in this article, "C 2-6 "Alkenyl" is an alkenyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. An alkenyl group can be unsubstituted or substituted by one or more substituents which may be the same or different.

[0069] As used herein, the term "alkynyl" refers to a hydrocarbon group having at least one C≡C triple bond. Alkynyl groups can be straight or branched and contain 2 to 15 carbon atoms. For example, in this document, "C 2-6 "Alkynyl" refers to an alkynyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. Alkynyl groups may be unsubstituted or substituted with one or more substituents which may be the same or different.

[0070] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence in the current context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0071] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.

[0072] If a substituent is described as being "independently selected" from a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0073] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0074] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0075] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0076] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H. 3 H, deuterium D, tritium T); carbon isotopes (such as 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S).

[0077] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0078] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0079] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0080] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients constituting the formulation and / or the mammal to be treated therewith.

[0081] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0082] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0083] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0084] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that themselves may have less pharmacological activity or no pharmacological activity, and when administered to the body or thereon, can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0085] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0086] The term "room temperature" used in the present invention refers to 20°C ± 5°C.

[0087] The term "about" as used in the present invention, when used to modify a certain numerical value or numerical range, refers to the numerical value or numerical range and the error range of the numerical value or numerical range acceptable to those skilled in the art, for example, the error range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0088] As used herein, the term "pharmaceutical composition" includes a product comprising a therapeutically effective amount of a compound of the invention, as well as any product that results, directly or indirectly, from the combination of the compounds of the invention.

[0089] Compound

[0090] One object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt, ester, solvate (such as a hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof,

[0091]

[0092] in,

[0093] A is selected from 3-8 membered heterocycloalkyl and a single bond;

[0094] Y and Z are each independently selected from carbon atoms and nitrogen atoms;

[0095] R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 6 replace;

[0096] R 6 Each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0097] When ring A is a 3-8 membered heterocycloalkyl group, R 2 Each occurrence is independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O) q R a 、-S(O) q NR b R c 、-O-(C 2-6Alkylene-O) t -R a and-OC 2-6 Alkylene-NR b R c , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0098] When A is a single bond, for R 2 , Z and the carbon atom adjacent to Z together form a carbon atom optionally substituted by one or more R 10 Substituted 5-10 membered heteroaryl or C 6-10 aryl;

[0099] R 10 Each occurrence is independently selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0100] R 3 Each occurrence is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a 、-NR b R c 、-C(O) q R a and -C(O)NR b R c , the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0101] R 7 is independently selected at each occurrence from deuterium, halogen, -OR a 、-NR b R c 、-C(O) q R a 、-C(O)NR b R c 、-S(O)q R a and -S(O) q NR b R c ;

[0102] R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0103] R 5 Selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0104] R a is independently selected at each occurrence from hydrogen, deuterium, -C(O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of deuterium, C 1-6 Alkyl, halogen, hydroxyl, -NR d R e 、-C(O) w R 9 and -S(O) w R 9 ;

[0105] R b 、R c is independently selected at each occurrence from hydrogen, deuterium, -C(O) w R 8 、-S(O) w R 8 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, the C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of deuterium, C 1-6 Alkyl, halogen, hydroxyl, -NR d R e 、-C(O) w R 9 and -S(O) w R 9 ;or

[0106] R b 、R c Together with the atoms to which it is attached, it forms a 3-7 membered ring;

[0107] R 8 and R 9 Each occurrence is independently selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0108] R d 、R e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl; or

[0109] R d 、R e Together with the atoms to which it is attached, it forms a 3-7 membered ring;

[0110] q and w are each independently selected from 1 and 2 at each occurrence;

[0111] t is independently selected at each occurrence from 1, 2, 3, and 4; and

[0112] m and n are each independently selected from 0, 1, 2 and 3.

[0113] According to some embodiments of the invention, A is a 5-6 membered heterocycloalkyl group.

[0114] In some embodiments of the present invention, A is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0115] According to some embodiments of the present invention, when A is a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),

[0116] R 2 Each occurrence is independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OR a 、-NR b R c 、-COOR a and -C(O)NR b R c , the C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more halogens;

[0117] R a Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0118] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;and

[0119] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0120] In some embodiments of the present invention, when A is a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),

[0121] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0122] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;and

[0123] R 8 Selected from C 1-6 Alkyl and C 3-6 In some embodiments of the present invention, when A is a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),

[0124] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0125] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;and

[0126] R 8 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0127] In some embodiments of the present invention, when A is a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),

[0128] R 2 is independently selected at each occurrence from hydrogen, cyano, amino, methyl, ethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, difluoromethoxy, -NHCH3, -N(CH3)2, morpholinyl, pyrrolidinyl, -NHC(O)CH3 and

[0129] In some embodiments of the present invention, when A is a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group, such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl),

[0130] R 2 is independently selected at each occurrence from hydrogen, cyano, amino, methyl, trifluoromethyl, cyclopentyl, methoxy, difluoromethoxy, -NHCH3, -N(CH3)2, morpholinyl, pyrrolidinyl, -NHC(O)CH3 and

[0131] According to some embodiments of the invention, A is a single bond.

[0132] According to some embodiments of the invention, when A is a single bond,

[0133] for wherein B is optionally replaced by one or more R 10 Substituted 5-6 membered heteroaryl or C 6-10 Aryl.

[0134] In some embodiments of the present invention, when A is a single bond, B is an unsubstituted 5-6 membered heteroaryl or C 6-10 Aryl.

[0135] In some embodiments of the present invention, when A is a single bond, B is a furan ring or a benzene ring.

[0136] According to some embodiments of the invention, Y is a nitrogen atom.

[0137] According to some embodiments of the invention, Z is a carbon atom.

[0138] According to some embodiments of the present invention, R 1 is optionally replaced by one or more R 6 Substituted 5-10 membered heteroaryl.

[0139] In some embodiments of the present invention, R 1 is optionally replaced by one or more R 6 Substituted 5-6 membered heteroaryl.

