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.

Description

[0001] The present application claims priority to the prior application of Patent Application No. 202410432241.7, filed on April 10, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202410524252.8, filed on April 28, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202410635112.8, filed on May 21, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202410772822.5, filed on June 14, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202411000825.3, filed on July 24, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202411319539.3, filed on September 20, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; Patent Application No. 202411707787.5, filed on November 26, 2024, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”; and Patent Application No. 202510397113.8, filed on March 31, 2025, with the China National Intellectual Property Office, entitled “SLC6A19 Inhibitor Compound, Pharmaceutical Composition and Preparation Method and Application Thereof”. The entire contents of the above prior applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a SLC6A19 inhibitor compound, a pharmaceutical composition, and a preparation method and application thereof. BACKGROUND

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

[0004] PKU patients generally have no special manifestations at birth, and untreated patients begin to gradually develop 3-4 months after birth, with hair turning from black to yellow, pale skin, and urine and sweat emitting a mouse urine odor. Adult patients with PKU may develop lower limb spasticity and cerebellar ataxia, tremor, encephalopathy and vision abnormalities, and severe cases may die.

[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. Most patients have low or no activity of the protein due to PAH mutations, and a small number of patients have PAH monomer folding and assembly disrupted due to dihydropteridine reductase (DHPR) deficiency or deletion of the chaperone protein DNAJC12, resulting in elevated phenylalanine levels.

[0006] Currently, food therapy and drug therapy are mainly used for PKU patients. Food therapy mainly supplements amino acid mixtures containing no phenylalanine and low-protein food, but long-term consumption of protein-deficient or phenylalanine-deficient food can cause growth restriction, anorexia, hair loss, drowsiness, and eczema outbreaks. Sapropterin dihydrochloride 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-pvyl is mainly used for the treatment of moderate to severe PKU patients, and needs to be injected subcutaneously every day, and long-term injection can easily produce adverse immune reactions.

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

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

[0009]

[0010] wherein,

[0011] Y1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R b substituted C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; each Rb the same or different, independently of one another, are selected from CN, halogen, unsubstituted or optionally substituted C b1 the following groups, which are unsubstituted or optionally substituted by one, two or more radicals R 1-12 alkyl, halo-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, S(=O)2R b2 or C(=O)R b3 ; each R b1 the same or different, independently of one another, are selected from oxo (=O), CN, halogen, unsubstituted or optionally substituted C b4 the following groups, which are unsubstituted or optionally substituted by one, two or more radicals R 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl; R b2 , R b3 the same or different, independently of one another, are selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; each R b4 the same or different, independently of one another, are selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl;

[0012] L1is absent or is selected from C 1-12 alkyl, halo-C 1-12 alkyl, C 1-12 alkoxy, halo-C 1-12 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; 1-12 alkylene;

[0013] R2, R3are the same or different and independently of one another selected from H, halogen, C 1-12 alkyl, halo-C 1-12 alkyl, C 1-12alkoxy, haloC 1-12 alkoxy, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;

[0014] L2is absent or selected from C 1-12 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-14 cycloalkylene, C 6-14 arylene or 5-14 membered heteroarylene;

[0015] X1is selected from CH or N;

[0016] each R a are the same or different, independently of each other, selected from oxo (=0), CN, halogen, no substitution or optionally one, two or more R a1 substituted groups: OH, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, methylenedioxy (=CH2), C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, NH2, S(=0)2R a2 or C(=0)R a3 ; or, two R a on the same carbon atom, together with the carbon atom to which they are attached, form a ring system which is unsubstituted or optionally substituted by one, two or more R a1 ; or, two R 3-14 on adjacent carbon atoms, together with the carbon atoms to which they are attached, respectively, form a ring system which is unsubstituted or optionally substituted by one, two or more R a ; or, two R a1 on adjacent carbon atoms, together with the carbon atoms to which they are attached, respectively, form a ring system which is unsubstituted or optionally substituted by one, two or more R 3-14 ; or, two non-adjacent R 6-14 are attached to the same carbon atom, together with the carbon atom to which they are attached, form a ring system which is unsubstituted or optionally substituted by one, two or more R a ; or, two non-adjacent R a1 are attached to the same carbon atom, together with the carbon atom to which they are attached, form a ring system which is unsubstituted or optionally substituted by one, two or more R 1-3 alkylene of C a1 are the same or different, independently of each other, selected from oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R a2 、R a3 The same or different, independently selected from H, OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0017] R1 is selected from any one of the following groups:

[0018] (i) 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 6-14 Aryl or 5-14 membered heteroaryl;

[0019] (ii) COR 11 ; R 11 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: H, OH, -NR 12 R 13 、C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group; R 12 、R 13 The same or different, independently selected from H, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl;

[0020] (iii) R 14 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 16 )(R 17 ), C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic group; R 16 、R 17 The same or different, independently selected from H, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl; or, R 16 、R 17 Together with the nitrogen atom to which it is attached, it forms a 3-14 membered nitrogen-containing heterocyclic ring; R 15Selected from H, CN, unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: OH, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0021] (iv) X2 is selected from O or NR X2 ; R X2 Selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R 18 Selected from H, CN, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic group; R 19 Selected from H, CN, unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 110 )(R 111 ), C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R 110 、R 111 The same or different, independently selected from H, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0022] Each R c The same or different, independently selected from D, oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, NH2, S(O)2H or COH; each R c1 The same or different, independently selected from oxo (=O), OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0023] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0024] n is selected from 0, 1, 2 or 3.

[0025] According to some embodiments, n is selected from 0 or 1.

[0026] According to some embodiments, n is 1.

[0027] According to some embodiments, L2 is absent.

[0028] According to some embodiments, R2 is selected from H.

[0029] According to some embodiments, R3 is selected from cyclopropyl.

[0030] According to some embodiments, L1 is selected from methylene.

[0031] According to some embodiments, m is selected from 0, 1 or 2.

[0032] According to some embodiments, m is selected from 0 or 1.

[0033] According to some embodiments, each R a The same or different, independently selected from oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, methylene (=CH2), C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; or, two R a Together with the carbon atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R a1 Substituted ring system: C 3-6 Carbocyclic or 3-6 membered heterocyclic ring; each R a1 the same or different, independently selected from CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0034] According to some embodiments, each R aare the same or different, independently of one another, selected from the group consisting of CN, halogen, OH, NH2, C a together with the carbon atom to which they are attached, form a cyclopropane ring.

[0035] According to some embodiments, is selected from the group consisting of wherein “*” is attached to L2and “#” is attached to R1.

[0036] According to some embodiments, Y1is selected from the group consisting of the following groups, which are unsubstituted or optionally substituted with one, two or more R b substituted groups: C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; each R b are the same or different, independently of one another, selected from the group consisting of CN, halogen, OH, NH2, C b1 substituted groups: OH, NH2, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R b2 or C(=O)R b3 ; each R b1 are the same or different, independently of one another, selected from the group consisting of oxo (=O), CN, halogen, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R b2 , R b3 are the same or different, independently of one another, selected from the group consisting of H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.

[0037] According to some embodiments, Y1is selected from the group consisting of the following groups, which are unsubstituted or optionally substituted with one, two or more R b substituted groups: phenyl, naphthyl or 5-10 membered heteroaryl.

[0038] According to some embodiments, Y1is selected from the group consisting of the following groups, which are unsubstituted or optionally substituted with one, two or three R bsubstituted phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, thienyl.

[0039] According to some embodiments, Y1is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, thienyl.

[0040] According to some embodiments, Y1is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, thienyl.

[0041] According to some embodiments, Y1is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, thienyl.

[0042] According to some embodiments, each R b are the same or different, independently of one another, selected from CN, halogen, unsubstituted or optionally substituted with one, two or more R b1 substituted C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, pyrazolyl; each R b1 are the same or different, independently of one another, selected from CN, halogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, unsubstituted or optionally substituted with one, two or more R b4 substituted phenyl or 5-6 membered heteroaryl; each R b4 are the same or different, independently of one another, selected from C 1-4 alkyl.

[0043] According to some embodiments, each R b are the same or different, independently of one another, selected from CN, halogen, unsubstituted or optionally substituted with one, two or more R b1 substituted C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, pyrazolyl; each R b1 are the same or different, independently of one another, selected from CN, halogen, C 1-4 alkyl, haloC 1-4 alkyl or C 1-4 alkoxy.

[0044] According to some embodiments, each R b are the same or different and are independently of each other selected from CN, halogen, unsubstituted or optionally substituted with one, two or more R b1 substituted with one, two or more R 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl or C 3-6 alkyl; each R b1 are the same or different and are independently of each other selected from CN, halogen, C 1-4 alkyl, haloC 1-4 alkyl or C 1-4 alkyl.

[0045] According to some embodiments, each R b are the same or different and are independently of each other selected from methyl, ethyl, isopropyl, cyclopropyl, phenyl, pyrazol methylpyrazole (e.g. ), CN, F, CI, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCF3or

[0046] According to some embodiments, each R b are the same or different and are independently of each other selected from methyl, ethyl, isopropyl, cyclopropyl, phenyl, pyrazol methylpyrazole (e.g. ), CN, F, CI, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3or OCF3.

[0047] According to some embodiments, each R b are the same or different and are independently of each other selected from CN, F, CI, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3or OCF3.

[0048] According to some embodiments, Y1is selected from

[0049]

[0050] According to some embodiments, Y1is selected from

[0051]

[0052] According to some embodiments, Y1is selected from

[0053]

[0054] According to some embodiments, Y1is selected from

[0055] According to some embodiments, R1is selected from any one of the following groups:

[0056] (i) unsubstituted or optionally substituted with one or two R c substituted phenyl or 5-6 membered heteroaryl;

[0057] (ii) COR 11 ; R 11 is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R c ; R 12 ; R 13 , C 1-6 alkyl or C 3-6 cycloalkyl; preferably, R 11 is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R c ; R 12 ; R 13 or C 1-6 alkyl; R 12 , R 13 are the same or different, independently from each other, selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or halogenated C 1-6 alkyl; preferably, R 12 , R 13 are the same or different, independently from each other, selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0058] (iii) R 14 is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R c ; R 16 ; R 17 , C 1-6 alkyl; R 16 , R 17 are the same or different, independently from each other, selected from H or C 1-6 alkyl; R 15 is selected from H, CN or OH;

[0059] (iv) X2is selected from O or NR X2 ; R X2 is selected from H or C 1-6Alkyl; R 18 Selected from H or C 1-6 Alkyl; R 19 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 110 )(R 111 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R 110 、R 111 The same or different, independently selected from H or C 1-6 alkyl;

[0060] According to some embodiments, each R c The same or different, independently selected from D, OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0061] According to some embodiments, each R c The same or different, independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0062] According to some embodiments, R1 is selected from any one of the following groups:

[0063] (i) unsubstituted or optionally substituted with one or two R c Substituted pyrimidinyl (e.g. ), pyridazinyl (e.g. );

[0064] (ii) COR 11 ; R 11 Selected from unsubstituted or optionally substituted by one or two R c Substituted with the following groups: -NR 12 R 13 、C 1-4 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 Selected from unsubstituted or optionally substituted by one or two R c Substituted with the following groups: -NR 12 R 13 or C 1-4 Alkyl; R 12, R 13 are the same or different, independently of one another, selected from H, C 1-4 alkyl (e.g. -CH3, -CD3, -CH2CH3) or C 3-6 cycloalkyl; preferably, R 12 , R 13 are the same or different, independently of one another, selected from H or C 1-6 alkyl;

[0065] (iii) R 14 is selected from -N(R 16 )(R 17 ); R 16 , R 17 are the same or different, independently of one another, selected from H or C 1-4 alkyl; R 15 is selected from CN or OH;

[0066] (iv) X2is selected from O; R 18 is selected from H or C 1-4 alkyl; R 19 is selected from C 1-4 alkyl;

[0067] According to some embodiments, each R c are the same or different, independently of one another, selected from D, OH, CN, F, Cl, methyl, ethyl, n-propyl, i-propyl or t-butyl.

[0068] According to some embodiments, each R c are the same or different, independently of one another, selected from OH, CN, F, Cl, methyl, ethyl, n-propyl, i-propyl or t-butyl.

[0069] According to some embodiments, R1is selected from

[0070] According to some embodiments, R1is selected from

[0071] According to some embodiments, R1is selected from

[0072] According to some embodiments, the compound of formula (I) has the structure as shown below:

[0073]

[0074] wherein Y1, R2, R3, R a , X2, R 12 , R13 , R 14 , R 15 , R 18 , R 19 , m has the definition as described herein. According to some embodiments, the compound of formula (I) has the structure as shown below:

[0075]

[0076]

[0077] wherein Y1, R a , R 13 , R 15 , R 17 , R 18 , R 19 , m has the definition as described herein.

[0078] According to some embodiments, the compound of formula (I) has the structure as shown below:

[0079]

[0080] wherein R a , R b , R 12 , R 13 , m has the definition as described herein.

[0081] X is halogen (e.g. F, Cl, Br);

[0082] m1 is selected from 0, 1, 2, 3 or 4; preferably, m1 is selected from 0, 1 or 2; preferably, m1 is selected from 0 or 1; preferably, m1 is 0; preferably, m1 is 1.

[0083] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] The present application also provides a method for preparing the compound of formula (I), comprising the following step A:

[0095]

[0096] wherein, R1, R2, R3, R a , L1, L22, X1, Y1, m, n have the definitions described herein.

[0097] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of formula (I), its racemate, stereoisomer, tautomer, deuterated compound, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0098] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0099] According to some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0100] The present application also provides a method for treating or preventing a SLC6A19-mediated disease or disorder, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compound of formula (I), its racemate, stereoisomer, tautomer, deuterated compound, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0101] The present application also provides a method for treating or preventing a SLC6A19-mediated disease or disorder, comprising administering to a patient a prophylactically or therapeutically effective amount of the above pharmaceutical composition.

[0102] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0103] According to some embodiments, the patient comprises a mammal, preferably a human.

[0104] The present application also provides at least one of the compound of formula (I), its racemate, stereoisomer, tautomer, deuterated compound, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or a pharmaceutical composition thereof, for use in treating or preventing a SLC6A19-mediated disease or disorder.

[0105] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0106] The present application also provides use of at least one of the compounds represented by Formula (I), its racemate, stereoisomer, tautomer, deuteride, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the manufacture of a medicament.

[0107] According to some embodiments, the use can be use in the manufacture of a medicament for treating or preventing a SLC6A19-mediated disease or disorder.

[0108] According to some embodiments, the SLC6A19-mediated disease or disorder is phenylketonuria.

[0109] Beneficial effects

[0110] The compounds provided by the present application have good SLC6A19 inhibitory effect, and can be used for treating or preventing disorders and diseases related to SLC6A19, and for preparing a medicament for treating or preventing such disorders and diseases.

[0111] Definitions and explanations of terms

[0112] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and coordinated with each other. The group definitions and compound structures after such combination and coordination should be understood as within the scope recited in the specification and / or claims hereof.

[0113] The term "optional" (or "optionally", "option") in the general formula definition of the present application means the case of being substituted by zero, one or more substituents, for example "optionally substituted by one, two or more R" means that it can be not substituted (unsubstituted) or can be optionally substituted by one, two or more R.

