WO2021027594A1 - 含有并环基团的咪唑并嘧啶类化合物、其制备方法及用途 - Google Patents

含有并环基团的咪唑并嘧啶类化合物、其制备方法及用途 Download PDF

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WO2021027594A1
WO2021027594A1 PCT/CN2020/106217 CN2020106217W WO2021027594A1 WO 2021027594 A1 WO2021027594 A1 WO 2021027594A1 CN 2020106217 W CN2020106217 W CN 2020106217W WO 2021027594 A1 WO2021027594 A1 WO 2021027594A1
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alkyl
group
compound
independently selected
occurrence
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PCT/CN2020/106217
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English (en)
French (fr)
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陈寿军
宋帅
张毅涛
刘春池
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202080044123.9A priority Critical patent/CN113993870B/zh
Publication of WO2021027594A1 publication Critical patent/WO2021027594A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an imidazopyrimidine compound containing a fused ring group or a pharmaceutically acceptable salt, ester, solvate (e.g. hydrate), stereoisomer, tautomer, polymorph, Metabolites or prodrugs, pharmaceutical compositions and kits containing the metabolites or prodrugs, their preparation methods and their use in preparing drugs for diseases (especially cancer) mediated by TGF ⁇ R1.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ is a multifunctional cytokine that regulates various cellular responses, such as cell proliferation, differentiation, migration, and apoptosis.
  • the TGF- ⁇ superfamily includes TGF- ⁇ 1, TGF- ⁇ 2, TGF- ⁇ 3, activin, inhibin, bone morphogenetic protein and so on.
  • TGF- ⁇ transduces signals through two highly conserved single-transmembrane serine/threonine kinases, namely TGF ⁇ R1 and TGF ⁇ R2 (ACS Med Chem Lett. 2018, 9, 1117).
  • TGF- ⁇ /Smads are important TGF- ⁇ signal transduction and regulatory molecules in cells, which can directly transduce TGF- ⁇ signals from the cell membrane to the nucleus.
  • the TGF- ⁇ /Smads signaling pathway plays an important role in the occurrence and development of tumors. .
  • activated TGF- ⁇ first binds to TGF ⁇ R2 on the cell membrane surface to form a heterodimer complex, and TGF ⁇ R1 recognizes and binds to the binary complex.
  • Activated TGF ⁇ R1 further phosphorylates Smad2/Smad3 protein, which further combines with Smad4 to form a heterotrimeric complex, which enters the nucleus and cooperates with auxiliary activation/repressor factors to regulate target gene transcription (Nature. 2003) ,425,577). Changes in any link of the TGF- ⁇ /Smads signaling pathway will cause abnormalities in the signal transduction pathway (PNAS.2019, 116, 9166).
  • TGF- ⁇ signaling pathway is dysregulated in many diseases including cancer.
  • TGF ⁇ R1 is found in gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, liver cancer, lung cancer, cervical cancer, and head and neck cancer cell lines and tumor tissues. The protein level increased significantly.
  • the activation of TGF- ⁇ signaling pathway triggers obvious pathological effects in tumor stroma, including immunosuppression, angiogenesis and connective tissue hyperplasia.
  • the TGF- ⁇ signaling pathway can enhance the invasiveness of tumor cells, promote the transformation of epithelial cells to mesenchyme, and enhance the tolerance of tumor epithelial cell therapy (Nat Neurosci.2014,17,943).
  • the present invention has unexpectedly discovered an imidazopyrimidine compound containing a bicyclic group, which can significantly inhibit the activity of TGF ⁇ R1, has good selectivity between TGF ⁇ R1 and TGF ⁇ R2, and has a good As a TGF ⁇ R1 inhibitor, it can be used to treat proliferative disorders and apoptotic disorders caused by the TGF- ⁇ signaling pathway, especially TGF ⁇ R1-mediated diseases such as cancer.
  • the first aspect of the present invention relates to a compound represented by formula I or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, or metabolite thereof Or prodrugs,
  • A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • X, Y, and Z are each independently selected from carbon atoms and nitrogen atoms;
  • R 1 is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group or a 5-10 membered heteroaryl group is optionally substituted by one or more R 6 ;
  • R 6 is independently selected from deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 2 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 -OC 2-6 alkylene group and - 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 Group or 5-10
  • R 3 is independently selected from hydrogen, deuterium, cyano, 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 , -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 -OC 2-6 alkylene group and -NR b R c, a C 1-6 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
  • Each occurrence of R 7 is independently selected 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 ;
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 5 is selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl
  • Each occurrence of R a is independently selected 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 are optionally selected by one or more Substitution from the following groups: deuterium, C 1-6 alkyl, halogen, hydroxyl, -NR d R e , -C(O) w R 9 and -S(O) w R 9 ;
  • R b and R c are independently selected 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 are optionally substituted by one or Multiple substitutions 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
  • R b , R c and the atoms to which they are connected together form a 3-7 membered ring; the 3-7 membered ring is optionally substituted by one or more oxo groups;
  • R 8 and R 9 are each independently selected from hydrogen, -NR d R e , C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6- 10 aryl and 5-10 membered heteroaryl groups, the C 1-6 alkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6-10 aryl group or 5-10 membered hetero
  • the aryl group is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-6 alkyl, -NR d R e , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonate Acyl, carboxyl, -O-(C 2-6 alkylene-O) t -R d and -(OC 2-6 alkylene) t -NR d R e ;
  • R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 member at each occurrence Heterocycloalkyl; or
  • R d, R e, and atom to which they are attached form a 3-7 membered ring
  • q and w are independently selected from 1 and 2 each time they appear;
  • Each occurrence of t is independently selected from 1, 2, 3, and 4;
  • n are each independently selected from 0, 1, 2 and 3.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, Tautomers, polymorphs, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition can be administered in a suitable dosage form, including but not limited to tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes Preparations, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.
  • the present invention provides a medicine kit comprising:
  • 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
  • the prodrug, or the pharmaceutical composition of the present invention, or the kit of the present invention is used to treat diseases or disorders (especially cancer) mediated by TGF ⁇ R1.
  • 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
  • a pharmaceutically acceptable salt, ester, solvate e.g. hydrate
  • stereoisomer e.g. hydrate
  • the present invention provides a method for preventing or treating diseases or disorders (especially cancer) mediated by TGF ⁇ R1, which comprises administering to an individual in need thereof a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutical thereof Acceptable salts, esters, solvates (such as hydrates), stereoisomers, tautomers, polymorphs, metabolites or prodrugs, or pharmaceutical compositions of the present invention, or Pill box.
  • the present invention provides a method for preparing the compound of the present invention, which includes the following steps shown in Reaction Scheme 1:
  • R 1 , R 2 , R 3 , R 4 , A, X, Y, Z, m, and n are as defined above;
  • R 5 is hydrogen
  • PG is the protecting group of amino group
  • LG is a leaving group
  • W is hydrogen
  • W is selected from a boronic acid group or a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group.
  • the compound of formula e can be prepared by reaction scheme 2 or 3:
  • R 1 , R 4 , LG, and PG are as defined above.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 8, such as 1 to 4 carbon atoms.
  • C 1-6 alkyl refers to a straight or branched group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.
  • alkylene refers to a linear or branched divalent alkyl group.
  • 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 ring, including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which are optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, cycloheptyl,
  • the cycloalkyl group has 3 to 15, for example 3 to 10 carbon atoms, 3 to 8 carbon atoms, or 3 to 6 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., bicyclic) having 3 to 8 ring-forming carbon atoms Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl .
  • alkoxy means an "alkyl” as defined above attached to the parent molecular moiety through an oxygen atom, for example, C 1-6 alkoxy, C 1-3 alkoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy
  • the alkoxy group may be optionally substituted by one or more (such as 1 to 3) substituents which are the same or different.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms.
  • C 1-6 haloalkyl refers to a haloalkyl group having 1 to 6 carbon atoms, such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 ,- CH 2 Cl or -CH 2 CH 2 CF 3 and so on.
  • the heterocycloalkyl group may be connected to the rest of the molecule through any carbon atom or heteroatom (if the valence allows) in the ring.
  • 3-8 membered heterocycloalkyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, Dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, sulfur Morpholinyl, piperazinyl, or trithianyl.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 aryl refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, which has, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially having 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in addition, may be benzo-fused in each case of.
  • the term "5-10 membered heteroaryl” means a monocyclic, bicyclic or tricyclic aromatic ring system with 5-10 ring atoms, and which contains at least one of which may be the same or different Heteroatoms (the heteroatoms are, for example, N, O, or S).
  • heteroaryl groups examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • the heteroaryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, C 1-6 alkyl, etc.).
  • alkenyl refers to a hydrocarbon group containing at least one C ⁇ C double bond.
  • the alkenyl group can be straight or branched and contains 2 to 15 carbon atoms.
  • C 2-6 alkenyl herein 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.
  • the alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different.
  • alkynyl refers to a hydrocarbon group having at least one C ⁇ C triple bond.
  • the alkynyl group can be a straight or branched chain alkynyl group and contains 2 to 15 carbon atoms.
  • C 2-6 alkynyl herein 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, 1,3-butadiynyl, and the like.
  • the alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different.
  • substitution means that one or more (for example, 1, 2, 3, or 4) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • substituents can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently The selected substituents are substituted or not substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected substituents Replaced or not replaced.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • one or more means one or more than one under reasonable conditions, such as two, three, four, five, six, seven, eight, nine Or 10.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
  • isotopes suitable 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); isotopes of carbon (e.g. 11 C, 13 C and 14 C); chlorine isotopes (e.g., 37 Cl); fluorine isotope (e.g.
  • iodine isotopes e.g., 123 I and 125 I
  • nitrogen isotope e.g., 13 N and 15 N
  • isotopes of oxygen e.g., 15 O, 17 O and 18 O
  • sulfur isotopes such as 35 S
  • stereoisomer means an isomer due to at least one asymmetric center. In compounds with one or more (for example, 1, 2, 3, or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures and Individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, when appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include but are not limited to: pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly administered to patients in need thereof. Or indirectly provide the compound of the present invention or its metabolite or residue. Therefore, when "the compound of the present invention” is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components constituting the formulation and/or the mammal to be treated with it.
  • the 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.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • metabolites of the compounds of the present invention that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.
  • the present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, when administered to the body or The above can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cracking.
  • prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo.
  • prodrugs please refer to "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 ( Edited by EBRoche, American Pharmaceutical Association).
  • prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as “pro-moiety (e.g., “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • room temperature used in the present invention means 20°C ⁇ 5°C.
  • the term "about” used in the present invention means that the value or value range and the error range acceptable to those skilled in the art of the value or value range are included.
  • the error range is ⁇ 10%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, etc.
  • An object of the present invention is to provide a compound represented by formula I or a pharmaceutically acceptable salt, ester, solvate (e.g. hydrate), stereoisomer, tautomer, polymorph Type, metabolite or prodrug,
  • A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • X, Y, and Z are each independently selected from carbon atoms and nitrogen atoms;
  • R 1 is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group or a 5-10 membered heteroaryl group is optionally substituted by one or more R 6 ;
  • R 6 is independently selected from deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 2 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 -OC 2-6 alkylene group and - 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 Group or 5-10
  • R 3 is independently selected from hydrogen, deuterium, cyano, 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 , -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 -OC 2-6 alkylene group and -NR b R c, a C 1-6 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
  • Each occurrence of R 7 is independently selected 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 ;
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 5 is selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl
  • Each occurrence of R a is independently selected 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 are optionally selected by one or more Substitution from the following groups: deuterium, C 1-6 alkyl, halogen, hydroxyl, -NR d R e , -C(O) w R 9 and -S(O) w R 9 ;
  • R b and R c are independently selected 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 are optionally substituted by one or Multiple substitutions 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
  • R b , R c and the atoms to which they are connected together form a 3-7 membered ring, which is optionally substituted by one or more oxo groups;
  • R 8 and R 9 are each independently selected from hydrogen, -NR d R e , C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6- 10 aryl and 5-10 membered heteroaryl groups, the C 1-6 alkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6-10 aryl group or 5-10 membered hetero
  • the aryl group is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-6 alkyl, -NR d R e , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonate Acyl, carboxyl, -O-(C 2-6 alkylene-O) t -R d and -(OC 2-6 alkylene) t -NR d R e ;
  • R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 member at each occurrence Heterocycloalkyl; or
  • R d, R e, and atom to which they are attached form a 3-7 membered ring
  • q and w are independently selected from 1 and 2 each time they appear;
  • Each occurrence of t is independently selected from 1, 2, 3, and 4;
  • n are each independently selected from 0, 1, 2 and 3.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, ester, solvate (such as hydrate), stereoisomer, tautomer, poly Crystalline form, metabolite or prodrug,
  • A is selected from C 6-10 aryl and 5-10 membered heteroaryl
  • X, Y, and Z are each independently selected from carbon atoms and nitrogen atoms;
  • R 1 is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group or a 5-10 membered heteroaryl group is optionally substituted by one or more R 6 ;
  • R 6 is independently selected from deuterium, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 2 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 -OC 2-6 alkylene group and - 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 Group or 5-10
  • R 3 is independently selected from hydrogen, deuterium, cyano, 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 , -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 -OC 2-6 alkylene group and -NR b R c, a C 1-6 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
  • Each occurrence of R 7 is independently selected 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 ;
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R 5 is selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl
  • Each occurrence of R a is independently selected 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 are optionally selected by one or more Substitution from the following groups: deuterium, C 1-6 alkyl, halogen, hydroxyl, -NR d R e , -C(O) w R 9 and -S(O) w R 9 ;
  • R b and R c are independently selected 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 are optionally substituted by one or Multiple substitutions 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
  • R b , R c and the atoms to which they are connected together form a 3-7 membered ring;
  • R 8 and R 9 are each independently selected from hydrogen, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl group, the C 1-6 alkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6-10 aryl group or 5-10 membered heteroaryl group optionally Ground is substituted by one or more groups selected from the group consisting of halogen, C 1-6 alkyl, -NR d R e , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy, -O-(C 2-6 alkylene-O) t -R d and -(OC 2-6 alkylene) t -NR d R e ;
  • R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 member at each occurrence Heterocycloalkyl; or
  • R d, R e, and atom to which they are attached form a 3-7 membered ring
  • q and w are independently selected from 1 and 2 each time they appear;
  • Each occurrence of t is independently selected from 1, 2, 3, and 4;
  • n are each independently selected from 0, 1, 2 and 3.
  • A is selected from phenyl and 5-10 membered heteroaryl.
  • A is 5-10 membered heteroaryl.
  • A is 5-6 membered heteroaryl.
  • A is a 5-membered heteroaryl group.
  • A is selected from pyrrolyl, pyrazolyl, furyl, thienyl and isothiazolyl.
  • A is selected from pyrrol-1-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, furan-3-yl, thiophen-3-yl and Isothiazol-3-yl.
  • X is selected from carbon atoms and nitrogen atoms.
  • Y is selected from carbon atoms and nitrogen atoms.
  • Z is selected from carbon atoms and nitrogen atoms.
  • R 1 is a C 6-10 aryl group or a 5-10 membered heteroaryl group optionally substituted with one or more R 6 .
  • R 1 is phenyl or 5-6 membered heteroaryl optionally substituted with one or more R 6 .
  • R 1 is phenyl or 6-membered heteroaryl optionally substituted with one or more R 6 .
  • R 1 is a 6-membered heteroaryl optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1 is a 5-membered heteroaryl optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1 is phenyl, pyridyl, pyridyl, optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl and halogen Pyrazolyl or thiazolyl.
  • R 1 is phenyl, pyridyl, pyrazolyl substituted with one or two substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl and halogen Or thiazolyl.
  • R 1 is phenyl optionally substituted with halogen.
  • R 1 is pyridyl optionally substituted with C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1 is pyridyl substituted with C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1 is pyridyl substituted by methyl, difluoromethyl, or trifluoromethyl.
  • R 1 is pyrazolyl and thiazolyl substituted by methyl.
  • R 1 is phenyl substituted with fluorine and chlorine.
  • R 1 is selected from Where the wavy line Indicates the point of attachment of the group to the rest of the molecule.
  • R 1 is selected from Where the wavy line Indicates the point of attachment of the group to the rest of the molecule.
  • each occurrence of R 2 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 group, C 3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group Is optionally substituted by one or more halogens, wherein,
  • R a is independently selected from hydrogen and C 1-6 alkyl
  • R b and R c are independently selected from hydrogen, -C(O) w R 8 , C 1-6 alkyl, 5-10 membered heteroaryl and C 6-10 aryl, said C 1-6 alkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of hydroxyl, -C(O) w R 9 and -S (O) w R 9 ; or
  • R b , R c and the atoms to which they are connected together form a 5-6 membered ring, which is optionally substituted by one or more oxo groups;
  • R 8 and R 9 is independently selected from hydrogen, -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-
  • the 8- cycloalkyl group is optionally substituted with one or more groups selected from: -NR d R e , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy, -O- (C 2-6 alkylene-O) t -R d and -(OC 2-6 alkylene) t -NR d R e ;
  • R d and R e are each independently selected from hydrogen and C 1-6 alkyl at each occurrence;
  • each occurrence of t is independently selected from 1 and 2;
  • Each occurrence of w is independently selected from 1 and 2.
  • each occurrence of R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkane Group, hydroxy group, C 1-6 alkoxy group, carboxy group, C 1-6 haloalkyl group, -NR b R c and -C(O)NR b R c , wherein,
  • R b and R c are independently selected from hydrogen, -C(O) w R 8 , C 1-6 alkyl, phenyl and 5-6 membered heteroaryl, said C 1-6
  • the alkyl group, phenyl group or 5-6 membered heteroaryl group is optionally substituted with one or more groups selected from the group consisting of hydroxyl, carboxy and sulfamoyl;
  • R b , R c and the atoms to which they are connected together form a 5-6 membered ring, and the 5-6 membered ring may be optionally substituted with one or two oxo groups;
  • R 8 is independently selected from -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, and the C 1-6 alkyl is optionally selected from the following groups Group substitution: amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy,- O-(C 2-6 alkylene-O)-C 1-6 alkyl, -(OC 2-6 alkylene)-NH 2 , -(OC 2-6 alkylene)-NH(C 1 -6 alkyl) and -(OC 2-6 alkylene)-N(C 1-6 alkyl) 2 ;
  • R d and R e are independently selected from hydrogen and C 1-6 alkyl
  • Each occurrence of w is independently selected from 1 and 2.
  • each occurrence of R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, morpholinyl, hydroxyl, C 1-6 alkoxy, carboxy, C 1-6 haloalkyl, -NR b R c and -C(O)NH 2 , wherein,
  • R b and R c are independently selected from hydrogen, -C (O) w R 8 , C 1-6 alkyl, phenyl and oxazolyl, the C 1-6 alkyl or benzene
  • the group is optionally substituted with one or more groups selected from the group consisting of hydroxy, carboxy and sulfamoyl; or
  • R b , R c and the atoms to which they are connected together form a pyrrolidine ring, which is optionally substituted by one or two oxo groups;
  • R 8 is independently selected from -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, and the C 1-6 alkyl is optionally selected from the following groups Group substitution: amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy,- O-(C 2-6 alkylene-O)-C 1-6 alkyl, -(OC 2-6 alkylene)-NH 2 , -(OC 2-6 alkylene)-NH(C 1 -6 alkyl), and -(OC 2-6 alkylene)-N(C 1-6 alkyl) 2 ;
  • R d and R e are independently selected from hydrogen and C 1-6 alkyl
  • Each occurrence of w is independently selected from 1 and 2.
  • each occurrence of R 2 is independently selected from hydrogen, cyano, halogen, methyl, cyclopropyl, cyclopentyl, morpholinyl, hydroxyl, methoxy, carboxyl. , Trifluoromethyl, difluoromethyl, amino, -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , -NHCOOCH 3 , -NH(CH 2 ) 2 OH, -N(CH 3 )CH 2 COOH, -NHCH 2 COOH, -CONH 2 , Where the wavy line Indicates the point of attachment of the group to the rest of the molecule.
  • each occurrence of R 3 is independently selected from hydrogen, C 1-6 alkyl, 3-8 membered heterocycloalkyl, hydroxyl, amino, methylamino, dimethylamino.
  • each occurrence of R 3 is independently selected from hydrogen and C 1-6 alkyl.
  • each occurrence of R 3 is independently selected from hydrogen and methyl.
  • R 4 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-8 cycloalkyl.
  • R 4 is hydrogen
  • R 5 is selected from hydrogen and C 1-6 alkyl.
  • R 5 is selected from hydrogen and methyl.
  • R 5 is hydrogen
  • n and n are each independently selected from 0, 1, and 2.
  • A is 5-6 membered heteroaryl
  • X is selected from carbon atoms and nitrogen atoms
  • Y is selected from carbon atoms and nitrogen atoms
  • Z is selected from carbon atoms and nitrogen atoms
  • R 1 is phenyl or 5-6 membered heteroaryl optionally substituted with one or two substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl and halogen;
  • Each occurrence of R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, hydroxy, C 1-6 alkane Oxy, carboxy, C 1-6 haloalkyl, -NR b R c and -C(O)NR b R c ;
  • R b and R c are independently selected from hydrogen, -C(O) w R 8 , C 1-6 alkyl, phenyl and 5-6 membered heteroaryl, said C 1-6
  • the alkyl group, phenyl group or 5-6 membered heteroaryl group is optionally substituted with one or more groups selected from the group consisting of hydroxy, carboxy and sulfamoyl; or
  • R b , R c and the atoms to which they are connected together form a 5-6 membered ring, and the 5-6 membered ring may be optionally substituted with one or two oxo groups;
  • R 8 is independently selected from -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, and the C 1-6 alkyl is optionally selected from the following groups Group substitution: amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy,- O-(C 2-6 alkylene-O)-C 1-6 alkyl, -(OC 2-6 alkylene)-NH 2 , -(OC 2-6 alkylene)-NH(C 1 -6 alkyl) and -(OC 2-6 alkylene)-N(C 1-6 alkyl) 2 ;
  • R d and R e are each independently selected from hydrogen and C 1-6 alkyl at each occurrence;
  • w is independently selected from 1 and 2;
  • R 3 is independently selected from hydrogen and C 1-6 alkyl
  • R 4 is hydrogen
  • R 5 is selected from hydrogen and C 1-6 alkyl
  • n and n are each independently selected from 0, 1, and 2.