[0140] In some embodiments of the present invention, R 1 is optionally replaced by one or more R 6 Substituted 6-membered heteroaryl.

[0141] In some embodiments of the present invention, R 1 is optionally replaced by one or more R 6 Substituted pyridyl.

[0142] In some embodiments of the present invention, R 1 For optionally C 1-6 Alkyl or C 1-6 6-membered heteroaryl substituted with haloalkyl.

[0143] In some embodiments of the present invention, R 1 For optionally C 1-6 Alkyl or C 1-6 Pyridyl substituted with haloalkyl.

[0144] In some embodiments of the present invention, R 1 To be C 1-6 Alkyl or C 1-6Pyridyl substituted with haloalkyl.

[0145] In some embodiments of the present invention, R 1 is pyridyl substituted by methyl, difluoromethyl or trifluoromethyl.

[0146] In some embodiments of the present invention, R 1 Selected from and The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0147] In some embodiments of the present invention, R 1 For optionally C 1-6 Alkyl-substituted pyridinyl.

[0148] In some embodiments of the present invention, R 1 To be C 1-6 Alkyl-substituted pyridinyl.

[0149] In some embodiments of the present invention, R 1 It is a pyridyl group substituted by a methyl group.

[0150] In some embodiments of the present invention, R 1 for The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0151] According to some embodiments of the present invention, R 3 are independently selected at each occurrence from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C(O)R a 、-COOR a and -C(O)NR b R c , R a 、R b and R c are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl.

[0152] In some embodiments of the present invention, R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl.

[0153] In some embodiments of the present invention, R 3 Each occurrence is independently selected from hydrogen and methyl.

[0154] According to some embodiments of the present invention, R4 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl.

[0155] In some embodiments of the present invention, R 4 For hydrogen.

[0156] According to some embodiments of the present invention, R 5 Selected from hydrogen and C 1-6 alkyl.

[0157] In some embodiments of the present invention, R 5 For hydrogen.

[0158] According to some embodiments of the present invention, m and n are each independently selected from 0, 1 and 2.

[0159] In some embodiments of the present invention, m is selected from 0 and 1.

[0160] In some embodiments of the present invention, n is 0.

[0161] In some embodiments of the present invention, m is selected from 0 and 1; and n is 0.

[0162] According to some embodiments of the present invention, in the compound of formula I,

[0163] A is a 5-6 membered heterocycloalkyl group;

[0164] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0165] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0166] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0167] Y is a nitrogen atom;

[0168] Z is a carbon atom;

[0169] R 1 For optionally C 1-6 Alkyl or C 1-6 6-membered heteroaryl substituted with haloalkyl;

[0170] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0171] R 4 is hydrogen;

[0172] R 5 is hydrogen; and

[0173] m and n are each independently selected from 0, 1 and 2.

[0174] According to some embodiments of the present invention, in the compound of formula I,

[0175] A is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl;

[0176] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0177] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0178] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0179] Y is a nitrogen atom;

[0180] Z is a carbon atom;

[0181] R 1 To be C 1-6 alkyl-substituted pyridyl;

[0182] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0183] R 4 is hydrogen;

[0184] R 5 is hydrogen; and

[0185] m and n are each independently selected from 0, 1 and 2.

[0186] According to some embodiments of the present invention, in the compound of formula I, A is a single bond;

[0187] for B is an unsubstituted 5-6 membered heteroaryl or C 6-10 aryl;

[0188] Y is a nitrogen atom;

[0189] Z is a carbon atom;

[0190] R 1 For optionally C 1-6 Alkyl or C 1-6 6-membered heteroaryl substituted with haloalkyl;

[0191] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0192] R 4 is hydrogen;

[0193] R 5 is hydrogen; and

[0194] m and n are each independently selected from 0, 1 and 2.

[0195] According to some embodiments of the present invention, in the compound of formula I, A is a single bond;

[0196] for B is a furan ring or a benzene ring;

[0197] Y is a nitrogen atom;

[0198] Z is a carbon atom;

[0199] R 1 To be C 1-6 alkyl-substituted pyridyl;

[0200] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0201] R 4 is hydrogen;

[0202] R 5 is hydrogen; and

[0203] m and n are each independently selected from 0, 1 and 2.

[0204] The present invention encompasses compounds of formula I obtained by any combination of the above preferred groups. According to some embodiments of the present invention, the compounds of the present invention have the structure of formula I-1:

[0205]

[0206] in,

[0207] A is a 3-8 membered heterocycloalkyl group;

[0208] R 2 Each occurrence is independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OR a 、-NR b R c 、-COOR a and -C(O)NR b R c , the C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more halogens;

[0209] R a Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0210] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0211] R 8 Selected from C 1-6 Alkyl and C 3-8 cycloalkyl; and

[0212] R 3 、R 6 , m and n are as defined above.

[0213] According to some embodiments of the present invention, in the compound of formula I-1,

[0214] A is a 5-6 membered heterocycloalkyl group;

[0215] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0216] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0217] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0218] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0219] R 6 Selected from C 1-6 Alkyl and C 1-6 haloalkyl; and

[0220] m and n are each independently selected from 0, 1 and 2.

[0221] According to some embodiments of the present invention, in the compound of formula I-1,

[0222] A is a 5-6 membered heterocycloalkyl group;

[0223] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0224] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0225] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0226] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0227] R 6 C 1-6 alkyl; and

[0228] m and n are each independently selected from 0, 1 and 2.

[0229] According to some embodiments of the present invention, the compound of the present invention has the structure of Formula I-1-1:

[0230]

[0231] Among them, R 2 、R 3 、R 6 , m and n are as defined above.

[0232] According to some embodiments of the present invention, in the compound of formula I-1-1,

[0233] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0234] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0235] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0236] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0237] R 6 C 1-6 alkyl; and

[0238] m and n are each independently selected from 0, 1 and 2.

[0239] According to some embodiments of the present invention, the compound of the present invention has the structure of Formula I-1-2:

[0240]

[0241] Among them, R2 、R 3 、R 6 , m and n are as defined above.

