SLC6A19 inhibitor compound, pharmaceutical composition as well as preparation method and application of SLC6A19 inhibitor compound and pharmaceutical composition

Abstract

The invention provides an SLC6A19 inhibitor compound, a pharmaceutical composition as well as a preparation method and application of the SLC6A19 inhibitor compound. The compound has a good SLC6A19 inhibition effect, is used for treating SLC6A19 mediated diseases and / or diseases, such as phenylketonuria, and is used for preparing medicines for the diseases or the diseases. # imgabs0 #

Description

[0001] This invention claims the priority of the prior applications titled "SLC6A19 Inhibitor Compounds, Pharmaceutical Compositions and Their Preparation Methods and Applications", with patent application number 202311618556.2, filed with the China National Intellectual Property Administration on November 29, 2023; and titled "SLC6A19 Inhibitor Compounds, Pharmaceutical Compositions and Their Preparation Methods and Applications", with patent application number 202410037978.9, filed with the China National Intellectual Property Administration on January 10, 2024. The full texts of the above prior applications are incorporated into this invention by reference. Technical Field

[0002] This invention belongs to the field of medicine, and specifically relates to an SLC6A19 inhibitor compound, a pharmaceutical composition and their preparation methods and applications. Background Art

[0003] Phenylketonuria (PKU) is a rare autosomal recessive genetic disease. Due to gene mutations in phenylalanine hydroxylase (PAH) in children, the activity of PAH is reduced or lost, phenylalanine cannot be converted into tyrosine, the metabolism of phenylalanine is blocked, and a large number of abnormal products accumulate in the body and cause the disease.

[0004] Newborns with PKU generally do not have special manifestations. Infants who are not treated start to gradually develop the disease 3 - 4 months after birth. Their hair turns from black to yellow, their skin color becomes lighter, and their urine and sweat emit a mousy odor. Adults with PKU may experience lower limb spasms, cerebellar ataxia, tremors, encephalopathy, and vision abnormalities, and severe cases may lead to death.

[0005] The PAH gene is located on chromosome 12 (12q22 - q24.2), and the PAH encoded by it is responsible for metabolizing phenylalanine and maintaining the homeostasis of phenylalanine in the body. In most patients, due to PAH mutations, the protein activity is low or inactive. In a small number of patients, due to the deficiency of dihydropteridine reductase (DHPR) or the deletion of the chaperone protein DNAJC12, the folding and assembly of PAH monomers are disrupted, resulting in an increase in phenylalanine levels.

[0006] Currently, for PKU patients, food therapy and drug therapy are mainly carried out. Food therapy mainly involves supplementing amino acid mixtures without phenylalanine and consuming low - protein foods. However, long - term consumption of foods lacking protein or phenylalanine can lead to growth restriction, anorexia, hair loss, lethargy, and eczema outbreaks. Sapropterin hydrochloride is mainly used for the treatment of mild PKU patients or BH4 - deficient patients, and the response rate for severe PKU patients is less than 10%; Pegvaliase is mainly used for the treatment of moderate - to - severe PKU patients and needs to be injected subcutaneously every day, and long - term injection is likely to cause adverse immune reactions.

[0007] Amino acid transporters mediate the transmembrane transport of amino acids and play an important role in amino acid nutrition of body cells and amino acid metabolism. SLC6A19 is the only transporter for phenylalanine in the apical membranes of small intestinal enterocytes and renal tubules, responsible for absorbing most of the free phenylalanine in the small intestine and reabsorbing phenylalanine by renal proximal tubular cells. Inhibiting SLC6A19 will help inhibit the reabsorption of phenylalanine by renal tubules and reduce the damage to the body caused by phenylalanine metabolic disorders. Summary of the Invention

[0008] To improve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or its prodrug compound:

[0009]

[0010] Wherein,

[0011] R 1 is selected from H, CN, -N(R 11 )(R 12 ), -S(O) 2 -R 13 , C 1-12 alkyl, C 1-12 alkoxy, halo C 1-12 alkyl, halo C 1-12 alkoxy, C 3-12 cycloalkyl, halo C 3-12 cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; R 11 , R 12 , R 13 are the same or different and are independently selected from H, C 1-12 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group;

[0012] R 2 is selected from CN, the following groups which are unsubstituted or optionally substituted by one, two or more R b : -N(R 21 )(R 22 ), -S(O) 2 -R 23 , 3- to 14-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; R 21 , R 22 , R 23 are the same or different and are independently selected from H, C 1-12 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group; each Rb Same or different, and each independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, halo C 1-12 Alkyl, C 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -NH 2 Or -S(O) 2 -C 1-12 Alkyl; each R b1 Same or different, and each independently selected from H, OH, NH 2 , CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 Alkyl;

[0013] R 3 、R 4 Same or different, and each independently selected from H, halogen, C 1-12 Alkyl, C 1-12 Alkoxy, halo C 1-12 Alkyl, halo C 1-12 Alkoxy, C 3-12 Cycloalkyl, halo C 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 Aryl or 5- to 10-membered heteroaryl;

[0014] L 1 Absent or selected from C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-14 Cycloalkylene, C 6-10 Arylene or 5- to 10-membered heteroarylene;

[0015] L 2 Absent or selected from C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-14 Cycloalkylene, C 6-10 Arylene or 5- to 10-membered heteroarylene;

[0016] Y 1 Selected from unsubstituted or optionally substituted by one, two or more R c Substituted with the following groups: C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 Aryl or 5- to 10-membered heteroaryl; each Rc identical or different, and independently selected from H, OH, CN, halogen, and the following groups which are unsubstituted or optionally substituted by one, two or more R c1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NH 2 or -S(O) 2 -C 1-12 alkyl; each R c1 identical or different, and independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0017] each R a identical or different, and independently selected from H, CN, oxo(=O), halogen, OH, and the following groups which are unsubstituted or optionally substituted by one, two or more R a1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -C(O)N(R a11 )(R a12 ), -N(R a13 )(R a14 ), -S(O) 2 -R a15 , -S(O)(=NR a16 )(R a17 ), or -P(O)(R a18 )(R a19 ); each R a1 identical or different, and independently selected from H, OH, CN, halogen, and the following groups which are unsubstituted or optionally substituted by one, two or more R a2 : C 1-12 alkyl, C 1-12 alkoxy, halo C 1-12 alkyl, C 3-12 cycloalkyl, 3- to 14-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NH 2 or -S(O) 2 -C 1-12 alkyl; each R a2 identical or different, and independently selected from H, OH, NH 2 , CN, halogen, C 1-6alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 are the same or different and are each independently selected from H, C 1-12 alkyl, C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group;

[0018] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0019] n is selected from 0, 1, 2 or 3.

[0020] According to some embodiments, R 1 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, halo-C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group.

[0021] According to some embodiments, R 1 is selected from H or methyl.

[0022] According to some embodiments, R 2 is selected from CN, an unsubstituted or optionally substituted by one, two or more R b substituted following groups: -N(R 21 )(R 22 ), -S(O) 2 -R 23 、a 3- to 8-membered heterocyclic group, phenyl or a 5- to 10-membered heteroaryl; R 21 、R 22 、R 23 are the same or different and are each independently selected from H, C 1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl) or C 3-6 cycloalkyl (such as cyclopropyl).

[0023] According to some embodiments, R 2 is selected from CN, an unsubstituted or optionally substituted by one, two or more R b substituted following groups: -N(R 21 )(R 22 ), -S(O) 2 -R23 、3 - to 8 - membered heterocyclic group, phenyl or 5 - to 6 - membered heteroaryl; R 21 、R 22 、R 23 are the same or different and are independently of each other selected from H, C 1-6 alkyl (such as methyl, ethyl, n - propyl, isopropyl, n - butyl or tert - butyl) or C 3-6 cycloalkyl (such as cyclopropyl).