  • A is selected from pyrrolyl, pyrazolyl, furyl, thienyl and isothiazolyl;
  • X is selected from carbon atoms and nitrogen atoms
  • Y is selected from carbon atoms and nitrogen atoms
  • Z is selected from carbon atoms and nitrogen atoms
  • R 1 is phenyl, pyridyl, pyrazolyl or thiazolyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl and halogen;
  • R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, morpholinyl, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 haloalkyl, -NR b R c and -C(O)NH 2 ;
  • R b and R c are independently selected from hydrogen, -C (O) w R 8 , C 1-6 alkyl, phenyl and oxazolyl, the C 1-6 alkyl or benzene
  • the group is optionally substituted with one or more groups selected from the group consisting of hydroxy, carboxy and sulfamoyl; or
  • R b , R c and the atoms to which they are connected together form a pyrrolidine ring, which is optionally substituted by one or two oxo groups;
  • R 8 is independently selected from -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, and the C 1-6 alkyl is optionally selected from the following groups Group substitution: amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy,- O-(C 2-6 alkylene-O)-C 1-6 alkyl, -(OC 2-6 alkylene)-NH 2 , -(OC 2-6 alkylene)-NH(C 1 -6 alkyl), and -(OC 2-6 alkylene)-N(C 1-6 alkyl) 2 ;
  • R d and R e are each independently selected from hydrogen and C 1-6 alkyl at each occurrence;
  • w is independently selected from 1 and 2;
  • R 3 is independently selected from hydrogen and C 1-6 alkyl
  • R 4 is hydrogen
  • R 5 is selected from hydrogen and C 1-6 alkyl
  • n and n are each independently selected from 0, 1, and 2.
  • the present invention encompasses compounds of formula I obtained by any combination of the above-mentioned preferred groups.
  • the compound of the present invention has the structure of formula I-1:
  • U and V are each independently selected from CR 3 , NR 3 , N, O, and S;
  • R 2 , R 3 , R 5 , R 6 , X, Y, Z and m are as defined above;
  • X is selected from carbon atoms and nitrogen atoms
  • Y is selected from carbon atoms and nitrogen atoms
  • Z is selected from carbon atoms and nitrogen atoms
  • U and V are each independently selected from CR 3 , NR 3 , N, O, and S;
  • R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, morpholinyl, hydroxy, C 1-6 alkoxy, carboxy, C 1-6 haloalkyl, -NR b R c and -C(O)NH 2 ;
  • R b and R c are independently selected from hydrogen, -C (O) w R 8 , C 1-6 alkyl, phenyl and oxazolyl, the C 1-6 alkyl or benzene
  • the group is optionally substituted with one or more groups selected from the group consisting of hydroxy, carboxy and sulfamoyl; or
  • R b , R c and the atoms to which they are connected together form a pyrrolidine ring, which is optionally substituted by one or two oxo groups;
  • R 8 is independently selected from -NR d R e , C 1-6 alkyl and C 3-8 cycloalkyl, and the C 1-6 alkyl is optionally selected from the following groups Group substitution: amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , hydroxyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, carboxy,- O-(C 2-6 alkylene-O)-C 1-6 alkyl, -(OC 2-6 alkylene)-NH 2 , -(OC 2-6 alkylene)-NH(C 1 -6 alkyl), and -(OC 2-6 alkylene)-N(C 1-6 alkyl) 2 ;
  • R d and R e are each independently selected from hydrogen and C 1-6 alkyl at each occurrence;
  • w is independently selected from 1 and 2;
  • R 3 is independently selected from hydrogen and C 1-6 alkyl
  • R 5 is selected from hydrogen and C 1-6 alkyl
  • R 6 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • n 0, 1 and 2;
  • the compound of the present invention has the structure of formula I-1-1:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-2:
  • R 2 , R 3 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-3:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-4:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-5:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-6:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-7:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-8:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the present invention has the structure of formula I-1-9:
  • R 2 , R 5 , R 6 and m are as defined above.
  • the compound of the invention is selected from:
  • Another object of the present invention is to provide a method for preparing the compound of the present invention, which includes the steps shown in the following reaction scheme 1:
  • R 1 , R 2 , R 3 , R 4 , A, X, Y, Z, m, and n are as defined above;
  • R 5 is hydrogen
  • PG is a protecting group for amino; preferably, PG is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl (Cbz), benzyl and p-methyl Oxybenzyl; more preferably, PG is p-methoxybenzyl;
  • 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 and phenoxy; and
  • W is hydrogen
  • W is selected from hydrogen, boronic acid group and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Step 1 Reacting compound e with compound f to obtain compound g.
  • This step can be performed by the following method one or two:
  • 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.), nitriles (such as acetonitrile, etc.), N -Methylpyrrolidone, DMF, DMA, tetrahydrofuran, dioxane, DMSO and any combination thereof, preferably DMSO or DMF.
  • 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 may be selected from DIPEA, triethylamine, potassium tert-butoxide and pyridine, and the inorganic base may be selected from phosphoric acid Potassium, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate and sodium hydroxide, preferably potassium carbonate or sodium hydride.
  • the base includes an organic base or an inorganic base
  • the organic base may be selected from DIPEA, triethylamine, potassium tert-butoxide and pyridine
  • the inorganic base may be selected from phosphoric acid Potassium, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate and sodium hydroxide, preferably potassium carbonate or sodium hydride.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 50-150°C.
  • 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.), methanol, ethanol, DMF, acetonitrile, ether (For example, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (for example, toluene, xylene) and any combination thereof, preferably dioxane.
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • methanol such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethanol ethanol
  • DMF acetonitrile
  • ether for example, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.
  • aromatic hydrocarbons for example,
  • 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 may 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 sodium carbonate or cesium carbonate.
  • the reaction is preferably carried out in the presence of a suitable catalyst, which is preferably a palladium catalyst, such as tetrakis(triphenylphosphine) palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd( PPh 3 ) 2 Cl 2 dichloromethane complex or Pd(dppf)Cl 2 , preferably palladium acetate, Pd(dppf)Cl 2 or tetrakis(triphenylphosphine)palladium.
  • a palladium catalyst such as tetrakis(triphenylphosphine) palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd( PPh 3 ) 2 Cl 2 dichloromethane complex or Pd(dppf)Cl 2 , preferably palladium acetate, Pd
  • the reaction is carried out in the presence of a suitable ligand, which may be selected from BINAP, tris(o-methylphenyl)phosphine, triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, X-PHOS or XantPHOS, preferably X-PHOS.
  • a suitable ligand which may be selected from BINAP, tris(o-methylphenyl)phosphine, triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, X-PHOS or XantPHOS, preferably X-PHOS.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 50-150°C.
  • Step 2 Remove the amino protecting group from compound g to obtain the compound of formula I.
  • the reaction is preferably carried out in the presence of a suitable acid, which can be selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid.
  • a suitable acid which can be selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 50-150°C.
  • the compound of the above formula e can be prepared by the following reaction scheme 2 or 3:
  • R 1 , R 4 , LG, and PG are as defined above.
  • Step 1 Compound a and compound b react to form compound c.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from DMF, DMA, N-methylpyrrolidone, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. toluene, xylene), water and any of them In combination, DMA is preferred.
  • 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.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 90-160°C.
  • Step 2 Compound c undergoes substitution reaction with substitution reagent to obtain compound d.
  • the substitution reagent is a halogenated reagent.
  • the halogenating reagent is phosphorus oxychloride, thionyl chloride, oxalyl chloride, preferably phosphorus oxychloride.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from phosphorus oxychloride, aromatic hydrocarbons (for example toluene, xylene) and any combination thereof, preferably phosphorus oxychloride.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, preferably 50-120°C.
  • Step 3 Protect the amino group of compound d to obtain compound e.
  • 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, DMF is preferred.
  • the amino protecting agent used in this reaction can be selected from p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, and 9 -Fluorenylmethyloxycarbonyl chloride, preferably p-methoxybenzyl chloride.
  • 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 may be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate, and the inorganic base may be selected from potassium carbonate, sodium carbonate , Sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 20-90°C.
  • R 1 , R 4 , LG, and PG are as defined above.
  • Step 1' Protect the amino group of compound k to obtain compound p.
  • 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, benzene xylene) and any combination thereof, DMF is preferred.
  • the amino protecting agent used in this reaction can be selected from p-methoxybenzyl chloride, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, allyloxycarbonyl chloride, and 9 -Fluorenylmethyloxycarbonyl chloride, preferably p-methoxybenzyl chloride.
  • 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 may be selected from triethylamine, DIPEA, pyridine, NMM, sodium tert-butoxide, potassium acetate and sodium acetate, and the inorganic base may be selected from potassium carbonate, sodium carbonate , Sodium bicarbonate, cesium carbonate, potassium phosphate and potassium dihydrogen phosphate, preferably potassium carbonate.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 20-90°C.
  • Step two' compound p undergoes diazotization and halogenation reaction to obtain compound q;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from ethers (for example, ethylene glycol dimethyl ether, THF, dioxane and any combination thereof), and THF is preferred.
  • the diazotization reagent used in this reaction can be selected from sodium nitrite and isoamyl nitrite, preferably isoamyl nitrite.
  • the halogenating reagent used in this reaction can be selected from diiodomethane, copper iodide, elemental iodine and hydroiodic acid, preferably diiodomethane.
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 20-90°C.
  • Step 3' Compound q and compound h undergo a coupling reaction to obtain compound e;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), methanol, ethanol, DMF, acetonitrile, ethers (e.g., ethylene glycol dimethyl ether, tetrahydrofuran) , Dioxane), aromatic hydrocarbons (such as toluene, xylene) and any combination thereof, preferably 1,2-dichloroethane.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • methanol e.g., methanol, ethanol, DMF, acetonitrile
  • ethers e.g., ethylene glycol dimethyl ether, tetrahydrofuran
  • Dioxane Dioxane
  • 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, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complexation Or Pd(dppf)Cl 2 , preferably Pd 2 (dba) 3 .
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complexation Or Pd(dppf)Cl 2 , preferably Pd 2 (dba) 3 .
  • the reaction is carried out at a suitable temperature, and the reaction temperature is preferably 0-200°C, more preferably 50-150°C.
  • the compound of the above formula e can be prepared by the method in patent WO2017035118.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, Tautomers, polymorphs, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a medicine kit comprising:
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting humans and/or other substances within the scope of reasonable medical judgment. Animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the 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 fish oil, docosahexaenoic acid or its esters, triglycerides, ⁇ - 3 fatty acids or their derivatives, dextrose, glucose, glycine, or mixtures thereof; b) lubricants, such as stearic acid, sodium oleate, sodium chloride, polyethylene glycol, or mixtures thereof; c) adhesion Agents, such as gelatin, magnesium carbonate, natural and synthetic gums (such as gum arabic, sodium alginate), polyvinylpyrrolidone, or mixtures thereof; d) disintegrating agents, such as agar, bentonite, xanthan gum, alginic acid or Sodium salts, effervescent agents, or mixtures thereof; e) absorbents, colorants, flavoring agents and/or sweeteners; f) emul
  • the pharmaceutical composition of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, such as parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes Or administered as an inhalant.
  • suitable routes such as parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes Or administered as an inhalant.
  • the pharmaceutical composition of the present invention can be administered in a suitable dosage form.
  • the dosage form includes but not limited to tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups, etc.
  • the pharmaceutical composition of the present invention can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions and the like.
  • 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 (such as Tween 60), 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical composition of the present invention can also be administered in the form of a sterile injection, including a sterile injection water or oil suspension, or a sterile injection water or oil solution.
  • usable carriers and solvents include but are not limited to: water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • the pharmaceutical composition of the present invention may contain 0.01 mg to 1000 mg of the compound of the present invention.
  • the present invention provides a method for preparing the pharmaceutical composition or pharmaceutical formulation of the present invention, the method comprising combining the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), Stereoisomers, tautomers, polymorphs, metabolites or prodrugs are combined with one or more pharmaceutically acceptable carriers.
  • a pharmaceutically acceptable salt, ester, solvate e.g., hydrate
  • Stereoisomers, tautomers, polymorphs, metabolites or prodrugs are combined with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention can be optionally administered in combination with other agents that have at least a certain effect in the treatment of various diseases.
  • the present invention provides a combined formulation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in treatment.
  • Another object of the present invention is to provide the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or
  • the prodrug, or the pharmaceutical composition of the present invention, or the kit of the present invention is used to treat diseases or disorders mediated by TGF ⁇ R1.
  • Another object of the present invention is to provide the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, polymorph, metabolite or Use of the prodrug, or the pharmaceutical composition of the present invention, or the kit of the present invention in the preparation of a medicament for the treatment of diseases or disorders mediated by TGF ⁇ R1.
  • a pharmaceutically acceptable salt, ester, solvate e.g., hydrate
  • stereoisomer e.g., hydrate
  • tautomer e.g., polymorph, metabolite or Use of the prodrug, or the pharmaceutical composition of the present invention, or the kit of the present invention in the preparation of a medicament for the treatment of diseases or disorders mediated by TGF ⁇ R1.
  • Another object of the present invention is to provide a method for preventing or treating diseases or disorders mediated by TGF ⁇ R1, which comprises administering to an individual in need thereof a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, Esters, solvates (such as hydrates), stereoisomers, tautomers, polymorphs, metabolites or prodrugs, or pharmaceutical compositions of the invention, or kits of the invention.
  • the disease or disorder mediated by TGF ⁇ R1 is cancer, such as lung cancer, colorectal cancer, multiple myeloma, acute myelogenous leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, Liver cancer, breast cancer, melanoma, neuroblastoma, other solid tumors or other blood cancers.
  • cancer such as lung cancer, colorectal cancer, multiple myeloma, acute myelogenous leukemia, T-acute lymphoblastic leukemia, pancreatic cancer, Liver cancer, breast cancer, melanoma, neuroblastoma, other solid tumors or other blood cancers.
  • an effective amount refers to an amount sufficient to achieve a desired preventive or therapeutic effect, for example, an amount that achieves relief of one or more symptoms associated with the disease to be treated.
  • the dosage regimen can be adjusted to provide the best 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 urgent need for the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.001 mg/kg body weight/day to about 10000 mg/kg body weight/day. Where appropriate, the effective dose is about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day. About 0.01 to 1000 mg/kg of the subject's body weight can be administered every day, every two days, or every three days, usually 0.1 to 500 mg/kg of the subject's body weight.
  • An exemplary treatment regimen is one or more administrations per day or one or more times per week or one or more times per month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the preparation may be administered in the form of a sustained-release preparation, in which case a lower frequency of administration is required.
  • the dosage and frequency vary according to the half-life of the preparation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment. In preventive applications, relatively low doses are given over a long period of time at relatively low frequency intervals. In therapeutic applications, it is sometimes necessary to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual shows partial or complete amelioration of disease symptoms, after which the patient can be administered Prevention program.
  • the amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • treatment used in the present invention is to reduce or eliminate the targeted disease state or disorder. If the subject receives a therapeutic amount of the compound, its optical isomer or its pharmaceutically acceptable salt or its pharmaceutical composition according to the method described herein, the subject exhibits one or more signs and symptoms Observable and/or detectable reduction or improvement, then the subject is successfully "treated”. It should also be understood that the treatment of the disease state or condition not only includes complete treatment, but also includes not achieving complete treatment, but achieving some biological or medical related results.
  • Treatment means any administration of a compound of the invention, including:
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “non-human animals” include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the measuring instrument of nuclear magnetic resonance is Bruker 400MHz nuclear magnetic resonance instrument, and the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexadeuterated dimethyl sulfoxide (DMSO-d 6 );
  • the internal standard substance is tetramethylsilane (TMS).
  • s singlet (singlet), d: doublet (doublet), t: triplet (triplet), q: quartet (quartet), dd: double doublet (double doublet), qd: quadruple doublet Peak (quartet doublet), ddd: double double doublet, ddt: double double triplet (double double triplet), dddd: double double double doublet (double double double doublet), m: multiplet (multiplet) , Br: broad peak (broad), J: coupling constant, Hz: Hertz, DMSO-d 6 : hexadeuterated dimethyl sulfoxide.
  • the measuring instrument of mass spectrometry uses Agilent (ESI) mass spectrometer, the model is Agilent 6120B.
  • the embodiment of the present invention adopts the following method for preparative high performance liquid chromatography purification.
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% TFA)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% ammonium bicarbonate)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% formic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Mobile phase A acetonitrile
  • mobile phase B water (containing 0.05% trifluoroacetic acid)
  • Step 4 9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-6-(1H-pyrrolo[3,2-c]pyridin-1-yl)- Synthesis of 9H-purine (Compound 1-6)
  • reaction solution was poured into water, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (50 mg, yield 79.2%).
  • reaction solution was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), combined the organic phases, washed with saturated brine (30 mL x 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure to obtain the title compound (50 mg).
  • Step 1 1-[9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-1H-pyrrolo[3,2- c) Preparation of pyridine-4-amine (compound 6-2)
  • Step 2 1-(2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3,2-c]pyridin-4-amine (compound 6) preparation
  • Step 1 9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-6-(1H-pyrazolo[4,3-c]pyridin-1-yl) Synthesis of -9H-purine (Compound 7-2)
  • Step 2 Synthesis of 2-(6-methylpyridin-2-yl)-6-(1H-pyrazolo[4,3-c]pyridin-1-yl)-9H-purine (compound 7)
  • Step 1 6-(4-Bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridine-2 -Yl)-9H-purine (compound 8-2) preparation
  • Step 2 6-(4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(6-methylpyridin-2-yl)-9H-purine (compound 8) preparation
  • Step 1 N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3 ,2-c)pyridin-4-yl)acetamide (compound 31-1) preparation
  • N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3,2 -c]pyridin-4-yl)cyclopropanamide (compound 32-1, 50mg, 0.09mmol) was dissolved in trifluoroacetic acid (5mL), heated to 80°C, and reacted for 4h. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The concentrate was purified by preparative high performance liquid chromatography (Method K). The solid obtained after lyophilization of the preparation solution was dissolved in acetonitrile (5ml), and water (30ml) was added. , Trifluoroacetic acid (0.5ml) was added and lyophilized to obtain the trifluoroacetic acid salt of the title compound (3.95mg, yield 8.37%).
  • the reaction system was cooled to room temperature and saturated sodium sulfite solution (200 mL) was added.
  • the reaction system changed from dark red to light yellow. It was extracted twice with ethyl acetate (400 mL), and the organic phases were combined. After drying with sodium sulfate and filtering off the desiccant, the filtrate was spin-dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the title compound (19.7 g, yield 47.77%).
  • Step 3 Synthesis of 6-chloro-9-(4-methoxybenzyl)-2-(6-trifluoromethylpyridin-2-yl)-9H-purine (Compound 43-4)
  • Step 4 6-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-9-(4-methoxybenzyl)-2-(6-trifluoromethyl Synthesis of pyridin-2-yl)-9H-purine (Compound 43-5)
  • 6-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-9-(4-methoxybenzyl)-2-(6-trifluoro Methylpyridin-2-yl)-9H-purine compound 43-5, 17mg, 32.98 ⁇ mol
  • trifluoroacetic acid 3mL
  • Step 1 9-(4-methoxybenzyl)-6-(1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((6-methylpyridin-2-yl) ))-9H-purine (Compound 75-2)
  • Step 1 2-((tert-butyldiphenylsilyl)oxy)-N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl) -9H-purin-6-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)acetamide (Compound 77-1)
  • Step 1 (1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3,2 -c) Preparation of pyridin-4-yl) ethyl carbamate (Compound 78-1)
  • Step 1 (2-((1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo Synthesis of [3,2-c]pyridin-4-yl)amino)-2-oxoethyl)carbamic acid tert-butyl ester (Compound 79-1)
  • Step 1 N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3 ,2-c)pyridin-4-yl)pivalamide (Compound 80-1)
  • reaction solution was diluted with dichloromethane (30 mL), washed with water (10 mL) and saturated brine (10 mL) each time, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the title compound ( 27mg, yield 98.5%).
  • N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo[3,2 -c]pyridin-4-yl)pivalamide (compound 80-1, 27mg, 0.05mmol) was dissolved in trifluoroacetic acid (2mL), heated to 80°C, and reacted for 4h. The reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography (Method T). The preparation solution was lyophilized to obtain the title compound trifluoroacetate (6.94 mg, yield 25.9%).
  • Step 1 2-Methoxy-N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)- Preparation of 1H-pyrrolo[3,2-c]pyridin-4-yl)acetamide (Compound 81-1)
  • the reaction solution was poured into water (20mL) cold, extracted with ethyl acetate (15mL*3), the organic phases were combined, washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure.
  • the crude product was obtained by drying, purified by preparative high performance liquid chromatography (Method U), and the preparation was freeze-dried to obtain the title compound (10 mg, yield 28.8%).