[0242] According to some embodiments of the present invention, in the compound of formula I-1-2,

[0243] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0244] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0245] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0246] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0247] R 6 C 1-6 alkyl; and

[0248] m and n are each independently selected from 0, 1 and 2.

[0249] According to some embodiments of the present invention, the compound of the present invention has the structure of Formula I-1-3:

[0250]

[0251] Among them, R 2 、R 3 、R 6 , m and n are as defined above.

[0252] According to some embodiments of the present invention, in the compound of formula I-1-3,

[0253] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0254] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0255] R 8 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0256] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0257] R 6 C 1-6 alkyl; and

[0258] m and n are each independently selected from 0, 1 and 2.

[0259] According to some embodiments of the present invention, the compound of the present invention has the structure of Formula I-1-4:

[0260]

[0261] Among them, R 2 、R 3 、R 6 , m and n are as defined above.

[0262] According to some embodiments of the present invention, in the compound of formula I-1-4,

[0263] R 2 Each occurrence is independently selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, morpholinyl, pyrrolidinyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -NR b R c ;

[0264] R b 、R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl and -C(O)R 8 ;

[0265] R 8Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl;

[0266] R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl;

[0267] R 6 C 1-6 alkyl; and

[0268] m and n are each independently selected from 0, 1 and 2.

[0269] According to some embodiments of the present invention, the compound of the present invention has the structure of Formula I-2:

[0270]

[0271] in,

[0272] B is an unsubstituted 5-6 membered heteroaryl or C 6-10 aryl; and

[0273] R 6 Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0274] According to some embodiments of the present invention, in the compound of formula I-2,

[0275] B is a furan ring or a benzene ring; and

[0276] R 6 C 1-6 alkyl.

[0277] According to some embodiments of the invention, the compound of the invention is selected from the group consisting of:

[0278]

[0279]

[0280] Preparation method

[0281] Another object of the present invention is to provide a method for preparing the compound of the present invention, which comprises the steps shown in the following reaction scheme 1:

[0282] Reaction Scheme 1

[0283]

[0284] in,

[0285] R 1 、R 2、R 3 、R 4 , A, Y, Z, m, n are as defined above;

[0286] R5 is hydrogen;

[0287] PG is a protecting group for amino; preferably, PG is selected from methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl (Cbz), benzyl, p-methoxybenzyl; more preferably, PG is p-methoxybenzyl; and

[0288] LG is a leaving group; preferably, LG is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy and phenoxy; more preferably, LG is selected from halogen, phenoxy; particularly preferably, LG is chlorine or phenoxy.

[0289] Step 1: Compound e is subjected to a substitution reaction with compound f to obtain compound g.

[0290] When LG is chlorine,

[0291] The reaction is preferably carried out in a suitable organic solvent, which can be selected from DMF, DMA, DMSO, N-methylpyrrolidone, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (such as toluene, xylene, etc.) and any combination thereof, preferably DMSO;

[0292] The reaction is preferably carried out in the presence of a suitable base, the base including an organic base or an inorganic base, the organic base can be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate, preferably triethylamine; the inorganic base can be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate;

[0293] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 50-150°C.

[0294] When LG is phenoxy,

[0295] The reaction is preferably carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (such as acetonitrile, etc.), N-methylpyrrolidone, DMF, DMA, tetrahydrofuran, dioxane, DMSO and any combination thereof, preferably DMSO or DMF;

[0296] The reaction is preferably carried out in the presence of a suitable base, the base including 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 and sodium hydroxide, preferably potassium carbonate or sodium hydride;

[0297] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 25-70°C.

[0298] Step 2: Removing the amino protecting group from compound g to obtain a compound of formula I.

[0299] The reaction is preferably carried out in the presence of a suitable acid, which may be selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid.

[0300] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 20-80°C.

[0301] The compound of formula e can be prepared by the following reaction scheme 2, scheme 3 or the method in patent WO2017035118:

[0302] Reaction Scheme 2

[0303]

[0304] in,

[0305] R 1 、R 4 , LG, and PG are as defined above.

[0306] Step 1: Compound a reacts with compound b to generate compound c.

[0307] The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from DMF, DMA, N-methylpyrrolidone, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, xylene), water and any combination thereof, preferably DMA.

[0308] The reaction is carried out in the presence of a suitable reducing agent. The reducing agent can be selected from anhydrous sodium sulfite, sodium bisulfite and sodium metabisulfite; preferably, the reducing agent is sodium bisulfite or sodium metabisulfite.

[0309] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 90-160°C.

[0310] Step 2: Compound c undergoes a substitution reaction with a substitution reagent to obtain compound d.

[0311] When LG is a halogen, the substitution agent is a halogenating agent. When LG is chlorine, the halogenating agent is phosphorus oxychloride, thionyl chloride, or oxalyl chloride, preferably phosphorus oxychloride.

[0312] The reaction is preferably carried out in a suitable organic solvent. When LG is a halogen (particularly chlorine), the organic solvent may be selected from phosphorus oxychloride, thionyl chloride, oxalyl chloride, DMF, acetonitrile, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), dichloromethane, aromatic hydrocarbons (e.g., toluene, xylene), and any combination thereof, preferably phosphorus oxychloride.

[0313] The reaction is carried out at a suitable temperature, preferably 0-200°C, preferably 90-150°C.

[0314] Step 3: Protect the amino group of compound d to obtain compound e.

[0315] The amino protecting agent used in the reaction is p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, preferably p-methoxybenzyl chloride.

[0316] The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from DMF, DMA, N-methylpyrrolidone, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably DMF.

[0317] The reaction is preferably carried out in the presence of a suitable base. The base includes an organic base or an inorganic base. The organic base can be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate. The inorganic base can be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.

[0318] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 20-50°C.