[0024] According to some embodiments, R 2 is selected from CN, the following unsubstituted or optionally substituted by one, two or more R b groups: -N(R 21 )(R 22 ), -S(O) 2 -R 23 、

[0025] R 21 、R 22 、R 23 are the same or different and are independently of each other selected from H or methyl.

[0026] According to some embodiments, R 2 is selected from CN, the following unsubstituted or optionally substituted by one, two or three R b groups: -N(CH 3 ) 2 、-S(O) 2 -CH 3 、

[0027] According to some embodiments, each R b is the same or different and is independently of each other selected from H, OH, NH 2 、CN, halogen, oxo(=O), C 1-6 alkyl, C 1-6 alkoxy, halo - C 1-6 alkyl or C 3-6 cycloalkyl.

[0028] According to some embodiments, each R b is the same or different and is independently of each other selected from H, OH, CN, F, Cl, Br, oxo(=O), methyl, methoxy, CF 3 or cyclopropyl.

[0029] According to some embodiments, R 2 is selected from CN, -N(CH 3 ) 2, -S(O) 2 -CH 3 ,

[0030] According to some embodiments, R 2 is selected from

[0031]

[0032] According to some embodiments, L 2 is absent.

[0033] According to some embodiments, R 3 is selected from H.

[0034] According to some embodiments, R 4 is selected from methyl, cyclopropyl or halocyclopropyl (e.g., ).

[0035] According to some embodiments, R 4 is selected from cyclopropyl.

[0036] According to some embodiments, L 1 is selected from methylene, ethylene (e.g., ) or cyclopropylene (e.g., ).

[0037] According to some embodiments, L 1 is selected from methylene.

[0038] According to some embodiments, Y 1 is selected from unsubstituted or optionally substituted by one, two or more R c substituted groups: phenyl, naphthyl, 3- to 10-membered heterocyclic group or 5- to 10-membered heteroaryl;

[0039] According to some embodiments, each R c is the same or different and independently selected from H, CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 substituted groups: C 1-6 alkyl or C 1-6 alkoxy; each R c1 is the same or different and independently selected from H, CN or halogen.

[0040] According to some embodiments, Y 1 is selected from unsubstituted or optionally substituted by one, two or more R c substituted phenyl or 5- to 6-membered heteroaryl; each R cIdentical or different, and each independently selected from H, CN, halogen, an unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: C 1-6 Alkyl or C 1-6 Alkoxy; each R c1 Identical or different, and each independently selected from H, CN or halogen.

[0041] According to some embodiments, Y 1 Is selected from an unsubstituted or optionally substituted by one, two or more R c Substituted with the following groups: phenyl, naphthyl,

[0042] According to some embodiments, each R c Identical or different, and each independently selected from H, F, Cl, CN, CH 3 , OCH 3 , CF 3 , OCHF 2 Or OCF 3 .

[0043] According to some embodiments, Y 1 Is selected from an unsubstituted or optionally substituted by one or two R c Substituted phenyl; each R c Identical or different, and each independently selected from H, F, Cl, CN, CH 3 , OCH 3 Or OCF 3 .

[0044] According to some embodiments, Y 1 Is selected from

[0045] According to some embodiments, Y 1 Is selected from

[0046] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0047]

[0048] Wherein, R 1 , R 2 , R 3 , R 4 , Y 1 , L 1 , R c Has the definitions as described herein. According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0049]

[0050] Wherein, R 1 and R 2 have the definitions as described herein.

[0051] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following step A:

[0063]

[0064] Wherein, R 1 and R 2 and R 3 and R 4 and R a and L 1 and L 2 and Y 1 and m, n have the definitions as described herein.

[0065] The present invention also provides a pharmaceutical composition, which comprises at least one of a therapeutically effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or its prodrug compound.

[0066] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0067] According to some embodiments, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0068] The present invention also provides a method for treating or preventing an SLC6A19-mediated disease or disorder, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds of formula (I), its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof.

[0069] The present invention also provides a method for treating or preventing an SLC6A19-mediated disease or disorder, comprising administering to a patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition.

[0070] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0071] According to some embodiments, the patient includes a mammal, preferably a human.

[0072] The present invention also provides at least one of the compounds of formula (I), its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, or a pharmaceutical composition thereof, for treating or preventing an SLC6A19-mediated disease or disorder.

[0073] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0074] The present invention also provides the use of at least one of the compounds of formula (I), its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of a medicament.

[0075] According to some embodiments, the use may be in the preparation of a medicament for treating or preventing an SLC6A19-mediated disease or disorder.

[0076] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0077] Advantageous Effects

[0078] The compounds provided by the present invention have good SLC6A19 inhibitory effects and can be used for treating or preventing SLC6A19-related conditions and diseases, as well as for preparing medicaments for treating or preventing such conditions and diseases.

[0079] Term Definitions and Explanations

[0080] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should be understood to be within the scope recited in the specification and / or claims of this application.

[0081] The term "optional" (or "optionally", "option") in the general formula definition of this application means a situation where it is substituted by zero, one or more substituents. For example, "optionally substituted by one, two or more Rs" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more Rs.

[0082] "More than" means three or more, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0083] Unless otherwise specified, the numerical ranges recited in this specification and claims are equivalent to at least recording each specific integer value therein. For example, the numerical range "1-12" is equivalent to recording each integer value in the numerical range "1-12", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0084] The term "C 1-12 alkyl" should be understood to mean a straight-chain and branched-chain alkyl having 1 to 12 carbon atoms, "C 1-8 alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyls are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

[0085] The term "C 3-12 cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 cycloalkyl", more preferably "C 3-8 cycloalkyl". The term "C 3-12"Cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0086] The term "C 6-14 "Aryl" shall be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C 6-10 "Aryl". The term "C 6-14 "Aryl" shall be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 "Aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, especially a ring having 6 carbon atoms ("C 6 "Aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 "Aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "Aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 "Aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "Aryl"), such as anthryl. When the C 6-20 aryl is substituted, it can be mono-substituted or multi-substituted. And there is no restriction on its substitution site, for example, it can be ortho-substituted, para-substituted or meta-substituted.

[0087] The term "5- to 14-membered heteroaryl" is to be understood as encompassing monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5- to 10-membered heteroaryl". The term "5- to 14-membered heteroaryl" is to be understood as including monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O, and S and, additionally, may be benzo-fused in each case. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, where the point of attachment or linkage is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazine, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thiopheno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrido[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]phthalazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]azolyl, 2-, 4- or 5 4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl. When the 5- to 14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, it can be the carbon atom on the 5- to 14-membered heteroaryl ring that is linked to other groups, or the heteroatom on the 5- to 14-membered heteroaryl ring that is linked to other groups. When the 5- to 14-membered heteroaryl group is substituted, it can be mono-substituted or multi-substituted. And there is no limitation on the substitution site, for example, the hydrogen atom linked to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom linked to the heteroatom on the heteroaryl ring can be substituted.,

[0088] Unless otherwise defined, the term "3- to 14-membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spiro ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) 2 - state. For example, the "3- to 14-membered heterocyclic group" can be a 3- to 14-membered N-containing heterocyclic group (containing at least one N). Preferably, the heterocyclic group can be selected from "3- to 10-membered heterocyclic groups". The term "3- to 10-membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spiro rings. In particular, the heterocyclic group can include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group can be bicyclic, for example, but not limited to, a 5,5-membered ring, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, that is, it can contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3- to 14-membered heterocyclic group is connected to other groups to form the compounds of the present invention, it can be the carbon atom on the 3- to 14-membered heterocyclic group connected to other groups, or the heteroatom on the 3- to 14-membered heterocyclic ring connected to other groups. For example, when the 3- to 14-membered heterocyclic group is selected from piperazinyl, it can be the nitrogen atom on piperazinyl connected to other groups. Or when the 3- to 14-membered heterocyclic group is selected from piperidinyl, it can be the nitrogen atom on the piperidinyl ring and the carbon atom at its para-position connected to other groups.