[0114] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0115] Unless otherwise indicated, the numerical ranges recited in the specification and claims hereof are intended to include each and every specific integer value within the range. For example, the range "1-12" is intended to include each and every specific integer value, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, within the range "1-12".

[0116] The term "C 1-12 "Alkyl" is understood to mean straight-chain and branched-chain alkyl groups having 1 to 12 carbon atoms, "C1-8 Alkyl" denotes straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 Alkyl" denotes straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl groups 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, and the like or isomers thereof.

[0117] The term "C 3-12 Cycloalkyl" is to be understood as meaning saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon rings having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 Cycloalkyl" is to be understood as meaning saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spiro) or tricyclic hydrocarbon rings having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 Cycloalkyl" is to be understood as meaning saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spiro) or tricyclic hydrocarbon rings having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C

[0118] The term "C 6-14 Aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which can be a single aromatic ring or multiple aromatic rings which are fused together, preferably "C 6-10 Aryl". The term "C 6-14 Aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14or a ring having 9 carbon atoms ("C9 aryl"), for example 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 anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0119] The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring system having 5 to 14 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, e.g. "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, additionally in each case, can be benzo-fused. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 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-quinolizyl, 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-, 5-, 6-, 7- or 8-quinoxalinyl, 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-oxazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[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]-ortho-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-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]thiophenyl, 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-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 5-14 membered heteroaryl ring or through a heteroatom on the 5-14 membered heteroaryl ring. When the 5-14 membered heteroaryl is substituted, it can be mono- or poly-substituted. Also, there is no limitation on the substitution site, for example, the hydrogen attached to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom on the heteroaryl ring can be substituted.

[0120] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic (e.g., fused, bridged, spirocyclic) or 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized into various oxidation states to form a nitro oxide, -S(O)- or -S(O)2- state. For example, the "3-14 membered heterocyclyl" can be a 3-14 membered N-containing heterocyclyl (containing at least one N). Preferably, the heterocyclyl can be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl 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 heterocyclyl can be benzo-fused. The heterocyclyl can be bicyclic, such as but not limited to a 5,5 membered ring such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl can be partially unsaturated, i.e., it can contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclyl is attached to other groups to form a compound of the invention, it can be attached to the 3-14 membered heterocyclyl through a carbon atom or a heteroatom of the 3-14 membered heterocyclyl ring. For example, when the 3-14 membered heterocyclyl is selected from piperazinyl, it can be attached to other groups through a nitrogen atom of the piperazinyl. Or when the 3-14 membered heterocyclyl is selected from piperidinyl, it can be attached to other groups through a nitrogen atom and the carbon atom in para position of the piperidinyl ring.

[0121] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0122] The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or a nitrogen-containing (hetero)aromatic ring compound structure.

[0123] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0124] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0125] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0126] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylenyl includes all possible isomeric forms thereof, e.g., positional isomers. Thus, for some illustrative, non-limiting examples, forms substituted or bonded at one, two or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc., if present, can be included, including pyridin-2-yl, pyridin-2- ylenyl, pyridin-3-yl, pyridin-3-yl enyl, pyridin-4-yl and pyridin-4-yl enyl; thienyl or thienylenyl includes thien-2-yl, thien-2-yl enyl, thien-3-yl and thien-3-yl enyl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0127] The term "oxo" refers to an oxo substituent (=0) formed by oxidation of a carbon atom, nitrogen atom or sulfur atom in a substituent.

[0128] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0129] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkyloxy groups can be optionally substituted or non-substituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.

[0130] The terms "alkyleneoxy" and "oxyalkylene" mean -alkylene-O- or -O-alkylene- wherein alkylene represents a straight or branched, saturated, divalent hydrocarbon radical. The definition of the number of carbon atoms for "alkylene" applies mutatis mutandis to the definition of "alkyl". The person skilled in the art will understand that alkyleneoxy or oxyalkylene can be attached to the rest of the molecule in which it is contained in either direction, i.e. both can be used interchangeably.

[0131] "Haloalkyl" means an alkyl group as defined above substituted by one or more halogens.

[0132] "Haloalkyl" means an alkyl group as defined above substituted by one or more halogens.

[0133] Wavy line crossing a chemical bond Used to indicate the position of attachment of a group to the rest of the molecule structure. As an example, in the case of a pyridyl group, when the position of attachment of a group is not fixed, it can be shown in the 3-position of the pyridyl group. When the position of attachment of a group is not fixed, in the case of a pyridyl group, for example, it can be shown in the manner, which indicates that attachment can occur to any available position on the pyridyl group. Similar expressions in the present application are to be interpreted in the same manner, unless otherwise stated.

[0134] In the chemical structures of the compounds according to the present application, the bond " / " indicates an unspecified configuration, or indicates the absolute configuration, i.e. if stereoisomers are present in the chemical structure, the bond " / " can be or or both configurations and are included.

[0135] In the present application, the compounds referred to also include isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having 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 a compound of the application include isotopes of H, C, N, O, S, F, and CI, 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 36Cl. Compounds of the application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs, containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. The isotopes 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e. 2 H or D, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, therefore, can be preferred in some circumstances. The presence of

[0136] It will be appreciated by those skilled in the art that the compounds of formula (I) can exist in various pharmaceutically acceptable salt forms. 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 (e.g. carboxyl group) and a basic center (e.g. amino group), they can also form inner salts.

[0137] The compounds of the present application can exist in the form of solvates (e.g. hydrates), wherein the compounds of the present application contain a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of said compounds. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0138] Depending on its molecular structure, a compound of the application can be chiral and therefore can exist as various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the application encompass the isomers of each chiral carbon in the R or S configuration or mixtures thereof, racemates. The compounds of the application or intermediates thereto can be separated into the enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art, or be synthesized in such form. In the case of racemic amines, the diastereomeric forms are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, binaphthyl-tartric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acid, for example N-benzoyl proline or N-benzenesulfonyl proline, or the various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously performed with optically active, derivatizing agents, for example, dinitrobenzoyl phenylglycine, cellulose or other carbohydrate derivatives, or chiral derivatizing reagents of the hoben-reiland type. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0139] The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.

[0140] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, goats, horses, or primates, most preferably humans.

[0141] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed pathogenesis or symptoms of the disease.(2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., stopping the pathology and / or symptoms from advancing).(3) relieving the disease: for example, causing the regression of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms). DETAILED DESCRIPTION

[0142] The technical solutions of the present application will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized on the basis of the above description of the present application is encompassed within the scope intended to be protected by the present application.

[0143] The starting materials and reagents used in the following examples are commercially available or can be prepared by known methods unless otherwise stated.

[0144] Example 1 N-((1R,3R)-3-(1-cyclopropyl-3-(3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1- yl)ureido)cyclohexyl)methanesulfonamide (Compound 1A)

[0145]

[0146] Synthesis of tert-butyl (1R,3R)-3-((2,4-dimethoxybenzyl)amino)cyclohexyl)carbamate (Compound 1A-3):

[0147] Compound tert-butyl (1R,3R)-3-aminocyclohexyl)carbamate (Compound 1A-1, 250.74 mg, 1.17 mmol) was dissolved in methanol (3 mL), 2,4-dimethoxybenzaldehyde (Compound 1A-2, 194.42 mg, 1.17 mmol) was added, the reaction solution was stirred at room temperature for 1 hour, then indium chloride (77.63 mg, 0.35 mmol), zinc perchlorate (217.85 mg, 0.58 mmol), triethylsilane (272.10 mg, 2.34 mmol) were added, and the reaction solution was stirred at room temperature overnight. To the reaction solution was added 4M aqueous potassium carbonate solution (30 mL) for dilution, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / methanol = 10 / 1) to give Compound 1A-3 (350 mg).

[0148] MS: (ESI, m / z): 365.1 [M+H] + , RT (min): 1.377

[0149] Synthesis of tert-butyl (1R,3R)-3-(cyclopropyl(2,4-dimethoxybenzyl)amino)cyclohexyl)carbamate (Compound 1A-5):

[0150] Compound (1R,3R)-tert-butyl 3-((2,4-dimethoxybenzyl)amino)cyclohexyl)carbamate (compound 1A-3, 340 mg, 0.93 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and ethanol (2 mL), 1-ethoxy-1-trimethylsiloxycyclopropane (compound 1A-4, 162.11 mg, 0.93 mmol), sodium cyanoborohydride (58.44 mg, 0.93 mmol), glacial acetic acid (55.85 mg, 0.93 mmol) were added, and the reaction solution was stirred at 80°C under a nitrogen atmosphere overnight. To the reaction solution was added 4M aqueous potassium carbonate solution (50 mL) for dilution, and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound 1A-5 (120 mg).

[0151] MS: (ESI, m / z): 405.2 [M+H] + , RT (min): 1.416

[0152] Third step: synthesis of (1R,3R)-N-cyclopropyl-N-(2,4-dimethoxybenzyl)cyclohexane-1,3-diamine (compound 1A-6):

[0153] Compound (1R,3R)-tert-butyl 3-((2,4-dimethoxybenzyl)amino)cyclohexyl)carbamate (compound 1A-5, 120 mg, 0.30 mmol) was dissolved in 1,4-dioxane (0.5 mL), and a 1,4-dioxane solution of hydrochloric acid (4M, 0.5 mL) was added, and the reaction solution was stirred at room temperature for 0.5 hours. Concentration obtained hydrochloride salt of compound 1A-6 (100 mg).

[0154] MS: (ESI, m / z): 305.0 [M+H] + , RT (min): 1.001

[0155] Fourth step: synthesis of N-((1R,3R)-3-(cyclopropyl(2,4-dimethoxybenzyl)amino)cyclohexyl)methanesulfonamide (compound 1A-8):

[0156] The hydrochloride salt of compound (1R,3R)-N-cyclopropyl-N-(2,4-dimethoxybenzyl)cyclohexane-1,3-diamine (compound 1A-6, 100 mg, 0.29 mmol) was dissolved in dichloromethane (1 mL), triethylamine (35.21 mg, 0.35 mmol) was added at 0 °C, methanesulfonyl chloride (compound 1A-7, 99.66 mg, 0.87 mmol), the reaction solution was stirred at 0 °C for 1 h. Water (30 mL) was added to dilute the reaction solution, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 4), dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / methanol = 10 / 1) to give compound 1A-8 (30 mg).

[0157] MS: (ESI, m / z): 383.1 [M+H] + , RT (min): 1.265

[0158] Step 5: Synthesis of N-((1R,3R)-3-(cyclopropylamino)cyclohexyl)methanesulfonamide (compound 1A-9):

[0159] Compound N-((1R,3R)-3-(cyclopropyl(2,4-dimethoxybenzyl)amino)cyclohexyl)methanesulfonamide (compound 1A-8, 30 mg, 0.078 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1.2 mL) and water (0.4 mL), the reaction solution was stirred at 95 °C for 8 h. Concentration gave trifluoroacetate salt of compound 1A-9 (25 mg).

[0160] MS: (ESI, m / z): 233.1 [M+H] + , RT (min): 0.722

[0161] Step 6: Synthesis of 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-amine (compound 1A-12):

[0162] To a solution of 1-iodo-3-(trifluoromethoxy)benzene (compound 1A-10, 100 mg, 3.47 mmol) and propargylamine (compound 1A-11, 290 mg, 5.21 mmol) in tetrahydrofuran (10 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane complex (280 mg, 0.35 mmol), cuprous iodide (66 mg, 0.35 mmol) and triethylamine (1.05 g, 10.41 mmol), the mixture was stirred at room temperature for 2 hours. Diluted with water (30 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 30%) to give compound 1A-12 (530 mg).

[0163] MS: (ESI, m / z): 216.0 [M+H] + , RT (min): 1.270.

[0164] Step 7. Synthesis of N-((1R,3R)-3-(1-cyclopropyl-3-(3-(3- (trifluoromethoxy)phenyl)prop-2-yn-1-yl)ureido)cyclohexyl)methanesulfonamide (compound 1A):

[0165] To a solution of 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1 -amine (compound 1A-12, 50 mg, 0.23 mmol) and N,N'-carbonyldiimidazole (37.29 mg, 0.23 mmol) in acetonitrile (2 mL) was added triethylamine (69.82 mg, 0.69 mmol), the mixture was stirred at room temperature for 1 h. The resulting N-(3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1 -yl)-1 H-imidazole-1 -carboxamide (60 mg) was used directly in the next step. To a solution of N-(3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1 -yl)-1 H-imidazole-1 -carboxamide (50 mg, 0.16 mmol) and N-((1 R,3R)-3-(cyclopropylamino)cyclohexyl)methanesulfonamide (compound 1A-9) trifluoroacetate salt (44.61 mg, 0.19 mmol) in acetonitrile (2 mL) was added triethylamine (48.57 mg, 0.48 mmol), the mixture was stirred at 50 °C for 1 h. The reaction was concentrated to remove the solvent, the resulting residue was purified by high performance liquid chromatography with the following conditions (column specification: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 58% B to 58% B in 17 min; detection wavelength: 254 nm / 214 nm; retention time (min): 8.9-10.4) to give compound 1A (27.1 mg).

[0166] MS: (ESI, m / z): 474.1 [M+H] + , RT (min): 1.848.

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.48 (m, 1H), 7.46 - 7.33 (m, 3H), 7.05 (d, 1H), 6.67 (t, 1H), 4.10 (d, 2H), 3.99 - 3.88 (m, 1H), 3.70 (brs, 1H), 2.90 (s, 3H), 2.36 - 2.29 (m, 1H), 2.09 - 1.96 (m, 1H), 1.79 - 1.57 (m, 5H), 1.53 - 1.29 (m, 2H), 0.89 - 0.79 (m, 2H), 0.71 - 0.52 (m, 2H).

[0168] Using similar conditions as described in the above examples, the following compounds in Table 1 were prepared, and the structural characterization data of these compounds are listed in Table 1.

[0169] Table 1

[0170]

[0171]

[0172] Example 2 (R)-3-(1-cyclopropyl-3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-yl)ureido)piperidine-1-carboxamide (Compound 2A)

[0173]

[0174] Compound 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-amine (Compound 1A-12, 200 mg, 0.93 mmol) was dissolved in acetonitrile (5 mL), N,N'-carbonyldiimidazole (380 mg, 2.33 mmol) was added at 0 °C, after 10 minutes of reaction, (3R)-3-(cyclopropylamino)piperidine-1-carboxamide (Compound 2A-1, 51 mg, 0.28 mmol, refer to the synthesis steps in the patent "WO2022192370A1") and triethylamine (188 mg, 1.86 mmol) were added, the reaction solution was stirred at 60 °C for 2 hours. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution for dilution, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography, the conditions were as follows (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 48% B to 48% B in 16 min; detection wavelength: 254 nm / 214 nm; retention time (min): 8.0-9.0), to obtain Compound 2A (2.5 mg).

[0175] MS: (ESI, m / z): 425.1 [M+H] + , RT(min): 1.795

[0176] 1H NMR(400MHz,DMSO-d6)δ7.51(t,1H),7.46–7.43(m,1H),7.42–7.36(m,2H),6 .77(t,1H),5.89(s,2H),4.11(d,2H),3.93–3.77(m,2H),3.54–3.43(m,2H), 3.04–2.90(m,1H),2.43–2.38(m,1H),2.02–1.83(m,1H),1.82–1.68(m,1H), 1.67–1.51(m,1H),1.47–1.22(m,1H),0.99–0.78(m,2H),0.75–0.36(m,2H).