[0319] Reaction Scheme 3

[0320]

[0321] in,

[0322] R 1 、R 4 , LG, PG are as defined above, X is halogen; and

[0323] M is -SnBu3, -SnMe3, -B(OH)2 and

[0324] Step 1': Protect the amino group of compound i to obtain compound j.

[0325] The amino protecting agent used in the reaction is p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, preferably p-methoxybenzyl chloride.

[0326] The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from DMF, DMA, N-methylpyrrolidone, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably DMF.

[0327] The reaction is preferably carried out in the presence of a suitable base. The base includes an organic base or an inorganic base. The organic base can be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate. The inorganic base can be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.

[0328] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 20-90°C.

[0329] Step 2': Compound j undergoes diazotization and halogenation reaction to obtain compound k;

[0330] The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from ethers (such as ethylene glycol dimethyl ether, THF, dioxane and any combination thereof), preferably THF.

[0331] The diazotizing agent used in the reaction can be selected from sodium nitrite and isoamyl nitrite, preferably isoamyl nitrite.

[0332] The halogenating agent used in the reaction can be selected from diiodomethane, copper iodide, elemental iodine and hydroiodic acid, preferably diiodomethane.

[0333] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 20-90°C.

[0334] Step 3': Compound k undergoes coupling reaction to obtain compound e;

[0335] The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), methanol, ethanol, DMF, acetonitrile, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, xylene), water, and any combination thereof, preferably 1,2-dichloroethane.

[0336] The reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex or Pd(dppf)Cl2, preferably Pd2(dba)3.

[0337] The reaction is carried out at a suitable temperature, preferably 0-200°C, more preferably 50-150°C.

[0338] Pharmaceutical compositions and kits

[0339] Another object of the present invention is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0340] Another object of the present invention is to provide a medicine box comprising:

[0341] a) a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention;

[0342] and b) optional packaging and / or instructions.

[0343] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0344] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition or pharmaceutical preparation of the present invention include, but are not limited to: a) diluents, such as water, hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, docosahexaenoic acid or its esters, triglycerides, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, glucose, glycine, or mixtures thereof; b) lubricants, such as silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, polyethylene glycol, or mixtures thereof; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, Sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, sodium alginate), waxes, polyvinyl pyrrolidone, or mixtures thereof; d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, effervescent agents, or mixtures thereof; e) absorbents, colorants, flavorings and / or sweeteners; f) emulsifiers or dispersants, such as caprylic / capric macrogol glycerides, oleic macrogol glycerides, oleic acid glyceride, diethylene glycol monoethyl ester, or other acceptable emulsifiers; and / or g) substances that enhance the absorption of the compound, for example, cyclodextrin, hydroxypropyl cyclodextrin, polyethylene glycol 200, polyethylene glycol 400, etc.

[0345] Pharmaceutical composition of the present invention can act systemically and / or act topically.For this purpose, they can be applicable to approach administration, for example, by parenteral, local, intravenous, oral, subcutaneous, intraarterial, intradermal, percutaneous, rectal, intracranial, intraperitoneal, intranasal, intramuscular approach or as inhalant administration.

[0346] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms, including but 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.

[0347] When administered orally, the pharmaceutical compositions of the present invention can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions, and the like. Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Diluents used in capsules generally include lactose and dried corn starch. Aqueous suspensions are typically prepared by mixing the active ingredient with a suitable emulsifier and suspending agent. Optionally, sweeteners, flavorings, colorants, and the like may also be added to the above oral formulations.

[0348] When administered topically, the pharmaceutical composition of the present invention can be prepared in the form of an appropriate ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers used in ointments include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Carriers used in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate (e.g., Tween 60), 2-octyldodecanol, benzyl alcohol, and water.

[0349] The pharmaceutical composition of the present invention can also be administered in the form of a sterile injection, including a sterile water for injection or oil suspension, or a sterile water for injection or oil solution. The carriers and solvents that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils, such as monoglycerides or diglycerides, can also be used as solvents or suspending media.

[0350] The pharmaceutical composition of the present invention may contain 0.01 mg to 1000 mg of the compound of the present invention.

[0351] In some embodiments, the present invention provides a method of preparing a pharmaceutical composition of the present invention, comprising combining a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite, or prodrug thereof, with one or more pharmaceutically acceptable carriers.

[0352] The pharmaceutical compositions of the present invention may optionally be administered in combination with other agents that are at least somewhat effective in treating various diseases. In some embodiments, the present invention provides a combined preparation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.

[0353] Treatment methods and uses

[0354] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention, for use in preventing or treating a disease or condition mediated by TGFβR1.

[0355] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention for the preparation of a medicament for preventing or treating a disease or condition mediated by TGFβR1.

[0356] Another object of the present invention is to provide a method for preventing or treating a disease or condition mediated by TGFβR1, which comprises administering to an individual in need thereof a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention.

[0357] According to some embodiments of the invention, the disease or condition mediated by TGFβR1 is cancer, such as lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors or other blood cancers.

[0358] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, for example, to achieve relief of one or more symptoms associated with the disease being treated.

[0359] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0360] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition being treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is from about 0.001 mg / kg body weight / day to about 10000 mg / kg body weight / day. In suitable cases, the effective dose is from about 0.01 mg / kg body weight / day to about 1000 mg / kg body weight / day. About 0.01 to 1000 mg / kg subject weight, typically 0.1 to 500 mg / kg subject weight, can be administered every day, every two days or every three days. An exemplary treatment regimen is once a day or multiple times or once a week or multiple times or once a month or multiple times. Typically, the preparation is administered multiple times, and the intervals between single doses can be daily, weekly, monthly or annual. Alternatively, the preparation can be administered in the form of a sustained-release formulation, in which case a lower frequency of administration is required. Dosage and frequency vary according to the half-life of the preparation in the subject. It can also vary depending on whether it is a preventive treatment or a therapeutic treatment. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. In therapeutic applications, it is sometimes necessary to administer a relatively high dosage at relatively short intervals until the progression of the disease is slowed or stopped, and preferably until the individual exhibits partial or complete amelioration of the symptoms of the disease, after which a prophylactic regimen can be administered to the patient.