[0089] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0090] The term "nitrogen oxides" refers to compounds formed by the oxidation of nitrogen atoms in the structures of tertiary amine compounds or nitrogen-containing (aromatic) heterocyclic compounds.

[0091] The term "spiro ring" refers to a ring system in which two rings share one ring-forming atom.

[0092] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0093] The term "bridged ring" refers to a ring system in which two rings share more than three ring-forming atoms.

[0094] Unless otherwise specified, heterocyclic groups, heteroaryl groups or heteroarylene groups include all possible isomeric forms thereof, such as their positional isomers. Thus, for some illustrative and non-limiting examples, forms substituted or bonded to other groups at one, two or more positions among their 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may be included, including pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl and pyridin-4-ylidene; thienyl or thienylidene includes thien-2-yl, thien-2-ylidene, thien-3-yl and thien-3-ylidene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0095] The term "oxo" refers to the replacement of a carbon atom, nitrogen atom or sulfur atom in a substituent by an oxygen group formed after oxidation (=O).

[0096] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl) 2 , where the definition of alkyl is as described above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0097] The term "alkyloxy" refers to -O-(alkyl), where the definition of alkyl is as described above. Non-limiting examples of alkyloxy include: methoxy, ethoxy, propoxy, butoxy. The alkyloxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.

[0098] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chain or branched-chain saturated divalent hydrocarbon group. The definition of the number of carbon atoms of "alkylene" applies to the definition of "alkyl" above. Those skilled in the art can understand that alkyleneoxy or oxyalkylene can be connected to the rest of the molecule containing it in any direction, that is, the two can be used interchangeably.

[0099] "Haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, where alkyl is defined as above.

[0100] A wavy line intersecting a chemical bond Is used to indicate the connection position of a group to other atoms in the molecular structure. For example Indicates connection to the 3-position of the pyridyl group. When the connection position of the group is not fixed, taking the pyridyl group as an example, it can be represented by To show that it can be connected to any connectable position on the pyridyl group. Another example is Which indicates that it can be connected to any connectable position on the heteroaromatic ring. For example, it can be connected to any one of the 4 carbon atoms on the benzene ring on the right side of the heteroaryl group, or it can be connected to the carbon atoms on the oxazole ring on the left side. Unless otherwise specified, similar expressions in this application are interpreted in the same way as above.

[0101] In the present invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in formula I, but in which one or more atoms are replaced by atoms with an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, or pharmaceutically acceptable salts of the compounds or the prodrugs are within the scope of the present invention. Some isotopically labeled compounds of the present invention, for example, compounds incorporating radioactive isotopes (such as 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14C) Isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2 H or D, can provide certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirements) resulting from higher metabolic stability and can thus be preferred in certain cases. The presence of hydrogen in the substituents of the present invention without separately listing the terms deuterium or tritium does not mean the exclusion of deuterium or tritium, but can also include deuterium or tritium.

[0102] Those skilled in the art will understand that the compounds represented by formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form inner salts.

[0103] The compounds of the present invention can exist in the form of solvates (such as hydrates), where the compounds of the present invention contain a polar solvent, especially for example water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

[0104] Depending on their molecular structure, the compounds of the present invention can be chiral and thus various enantiomeric forms may exist. Thus, these compounds can exist in a racemic form or an optically active form. The compounds of the present invention cover isomers or mixtures thereof, racemates, in which each chiral carbon has an R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art or can be used in synthesis in this form. In the case of a racemic amine, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (such as N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously carried out with the aid of an optically active resolving agent (such as dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0105] The corresponding stable isomers can be separated according to known methods, for example, by extraction, filtration or column chromatography.

[0106] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

[0107] The term "therapeutically effective amount" refers to the amount of an active compound or drug that a researcher, veterinarian, physician or other clinician is seeking in an organism, system, animal, individual or human that elicits a biological or medical response, and it includes one or more of the following: (1) preventing a disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or exhibited the pathology or symptoms of the disease. (2) inhibiting a disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition. (3) alleviating a disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition. Detailed implementation manners

[0108] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate and explain the present invention by way of example, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0109] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0110] Example 1 (3R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(tetrahydrofuran-3-yl)piperidine-1-carboxamide (Compound 1)

[0111]

[0112] The first step: Synthesis of tert-butyl N-[(2-fluoro-4-(trifluoromethoxy)phenyl)methyl]carbamate (Compound 1-3):

[0113] To a mixed solution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (Compound 1-1, 8 g, 30.89 mmol) in 1,4-dioxane (120 mL) and water (15 mL), potassium trifluoro[({[(2-methyl-2-propionyloxy)carbonyl]amino}methyl)borate] (Compound 1-2, 8.06 g, 33.98 mmol), palladium(II) acetate (0.35 g, 1.54 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (1.47 g, 3.09 mmol), and potassium carbonate (12.81 g, 92.67 mmol) were added. The gas was displaced, and the reaction solution was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then stirred at 105 °C overnight. After cooling to room temperature, the mixture was filtered, water (100 mL) was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Compound 1-3 (6.6 g).

[0114] MS: (ESI, m / z): 295.1 [M - 56 + ACN + H] + , RT(min): 1.994

[0115] The second step: Synthesis of (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine hydrochloride (Compound 1-4):

[0116] To a solution of N-[(2-fluoro-4-(trifluoromethoxy)phenyl)methyl]carbamic acid tert-butyl ester (Compound 1-3, 6.5 g, 21.02 mmol) in ethyl acetate (35 mL), a hydrogen chloride - ethyl acetate solution (35 mL, 4 M) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain Compound 1-4 (5.1 g).

[0117] MS: (ESI, m / z): 193.0 [M - 16] + , RT(min): 1.191

[0118] The third step: Synthesis of N-[(2-fluoro-4-(trifluoromethoxy)phenyl)methyl]-1H-imidazole-1-carboxamide (Compound 1-5):

[0119] To a solution of (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine hydrochloride (Compound 1-4, 1.17 g, 4.78 mmol) in N,N-dimethylformamide (15 mL), 1-(1H-imidazol-1-carbonyl) (0.78 g, 4.78 mmol) and N,N-diisopropylethylamine (1.54 g, 11.95 mmol) were slowly added. The reaction mixture was stirred at room temperature for 16 h. Water (30 mL) was added to the reaction mixture for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain Compound 1-5 (1.25 g).

[0120] MS:(ESI,m / z):304.0[M+H] + ,RT(min):1.416

[0121] Step 4 Synthesis of tert-butyl (3R)-3-(cyclopropylamino)piperidine-1-carboxylate (Compound 1-8):

[0122] To a solution of Compound (3R)-3-aminopiperidine-1-carboxylate tert-butyl (Compound 1-6, 10 g, 49.93 mmol) in 1,4-dioxane (100 mL), (1-ethoxycyclopropyl)oxymethyltrimethylsilane (4.35 g, 24.96 mmol), sodium cyanoborohydride (6.28 g, 99.86 mmol), and acetic acid (6.0 g, 99.86 mmol) were added. The reaction mixture was stirred at 60 °C overnight. After cooling to room temperature, water (150 mL) was added to the reaction mixture for dilution, and the pH was adjusted to 9-10 with 50% potassium carbonate solution. The mixture was extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid) to obtain Compound 1-8 (3.7 g).

[0123] MS:(ESI,m / z):241.1[M+H] + ,RT(min):1.210

[0124] Step 5 Synthesis of tert-butyl (R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxylate (Compound 1-9):

[0125] To a solution of N-[(2-fluoro-4-(trifluoromethoxy)phenyl)methyl]-1H-imidazole-1-carboxamide (Compound 1-5, 1.0 g, 3.30 mmol) in acetonitrile (10 mL) was added tert-butyl (3R)-3-(cyclopropylamino)piperidine-1-carboxylate (Compound 1-8, 0.79 g, 3.3 mmol) and triethylamine (1.00 g, 9.9 mmol), and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added for dilution, and the mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 1-9 (1.5 g).