[0177] Using conditions similar to those in the above examples, the compounds listed in Table 2 below were prepared, and the structural characterization data of these compounds are listed in Table 2.

[0178] Table 2

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] Example 3 4-(1-cyclopropyl-3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-yl)ureido)-2- azabicyclo[4.1.0]heptane-2-carboxamide (Compound 25)

[0196]

[0197] Note: There is chirality, i.e. 25-4-P1 and 25-4-P2 are Any one of the following, and 25-4-P1 and 25-4-P2 are different.

[0198] There is chirality, i.e. 25-6-P1 is a mixture of a mixture of.

[0199] There is chirality, i.e. 25-P1-P1 and 25-P1-P2 one is one is or 25-P1-P1 and 25-P1-P2 one is one is

[0200] Synthesis of 3-hydroxy-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (Compound 25-2) in the first step:

[0201] Sodium borohydride (17 g, 450 mmol) was added to a solution of pyridine-3-ol (Compound 25-1, 20 g, 210 mmol) in methanol (400 mL) at -78 °C, slowly added and kept the temperature below -60 °C, sodium bicarbonate (13 g, 156 mmol) and benzyl chloroformate (53 g, 309 mmol) were added to the reaction solution in turn, gradually warmed to room temperature and stirred overnight. The reaction was quenched with 1 N aqueous sodium hydroxide solution (100 mL), then water (300 mL) was added to the reaction solution, extracted with ethyl acetate (300 mL x 3), the organic phase was combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give Compound 25-2 (20 g).

[0202] MS: (ESI, m / z): 234.1 [M+H] + , RT (min): 9.337

[0203] Synthesis of 4-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (Compound 25-3) in the second step:

[0204] To a solution of 3-hydroxy-3,4-dihydropyridine-1 (2H)-carboxylic acid benzyl ester (compound 25-2, 5 g, 21.44 mmol) in 1,2-dichloroethane (40 mL) was added diethylzinc (85.76 mL, 85.76 mmol) and diiodomethane (31 g, 11.63 mmol) sequentially at room temperature. The reaction system was stirred at room temperature for 1 h. The reaction was quenched by adding saturated sodium bicarbonate (50 mL) to the reaction solution, followed by dilution with water (200 mL) and extraction with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 25-3 (2.6 g).

[0205] MS: (ESI, m / z): 248.0 [M+H] + , RT (min): 1.595

[0206] Synthesis of 4-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-4):

[0207] To a solution of oxalyl chloride (1.60 g, 12.61 mmol) in dichloromethane (25 mL) was added dimethyl sulfoxide (1.97 g, 25.22 mmol) at -78 °C, stirred for 15 min, followed by the addition of 4-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-3, 2.60 g, 10.51 mmol), stirred for 35 min, then triethylamine (5.32 g, 52.55 mmol) was added dropwise, and the reaction was continued at -78 °C for 10 min and at room temperature for 1 h. The reaction was quenched by adding water (150 mL) to the reaction solution, extracted with ethyl acetate (150 mL x 3), and the combined organic phase was washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the product 25-4 (2.2 g). The product was separated by chiral SFC with the following conditions (column specifications: AD 250*25mm 10μm; mobile phase A: Supercritical CO 2,, mobile phase B: EtOH (+0.1% 7.0 mol / l Ammonia in EtOH); flow rate: 120 mL / min; elution gradient: isocratic 80; detection wavelength: UV 214 nm; pre-peak retention time (min): 4.15; post-peak retention time (min): 11.55; sample dissolution solvent: EtOH; single injection volume: 8.0 mL) to give compound 25-4-P1 (pre-peak, 700 mg) and compound 25-4-P2 (post-peak, 750 mg).

[0208] 25-4-P1: MS: (ESI, m / z): 246.1 [M+H] + , RT (min): 10.158

[0209] 25-4-P2: MS: (ESI, m / z): 246.1 [M+H] + , RT (min): 10.289

[0210] Synthesis of 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-6-P1):

[0211] To a solution of 4-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-4-P1, 650 mg, 2.65 mmol) in ethanol (10 mL) was added cyclopropylamine (compound 25-5, 605 mg, 10.60 mmol), tetraisopropyl titanate (1.5 g, 5.30 mmol) at room temperature, stirred for 2 hours, then sodium borohydride (301 mg, 7.95 mmol) was added to the reaction system, stirred for 2 hours at room temperature. The reaction was quenched by adding water (70 mL) to the reaction solution, filtered, extracted with ethyl acetate (70 mL x 3), the organic phase was combined and washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 25-6-P1 (300 mg).

[0212] MS: (ESI, m / z): 287.1 [M+H] + , RT (min): 6.760

[0213] Synthesis of 4-(1-cyclopropyl-3-(3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-yl)ureido)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-7-P1):

[0214] Dissolve 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1 -amine (compound 1A-12, 150 mg, 0.70 mmol) in acetonitrile (2 mL), add N,N'-carbonyldiimidazole (114 mg, 0.70 mmol) and triethylamine (213 mg, 2.10 mmol) successively. The reaction solution is stirred at room temperature for 1 h. LCMS shows that the reaction is complete, and the reaction solution is concentrated. Dissolve the residue in acetonitrile (3 mL), then add 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-6-P1, 100 mg, 0.35 mmol) and triethylamine (106 mg, 1.05 mmol), and stir the reaction at 50°C for 0.5 h. Add water (50 mL) to the reaction solution to dilute, extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the target product crude. Purify the crude by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound 25-7-P1 (100 mg).

[0215] MS: (ESI, m / z): 528.2 [M+H] + , RT (min): 2.101

[0216] Step 6: Synthesis of 1-(2-azabicyclo[4.1.0]heptan-4-yl)-1-cyclopropyl-3-(3- (trifluoromethoxy)phenyl)prop-2-yn-1-yl)urea (compound 25-8-P1):

[0217] Dissolve 4-(3-cyclopropyl[(3-(trifluoromethoxy)phenyl)prop-2-yn-1-yl)carbamoyl]amino)- 2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-7-P1, 90 mg, 0.17 mmol) in a mixed solvent of acetic acid (2 mL) and hydrogen bromide (1 mL), and stir the reaction at room temperature for 6 h. Add saturated aqueous sodium bicarbonate solution (50 mL) to the reaction solution to dilute, extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound 25-8-P1 (30 mg).

[0218] MS: (ESI, m / z): 394.2 [M+H] + , RT (min): 0.873

[0219] Step 7: Synthesis of 4-(1-cyclopropyl-3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-yl)ureido)- 2-azabicyclo[4.1.0]heptane-2-carboxamide (compound 25-P1):

[0220] To a solution of 3-(2-azabicyclo[4.1.0]heptan-4-yl)-3-cyclopropyl-1-(3- (trifluoromethoxy)phenyl)prop-2-yn-1-yl)urea (compound 25-8-P1, 20 mg, 0.05 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (33 mg, 0.26 mmol) and trimethylsilyl isocyanate (12 mg, 0.10 mmol) successively. The reaction was stirred at room temperature for 0.5 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 25-P1. The crude compound 25-P1 was purified by high performance liquid chromatography with the following conditions: column specification: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (10mmol ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 45% B to 45% B in 18 min; detection wavelength: 254 nm / 220 nm; front peak retention time (min): 8.60-9.20, back peak retention time (min): 9.60-10.30, to give compound 25-P1-P1 (front peak, 0.68 mg) and compound 25-P1-P2 (back peak, 0.95 mg).

[0221] 25-P1-P1: MS: (ESI, m / z): 437.3 [M+H] + , RT (min): 10.158

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 7.53-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.41-7.37 (m, 2H), 6.79 (t, 1H), 5.88 (s, 2H), 4.11 (d, 2H), 3.99-3.92 (m, 1H), 3.19 (d, 1H), 3.14-3.10 (m, 1H), 2.42-2.39 (m, 1H), 2.38-2.34 (m, 1H), 2.16-2.10 (m, 1H), 1.50-1.42 (m, 1H), 1.28-1.22 (m, 1H), 0.87-0.82 (m, 3H), 0.63-0.55 (m, 2H), 0.23-0.20 (m, 1H).

[0223] 25-P1-P2: MS: (ESI, m / z): 437.3 [M+H] + , RT (min): 10.289

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 7.54-7.48 (m, 1H), 7.47-7.43 (m, 1H), 7.42-7.35 (m, 2H), 6.78 (t, 1H), 5.89 (s, 2H), 4.10 (d, 2H), 3.77 (d, 1H), 2.77 (t, 1H), 2.66-2.61 (m, 1H), 2.53-2.51 (m, 1H), 2.41-2.35 (m, 1H), 2.34-2.25 (m, 1H), 1.91 (dd, 1H), 1.40-1.30 (m, 1H), 0.88-0.78 (m, 3H), 0.64-0.55 (m, 2H), 0.23-0.17 (m, 1H).

[0225] The structure of compound 25-P1-P2 was detected as Example 4 (R)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N-methylpiperidine-1-carboxamide (compound 37A)

[0226]

[0227] Synthesis of 3-(3-chloro-5-(fluoro)phenyl)prop-2-yn-1-amine (compound 37A-2) in the first step:

[0228] Dissolve 1-bromo-3-chloro-5-fluorobenzene (compound 37A-1, 1 g, 4.77 mmol), propargylamine (0.39 g, 7.15 mmol) in tetrahydrofuran (10 mL), add potassium iodonitrite (0.091 g, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (0.39 g, 0.48 mmol) and triethylamine (1.45 g, 14.31 mmol), stir at room temperature for 16 hours under nitrogen atmosphere. Dilute with water (30 mL), extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated brine (30 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate to get the crude product, purify the crude product by silica gel column chromatography (eluent: ethyl acetate = 100%) to get compound 37A-2 (0.17 g).

[0229] MS: (ESI, m / z): 225.0 [M+H+ACN] + , RT (min): 1.253.

[0230] Synthesis of (3R)-3-(cyclopropylamino)piperidine-1-carboxylic acid tert-butyl ester (compound 37A-4) in the second step:

[0231] To a solution of compound (3R)-3-amino piperidine-1-carboxylic acid tert-butyl ester (compound 37A-3, 10 g, 49.93 mmol) in 1,4-dioxane (100 mL) was added (1-ethoxycyclopropyl)oxytrimethylsilane (4.35 g, 24.96 mmol), sodium cyanoborohydride (6.28 g, 99.86 mmol), acetic acid (6.0 g, 99.86 mmol), the reaction was stirred at 60 °C overnight. After cooling to room temperature, water (150 mL) was added to dilute the reaction, the pH was adjusted to 9-10 with 50% potassium carbonate solution, extracted with ethyl acetate (150 mL x 3), the organic phase was combined and washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid) to give compound 37A-4 (3.7 g).

[0232] MS: (ESI, m / z): 241.1 [M+H] + , RT (min): 1.210

[0233] Step 3: Synthesis of (R)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxylic acid tert-butyl ester (compound 37A-5):

[0234] To a solution of 3-(3-chloro-5-fluorophenyl)prop-2-yn-1-amine (compound 37A-2, 150 mg, 0.82 mmol) and N,N'-carbonyldiimidazole (130 mg, 0.82 mmol) in acetonitrile (5 mL) was added triethylamine (410 mg, 4.10 mmol), the mixture was stirred at room temperature for 0.5 h, then (R)-3-(cyclopropylamino)piperidine-1-carboxylic acid tert-butyl ester (compound 37A-4, 200 mg, 0.82 mmol) was added, the mixture was stirred at 50 °C for 2 h. The reaction was concentrated to remove the solvent, the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 50%) to give compound 37A-5 (90 mg).

[0235] MS: (ESI, m / z): 450.2 [M+H] + , RT (min): 2.058

[0236] Step 4: Synthesis of (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (compound 37A-6):

[0237] To a solution of (R)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxylic acid tert-butyl ester (compound 37A-5, 80 mg, 0.18 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated to give compound 37A-6 (80 mg).

[0238] MS: (ESI, m / z): 350.4 [M+H] + , RT (min): 0.758

[0239] Step 5: Synthesis of (R)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N-methylpiperidine-1-carboxamide (compound 37A):

[0240] To a solution of methylamine hydrochloride (compound 37A-7, 87 mg, 1.29 mmol) and N,N'-carbonyldiimidazole (210 mg, 1.29 mmol) in acetonitrile (6 mL) was added triethylamine (260 mg, 2.58 mmol) and the mixture was stirred at room temperature for 0.5 h. Then (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (compound 37A-6, 30 mg, 0.09 mmol) was added and the mixture was stirred at 50 °C for 2 h. The reaction was concentrated to remove the solvent and the resulting crude was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 70%) and then by reverse phase column chromatography (eluent: water (0.1% ammonia) / methanol = 0% to 50%) to give compound 37A (14.66 mg).

[0241] MS: (ESI, m / z): 407.0 [M+H] + , RT (min): 1.713

[0242] 1H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.46 (m, 1H), 7.36 - 7.32 (m, 1H), 7.31 - 7.26 (m, 1H), 6.78 (t, 1H), 6.36 (q, 1H), 4.11 (d, 2H), 3.91 - 3.80 (m, 2H), 3.55 - 3.44 (m, 1H), 2.94 (t, 1H), 2.55 (d, 3H), 2.49 - 2.43 (m, 1H), 2.43 - 2.36 (m, 1H), 2.01 - 1.87 (m, 1H), 1.79 - 1.58 (m, 2H), 1.40 - 1.25 (m, 1H), 0.91 - 0.83 (m, 2H), 0.67 - 0.59 (m, 2H).

[0243] Using similar conditions as described in the above examples, the following compounds in Table 3 were prepared, and the structural characterization data of these compounds are listed in Table 3.

[0244] Table 3

[0245]

[0246]

[0247]

[0248] Example 5 (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1-(1-(cyclopropanecarbonyl)piperidin-3-yl)-1-cyclopropylurea (Compound 38A)

[0249]

[0250] To a solution of (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(piperidin-3-yl)urea (Compound 37A-6, 30 mg, 0.09 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (410 mg, 4.10 mmol), cyclopropylcarboxylic acid (Compound 38A-1, 15 mg, 0.17 mmol) and n-butylphosphonic anhydride (120 mg, 0.17 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added for dilution, extracted with ethyl acetate (20 mL x 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 50%), and the obtained crude product was purified by reverse phase column chromatography (eluent: water (0.1% ammonia water) / methanol = 0% to 60%) to obtain Compound 38A (3.94 mg).

[0251] MS: (ESI, m / z): 418.0 [M+H] + , RT (min): 1.842

[0252] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.46 (m, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 6.87 - 6.75 (m, 1H), 4.36 - 4.16 (m, 2H), 4.11 (d, 2H), 3.70 - 3.42 (m, 1H), 3.31 - 3.22 (m, 1H), 2.99 - 2.80 (m, 1H), 2.47 - 2.34 (m, 1H), 2.15 - 1.90 (m, 2H), 1.88 - 1.63 (m, 2H), 1.54 - 1.26 (m, 1H), 0.96 - 0.82 (m, 2H), 0.77 - 0.57 (m, 6H).