  • Step 1 1-Methyl-3- ⁇ 1-[9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-1H -Pyrrolo[3,2-c]pyridin-4-yl ⁇ urea (Compound 82-1)
  • Step 1 2-(Dimethylamino)-N-[1-[9-[(4-methoxyphenyl)methyl]-2-(6-methylpyridin-2-yl)-9H-purine -6-yl]-1H-pyrrolo[3,2-c]pyridin-4-yl]acetamide (Compound 83-1)
  • Step 1 1-[1-[9-[(4-methoxyphenyl)methyl]-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-1H- Synthesis of pyrrolo[3,2-c]pyridin-4-yl]pyrrolidine-2,5-dione (Compound 84-1)
  • Step 1 4-[[1-[9-[(4-methoxyphenyl)methyl]-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-1H -Pyrrolo[3,2-c]pyridin-4-yl]amino]-4-oxobutanoic acid (Compound 85-1)
  • 6-(4-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridine -2-yl)-9H-purine compound 8-2, 200mg, 379.95 ⁇ mol
  • oxazol-2-ylamine 159.72mg, 1.90mmol
  • Pd 2 (dba) 3 34.79mg, 37.99 ⁇ mol
  • Xantphos 43.97mg, 75.99 ⁇ mol
  • cesium carbonate (247.57mg, 759.90 ⁇ mol
  • N-(1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl)-1H-pyrrolo [3,2-c]pyridin-4-yl)oxazol-2-ylamine (compound 87-1, 40mg, 75.54 ⁇ mol) was dissolved in trifluoroacetic acid (2mL), heated to 80°C and reacted for 16h; The solvent was evaporated under reduced pressure. Methyl tert-butyl ether (5 mL) was added to the crude product. A large amount of solid precipitated out. Stirred for 20 min. Filtered. The filter cake was dissolved in water (5 mL) and filtered. The filtrate was lyophilized to obtain the title compound. Trifluoroacetate (28mg, yield 67.28%).
  • Step 1 6-(4-Chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridine- Synthesis of 2-yl)-9H-purine (Compound 88-1)
  • Step 2 9-(4-methoxybenzyl)-6-(4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-(6-methylpyridine Synthesis of -2-yl)-9H-purine (Compound 88-2)
  • reaction solution was cooled to room temperature, it was diluted with dichloromethane (30 mL), and then washed with water (10 mL) and saturated brine (10 mL) each time, the organic phase was dried, and the solvent was evaporated under reduced pressure to obtain a crude product.
  • the crude product was purified with a 40g C18 reverse phase column (46% acetonitrile/54% 0.05% HCOOH aqueous solution system) to obtain the title compound (30 mg, yield 14.75%).
  • Step 1 Synthesis of N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-ylamine (Compound 89-2)
  • Step 2 N-(4-methoxybenzyl)-1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purine-6- Yl)-1H-pyrazolo[4,3-c]pyridin-4-ylamine (Compound 89-3)
  • 6-chloro-9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purine compound 1-5, 50mg, 136.68 ⁇ mol
  • N-[(4-methoxybenzyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-ylamine compound 89-2, 41.71mg, 164.02 ⁇ mol
  • potassium carbonate 37.78mg, 273.36 ⁇ mol
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by a silica gel column (20 g, 50% ethyl acetate: 50% petroleum ether) to obtain the title compound (20 mg, yield 23.82%).
  • N-(4-methoxybenzyl)-1-(9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purine- 6-yl)-1H-pyrazolo[4,3-c]pyridin-4-ylamine (Compound 89-3, 20mg, 34.27 ⁇ mol) was dissolved in trifluoroacetic acid (2mL), heated to 80°C, and reacted 4h.
  • reaction solution was evaporated under reduced pressure to dry the solvent, dissolved in dimethyl sulfoxide (2 mL) and filtered, and the filtrate was purified by preparative high performance liquid chromatography (Method d) to obtain the title compound (10 mg, yield 60.61%).
  • reaction solution was directly filtered, and the filtrate was purified with a flash silica gel column (C18 column, mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the title compound (800 mg, yield 43.09%).
  • Step 3 9-(4-methoxybenzyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(1H-pyrazolo[4,3-c]pyridine- Synthesis of 1-yl)-9H-purine (Compound 90-3)
  • reaction solution was directly filtered, and the filter cake was purified with a 40 g C18 reverse phase column (46% acetonitrile/54% 0.05% trifluoroacetic acid aqueous solution system) to obtain the title compound (30 mg, yield 14.75%).
  • Step 5 Preparation of 2-(6-(1H-pyrazolo[4,3-c]pyridin-1-yl)-9H-purin-2-yl)-4-methylthiazole (Compound 91)
  • the 2-chloro-9-(4-methoxybenzyl)-6-phenoxy-9H-purine (compound 92-1, 100mg, 272.63 ⁇ mol), (5-chloro-2-fluorobenzene)boronic acid (57mg ,327.15 ⁇ mol), dichlorodi-tert-butyl-(4-dimethylaminophenyl) phosphine palladium (II) (19.30mg, 27.26 ⁇ mol) and sodium carbonate (76mg, 545 ⁇ mol) were added to the single-mouth bottle, and 1 , 4-Dioxane (50 mL), replaced with nitrogen, and reacted in microwave at 90°C for 1 hour.
  • Step 2 2-(5-chloro-2-fluorophenyl)-9-(4-methoxybenzyl)-6-(1H-pyrazolo[4,3-c]pyridin-1-yl) Synthesis of -9H-purine (Compound 92-3)
  • Step 3 Synthesis of 2-(5-chloro-2-fluorophenyl)-6-(1H-pyrazolo[4,3-c]pyridin-1-yl)-9H-purine (Compound 92)
  • Step 1 3-[9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-yl]-thieno[2,3-c] Preparation of pyridine (compound 93-1)
  • Test Example 1 In vitro enzyme activity inhibition test (TGF ⁇ R1)
  • TGF ⁇ R1 peptide and adenosine triphosphate were added to initiate the reaction.
  • ADP-Glo TM reagent After incubating at room temperature for 90 minutes, add kinase detection reagent. After incubating at room temperature for 30 min, the detection was performed.
  • the solvent group (DMSO) was used as a negative control, and the buffer group (without TGF ⁇ R1 enzyme) was used as a blank control.
  • Percent inhibition rate (1-(chemiluminescence signal value of different concentration compound group-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))*100%
  • the half inhibitory concentration (IC 50 ) or range of the compound on TGF ⁇ R1 is estimated according to the following formula:
  • IC 50 X ⁇ (1-percent inhibition rate)/percent inhibition rate
  • Example number IC 50 for TGF ⁇ R1 (nM) 1 2.54 ⁇ 0.80 2 2.09 ⁇ 0.15 5 2.54 ⁇ 0.11 6 12.41 ⁇ 1.34 8 1.49 ⁇ 0.04 9 1.61 ⁇ 0.28 11 7.82 ⁇ 1.63 12 24.28 ⁇ 2.61 13 7.58 ⁇ 0.20 14 6.96 ⁇ 1.18 15 3.00 ⁇ 0.16 17 10.39 ⁇ 0.74 18 8.44 ⁇ 0.51 19 2.00 ⁇ 0.48 20 153.60 ⁇ 32.57 twenty one 9.64 ⁇ 0.74 twenty two 3.00 ⁇ 1.36
  • Test Example 2 In vitro enzyme activity inhibition test (TGF ⁇ R2)
  • Percent inhibition rate (1-(chemiluminescence signal value of different concentration compound group-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control)*100%
  • the half inhibitory concentration (IC 50 ) or range of the compound on TGF ⁇ R2 is estimated according to the following formula:
  • IC 50 X ⁇ (1-percent inhibition rate)/percent inhibition rate
  • Example number IC 50 for TGF ⁇ R2 (nM) 1 548.49 ⁇ 25.53 2 89.63 ⁇ 1.88 5 535.07 ⁇ 2.35 6 860.82 ⁇ 14.21 8 159.36 ⁇ 16.42 11 1814.38 ⁇ 186.28 13 458.03 ⁇ 11.97 15 319.12 ⁇ 27.77 17 386.07 ⁇ 59.37 18 1377.62 ⁇ 39.29 19 859.05 ⁇ 1.88 twenty one 580.32 ⁇ 94.98 twenty two 216.00 ⁇ 4.68 27 527.74 ⁇ 85.08
  • Test Example 3 In vitro cell activity inhibition test
  • HEK293-SBE cells (Bpsbioscience) were spread on a 96-well plate (MEM medium containing 10% FBS), 30,000/well, 37°C, 5% CO 2 culture overnight.
  • Day 2 Change the medium to 0.5% FBS MEM medium, and add 0.5% FBS medium diluted compound, the final concentration of the compound is up to 10uM, 4-fold dilution, 8 concentration gradients. After culturing for 4-5 hours, add 10 ⁇ l TGF ⁇ . The final concentration of TGF ⁇ is 0.5ng/ml. Add 10ul medium to the blank control. No compound was added to the negative control, but TGF ⁇ was added.
  • Percent inhibition rate (1-(chemiluminescence signal value of different concentration compound group-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))*100%
  • y is the percentage inhibition rate
  • Max and Min are the maximum and minimum values of the fitted curve, respectively
  • x is the test concentration of the compound
  • Hillslope is the slope of the curve.
  • Example number IC 50 (nM) 1 6.46 ⁇ 0.99 2 3.93 ⁇ 1.11 5 6.60 ⁇ 0.65 6 8.51 ⁇ 0.84 8 4.70 ⁇ 0.18 11 6.87 ⁇ 0.80 13 8.79 ⁇ 1.34 14 13.02 ⁇ 1.37 15 15.39 ⁇ 7.31 17 4.17 ⁇ 0.88 18 11.60 ⁇ .44 19 8.83 ⁇ 0.73 twenty two 10.29 ⁇ 2.18 25 12.10 ⁇ 0.62 27 14.49 ⁇ 1.17 29 15.41 ⁇ 2.19
  • Kit Predictor TM hERG Fluorescence Polarization Assay, (ThermoFisher),
  • the kit contains:
  • Test group Add different concentrations of the test compound to the microplate containing hERG cell membrane, and add the tracer with high hERG affinity to each well. After incubating the microplate at room temperature for 2 hours, use more The functional microplate reader detects the change of fluorescence polarization (Excitation: 540nm; Emission: 590nm) value.
  • Positive control group 30 ⁇ M positive control compound E4031 was used instead of the test compound, and the experimental method was the same as the test group.
  • Blank control group replace the test compound with hERG buffer, and no hERG cell membrane, the experimental method is the same as the test group.
  • the percentage inhibition rate of the compound of the present invention on hERG at different concentrations is calculated.
  • 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%
  • IC 50 X ⁇ (1-percent inhibition rate)/percent inhibition rate
  • the compounds of the present invention have a lower risk of cardiotoxicity associated with hERG ion channels.
  • Test Example 5 Biochemical CYP enzyme (cytochrome P450) inhibition test
  • Test group add different concentrations of test compounds to the microplate, add Luciferin-ME (100 ⁇ M), K 3 PO 4 (100mM) and CYP1A2 (0.01pmol/ ⁇ L) to each well, and pre-incubate at room temperature 10min, then add the NADPH regeneration system, react at room temperature for 30min, finally add an equal volume of detection buffer, incubate at room temperature for 20min, and then perform chemiluminescence detection.
  • Luciferin-ME 100 ⁇ M
  • K 3 PO 4 100mM
  • CYP1A2 CYP1A2 (0.01pmol/ ⁇ L
  • Negative control group The experimental method is the same as that of the test group, except that the test compound is not added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP1A2Membrance (0.01pmol/ ⁇ L) is used instead of CYP1A2.
  • Test group add different concentrations of the test compound to the microtiter plate, add Luciferin-ME EGE (3 ⁇ M), K 3 PO 4 (100mM) and CYP2D6 (5nM) to each well, pre-incubate at room temperature for 10 min, Then add the NADPH regeneration system, react at 37°C for 30 minutes, and finally add an equal volume of detection buffer, incubate at room temperature for 20 minutes, and then perform chemiluminescence detection.
  • Luciferin-ME EGE 3 ⁇ M
  • K 3 PO 4 100mM
  • CYP2D6 5nM
  • Negative control group The experimental method is the same as that of the test group, except that the test compound is not added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP2D6Membrance (5nM) is used instead of CYP2D6.
  • Test group add different concentrations of test compounds to the microtiter plate, add Luciferin-IPA (3 ⁇ M), K 3 PO 4 (100mM) and CYP3A4 (2nM) to each well, pre-incubate for 10 min at room temperature, and then Add the NADPH regeneration system, react at room temperature for 30 minutes, and finally add an equal volume of detection buffer, incubate at room temperature for 20 minutes, and then perform chemiluminescence detection.
  • Luciferin-IPA 3 ⁇ M
  • K 3 PO 4 100mM
  • CYP3A4 2nM
  • Negative control group The experimental method is the same as that of the test group, except that the test compound is not added.
  • Blank control group The experimental method is the same as the test group, except that no test compound is added, and CYP3A4Membrance (2nM) is used instead of CYP3A4.
  • Percent inhibition rate (1-(chemiluminescence signal value of the test compound concentration group-chemiluminescence signal value of the blank control group)/(chemiluminescence signal value of the negative control group-chemiluminescence signal value of the blank control group)) ⁇ 100%.
  • IC 50 X ⁇ (1-percent inhibition rate)/percent inhibition rate
  • the compound of Example 1 was administered intravenously (IV) and intragastrically (PO) to male SD rats to investigate the pharmacokinetic properties.
  • IV and PO are 1 mg/kg and 5 mg/kg, respectively, the solvent of IV is physiological saline, and the solvent of PO is 0.5% MC (sodium methylcellulose).
  • Blood was collected at different time points after IV and PO administration. The blood was anticoagulated with EDTA.K2, and a plasma sample was obtained after centrifugation, which was stored at -80°C.
  • Plasma samples were processed with precipitated protein and analyzed by LC-MS/MS. Using WinNonlin 6.3 software, the non-compartmental model was used to calculate the pharmacokinetic parameters. The results are shown in Table 6 below.
  • the exposure (AUC last ) of the compound of Example 1 administered IV at a dose of 1 mg/kg in rats was 764 h*ng/mL, and the corresponding maximum blood concentration (C max ) was The clearance rate was 2170ng/mL and the clearance rate was 21.8ml/min/kg, indicating that the compound of the present invention has excellent drug exposure in rats by IV administration.
  • the AUC last of the compound of Example 1 administered by PO at a dose of 5 mg/kg in rats was 2357h*ng/mL, and the corresponding maximum blood concentration was 2437ng/mL, indicating that the compound of the present invention was administered via PO.
  • the rats have excellent drug exposure in the blood system.
  • the half-life of the compound of Example 1 taken orally in rats is 1.35h, and the bioavailability is 62.4%.
  • the compound of Example 1 has excellent pharmacokinetic properties in rats.
  • the compound of Example 6 was administered intravenously (IV) and intragastrically (PO) to male SD rats to investigate the pharmacokinetic properties.
  • IV and PO are 1 mg/kg and 5 mg/kg, respectively, the solvent of IV is physiological saline, and the solvent of PO is 0.5% MC (sodium methylcellulose).
  • Blood was collected at different time points after IV and PO administration. The blood was anticoagulated with EDTA.K2, and a plasma sample was obtained after centrifugation, which was stored at -80°C.
  • Plasma samples were processed with precipitated protein and analyzed by LC-MS/MS. Using WinNonlin 6.3 software, the non-compartmental model was used to calculate the pharmacokinetic parameters. The results are shown in Table 7 below.
  • the exposure (AUC last ) of the compound of Example 6 administered IV at a dose of 1 mg/kg in rats was 344 h*ng/mL, and the corresponding maximum plasma concentration (C max ) was 867ng/mL and a clearance rate of 49.4ml/min/kg, indicating that the compound of the present invention has a higher blood concentration in rats by IV administration, a faster clearance, and a lower overall exposure to the systemic circulation.
  • the AUC last of the compound of Example 6 administered by PO at a dose of 5 mg/kg in rats was 905 h*ng/mL, and the corresponding maximum plasma concentration was 1518 ng/mL, indicating that the compound of the present invention was administered via PO.
  • the rat blood system has good drug exposure.
  • the compound of Example 6 has good pharmacokinetic properties in rats.