[0126] MS: (ESI, m / z): 476.1 [M+H] + , RT(min): 2.018

[0127] Step 6 Synthesis of the hydrochloride salt of (R)-1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)-1-(piperidin-3-yl)urea (Compound 1-10):

[0128] 4M hydrogen chloride in 1,4-dioxane solution (10.0 mL) was added to a solution of tert-butyl (R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxylate (Compound 1-9, 1.5 g, 3.15 mmol) in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to obtain the crude hydrochloride salt of Compound 1-10 (1.25 g), which was directly used in the next step of the reaction.

[0129] MS: (ESI, m / z): 376.1 [M+H] + , RT(min): 0.829

[0130] Step 7 Synthesis of 3-isocyanatooxolane (Compound 1-12):

[0131] At 0 °C, a solution of trichloromethyl chloroformate (510 mg, 1.72 mmol) in dichloromethane (3 mL) and triethylamine (1044 mg, 10.32 mmol) were slowly added dropwise to a solution of oxolane-3-amine (Compound 1-11, 300 mg, 3.44 mmol) in dichloromethane (7 mL). The reaction solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo to obtain the crude Compound 1-12 (350 mg), which was directly used in the next step of the reaction.

[0132] Step 8. Synthesis of (3R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(tetrahydrofuran-3-yl)piperidine-1-carboxamide (Compound 1):

[0133] At 0 °C, a solution of dichloromethane (3 mL) of hydrochloride salt of (R)-1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)-1-(piperidin-3-yl)urea (Compound 1-10, 100 mg, 0.24 mmol) was slowly added dropwise with a solution of dichloromethane (1 mL) of 3-isocyanatooxolane (Compound 1-12, 135.73 mg, 1.2 mmol) and triethylamine (72.86 mg, 0.72 mmol). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specification: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: from 48% B to 48% B in 17 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.00 - 10.00), to obtain Compound 1 (9.83 mg).

[0134] MS: (ESI, m / z): 489.2 [M+H] + , RT(min): 1.684

[0135] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (t, 1H), 7.33 (d, 1H), 7.23 (d, 1H), 6.93 (t, 1H), 6.42 (d, 1H), 4.31 (d, 2H), 4.17–4.07 (m, 1H), 3.96–3.82 (m, 2H), 3.79–3.70 (m, 2H), 3.67–3.59 (m, 1H), 3.52–3.37 (m, 2H), 2.95 (t, 1H), 2.48–2.38 (m, 2H), 2.06–1.87 (m, 2H), 1.81–1.69 (m, 2H), 1.67–1.57 (m, 1H), 1.39–1.21 (m, 1H), 0.94–0.81 (m, 2H), 0.72–0.59 (m, 2H).

[0136] Example 2 (R)-3-(1-Cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxamide (Compound 2)

[0137]

[0138] Synthesis of the first step (R)-3-(1-Cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxamide (Compound 2):

[0139] Under the condition of 0 °C, dissolve 1-methyl-1H-pyrazol-4-amine (Compound 2-1, 38 mg, 0.29 mmol) in dichloromethane (2 mL), add triethylamine (58 mg, 0.57 mmol) and N,N'-carbonyldiimidazole (46 mg, 0.29 mmol). After stirring the reaction solution overnight at room temperature, concentrate the reaction solution. Dissolve the obtained residue in dichloromethane (2 mL), and successively add triethylamine (58 mg, 0.57 mmol) and the hydrochloride salt (80 mg, 0.19 mmol) of (R)-1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)-1-(piperidin-3-yl)urea (Compound 1-10). After the addition, stir at room temperature for 2 hours. Concentrate the reaction solution to remove the solvent, and purify the obtained residue by high performance liquid chromatography with the following conditions (chromatographic column specifications: Waters 2767 / QDA Column: SunfireC18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: from 50% B to 50% B within 16 minutes; detection wavelength: 254 nm / 220 nm; retention time (min): 8.0–10.0) to obtain Compound 2 (27 mg).

[0140] MS: (ESI, m / z): 499.4 [M+H] + , RT(min): 1.692

[0141] 1 H NMR (400 MHz, DMSO-d 6)δ8.45(s,1H),7.64(s,1H),7.43(t,1H),7.33(d,1H),7.23(d,1H),6.95(t,1H),4.32(d,2H),4.09–3.88(m,2H),3.74(s,3H),3.52(t,1H),3.06(t,1H),2.58(t,1H),2.48–2.42(m,1H),2.08–1.89(m,1H),1.83–1.61(m,2H),1.47–1.29(m,1H),0.99–0.79(m,2H),0.76–0.56(m,2H).

[0142] Using conditions similar to those in Example 2 above, the compounds in Table 1 below were prepared, and the structural characterization data of these compounds are listed in Table 1 together.

[0143] Table 1

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] Example 3 (R)-3-(3-(4-Chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxamide (Compound 71)

[0152]

[0153] The first step: Synthesis of tert-butyl (4-chloro-2-fluoro-5-methylbenzyl)carbamate (Compound 71-3):

[0154] Compound 1-bromo-4-chloro-2-fluoro-5-methylbenzene (Compound 71-1, 1.00 g, 4.47 mmol), potassium N-aminomethyltrifluoroborate (Compound 71-2, 1.17 g, 4.92 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 mL) and water (2 mL). Potassium carbonate (1.85 g, 13.41 mmol), palladium acetate (50 mg, 0.22 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (210 mg, 0.45 mmol) were added. The reaction system was purged with nitrogen three times and stirred at 110 °C under a nitrogen atmosphere for 16 hours. Water (60 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain Compound 71-3 (700 mg).

[0155] MS:(ESI,m / z):218.0[M+H-56] + ,RT(min):2.041

[0156] Step 2: Synthesis of hydrochloride of (4-chloro-2-fluoro-5-methylphenyl)methanamine (Compound 71-4):

[0157] Hydrogen chloride-ethyl acetate solution (3 mL, 4 M EtOAc solution) was added to a solution of tert-butyl (4-chloro-2-fluoro-5-methylbenzyl)carbamate (Compound 71-3, 400 mg, 1.46 mmol) in ethyl acetate (3 mL). The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated to obtain the hydrochloride of Compound 71-4 (300 mg).

[0158] MS:(ESI,m / z):174.1[M+H] + ,RT(min):1.207

[0159] Step 3: Synthesis of N-(4-chloro-2-fluoro-5-methylbenzyl)-1H-imidazole-1-carboxamide (Compound 71-5):

[0160] The hydrochloride (54 mg, 0.26 mmol) of the compound (4-chloro-2-fluoro-5-methylphenyl)methanamine (Compound 71-4) was dissolved in acetonitrile (1 mL), and Compound N,N'-carbonyldiimidazole (44.3 mg, 0.27 mmol) and triethylamine (78.9 mg, 0.78 mmol) were added. The reaction solution was stirred at 50 °C for 1 hour. Water (15 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 71-5 (64.0 mg).

[0161] MS:(ESI,m / z):268.1[M+H] + ,RT(min):1.396

[0162] Step 4. Synthesis of tert-butyl (R)-3-(3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)piperidine-1-carboxylate (Compound 71-6):

[0163] Compound N-(4-chloro-2-fluoro-5-methylbenzyl)-1H-imidazole-1-carboxamide (Compound 71-5, 64.0 mg, 0.24 mmol) was dissolved in acetonitrile (2 mL), and Compound (R)-3-(cyclopropylamino)piperidine-1-carboxylate tert-butyl ester (Compound 1-8, 57.7 mg, 0.24 mmol) and N,N'-diisopropylethylamine (93.0 mg, 0.72 mmol) were added. The reaction solution was stirred at 50 °C for 1 hour. Water (15 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 71-6 (100.0 mg).