[0253] Example 6 (R)-3-(3-(3-(chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N-cyclopropylpiperidine-1-carboxamide (Compound 60A)

[0254]

[0255] Cyclopropylamine (Compound 25-5, 26.2 mg, 0.46 mmol) was dissolved in acetonitrile (5 mL), to which N,N'-carbonyldiimidazole (74.5 mg, 0.46 mmol) and triethylamine (139.6 mg, 1.38 mmol) were added, and stirred at room temperature for 30 minutes. To the above reaction solution, (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (Compound 37A-6, 160.5 mg, 0.46 mmol) was added, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated to remove the solvent, and the resulting residue was purified by high performance liquid chromatography under the following conditions: Column specification: Waters 2767 / QDA Column: Sunfire C18 19x250mm; 10μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 55% B to 55% B in 16 min; Detection wavelength: 254 nm / 220 nm; Retention time (min) 7.9-9.1, to obtain Compound 60A (11.8 mg).

[0256] MS: (ESI, m / z): 418.0 [M+H] + , RT (min): 1.947.

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.44 (m, 1H), 7.34 (s, 1H), 7.32 - 7.26 (m, 1H), 6.77 (t, 1H), 6.50 (d, 1H), 4.11 (d, 2H), 3.90 - 3.78 (m, 2H), 3.53 - 3.42 (m, 1H), 2.92 (t, 1H), 2.48 - 2.35 (m, 3H), 1.97 - 1.86 (m, 1H), 1.77 - 1.70 (m, 1H), 1.66 - 1.58 (m, 1H), 1.39 - 1.27 (m, 1H), 0.90 - 0.83 (m, 2H), 0.66 - 0.59 (m, 2H), 0.55 - 0.49 (m, 2H), 0.39 - 0.33 (m, 2H).

[0258] Example 7 4-(3-(3-(-3-(3-Cloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-2-azabicyclo[4.1.0]heptane-2-carboxamide (Compound 68)

[0259]

[0260] Note: There is chirality, i.e. 68-P1-P1 and 68-P1-P2 one is one is or 68-P1-P1 and 68-P1-P2 one is one is

[0261] Synthesis of benzyl-4-((tert-butoxycarbonyl)(cyclopropyl)amino)-2- azabicyclo[4.1.0]heptane-2-carboxylate (Compound 68-1-P1) in the first step:

[0262] To a solution of benzyl 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2- carboxylate (Compound 25-6-P1, 645 mg, 2.25 mmol) in 1,4-dioxane (4 mL) was added di-tert-butyl dicarbonate (1470 mg, 6.75 mmol) and aqueous sodium carbonate (720 mg, 6.75 mmol), stirred at room temperature overnight. To the reaction was added water (70 mL) to dilute, extracted with dichloromethane (70 mL x 3), combined organic phase was washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to give Compound 68-1-P1 (700 mg).

[0263] MS: (ESI, m / z) : 287.2 [M+H-100] + , RT (min) : 13.157; 13.371

[0264] Synthesis of tert-butyl N-(2-azabicyclo[4.1.0]heptan-4-yl)-N- cyclopropylcarbamate (compound 68-2-P1) in the second step:

[0265] To a solution of benzyl-4-((tert-butoxycarbonyl)(cyclopropyl)amino)-2- azabicyclo[4.1.0]heptane-2-carboxylate (compound 68-1-P1, 500 mg, 1.29 mmol) in tetrahydrofuran (6 mL) was added palladium on carbon (180 mg), and hydrogen was replaced for three times. The reaction was stirred at room temperature for 1 h. The reaction was filtered and concentrated to give compound 68-2-P1 (230 mg), which was used directly in the next step.

[0266] MS: (ESI, m / z) : 253.2 [M+H] + , RT (min) : 6.827

[0267] Synthesis of tert-butyl (2-carbamoyl-2-azabicyclo[4.1.0]heptan-4-yl)(cyclopropyl) carbamate (compound 68-3-P1) in the third step:

[0268] To a solution of tert-butyl N-(2-azabicyclo[4.1.0]heptan-4-yl)-N- cyclopropylcarbamate (compound 68-2-P1, 115 mg, 0.46 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (297 mg, 2.30 mmol) and trimethylsilyl isocyanate (64 mg, 0.55 mmol) sequentially. The reaction was stirred at room temperature overnight. The reaction was diluted with water (40 mL) and extracted with dichloromethane (40 mL x 3). The combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give compound 68-3-P1 (120 mg).

[0269] MS: (ESI, m / z) : 296.2 [M+H] + , RT (min) : 9.035; 9.309

[0270] Synthesis of hydrochloride salt of 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane- 2-carboxamide (compound 68-4-P1) in the fourth step:

[0271] Dissolve tert-butyl (2-carbamoyl-2-azabicyclo[4.1.0]heptane-4-yl)(cyclopropyl)carbamate (compound 68-3-P1, 120 mg, 0.41 mmol) in hydrogen chloride dioxane (2.5 mL) and react at room temperature for 0.5 h. The reaction mixture was concentrated to afford the hydrochloride salt of compound 68-4-P1 (90 mg), which was used directly in the next reaction.

[0272] MS:(ESI,m / z):196.1[M+H] + ,RT(min):0.512

[0273] Step 5: Synthesis of 4-(3-(3-(-3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-2-azabicyclo[4.1.0]heptane-2-carboxamide (Compound 68-P1):

[0274] 3-(3-Chloro-5-fluorophenyl)prop-2-yn-1-amine (compound 37A-2, 150 mg, 0.82 mmol) was dissolved in acetonitrile (2 mL), and N,N'-carbonyldiimidazole (133 mg, 0.82 mmol) and triethylamine (249 mg, 2.46 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 0.5 h. LCMS showed the reaction was complete, and the reaction mixture was concentrated. The residue was partially dissolved in acetonitrile (4 mL), and triethylamine (143 mg, 1.41 mmol) and 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxamide (compound 68-4-P1) hydrochloride (90 mg, 0.47 mmol) were added. The reaction was allowed to react at 50°C for 3 h. The reaction mixture was diluted with water (50 mL) and 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. The crude product was purified by high performance liquid chromatography under the following conditions: chromatographic 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 47% B to 47% B in 18 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.60-10.20 to obtain compound 68-P1 (80 mg). Chiral SFC separation (conditions as follows: chromatographic column specifications: IA250×25mm; 10μm; mobile phase A: supercritical CO 2,, mobile phase B: MeOH (+0.1% 7.0 mol / l ammonia in MeOH); flow rate: 120 ml / min; elution gradient: isocratic 60; detection wavelength: UV 214 nm; pre-peak retention time (min): 4.7; post-peak retention time (min): 6.6; sample dissolution solvent: methanol; single injection volume: 1.0 mL) to give compound 68-P1-P1 (pre-peak, 27 mg) and compound 68-P1-P2 (post-peak, 30 mg).

[0275] 68-P1-P1:

[0276] MS: (ESI, m / z): 405.3 [M+H] + , RT (min): 10.186

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.46 (m, 1H), 7.37 - 7.32 (m, 1H), 7.31 - 7.27 (m, 1H), 6.78 (t, 1H), 5.89 (s, 2H), 4.10 (d, 2H), 3.83 - 3.72 (m, 1H), 2.81 - 2.72 (m, 1H), 2.65 - 2.61 (m, 1H), 2.38 - 2.35 (m, 1H), 2.33 - 2.21 (m, 2H), 1.95 - 1.88 (m, 1H), 1.38 - 1.30 (m, 1H), 0.88 - 0.80 (m, 3H), 0.63 - 0.55 (m, 2H), 0.24 - 0.16 (m, 1H).

[0278] 68-P1-P2:

[0279] MS: (ESI, m / z): 405.3 [M+H] + , RT (min): 10.038

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.47 (m, 1H), 7.34 (s, 1H), 7.31 - 7.27 (m, 1H), 6.79 (t, 1H), 5.88 (s, 2H), 4.11 (d, 2H), 3.99 - 3.91 (m, 1H), 3.20 (t, 1H), 3.14 - 3.08 (m, 1H), 2.41 - 2.38 (m, 1H), 2.18 - 2.06 (m, 1H), 1.48 - 1.40 (m, 1H), 1.29 - 1.11 (m, 2H), 0.87 - 0.80 (m, 3H), 0.66 - 0.54 (m, 2H), 0.24 - 0.18 (m, 1H).

[0281] Compound 68-P1-P1 was detected to have the structure of

[0282] Using similar conditions as in the above examples, the following compounds in Table 4 were prepared, and the structural characterization data of these compounds are listed in Table 4.

[0283] Table 4

[0284]

[0285]

[0286]

[0287] Example 8 4-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N-methyl-2-azabicyclo[4.1.0]heptane-2-carboxamide (Compound 81)

[0288]

[0289] Note: There is chirality, i.e. one of 81-2-P1-P1 and 81-2-P1-P2 is and the other is or one of 81-2-P1-P1 and 81-2-P1-P2 is and the other is

[0290] There is chirality, i.e. one of 81-P1-P1 and 81-P1-P2 is and the other is or one of 81-P1-P1 and 81-P1-P2 is and the other is The synthesis of compounds 81-2-P1-P1 and 81-2-P1-P2 in the first step:

[0291] To a solution of tert-butyl N-(2-azabicyclo[4.1.0]heptan-4-yl)-N- cyclopropylcarbamate (compound 68-2-P1, 100 mg, 0.40 mmol) in N,N- dimethylformamide (3 mL) were added 2,5-dioxopyrrolidin-1-yl methyl carbamate (compound 81-1, 83 mg, 0.48 mmol), ethyldiisopropylamine (155 mg, 1.20 mmol) and 1-hydroxybenzotriazole (11 mg, 0.08 mmol) successively, and stirred at room temperature for 1 hour. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give 82-2-P1. Purification by high performance liquid chromatography, conditions as follows: column specifications: Sunfire C18, 19 x 250 mm; 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 43% B to 43% B in 16 min; detection wavelength: 254 nm / 220 nm; pre-peak retention time (min): 7.5; post-peak retention time (min): 8.6, to give compound 81-2-P1-P1 (pre-peak, 36 mg) and compound 81-2-P1-P2 (post-peak, 35 mg).

[0292] 81-2-P1-P1:

[0293] MS: (ESI, m / z): 310.1 [M+H] + , RT (min): 3.521

[0294] 1 H NMR (400 MHz, DMSO-d6) δ 6.22 (q, 1H), 3.76 - 3.67 (m, 1H), 3.30 - 3.23 (m, 1H), 3.16 - 3.10 (m, 1H), 2.60 (d, 3H), 2.41 - 2.31 (m, 2H), 2.18 - 2.09 (m, 1H), 1.47 - 1.40 (m, 1H), 1.38 (s, 9H), 1.31 - 1.24 (m, 1H), 0.90 - 0.82 (m, 1H), 0.72 - 0.63 (m, 2H), 0.59 - 0.48 (m, 2H), 0.22 - 0.16 (m, 1H).

[0295] 81-2-P1-P2:

[0296] MS: (ESI, m / z): 310.1 [M+H] + , RT (min): 3.661

[0297] 1H NMR (400 MHz, DMSO-d6) δ 6.21 (q, 1H), 3.87 - 3.80 (m, 1H), 3.16 - 3.08 (m, 1H), 2.74 (t, 1H), 2.62 (d, 3H), 2.60 - 2.56 (m, 1H), 2.40 - 2.33 (m, 1H), 2.32 - 2.21 (m, 1H), 2.03 - 1.89 (m, 1H), 1.39 (s, 9H), 1.30 - 1.22 (m, 1H), 0.88 - 0.78 (m, 1H), 0.74 - 0.65 (m, 2H), 0.58 - 0.47 (m, 2H), 0.21 - 0.14 (m, 1H).

[0298] Synthesis of hydrochloride salt of compound 81-3-P1-P1 and compound 81-3-P1-P2:

[0299] To a solution of tert-butyl cyclopropyl(2-(methylcarbamoyl)-2-azabicyclo[4.1.0]heptan-4- yl)carbamate (compound 81-2-P1-P1, 31 mg, 0.1 mmol) in 1,4-dioxane (2 mL), hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) was added slowly dropwise and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give the hydrochloride salt of compound 81-3-P1-P1 (30 mg), which was used directly in the next step.

[0300] MS: (ESI, m / z): 210.1 [M+H] + , RT (min): 0.494

[0301] Tert-butyl cyclopropyl(2-(methylcarbamoyl)-2-azabicyclo[4.1.0]heptan-4-yl)carbamate (compound 81-2-P1-P2, 30 mg, 0.097 mmol) was dissolved in hydrogen chloride in dioxane (1 mL, 4N) and the reaction was stirred at room temperature for 0.5 hour. The reaction was concentrated to give the hydrochloride salt of compound 81-3-P1-P2 (23 mg), which was used directly in the next step.

[0302] MS: (ESI, m / z): 210.1 [M+H] + , RT (min): 0.515

[0303] Synthesis of compound 81-P1-P1 and compound 81-P1-P2:

[0304] To a solution of 3-(3-chloro-5-fluorophenyl)prop-2-yn-l -amine (compound 37A-2, 150 mg, 0.82 mmol) in acetonitrile (2 mL) was added N,N'-carbonyldiimidazole (133 mg, 0.82 mmol) followed by triethylamine (249 mg, 2.46 mmol). The reaction was stirred at room temperature for 1 h. TLC showed the reaction was complete. To the above solution was added triethylamine (22 mg, 0.22 mmol) and the hydrochloride salt of compound 81-3-P1-P1 (15 mg, 0.07 mmol). The reaction was stirred at 50 °C for 2 h. The reaction was concentrated to give a crude product, which was purified by HPLC with the following conditions: Column size: Sunfire C18, 19 x 250 mm; 10 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 49% B to 49% B in 16 min; Detection wavelength: 254 nm / 220 nm; Retention time (min): 8.60-9.60, to give compound 81-P1-P1 (12 mg).

[0305] MS: (ESI, m / z): 419.1 [M+H] + , RT (min): 10.274

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.45 (m, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 6.79 (t, 1H), 6.30 - 6.14 (m, 1H), 4.10 (d, 2H), 4.03 - 3.88 (m, 1H), 3.22 (t, 1H), 3.15 - 3.07 (m, 1H), 2.60 (d, 3H), 2.41 - 2.26 (m, 2H), 2.21 - 2.03 (m, 1H), 1.52 - 1.35 (m, 1H), 1.34 - 1.18 (m, 1H), 0.96 - 0.74 (m, 3H), 0.72 - 0.49 (m, 2H), 0.25 - 0.15 (m, 1H).

[0307] To a solution of 3-(3-chloro-5-fluorophenyl)prop-2-yn-l -amine (compound 37A-2, 150 mg, 0.82 mmol) in acetonitrile (2 mL) was added N,N'-carbonyldiimidazole (133 mg, 0.82 mmol) followed by triethylamine (249 mg, 2.46 mmol). The reaction was stirred at room temperature for 1 h. TLC showed the reaction was complete. To the above solution was added triethylamine (22 mg, 0.22 mmol) and the hydrochloride salt of compound 81-3-P1-P2 (15 mg, 0.07 mmol). The reaction was stirred at 50 °C for 3 h. The reaction was concentrated to give a crude product, which was purified by HPLC with the following conditions: Column size: Sunfire C18, 19 x 250 mm; 10 μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow rate: 20 mL / min; Gradient elution: 51% B to 51% B in 16 min; Detection wavelength: 254 nm / 220 nm; Retention time (min): 8.00-9.00, to give compound 81-P1-P2 (13 mg).