[0361] The amount of a compound of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician.

[0362] As used herein, the term "treating" is intended to alleviate or eliminate the targeted disease state or condition. If a subject receives a therapeutic amount of a compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, the subject is successfully "treated." It should also be understood that treatment of the disease state or condition includes not only complete treatment but also achieving some biologically or medically relevant outcome while not achieving complete treatment.

[0363] "Treatment" refers to any administration of a compound of the invention, including:

[0364] (1) Preventing disease in animals that may be predisposed to the disease but do not yet experience or display disease pathology or symptomatology;

[0365] (2) inhibiting disease (i.e., preventing further development of pathology and / or symptomology) in an animal that is experiencing or displaying disease pathology or symptomology; or

[0366] (3) Ameliorating disease (i.e., reversing pathology and / or symptomology) in an animal experiencing or displaying disease pathology or symptomology.

[0367] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). DETAILED DESCRIPTION

[0368] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's advice.Reagents used or instruments not indicated by manufacturer are all conventional products that can be obtained commercially.

[0369] In the conventional synthesis methods, examples and intermediate synthesis examples, the meanings of the abbreviations are shown in the following table.

[0370]

[0371] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance ( 1 H-NMR) or mass spectrometry (MS).

[0372] Nuclear magnetic resonance (NMR) 1 H-NMR) was measured using a Bruker 400 MHz nuclear magnetic resonance instrument. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6); the internal standard was tetramethylsilane (TMS).

[0373] The abbreviations in the nuclear magnetic resonance (NMR) spectra in the following examples have the following meanings:

[0374] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d6: deuterated dimethyl sulfoxide.

[0375] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0376] The mass spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0377] The embodiments of the present invention use the following method for preparative high performance liquid chromatography purification.

[0378] Method A:

[0379] Chromatographic column: GeLai Prep C18 ODS 10μm 150×450mm

[0380] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0381] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10.0 90.0 200 7.00 10.0 90.0 200 40.00 40.0 60.0 200

[0382] Method B:

[0383] Chromatographic column: GeLai Prep C18 ODS 8μm 45×450mm

[0384] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0385] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 15.0 85.0 60 7.00 15.0 85.0 60 50.00 60.0 40.0 60

[0386] Method C:

[0387] Column: SunFire Prep C18 OBD 5μm 19×150mm

[0388] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0389] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10.0 90.0 26 16.00 90.0 10.0 26

[0390] Method D:

[0391] Column: XBridge Prep C18 OBD 5μm 19×150mm

[0392] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0393] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10.0 90.0 26 2.00 10.0 90.0 26 18.00 90 10 26

[0394] Method E:

[0395] Column: SunFire Prep C18 OBD 5μm 19×150mm

[0396] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0397] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 30.0 70.0 28 16.00 70.0 30.0 28

[0398] Method F:

[0399] Chromatographic column: Waters XBridge Prep C18 OBD 5μm 19×150mm

[0400] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0401] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 5.0 95.0 28 4.00 5.0 95.0 28 20.00 85.0 15.0 28

[0402] Method G:

[0403] Chromatographic column: Waters XBridge Prep C18 OBD 5μm 19×150mm

[0404] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% TFA)

[0405] 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

[0406] Method H:

[0407] Chromatographic column: Waters XBridge Prep C18 OBD 5μm 19×150mm Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% TFA)

[0408] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10.0 90.0 28 4.00 10.0 90.0 28

[0409] Example

[0410] Example 1: Synthesis of 1-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine (Compound 1)

[0411]

[0412] Step 1: Synthesis of 1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine (Compound 1-2)

[0413] Compound 1-1 (100 mg, 0.24 mmol, synthesis method reference patent WO2017035118) and 1,2,3,4-tetrahydro-1,6-naphthyridine (47.53 mg, 0.35 mmol) were dissolved in DMF (2 mL). Sodium hydride (47.23 mg, 1.18 mmol, 60% dispersion in mineral oil) was added all at once and the mixture was allowed to react at 25°C for 16 h. Water (30 mL) was added to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to obtain the crude product, which was purified by preparative high-performance liquid chromatography (Method C). The prepared solution was freeze-dried to obtain the title compound (10 mg).

[0414] ESI-MS (m / z): 464.2 [M+H] + .

[0415] Step 2: Synthesis of 1-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine (Compound 1)

[0416] Compound 1-2 (20 mg, 0.043 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 80°C, and reacted for 16 h. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was purified by preparative HPLC (Method D) and lyophilized to obtain the title compound (1.74 mg).

[0417] Its structural characterization is as follows:

[0418] 1H-NMR (400MHz, DMSO-d6) δ13.55(s,1H),8.45(s,1H),8.34(s,1H),8.21(d,J=5.9Hz,1H),8.09(d,J=7.8Hz,1H),7.81(t,J=7.7Hz ,1H),7.75(d,J=5.9Hz,1H),7.33(d,J=7.6Hz,1H),4.50(t,J=5.8Hz,2H),2.88(t,J=6.4Hz,2H),2.57(s,3H),2.12-1.98(m,2H).

[0419] ESI-MS (m / z): 344.2 [M+H] + .

[0420] Example 2: Synthesis of 1-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (Compound 2)

[0421]

[0422] Step 1: Synthesis of 1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (Compound 2-1)

[0423] Compound 1-1 (50 mg, 0.12 mmol) and 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (24.11 mg, 0.18 mmol) were dissolved in DMF (2 mL). Sodium hydride (23.61 mg, 0.59 mmol, 60% dispersion in mineral oil) was added all at once. The mixture was stirred at 25°C for 3 h. Water (0.5 mL) was added to the reaction solution to quench the reaction. The crude product was purified by preparative HPLC (Method E) and lyophilized to obtain the title compound (30 mg).

[0424] ESI-MS (m / z): 466.2 [M+H] + .