[0164] MS:(ESI,m / z):440.2[M+H] + ,RT(min):2.099

[0165] Step 5. Synthesis of the hydrochloride of (R)-3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropyl-1-(piperidin-3-yl)urea (Compound 71-7):

[0166] Hydrogen chloride-ethyl acetate solution (1 mL, 4 M) was added to a solution of Compound (R)-3-(3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)piperidine-1-carboxylate tert-butyl ester (Compound 71-6, 100 mg, 0.23 mmol) in ethyl acetate (1 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the hydrochloride of Compound 71-7 (80.0 mg).

[0167] MS: (ESI, m / z): 340.1 [M+H] + , RT (min): 1.394

[0168] Synthesis of the sixth step (R)-3-(3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)-N-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxamide (Compound 71):

[0169] Under the condition of 0 °C, dissolve 1-methyl-1H-pyrazol-4-amine (Compound 2-1, 32 mg, 0.24 mmol) in dichloromethane (2 mL), add triethylamine (48 mg, 0.48 mmol) and N,N'-carbonyldiimidazole (38 mg, 0.24 mmol). After stirring the reaction solution overnight at room temperature, concentrate the reaction solution. Dissolve the obtained residue in dichloromethane (2 mL), and successively add N,N'-diisopropylethylamine (93.0 mg, 0.72 mmol) and the hydrochloride salt of (R)-3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropyl-1-(piperidin-3-yl)urea (Compound 71) (80.0 mg, 0.21 mmol). Stir the reaction solution at 50 °C for 2 hours. Dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by reverse-phase preparative chromatography (conditions are as follows: column specification: prep-HPLC (Waters 2767 / QDA) Column: Sunfire C18 19*250 nm*10 μm; flow rate: 20 mL / min; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile; elution gradient: 46 - 54%; retention time (min): 8.5–9.7) to obtain Compound 71 (18.5 mg).

[0170] MS: (ESI, m / z): 463.2 [M+H] + , RT (min): 1.717

[0171] 1 H NMR (400 MHz, DMSO-d 6)δ8.44(s,1H),7.64(s,1H),7.33(d,1H),7.30(s,1H),7.26(d,1H),6.86(t,1H),4.26(d,2H),4.04–3.93(m,2H),3.74(s,3H),3.56–3.47(m,1H),3.06(t,1H),2.58(m,1H),2.48–2.42(m,1H),2.28(s,3H),2.03–1.92(m,1H),1.80–1.73(m,1H),1.72–1.63(m,1H),1.45–1.31(m,1H),0.92–0.85(m,2H),0.69–0.60(m,2H).

[0172] Using conditions similar to those in Example 3 above, the compounds in Table 2 below were prepared, and the structural characterization data of these compounds are listed in Table 2 together.

[0173] Table 2

[0174]

[0175] Example 4 (R)-3-(1-Cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 73)

[0176]

[0177] First step Synthesis of tert-butyl (2,5-difluoro-4-(trifluoromethoxy)benzyl)carbamate (Compound 73-3):

[0178] Under argon protection, 1-bromo-2,5-difluoro-4-(trifluoromethoxy)benzene (Compound 73-1, 1.0 g, 3.6 mmol), potassium N-aminomethyltrifluoroborate (Compound 71-2, 0.94 g, 3.96 mmol), palladium acetate (82 mg, 0.36 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (172 mg, 0.36 mmol), and potassium carbonate (1.49 g, 10.8 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL). The mixture was heated and stirred at 90 °C for 16 hours. After monitoring the disappearance of the starting materials, water and ethyl acetate were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 73-3 (650 mg).

[0179] 1 H NMR(400MHz,DMSO-d 6)δ 7.60 (dd, 1H), 7.47 (t, 1H), 7.36 (dd, 1H), 4.18 (d, 2H), 1.39 (s, 9H).

[0180] Step 2: Synthesis of (2,5-difluoro-4-(trifluoromethoxy)phenyl)methanamine (Compound 73-4):

[0181] Dissolve tert-butyl (2,5-difluoro-4-(trifluoromethoxy)benzyl)carbamate (Compound 73-3, 0.6 g, 1.83 mmol) in 6 mL of hydrochloric acid ethyl acetate solution. Stir the reaction solution at room temperature for 2 hours. After monitoring the disappearance of the raw materials, rotary evaporate the reaction solution to obtain Compound 73-4 (350 mg).

[0182] MS: (ESI, m / z): 228.0 [M+H] + , RT(min): 0.827

[0183] Step 3: Synthesis of N-(2,5-difluoro-4-(trifluoromethoxy)benzyl)-1H-imidazole-1-carboxamide (Compound 73-5):

[0184] Under argon protection, dissolve (2,5-difluoro-4-(trifluoromethoxy)phenyl)methanamine (Compound 73-4, 0.3 g, 1.32 mmol) in acetonitrile, and add triethylamine (0.267 g, 2.64 mmol) and N,N'-carbonyldiimidazole (0.213 g, 1.32 mmol) to its acetonitrile solution. Stir the reaction at room temperature for 2 hours. After monitoring the disappearance of the raw materials, add water and ethyl acetate to the reaction solution for extraction. The organic phase is dried with anhydrous sodium sulfate and then concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain Compound 73-5 (420 mg).

[0185] MS: (ESI, m / z): 321.9 [M+H] + , RT(min): 0.575

[0186] Step 4: Synthesis of tert-butyl (R)-3-(1-cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxylate (Compound 73-6):

[0187] Under argon protection, N-(2,5-difluoro-4-(trifluoromethoxy)benzyl)-1H-imidazole-1-carboxamide (Compound 73-5, 0.1 g, 0.31 mmol) was dissolved in acetonitrile, and triethylamine (62 mg, 0.62 mmol) and tert-butyl (R)-3-(cyclopropylamino)piperidine-1-carboxylate (Compound 1-8, 75 mg, 0.31 mmol) were added to its acetonitrile solution. The reaction was stirred at 50 °C for 2 hours. After monitoring the disappearance of the starting materials, water and ethyl acetate were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under vacuum to obtain Compound 73-6 (130 mg).

[0188] MS:(ESI,m / z):494.1[M+H] + ,RT(min):1.896

[0189] Step 5 Synthesis of the hydrochloride salt of (R)-1-cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)-1-(piperidin-3-yl)urea (Compound 73-7):

[0190] tert-Butyl (R)-3-(1-cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxylate (Compound 73-6, 0.13 g, 0.26 mmol) was dissolved in 2 mL of hydrochloric acid ethyl acetate solution. The reaction solution was stirred at room temperature for 1 hour. After monitoring the disappearance of the starting materials, the reaction solution was evaporated to dryness to obtain the hydrochloride salt of Compound 73-7 (170 mg).

[0191] MS:(ESI,m / z):394.1[M+H] + ,RT(min):0.465

[0192] Step 6 Synthesis of (R)-3-(1-cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 73):

[0193] Dissolve pyridin-2-amine (Compound 73-8, 250 mg, 2.3 mmol) in acetonitrile (10 mL). Then add N,N'-carbonyldiimidazole (370 mg, 2.3 mmol) and triethylamine (0.65 mL, 4.6 mmol) to the acetonitrile solution of pyridin-2-amine. The reaction is carried out at 50 °C for one hour. After monitoring the disappearance of the starting material, concentrate the reaction solution. Dissolve the residue in acetonitrile (10 mL), then add (R)-1-cyclopropyl-3-(2,5-difluoro-4-(trifluoromethoxy)benzyl)-1-(piperidin-3-yl)urea (Compound 73-7) hydrochloride (50 mg, 0.12 mmol) and triethylamine (24.8 mg, 0.26 mmol), and stir the reaction at 50 °C for 2 hours. After monitoring the disappearance of the starting material, concentrate the reaction solution. The crude product is purified by basic preparation (conditions are as follows: chromatography column specification: Pprep-HPLC (Waters2767 / 2545 / 2489) Column: Waters Xbridge C18 19*250mm 10μm; flow rate: 20 mL / min; mobile phase A: 0.1% ammonia water / water, mobile phase B: acetonitrile; elution gradient: 45 - 70%; retention time (min): 10.1 - 16.0) to obtain Compound 73 (15.8 mg).