[0308] MS: (ESI, m / z): 419.3 [M+H] + , RT (min): 10.668

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.46 (m, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 6.78 (t, 1H), 6.23 - 6.16 (m, 1H), 4.09 (d, 2H), 3.79 (d, 1H), 3.31 - 3.25 (m, 1H), 2.79 (t, 1H), 2.61 (d, 3H), 2.59 - 2.56 (m, 1H), 2.39 - 2.27 (m, 2H), 1.94 - 1.88 (m, 1H), 1.41 - 1.32 (m, 1H), 0.88 - 0.80 (m, 3H), 0.61 - 0.55 (m, 2H), 0.21 - 0.16 (m, 1H).

[0310] The structure of compound 81-P1-P2 was determined to be

[0311] Using similar conditions as described in the above examples, the following compounds in Table 5 were prepared, and their structural characterization data are listed in Table 5.

[0312] Table 5

[0313]

[0314]

[0315] Example 9 4-(3-(3-(3-bromo-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N-methyl-2-azabicyclo[4.1.0]heptane-2-carboxamide (Compound 80)

[0316]

[0317] Note: There is chirality, i.e. 80-P1-P1 and 80-P1-P2 one is one is or 80-P1-P1 and 80-P1-P2 one is one is

[0318] First step (synthesis of N-(3-(3-bromo-5-fluorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (Compound 80-2):

[0319] To a solution of 3-(3-bromo-5-fluorophenyl)prop-2-yn-1-amine (Compound 80-1, 65 mg, 0.29 mmol) in acetonitrile (2 mL), triethylamine (88 mg, 0.87 mmol) was added slowly dropwise and stirred for 10 min. The mixture was added slowly dropwise into a solution of bis(1H-imidazol-1-yl)methanone (47 mg, 0.29 mmol) in acetonitrile (2 mL) at 0 °C and stirred for 1 h to give crude Compound 80-2, which was used directly in the next step.

[0320] MS: (ESI, m / z): 361.0 [M+H+ACN] + , RT (min): 1.474

[0321] Second step synthesis of Compound 80-P1-P1 and Compound 80-P1-P2:

[0322] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P1) (27 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), triethylamine (34 mg, 0.33 mmol) was added dropwise slowly and stirred for 10 minutes. The mixture was added dropwise slowly into a solution of (N-(3-(3-bromo-5-fluorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 80-2, 36 mg, 0.11 mmol) in acetonitrile (2 mL). The reaction was reacted at 50 °C for 1 hour. Water (20 mL) was added to dilute the reaction, extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 3), 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 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 49% B to 49% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.20-10.20) to give compound 80-P1-P1 (7.65 mg).

[0323] MS: (ESI, m / z): 463.1 [M+H] + , RT (min): 10.438

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 - 7.57 (m, 1H), 7.46 (s, 1H), 7.38 - 7.28 (m, 1H), 6.79 (t, 1H), 6.28 - 6.16 (m, 1H), 4.11 (d, 2H), 4.02 - 3.90 (m, 1H), 3.23 (t, 1H), 3.16 - 3.06 (m, 1H), 2.61 (d, 3H), 2.38 - 2.30 (m, 2H), 2.19 - 2.08 (m, 1H), 1.49 - 1.38 (m, 1H), 1.32 - 1.20 (m, 1H), 0.94 - 0.72 (m, 3H), 0.70 - 0.49 (m, 2H), 0.23 - 0.11 (m, 1H).

[0325] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P2) (22 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), triethylamine (28 mg, 0.27 mmol) was added dropwise slowly and stirred for 10 min. The mixture was added dropwise slowly into a solution of (N-(3-(3-bromo-5-fluorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 80-2, 29 mg, 0.09 mmol) in acetonitrile (2 mL). The reaction was heated at 50 °C for 1 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography with the following conditions: column specification: Sunfire C18, 19 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 51% B to 51% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.80-9.80, to give compound 80-P1-P2 (6.90 mg).

[0326] MS: (ESI, m / z): 465.1 [M+H] + , RT(min): 10.572

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.56 (m, 1H), 7.46 (s, 1H), 7.38 - 7.25 (m, 1H), 6.78 (t, 1H), 6.26 - 6.10 (m, 1H), 4.09 (d, 2H), 3.83 - 3.75 (m, 1H), 2.79 (t, 1H), 2.61 (d, 3H), 2.59 - 2.56 (m, 1H), 2.39 - 2.32 (m, 2H), 2.32 - 2.24 (m, 1H), 1.96 - 1.84 (m, 1H), 1.42 - 1.29 (m, 1H), 0.89 - 0.76 (m, 3H), 0.63 - 0.51 (m, 2H), 0.24 - 0.12 (m, 1H).

[0328] The structure of compound 80-P1-P2 was determined to be Example 10 4-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-N-methyl-2- azabicyclo[4.1.0]heptane-2-carboxamide (compound 83)

[0329]

[0330] Note: There is chirality, i.e. 83-P1-P1 and 83-P1-P2 one is one is or 83-P1-P1 and 83-P1-P2 one is one is

[0331] Synthesis of N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 83-2) in the first step:

[0332] To a solution of 3-(3-chlorophenyl)prop-2-yn-1-amine (compound 83-1, 390 mg, 1.84 mmol) in acetonitrile (4 mL), triethylamine (559 mg, 5.52 mmol) was added slowly dropwise and stirred for 10 min. The mixture was slowly dropped into a solution of bis(1H-imidazol-1-yl)methanone (299 mg, 1.84 mmol) in acetonitrile (4 mL) at 0 °C, and the reaction was stirred for 1 h. The reaction was diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 1:1) to give compound 83-2 (114 mg).

[0333] MS: (ESI, m / z): 260.0 [M+H] + , RT (min): 7.521

[0334] Synthesis of compound 83-P1-P1 and compound 83-P1-P2 in the second step:

[0335] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P1) (27 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), triethylamine (34 mg, 0.33 mmol) was added dropwise slowly and stirred for 10 minutes. The mixture was added dropwise slowly into a solution of N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 83-2, 29 mg, 0.11 mmol) in acetonitrile (2 mL). The reaction was reacted at 50 °C for 1 hour. Water (20 mL) was added to dilute the reaction, extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 3), 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 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 45% B to 45% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.60-9.60, to give compound 83-P1-P1 (6.45 mg).

[0336] MS: (ESI, m / z): 401.1 [M+H] + , RT (min): 10.012

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.43 (m, 2H), 7.42 - 7.35 (m, 2H), 6.78 (t, 1H), 6.30 - 6.14 (m, 1H), 4.10 (d, 2H), 4.01 - 3.91 (m, 1H), 3.21 (t, 1H), 3.15 - 3.07 (m, 1H), 2.61 (d, 3H), 2.39 - 2.32 (m, 2H), 2.18 - 2.08 (m, 1H), 1.51 - 1.36 (m, 1H), 1.32 - 1.20 (m, 1H), 0.93 - 0.74 (m, 3H), 0.68 - 0.51 (m, 2H), 0.25 - 0.14 (m, 1H).

[0338] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P2) (22 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), triethylamine (28 mg, 0.27 mmol) was added dropwise slowly and stirred for 10 min. The mixture was added dropwise slowly into a solution of N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 83-2, 24 mg, 0.09 mmol) in acetonitrile (2 mL). The reaction was stirred at 50 °C for 1 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography with the following conditions: column specification: Sunfire C18, 19 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 46% B to 46% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.80-9.80, to give compound 83-P1-P2 (5.86 mg).

[0339] MS: (ESI, m / z): 401.1 [M+H] + , RT (min): 10.140

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.43 (m, 2H), 7.42 - 7.34 (m, 2H), 6.77 (t, 1H), 6.29 - 6.11 (m, 1H), 4.09 (d, 2H), 3.80 (d, 1H), 3.29 - 3.24 (m, 1H), 2.79 (t, 1H), 2.61 (d, 3H), 2.60 - 2.57 (m, 1H), 2.41 - 2.26 (m, 2H), 1.98 - 1.78 (m, 1H), 1.42 - 1.30 (m, 1H), 0.92 - 0.77 (m, 3H), 0.67 - 0.53 (m, 2H), 0.24 - 0.14 (m, 1H).

[0341] The structure of compound 83-P1-P2 was determined to be Example 11 4-(3-(3-(3-bromophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-N-methyl-2- azabicyclo[4.1.0]heptane-2-carboxamide (compound 85)

[0342]

[0343] Note: There is chirality, i.e. 85-P1-P1 and 85-P1-P2 one is one is or 85-P1-P1 and 85-P1-P2 one is one is

[0344] Synthesis of N-(3-(3-bromophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 85-2) in the first step:

[0345] To a solution of 3-(3-bromophenyl)prop-2-yn-1-amine (compound 85-1, 60 mg, 0.29 mmol) in acetonitrile (2 mL), triethylamine (88 mg, 0.87 mmol) was added slowly dropwise and stirred for 10 min. The mixture was added slowly dropwise into a solution of bis(1H-imidazol-1-yl)methanone (47 mg, 0.29 mmol) in acetonitrile (2 mL) at 0 °C and stirred at room temperature for 1 h. The reaction solution was used directly for the next step.

[0346] MS: (ESI, m / z): 304.0 [M+H] + , RT (min): 1.451

[0347] Synthesis of compound 85-P1-P1 and compound 85-P1-P2 in the second step:

[0348] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P1) (27 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL) solution, triethylamine (34 mg, 0.33 mmol) was added slowly dropwise and stirred for 10 min. The mixture was added slowly dropwise into a solution of N-(3-(3-bromophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 85-2, 34 mg, 0.11 mmol) in acetonitrile (2 mL). The reaction solution was reacted at 50 °C for 1 h. Water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 3), 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 x 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 47% B to 47% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.00-10.20) to give compound 85-P1-P1 (21.8 mg).

[0349] MS: (ESI, m / z): 445.1 [M+H] + , RT (min): 10.163

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.53 (m, 2H), 7.46 - 7.39 (m, 1H), 7.38 - 7.28 (m, 1H), 6.78 (t, 1H), 6.28 - 6.11 (m, 1H), 4.10 (d, 2H), 4.03 - 3.89 (m, 1H), 3.21 (t, 1H), 3.16 - 3.07 (m, 1H), 2.61 (d, 3H), 2.40 - 2.31 (m, 2H), 2.18 - 2.07 (m, 1H), 1.49 - 1.38 (m, 1H), 1.30 - 1.20 (m, 1H), 0.89 - 0.76 (m, 3H), 0.67 - 0.52 (m, 2H), 0.24 - 0.14 (m, 1H).

[0351] The hydrochloride salt of 4-(cyclopropylamino)-N-methyl-2-azabicyclo[4.1.0]heptane-2- carboxamide (compound 81-3-P1-P2) (22 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL) solution, triethylamine (28 mg, 0.27 mmol) was added slowly dropwise and stirred for 10 minutes. The mixture was slowly dropped into a solution of N-(3-(3-bromophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 85-2, 28 mg, 0.09 mmol) in acetonitrile (2 mL). The reaction was reacted at 50 °C for 1 hour. Water (20 mL) was added to the reaction to dilute, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 3), 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 x 250 mm, 10 pm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 48% B to 48% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.60-9.60, to obtain compound 85-P1-P2 (11.54 mg).

[0352] MS: (ESI, m / z): 445.1 [M+H] + , RT (min): 10.296

[0353] 1H NMR (400 MHz, DMSO-d6) δ 7.67 - 7.50 (m, 2H), 7.46 - 7.38 (m, 1H), 7.36 - 7.28 (m, 1H), 6.77 (t, 1H), 6.29 - 6.08 (m, 1H), 4.09 (d, 2H), 3.80 (d, 1H), 3.32 - 3.28 (m, 1H), 2.79 (t, 1H), 2.62 (d, 3H), 2.60 - 2.56 (m, 1H), 2.40 - 2.35 (m, 1H), 2.35 - 2.26 (m, 1H), 2.02 - 1.83 (m, 1H), 1.45 - 1.28 (m, 1H), 0.94 - 0.76 (m, 3H), 0.66 - 0.51 (m, 2H), 0.24 - 0.12 (m, 1H).

[0354] The structure of compound 85-P1-P2 was detected as Example 12 (R)-3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-N-(methyl-d3)piperidine-1-carboxamide (compound 101A)

[0355]

[0356] The synthesis of the first step (R)-tert-butyl 3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)piperidine-1-carboxylate (compound 101A-1):

[0357] To a solution of 3-(3-chlorophenyl)prop-2-yn-1-amine trifluoroacetate salt (compound 83-1, 388 mg, 1.83 mmol) in acetonitrile (5 mL) was added triethylamine (556 mg, 5.49 mmol) dropwise at 0 °C. To the mixture was added N,N'-carbonyldiimidazole (297 mg, 1.83 mmol). The reaction was stirred at 0 °C for 0.5 h. To the reaction was added (R)-tert-butyl 3-(cyclopropylamino)piperidine-1-carboxylate (compound 37A-4, 440 mg, 1.83 mmol) and triethylamine (556 mg, 5.49 mmol). The reaction was stirred at 50 °C for 1 h. To the reaction was added water (50 mL) to dilute, extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography column (petroleum ether: ethyl acetate = 1:1) to give compound 101A-1 (640 mg).

[0358] MS: (ESI, m / z): 432.2 [M+H] + , RT (min): 12.713

[0359] Step 2. Synthesis of trifluoroacetate salt of (R)-3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxylic acid tert-butyl ester (Compound 101A-1):

[0360] To a solution of (R)-3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)piperidine-1- carboxylic acid tert-butyl ester (Compound 101A-1, 640 mg, 1.48 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) slowly at 0 °C, slowly raised to room temperature and stirred the reaction for 0.5 h, the reaction was concentrated in vacuum to get Compound 101A-2 (640 mg).

[0361] MS: (ESI, m / z): 332.1 [M+H] + , RT (min): 7.177

[0362] Step 3. Synthesis of (R)-3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-N-(methyl- d3)piperidine-1-carboxamide (Compound 101A):

[0363] To a solution of deuterated methylamine hydrochloride (Compound 101A-3, 190 mg, 2.70 mmol) in acetonitrile (5 mL) was added triethylamine (546 mg, 5.40 mmol) slowly at 0 °C and stirred for 10 min. The mixture was added into a solution of carbonyldiimidazole (416 mg, 2.56 mmol) in acetonitrile (5 mL) slowly. The reaction was stirred at 0 °C for 0.5 h. To the reaction was added a solution of trifluoroacetate salt of (R)-3-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)- piperidine-1-carboxylic acid tert-butyl ester (Compound 101A-2, 600 mg, 1.35 mmol) in acetonitrile (5 mL) at 0 °C and stirred for 10 min before heating to 50 °C for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by high performance liquid chromatography with the following conditions (column specification: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 46% B to 46% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.00-10.00 to get Compound 101A (313.02 mg).