[0425] Step 2: Synthesis of 1-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (Compound 2)

[0426] Compound 2-1 (30 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 80°C, and reacted for 16 h. The reaction solution was slowly added to methyl tert-butyl ether (40 mL) and stirred for 0.5 h. A solid precipitated and was filtered. The solid was dissolved in water and lyophilized to obtain the trifluoroacetic acid salt of the title compound (4 mg).

[0427] Its structural characterization is as follows:

[0428] 1 H-NMR (400MHz, DMSO-d6) δ13.85(s,1H),8.64(s,1H),8.56(s,2H),8.28(d,J=6.6Hz,1H),8.20(d,J=7.8Hz, 1H), 7.90 (t, J = 7.7Hz, 1H), 7.42 (d, J = 7.6Hz, 1H), 4.73 (t, J = 4.4Hz, 2H), 4.59 (t, J = 4.4Hz, 2H), 2.62 (s, 3H).

[0429] ESI-MS (m / z): 346.1 [M+H] + .

[0430] Example 3: Synthesis of 6-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(6-methylpyridin-2-yl)-9H-purine (Compound 3)

[0431]

[0432] Step 1: Synthesis of 2-(6-methylpyridin-2-yl)-9H-purin-6-ol (Compound 3-3)

[0433] Compound 3-1 (8.64 g, 71.36 mmol) and 5-amino-1H-imidazole-4-carboxamide (compound 3-2, 9 g, 71.36 mmol) were dissolved in DMA (150 mL). NaHSO₃ (5.57 g, 53.52 mmol) was added, and the temperature was raised to 150°C for 24 h. The reaction solution was cooled to room temperature, and water (1.5 L) was added. After stirring for 0.5 h, the mixture was filtered and the filtrate was purified by preparative HPLC (Method A) and lyophilized to obtain the title compound (3.1 g).

[0434] ESI-MS (m / z): 228.2 [M+H] + .

[0435] Step 2: Synthesis of 6-chloro-2-(6-methylpyridin-2-yl)-9H-purine (Compound 3-4)

[0436] Compound 3-3 (1.3 g, 5.72 mmol) was dissolved in phosphorus oxychloride (7 mL), heated to 117°C, and reacted for 12 h. The phosphorus oxychloride was removed by concentration, and ice water (100 mL) was added to the concentrate. The pH was adjusted to 8 with solid sodium bicarbonate while stirring. A solid precipitated and was filtered. The filter cake was washed with water (30 mL x 3) and dried to obtain the title compound (0.8 g).

[0437] ESI-MS (m / z): 246.7 [M+H] + .

[0438] Step 3: Synthesis of 6-chloro-9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purine (Compound 3-5)

[0439] Compound 3-4 (0.8 g, 3.26 mmol), 4-benzyloxybenzyl chloride (509.99 mg, 3.26 mmol), and K2CO3 (900.11 mg, 6.51 mmol) were dissolved in DMF (15 mL) and reacted at 25°C for 12 h. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Method B) and lyophilized to obtain the title compound (527 mg).

[0440] Its structural characterization is as follows:

[0441] 1 H-NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.26(d,J=7.8Hz,1H),7.90(t,J=7.8Hz,1H),7 .42(dd,J=8.4,3.0Hz,3H),6.96–6.87(m,2H),5.52(s,2H),3.71(s,3H),2.61(s,3H).

[0442] ESI-MS (m / z): 366.8 [M+H] + .

[0443] Step 4: Preparation of 6-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purine (Compound 3-6)

[0444] Compound 3-5 (100 mg, 0.27 mmol), 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (46.51 mg, 0.30 mmol), and potassium carbonate (75.56 mg, 0.55 mmol) were dissolved in DMSO (5 mL), heated to 80°C, and reacted for 12 h. The reaction solution was cooled to room temperature and poured into water (20 mL). Solid precipitated and was filtered. The filter cake was dried to obtain the title compound (100 mg).

[0445] ESI-MS (m / z): 450.2 [M+H] + .

[0446] Step 5: Preparation of 6-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(6-methylpyridin-2-yl)-9H-purine (Compound 3)

[0447] Compound 3-6 (50 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (5 mL) and heated to 80°C for 4 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (Method F) and lyophilized to obtain the trifluoroacetic acid salt of the title compound (8 mg).

[0448] Its structural characterization is as follows:

[0449] 1 H-NMR (400MHz, DMSO-d6) δ: 13.71 (s, 1H), 9.39 (d, J = 8.0Hz, 1H), 8.63 (d, J = 8.0Hz, 1H), 8.53 (s, 2H), 8.23 ​​(d, J = 8. 0Hz, 1H), 7.89 (t, J = 8.0Hz, 1H), 7.41 (d, J = 8.0Hz, 1H), 4.99 (t, J = 8.0Hz, 2H), 3.45 (t, J = 8.0Hz, 2H), 2.66 (s, 3H).

[0450] ESI-MS (m / z): 330.1 [M+H] + .

[0451] Example 4: Synthesis of N-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-quinolin-4-amine (Compound 18)

[0452]

[0453] Step 1: Preparation of N-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-quinolin-4-amine (Compound 18-1)

[0454] Compound 1-1 (20 mg, 0.05 mmol) and 4-aminoquinoline (14 mg, 0.09 mmol) were dissolved in DMF (2 mL), and NaH (9.45 mg, 0.24 mmol) was added. The mixture was stirred at 25 ° C for 3 h. Water (60 mL) was added to the reaction solution to quench the reaction. The solid precipitated and was filtered. The filter cake was dried to obtain the title compound (20 mg), which was used directly in the next reaction without further purification.

[0455] ESI-MS (m / z): 474.2 [M+H] + .

[0456] Step 2: Preparation of N-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-quinolin-4-amine (Compound 18)

[0457] Compound 18-1 (30 mg, 0.063 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 80°C, and reacted for 16 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative high performance liquid chromatography (Method D) and lyophilized to obtain the title compound (5.0 mg).