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Abstract

本发明涉及含有并环基团的咪唑并嘧啶类化合物、其制备方法及用途。具体而言，本发明涉及式(I)的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，包含其的药物组合物和药盒，其制备方法及其在制备用于预防或治疗疾病或病症(尤其是癌症)的药物中的用途。

Description

含有并环基团的咪唑并嘧啶类化合物、其制备方法及用途 技术领域
本发明涉及一种含有并环基团的咪唑并嘧啶类化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，包含其的药物组合物和药盒，其制备方法及其在制备由TGFβR1介导的疾病(尤其是癌症)的药物中的用途。
背景技术
转化生长因子-β(TGF-β)是一种多功能细胞因子，其调节各种细胞应答，例如细胞增殖、分化、迁移和凋亡。TGF-β超家族包含TGF-β1、TGF-β2、TGF-β3、活化素、抑制素、骨形态发生蛋白等。TGF-β通过两种高保守性单跨膜丝氨酸/苏氨酸激酶转导信号，即TGFβR1和TGFβR2(ACS Med Chem Lett.2018,9,1117)。
Smads是细胞内重要的TGF-β信号转导和调节分子，可以将TGF-β信号直接由细胞膜转导至细胞核内，TGF-β/Smads信号通路在肿瘤的发生和发展中起到重要的作用。在TGF-β/Smads信号转导中，活化的TGF-β首先与细胞膜表面的TGFβR2结合，形成异源二聚体复合物，TGFβR1识别并结合该二元复合物。活化的TGFβR1进一步磷酸化Smad2/Smad3蛋白，后者再进一步与Smad4结合成异三聚体复合物，这一复合物进入细胞核内与辅助活化/抑制因子协同作用调节靶基因的转录(Nature.2003,425,577)。TGF-β/Smads信号通路任一环节改变，都会导致信号转导通路的异常(PNAS.2019,116,9166)。
TGF-β信号通路在包括癌症在内的许多疾病中失调，在胃癌、结肠直肠癌、前列腺癌、卵巢癌、胰腺癌、肝癌、肺癌、宫颈癌和头颈部癌细胞系和肿瘤组织中TGFβR1蛋白水平显著升高。TGF-β信号通路的活化在肿瘤基质中引发明显的病理效应，包括免疫抑制、血管再生和结缔组织增生。此外，TGF-β信号通路能够增强肿瘤细胞的侵袭力，促进上皮细胞向间充质转化以及增强对肿瘤上皮细胞治疗的耐受度(Nat Neurosci.2014,17,943)。
目前，针对TGF-β信号通路关键靶点TGFβR1抑制剂的开发在医药工业界已逐渐得到重视，已公开的专利申请包括WO2002094833A1、WO2009150547A2、WO2017035118A1、WO2018019106A1等。但本领域仍然亟需新的TGFβR1抑制剂，特别是具有高活性、高选择性的TGFβR1抑制剂。
发明概述
本发明通过大量的研究，意外地发现了一种含有并环基团的咪唑并嘧啶类化合物，该类化合物可显著抑制TGFβR1的活性，在TGFβR1和TGFβR2之间具有良好的选择性，同时具有良好的药代动力学性质，其作为TGFβR1抑制剂可用于治疗由TGF-β信号通路引起的增殖性病症及细胞凋亡失调性病症，尤其是TGFβR1介导的疾病如癌症。
本发明的第一方面涉及式I所示的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，
Figure PCTCN2020106217-appb-000001
其中，
A选自C 6-10芳基和5-10元杂芳基；
X、Y、Z各自独立地选自碳原子和氮原子；
R 1选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基任选地被一或多个R 6取代；
R 6在每次出现时各自独立地选自氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 2在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 3在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 7在每次出现时各自独立地选自氘、卤素、-OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a和-S(O) qNR bR c；
R 4选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 5选自氢、C 1-6烷基和C 3-8环烷基；
R a在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；
R b、R c在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；或者
R b、R c和与其所连接的原子共同形成3-7元环；所述3-7元环任选地被一或多个氧代基取代；
R 8、R 9在每次出现时各自独立地选自氢、-NR dR e、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：卤素、C 1-6烷基、-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
R d、R e在每次出现时各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基；或者
R d、R e和与其所连接的原子共同形成3-7元环；
q、w在每次出现时各自独立地选自1和2；
t在每次出现时各自独立地选自1、2、3和4；且
m、n各自独立地选自0、1、2和3。
另一方面，本发明提供了一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，以及一种或多种药学可接受的载体。所述药物组合物可以适合的剂型给药，所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂等。
另一方面，本发明提供了一种药盒，其包含：
a)本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物；
和
b)任选存在的包装和/或说明书。
另一方面，本发明提供了本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒，其用于治疗由TGFβR1介导的疾病或病症(尤其是癌症)。
另一方面，本发明提供了本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒在制备用于治疗由TGFβR1介导的疾病或病症(尤其是癌症)的药物中的用途。
另一方面，本发明提供了预防或治疗由TGFβR1介导的疾病或病症(尤其是癌症)的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒。
另一方面，本发明提供了制备本发明的化合物的方法，其包括以下反应路线1所示的步骤：
反应路线1
Figure PCTCN2020106217-appb-000002
其中，
R 1、R 2、R 3、R 4、A、X、Y、Z、m、n如上文中所定义；
R 5为氢；
PG为氨基的保护基；
LG为离去基团；且
当X为氮原子时，W为氢；
当X为碳原子时，W选自硼酸基或4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基。
所述式e的化合物可通过反应路线2或3制备：
反应路线2
Figure PCTCN2020106217-appb-000003
或者
反应路线3
Figure PCTCN2020106217-appb-000004
其中，
R 1、R 4、LG、PG如上文中所定义。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“烷基”定义为直链或支链的饱和脂肪族烃基。在一些实施方案中，烷基具有1至8个，例如1至4个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指具有1至6个碳原子的直链或支链的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被一或多个(诸如1至3个)适合的取代基如卤素取代。
如本文中所使用，术语“亚烷基”指直链或支链的二价烷基。
如本文中所使用，术语“环烷基”指饱和或部分不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被一个或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个，例如3至10个碳原子、3至8个碳原子或3至6个碳原子。例如，如本文中所使用，术语“C 3-8环烷基”指具有3至8个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基、环己基、环庚基)，其任选地被一或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“烷氧基”意指通过氧原子连接至母体分子部分的如上文所定义的“烷基”，例如C 1-6烷氧基、C 1-3烷氧基。C 1-6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基等，所述烷氧基可以任选地被一或多个(诸如1至3个)相同或不同的取代基取代。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括氟、氯、溴或碘。
如本文中所使用，术语“卤代烷基”是指被一或多个(诸如1至3个)相同或不同的卤素原子取代的烷基。例如，术语“C 1-6卤代烷基”指具有1至6个碳原子的卤代烷基，例如-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等。
如本文中所使用，术语“杂环烷基”指饱和的或部分饱和的且不具有芳香性的单环或双环基团，其在环中具有例如2、3、4、5、6、7、8或9个碳原子和一个或多个(例如1个、2个、3个或4个)选自O、S、N、S(＝O)、S(＝O) 2的含杂原子的基团。所述杂环烷基可以通过所述环中的任一个碳原子或杂原子(如果价态允许)与分子的其余部分连接。3-8元杂环烷基的代表性实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，术语“C 6-10芳基”指含有6至10个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被一或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“杂芳基”指含有至少一个选自N、O和S的杂原子的单环、双环或三环芳族环系，其具有例如5、6、8、9、10、11、12、13或14个环原子，特别是具有1或2或3或4或5或6或9或10个碳原子，并且，另外在每一种情况下可为苯并稠合的。例如，如本文中所使用，术语“5-10元杂芳基”意指具有5-10个环原子的单环、双环或三环芳族环系统，并且其中包含至少一个可以相同或不同的杂原子(所述杂原子是例如N、O或S)。5-10元杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。杂芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、C 1-6烷基等)取代。
如本文中所使用，术语“烯基”是指含有至少一个C＝C双键的烃基。烯基可以是直链或支链烯基， 并且含有2至15个碳原子。例如本文中“C 2-6烯基”为含有2至6个碳原子的烯基。烯基的非限制性例子包括乙烯基、丙烯基、正丁烯基、3-甲基丁-2-烯基、正戊烯基、辛烯基和癸烯基。烯基可以是未取代的，也可以被一或多个相同或不同的取代基取代。
如本文中所使用，术语“炔基”是指具有至少一个C≡C三键的烃基。炔基可以是直链或支链炔基，并且含有2至15个碳原子。例如本文中“C 2-6炔基”为含有2至6个碳原子的炔基。炔基的非限制性实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。炔基可以是未取代的，也可以被一或多个相同或不同的取代基取代。
术语“取代”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被….取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的取代基替代或未替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的取代基替代或未替代。
如果取代基被描述为“独立地选自”一组基团，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括但不限于氢的同位素(例如 2H、 3H、氘D、氚T)；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 37Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；及硫的同位素(例如 35S)。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于：药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明所用术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学上可接受盐的酸来形成。适合的碱加成盐由形成药学上可接受盐的碱来形成。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计 量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物，当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，可以在适当的后续阶段移除保护基。
本发明所用术语“室温”是指20℃±5℃。
本发明所用术语“约”在用于修饰某一数值或数值范围时，是指包括该数值或数值范围以及该数值或数值范围的本领域技术人员可接受的误差范围，例如该误差范围为±10％、±5％、±4％、±3％、±2％、±1％、±0.5％等。
化合物
本发明的一个目的在于提供一种提供一种式I所示的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，
Figure PCTCN2020106217-appb-000005
其中，
A选自C 6-10芳基和5-10元杂芳基；
X、Y、Z各自独立地选自碳原子和氮原子；
R 1选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基任选地被一或多个R 6取代；
R 6在每次出现时各自独立地选自氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 2在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 3在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 7在每次出现时各自独立地选自氘、卤素、-OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a和-S(O) qNR bR c；
R 4选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 5选自氢、C 1-6烷基和C 3-8环烷基；
R a在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；
R b、R c在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；或者
R b、R c和与其所连接的原子共同形成3-7元环，所述3-7元环任选地被一或多个氧代基取代；
R 8、R 9在每次出现时各自独立地选自氢、-NR dR e、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：卤素、C 1-6烷基、-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
R d、R e在每次出现时各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基；或者
R d、R e和与其所连接的原子共同形成3-7元环；
q、w在每次出现时各自独立地选自1和2；
t在每次出现时各自独立地选自1、2、3和4；且
m、n各自独立地选自0、1、2和3。
根据本发明的一些实施方案，本发明提供一种式I所示的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，
Figure PCTCN2020106217-appb-000006
其中，
A选自C 6-10芳基和5-10元杂芳基；
X、Y、Z各自独立地选自碳原子和氮原子；
R 1选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基任选地被一或多个R 6取代；
R 6在每次出现时各自独立地选自氘、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 2在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 3在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6 亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
R 7在每次出现时各自独立地选自氘、卤素、-OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a和-S(O) qNR bR c；
R 4选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
R 5选自氢、C 1-6烷基和C 3-8环烷基；
R a在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；
R b、R c在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；或者
R b、R c和与其所连接的原子共同形成3-7元环；
R 8、R 9在每次出现时各自独立地选自氢、氨基、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：卤素、C 1-6烷基、-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
R d、R e在每次出现时各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基；或者
R d、R e和与其所连接的原子共同形成3-7元环；
q、w在每次出现时各自独立地选自1和2；
t在每次出现时各自独立地选自1、2、3和4；且
m、n各自独立地选自0、1、2和3。
根据本发明的一些实施方案，A选自苯基和5-10元杂芳基。
在本发明的一些实施方案中，A为5-10元杂芳基。
在本发明的一些实施方案中，A为5-6元杂芳基。
在本发明的一些实施方案中，A为5元杂芳基。
在本发明的一些实施方案中，A选自吡咯基、吡唑基、呋喃基、噻吩基和异噻唑基。
在本发明的一些实施方案中，A选自吡咯-1-基、吡咯-3-基、吡唑-1-基、吡唑-3-基、呋喃-3-基、噻吩-3-基和异噻唑-3-基。
根据本发明的一些实施方案，X选自碳原子和氮原子。
根据本发明的一些实施方案，Y选自碳原子和氮原子。
根据本发明的一些实施方案，Z选自碳原子和氮原子。
根据本发明的一些实施方案，R 1为任选地被一或多个R 6取代的C 6-10芳基或5-10元杂芳基。
在本发明的一些实施方案中，R 1为任选地被一或多个R 6取代的苯基或5-6元杂芳基。
在本发明的一些实施方案中，R 1为任选地被一或多个R 6取代的苯基或6元杂芳基。
在本发明的一些实施方案中，R 1为任选地被C 1-6烷基或C 1-6卤代烷基取代的6元杂芳基。
在本发明的一些实施方案中，R 1为任选地被C 1-6烷基或C 1-6卤代烷基取代的5元杂芳基。
在本发明的一些实施方案中，R 1为任选地被一或多个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基、吡啶基、吡唑基或噻唑基。
在本发明的一些实施方案中，R 1为被一或二个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基、吡啶基、吡唑基或噻唑基。
在本发明的一些实施方案中，R 1为任选地被卤素取代的苯基。
在本发明的一些实施方案中，R 1为任选地被C 1-6烷基或C 1-6卤代烷基取代的吡啶基。
在本发明的一些实施方案中，R 1为被C 1-6烷基或C 1-6卤代烷基取代的吡啶基。
在本发明的一些实施方案中，R 1为被甲基、二氟甲基或三氟甲基取代的吡啶基。
在本发明的一些实施方案中，R 1为被甲基取代的吡唑基和噻唑基。
在本发明的一些实施方案中，R 1为被氟和氯取代的苯基。
在本发明的一些实施方案中，R 1选自
Figure PCTCN2020106217-appb-000007
其中波浪线
Figure PCTCN2020106217-appb-000008
表示该基团与分子其余部分的连接点。
在本发明的一些实施方案中，R 1选自
Figure PCTCN2020106217-appb-000009
其中波浪线
Figure PCTCN2020106217-appb-000010
表示该基团与分子其余部分的连接点。
根据本发明的一些实施方案，R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、OR a、-NR bR c、-COOR a和-C(O)NR bR c，所述C 1-6烷基、C 3-8环烷基或3-8元杂环烷基任选地被一或多个卤素取代，其中，
R a在每次出现时各自独立地选自氢和C 1-6烷基；
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、5-10元杂芳基和C 6-10芳基，所述C 1-6烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：羟基、-C(O) wR 9和-S(O) wR 9；或者
R b、R c和与其所连接的原子共同形成5-6元环，所述5-6元环任选地被一或多个氧代基取代；
R 8、R 9在每次出现时各自独立地选自氢、-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基或C 3-8环烷基任选地被一或多个选自以下的基团取代：-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
t在每次出现时各自独立地选自1和2；且
w在每次出现时各自独立地选自1和2。
在本发明的一些实施方案中，R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、5-6元杂环烷基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NR bR c，其中，
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和5-6元杂芳基，所述C 1-6烷基、苯基或5-6元杂芳基任选地被一或多个选自以下的基团取代：羟基、羧基和氨磺酰基；或者
R b、R c和与其所连接的原子共同形成5-6元环，所述5-6元环可任选地被一或二个氧代基取代；
R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；且
w在每次出现时各自独立地选自1和2。
在本发明的一些实施方案中，R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、吗啉基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NH 2，其中，
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和噁唑基，所述C 1-6烷基或苯基任选地被一或多个选自以下的基团取代：羟基、羧基和氨磺酰基；或者
R b、R c和与其所连接的原子共同形成吡咯烷环，所述吡咯烷环任选地被一或二个氧代基取代；
R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、 -O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)、和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；且
w在每次出现时各自独立地选自1和2。
在本发明的一些实施方案中，R 2在每次出现时各自独立地选自氢、氰基、卤素、甲基、环丙基、环戊基、吗啉基、羟基、甲氧基、羧基、三氟甲基、二氟甲基、氨基、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-NHCOOCH 3、-NH(CH 2) 2OH、-N(CH 3)CH 2COOH、-NHCH 2COOH、-CONH 2、
Figure PCTCN2020106217-appb-000011
Figure PCTCN2020106217-appb-000012
Figure PCTCN2020106217-appb-000013
其中波浪线
Figure PCTCN2020106217-appb-000014
表示该基团与分子其余部分的连接点。
根据本发明的一些实施方案，R 3在每次出现时各自独立地选自氢、C 1-6烷基、3-8元杂环烷基、羟基、氨基、甲氨基、二甲氨基。
在本发明的一些实施方案中，R 3在每次出现时各自独立地选自氢和C 1-6烷基。
在本发明的一些实施方案中，R 3在每次出现时各自独立地选自氢和甲基。
根据本发明的一些实施方案，R 4选自氢、氘、C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基。
在本发明的一些实施方案中，R 4为氢。
根据本发明的一些实施方案，R 5选自氢和C 1-6烷基。
在本发明的一些实施方案中，R 5选自氢和甲基。
在本发明的一些实施方案中，R 5为氢。
根据本发明的一些实施方案，m、n各自独立地选自0、1和2。
根据本发明的一些实施方案，在式I的化合物中，
A为5-6元杂芳基；
X选自碳原子和氮原子；
Y选自碳原子和氮原子；
Z选自碳原子和氮原子；
R 1为任选地被一或二个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基或5-6元杂芳基；
R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、5-6元杂环烷基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NR bR c；
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和5-6元杂芳基，所述C 1-6 烷基、苯基或5-6元杂芳基任选地被一或多个选自以下的基团取代：羟基、羧基和氨磺酰基；或者
R b、R c和与其所连接的原子共同形成5-6元环，所述5-6元环可任选地被一或二个氧代基取代；
R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
w在每次出现时各自独立地选自1和2；
R 3在每次出现时各自独立地选自氢和C 1-6烷基；
R 4为氢；
R 5选自氢和C 1-6烷基；且
m、n各自独立地选自0、1和2。
根据本发明的一些实施方案，在式I的化合物中，
A选自吡咯基、吡唑基、呋喃基、噻吩基和异噻唑基；
X选自碳原子和氮原子；
Y选自碳原子和氮原子；
Z选自碳原子和氮原子；
R 1为任选地被一或二个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基、吡啶基、吡唑基或噻唑基；
R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、吗啉基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NH 2；
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和噁唑基，所述C 1-6烷基或苯基任选地被一或多个选自以下的基团取代：羟基、羧基和氨磺酰基；或者
R b、R c和与其所连接的原子共同形成吡咯烷环，所述吡咯烷环任选地被一或二个氧代基取代；
R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)、和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
w在每次出现时各自独立地选自1和2；
R 3在每次出现时各自独立地选自氢和C 1-6烷基；
R 4为氢；
R 5选自氢和C 1-6烷基；且
m、n各自独立地选自0、1和2。
本发明涵盖对上述优选基团进行任意组合所得的式I的化合物。
根据本发明的一些实施方案，本发明的化合物具有式I-1的结构：
Figure PCTCN2020106217-appb-000015
其中，
U和V各自独立地选自C-R 3、N-R 3、N、O和S；且
R 2、R 3、R 5、R 6、X、Y、Z和m如上文所定义；
条件是当X为碳原子时，U和V不同时为C-R 3。
根据本发明的一些实施方案，在式I-1的化合物中，
X选自碳原子和氮原子；
Y选自碳原子和氮原子；
Z选自碳原子和氮原子；
U和V各自独立地选自C-R 3、N-R 3、N、O和S；
R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、吗啉基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NH 2；
R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和噁唑基，所述C 1-6烷基或苯基任选地被一或多个选自以下的基团取代：羟基、羧基和氨磺酰基；或者
R b、R c和与其所连接的原子共同形成吡咯烷环，所述吡咯烷环任选地被一或二个氧代基取代；
R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)、和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
w在每次出现时各自独立地选自1和2；
R 3在每次出现时各自独立地选自氢和C 1-6烷基；
R 5选自氢和C 1-6烷基；
R 6选自C 1-6烷基和C 1-6卤代烷基；且
m选自0、1和2；
条件是当X为碳原子时，U和V不同时为C-R 3。
根据本发明的一些实施方案，本发明的化合物具有式I-1-1的结构：
Figure PCTCN2020106217-appb-000016
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-2的结构：
Figure PCTCN2020106217-appb-000017
其中，R 2、R 3、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-3的结构：
Figure PCTCN2020106217-appb-000018
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-4的结构：
Figure PCTCN2020106217-appb-000019
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-5的结构：
Figure PCTCN2020106217-appb-000020
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-6的结构：
Figure PCTCN2020106217-appb-000021
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-7的结构：
Figure PCTCN2020106217-appb-000022
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-8的结构：
Figure PCTCN2020106217-appb-000023
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式I-1-9的结构：
Figure PCTCN2020106217-appb-000024
其中，R 2、R 5、R 6和m如上文所定义。
根据本发明的一些实施方案，本发明的化合物选自：
Figure PCTCN2020106217-appb-000025
Figure PCTCN2020106217-appb-000026
Figure PCTCN2020106217-appb-000027
Figure PCTCN2020106217-appb-000028
Figure PCTCN2020106217-appb-000029
制备方法
本发明的另一目的在于提供制备本发明的化合物的方法，其包括以下反应路线1所示的步骤：
反应路线1
Figure PCTCN2020106217-appb-000030
其中，
R 1、R 2、R 3、R 4、A、X、Y、Z、m、n如上文中所定义；
R 5为氢；
PG为氨基的保护基；优选地，PG选自甲氧羰基、乙氧羰基、叔丁氧羰基、烯丙氧羰基、9-芴甲氧羰基、苄氧羰基(Cbz)、苄基和对甲氧基苄基；更优选地，PG为对甲氧基苄基；
LG为离去基团；优选地，LG选自卤素、甲磺酰氧基、三氟甲磺酰氧基和苯氧基；更优选地，LG选自卤素、苯氧基；特别优选地，LG为氯和苯氧基；且
当X为氮原子时，W为氢；
当X为碳原子时，W选自氢、硼酸基和4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基。
步骤1：使化合物e与化合物f反应以得到化合物g。
该步骤可通过以下方法一或方法二进行：
方法一：取代反应
该反应优选在适合的有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、DMF、DMA、四氢呋喃、二氧六环、DMSO及其任意组合，优选DMSO或DMF。
该反应优选在适合的碱的存在下进行，所述碱包括有机碱或无机碱，所述有机碱可选自DIPEA、三乙胺、叔丁醇钾和吡啶，所述无机碱可选自磷酸钾、氢化钠、碳酸钾、碳酸钠、碳酸铯和氢氧化钠，优选碳酸钾或氢化钠。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选50-150℃。
方法二：偶联反应
该反应优选在适合的有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、甲醇、乙醇、DMF、乙腈、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环等)、芳烃类(例如甲苯、二甲苯)及其任意组合，优选二氧六环。
该反应优选在适合的碱的存在下进行，所述碱包括有机碱或无机碱，所述有机碱可选自三乙胺、DIPEA、吡啶、NMM、叔丁醇钠、乙酸钾和乙酸钠，所述无机碱可选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾和磷酸二氢钾，优选碳酸钠或碳酸铯。
该反应优选在适合的催化剂的存在下进行，所述催化剂优选钯催化剂，例如四(三苯基膦)钯、乙酸钯、Pd 2(dba) 3、Pd(PPh 3) 2Cl 2、Pd(PPh 3) 2Cl 2二氯甲烷络合物或Pd(dppf)Cl 2，优选乙酸钯、Pd(dppf)Cl 2或四(三苯基膦)钯。
该反应在适合的配体的存在下进行，所述配体可选自BINAP、三(邻甲基苯基)膦、三苯基膦、三环己基膦四氟硼酸盐、X-PHOS或XantPHOS，优选X-PHOS。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选50-150℃。
步骤2：使化合物g脱除氨基保护基得到式I的化合物。
该反应优选在适合的酸的存在下进行，所述酸可选自三氟乙酸和盐酸，优选三氟乙酸。
所述反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选50-150℃。
上述式e的化合物可通过以下反应路线2或3制得：
反应路线2
Figure PCTCN2020106217-appb-000031
其中，
R 1、R 4、LG、PG如上文中所定义。
步骤一：化合物a与化合物b反应生成化合物c。
该反应优选在适合的有机溶剂中进行。所述有机溶剂可选自DMF、DMA、N-甲基吡咯烷酮、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环)、芳烃类(例如甲苯、二甲苯)、水及其任意组合，优选DMA。
该反应在适合的还原剂的存在下进行。所述还原剂可选自无水亚硫酸钠、亚硫酸氢钠和偏重亚硫酸钠；优选地，所述还原剂为亚硫酸氢钠或偏重亚硫酸钠。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选90-160℃。
步骤二：化合物c与取代试剂发生取代反应得到化合物d。
当LG为卤素时，所述取代试剂为卤代试剂。当LG为氯时，所述卤代试剂为三氯氧磷、氯化亚砜、草酰氯，优选三氯氧磷。
该反应优选在适合的有机溶剂中进行。当LG为卤素(特别是氯)时，所述有机溶剂可选三氯氧磷、芳烃类(例如甲苯、二甲苯)及其任意组合，优选三氯氧磷。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，优选50-120℃。
步骤三：对化合物d的氨基进行保护得到化合物e。
该反应优选在适合的有机溶剂中进行。所述有机溶剂可选自DMF、DMA、N-甲基吡咯烷酮、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环)、芳烃类(例如甲苯、二甲苯)及其任意组合，优选DMF。
该反应中使用的氨基保护剂可选自对甲氧基苄氯、苄氯、二碳酸二叔丁酯、苄氧羰基氯、甲氧羰基氯、乙氧羰基氯、烯丙氧羰基氯和9-芴甲氧羰基氯，优选对甲氧基苄氯。
该反应优选在适合的碱的存在下进行。所述碱包括有机碱或无机碱，所述有机碱可选自三乙胺、DIPEA、吡啶、NMM、叔丁醇钠、乙酸钾和乙酸钠，所述无机碱可选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾和磷酸二氢钾，优选为碳酸钾。该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选20-90℃。
反应路线3
Figure PCTCN2020106217-appb-000032
其中，
R 1、R 4、LG、PG如上文中所定义。
步骤一’：对化合物k的氨基进行保护得到化合物p。
该反应优选在适合的有机溶剂中进行。所述有机溶剂可选DMF、DMA、N-甲基吡咯烷酮、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环)、芳烃类(例如甲苯、苯二甲苯)及其任意组合，优选 DMF。
该反应中使用的氨基保护剂可选自对甲氧基苄氯、苄氯、二碳酸二叔丁酯、苄氧羰基氯、甲氧羰基氯、乙氧羰基氯、烯丙氧羰基氯和9-芴甲氧羰基氯，优选对甲氧基苄氯。
该反应优选在适合的碱的存在下进行。所述碱包括有机碱或无机碱，所述有机碱可选自三乙胺、DIPEA、吡啶、NMM、叔丁醇钠、乙酸钾和乙酸钠，所述无机碱可选自碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、磷酸钾和磷酸二氢钾，优选碳酸钾。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选20-90℃。
步骤二’：化合物p发生重氮化卤化反应得到化合物q；
该反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醚类(例如乙二醇二甲醚、THF、二氧六环及其任意组合)，优选THF。
该反应中使用的重氮化试剂可选自亚硝酸钠和亚硝酸异戊酯，优选亚硝酸异戊酯。
该反应中使用的卤化试剂可选自二碘甲烷、碘化铜、碘单质和氢碘酸，优选二碘甲烷。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选20-90℃。
步骤三’：化合物q和化合物h发生偶联反应得到化合物e；
该反应优选在适合的有机溶剂中进行。所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、甲醇、乙醇、DMF、乙腈、醚类(例如乙二醇二甲醚、四氢呋喃、二氧六环)、芳烃类(例如甲苯、二甲苯)及其任意组合，优选1,2-二氯乙烷。
该反应优选在催化剂的存在下进行。所述催化剂优选为钯催化剂，例如四(三苯基膦)钯、乙酸钯、Pd 2(dba) 3、Pd(PPh 3) 2Cl 2、Pd(PPh 3) 2Cl 2二氯甲烷络合物或Pd(dppf)Cl 2，优选Pd 2(dba) 3。
该反应在适合的温度下进行，所述反应温度优选为0-200℃，更优选50-150℃。
当LG为苯氧基时，上述式e的化合物可通过专利WO2017035118中的方法制得。
药物组合物和药盒
本发明的另一目的在于提供一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，以及一种或多种药学可接受的载体。
本发明的另一目的在于提供一种药盒，其包含：
a)本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物；和
b)任选存在的包装和/或说明书。