[0364] MS: (ESI, m / z): 392.3 [M+H] + , RT (min): 10.265

[0365] 1 H NMR (400 MHz, DMSO) d 7.57 - 7.30 (m, 4H), 6.77 (t, 1H), 6.33 (s, 1H), 4.10 (d, 2H), 3.95 - 3.78 (m, 2H), 3.54 - 3.44 (m, 1H), 2.95 (t, 1H), 2.48 - 2.43 (m, 1H), 2.42 - 2.37 (m, 1H), 2.04 - 1.86 (m, 1H), 1.79 - 1.58 (m, 2H), 1.41 - 1.23 (m, 1H), 0.96 - 0.78 (m, 2H), 0.70 - 0.55 (m, 2H). Example 13 (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1-(4-hydroxy pyrimidin-2-yl)piperidin-3-yl)urea (Compound 102A)

[0366]

[0367] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine (Compound 102A-2):

[0368] To a solution of (4-methoxyphenyl)methanol (1 g, 7.24 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.6 g, 14.48 mmol) at 0 °C, stirred for 15 min, then 2,4-dichloropyrimidine (Compound 102A-1, 1.6 g, 10.86 mmol) was added, the reaction was continued to room temperature for 1 h. The reaction was quenched by adding saturated ammonium chloride (20 mL) to the reaction, then water (100 mL) was added to dilute the reaction, filtered, extracted with ethyl acetate (150 mL x 3), the organic phases were combined, washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give Compound 102A-2 (600 mg).

[0369] MS: (ESI, m / z): 392.3 [M+H] + , RT (min): 11.424

[0370] Synthesis of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1-(4-(4- methoxybenzyl)oxy)pyrimidin-2-yl)piperidin-3-yl)urea (Compound 102A-3):

[0371] To a solution of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(piperidin-3- yl)urea trifluoroacetate (compound 101A-2, 300 mg, 0.67 mmol) in isopropanol (5 mL) was added 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine (compound 102A-2, 251 mg, 1.01 mmol) and N,N-diisopropylethylamine (260 mg, 2.01 mmol) and reacted at 100 °C for 16 h. The reaction was diluted with water (50 mL) and filtered, extracted with ethyl acetate (50 mL x 3), the organic phases were combined and washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (10 mmol ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 73% B to 73% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 5.00-6.00) to give compound 102A-3 (60 mg).

[0372] MS: (ESI, m / z): 546.3 [M+H] + , RT(min): 1.915

[0373] Step 3: Synthesis of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1-(4- hydroxypyrimidin-2-yl)piperidin-3-yl)urea (compound 102A):

[0374] To a solution of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1-(4-(4- methoxybenzyl)oxy)pyrimidin-2-yl)piperidin-3-yl)urea (compound 102A-3, 40 mg, 0.07 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and reacted at room temperature for 0.5 h. The reaction was directly rotary evaporated to give a crude product, which was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 37% B to 40% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 6.10-8.80) to give compound 102A (20 mg).

[0375] MS: (ESI, m / z): 426.2 [M+H] +RT (min): 7.987

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.60 (d, 1H), 7.47 - 7.43 (m, 2H), 7.43 - 7.39 (m, 1H), 7.39 - 7.37 (m, 1H), 6.86 (t, 1H), 6.20 (d, 1H), 4.57 (s, 1H), 4.12 (d, 2H), 3.63 - 3.51 (m, 4H), 2.46 - 2.44 (m, 1H), 2.14 - 2.07 (m, 1H), 1.85 - 1.75 (m, 2H), 1.50 - 1.41 (m, 1H), 0.92 - 0.86 (m, 2H), 0.72 - 0.62 (m, 2H).

[0377] Example 14 (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1-(pyridazin-3- yl)piperidin-3-yl)urea (Compound 103A)

[0378]

[0379] First Step Synthesis of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(1- (pyridazin-3-yl)piperidin-3-yl)urea (Compound 103A)

[0380] To a solution of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropyl-1-(piperidin-3- yl)urea trifluoroacetate salt (Compound 101A-2, 100 mg, 0.22 mmol) in isopropanol (2 mL) was added 3-chloropyridazine hydrochloride (Compound 103A-1, 66 mg, 0.44 mmol), cesium fluoride (33 mg, 0.22 mmol) and triethylamine (67 mg, 0.66 mmol) and the reaction was heated at 100 °C for 16 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography with the following conditions (column specification: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 33% B to 33% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.20-9.30, to give Compound 103A (2.08 mg).

[0381] MS: (ESI, m / z): 410.3 [M+H] + , RT (min): 8.148

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (t, 1H), 7.57 (d, 2H), 7.47 - 7.43 (m, 2H), 7.42 - 7.36 (m, 2H), 6.85 (t, 1H), 4.35 (d, 1H), 4.26 (d, 1H), 4.12 (d, 2H), 3.68 - 3.62 (m, 2H), 2.93 - 2.85 (m, 1H), 2.46 - 2.43 (m, 1H), 2.19 - 2.08 (m, 1H), 1.88 - 1.77 (m, 2H), 1.58 - 1.47 (m, 1H), 0.93 - 0.86 (m, 2H), 0.73 - 0.64 (m, 2H).

[0383] Example 15 4-(3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)-N-(methyl-d3)- 2-azabicyclo[4.1.0]heptane-2-carboxamide (Compound 104)

[0384]

[0385] Note: There is chirality, i.e. one of 104-2-P1-P1 and 104-2-P1-P2 is and one is or one of 104-2-P1-P1 and 104-2-P1-P2 is and one is

[0386]

[0387] There is chirality, i.e. one of 104-P1-P1 and 104-P1-P2 is and one is or one of 104-P1-P1 and 104-P1-P2 is and one is

[0388] First step synthesis of compounds 104-2-P1-P1 and 104-2-P1-P2:

[0389] To a solution of deuterated methylamine hydrochloride (compound 101A-3, 1 g, 14.18 mmol) in acetonitrile (10 mL) were added carbonyldiimidazole (2.3 g, 14.18 mmol) and triethylamine (4.30 g, 42.54 mmol), and the mixture was reacted at room temperature for 0.5 h. The reaction solution was concentrated. Subsequently, to a solution of tert-butyl N-(2-azabicyclo[4.1.0]hept-4-yl)-N-cyclopropylcarbamate (compound 68-2-P1, 230 mg, 0.91 mmol) in acetonitrile (3 mL) were added N-(methyl-d3)-1H-imidazole-1-carboxamide (117 mg, 0.91 mmol) and triethylamine (276 mg, 2.73 mmol), and the mixture was reacted at 50°C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 104-2-P1. The crude product was purified by HPLC using 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: 44% B to 44% B over 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 7.60-8.50 for the front peak, yielding compound 104-2-P1-P1 (front peak, 60 mg); retention time (min): 8.90-10.20 for the back peak, yielding compound 104-2-P1-P2 (back peak, 50 mg).

[0390] 104-2-P1-P1:MS:(ESI,m / z):313.3[M+H] + ,RT(min):9.733

[0391] 104-2-P1-P2:MS:(ESI,m / z):313.3[M+H] + ,RT(min):9.997

[0392] Step 2: Synthesis of the hydrochloride of compound 104-3-P1-P1 and the hydrochloride of 104-3-P1-P2:

[0393] To tert-butyl cyclopropyl(2-((methyl-d3)carbamoyl)-2-azabicyclo[4.1.0]hept-4-yl)carbamate (compound 104-2-P1-P1, 60 mg, 0.19 mmol) was added dioxane hydrochloride (2 mL) and reacted at room temperature for 0.5 h. The reaction solution was spin-dried to give the hydrochloride salt of compound 104-3-P1-P1 (47 mg).

[0394] MS: (ESI, m / z): 213.2 [M+H] + , RT (min): 0.235

[0395] To tert-butyl cyclopropyl(2-((methyl-d3)carbamoyl)-2-azabicyclo[4.1.0]heptan-4- yl)carbamate (compound 104-2-P1-P2, 50 mg, 0.16 mmol) was added a solution of hydrochloric acid in dioxane (2 mL) and the reaction was stirred at room temperature for 0.5 h. The reaction was directly spin-dried to give compound 104-3-P1-P2 hydrochloride (39 mg).

[0396] MS: (ESI, m / z): 213.2 [M+H] + , RT (min): 0.235

[0397] Synthesis of compound 104-P1-P1 and 104-P1-P2 in the third step:

[0398] To a solution of compound 104-3-P1-P1 hydrochloride (47 mg, 0.19 mmol) in acetonitrile (2 mL) was added triethylamine (58 mg, 0.57 mmol) and N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 83-2, 49.34 mg, 0.19 mmol) and the reaction was stirred at 50 °C for 0.5 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography with the following conditions (column specifications: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 47% B to 48% B in 18 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.30-10.60, to give compound 104-P1-P1 (18.96 mg).

[0399] MS: (ESI, m / z): 404.3 [M+H] + , RT (min): 10.242

[0400] 1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.43 (m, 2H), 7.42 - 7.39 (m, 1H), 7.39 - 7.37 (m, 1H), 6.78 (t, 1H), 6.18 (s, 1H), 4.10 (d, 2H), 3.98 - 3.92 (m, 1H), 3.21 (t, 1H), 3.15 - 3.09 (m, 1H), 2.38 - 2.33 (m, 2H), 2.15 - 2.08 (m, 1H), 1.49 - 1.40 (m, 1H), 1.29 - 1.22 (m, 1H), 0.88 - 0.80 (m, 3H), 0.64 - 0.55 (m, 2H), 0.22 - 0.17 (m, 1H).

[0401] To the solution of compound 104-3-P1-P2 hydrochloride (39 mg, 0.16 mmol) in acetonitrile (2 mL) was added triethylamine (49 mg, 0.48 mmol) and N-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 83-2, 42 mg, 0.16 mmol) at 50 °C for 0.5 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high performance liquid chromatography with the following conditions (column specification: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 49%B to 52%B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.50-9.70, to give compound 104-P1-P2 (16.27 mg).

[0402] MS: (ESI, m / z): 404.3 [M+H] + , RT (min): 10.387

[0403] 1H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.45 (m, 1H), 7.44 - 7.41 (m, 1H), 7.41 - 7.34 (m, 2H), 6.77 (t, 1H), 6.16 (s, 1H), 4.08 (d, 2H), 3.81 - 3.77 (m, 1H), 2.79 (t, 1H), 2.59 - 2.57 (m, 1H), 2.40 - 2.33 (m, 2H), 2.33 - 2.28 (m, 1H), 1.95 - 1.87 (m, 1H), 1.43 - 1.30 (m, 1H), 0.88 - 0.79 (m, 3H), 0.63 - 0.55 (m, 2H), 0.21 - 0.14 (m, 1H).

[0404] The structure of compound 104-P1-P2 was detected as Example 16 (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)piperidine-1- carboxamide (compound 11A)

[0405]

[0406] The synthesis of (R)-3-(3-(3-chlorophenyl)prop-2-yn-1-yl)-1-cyclopropylureido)piperidine-1- carboxamide (compound 11A) in the first step:

[0407] Phenyl chloroformate (4.63 g, 27.16 mmol) was added dropwise to a solution of 3-(3- chlorophenyl)prop-2-yn-1-amine (compound 83-1, 3 g, 18.11 mmol) and triethylamine (5.50 g, 54.33 mmol) in N,N-dimethylformamide (30 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was completed. Triethylamine (3.67 g, 36.22 mmol) and (3R)-3-(cyclopropylamino)piperidine-1-carboxamide (compound 2A-1, 3.32 g, 18.11 mmol) were added to the reaction solution, and the mixture was stirred at 50 °C for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The obtained residue was purified by reverse phase, with the following conditions (chromatography column: C18 (330 g); mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; elution gradient: 0-20% B, 30 min) to give compound 11A (1.8 g).

[0408] MS: (ESI, m / z): 375.1 [M+H] + , RT (min): 9.767.

[0409] MS: (ESI, m / z): 375.1 [M+H]1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.34 (m, 4H), 6.76 (t, 1H), 5.88 (s, 2H), 4.10 (d, 2H), 3.86 (t, 2H), 3.53 - 3.45 (m, 1H), 2.96 (t, 1H), 2.55 - 2.51 (m, 1H), 2.43 - 2.37 (m, 1H), 1.99 - 1.88 (m, 1H), 1.78 - 1.71 (m, 1H), 1.66 - 1.58 (m, 1H), 1.40 - 1.28 (m, 1H), 0.91 - 0.82 (m, 2H), 0.68 - 0.58 (m, 2H).

[0410] Example 17 (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxamide (Compound 13A)

[0411]

[0412] First step synthesis of N-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (Compound 13A-1):

[0413] To a solution of 3-(3-chloro-5-fluorophenyl)prop-2-yn-1-amine (Compound 37A-2, 1900 mg, 10.35 mmol) and N,N'-carbonyldiimidazole (1678.25 mg, 10.35 mmol) in acetonitrile (50 mL) was added at room temperature. The reaction was stirred at room temperature for 2 hours. No work-up was performed and the reaction was used directly in the next step.

[0414] Second step synthesis of (R)-3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxamide (Compound 13A):

[0415] To a solution of (3R)-3-(cyclopropylamino)piperidine-1-carboxamide (Compound 2A-1, 2370.80 mg, 10.35 mmol) and triethylamine (5.74 mL, 41.4 mmol) in acetonitrile (50 mL) was added at room temperature. The reaction was stirred at 50 °C for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse phase preparative chromatography (mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, gradient 60%-80%, 30 min) to give Compound 13A (930 mg).

[0416] MS: (ESI, m / z): 392.8 [M+H] + , RT (min): 1.690

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.45 (m, 1H), 7.39 - 7.32 (m, 1H), 7.31 - 7.23 (m, 1H), 6.77 (t, 1H), 5.89 (s, 2H), 4.11 (d, 2H), 3.91 - 3.81 (m, 2H), 3.55 - 3.44 (m, 1H), 2.96 (t, 1H), 2.55 - 2.51 (m, 1H), 2.42 - 2.36 (m, 1H), 2.00 - 1.87 (m, 1H), 1.82 - 1.72 (m, 1H), 1.69 - 1.57 (m, 1H), 1.39 - 1.26 (m, 1H), 0.95 - 0.82 (m, 2H), 0.69 - 0.56 (m, 2H).

[0418] Example 18 (R)-3-(3-(3-(3-bromophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxamide (Compound 18A)

[0419]

[0420] Synthesis of tert-butyl (3-(3-bromophenyl)prop-2-yn-1-yl)carbamate (Compound 18A-3) in the first step:

[0421] Dissolve 1-bromo-3-iodobenzene (Compound 18A-1, 5 g, 17.67 mmol) in tetrahydrofuran (200 mL), add tert-butyl prop-2-yn-1-ylcarbamate (Compound 18A-2, 4.11 g, 26.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.65 g, 0.88 mmol), copper iodide (0.34 g, 1.77 mmol), triethylamine (5.36 g, 53.01 mmol), replace nitrogen, and stir the reaction solution at room temperature for 2 hours. Filter, concentrate the liquid, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Compound 18A-3 (5 g).

[0422] MS: (ESI, m / z): 253.9 [M-56+H] + , RT (min): 2.209

[0423] Synthesis of trifluoroacetate salt of 3-(3-bromophenyl)prop-2-yn-1-amine (Compound 18A-4) in the second step:

[0424] Dissolve tert-butyl (3-(3-bromophenyl)prop-2-yn-1-yl)carbamate (compound 18A-3, 5 g, 16.12 mmol) in dichloromethane (60 mL) solution, add trifluoroacetic acid (20 mL). The reaction solution is stirred at room temperature for 30 minutes. Concentration to obtain trifluoroacetate salt of crude compound 18A-4 (4 g).