[0458] Its structural characterization is as follows:

[0459] 1 H-NMR (400MHz, DMSO-d6) δ8.83(d,J=5.1Hz,1H),8.51(d,J=5.1Hz,1H),8.38(d,J=9.8Hz,2H),8.09(d,J=7.8Hz,1H),8.02(d,J=8.2Hz,1H),7.82 -7.72(m,2H),7.65-7.58(m,1H),7.31(d,J=7.6Hz,1H),2.59(s,3H).

[0460] ESI-MS (m / z): 354.2 [M+H] + .

[0461] Example 5: Synthesis of N-[2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-furo[3,2-b]pyridin-7-amine (Compound 19)

[0462]

[0463] Step 1: Preparation of N-[9-(4-methoxyphenyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-furo[3,2-b]pyridin-7-amine (Compound 19-1)

[0464] Compound 3-5 (50 mg, 0.14 mmol), furo[3,2-b]pyridin-7-amine (20.17 mg, 0.15 mmol), and potassium carbonate (37.8 mg, 0.27 mmol) were dissolved in DMSO (1 mL) and heated to 80°C for 12 h. The reaction solution was cooled to room temperature, purified by preparative HPLC (Method G), and lyophilized to give the title compound (29 mg).

[0465] ESI-MS (m / z): 464.2 [M+H] + .

[0466] Step 2: Preparation of N-[2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-furo[3,2-b]pyridin-7-amine (Compound 19)

[0467] Compound 19-1 (29 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (1 mL), heated to 80°C, and reacted for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (Method H) and lyophilized to obtain the trifluoroacetic acid salt of the title compound (3.67 mg).

[0468] Its structural characterization is as follows:

[0469] 1 H-NMR (400MHz, DMSO-d6) δ8.50(d,J=5.7Hz,3H),8.31(d,J=2.2Hz,1H),8.09(d,J=7.8H z, 1H), 7.84 (t, J = 7.7Hz, 1H), 7.37 (d, J = 7.6Hz, 1H), 7.17 (d, J = 2.3Hz, 1H), 2.61 (s, 3H).

[0470] ESI-MS (m / z): 343.9 [M+H] + .

[0471] Pharmacological activity test

[0472] Test Example 1: In vitro enzyme activity inhibition test (TGFβR1)

[0473] Experimental method: According to ADP-Glo TM Instructions for the Kinase Assay Kit (Promega, Cat V9102) The inhibitory effect of the compounds of the present invention on TGFβR1 enzyme activity was determined as follows:

[0474] After preincubation of the TGFβR1 enzyme with various concentrations of the test compound (1000 nM, 100 nM, and 10 nM) at 30°C for 30 minutes, the reaction was initiated by adding TGFβR1 peptide and adenosine triphosphate (ATP). After incubation at 30°C for 3 hours, the ADP-Glo™ reagent was added. After incubation at room temperature for 90 minutes, the kinase detection reagent was added, and the chemiluminescence signal was measured after incubation at room temperature for 30 minutes.

[0475] The solvent group (DMSO) was used as the negative control, and the buffer group (without TGFβR1 enzyme) was used as the blank control.

[0476] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0477] Percent inhibition rate=(1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control))*100%.

[0478] When the percentage inhibition rate is between 30% and 80%, the half-maximal inhibitory concentration (IC) of the compound on TGFβR1 is calculated according to the following formula: 50 ):

[0479] IC 50 =X×(1-percent inhibition rate) / percent inhibition rate,

[0480] Where X is the test concentration of the compound.

[0481] The experimental results are shown in Table 1 below:

[0482] Table 1. Inhibition of TGFβR1 enzyme by the compounds of the present invention

[0483] Example No. <![CDATA[IC 50 (nM)]]> 1 2.47±0.16 2 2.92±0.21 3 3.47±0.07

[0484] As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on TGFβR1 enzyme.

[0485] Test Example 2: In vitro enzyme activity inhibition test (TGFβR2)

[0486] Experimental method: According to ADP-Glo TM Instructions for the Kinase Assay Kit (Promega, Cat# V9102) The inhibitory effect of the compounds of the present invention on TGFβR2 enzyme activity was determined as follows:

[0487] After pre-incubation of TGFβR2 enzyme with different concentrations of test compounds (1000nM, 100nM, 10nM) at 30°C for 30min, myelin basic protein (MBP) and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at 30°C for 3h, ADP-Glo ​​was added. TM After incubation at room temperature for 90 minutes, add the kinase detection reagent and incubate at room temperature for 30 minutes to detect the chemiluminescence signal.

[0488] The solvent group (DMSO) was used as the negative control, and the buffer group (without TGFβR2 enzyme) was used as the blank control.

[0489] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0490] Percent inhibition rate=(1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control))*100%.

[0491] When the percentage inhibition rate is between 30% and 80%, the half-maximal inhibitory concentration (IC) of the compound on TGFβR2 is calculated according to the following formula: 50 ) or range:

[0492] IC 50 =X×(1-percent inhibition rate) / percent inhibition rate,

[0493] Where X is the test concentration of the compound.

[0494] The experimental results are shown in Table 2 below:

[0495] Table 2. Inhibition of TGFβR2 enzyme by compounds of the present invention

[0496] Example No. <![CDATA[IC 50 (nM)]]> 1 1248.18±77.14 3 665.55±174.86

[0497] As can be seen from Table 2, the compounds of the present invention have weak inhibitory activity on TGFβR2.

[0498] As can be seen from Table 1 and Table 2, the compounds of the present invention have a highly selective inhibitory effect on TGFβR1.