本发明中“药学可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物或药物制剂中可使用的药学上可接受的载体包括但不限于：a)稀释剂，例如鱼油、二十二碳六烯酸或其酯、甘油三酯、ω-3脂肪酸或其衍生物、右旋糖、葡萄糖、甘氨酸，或其混合物；b)润滑剂，例如硬脂酸、油酸钠、氯化钠、聚乙二醇，或其混合物；c)粘合剂，例如明胶、碳酸镁、天然和合成树胶(诸如阿拉伯胶、海藻酸钠)、聚乙烯吡咯烷酮，或其混合物；d)崩解剂，例如琼脂、、膨润土、黄原胶、海藻酸或其钠盐、泡腾剂，或其混合物；e)吸收剂、着色剂、调味剂和/或甜味剂；f)乳化剂或分散剂，诸如辛酸/癸酸聚乙二醇甘油酯、油酸聚乙二醇甘油酯、油酸甘油酯、二乙二醇单乙酯，或其他可接受的乳化剂：和/或g)增强化合物的吸收的物质，例如聚乙二醇200、聚乙二醇400等。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂等。
当口服给药时，可将本发明的药物组合物制成任意口服可接受的制剂形式，包括但不限于片剂、 胶囊剂、水溶液剂、水混悬剂等。当局部给药时，可将本发明的药物组合物制成适当的软膏剂、洗剂或乳膏剂形式，其中通过将活性成分悬浮或溶解于一种或多种载体中而制得的。软膏剂中使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水。洗剂或乳膏剂中使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯(如吐温60)、2-辛基十二烷醇、苄醇和水。
本发明的药物组合物还可以无菌注射剂的形式给药，包括无菌注射水或油混悬剂、或者无菌注射水或油溶液剂。其中，可使用的载体和溶剂包括但不限于：水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
本发明的药物组合物可以包含0.01mg至1000mg的本发明的化合物。
在一些实施方案中，本发明提供制备本发明的药物组合物或药物制剂的方法，所述方法包括将本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药与一种或多种药学上可接受的载体组合。
本发明的药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它药剂联合给药。在一些实施方案中，本发明提供同时、分开或依次用于治疗的本发明化合物与额外治疗剂的组合制剂。
治疗方法和用途
本发明的另一目的在于提供本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒，其用于治疗由TGFβR1介导的疾病或病症。
本发明的另一目的在于提供本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒在制备用于治疗由TGFβR1介导的疾病或病症的药物中的用途。
本发明的另一目的在于提供预防或治疗由TGFβR1介导的疾病或病症的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒。
根据本发明的一些实施方案，所述由TGFβR1介导的疾病或病症为癌症，例如肺癌、结直肠癌、多发性骨髓瘤、急性骨髓性白血病、T‐急性淋巴母细胞性白血病、胰腺癌、肝癌、乳腺癌、黑色素瘤、神经母细胞瘤、其它实体肿瘤或其它血液癌症。
如本文中所使用的术语“有效量”是指足以实现所需预防或治疗效果的量，例如，实现减轻与待治疗疾病相关的一或多种症状的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量为约0.001mg/千克体重/天至约10000mg/千克体重/天。在合适的情况下，有效剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。可以每天、每两天或每三天给药约0.01至1000mg/kg受试者体重，通常0.1至500mg/kg受试者体重。示例性的治疗方案为每天一次或多次或每周一次或多次或每月一次或多次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以缓释制剂的形式给予所述制剂，在这种情况下，需要较低的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。
本发明所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一 种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
“治疗”表示本发明化合物的任何给药，包括：
(1)在可能有疾病倾向、但是尚未经历或显示疾病病理学或症状学的动物中防止疾病发生；
(2)在正在经历或显示疾病病理学或症状学的动物中抑制疾病(也就是阻止病理学和/或症状学的进一步发展)；或者
(3)在正在经历或显示疾病病理学或症状学的动物中改善疾病(也就是逆转病理学和/或症状学)。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合实施例对本发明的实施方案进行详细描述。但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，均按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
在常规的合成法以及实施例和中间体合成例中，各缩写的含义如下表所示。
Figure PCTCN2020106217-appb-000033
Figure PCTCN2020106217-appb-000034
以下的实施例中记载的化合物的结构通过核磁共振( 1H NMR)或质谱(MS)来确定。
核磁共振( 1H NMR)的测定仪器使用Bruker 400MHz核磁共振仪，测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)、六氘代二甲基亚砜(DMSO-d 6)；内标物质为四甲基硅烷(TMS)。
以下的实施例中的核磁共振(NMR)图谱中的缩写代表的含义如下：
s：单峰(singlet)、d：二重峰(doublet)、t：三重峰(triplet)、q：四重峰(quartet)、dd：双二重峰(double doublet)、qd：四二重峰(quartet doublet)、ddd：双双二重峰(double double doublet)、ddt：双双三重峰(double double triplet)、dddd：双双双二重峰(double double double doublet)、m：多重峰(multiplet)、br：宽峰(broad)、J：偶合常数、Hz：赫兹、DMSO-d 6：六氘代二甲基亚砜。
全部化学位移(δ)值以百万分之一(ppm)的单位给出。
质谱(MS)的测定仪器使用Agilent(ESI)质谱仪，型号为Agilent 6120B。
本发明的实施例采用如下所示方法进行制备型高效液相色谱纯化。
方法A：
色谱柱：GeLai Prep C18 ODS(10μm 150x450mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 200
7.00 10.0 90.0 200
40.00 40.0 60.0 200
方法B：
色谱柱：GeLai Prep C18 ODS(8μm 45x450mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 15.0 85.0 60
7.00 15.0 85.0 60
50.00 60.0 40.0 60
方法C：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 30.0 70.0 24
16.00 90.0 10.0 24
方法D：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 26
16.00 90.0 10.0 26
方法E：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 20
16.00 90.0 10.0 20
方法F：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 24
3.00 10.0 90.0 24
18.00 50.0 50.0 24
方法G：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 25.0 75.0 24
3.00 25.0 75.0 24
18.00 70.0 30.0 24
方法H：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％TFA)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 28
16.00 90.0 10.0 28
方法I：
色谱柱：XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 30.0 70.0 24
2.00 30.0 70.0 24
11.00 90 10 26
方法J：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 28
2.00 10.0 90.0 28
16.00 70.0 30.0 28
方法K：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 28
2.00 10.0 90.0 28
18.00 90.0 10.0 28
方法L：
色谱柱：Gelai Prep C18 OBD(8μm 45x450mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 35.0 65.0 70
7.00 35.0 65.0 70
50.00 80.0 20.0 70
方法M：
色谱柱：Waters SunFire Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 28
2.00 10.0 90.0 28
18.00 90.0 10.0 28
方法N：
色谱柱：Waters SunFire Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 26
16.00 70.0 30.0 26
方法O：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19x150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10.0 90.0 28
2.00 10.0 90.0 28
16.00 90.0 10.0 28
方法P：
色谱柱：Waters XBridge Prep C18 OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
20.00 90 10 28
方法Q：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 5 95 28
2.00 5 95 28
18.00 60 40 28
方法R：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 90 10 28
方法S：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 5 95 28
10.00 60 40 28
方法T：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
3.00 10 90 28
16.00 70 30 28
方法U：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
16.00 90 10 28
方法V：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
16.00 90 10 28
方法W：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 30
3.00 10 90 30
16.00 60 40 30
方法X：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
16.00 90 10 28
方法Y：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 90 10 28
方法Z：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
16.00 90 10 28
方法a：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 70 10 28
方法b：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 90 10 28
方法c：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％碳酸氢铵)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
16.00 90 10 28
方法d：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％甲酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
16.00 90 10 28
方法e：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 90 10 28
方法f：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 40 60 28
2.00 40 60 28
16.00 90 10 28
方法g：
色谱柱：Waters XBridge Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 10 90 28
2.00 10 90 28
18.00 70 30 28
方法h：
色谱柱：Waters SunFire Prep C 18OBD(5μm 19mm×150mm)
流动相A：乙腈；流动相B：水(含有0.05％三氟乙酸)
时间[min] 流动相A[％] 流动相B[％] 流速[mL/min]
0.00 20 80 30
3.00 20 80 30
16.00 70 30 30
实施例一：2-(6-甲基吡啶-2-基)-6-(1H-吡咯并[3,2-c]吡啶-1-基)-9H-嘌呤(化合物1)的合成
Figure PCTCN2020106217-appb-000035
步骤一：2-(6-甲基吡啶-2-基)-9H-嘌呤-6-醇(化合物1-3)的合成
称取4-氨基-5-咪唑甲酰胺(化合物1-2,9g,71.36mmol)和6-甲基-2-吡啶甲醛(化合物1-1,8.64g,71.36mmol)溶解于DMA(150mL)中，加入NaHSO 3(5.57g,53.52mmol)，升温到150℃，反应24h。向反应液中加入1.5L水，搅拌30分钟后，垫硅藻土过滤。将滤液用制备高效液相色谱纯化(方法A)，冻干得标题化合物(3.1g，收率19.12％)。
ESI-MS(m/z):228.2[M+H] +。
步骤二：6-氯-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-4)的合成
称取2-(6-甲基吡啶-2-基)-9H-嘌呤-6-醇(化合物1-3,1.3g,5.72mmol)溶解于三氯氧磷(7mL)中，升温到117℃，反应12h。降温至室温，浓缩除去三氯氧磷，加入冰水(100mL)，在搅拌下用饱和碳酸氢钠溶液调节至pH＝8，有固体析出，搅拌30min，抽滤，将滤饼水洗并干燥得标题化合物(0.8g，收率56.9％)。
ESI-MS(m/z):246.7[M+H] +。
步骤三：6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5)的合成
将6-氯-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-4,0.8g,3.26mmol)、4-苄氧基氯苄(509.99mg,3.26mmol)、K 2CO 3(900.11mg,6.51mmol)溶于DMF(15mL)中，于25℃反应12h。将反应液倾入水中，用乙酸乙酯(30mL)萃取，合并有机相，干燥浓缩得到粗品。经制备高效液相色谱纯化(方法B)，冻干得标题化合物(527mg，收率44.24％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)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)。
ESI-MS(m/z):366.8[M+H] +。
步骤四：9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-6-(1H-吡咯并[3,2-c]吡啶-1-基)-9H-嘌呤(化合物1-6)的合成
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,50.00mg,136.68μmol)、1H-吡咯并[3,2-c]吡啶(32.29mg,273.36μmol)和碳酸钾(56.59mg,410.04μmol)加入到DMF(2mL)中，80℃下搅拌16h。降温至室温，滤除不溶物，将滤液经制备高效液相色谱纯化(方法C)，得标题化合物(30mg，收率49.05％)。ESI-MS(m/z):448.5[M+H] +。
步骤五：2-(6-甲基吡啶-2-基)-6-(1H-吡咯并[3,2-c]吡啶-1-基)-9H-嘌呤(化合物1)的合成
25℃下，将9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-6-(1H-吡咯并[3,2-c]吡啶-1-基)-9H-嘌呤(化合物1-6,25mg,55.87μmol)和三氟乙酸(3mL)加入到反应瓶中，将反应升温到80℃，搅拌16h。将反应液降到室温，减压蒸除三氟乙酸，加DMF(2mL)，滤除不溶物，将滤液经制备高效液相色谱纯化(方法D)，将制备液冻干后得到的固体溶于乙腈(5ml)，加水(30ml)，加入盐酸(0.5ml)，冻干得标题化合物的盐酸盐(13mg，收率51.7％)。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.17(s,1H),9.96(d,J＝6.8Hz,1H),9.57(d,J＝4.0Hz,1H),9.50(s,1H),8.89-8.84(m,2H),8.33(t,J＝6.9Hz,1H),7.99-7.94(m,1H),7.53-7.41(m,2H),2.73(s,3H)。
ESI-MS(m/z):328.3[M+H] +。
实施例二：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物2)的合成
Figure PCTCN2020106217-appb-000036
步骤一：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物2-2)的合成
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,50mg,0.14mmol)、1-甲基-吡咯并[2,3-c]吡啶-3-硼酸频哪醇酯(38.81mg,0.15mmol)、Pd(dppf)Cl 2(5.58mg,6.83μmol)、碳酸钾(37.78mg,0.28mmol)溶于1,4-二氧六环/水(6mL,v/v＝1/1)混合溶液中，在氮气保护下加热至100℃，反应12h。将反应液倾入水中，用乙酸乙酯(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤并将滤液减压浓缩，得到标题化合物(50mg，收率79.2％)。
ESI-MS(m/z):462.2[M+H] +。
步骤二：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物2)的合成
将6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物2-2,37.78mg,0.11mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液减压浓缩，将浓缩物经制备高效液相色谱纯化(方法E)，得到标题化合物(20mg，收率38.5％)。
其结构表征如下：
1H-NMR(400MHz,DMSO-d 6)δ:13.56(s,1H),9.11(s,1H),9.00(s,1H),8.91(d,J＝4.0Hz,1H),8.62(s,1H),8.43-8.39(m,2H),7.94(t,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),4.12(s,3H),2.65(s,3H)。
ESI-MS(m/z):342.1[M+H] +。
实施例三：1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-腈(化合物3)的合成
Figure PCTCN2020106217-appb-000037
步骤一：1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-腈(化合物3-2)的制备
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,90mg,0.25mmol)、1H-吡咯并[3,2-c]吡啶-4-腈(38.74mg,0.27mmol)、碳酸钾(51mg,0.37mmol)溶于DMSO(5mL)中，加热至80℃，反应12h。将反应液冷却至室温，倾入水(30mL)中，用乙酸乙酯(30mL x 3)萃取，合并有机相，用饱和食盐水(30mLx3)洗涤，用无水硫酸钠干燥，过滤，将滤液减压浓缩，得标题化合物(50mg)。
ESI-MS(m/z):473.2[M+H] +。
步骤二：1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-腈(化合物3)的制备
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-腈(化合物3-2,50mg,0.11mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，向浓缩物中加入甲醇(5mL)，室温搅拌1h，抽滤，将滤饼干燥，得到标题化合物的三氟乙酸盐(45mg，收率87.8％)。
其结构表征如下：
1H-NMR(400MHz,DMSO-d 6)δ:13.97(s,1H),9.60(d,J＝5.1Hz,1H),9.38(s,1H),8.71(s,1H),8.61(d,J＝5.1Hz,1H),8.23(d,J＝7.6Hz,1H),7.90(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.13(s,1H),2.66(s,3H)。
ESI-MS(m/z):353.1[M+H] +。
实施例四：6-(4-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物4)的合成
Figure PCTCN2020106217-appb-000038
步骤一：9-(4-甲氧基苄基)-6-(4-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物4-2)的合成
25℃下，将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,50mg,0.14mmol)、4-甲基-1H-吡咯并[3,2-c]吡啶(27.10mg,0.2mmol)溶于DMSO(2mL)中，一次性加入K 2CO 3(56.67mg,0.41mmol)，加毕，90℃下搅拌16h。滤除不溶物，将滤液经制备高效液相色谱纯化(方法I)，将制备液冷冻干燥，得标题化合物(50mg)。
ESI-MS(m/z):462.2[M+H] +。
步骤二：6-(4-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物4)的合成
25℃下，将9-(4-甲氧基苄基)-6-(4-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物4-2,50mg,0.11mmol)溶于三氟乙酸(3mL)中，升温至80℃，反应16h。冷却至室温，将反应液缓慢加入甲基叔丁基醚(40mL)中，搅拌30min，过滤，将滤饼用水(30mL)溶解，冷冻干燥，得标题化合物的三氟乙酸盐(45mg，收率89.9％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.13(s,1H),9.71(d,J＝6.8Hz,1H),9.41(d,J＝3.7Hz,1H),8.77(s,1H),8.64(d,J＝6.8Hz,1H),8.24(d,J＝7.8Hz,1H),7.92(t,J＝7.7Hz,1H),7.49(d,J＝3.7Hz,1H),7.45(d,J＝7.6Hz,1H),3.00(s,3H),2.69(s,3H)。
ESI-MS(m/z):342.2[M+H] +。
实施例五：1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6)的合成
Figure PCTCN2020106217-appb-000039
步骤一：1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6-2)的制备
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,100mg,0.27mmol)、1H-吡咯并[3,2-c]吡啶-4-胺(40.04mg,0.30mmol)、碳酸钾(75.56mg,0.55mmol)溶于DMSO(5mL)中，加热至80℃，反应12h。将反应液冷却至室温，倾入水(30mL)中，与乙酸乙酯(30mLx3)萃取，合并有机相，用饱和食盐水(30mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得标题化合物(80mg)。
ESI-MS(m/z):463.2[M+H] +。
步骤二：1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6)的制备
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6-2,50mg,0.11mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱纯化(方法F)得到标题化合物的三氟乙酸盐(12mg，收率23.9％)。
其结构表征如下：
1H-NMR(400MHz,DMSO-d 6)δ:9.16(s,1H),8.90(d,J＝6.8Hz,1H),8.75(s,1H),8.28(d,J＝7.6Hz,1H),7.94(t,J＝7.6Hz,1H),7.84(d,J＝6.4Hz,1H),7.46(d,J＝7.6Hz,1H),7.40(s,1H),2.67(s,3H)。
ESI-MS(m/z):343.1[M+H] +。
实施例六：2-(6-甲基吡啶-2-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物7)的合成
Figure PCTCN2020106217-appb-000040
步骤一：9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物7-2)的合成
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,100.00mg,273.36μmol)、1H-吡唑并[4,3-c]吡啶(35.82mg,300.70μmol)和碳酸钾(75.56mg,546.72μmol)加入到DMSO(4mL)中，80℃下搅拌12h。降温至室温，倒入水(50mL)中析出固体，过滤，将滤饼水洗后干燥，得标题化合物(120mg)。
ESI-MS(m/z):449.2[M+H]+。
步骤二：2-(6-甲基吡啶-2-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物7)的合成
25℃下，将9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物7-2,120mg,267.57μmol)和三氟乙酸(4mL)加入到反应瓶中，升温到80℃，搅拌6h。将反应液降 温至室温，减压蒸除三氟乙酸，经制备高效液相色谱(方法H)纯化，得标题化合物的三氟乙酸盐(66.7mg，收率56.4％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.66(d,J＝6.8Hz,1H),9.35(d,J＝4.0Hz,1H),9.19(s,1H),8.94-8.90(m,2H),8.63(d,J＝6.9Hz,1H),8.33(t,J＝2.4Hz,1H),7.78(d,J＝8.0Hz,1H),2.85(s,3H)。
ESI-MS(m/z):329.1[M+H] +。
实施例七：6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8)的合成
Figure PCTCN2020106217-appb-000041
步骤一：6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8-2)的制备
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5,150mg,0.41mmol)、4-溴-1H-吡咯并[3,2-c]吡啶(88.87mg,0.45mmol)、碳酸钾(113.34mg,0.82mmol)溶于DMSO(5mL)中，加热至80℃，反应12h。将反应液冷却至室温，倾入水(30mL)中，析出固体，抽滤，干燥滤饼，得标题化合物(200mg)。
ESI-MS(m/z):526.1[M+H] +。
步骤二：6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8)的制备
将6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8-2,80mg,0.15mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱纯化(方法G)，得到标题化合物的三氟乙酸盐(15mg，收率19.3％)。
其结构表征如下：
1H-NMR(400MHz,DMSO-d 6)δ9.31(d,J＝3.6Hz,1H),8.94-8.93(m,2H),8.71(d,J＝7.6Hz,1H),8.60(t,J＝8.0Hz,1H),8.34(d,J＝5.6Hz,1H),8.03(d,J＝8.0Hz,1H),7.02(d,J＝3.6Hz,1H),2.92(s,3H)。
ESI-MS(m/z):406.0[M+H] +。
实施例八：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物31)的合成
Figure PCTCN2020106217-appb-000042
步骤一：N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物31-1)的制备
将6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物 8-2,110mg,0.21mmol)、乙酰胺(74.06mg,1.25mmol)、Pd 2(dba) 3(19.14mg,0.02mmol)、XantPhos(24.18mg,0.42mmol)、碳酸铯(136.17mg,0.42mmol)溶于1,4-二氧六环(10mL)中，加热至110℃，反应24h。将反应液冷却至室温，过滤，浓缩滤液，得标题化合物粗品(200mg，收率75.9％)。
ESI-MS(m/z):505.2[M+H] +。
步骤二：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物31)的制备
将N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物31-1,45mg,0.09mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱纯化(方法J)，冻干得标题化合物的三氟乙酸盐(25mg，收率53.4％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.11(s,1H),11.69(s,1H),9.43(d,J＝6.4Hz,1H),9.36(s,1H),8.80(s,1H),8.31(d,J＝6.8Hz,2H),7.94(t,J＝8.0Hz,1H),7.55(s,1H),7.46(d,J＝7.6Hz,1H),2.68(s,3H),2.38(s,3H)。
ESI-MS(m/z):406.0[M+H] +。
实施例九：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)环丙甲酰胺(化合物32)的合成
Figure PCTCN2020106217-appb-000043
步骤一：N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)环丙甲酰胺(化合物32-1)的合成
将1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6-2,110mg,0.24mmol)、环丙甲酸(20.48mg,0.24mmol)溶于DMF(5mL)中，加入HATU(180.87mg,0.48mmol)和DIPEA(61.48mg,0.48mmol)，于25℃下反应24h。将反应液冷倾入水(30mL)中，固体析出，过滤，干燥滤饼，得标题化合物(50mg，收率39.2％)。
ESI-MS(m/z):531.2[M+H] +。
步骤二：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)环丙甲酰胺(化合物32)的合成
将N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)环丙甲酰胺(化合物32-1,50mg,0.09mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法K)，将制备液冻干后得到的固体溶于乙腈(5ml)中，加水(30ml)，加入三氟乙酸(0.5ml)，冻干得标题化合物的三氟乙酸盐(3.95mg，收率8.37％)。
其结构表征如下：
1H-NMR(400MHz,DMSO-d 6)δ:13.98(s,1H),10.95(s,1H),9.30(d,J＝6.0Hz,1H),9.22(d,J＝3.6Hz,1H),8.74(s,1H),8.32～8.30(m,2H),7.95(t,J＝8.0Hz,1H),7.45(d,J＝7.6Hz,1H),7.04(s,1H),2.69(s,3H),2.12(s,1H),0.92～0.90(m,4H)。
ESI-MS(m/z):411.2[M+H] +。
实施例十：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43)的合成
Figure PCTCN2020106217-appb-000044
步骤一：6-氯-9-(4-甲氧基苄基)-9H-嘌呤-2-胺(化合物43-2)的合成
称取6-氯-9H-嘌呤-2-胺(化合物43-1,50g,291.91mmol)和碳酸钾(48.90g,350.29mmol)溶解于DMF(500mL)中，滴加入4-甲氧基苄氯(48.49g,306.51mmol)，将反应体系于20℃下反应16小时。LCMS显示反应完全，加入到5L水中，搅拌30分钟后，过滤，将滤饼干燥得标题化合物(82g，收率96.38％)。
ESI-MS(m/z):290.1[M+H] +。
步骤二：6-氯-2-碘-9-(4-甲氧基苄基)-9H-嘌呤(化合物43-3)的合成
称取6-氯-9-(4-甲氧基苄基)-9H-嘌呤-2-胺(化合物43-2,30g,101.71mmol)溶解于THF(400mL)中，加入CuI(20.54g,106.79mmol)和碘(26.07g,101.71mmol)，用氮气置换3次后，在氮气氛围下加入亚硝酸异戊酯(36.10g,305.12mmol)和二碘甲烷(275.15g,1020mmol)，升温到80℃，反应1h，随着反应的进行，反应体系呈现深红色。LCMS显示反应完全，将反应体系降温至室温，加入饱和亚硫酸钠溶液(200mL)，反应体系由深红色变为淡黄色，用乙酸乙酯(400mL)萃取2次，合并有机相，将有机相用无水硫酸钠干燥，滤除干燥剂，将滤液减压旋干得粗品，对其进行柱层析纯化得标题化合物(19.7g，收率47.77％)。
ESI-MS(m/z):401.0[M+H] +。
步骤三：6-氯-9-(4-甲氧基苄基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43-4)的合成
将6-氯-2-碘-9-(4-甲氧基苄基)-9H-嘌呤(化合物43-3,，1.5g,3.74mmol)、6-(三氟甲基)-2-吡啶硼酸(1.07g,5.62mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(547.95mg,748.87μmol)和碳酸钠(793.72mg,7.49mmol)加入到单口瓶中，加入1,4-二氧六环(50mL)，用氮气置换后中，升温至90℃，搅拌16小时。将反应液过滤浓缩后，倾入水中，用乙酸乙酯(50mL)萃取，合并有机相，干燥浓缩得到粗品，经高效液相色谱制备纯化(方法L)，得到标题化合物(315mg,收率18.68％)。
ESI-MS(m/z):420.1[M+H] +。
步骤四：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-9-(4-甲氧基苄基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43-5)的合成
将6-氯-9-(4-甲氧基苄基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43-4,50mg,119.11μmol)、1-甲基吡咯并[2,3-c]吡啶-3-硼酸频哪醇酯(33.82mg,131.02μmol)、Pd(dppf)Cl 2(4.86mg,5.96μmol)、碳酸钾(32.92mg,238.21μmol)溶于1,4-二氧六环(5mL)，在氮气保护下加热至100℃，反应12小时。降温至室温，滤除不溶物，将滤液浓缩后，经高效液相色谱制备纯化(方法M)，得标题化合物(17mg，收率27.69％)。
ESI-MS(m/z):516.2[M+H] +。
步骤五：6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43)的合成
25℃下，将6-(1-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-9-(4-甲氧基苄基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43-5,17mg,32.98μmol)和三氟乙酸(3mL)加入到反应瓶中，将反应升温到90℃，搅拌3h。将反应液降温到室温，减压蒸除三氟乙酸，经高效液相色谱制备纯化(方法N)，将制备液冻干后得到的固体溶于乙腈(5ml)中，加水(30ml)中，加入三氟乙酸(0.5ml)，冻干得标题化合物的三氟乙酸盐(1.11mg，收率6.54％)。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.90(s,1H),9.53(s,1H),9.45(s,1H),9.42(d,J＝6.1Hz,1H),8.85(d,J＝8.0Hz,1H),8.77(s,1H),8.54(d,J＝6.2Hz,1H),8.36(t,J＝7.9Hz,1H),8.09(d,J＝7.7Hz,1H),4.25(s,3H)。
ESI-MS(m/z):396.1[M+H] +。
实施例十一：6-(1H-吡唑并[4,3-c]吡啶-3-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物75)的合成
Figure PCTCN2020106217-appb-000045
步骤一：9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-3-基)-2-((6-甲基吡啶-2-基))-9H-嘌呤(化合物75-2)的制备
将9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-6-苯氧基-9H-嘌呤(化合物75-1，400mg,0.94mmol，合成方法参考WO2017035118)、1H-吡唑并[4,3-c]吡啶(123.8mg,1.04mmol)溶于干燥DMF(8mL)中，分批加入NaH(56.7mg，1.42mmol，60％含量)，室温反应12小时。滴入水30mL淬灭反应，用乙酸乙酯萃取(20mLx3)，合并有机相，水洗，然后用无水硫酸钠干燥，滤除干燥剂，将滤液减压浓缩，加入甲醇(10mL)，搅拌10分钟析出固体，过滤，将固体用少量甲醇洗涤后干燥得白色固体(133mg，收率31.40％)。
1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.93(s,1H),8.74(d,J＝5.8Hz,1H),8.58(s,1H),8.32(d,J＝5.9Hz,1H),8.18(d,J＝7.8Hz,1H),7.85(t,J＝7.7Hz,1H),7.44–7.33(m,3H),6.96–6.89(m,2H),5.49(s,2H),3.71(s,3H),2.60(s,3H).