[0425] MS: (ESI, m / z): 209.9 [M+H] + , RT (min): 1.480

[0426] Synthesis of (R)-3-(3-(3-(3-bromophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxamide (compound 18A):

[0427] Dissolve trifluoroacetate salt of 3-(3-bromophenyl)prop-2-yn-1-amine (compound 18A-4) (4 g, 12.34 mmol) in acetonitrile (50 mL), add N,N'-carbonyldiimidazole (2.40 g, 14.81 mmol), slowly drop compound triethylamine (3.75 g, 37.02 mmol), the reaction solution is stirred at room temperature for 0.5 hours. Add (3R)-3-(cyclopropylamino)piperidine-1-carboxamide (compound 2A-1, 6.78 g, 37.02 mmol), the reaction solution is stirred at 60°C for 1 hour. After the reaction is completed, water (100 mL) is added to the reaction solution to dilute, extracted with ethyl acetate (100 mL x 3), the organic phase is washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography (ethyl acetate / methanol = 10 / 1) and high performance liquid, conditions as follows (column specifications: C18 reverse phase column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 70 mL / min; elution gradient: 0% B to 80% B in 30 min; detection wavelength: 254 nm / 214 nm), to obtain compound 18A (910 mg).

[0428] MS: (ESI, m / z): 419.0 [M+H] + , RT (min): 9.907

[0429] 1 ​​​​​H NMR (400 MHz, DMSO-d6) δ 7.64-7.52 (m, 2H), 7.45-7.38 (m, 1H), 7.37-7.29 (m, 1H), 6.76 (t, 1H), 5.89 (s, 2H), 4.10 (d, 2H), 3.92-3.79 (m, 2H), 3.59-3.43 (m, 1H), 2.97 (t, 1H), 2.49-2.44 (m, 1H), 2.43-2.37 (m, 1H), 2.03-1.88 (m, 1H), 1.82-1.70 (m, 1H), 1.67-1.55 (m, 1H), 1.44-1.24 (m, 1H), 0.95-0.81 (m, 2H), 0.68-0.53 (m, 2H).

[0430] Example 19 (R)-3-(l-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-l- yl)ureido)piperidine-l-carboxamide (Compound 59A)

[0431]

[0432] Synthesis of tert-butyl (3-(3,5-difluorophenyl)prop-2-yn-l- yl)carbamate (Compound 59A-2):

[0433] To a solution of 1,3-difluoro-5-iodobenzene (Compound 59A-1, 10.00 g, 41.67 mmol) in tetrahydrofuran (100 mL) was added tert-butyl prop-2-yn-l-ylcarbamate (Compound 18A-2, 9.70 g, 62.51 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.52 g, 2.08 mmol), copper(I) iodide (0.79 g, 4.17 mmol) and triethylamine (12.65 g, 125.01 mmol) were added at room temperature. The reaction was stirred at room temperature for 1 h under nitrogen protection. The reaction was filtered, diluted with water (400 mL), extracted with dichloromethane (400 mL x 3), the organic phases were combined, washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10: 1) to give Compound 59A-2 (7.6 g).

[0434] MS: (ESI, m / z): 253.1 [M-56+41+H] + , RT (min): 12.138

[0435] Synthesis of trifluoroacetate salt of 3-(3,5-difluorophenyl)prop-2-yn-l-amine (Compound 59A-3):

[0436] To a solution of tert-butyl (3-(3,5-difluorophenyl)prop-2-yn-1-yl)carbamate (compound 59A-2, 7.5 g, 28.06 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (30 mL) and the reaction was stirred at room temperature for 0.5 h. The reaction was concentrated to dryness to give the trifluoroacetate salt of compound 59A-3 (7.8 g).

[0437] MS: (ESI, m / z): 168.1 [M+H] + , RT (min): 0.420

[0438] Step 3: Synthesis of N-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)-1H-imidazole-1- carboxamide (compound 59A-4):

[0439] To a solution of 3-(3,5-difluorophenyl)prop-2-yn-1-amine hydrochloride (compound 59A-3, 7.7 g, 27.38 mmol) in acetonitrile (70 mL) was added a mixture of 1-(1H- imidazole-1-carbonyl)-1H-imidazole (4.44 g, 27.38 mmol) and triethylamine (8.31 g, 82.14 mmol) in acetonitrile (70 mL) and the reaction was stirred at room temperature for 0.5 h. It was used directly in the next step without further purification.

[0440] MS: (ESI, m / z): 262.1 [M+H] + , RT (min): 0.763

[0441] Step 4: Synthesis of (R)-3-(1-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-1- yl)ureido)piperidine-1-carboxamide (compound 59A):

[0442] To a solution of N-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 59A-4, 7.1 g, 27.18 mmol) in acetonitrile (70 mL) was added (3R)-3- (cyclopropylamino)piperidine-1-carboxamide (compound 2A-1, 29.88 g, 163.08 mmol) and triethylamine (13.75 g, 135.9 mmol) and the reaction was stirred at 60 °C for 0.5 h. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give a crude product. The crude product was further purified by reverse phase chromatography with formic acid system (10% to 40%) to give compound 59A (4 g).

[0443] MS: (ESI, m / z): 377.2 [M+H] + , RT (min): 9.500

[0444] 1 H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.27 (m, 1H), 7.20 - 7.11 (m, 2H), 6.77 (t, 1H), 5.89 (s, 2H), 4.11 (d, 2H), 3.92 - 3.77 (m, 2H), 3.55 - 3.43 (m, 1H), 2.96 (t, 1H), 2.49 - 2.45 (m, 1H), 2.43 - 2.36 (m, 1H), 2.01 - 1.87 (m, 1H), 1.78 - 1.70 (m, 1H), 1.67 - 1.58 (m, 1H), 1.41 - 1.26 (m, 1H), 0.91 - 0.82 (m, 2H), 0.68 - 0.57 (m, 2H).

[0445] Example 20 4-(1-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)ureido)-2- azabicyclo[4.1.0]heptane-2-carboxamide (Compound 105)

[0446]

[0447] Note: There is chirality, i.e. 105-P1-P1 and 105-P1-P2 one is one is or 105-P1-P1 and 105-P1-P2 one is one is

[0448] Synthesis of compound 105-2-P1 in the first step:

[0449] To a solution of 4-(cyclopropylamino)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 25-6-P1, 1.1 g, 3.84 mmol) in acetonitrile (10 mL) was added triethylamine (1.2 g, 11.52 mmol) and N-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 59A-4, 1.1 g, 4.22 mmol), and the mixture was stirred at 60 °C for 0.5 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 105-2-P1 (1.6 g).

[0450] MS: (ESI, m / z): 502.1 [M+Na] + , RT (min): 2.185

[0451] Synthesis of compound 105-3-P1 in the second step:

[0452] To a solution of 4-(l-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-l- yl)ureido)-2-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound 105-2-P1, 1.5 g, 3.13 mmol) in trifluoroacetic acid (7.5 mL) was added methyl ethyl sulfide (0.36 g, 4.70 mmol) at 50 °C for 2 h. To the reaction mixture was added saturated potassium carbonate aqueous solution (10 mL) followed by water (100 mL) to dilute, extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 105-3-P1, which was used directly in the next step.

[0453] MS: (ESI, m / z): 346.1 [M+H] + , RT (min): 1.581

[0454] Synthesis of compound 105-P1-P2 in the third step:

[0455] To a solution of l-(2-azabicyclo[4.1.0]heptan-4-yl)-l-cyclopropyl-3-(3-(3,5- difluorophenyl)prop-2-yn-l-yl)urea (compound 105-3-P1, 500 mg, 1.45 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (562 mg, 4.35 mmol) and trimethylsilyl isocyanate (286 mg, 1.74 mmol) successively at room temperature for 0.5 h. To the reaction mixture was added water (50 mL) to dilute, extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by high performance liquid chromatography with the following conditions (column specification: Sunfire C18, 19*250mm, 10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 43% B to 43% in 18 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.30-10.30) to give compound 105-P1-P2 (22 mg).

[0456] MS:(ESI,m / z):389.3[M+H] + ,RT(min):9.627

[0457] 1 H NMR(400MHz,DMSO-d6)δ7.33–7.27(m,1H),7.17–7.14(m,2H),6.79(t,1H),5.8 9(s,2H),4.09(d,2H),3.77(d,1H),3.37–3.36(m,1H),2.77(t,1H),2.65–2.61( m,1H),2.39–2.34(m,1H),2.34–2.25(m,1H),1.94–1.88(m,1H),1.38–1.31(m,1 H),0.87–0.84(m,2H),0.83–0.79(m,1H),0.61–0.56(m,2H),0.22–0.18(m,1H).

[0458] After testing, the structure of compound 105-P1-P2 is Example 21 4-(1-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)ureido)-N-methyl-2-azabicyclo(4.1.0)heptane-2-carboxamide (Compound 106)

[0459]

[0460] Note: There is chirality, that is, 106-P1-P1 and 106-P1-P2 are One for Or 106-P1-P1 and 106-P1-P2 one for One for The first step is the synthesis of compound 4-(1-cyclopropyl-3-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)ureido)-N-methyl-2-azabicyclo(4.1.0)heptane-2-carboxamide:

[0461] To a solution of (R,E)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N'-cyano-N-methylazepane-1-carboxamidine (compound 107A, 50 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was added 2,5-dioxopyrrolidin-1- yl) N-methylcarbamate (21.0 mg, 0.12 mmol), triethylamine (22.86 mg, 0.22 mmol) and 1-hydroxybenzotriazole (2.18 mg, 0.01 mmol) at room temperature. The reaction was stirred for 0.5 h. Water (20 mL) was added to dilute, extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by acid method (conditions as follows: column specification: Prep-HPLC (Waters 2767 / Qda) Column: Sunfire C18 19*250mm 10μm; flow rate: 20 mL / min; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile; elution gradient: 43-43%; retention time: 8.4-9.2) to give compound 107B (10.0 mg).

[0462] MS: (ESI, m / z): 403.0 [M+H] + , RT(min): 1.645

[0463] 1 H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.25 (m, 1H), 7.20 - 7.14 (m, 2H), 6.78 (t, 1H), 6.20 (q, 1H), 4.09 (d, 2H), 3.84 - 3.75 (m, 1H), 3.28 - 3.20 (m, 1H), 2.79 (t, 1H), 2.63 - 2.57 (m, 4H), 2.39 - 2.29 (m, 2H), 1.95 - 1.88 (m, 1H), 1.41 - 1.32 (m, 1H), 0.88 - 0.79 (m, 3H), 0.62 - 0.55 (m, 2H), 0.21 - 0.16 (m, 1H).

[0464] The structure of compound 106-P1-P2 was detected as Example 22 (R,E)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N'-cyano-N-methylazepane-1-carboxamidine (compound 107A)

[0465]

[0466] The first step is the synthesis of tert-butyl (R)-3-(N-cyclopropyl-2,2,2-trifluoroacetamido)piperidine-1-carboxylate (Compound 107A-1):

[0467] At 0°C, tert-butyl (R)-3-(cyclopropylamino)piperidine-1-carboxylate (compound 37A-4, 5.3 g, 22.05 mmol) was dissolved in dichloromethane (50 mL). 4-Dimethylaminopyridine (0.27 g, 2.21 mmol), triethylamine (8.92 g, 88.2 mmol), and trifluoroacetic anhydride (23.16 g, 110.25 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, which was then extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 107A-1 (7.2 g).

[0468] MS:(ESI,m / z):337.1[M+H] + ,RT(min):2.245

[0469] Step 2: Synthesis of (R)-N-cyclopropyl-2,2,2-trifluoro-N-(piperidin-3-yl)acetamide (Compound 107A-2):

[0470] (R)-3-(N-cyclopropyl-2,2,2-trifluoroacetamido)piperidine-1-carboxylic acid tert-butyl ester (Compound 107A-1, 6.8 g, 20.22 mmol) was dissolved in dichloromethane (40 mL) solution, trifluoroacetic acid (20 mL) was added, and the reactants were stirred at room temperature for 2 hours. Dichloromethane (30 mL) was added to the reaction solution to dilute it, and the reaction solution was concentrated to obtain Compound 107A-2 (4.7 g).

[0471] MS:(ESI,m / z):237.1[M+H] + ,RT(min):1.525

[0472] Step 3: Synthesis of (R,E)-N-(1-(N'-cyano-N-methylaminoacyl)piperidin-3-yl)-N-cyclopropyl-2,2,2-trifluoroacetamide (Compound 107A-4):

[0473] (R)-N-cyclopropyl-2,2,2-trifluoro-N-(piperidin-3-yl)acetamide (compound 107A-2, 1.5 g, 6.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), (E)-N'-cyano-N-methylcarbamothioic acid sulfide (compound 107A-3, 0.82 g, 6.35 mmol) and triethylamine (2.57 g, 25.4 mmol) were added at room temperature, silver trifluoromethanesulfonate (2.12 g, 8.25 mmol) was added at 0 °C, after stirring at 0 °C for 10 min, stirring at room temperature for 20 min. After the reaction was completed, water (50 mL) was added to the reaction system to dilute, extracted with ethyl acetate (55 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate) to give compound 107A-4 (1.5 g).

[0474] MS: (ESI, m / z): 318.5 [M+H] + , RT(min): 1.927

[0475] Fourth step: synthesis of (R,E)-N'-cyano-3-(cyclopropylamino)-N-methylpiperidine-1- carboxamidine (compound 107A-5):

[0476] To (R,E)-N-(1-(N'-cyano-N-methylaminoacyl)piperidin-3-yl)-N-cyclopropyl-2,2,2- trifluoroacetamide (compound 107A-4, 2.0 g, 6.30 mmol), methanol (15 mL) and water (15 mL) solution were added, potassium carbonate (17.41 g, 6.3 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added to the reaction system to dilute, extracted with ethyl acetate (55 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 107A-5 (1.35 g, yield 96.78%).

[0477] MS: (ESI, m / z): 222.3 [M+H]+, RT(min): 0.811

[0478] Fifth step: synthesis of (R,E)-3-(3-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1- cyclopropylureido)-N'-cyano-N-methylpiperidine-1-carboxamidine (compound 107A):

[0479] To (R,E)-N'-cyano-3-(cyclopropylamino)-N-methylpiperidine-1-carboxamidine (compound 107A-5, 1.3 g, 5.87 mmol) in acetonitrile (15 mL) was added N-(3-(3-chloro-5-fluorophenyl)prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (compound 13A-1, 1.63 g, 5.87 mmol) and triethylamine (1.78 g, 17.61 mmol), after the addition was completed, it was stirred at 60 °C for 0.5 h. To the reaction solution was added water (70 mL) for dilution, extracted with ethyl acetate (70 mL x 3), the organic phase was combined, washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, the crude product was purified by silica gel column (petroleum ether / ethyl acetate = 1:1) to give the target product, the crude product was purified by reverse phase preparative chromatography (column specifications: Xselect CHS C18, 19*250mm, 10μm; mobile phase A: water (ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 47% B to 48% B in 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 9.4-10.8) to give compound 107A (390 mg).