[0499] Test Example 3: In vitro cell activity inhibition test

[0500] Experimental method: The inhibitory effect of the compound of the present invention on HEK293-SBE cells was determined according to the instructions of the Bright-Glo luciferase assay kit (Promega, Cat# E2620), and the steps are as follows:

[0501] HEK293-SBE cells (Bpsbioscience, Cat#60653) were plated in a 96-well plate (10% FBS medium) at 30,000 cells / well and cultured overnight at 37°C, 5% CO2. The medium was replaced with 0.5% FBS medium, and the test compound diluted in 0.5% FBS medium was added. The test compound was diluted 4-fold in 0.5% FBS medium to a maximum final concentration of 10 μM, with a total of 8 concentration gradients. After 4-5 hours of incubation, 10 μl of TGFβ was added. The final concentration of TGFβ was 0.5 ng / ml. 10 μl of culture medium was added to replace TGFβ as a negative control. A blank control was prepared without the test compound, but TGFβ was added. Bright Glo reagent was added to each well, and the chemiluminescent signal was read on a microplate reader.

[0502] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0503] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control))*100%.

[0504] The percentage inhibition rate of the compound at different concentrations was plotted against the compound concentration, and the curve was fitted according to the four-parameter model to calculate the IC 50 value:

[0505] y=Min+(Max-Min) / (1+(x / IC 50 )^(-Hillslope))

[0506] Where y is the percentage inhibition rate; Max and Min are the maximum and minimum values ​​of the fitting curve, respectively; x is the test concentration of the compound; Hillslope is the slope of the curve.

[0507] The experimental results are shown in Table 3 below:

[0508] Table 3. Inhibitory effect of the compounds of the present invention on the luciferase reporter gene in HEK293-SBE cells

[0509] Example No. <![CDATA[IC 50 (nM)]]> 1 10.79±3.78 2 5.08±2.78 3 2.67±0.73

[0510] As can be seen from Table 3, the compounds of the present invention have a significant inhibitory effect on the luciferase reporter gene of HEK293-SBE cells induced by TGFβ.

[0511] Test Example 4. Biochemical hERG inhibition test

[0512] Test system:

[0513] Kit: Predictor TMhERG Fluorescence Polarization Assay,(ThermoFisherCatalog:PV5365),

[0514] The kit contains:

[0515] Positive control compound: hERG potassium channel blocker E-4031;

[0516] hERG cell membrane;

[0517] Affinity tracer Tracer and

[0518] hERG buffer.

[0519] Test parameters:

[0520] hERG concentration: 1×

[0521] Tracer concentration: 1nM

[0522] Incubation time: 2h

[0523] BMG PHERAstar FS FP

[0524] Test method:

[0525] Carry out the test according to the kit instructions, the steps are as follows:

[0526] Test group: 10 μM and 1 μM of the test compound were added to a microplate containing hERG cell membranes, and a tracer with high hERG affinity, Tracer, was added to each well. The microplate was incubated at room temperature for 2 hours, and the changes in fluorescence polarization (Excitation: 540 nm; Emission: 590 nm) were detected using a multifunctional microplate reader.

[0527] Positive control group: 30 μM positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.

[0528] Blank control group: hERG buffer was used instead of the test compound, and no hERG cell membrane was added. The experimental method was the same as that of the test group.

[0529] Data processing:

[0530] According to the following formula, the hERG inhibition percentage of the compound of the present invention at different concentrations was calculated to determine the half-maximal inhibitory concentration (IC 50 )’s scope.

[0531] Percent inhibition rate = (1-(fluorescence polarization value of the test compound-fluorescence polarization value of the positive control group) / (fluorescence polarization value of the blank control group-fluorescence polarization value of the positive control group))*100%

[0532] Experimental results:

[0533] The hERG inhibition of the compounds was determined using the above method. The results are shown in Table 4 below.

[0534] Table 4. hERG inhibition test results

[0535] Example No. <![CDATA[IC 50 (μM)]]> 2 ＞10

[0536] The test results show that the compound of the present invention has low affinity to hERG and competes with the affinity tracer Tracer with IC 50 All of them are >10 μM. This demonstrates that the compound of the present invention has a low risk of hERG ion channel-related cardiac toxicity.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, in, A is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; Y is a nitrogen atom; Z is a carbon atom; R 1 To be C 1-6 alkyl-substituted pyridyl; R 2 are independently selected at each occurrence from hydrogen; R 3 Each occurrence is independently selected from hydrogen and C 1-6 alkyl; R 4 selected from hydrogen and deuterium; R 5 Selected from hydrogen and C 1-6 alkyl; and m and n are each independently selected from 0, 1, 2 and 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a pyridyl group substituted by a methyl group.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 for The wavy line Indicates the point of attachment of the group to the rest of the molecule.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected at each occurrence from hydrogen and methyl; R 4 is hydrogen; R 5 For hydrogen.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m and n are each independently selected from 0, 1 and 2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I-1: R 2 selected from hydrogen; R 3 Selected from hydrogen and C 1-6 alkyl; R 6 C 1-6 alkyl; and m and n are each independently selected from 0, 1 and 2.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I-1-1, I-1-2, I-1-3 or I-1-4: in, R 2 selected from hydrogen; R 3 Selected from hydrogen and C 1-6 alkyl; R 6 C 1-6 alkyl; and m and n are each independently selected from 0, 1 and 2.

8. A pharmaceutical composition comprising a preventively or therapeutically effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

9. A kit comprising: a) the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8; and b) optional packaging and / or instructions.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, or the pharmaceutical kit according to claim 9 in the preparation of a medicament for preventing or treating a disease or condition mediated by TGFβR1. The use according to claim 10 , wherein the disease or condition mediated by TGFβR1 is selected from cancer.

12. The method of claim 11, wherein the cancer is selected from lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors or other blood cancers.

13. A method for preparing the compound according to any one of claims 1 to 7, comprising the steps shown in Reaction Scheme 1: Reaction Scheme 1 in, R 1 、R 2 、R 3 、R 4 , A, Y, Z, m, n are as defined in any one of 1-7; R5 is hydrogen; PG is a protecting group for an amino group; and LG is a leaving group.

14. The method of claim 13, wherein the compound of formula e is prepared by reaction scheme 2 or scheme 3: Reaction Scheme 2 or Reaction Scheme 3 in, R 1 、R 4 , LG, PG as defined in claim 13, X is halogen; and M is selected from -SnBu3, -SnMe3, -B(OH)2 and

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