[0194] MS: (ESI, m / z): 514.4 [M+H] + , RT(min): 0.843

[0195] 1 1H NMR (400 MHz, MeOD) δ 8.20 (d, 1H), 7.75 (d, 1H), 7.70 (t, 1H), 7.33–7.23 (m, 2H), 7.03–6.97 (m, 1H), 4.43 (s, 2H), 4.12 (t, 2H), 3.77–3.66 (m, 1H), 3.30–3.27 (m, 1H), 2.80 (t, 1H), 2.62–2.54 (m, 1H), 2.24–2.11 (m, 1H), 1.99–1.78 (m, 2H), 1.66–1.54 (m, 1H), 1.02–0.93 (m, 2H), 0.82–0.73 (m, 2H).

[0196] Example 5 (R)-3-(1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 74)

[0197]

[0198] The first step: Synthesis of 3-fluoro-2-naphthaldehyde (Compound 74-3):

[0199] Under nitrogen protection, N,N,N'-trimethylethylenediamine (0.72 g, 7.04 mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was lowered to -20 °C, and n-butyllithium (4.8 mL, 7.68 mmol) was slowly added dropwise, and the mixture was stirred for 20 minutes. 2-Naphthaldehyde (Compound 74-1, 1.0 g, 6.40 mmol) was added and stirred for 20 minutes. Then n-butyllithium (12 mL, 19.2 mmol) was added, the temperature was raised to room temperature and stirred for 20 minutes, then the temperature was lowered to -78 °C, and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (Compound 74-2, 12.11 g, 38.40 mmol) was added in portions, and the mixture was restored to room temperature and stirred for 4 h. Water (30 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to obtain Compound 74-3 (230 mg).

[0200] Synthesis of the second step (E)-3-fluoro-2-naphthaldehyde oxime (Compound 74-4):

[0201] At 0 °C, hydroxylamine hydrochloride (183.45 mg, 2.64 mmol) was dissolved in a solution of ethanol (1 mL) and water (0.5 mL). 3-Fluoro-2-naphthaldehyde (Compound 74-3, 230 mg, 1.32 mmol) and sodium acetate (234.84 mg, 3.96 mmol) were added, and the reaction mixture was heated to room temperature and stirred for 2 hours. The solution was rotary evaporated to remove ethanol, then water (5 mL) was added, and the product was extracted into dichloromethane (2 × 5 mL). The combined organic extracts were dried over magnesium sulfate, and the solvent was removed under vacuum to obtain Compound 74-4 (240 mg).

[0202] MS: (ESI, m / z): 190.1 [M+H] + , RT(min): 1.859

[0203] Synthesis of the third step (3-fluoronaphthalen-2-yl)methanamine (Compound 74-5):

[0204] (E)-3-Fluoro-2-naphthaldehyde oxime (Compound 74-4, 240 mg, 1.27 mmol) was dissolved in acetic acid (3 mL) solution. Zinc powder (498.42 mg, 6.0 mmol) was added at room temperature, and the reaction was carried out at 50 °C for 2 h. Saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 10, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 74-5 (75 mg).

[0205] MS: (ESI, m / z): 176.3 [M-H] + , RT (min): 1.141

[0206] Step 4. Synthesis of N-((3-fluoronaphthalen-2-yl)methyl)-1H-imidazole-1-carboxamide (Compound 74-6):

[0207] At room temperature, to a stirred solution of (3-fluoronaphthalen-2-yl)methanamine (Compound 74-5, 75 mg, 0.43 mmol) in acetonitrile (2 mL) were added N,N'-carbonyldiimidazole (69.72 mg, 0.4 mmol) and ethyldiisopropylamine (166.72 mg, 1.29 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. TLC showed the reaction was complete. Water (5 mL) was added to dilute the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 74-6 (100 mg).

[0208] Step 5. Synthesis of tert-butyl (R)-3-(1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)ureido)piperidine-1-carboxylate (Compound 74-7):

[0209] At room temperature, to a stirred solution of N-((3-fluoronaphthalen-2-yl)methyl)-1H-imidazole-1-carboxamide (Compound 74-6, 100 mg, 0.37 mmol) in acetonitrile (2 mL) were added (3R)-3-(cyclopropylamino)piperidine-1-carboxylate tert-butyl ester (Compound 1-8, 88.93 mg, 0.37 mmol) and triethylamine (112.32 mg, 1.11 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. Water (5 mL) was added to dilute the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target compound. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain Compound 74-7 (120 mg).

[0210] MS: (ESI, m / z): 442.2 [M+H] + , RT (min): 2.001

[0211] Step 6. Synthesis of hydrochloride of (R)-1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)-1-(piperidin-3-yl)urea (Compound 74-8):

[0212] To a solution of tert-butyl (R)-3-(1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)ureido)piperidine-1-carboxylate (Compound 74-7, 120 mg, 0.27 mmol) in dioxane (1 mL) was added hydrogen chloride-dioxane solution (1 mL, 4 M), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the hydrochloride salt of Compound 74-8 (92.76 mg).

[0213] MS: (ESI, m / z): 342.2 [M+H] + , RT(min): 0.776

[0214] Step 7. Synthesis of (R)-3-(1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 74):

[0215] At room temperature, to a stirred solution of the hydrochloride salt of (R)-1-cyclopropyl-3-((3-fluoronaphthalen-2-yl)methyl)-1-(piperidin-3-yl)urea (Compound 74-8, 90 mg, 0.26 mmol) in acetonitrile (2 mL) was added N-(pyridin-2-yl)-1H-imidazole-1-carboxamide (Compound 74-9, 48.93 mg, 0.26 mmol) and triethylamine (78.93 mg, 0.78 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours. Water (10 mL) was added to dilute the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The conditions were as follows (column specifications: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 31% B to 34% B in 17 minutes; detection wavelength: 254 nm / 220 nm; retention time (min): 8.5 - 11.5), to give Compound 74 (12.3 mg).

[0216] MS: (ESI, m / z): 462.0 [M+H] + , RT(min): 1.464

[0217] 1 H NMR (400 MHz, DMSO-d 6)δ9.07(s,1H),8.24–8.17(m,1H),7.90(dd,2H),7.81–7.75(m,2H),7.70–7.63(m,2H),7.53–7.44(m,2H),7.00–6.87(m,2H),4.48(d,2H),4.12(d,2H),3.62–3.56(m,1H),3.16–3.10(m,1H),2.71–2.64(m,1H),2.49–2.45(m,1H),2.08–1.98(m,1H),1.85–1.66(m,2H),1.50–1.35(m,1H),0.96–0.88(m,2H),0.78–0.69(m,2H).

[0218] Example 6 (R)-3-(1-Cyclopropyl-3-(naphthalen-2-ylmethyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 75)

[0219]

[0220] First step: Synthesis of tert-butyl (R)-3-(N-cyclopropyl-1H-imidazole-1-carboxamido)piperidine-1-carboxylate (Compound 75-1):

[0221] Dissolve tert-butyl (R)-3-(cyclopropylamino)piperidine-1-carboxylate (Compound 1-8, 200 mg, 0.79 mmol) in acetonitrile (5 mL), add N,N'-carbonyldiimidazole (153.72 mg, 0.95 mmol) and triethylamine (239.82 mg, 2.37 mmol), and then stir at 50 °C for 2 hours. Monitor the reaction by TLC until completion, quench with water (30 mL), extract with ethyl acetate (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate. The resulting crude Compound 75-1 (80 mg) is directly used in the next step.