步骤二：6-(1H-吡唑并[4,3-c]吡啶-3-基)-2-((6-甲基吡啶-2-基))-9H-嘌呤(化合物75)的制备
将9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-3-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物75-2,130mg,0.29mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应12h。将反应液冷却至室温，将反应液减压浓缩，制备纯化(方法O)，冻干得标题化合物的三氟乙酸盐(27mg，收率21.06％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.00(s,1H),8.77(d,J＝5.8Hz,1H),8.64(s,1H),8.35(d,J＝7.8Hz,1H),8.26(t,J＝7.8Hz,1H),8.13(d,J＝5.9Hz,1H),7.73(d,J＝7.7Hz,1H),2.75(s,3H).
ESI-MS(m/z):329.0[M+H] +.
实施例十二：N-[1-[2-[6-三氟甲基-吡啶-2-基]-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物76)的合成
Figure PCTCN2020106217-appb-000046
步骤一：6-(4-氯吡咯并[3,2-c]吡啶-1-基)-9-[(4-甲氧基苯基)甲基]-2-[6-三氟甲基-吡啶-2-基]嘌呤(化合物76-1)的合成
称取6-氯-9-(4-甲氧基苄基)-2-(6-三氟甲基吡啶-2-基)-9H-嘌呤(化合物43-4,100mg,238.22μmol)、4-氯-1H-吡咯并[3,2-c]吡啶(43.62mg,285.86μmol)和碳酸钾(65.85mg,476.43μmol)溶解于DMSO(2mL)中，升温至80℃，反应12小时。冷却至室温，加入10mL水搅拌，过滤，将固体水洗后真空干燥得标题化合物(100mg，收率78.33％)。
步骤二：N-[1-[9-[(4-甲氧基苯基)甲基]-2-[6-三氟甲基-吡啶-2-基]嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物76-2)的合成
称取6-(4-氯吡咯并[3,2-c]吡啶-1-基)-9-[(4-甲氧基苯基)甲基]-2-[6-三氟甲基-吡啶-2-基]嘌呤(化合物76-1,30mg,55.98μmol)、乙酰胺(19.84mg,335.88μmol)、Pd 2(dba) 3(5.13mg,5.60μmol)、XantPhos(6.48mg,11.20μmol)、碳酸铯(36.48mg,111.96μmol)溶解于1,4-二氧六环(2mL)中，用氮气置换3次后，在氮气氛围下微波120℃反应2小时。LCMS显示有产物生成，将反应体系冷却至室温，加入二氯甲烷(10mL)稀释，过滤，将滤液减压蒸干得标题化合物(30mg，收率95.95％)。
ESI-MS(m/z):558.8[M+H]+。
步骤三：N-[1-[2-[6-三氟甲基-吡啶-2-基]-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物76)的合成
将N-[1-[9-[(4-甲氧基苯基)甲基]-2-[6-三氟甲基-吡啶-2-基]嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物76-2,30mg,53.71μmol)溶于三氟乙酸(3mL)中，升温至80℃，搅拌反应12小时。LCMS显示有产物生成，将反应液减压浓缩后经高效液相色谱制备纯化(方法P)，得到标题化合物(3.32mg,收率10.63％)。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.23(s,2H),9.45(d,J＝6.4Hz,1H),9.35(s,1H),8.85(d,J＝1.8Hz,1H),8.78(d,J＝8.4Hz,1H),8.38(t,J＝7.9Hz,1H),8.25–8.17(m,1H),8.12(d,J＝7.8Hz,1H),7.46(s,1H),2.35(s,3H).
ESI-MS(m/z):438.8[M+H] +。
实施例十三：2-羟基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物77)的合成
Figure PCTCN2020106217-appb-000047
步骤一：2-((叔丁基二苯基硅基)氧)-N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物77-1)的制备
将6-(4-溴-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8-2,35mg,0.19mmol)、2-((叔丁基二苯基)硅氧基)乙酰胺(178.65mg,0.57mmol)、Pd 2(dba) 3(17.04mg,0.02mmol)、XantPhos(21.98mg,0.04mmol)、碳酸铯(123.79mg,0.38mmol)溶于1,4-二氧六环(5mL)中，微波110℃反应2小时。将反应液冷却至室温，过滤，浓缩滤液，得粗品。经C 18柱层析纯化(乙腈：0.05％碳酸氢铵水溶液＝25:75)得标题化合物(38mg，收率26.3％)。
ESI-MS(m/z):758.7[M+H] +。
步骤二：2-羟基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物77)的制备
将2-((叔丁基二苯基硅基)氧)-N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物77-1,38mg,0.05mmol)溶于三氟乙酸(2mL)中，加热至80℃，反应3h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法A)，将制备液冻干后得标题化合物的三氟乙酸盐(6.68mg，收率28.1％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.01(s,1H),10.44(s,1H),9.34(d,J＝6.2Hz,1H),9.27(d,J＝4.0Hz,1H),8.76(s,1H),8.32(dd,J＝6.9,4.8Hz,2H),7.95(t,J＝7.6Hz,1H),7.46(d,J＝7.7Hz,1H),7.20(s,1H),5.73(s,1H),4.24(s,2H),2.69(s,3H)。
ESI-MS(m/z):400.9[M+H] +。
实施例十四：(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基甲酸乙酯(化合物78)的合成
Figure PCTCN2020106217-appb-000048
步骤一：(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基甲酸乙酯(化合物78-1)的制备
将1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2，20mg,0.04mmol)、氯甲酸乙酯(9.4mg,0.08mmol)、三乙胺(17.5mg,0.17mmol)溶于二氯甲烷(5mL)中，室温反应12小时。浓缩反应液，将浓缩物溶于乙醇(5mL)中，滴加氢氧化钠水溶液(1mol/L,2mL)，室温反应12小时。滴入水30mL淬灭反应，用乙酸乙酯萃取(20mLx3)，合并有机相，饱和食盐水洗涤，用无水硫酸钠干燥，滤除干燥剂，将滤液减压浓缩得到黄色固体(15mg，收率65.27％)。
ESI-MS(m/z):535.2[M+H] +.
步骤二：(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基甲酸乙酯(化合物78)的制备
将(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基甲酸乙酯(化合物78-1,15mg,0.03mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应12小时。将反应液冷却至室温，将反应液减压浓缩，经制备高效液相色谱纯化(方法R)，冻干得标题化合物的三氟乙酸盐(6mg，收率19.62％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.14(s,1H),11.97(s,1H),9.40(d,J＝6.8Hz,1H),9.33(s,1H), 8.82(s,1H),8.31(t,J＝6.0Hz,2H),7.95(t,J＝7.7Hz,1H),7.65(s,1H),7.47(d,J＝7.7Hz,1H),4.38(q,J＝7.1Hz,2H),2.69(s,3H),1.38(t,J＝7.1Hz,3H).
ESI-MS(m/z):415.2[M+H] +
实施例十五：2-氨基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物79)的合成
Figure PCTCN2020106217-appb-000049
步骤一：(2-((1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基)-2-氧代乙基)氨基甲酸叔丁酯(化合物79-1)的合成
将1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2，43mg,92.97μmol)和Boc-甘氨酸(16.29mg,92.97μmol)溶于N,N-二甲基甲酰胺(1mL)，加入HATU(70.66mg,185.94μmol)、DIEA(24.03mg,185.94μmol)，置于25℃反应24h；反应液倾入水中，固体析出，过滤，干燥滤饼得标题化合物(30mg，收率49.47％)。
ESI-MS(m/z):620.3[M+H] +。
步骤二：2-氨基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物79)的合成
25℃下，将(2-((1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)氨基)-2-氧代乙基)氨基甲酸叔丁酯(化合物79-1，30mg,48.41μmol)溶于三氟乙酸(2mL)中，升温至80℃反应16h。将反应液减压蒸干溶剂得粗品。向粗品中加入甲基叔丁基醚(10mL)，有大量固体析出，过滤，将所得滤饼溶于7mL水中，过滤。将滤液用制备高效液相色谱纯化(方法：S)，得标题化合物的三氟乙酸盐(21mg,收率80.26％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.35-9.20(m,2H),8.81(s,1H),8.39(dd,J＝15.2,7.1Hz,2H),8.11(t,J＝7.8Hz,1H),7.60(d,J＝7.7Hz,1H),7.51(d,J＝3.8Hz,1H),4.17(s,2H),2.74(s,3H).
ESI-MS(m/z):399.9[M+H] +。
实施例十六：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)特戊酰胺(化合物80)的合成
Figure PCTCN2020106217-appb-000050
步骤一：N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)特戊酰胺(化合物80-1)的制备
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2,25mg,0.05mmol)和三乙胺(15.21mg,0.15mmol)溶于二氯甲烷(2mL)中，然后再加入特戊酰氯(9.06mg,0.7mmol)，加毕，室温反应1h。将反应液用二氯甲烷(30mL)稀释，用清水(10mL)和饱和 食盐水(10mL)各洗一次，将有机相用无水硫酸钠干燥，过滤，将滤液减压蒸干得标题化合物(27mg，收率98.5％)。
ESI-MS(m/z):547.2[M+H] +。
步骤二：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)特戊酰胺(化合物80)的制备
将N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)特戊酰胺(化合物80-1,27mg,0.05mmol)溶于三氟乙酸(2mL)中，加热至80℃，反应4h。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法T)，将制备液冻干后得标题化合物的三氟乙酸盐(6.94mg，收率25.9％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.01(s,1H),10.24(s,1H),9.40(d,J＝6.1Hz,1H),9.28(d,J＝3.7Hz,1H),8.76(s,1H),8.34(dd,J＝19.8,6.9Hz,2H),7.95(t,J＝7.7Hz,1H),7.46(d,J＝7.6Hz,1H),6.99(s,1H),2.70(s,3H),1.35(s,9H)。
ESI-MS(m/z):427.9[M+H] +。
实施例十七：2-甲氧基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物81)的合成
Figure PCTCN2020106217-appb-000051
步骤一：2-甲氧基-N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物81-1)的制备
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2,30mg,0.06mmol)、甲氧基乙酸(7.01mg,0.08mmol)溶于N,N二甲基甲酰胺(2mL)中，然后加入HATU(36.97mg,0.10mmol)和N,N二异丙基乙胺(33.53mg,0.26mmol)，加毕，室温反应15小时。将反应液冷倾入水(20mL)中，用乙酸乙酯(15mL*3)萃取，合并有机相，用饱和食盐水(15mL)洗涤，用无水硫酸钠干燥有机相，过滤，滤液减压蒸干得到粗品，经制备高效液相色谱仪纯化(方法U)，将制备液冻干后得标题化合物(10mg，收率28.8％)。
ESI-MS(m/z):535.2[M+H] +。
步骤二：2-甲氧基-N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物81)的制备
将2-甲氧基-N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)乙酰胺(化合物81-1,10mg,0.02mmol)溶于三氟乙酸(1mL)中，加热至80℃，反应4小时。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法V)，将制备液冻干后得标题化合物的三氟乙酸盐(1.47mg，收率14.8％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.08(s,1H),11.28(s,1H),9.43(d,J＝6.5Hz,1H),9.35(d,J＝3.7Hz,1H),8.80(s,1H),8.34(dd,J＝12.4,7.1Hz,2H),7.96(t,J＝7.7Hz,1H),7.47(d,J＝7.7Hz,1H),7.40(s,1H),4.33(s,2H),3.47(s,3H),2.70(s,3H)。
ESI-MS(m/z):415.1[M+H] +。
实施例十八：1-甲基-3-{1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基}脲(化 合物82)的合成
Figure PCTCN2020106217-appb-000052
步骤一：1-甲基-3-{1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基}脲(化合物82-1)的制备
将6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8-2，80mg,0.15mmol)、1-甲基脲(56.3mg,0.76mmol)、Pd 2(dba) 3(13.9mg,0.01mmol)、XantPhos(17.59mg,0.03mmol)、碳酸铯(99.03mg,0.30mmol)溶于1,4-二氧六环(5mL)中，加热至110℃，反应24小时。将反应液冷却至室温，过滤，浓缩滤液，得标题化合物粗品(70mg，收率88.65％)。
ESI-MS(m/z):520.2[M+H] +.
步骤二：1-甲基-3-{1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基}脲(化合物82)的制备
将1-甲基-3-{1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基}脲(化合物82-1,60mg,0.12mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应12小时。将反应液冷却至室温，将反应液减压浓缩，经制备高效液相色谱纯化(方法W)，冻干得标题化合物的三氟乙酸盐(40mg，收率64.09％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.50–14.27(m,1H),14.13(s,1H),11.23(s,1H),9.30(d,J＝24.0Hz,2H),8.81(s,1H),8.31(d,J＝7.7Hz,1H),8.18(d,J＝5.1Hz,1H),7.96(t,J＝7.3Hz,1H),7.48(d,J＝7.0Hz,2H),2.85(d,J＝4.5Hz,3H),2.68(s,3H).
ESI-MS(m/z):400.2[M+H] +.
实施例十九：2-(二甲氨基)-N-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物83)的合成
Figure PCTCN2020106217-appb-000053
步骤一：2-(二甲氨基)-N-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物83-1)的合成
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2,30mg,60.12μmol)、2-(二甲氨基)乙酸(7.44mg,72.15μmol)溶于DMF(1mL)中，加入HATU(45.72mg,120.25μmol)和DIPEA(15.54mg,120.25μmol)，于25℃下反应24h。将反应液经制备高效液相色谱仪纯化(方法X)，将制备液冻干得标题化合物(22mg，收率60.59％)。
ESI-MS(m/z):547.9[M+H] +。
步骤二：2-(二甲氨基)-N-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物2)的合成
将2-(二甲氨基)-N-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]乙酰胺(化合物83-1,20mg,36.52μmol)溶于三氟乙酸(2mL)中，加热至80℃，反应12小时。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法Y)，将制备液冻干得标题化合物的三氟乙酸盐(5.16mg，收率25.36％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.06(s,1H),11.36(s,1H),9.87(s,1H),9.28(d,J＝3.8Hz,2H),8.77(s,1H),8.34(d,J＝7.6Hz,2H),7.99(t,J＝7.7Hz,1H),7.50(d,J＝7.6Hz,1H),7.20(s,1H),4.08(s,2H),2.94(s,6H),2.71(s,3H).
ESI-MS(m/z):428.9[M+H] +。
实施例二十：1-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]吡咯烷-2,5-二酮(化合物84)的合成
Figure PCTCN2020106217-appb-000054
步骤一：1-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]吡咯烷-2,5-二酮(化合物84-1)的合成
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-胺(化合物6-2,100mg,216.21μmol)和丁二酸酐(25.96mg,259.46μmol)溶于DMF(0.5mL)中，加入DMAP(39.62mg,324.32μmol)，于25℃下反应24h。向反应液加水析出固体，过滤，将固体干燥后得标题化合物(31mg，收率26.33％)。
ESI-MS(m/z):546.2[M+H] +。
步骤二：1-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]吡咯烷-2,5-二酮(化合物84)的合成
1-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]吡咯烷-2,5-二酮(化合物84-1,30mg,55.09μmol)溶于三氟乙酸(2mL)中，加热至80℃，反应12小时。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法Z)，得标题化合物的三氟乙酸盐(5.53mg，收率18.07％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.02(s,1H),9.43(d,J＝6.4Hz,1H),9.34–9.27(m,1H),8.77(s,1H),8.54(d,J＝5.8Hz,1H),8.37(d,J＝7.9Hz,1H),8.02(s,1H),7.52(d,J＝7.8Hz,1H),7.05(d,J＝3.7Hz,1H),2.97(s,4H),2.72(d,J＝2.1Hz,3H).