[0222] Second step: Synthesis of tert-butyl (R)-3-(1-cyclopropyl-3-(naphthalen-2-ylmethyl)ureido)piperidine-1-carboxylate (Compound 75-3):

[0223] Dissolve tert-butyl (R)-3-(N-cyclopropyl-1H-imidazole-1-carboxamido)piperidine-1-carboxylate (Compound 75-1, 80 mg, 0.24 mmol) in acetonitrile (5 mL), add 2-naphthalenemethanamine (Compound 75-2, 45.28 mg, 0.29 mmol) and triethylamine (72.86 mg, 0.72 mmol). After addition, stir at 50 °C for 2 hours. Quench the reaction mixture with water (30 mL), extract with ethyl acetate (30 mL × 3). Dry the organic phase over anhydrous sodium sulfate and concentrate. Purify the residue by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1) to obtain Compound 75-3 (80 mg).

[0224] MS: (ESI, m / z): 424.2 [M+H] + , RT(min): 1.995.

[0225] Synthesis of hydrochloride salt of (R)-1-cyclopropyl-3-(naphthalen-2-ylmethyl)-1-(piperidin-3-yl)urea (Compound 75-4) in the third step:

[0226] Dissolve tert-butyl (R)-3-(1-cyclopropyl-3-(naphthalen-2-ylmethyl)ureido)piperidine-1-carboxylate (Compound 75-3, 80 mg, 0.19 mmol) in ethyl acetate (2 mL), add hydrochloric acid ethyl acetate solution (4 mL, 4 N). After addition, stir at room temperature for 1 hour. Concentrate the reaction mixture to remove the solvent to obtain Compound 75-4 (60 mg).

[0227] MS: (ESI, m / z): 324.2 [M+H] + , RT(min): 0.712.

[0228] Synthesis of (R)-3-(1-cyclopropyl-3-(naphthalen-2-ylmethyl)ureido)-N-(pyridin-2-yl)piperidine-1-carboxamide (Compound 75) in the fourth step:

[0229] Dissolve pyridin-2-amine (Compound 73-9, 200 mg, 2.13 mmol) in acetonitrile (5 mL), add N,N'-carbonyldiimidazole (345.38 mg, 2.13 mmol) and triethylamine (646.60 mg, 6.39 mmol). After addition, stir at 50 °C for 2 hours. Monitor the reaction by TLC until completion. Quench the reaction mixture with water (30 mL), extract with ethyl acetate (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate to obtain crude N-(pyridin-2-yl)-1H-imidazole-1-carboxamide. Dissolve the hydrochloride salt of (R)-1-cyclopropyl-3-(naphthalen-2-ylmethyl)-1-(piperidin-3-yl)urea (Compound 75-4, 60 mg, 0.14 mmol) in acetonitrile (3 mL), add N-(pyridin-2-yl)-1H-imidazole-1-carboxamide and triethylamine (42.50 mg, 0.42 mmol). After addition, stir at 50 °C for 2 hours. Concentrate the reaction mixture to remove the solvent. Purify the resulting residue by high performance liquid chromatography under the following conditions (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: from 30% B to 40% B in 16 minutes; detection wavelength: 254 nm / 220 nm; retention time (min): 9.2 - 10.9) to obtain Compound 75 (15.61 mg).

[0230] MS: (ESI, m / z): 444.2 [M+H] + , RT(min): 1.048.

[0231] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.21 (dd, 1H), 7.90–7.83 (m, 3H), 7.80–7.71 (m, 2H), 7.69–7.62 (m, 1H), 7.52–7.43 (m, 3H), 7.02–6.92 (m, 2H), 4.45 (d, 2H), 4.19–4.06 (m, 2H), 3.63–3.54 (m, 1H), 3.13 (t, 1H), 2.69–2.60 (m, 1H), 2.49–2.45 (m, 1H), 2.10–1.95 (m, 1H), 1.85–1.65 (m, 2H), 1.50–1.35 (m, 1H), 0.96–0.85 (m, 2H), 0.76–0.66 (m, 2H).

[0232] Using conditions similar to those in Example 6 above, the compounds in Table 3 below were prepared, and the structural characterization data of these compounds are listed in Table 3 together.

[0233] Table 3

[0234]

[0235]

[0236]

[0237] Example 7 (R)-3-(3-(4-Chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89)

[0238]

[0239] First step Synthesis of N-(1,3,4-thiadiazol-2-yl)-1H-imidazole-1-carboxamide (Compound 89-2):

[0240] At room temperature, N,N'-carbonyldiimidazole (2.41 g, 14.83 mmol) and N,N-diisopropylethylamine (5.75 g, 44.50 mmol) were added to a stirred solution of 1,3,4-thiadiazol-2-amine (Compound 89-2, 1.50 g, 14.83 mmol) in acetonitrile (20 mL). The reaction mixture was heated to 50 °C and stirred for 3 hours. TLC showed that the reaction was complete, and the crude product Compound 89-2 (2.50 g) was obtained by concentration.

[0241] Second step Synthesis of (R)-3-(cyclopropyl(2,4-dimethoxybenzyl)amino)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89-4):

[0242] At room temperature, (R)-N-cyclopropyl-N-(2,4-dimethoxybenzyl)piperidin-3-amine (Compound 89-3, 2.10 g, 7.23 mmol) and N,N-diisopropylethylamine (0.93 g, 7.23 mmol) were added to a stirred acetonitrile (30 mL) solution of N-(1,3,4-thiadiazol-2-yl)-1H-imidazole-1-carboxamide (Compound 89-2, 2.50 g, 13.02 mmol). The reaction mixture was heated to 50 °C and stirred for 3 hours. Water (100 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target compound. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give Compound 89-4 (1.6 g).

[0243] MS:(ESI,m / z):418.1[M+H] + ,RT(min):1.223

[0244] Synthesis of the third step, (R)-3-(cyclopropylamino)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89-5):

[0245] (R)-3-(Cyclopropyl(2,4-dimethoxybenzyl)amino)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89-4, 1.60 g, 3.83 mmol) was dissolved in trifluoroacetic acid (10 mL), and the mixture was stirred at 80 °C in an oil bath for 3 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of crude Compound 89-5 (1.00 g), which was directly used in the next step without further purification.

[0246] MS:(ESI,m / z):268.0[M+H] + ,RT(min):0.987

[0247] Synthesis of the fourth step, (R)-3-(3-(4-chloro-2-fluoro-5-methylbenzyl)-1-cyclopropylureido)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89):

[0248] To a solution of trifluoroacetate (150 mg, 0.12 mmol) of (R)-3-(cyclopropylamino)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide (Compound 89-5) in acetonitrile (3 mL) were successively added N-(4-chloro-2-fluoro-5-methylbenzyl)-1H-imidazole-1-carboxamide (Compound 71-5, 32.12 mg, 0.12 mmol) and triethylamine (36 mg, 0.36 mmol), and the reaction was carried out at 50 °C for 0.5 h. Water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19 * 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: from 52% B to 62% B within 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.8 min), to obtain Compound 89 (19.41 mg).

[0249] MS:(ESI,m / z):467.1[M+H] + ,RT(min):1.717

[0250] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.98(s,1H),7.33(d,1H),7.25(d,1H),6.88(t,1H),4.27(d,2H),4.23–4.11(m,2H),3.57–3.47(m,1H),3.23–3.11(m,1H),2.75–2.63(m,1H),2.29(s,3H),2.06–1.97(m,1H),1.80–1.68(m,2H),1.47–1.18(m,2H),0.91–0.86(m,2H),0.70–0.64(m,2H).

[0251] Using conditions similar to those in Example 7 above, the compounds in Table 4 below were prepared, and the structural characterization data of these compounds are listed in Table 4 together.

[0252] Table 4

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Biological evaluation

[0260] Test Example 1

[0261] Test Name: SLC6A19 Isoleucine Transport Assay

[0262] Cell Line Generation and Maintenance:

[0263] The Flp-In™-CHO™ cell line was purchased from Thermo Fisher Scientific. A stable cell line was generated by transfecting the TMEM27 and hSLC6A19 encoding plasmids using standard protocols followed by antibiotic selection. The cell line was used to generate an inducible cell line expressing TMEM27 and hSLC6A19. The stable cells were maintained in DMEM / F12 (Thermo Fisher) supplemented with 10% fetal bovine serum, 800 μg / ml G418, and 2 mM L-glutamine.