ESI-MS(m/z):424.8[M+H] +。
实施例二十一：4-[[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基]-4-氧代丁酸(化合物85)的合成
Figure PCTCN2020106217-appb-000055
步骤一：4-[[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基]-4-氧代丁酸(化合物85-1)的合成
将1-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]吡咯烷-2,5-二酮(化合物84-1,86mg,157.92μmol)溶于乙醇(5mL)和水(1mL)中，加入氢氧化钠(12.63mg,315.85μmol)，于25℃下反应12h。加水稀释后滴入1N稀盐酸调pH＝7，用二氯甲烷萃取3次，有机相合并水洗后，用无水硫酸钠干燥，浓缩得标题化合物(52mg，收率58.53％)。
ESI-MS(m/z):562.9[M+H]+。
步骤二：4-[[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基]-4-氧代丁酸(化合物85)的合成
将4-[[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基]-4-氧代丁酸(化合物85-1,50mg,88.88μmol)溶于三氟乙酸(2mL)中，加热至80℃，反应6小时。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法a)，得标题化合物的三氟乙酸盐(4.29mg，收率8.24％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.09(s,1H),12.34(s,1H),9.43(d,J＝6.7Hz,1H),9.36(s,1H),8.80(s,1H),8.32(dd,J＝7.1,3.2Hz,2H),7.95(s,1H),7.46(d,J＝7.7Hz,2H),2.91(s,2H),2.69(s,3H),2.67(d,J＝6.5Hz,2H).
ESI-MS(m/z):442.9[M+H]+。
实施例二十二：2-甲氧基乙基N-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]氨基甲酸酯(化合物86)的合成
Figure PCTCN2020106217-appb-000056
步骤一：2-甲氧基乙基N-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基甲酸酯(化合物86-1)的合成
将1-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基胺(化合物6-2,50mg,108.11μmol)、三乙胺(43.68mg,432.43μmol)溶于二氯甲烷(5mL)中，滴入氯甲酸2-甲氧基乙酯(29.96mg,216.21μmol)，于25℃下反应12h。加入二氯甲烷稀释，水洗2次后，将有机相用无水硫酸钠干燥，浓缩得标题化合物(56mg，收率91.75％)。
ESI-MS(m/z):565.3[M+H]+。
步骤二：2-甲氧基乙基N-[1-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]吡咯并[3,2-c]吡啶-4-基]氨基甲 酸酯(化合物86)的合成
将2-甲氧基乙基N-[1-[9-[(4-甲氧基苯基)甲基]-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-1H-吡咯并[3,2-c]吡啶-4-基]氨基甲酸酯(化合物86-1,56mg,99.19μmol)溶于三氟乙酸(2mL)中，加热至80℃，反应3小时。将反应液冷却至室温，减压浓缩反应液，将浓缩物经制备高效液相色谱仪纯化(方法b)，得标题化合物的三氟乙酸盐(16.53mg，收率28.35％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ14.03(s,1H),11.05(s,1H),9.28(dd,J＝13.8,5.0Hz,2H),8.76(s,1H),8.29(dd,J＝9.5,7.0Hz,2H),7.94(t,J＝7.8Hz,1H),7.45(d,J＝7.6Hz,1H),7.33(s,1H),4.43–4.30(m,2H),3.70–3.62(m,2H),3.33(s,4H),2.68(s,3H).
ESI-MS(m/z):444.9[M+H]+。
实施例二十三：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)噁唑-2-基胺(化合物87)的合成
Figure PCTCN2020106217-appb-000057
步骤一：N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)噁唑-2-基胺(化合物87-1)的合成
25℃下，将6-(4-溴-1H-吡咯并[3,2-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物8-2，200mg,379.95μmol)、噁唑-2-基胺(159.72mg,1.90mmol)、Pd 2(dba) 3(34.79mg,37.99μmol)、Xantphos(43.97mg,75.99μmol)、碳酸铯(247.57mg,759.90μmol)溶于1,4-二氧六环(1mL)，氮气保护下加热至110℃，反应24h。冷却至室温，过滤，浓缩滤液。将粗品用乙腈溶解，然后用快速硅胶柱(C18)纯化(乙腈:0.05％三氟乙酸水溶液＝60:40)，得标题化合物(40mg,收率18.89％)。
ESI-MS(m/z):530.2[M+H] +。
步骤二：N-(1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)噁唑-2-基胺(化合物87)的合成
25℃下，将N-(1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡咯并[3,2-c]吡啶-4-基)噁唑-2-基胺(化合物87-1，40mg,75.54μmol)溶于三氟乙酸(2mL)中，升温至80℃反应16h；将反应液减压蒸干溶剂，向粗品中加入甲基叔丁基醚(5mL)，有大量固体析出，搅拌20min，过滤，将滤饼用水(5mL)溶解，过滤，将滤液冻干得标题化合物的三氟乙酸盐(28mg，收率67.28％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝3.7Hz,1H),9.15(d,J＝7.1Hz,1H),8.80(s,1H),8.33(d,J＝7.8Hz,1H),8.22(d,J＝7.1Hz,1H),8.02-7.93(m,2H),7.49(d,J＝7.8Hz,2H),7.40(s,1H),2.69(s,3H)。
ESI-MS(m/z):410.1[M+H] +。
实施例二十四：6-(4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88)的合成
Figure PCTCN2020106217-appb-000058
步骤一：6-(4-氯-1H-吡唑并[4,3-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88-1)的合成
25℃下，将6-氯-9-(4-甲氧基苄基)-2-(6-甲基-吡啶-2-基)-9H-嘌呤(化合物1-5，500mg,1.37mmol)、4-氯-1H-吡唑并[4,3-c]吡啶(化合物3-2，209.90mg,1.37mmol)溶于二甲基亚砜(10mL)中，一次性加入碳酸钾(377.79mg,2.73mmol)，加毕，升温至80℃，搅拌3h。将反应液降温至25℃，将反应液加入水(200mL)中，剧烈搅拌，有大量固体析出，过滤，将滤饼烘干得标题化合物(500mg,收率68.18％)。
ESI-MS(m/z):483.1[M+H] +。
步骤二：9-(4-甲氧基苄基)-6-(4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88-2)的合成
25℃下，将6-(4-氯-1H-吡唑并[4,3-c]吡啶-1-基)-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88-1，200mg,335.04μmol)和甲基硼酸(60.17mg,1.01mmol)溶于1,4-二氧六环(1mL)和水(0.3mL)的混合溶剂中，然后加入二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II)(71.17mg,100.51μmol)和碳酸钾(92.61mg,670.08μmol)，加毕，用氮气置换反应体系3次，并在氮气保护下，油浴升温至95℃反应2h。将反应液冷却至室温后，用二氯甲烷(30mL)稀释，然后用水(10mL)和饱和食盐水(10mL)各洗涤一次，干燥有机相，并减压蒸干溶剂得到粗品。将粗品用40g的C18反相柱纯化(46％乙腈/54％0.05％HCOOH水溶液体系)，得标题化合物(30mg,收率14.75％)。
ESI-MS(m/z):463.2[M+H] +。
步骤三：6-(4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88)的合成
25℃下，将9-(4-甲氧基苄基)-6-(4-甲基-1H-吡唑并[4,3-c]吡啶-1-基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物88-2，30mg,64.86μmol)溶于三氟乙酸(2mL)中，升温至80℃，反应16h。将反应液减压蒸干溶剂，向粗品中加入甲基叔丁基醚(5mL)，有大量固体析出，搅拌20min，过滤，将滤饼用水(5mL)溶解，过滤，用制备高效液相色谱再次纯化(方法c)，得标题化合物的三氟乙酸盐(3.73mg,收率11.97％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.44(s,1H),9.09(d,J＝5.9Hz,1H),8.99(s,1H),8.72(s,1H),8.60(d,J＝5.9Hz,1H),8.36(d,J＝7.7Hz,1H),7.94(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),2.89(s,3H),2.70(s,3H).
ESI-MS(m/z):343.1[M+H] +。
实施例二十五：1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89)的合成
Figure PCTCN2020106217-appb-000059
步骤一：N-(4-甲氧基苄基)-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89-2)的合成
25℃下，将(4-甲氧基苄基)甲胺(893.27mg,6.51mmol)、4-氯-1H-吡唑并[4,3-c]吡啶(化合物89-1，100mg,651.17μmol)加入反应瓶中，氮气保护下升温至150℃，反应4h。将反应液用二氯甲烷(4mL)溶解，将粗品用快速硅胶柱纯化(20g，87％乙酸乙酯：13％石油醚)，得标题化合物(80mg,收率43.48％)。
ESI-MS(m/z):255.1[M+H] +。
步骤二：N-(4-甲氧基苄基)-1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89-3)的合成
25℃下，将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5，50mg,136.68μmol)、N-[(4-甲氧基苄基)甲基]-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89-2，41.71mg,164.02μmol)溶于二甲基亚砜(2mL)中，一次性加入碳酸钾(37.78mg,273.36μmol)，升温至80℃，反应4h。将反应液降至室温，过滤，将滤液快速硅胶柱纯化(20g，50％乙酸乙酯：50％石油醚)，得标题化合物(20mg,收率23.82％)。
ESI-MS(m/z):584.3[M+H] +。
步骤三：1-(2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89)的合成
25℃下，将N-(4-甲氧基苄基)-1-(9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基)-1H-吡唑并[4,3-c]吡啶-4-基胺(化合物89-3，20mg,34.27μmol)溶于三氟乙酸(2mL)中，升温至80℃，反应4h。将反应液减压蒸干溶剂，用二甲基亚砜(2mL)溶解并过滤，将滤液用制备高效液相色谱纯化(方法d)，得标题化合物(10mg,收率60.61％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.61(s,1H),9.72-8.86(m,4H),8.81(s,1H),8.70(d,J＝7.3Hz,1H),8.36(d,J＝7.7Hz,1H),8.07(d,J＝7.3Hz,1H),7.98(t,J＝7.8Hz,1H),7.49(d,J＝7.7Hz,1H),2.71(s,3H).
ESI-MS(m/z):344.2[M+H] +。
实施例二十六：2-(3-甲基-1H-吡唑-1-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90)的合成
Figure PCTCN2020106217-appb-000060
步骤一：9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基胺(化合物90-1)的合成
25℃下，将6-氯-9-[(4-甲氧基苄基)甲基]嘌呤-2-基胺(化合物43-2，1.3g,4.49mmol)、1H-吡唑并[4,3-c]吡啶(534.52mg,4.49mmol)溶于二甲基亚砜(15mL)中，一次性加入碳酸钾(1.24g,8.97mmol)，加毕，升温至80℃，搅拌3h。将反应液直接过滤，将滤液用快速硅胶柱纯化(C18柱，流动相A：乙腈，流动相B：0.05％三氟乙酸水溶液)，得标题化合物(800mg，收率43.09％)。
ESI-MS(m/z):373.1[M+H] +。
步骤二：2-氯-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90-2)的合成
25℃下，将9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基胺(化合物90-1，100mg,268.54μmol)溶于浓盐酸(2mL)中，降温至0℃，缓慢滴加亚硝酸钠(22.23mg,322.25μmol)的水(0.5mL)溶液，加毕，0℃搅拌30min，移至25℃环境，搅拌30min。将反应液直接过滤，将滤液用快速硅胶柱(C18)纯化(乙腈：0.05％三氟乙酸水溶液＝60:40)，将洗脱液冻干得标题化合物(40mg,收率27.97％)。
ESI-MS(m/z):392.1[M+H] +。
步骤三：9-(4-甲氧基苄基)-2-(3-甲基-1H-吡唑-1-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90-3)的合成
25℃下，将3-甲基-1H-吡唑(29.34mg,357.31μmol)、2-氯-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90-2，70mg,178.66μmol)溶于叔丁醇(1mL)中，一次性加入t-Bu XPhos(37.93mg,89.33μmol)、Pd 2(dba) 3(81.80mg,89.33μmol)、磷酸钾(56.88mg,267.98μmol)，升温至80℃，搅拌反应12hr。将反应液直接过滤，将滤饼用40g的C18反相柱纯化(46％乙腈/54％0.05％三氟乙酸水溶液体系)，得标题化合物(30mg,收率14.75％)。
ESI-MS(m/z):438.2[M+H] +。
步骤四：：2-(3-甲基-1H-吡唑-1-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90)的合成
25℃下，将9-(4-甲氧基苄基)-2-(3-甲基-1H-吡唑-1-基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物90-3，15mg,34.29μmol)溶于三氟乙酸(2mL)中，升温至80℃，反应4h。将反应液过滤；将滤液用快速硅胶柱(C18)纯化(乙腈：0.05％三氟乙酸水溶液＝32:68)，得标题化合物(4.58mg，收率29.42％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),9.16(d,J＝6.1Hz,1H),9.07(s,1H),8.87(d,J＝6.2Hz,1H),8.72(s,1H),8.69(d,J＝2.5Hz,1H),6.49(d,J＝2.5Hz,1H),2.40(s,3H).
ESI-MS(m/z):318.2[M+H] +。
实施例二十七：2-(6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基)-4-甲基噻唑(化合物91)的合成
Figure PCTCN2020106217-appb-000061
步骤一：2-碘-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物91-1)的制备
将6-氯-2-碘-9-(4-甲氧基苄基)-9H-嘌呤(化合物43-3，1g,2.5mmol)和1H-吡唑并[4,3-c]吡啶(297.36mg,2.50mmol)溶于到二甲基亚砜(20mL)中，然后加入碳酸钾(689.99mg,4.99mmol)，加毕，氮气保护下升温至90℃，搅拌反应2小时。反应液冷却至室温后，过滤，将滤液浓缩干得到粗品，经C 18柱层析纯化(乙腈：0.05％三氟乙酸水溶液＝34:66)得标题化合物(905mg，收率74.9％)。
ESI-MS(m/z):484.0[M+H] +。
步骤二：9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-甲腈(化合物91-2)的制备
称取2-碘-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物91-1，700mg,1.40mmol)溶于N,N二甲基甲酰胺(10mL)中，加入氰化锌(164.47mg,1.40mmol)和四三苯基膦钯(161.86mg,140.07μmol)，氮气保护下升温至90℃，搅拌反应15小时。反应液冷却至室温后，过滤，将滤液浓缩干得到粗品，经C 18柱层析纯化(乙腈：0.05％三氟乙酸水溶液＝28:72))得标题化合物(398mg，收率83.7％)。
ESI-MS(m/z):383.1[M+H] +。
步骤三：9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-硫代甲酰胺(化合物91-3)的制备
称取9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-甲腈(化合物91-2，100mg,261.52μmol)溶于N,N-二甲基甲酰胺(2mL)，然后加入三乙胺(52.93mg,523.04μmol)和20％硫化铵水溶液(178.20mg,523.04μmol)，加毕，室温反应0.5小时。将反应液过滤，滤液经C 18柱层析纯化(乙腈：0.05％三氟乙酸水溶液＝27:73)得标题化合物(64mg，收率61.2％)。
ESI-MS(m/z):417.1[M+H] +。
步骤四：2-(9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基)-4-甲基噻唑(化合物91-4)的制备
将9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-硫代甲酰胺(化合物91-3，100mg,240.12μmol)和1-溴丙酮(49.34mg,360.18μmol)溶于到乙酸(5mL)中，升温至100℃，反应2小时。将反应液直接减压蒸干得标题化合物(105mg，收率96.3％)。
ESI-MS(m/z):455.0[M+H] +。
步骤五：2-(6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基)-4-甲基噻唑(化合物91)的制备
将2-(9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤-2-基)-4-甲基噻唑(化合物91-4,105mg,231.01μmol)溶于三氟乙酸(3mL)中，加热至80℃，反应15小时。将反应液减压浓缩干，将浓缩物经制备高效液相色谱仪纯化(方法e)，将制备液冻干后得标题化合物的三氟乙酸盐(5.88mg， 收率5.6％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),9.03(d,J＝5.9Hz,1H),9.02(s,1H),8.85(d,J＝6.0Hz,1H),8.78(s,1H),7.58(d,J＝1.1Hz,1H),2.56(d,J＝1.0Hz,3H)。
ESI-MS(m/z):335.0[M+H] +。
实施例二十八：2-(5-氯-2-氟苯基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物92)的合成
Figure PCTCN2020106217-appb-000062
步骤一：2-(5-氯-2-氟苯基)-9-(4-甲氧基苄基)-6-苯氧基-9H-嘌呤(化合物92-2)的合成
将2-氯-9-(4-甲氧苄基)-6-苯氧基-9H-嘌呤(化合物92-1，100mg,272.63μmol)、(5-氯-2-氟苯)硼酸(57mg,327.15μmol)、二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(19.30mg,27.26μmol)和碳酸钠(76mg,545μmol)加入到单口瓶中，加入1,4-二氧六环(50mL)，用氮气置换后中，微波90℃反应1小时。将反应液过滤浓缩后，倾入水中，用乙酸乙酯(50mL)萃取，合并有机相，干燥浓缩得到粗品，经高效液相色谱制备纯化(方法f)，得到标题化合物(80mg)。
ESI-MS(m/z):460.1[M+H] +。
步骤二：2-(5-氯-2-氟苯基)-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物92-3)的合成
将2-(5-氯-2-氟苯基)-9-(4-甲氧基苄基)-6-苯氧基-9H-嘌呤(化合物92-2,28.00mg,60.75μmol)、1H-吡唑并[4,3-c]吡啶(7.96mg,66.83μmol)和碳酸钾(12.58mg,91.13μmol)加入到DMF(2mL)中，80℃下搅拌5h。降温至室温，倒入水(10mL)中析出固体，过滤，将滤饼水洗后干燥，得标题化合物(20mg)。
ESI-MS(m/z):486.0[M+H] +。
步骤三：2-(5-氯-2-氟苯基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物92)的合成
25℃下，将2-(5-氯-2-氟苯基)-9-(4-甲氧基苄基)-6-(1H-吡唑并[4,3-c]吡啶-1-基)-9H-嘌呤(化合物92-3,20.04mg,41.24μmol)和三氟乙酸(4mL)加入到反应瓶中，升温到80℃，搅拌5h。将反应液降温至室温，减压蒸除三氟乙酸，经制备高效液相色谱(方法g)纯化，得标题化合物的三氟乙酸盐(18mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),9.04(d,J＝0.8Hz,1H),8.88(d,J＝6.2Hz,1H),8.80(d,J＝6.6Hz,2H),8.24(dd,J＝6.7,2.8Hz,1H),7.72-7.66(m,1H),7.56(dd,J＝10.9,8.8Hz,1H).
ESI-MS(m/z):365.7[M+H] +。
实施例二十九：3-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-噻吩并[2,3-c]吡啶(化合物93)的合成
Figure PCTCN2020106217-appb-000063
步骤一：3-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-噻吩并[2,3-c]吡啶(化合物93-1)的制备
将6-氯-9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤(化合物1-5，100mg,0.27mmol)、噻吩并[2,3-c]吡啶-3-硼酸频哪醇酯(78.5mg,0.30mmol)、Pd(dppf)Cl 2(11.2mg,0.01mmol)、碳酸钾(75.56mg,0.55mmol)溶于1,4-二氧六环/水(5mL/1mL)中，加热至100℃，反应12小时。将反应液冷却至室温，将反应液倾入水中，固体析出，过滤，干燥滤饼得标题化合物粗品(120mg，收率94.5％)。
ESI-MS(m/z):465.1[M+H] +.
步骤二：3-[2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-噻吩并[2,3-c]吡啶(化合物93)的制备
将3-[9-(4-甲氧基苄基)-2-(6-甲基吡啶-2-基)-9H-嘌呤-6-基]-噻吩并[2,3-c]吡啶(化合物93-1,50mg,0.11mmol)溶于三氟乙酸(5mL)中，加热至80℃，反应12小时。将反应液冷却至室温，将反应液减压浓缩，经制备高效液相色谱纯化(方法h)，冻干得标题化合物的三氟乙酸盐(36mg，收率69.31％)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ13.95(s,1H),10.16(s,1H),9.85(s,1H),9.72(s,1H),8.85(d,J＝5.5Hz,2H),8.42(d,J＝7.7Hz,1H),8.06(t,J＝7.7Hz,1H),7.55(d,J＝7.7Hz,1H),2.74(s,3H).
ESI-MS(m/z):345.1[M+H] +.