[0264] Buffer Preparation:

[0265] 1. Component A (FLIPR Membrane Potential Assay Kit)

[0266] 2. Component B: 20 mM HEPES dissolved in 1×HBSS buffer, adjusted to pH 7.4 with 1N NaOH.

[0267] Compound Preparation:

[0268] 1. Dissolve the compound in DMSO to make a 10 mM stock solution, aliquot and store at -20°C.

[0269] 2. Dilute the compound with buffer to the highest test concentration of 10000 nM, with 2-fold dilutions.

[0270] a) The final test concentrations of JNT-517 were: 10000, 5000, 2500, 1250, 625, 312.5, 156.3, 78.1, 39.1, 19.5 nM.

[0271] b) For the test compound, the final test concentrations were: 10000, 5000, 2500, 1250, 625, 312.5, 156.3, 78.1, 39.1, 19.5 nM.

[0272] Seed the cells into a 384-well cell culture plate

[0273] 1. Culture TMEM27 / hSLC6A19 CHO cells in cell culture medium (F12, 10% FBS, 800 μg / ml G418, 2 mM L-glutamine).

[0274] 2. When the cell confluence reaches 80%, dissociate the cells with 0.25% trypsin. Measure the cell density and dilute the cells to 1.0×10 6 cells / mL with the medium.

[0275] 3. Add 20 μL of cells to each well of a 384-well black assay plate (pre-coated with poly-D-lysine or matrix), and culture overnight at 37 °C with 5% CO2.

[0276] Detection:

[0277] 1. On the day of the experiment, wash several times with Component B to completely dissolve the contents of the Component A bottle, making the total volume 10 mL.

[0278] 2. Gently centrifuge to remove the cell plate medium, add 20 μL of Component B and 20 μL of buffer to each well, and incubate at room temperature for 30 minutes.

[0279] 3. After incubation, add 10 μL of the compound at 5 times the final concentration and 10 μL of L-isoleucine at 6 times the final concentration to a final concentration of 10 mM in the detection plate. Read the plate and incubate for 15 minutes. Read the fluorescence value using FLIPR (510 - 545 / 565 - 625 excitation / emission wavelength, 5 minutes).

[0280] Data analysis:

[0281] Inhibition rate (%) = 100 - (reading value of the compound well - reading value of the low-reading control well) / (reading value of the high-reading control well - reading value of the low-reading control well) × 100

[0282] High-reading control well: 0.1% DMSO; Low-reading control well: 10 μM JNT-517.

[0283] Use GraphPad Prism 9 software to calculate IC 50 (nM) and plot the effect-dose curve of the compound.

[0284] Table 5 Biological activity data of the compounds of this application

[0285]

[0286]

[0287] The above has given an exemplary description of the implementation manner of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation manner. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included within the protection scope of the claims of this application.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound: in, R1 is selected from H, CN, -N(R 11 )(R 12 )、-S(O)2-R 13 , C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 11 , R 12 , R 13 The same or different, independently selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R2 is selected from CN, unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: -N(R 21 )(R 22 )、-S(O)2-R 23 , 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 21 , R 22 , R 23 The same or different, independently selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; each R b are the same or different and are independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NH2 or -S(O)2-C 1-12 Alkyl; each R b1 are the same or different and are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; R3 and R4 are the same or different and are independently selected from H, halogen, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is absent or selected from C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, C 6-10 Arylene or 5-10 membered heteroarylene; L2 does not exist or is selected from C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, C 6-10 Arylene or 5-10 membered heteroarylene; Y1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; each R c are the same or different and are independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NH2 or -S(O)2-C 1-12 Alkyl; each R c1 are the same or different and are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; Each R a are the same or different and are independently selected from H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)N(R a11 )(R a12 )、-N(R a13 )(R a14 )、-S(O)2-R a15 、-S(O)(=NR a16 )(R a17 ) or -P(O)(R a18 )(R a19 ); each R a1 are the same or different and are independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R a2 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NH2 or -S(O)2-C 1-12 Alkyl; each R a2 are the same or different and are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl; R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 The same or different, independently selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; Preferably, R1 is selected from H or methyl.

3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: R2 is selected from CN, unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: -N(R 21 )(R 22 )、-S(O)2-R 23 , 3-8 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group; R 21 , R 22 , R 23 The same or different, independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl; Preferably, R2 is selected from CN, unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: -N(R 21 )(R 22 )、-S(O)2-R 23 , 3-8 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group; R 21 , R 22 , R 23 The same or different, independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl; Preferably, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, and the C 3-6 Cycloalkyl is cyclopropyl; Preferably, R2 is selected from CN, unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: -N(R 21 )(R 22 )、-S(O)2-R 23 , R 21 , R 22 , R 23 are the same or different and are independently selected from H or methyl; Preferably, R2 is selected from CN, unsubstituted or optionally substituted with one, two or three R b Substituted with the following groups: -N(CH3)2, -S(O)2-CH3, Preferably, each R b are the same or different and are independently selected from H, OH, NH2, CN, halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl; Preferably, each R b are the same or different and are independently selected from H, OH, CN, F, Cl, Br, oxo (=O), methyl, methoxy, CF3 or cyclopropyl; Preferably, R2 is selected from CN, -N(CH3)2, -S(O)2-CH3, Preferably, R2 is selected from 4. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: L2 does not exist; Preferably, R3 is selected from H; Preferably, R4 is selected from methyl, cyclopropyl or halocyclopropyl (e.g. ); Preferably, R4 is selected from cyclopropyl; Preferably, L1 is selected from methylene, ethylene (e.g. ) or cyclopropylene (e.g. ); Preferably, L1 is selected from methylene; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: phenyl, naphthyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; Preferably, each R c are the same or different and are independently selected from H, CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: C 1-6 Alkyl or C 1-6 Alkoxy; each R c1 are the same or different and are independently selected from H, CN or halogen; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted phenyl or 5-6 membered heteroaryl; each R c are the same or different and are independently selected from H, CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: C 1-6 Alkyl or C 1-6 Alkoxy; each R c1 are the same or different and are independently selected from H, CN or halogen; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: phenyl, naphthyl, Preferably, each R c The same or different, independently selected from H, F, Cl, CN, CH3, OCH3, CF3, OCHF2 or OCF3; Preferably, Y1 is selected from unsubstituted or optionally substituted with one or two R c Substituted phenyl; each R c The same or different, independently selected from H, F, Cl, CN, CH3, OCH3 or OCF3; Preferably, Y1 is selected from Preferably, Y1 is selected from 5. The compound according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: The compound represented by formula (I) has the structure shown below: Among them, R1, R2, R3, R4, Y1, L1, R c As defined in any one of claims 1 to 4; Preferably, the compound represented by formula (I) has the structure shown below: Wherein, R1 and R2 have the definitions as defined in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: The compound represented by formula (I) is selected from the following structures:

7. A method for preparing a compound of formula (I) according to any one of claims 1 to 6, comprising the following steps A: in, R1, R2, R3, R4, R a , L1, L2, Y1, m, n have the definitions as described in any one of claims 1-4.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of formula (I) according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof; Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition further contains one or more additional therapeutic agents.

9. A method for treating or preventing a disease or condition mediated by SLC6A19, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound of formula (I) according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or the pharmaceutical composition according to claim 8; Preferably, the SLC6A19-mediated disease or disorder is phenylketonuria; and the patient comprises a mammal, preferably a human.

10. Use of the compound of formula (I) according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug; Preferably, the use may be for preparing a drug for treating or preventing a disease or condition mediated by SLC6A19; Preferably, the SLC6A19-mediated disease or disorder is phenylketonuria.

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