参照实施例一至实施例十一的合成方法，类似地合成以下化合物：
Figure PCTCN2020106217-appb-000064
Figure PCTCN2020106217-appb-000065
Figure PCTCN2020106217-appb-000066
Figure PCTCN2020106217-appb-000067
药理活性测试
试验例1：体外酶学活性抑制试验(TGFβR1)
实验方法：根据ADP-Glo TM激酶检测试剂盒(Promega)的说明测定本发明的化合物对TGFβR1酶活性的抑制作用，步骤如下：
将TGFβR1酶分别与1000nM、100nM、10nM的测试化合物在30℃下预孵育30min后，加入TGFβR1肽和三磷酸腺苷(ATP)启动反应。在30℃下孵育3h后加入ADP-Glo TM试剂，室温下孵育90min后加入激酶检测试剂。室温下孵育30min后进行检测。以溶剂组(DMSO)为阴性对照，缓冲液组(不含TGFβR1酶)为空白对照，按照下式计算不同浓度化合物的百分比抑制率：
百分比抑制率＝(1-(不同浓度化合物组的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值))*100％
当百分比抑制率介于30-80％之间时，根据下述公式估算化合物对TGFβR1的半数抑制浓度(IC 50)或范围：
IC 50＝X×(1-百分比抑制率)/百分比抑制率，
其中X为化合物的测试浓度。
实验结果如下表1所示：
表1.本发明的化合物对TGFβR1的抑制活性
实施例编号 对TGFβR1的IC 50(nM)
1 2.54±0.80
2 2.09±0.15
5 2.54±0.11
6 12.41±1.34
8 1.49±0.04
9 1.61±0.28
11 7.82±1.63
12 24.28±2.61
13 7.58±0.20
14 6.96±1.18
15 3.00±0.16
17 10.39±0.74
18 8.44±0.51
19 2.00±0.48
20 153.60±32.57
21 9.64±0.74
22 3.00±1.36
23 116.23±1.25
25 2.66±0.03
27 63.81±2.65
29 1.80±0.10
由表1可以看出，本发明的化合物对TGFβR1具有明显的抑制作用。
试验例2：体外酶学活性抑制试验(TGFβR2)
实验方法：根据ADP-Glo TM激酶检测试剂盒(Promega)的说明测定本发明化合物对TGFβR2酶活性的抑制作用，步骤如下：
将TGFβR2酶与1000nM、100nM、10nM的测试化合物在30℃下预孵育30min后，加入髓鞘碱性蛋白(MBP)和三磷酸腺苷(ATP)启动反应。在30℃下孵育3h后加入ADP-Glo TM试剂，室温下孵育90min后加入激酶检测试剂。室温下孵育30min后进行检测。以溶剂组(DMSO)为阴性对照，缓冲液组(不含TGFβR2酶)为空白对照，按照下式计算不同浓度化合物的百分比抑制率：
百分比抑制率＝(1-(不同浓度化合物组的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值)*100％
当百分比抑制率介于30-80％之间时，根据下述公式估算化合物对TGFβR2的半数抑制浓度(IC 50)或范围：
IC 50＝X×(1-百分比抑制率)/百分比抑制率，
其中X为化合物的测试浓度。
实验结果如下表2所示：
表2.本发明的化合物对TGFβR2酶活性的抑制率
实施例编号 对TGFβR2的IC 50(nM)
1 548.49±25.53
2 89.63±1.88
5 535.07±2.35
6 860.82±14.21
8 159.36±16.42
11 1814.38±186.28
13 458.03±11.97
15 319.12±27.77
17 386.07±59.37
18 1377.62±39.29
19 859.05±1.88
21 580.32±94.98
22 216.00±4.68
27 527.74±85.08
由表2可以看出，本发明的化合物对TGFβR2具有较弱的抑制活性。
由表1和表2可以看出，本发明的化合物对TGFβR1具有选择性抑制作用。
试验例3：体外细胞活性抑制试验
实验方法：根据Bright-Glo荧光素酶检测试剂盒(Promega)的说明测定本发明化合物对HEK293-SBE细胞的抑制作用，步骤如下：
第1天：HEK293-SBE细胞(Bpsbioscience)铺96孔板(含10％FBS的MEM培养基)，3万/ 孔，37℃，5％CO 2培养过夜。
第2天：将培养基换成0.5％FBS的MEM培养基，并加入0.5％FBS培养基稀释的化合物，化合物终浓度最高10uM，4倍稀释，8个浓度梯度。培养4-5小时后，加入10μl TGFβ。TGFβ的终浓度为0.5ng/ml。在空白对照中加入10ul培养基。阴性对照中不加化合物，而加入TGFβ。
第3天：每孔加入Bright Glo试剂，在酶标仪上读取化学发光信号值。
数据分析：将化学发光信号值换算成百分比抑制率，
百分比抑制率＝(1-(不同浓度化合物组的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值))*100％
将不同浓度的化合物的百分比抑制率相对于化合物浓度作图，按照四参数模型拟合曲线，通过下式计算IC 50值：
y＝Min+(Max-Min)/(1+(x/IC 50)^(-Hillslope))
其中y为百分比抑制率；Max和Min分别为拟合曲线的最大值与最小值；x为化合物的测试浓度；且Hillslope为曲线斜率。
实验结果如下表3所示：
表3.本发明的化合物对HEK293-SBE细胞荧光素酶报告基因的抑制作用
实施例编号 IC 50(nM)
1 6.46±0.99
2 3.93±1.11
5 6.60±0.65
6 8.51±0.84
8 4.70±0.18
11 6.87±0.80
13 8.79±1.34
14 13.02±1.37
15 15.39±7.31
17 4.17±0.88
18 11.60±.44
19 8.83±0.73
22 10.29±2.18
25 12.10±0.62
27 14.49±1.17
29 15.41±2.19
由表3可以看出，本发明的化合物对HEK293-SBE细胞TGFβ/Smad信号通路具有显著的抑制作用。
试验例4.生化hERG抑制试验
试验系统：
试剂盒：Predictor TM hERG Fluorescence Polarization Assay,(ThermoFisher)，
试剂盒中含有：
阳性对照化合物hERG钾通道阻断剂E4031；
hERG细胞膜；
亲和性示踪剂Tracer；
hERG缓冲液。
试验参数：
hERG浓度：1×
Tracer浓度：1nM
孵育时间：2h
BMG PHERAstar FS FP
试验方法：
按照试剂盒说明书进行试验，步骤如下：
测试组：将不同浓度的待测化合物加入到含有hERG细胞膜的微孔板中，每孔中再加入具有高hERG亲和性示踪剂Tracer，将微孔板在室温孵育2小时后，使用多功能酶标仪检测荧光偏振(Excitation：540nm；Emission：590nm)值的变化。
阳性对照组：用30μM阳性对照化合物E4031代替待测化合物，实验方法与测试组相同。
空白对照组：用hERG缓冲液代替待测化合物，并且不加hERG细胞膜，实验方法与测试组相同。
数据处理：
根据下述公式，计算本发明的化合物在不同浓度下对hERG的百分比抑制率。
百分比抑制率＝(1-(待测化合物的荧光偏振值-阳性对照组的荧光偏振值)/(空白对照组的的荧光偏振值-阳性对照组的荧光偏振值))*100％
当百分比抑制率介于30-80％之间时，根据下述公式，估算化合物对CYP酶的半数抑制浓度(IC 50)或范围：
IC 50＝X×(1-百分比抑制率)/百分比抑制率，
其中X为化合物的测试浓度。
实验结果：
采用上述方法测定化合物对hERG的抑制，结果如下表4中所示。
表4.hERG抑制试验结果
实施例编号 IC 50(μM)
3 ＞10
6 ＞10
9 ＞10
11 ＞10
13 ＞10
14 ＞10
18 ＞10
27 ＞10
29 ＞10
测试结果表明，本发明化合物与hERG亲和性低，与亲和性示踪剂Tracer竞争的IC 50均＞10μM。
证明本发明的化合物具有hERG离子通道相关的心脏毒性风险较低。
试验例5：生化CYP酶(细胞色素P450)抑制试验
试验系统：
P450-Glo TM CYP1A2 Screening System,(Promega)
P450-Glo TM CYP2D6 Screening System,(Promega)
P450-Glo TM CYP3A4 Screening System,(Promega)
测试仪器：
BMG PHERAstar FS Luminescent
试验方法：
分别按照试剂盒说明书进行试验，步骤如下：
5.1.对CYP1A2的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME(100μM)、K 3PO 4(100mM)和CYP1A2(0.01pmol/μL)，在室温下预孵育10min，随后加入NADPH再生系统，在室温下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP1A2Membrance(0.01pmol/μL)代替CYP1A2。
5.2.对CYP2D6的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-ME EGE(3μM)、K 3PO 4(100mM)和CYP2D6(5nM)，在室温下预孵育10min，随后加入NADPH再生系统，在37℃下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP2D6Membrance(5nM)代替CYP2D6。
5.3.对CYP3A4的抑制：
测试组：将不同浓度的待测化合物加入到微孔板中，向每孔中加入Luciferin-IPA(3μM)、K 3PO 4(100mM)和CYP3A4(2nM)，在室温下预孵育10min，随后加入NADPH再生系统，在室温下反应30min，最后加入等体积的检测缓冲液，在室温下孵育20min，然后进行化学发光检测。
阴性对照组：实验方法同测试组，只是不加待测化合物。
空白对照组：实验方法同测试组，只是不加待测化合物，并且用CYP3A4Membrance(2nM)代替CYP3A4。
数据处理：
百分比抑制率＝(1-(待测化合物浓度组的化学发光信号值-空白对照组的化学发光信号值)/(阴性对照组的化学发光信号值-空白对照组的化学发光信号值))×100％。
当百分比抑制率介于30-80％之间时，根据下述公式，估算化合物对CYP酶的半数抑制浓度(IC 50)或范围：
IC 50＝X×(1-百分比抑制率)/百分比抑制率，
其中X为化合物的测试浓度。
实验结果：
按照上述方法测定本发明化合物对三种CYPs的抑制，结果如下表5中所示。
表5.CYPs抑制试验结果
Figure PCTCN2020106217-appb-000068
Figure PCTCN2020106217-appb-000069
结论：
上述结果表明，本发明化合物对3种主要CYP亚型均无明显抑制作用，表明其潜在的药物相互作用可能性相对较低。
药代动力学研究
试验例6.SD大鼠药代动力学(PK)研究
分别通过静脉(IV)和灌胃(PO)向雄性SD大鼠给药实施例1化合物，考察药代动力学特性。IV和PO的给药剂量分别是1mg/kg和5mg/kg，IV的溶剂为生理盐水，PO的溶剂为0.5％MC(甲基纤维素钠)。IV和PO给药后在不同时间点收集血液。血液采用EDTA.K2抗凝，离心后得到血浆样品，于-80℃条件下保存。
血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见下表6。
表6.化合物在大鼠体内血液中的药代动力学参数
Figure PCTCN2020106217-appb-000070
如表6所示，通过以1mg/kg的剂量IV给药的实施例1化合物在大鼠体内的暴露量(AUC last)为764h*ng/mL，对应的最大血药浓度(C max)为2170ng/mL，清除率为21.8ml/min/kg，表明本发明的化合物通过IV给药在大鼠体内具有优良的药物暴露量。
通过以5mg/kg的剂量PO给药的实施例1化合物在大鼠体内的AUC last为2357h*ng/mL，对应的最大血药浓度为2437ng/mL，表明本发明的化合物通过PO给药在大鼠血液系统中具有优良的药物暴露量。
经计算，与静脉给药相比，大鼠口服实施例1化合物的半衰期为1.35h，生物利用度为62.4％。
综上表明，实施例1的化合物在大鼠体内具有优良的药代动力学性质。
试验例7.SD大鼠药代动力学(PK)研究
分别通过静脉(IV)和灌胃(PO)向雄性SD大鼠给药实施例6化合物，考察药代动力学特性。IV和PO的给药剂量分别是1mg/kg和5mg/kg，IV的溶剂为生理盐水，PO的溶剂为0.5％MC(甲基纤维素钠)。IV和PO给药后在不同时间点收集血液。血液采用EDTA.K2抗凝，离心后得到血浆样品，于-80℃条件下保存。
血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见下表7。
表7.化合物在大鼠体内血液中的药代动力学参数
Figure PCTCN2020106217-appb-000071
如表7所示，通过以1mg/kg的剂量IV给药的实施例6化合物在大鼠体内的暴露量(AUC last)为344h*ng/mL，对应的最大血药浓度(C max)为867ng/mL，清除率为49.4ml/min/kg，表明本发明的化合物通过IV给药在大鼠体内的血药浓度较高，清除较快，体循环的整体暴露量较低。
通过以5mg/kg的剂量PO给药的实施例6化合物在大鼠体内的AUC last为905h*ng/mL，对应的最大血药浓度为1518ng/mL，表明本发明的化合物通过PO给药在大鼠血液系统中具有良好的药物暴露量。
经计算，与静脉给药相比，大鼠PO给药实施例6化合物的半衰期为1.41h，生物利用度为52.7％。
综上表明，实施例6的化合物在大鼠体内具有良好的药代动力学性质。

Claims (20)

  1. 式I所示的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，
    Figure PCTCN2020106217-appb-100001
    其中，
    A选自C 6-10芳基和5-10元杂芳基；
    X、Y、Z各自独立地选自碳原子和氮原子；
    R 1选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基任选地被一或多个R 6取代；
    R 6在每次出现时各自独立地选自氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
    R 2在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
    R 3在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
    R 7在每次出现时各自独立地选自氘、卤素、-OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a和-S(O) qNR bR c；
    R 4选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
    R 5选自氢、C 1-6烷基和C 3-8环烷基；
    R a在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；
    R b、R c在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；或者
    R b、R c和与其所连接的原子共同形成3-7元环，所述3-7元环任选地被一或多个氧代基取代；
    R 8、R 9在每次出现时各自独立地选自氢、-NR dR e、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：卤素、C 1-6烷基、-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
    R d、R e在每次出现时各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元 杂环烷基；或者
    R d、R e和与其所连接的原子共同形成3-7元环；
    q、w在每次出现时各自独立地选自1和2；
    t在每次出现时各自独立地选自1、2、3和4；且
    m、n各自独立地选自0、1、2和3。
  2. 权利要求1所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    A选自C 6-10芳基和5-10元杂芳基；
    X、Y、Z各自独立地选自碳原子和氮原子；
    R 1选自C 6-10芳基和5-10元杂芳基，所述C 6-10芳基或5-10元杂芳基任选地被一或多个R 6取代；
    R 6在每次出现时各自独立地选自氘、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
    R 2在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
    R 3在每次出现时各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a、-S(O) qNR bR c、-O-(C 2-6亚烷基-O) t-R a和-O-C 2-6亚烷基-NR bR c，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个R 7取代；
    R 7在每次出现时各自独立地选自氘、卤素、-OR a、-NR bR c、-C(O) qR a、-C(O)NR bR c、-S(O) qR a和-S(O) qNR bR c；
    R 4选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基和3-8元杂环烷基；
    R 5选自氢、C 1-6烷基和C 3-8环烷基；
    R a在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；
    R b、R c在每次出现时各自独立地选自氢、氘、-C(O) wR 8、-S(O) wR 8、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：氘、C 1-6烷基、卤素、羟基、-NR dR e、-C(O) wR 9和-S(O) wR 9；或者
    R b、R c和与其所连接的原子共同形成3-7元环；
    R 8、R 9在每次出现时各自独立地选自氢、氨基、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：卤素、C 1-6烷基、-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
    R d、R e在每次出现时各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基；或者
    R d、R e和与其所连接的原子共同形成3-7元环；
    q、w在每次出现时各自独立地选自1和2；
    t在每次出现时各自独立地选自1、2、3和4；且
    m、n各自独立地选自0、1、2和3。
  3. 权利要求1或2所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    A选自苯基和5-10元杂芳基；
    优选地，A为5-6元杂芳基；
    更优选地，A为5元杂芳基；
    特别优选地，A选自吡咯基、吡唑基、呋喃基、噻吩基和异噻唑基。
  4. 权利要求1-3中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    X选自碳原子和氮原子；
    Y选自碳原子和氮原子；且
    Z选自碳原子和氮原子。
  5. 权利要求1-4中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 1为任选地被一或多个R 6取代的苯基或5-6元杂芳基；
    优选地，R 1为任选地被一或多个R 6取代的苯基、吡啶基、吡唑基或噻唑基；
    更优选地，R 1为任选地被一或多个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基、吡啶基、吡唑基或噻唑基；
    更优选地，R 1为被一或二个独立地选自C 1-6烷基、C 1-6卤代烷基和卤素的取代基取代的苯基、吡啶基、吡唑基或噻唑基；
    更优选地，R 1为被一或二个独立地选自甲基、二氟甲基、三氟甲基、氟和氯的取代基取代的苯基、吡啶基、吡唑基或噻唑基；
    特别优选地，R 1选自
    Figure PCTCN2020106217-appb-100002
    进一步优选的，R 1选自
    Figure PCTCN2020106217-appb-100003
    其中波浪线
    Figure PCTCN2020106217-appb-100004
    表示该基团与分子其余部分的连接点。
  6. 权利要求1-5中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、OR a、-NR bR c、-COOR a和-C(O)NR bR c，所述C 1-6烷基、C 3-8环烷基或3-8元杂环烷基任选地被一或多个卤素取代；
    R a在每次出现时各自独立地选自氢和C 1-6烷基；
    R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 6-10芳基或5-10元杂芳基任选地被一或多个选自以下的基团取代：羟基、-C(O) wR 9和-S(O) wR 9；或者
    R b、R c和与其所连接的原子共同形成5-6元环，所述5-6元环任选地被一或多个氧代基取代；
    R 8、R 9在每次出现时各自独立地选自氢、-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基或C 3-8 环烷基任选地被一或多个选自以下的基团取代：-NR dR e、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O) t-R d和-(O-C 2-6亚烷基) t-NR dR e；
    R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
    t在每次出现时各自独立地选自1和2；且
    w在每次出现时各自独立地选自1和2。
  7. 权利要求6所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、5-6元杂环烷基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NR bR c；
    R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和5-6元杂芳基，所述C 1-6烷基、苯基或5-6元杂芳基任选地被选自以下的基团取代：羟基、羧基和氨磺酰基；或者
    R b、R c和与其所连接的原子共同形成5-6元环，所述5-6元环可任选地被一或二个氧代基取代；
    R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
    R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；且
    w在每次出现时各自独立地选自1和2；
    优选地，R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、吗啉基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NH 2；
    R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和噁唑基，所述C 1-6烷基或苯基任选地被选自以下的基团取代：羟基、羧基和氨磺酰基；或者
    R b、R c和与其所连接的原子共同形成吡咯烷环，所述吡咯烷环任选地被一或二个氧代基取代；
    R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)、和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
    R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；且
    w在每次出现时各自独立地选自1和2；
    更优选地，R 2在每次出现时各自独立地选自氢、氰基、卤素、甲基、环丙基、环戊基、吗啉基、羟基、甲氧基、羧基、三氟甲基、二氟甲基、氨基、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-NHCOOCH 3、-NH(CH 2) 2OH、-N(CH 3)CH 2COOH、-NHCH 2COOH、-CONH 2、
    Figure PCTCN2020106217-appb-100005
    Figure PCTCN2020106217-appb-100006
    Figure PCTCN2020106217-appb-100007
    其中波浪线
    Figure PCTCN2020106217-appb-100008
    表示该基团与分子其余部分的连接点。
  8. 权利要求1-7中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 3在每次出现时各自独立地选自氢、C 1-6烷基、3-8元杂环烷基、羟基、氨基、甲氨基、二甲氨基；
    优选地，R 3在每次出现时各自独立地选自氢和C 1-6烷基。
  9. 权利要求1-8中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 4选自氢、氘、C 1-6烷基、C 1-6卤代烷基和C 3-8环烷基；
    优选地，R 4为氢。
  10. 权利要求1-9中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    R 5选自氢和C 1-6烷基。
  11. 权利要求1-10中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    m、n各自独立地选自0、1和2。
  12. 权利要求1-11中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中所述化合物为式I-1的化合物：
    Figure PCTCN2020106217-appb-100009
    其中，
    U和V各自独立地选自C-R 3、N-R 3、N、O和S；
    条件是当X为碳原子时，U和V不同时为C-R 3；
    R 2、R 3、R 5、R 6、X、Y、Z和m如权利要求1至11任一项所定义。
  13. 权利要求12所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中，
    X选自碳原子和氮原子；
    R 2在每次出现时各自独立地选自氢、氰基、卤素、C 1-6烷基、C 3-6环烷基、吗啉基、羟基、C 1-6烷氧基、羧基、C 1-6卤代烷基、-NR bR c和-C(O)NH 2；
    R b、R c在每次出现时各自独立地选自氢、-C(O) wR 8、C 1-6烷基、苯基和噁唑基，所述C 1-6烷基或苯基任选地被选自以下的基团取代：羟基、羧基和氨磺酰基；或者
    R b、R c和与其所连接的原子共同形成吡咯烷环，所述吡咯烷环任选地被一或二个氧代基取代；
    R 8在每次出现时各自独立地选自-NR dR e、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基任选地被选自以下的基团取代：氨基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、羟基、C 1-6烷氧基、C 1-6烷基磺酰基、羧基、-O-(C 2-6亚烷基-O)-C 1-6烷基、-(O-C 2-6亚烷基)-NH 2、-(O-C 2-6亚烷基)-NH(C 1-6烷基)、和-(O-C 2-6亚烷基)-N(C 1-6烷基) 2；
    R d、R e在每次出现时各自独立地选自氢和C 1-6烷基；
    w在每次出现时各自独立地选自1和2；
    R 3在每次出现时各自独立地选自氢和C 1-6烷基；
    R 5选自氢和C 1-6烷基；
    R 6选自C 1-6烷基和C 1-6卤代烷基；且
    m选自0、1和2。
  14. 权利要求12或13所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中所述化合物为式I-1-1、I-1-2、I-1-3、I-1-4、I-1-5、I-1-6、I-1-7、I-1-8或I-1-9的化合物：
    Figure PCTCN2020106217-appb-100010
    Figure PCTCN2020106217-appb-100011
    Figure PCTCN2020106217-appb-100012
    其中，R 2、R 3、R 5、R 6和m如权利要求1至11任一项所定义。
  15. 权利要求1-14中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2020106217-appb-100013
    Figure PCTCN2020106217-appb-100014
    Figure PCTCN2020106217-appb-100015
    Figure PCTCN2020106217-appb-100016
    Figure PCTCN2020106217-appb-100017
  16. 药物组合物，其包含预防或治疗有效量的权利要求1-15中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，以及一种或多种药学可接受的载体。
  17. 药盒，其包含：
    a)权利要求1-15中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者权利要求16所述的药物组合物；和
    b)任选存在的包装和/或说明书。
  18. 权利要求1-15中任一项所述的化合物或其药学可接受的盐、酯、溶剂合物(例如水合物)、立体异构体、互变异构体、多晶型物、代谢物或前药，或者权利要求16所述的药物组合物，或者权利要求17所述的药盒在制备用于治疗由TGFβR1介导的疾病或病症(尤其是癌症，例如肺癌、结直肠癌、多发性骨髓瘤、急性骨髓性白血病、T-急性淋巴母细胞性白血病、胰腺癌、肝癌、乳腺癌、黑色素瘤、神经母细胞瘤、其它实体肿瘤或其它血液癌症)的药物中的用途。
  19. 制备权利要求1-15中任一项所述的化合物的方法，其包括反应路线1所示的步骤：
    反应路线1
    Figure PCTCN2020106217-appb-100018
    其中，
    R 1、R 2、R 3、R 4、A、X、Y、Z、m、n如1-15中任一项所定义；
    R 5为氢；
    PG为氨基的保护基；
    LG为离去基团；且
    当X为氮原子时，W为氢；
    当X为碳原子时，W选自硼酸基或4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基。
  20. 权利要求19所述的方法，其中所述式e的化合物是通过反应路线2或3制备的：
    反应路线2
    Figure PCTCN2020106217-appb-100019
    或者
    反应路线3
    Figure PCTCN2020106217-appb-100020
    其中，
    R 1、R 4、LG、PG如权利要求19中所定义。
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