[0480] MS: (ESI, m / z): 430.8 [M+H] + , RT(min): 1.790

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.46 (m, 1H), 7.34 (s, 1H), 7.31 - 7.26 (m, 1H), 7.22 - 7.13 (m, 1H), 6.84 (t, 1H), 4.12 (d, 2H), 3.98 - 3.81 (m, 2H), 3.58 - 3.49 (m, 1H), 3.18 (t, 1H), 2.82 (d, 3H), 2.79 - 2.70 (m, 1H), 2.44 - 2.38 (m, 1H), 2.07 - 1.94 (m, 1H), 1.84 - 1.68 (m, 2H), 1.53 - 1.41 (m, 1H), 0.91 - 0.83 (m, 2H), 0.70 - 0.60 (m, 2H).

[0482] Using similar conditions as described in the above examples, the following compounds in Table 6 were prepared, and the structural characterization data of these compounds are listed in Table 6.

[0483] Table 6

[0484]

[0485] Example 23 (R)-3-(3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropylcarbamoyl)piperidine-1-carboxamide (Compound 113)

[0486]

[0487] Synthesis of 3-((3-bromo-5-fluorophenoxy)methyl)-5-methylisoxazole (Compound 113-3):

[0488] To a solution of 3-(chloromethyl)-5-methylisoxazole (Compound 113-1, 900 mg, 6.84 mmol) in dimethylformamide (10 mL) was added 3-bromo-5-fluorophenol (Compound 113-2, 1437.08 mg, 7.52 mmol) and potassium carbonate (2836.07 mg, 20.52 mmol) at room temperature. The reaction was stirred at 50 °C overnight. Upon completion, the reaction was quenched by water solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by normal phase (petroleum ether: ethyl acetate = 3: 1) to give Compound 113-3 (0.3 g).

[0489] MS: (ESI, m / z): 286.0 [M+H] + , RT (min): 1.987

[0490] Synthesis of tert-butyl (3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)carbamate (Compound 113-4):

[0491] To a solution of 3-((3-bromo-5-fluorophenoxy)methyl)-5-methylisoxazole (Compound 113-3, 280 mg, 0.98 mmol) in dimethylformamide (2 mL) was added tert-butyl N-(prop-2-yn-1-yl)carbamate (228.13 mg, 1.47 mmol), copper(I) iodide (18.66 mg, 0.098 mmol), chloro(bis(triphenylphosphine))palladium(II) (68.79 mg, 0.098 mmol) and triethylamine (297.5 mg, 2.94 mmol) at room temperature. The reaction was stirred at 60 °C overnight. Upon completion, the reaction was quenched by water solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by normal phase (petroleum ether: ethyl acetate = 10: 1) to give Compound 113-4 (180 mg).

[0492] MS: (ESI, m / z): 361.1 [M+H] + , RT (min): 1.988

[0493] Step 3: Synthesis of 3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-amine (Compound 113-5):

[0494] To a solution of tert-butyl (3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)carbamate (Compound 113-4, 150 mg, 0.42 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 0.5 h. Upon completion, the reaction was concentrated to give Compound 113-5 (360 mg).

[0495] MS: (ESI, m / z): 261.2 [M+H] + , RT (min): 1.292

[0496] Step 4: Synthesis of 3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-amine (Compound 113-6):

[0497] To a solution of 3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-amine (Compound 113-5, 110 mg, 0.42 mmol) in acetonitrile (1 mL) was added N,N'-carbonyldiimidazole (102.15 mg, 0.63 mmol) and triethylamine (127.50 mg, 1.26 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was quenched with water solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated and the crude (150 mg) was used directly in the next step. To a solution of the above crude in acetonitrile (1 mL) was added tert-butyl (3R)-3-(cyclopropylamino)piperidine-1-carboxylate (Compound 37A-4, 100.94 mg, 0.42 mmol) and triethylamine (255.00 mg, 2.52 mmol) and stirred at 50 °C for 1 h. Upon completion, the reaction was quenched with water solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude which was purified by normal phase (petroleum ether: ethyl acetate = 1:1) to give Compound 113-6 (200 mg).

[0498] MS: (ESI, m / z): 527.3 [M+H] + , RT (min): 2.023

[0499] Step 5: Synthesis of (R)-3-(3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (Compound 113-7):

[0500] To a solution of tert-butyl (R)-3-(3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxylate (Compound 113-6, 200 mg, 0.38 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 0.5 h. Upon completion, the reaction was concentrated to give Compound 113-7 (140 mg).

[0501] MS: (ESI, m / z): 427.3 [M+H] + , RT (min): 0.826

[0502] Step 6: Synthesis of (R)-3-(3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxamide (Compound 113):

[0503] To a solution of (R)-3-(3-(3-fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (Compound 113-7, 140 mg, 0.33 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (213.25 mg, 1.65 mmol), followed by trimethylsilyl isocyanate (76.04 mg, 0.66 mmol) at room temperature. The reaction was stirred at room temperature overnight. Upon completion, the reaction was concentrated to give the crude product, which was purified by reverse phase preparative chromatography (conditions as follows: column specification: Prep-HPLC (Waters 2767 / QDA), Column: SunFire C18, 19*250mm, 10μm; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 45%~45%; retention time: 8.4~9.2 min, 16 min) to give Compound 113 (41.25 mg).

[0504] MS: (ESI, m / z): 470.3 [M+H] + , RT (min): 1.671

[0505] 1 H NMR (400 MHz, DMSO-d6) δ 6.99 - 6.95 (m, 1H), 6.90 - 6.84 (m, 2H), 6.76 (t, 1H), 6.33 (s, 1H), 5.89 (s, 2H), 5.19 (s, 2H), 4.10 (d, 2H), 3.90 - 3.82 (m, 2H), 3.54 - 3.42 (m, 2H), 2.96 (t, 1H), 2.43 - 2.38 (m, 4H), 1.99 - 1.88 (m, 1H), 1.77 - 1.60 (m, 2H), 1.40 - 1.29 (m, 1H), 0.90 - 0.83 (m, 2H), 0.66 - 0.59 (m, 2H).

[0506] Example 24 (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)-1-cyclopropylcarbamoyl)piperidine-1-carboxamide (Compound 114)

[0507]

[0508] Synthesis of 3-((3-chloro-5-iodophenoxy)methyl)-5-methylisoxazole (Compound 114-2):

[0509] To a solution of 3-(chloromethyl)-5-methylisoxazole (Compound 113-1, 500 mg, 3.80 mmol) in dimethylformamide (5 mL) was added 3-chloro-5-iodophenol (Compound 114-1, 1063.60 mg, 4.18 mmol) and potassium carbonate (1575.59 mg, 11.40 mmol) at room temperature, and the reaction was stirred at 50 °C overnight. After the reaction was completed, the reaction was quenched by adding water solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 3: 1) to give Compound 114-2 (1.3 g).

[0510] MS: (ESI, m / z): 349.9 [M+H] + , RT (min): 2.106

[0511] Synthesis of tert-butyl (3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)carbamate (Compound 114-3):

[0512] To a solution of 3-((3-chloro-5-iodophenoxy)methyl)-5-methylisoxazole (compound 114-2, 1.2 g, 3.43 mmol) in dimethylformamide (12 mL) was added tert-butyl N-(prop-2-yn-1-yl)carbamate (0.64 g, 4.12 mmol), cuprous iodide (130 mg, 0.69 mmol), chlorobis(triphenylphosphine)palladium(II) (120 mg, 1.72 mmol) and triethylamine (1.74 g, 17.15 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched by water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by normal phase (petroleum ether: ethyl acetate = 20: 1) to give compound 114-3 (1.0 g).

[0513] MS: (ESI, m / z): 377.0 [M+H] + , RT (min): 2.059

[0514] Step 3: Synthesis of 3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-amine (compound 114-4):

[0515] To a solution of tert-butyl (3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)carbamate (compound 114-3, 500 mg, 1.33 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at room temperature. The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction was concentrated to give compound 114-4 (360 mg).

[0516] MS: (ESI, m / z): 277.1 [M+H] + , RT (min): 1.334

[0517] Step 4: Synthesis of tert-butyl (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropylureido)piperidine-1-carboxylate (compound 114-5):

[0518] To a solution of 3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- amine (compound 114-4, 360 mg, 1.30 mmol) in acetonitrile (3 mL) was added N,N'- carbonyldiimidazole (316.19 mg, 1.95 mmol) and triethylamine (394.64 mg, 3.90 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction was quenched by adding water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated and the residue (450 mg) was used directly in the next step. To a solution of the above residue in acetonitrile (5 mL) was added tert-butyl (3R)-3-(cyclopropylamino)piperidine-1-carboxylate (compound 37A-4, 305.23 mg, 1.27 mmol) and triethylamine (771.07 mg, 7.62 mmol) at 50 °C. The reaction was stirred at 50 °C for 1 h. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by normal phase (petroleum ether: ethyl acetate = 1:1) to give compound 114-5 (650 mg).

[0519] MS: (ESI, m / z): 543.1 [M+H] + , RT (min): 2.071

[0520] Step 5. Synthesis of (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)-1-cyclopropyl-1-(piperidin-3-yl)urea (compound 114-6):

[0521] To a solution of tert-butyl (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2- yn-1-yl)-1-cyclopropylureidyl)piperidine-1-carboxylate (compound 114-5, 250 mg, 0.46 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated to give compound 114-6 (130 mg).

[0522] MS: (ESI, m / z): 443.2 [M+H] + , RT (min): 0.843

[0523] Step 6: Synthesis of (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (Compound 114-6)

[0524] To a solution of (R)-3-(3-(3-chloro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1- cyclopropyl-1-(piperidin-3-yl)urea (Compound 114-6, 130 mg, 0.29 mmol) in dichloromethane (2 mL) was added diisopropylethylamine (187.4 mg, 1.45 mmol) at room temperature, then trimethylsilyl isocyanate (66.82 mg, 0.58 mmol) was added, after the addition was completed, the reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated to give a crude product, the crude product was purified by reverse phase preparative chromatography (conditions as follows: column specifications: Prep-HPLC (Waters 2767 / QDA), Column: SunFire C18, 19*250mm, 10μm; mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 50%~50%; retention time: 7.5-8.4 min, 16 min) to give Compound 114 (41.25 mg).

[0525] MS: (ESI, m / z): 486.1 [M+H] + , RT(min): 1.757

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 7.18 - 7.13 (m, 1H), 7.09 - 7.03 (m, 1H), 7.03 - 6.99 (m, 1H), 6.76 (t, 1H), 6.32 (d, 1H), 5.89 (s, 2H), 5.21 (s, 2H), 4.10 (d, 2H), 3.91 - 3.82 (m, 2H), 3.57 - 3.42 (m, 2H), 2.96 (t, 1H), 2.43 - 2.38 (m, 4H), 1.99 - 1.88 (m, 1H), 1.78 - 1.60 (m, 2H), 1.39 - 1.28 (m, 1H), 0.90 - 0.83 (m, 2H), 0.66 - 0.58 (m, 2H).

[0527] Example 25 (R)-3-(1-cyclopropyl-3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)ureido)piperidine-1- carboxamide (Compound 115)

[0528]

[0529] Synthesis of 3-((3-iodophenoxy)methyl)-5-methylisoxazole (compound 115-2):

[0530] 3-(Chloromethyl)-5-methyl-1,2-oxazole (compound 113-1, 1 g, 7.60 mmol) was dissolved in N,N-dimethylformamide (10 mL), 3-iodophenol (compound 115-1, 1.84 g, 8.36 mmol) was added, potassium carbonate (3.15 g, 22.80 mmol) was added, and the reaction solution was stirred at 50°C for 3 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to dilute it, ethyl acetate (100 mL x 3) was added to extract it, the combined organic phase was washed with saturated brine (50 mL x 3), anhydrous sodium sulfate was added for drying, filtration was performed, and concentration was performed to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 115-2 (2.1 g).

[0531] MS: (ESI, m / z): 315.9 [M+H] + , RT (min): 1.964

[0532] Synthesis of tert-butyl (3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1- yl)carbamate (compound 115-3):

[0533] 3-[(3-Iodophenoxy)methyl]-5-methyl-1,2-oxazole (compound 115-2, 1 g, 3.17 mmol) was dissolved in N,N-dimethylformamide (10 mL), N-Boc-propargylamine (0.64 g, 4.12 mmol) was added, cuprous iodide (0.12 g, 0.63 mmol), chlorobis(triphenylphosphine)palladium(II) (0.22 g, 0.32 mmol), and triethylamine (1.60 g, 15.85 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water (50 mL) was added to the reaction solution to dilute it, ethyl acetate (50 mL x 3) was added to extract it, the combined organic phase was washed with saturated brine (50 mL x 3), anhydrous sodium sulfate was added for drying, filtration was performed, and concentration was performed to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 115-3 (900 mg).

[0534] MS: (ESI, m / z): 343.1 [M+H] + , RT (min): 1.918

[0535] Synthesis of 3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-amine (compound 115-4):

[0536] N-(3-(3-[(5-methyl-1,2-oxazol-3-yl)methoxy]phenyl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (compound 115-3, 300 mg, 0.88 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, it was concentrated to obtain a crude product (200 mg, yield 94.22%).

[0537] MS: (ESI, m / z): 243.1 [M+H] + , RT (min): 1.235

[0538] Step 4. Synthesis of N-(3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1H- imidazole-1-carboxamide (compound 115-5):

[0539] 3-(3-[(5-methyl-1,2-oxazol-3-yl)methoxy]phenyl)prop-2-yn-1-amine (compound 115-4, 212 mg, 0.88 mmol) was dissolved in acetonitrile (3 mL), N,N'-carbonyldiimidazole (142.69 mg, 0.88 mmol), triethylamine (267.14 mg, 2.64 mmol) were added, the reaction was stirred at room temperature for 10 minutes. After the reaction was completed, it was directly used for the next step without treatment.

[0540] MS: (ESI, m / z): 337.1 [M+H] + , RT (min): 1.381

[0541] Step 5. Synthesis of tert-butyl (R)-3-(1-cyclopropyl-3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)ureido)piperidine-1-carboxylate (compound 115-6):

[0542] (3R)-3-(cyclopropylamino)piperidine-1-carboxylic acid tert-butyl ester (compound 37A-4, 209 mg, 0.87 mmol) was added to the reaction system of the previous step, triethylamine (176.07 mg, 1.74 mmol) was added, the reaction was stirred at 60 degrees Celsius for 1 hour. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 115-6 (60 mg).

[0543] MS: (ESI, m / z): 509.2 [M+H] + , RT (min): 1.988

[0544] Step 6: Synthesis of (R)-1-cyclopropyl-3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)-1-(piperidin-3-yl)urea (Compound 115-7):

[0545] Tert-butyl (3R)-3-(3-cyclopropyl[(3-(3-[(5-methyl-1,2-oxazol-3-yl)methoxy]phenyl)prop-2-yn-1-yl)carbamoyl]amino)piperidine-1-carboxylate (Compound 115-6, 60 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the compound 115-7 (45 mg) was obtained by concentration.

[0546] MS: (ESI, m / z): 409.1 [M+H] + , RT (min): 1.363

[0547] Step 7: Synthesis of (R)-3-(1-cyclopropyl-3-(3-((5-methylisoxazol-3-yl)methoxy)phenyl)prop-2-yn-1-yl)ureido)piperidine-1-carboxamide (Compound 115):

[0548] 3-cyclopropyl-1-(3-(3-[(5-methyl-1,2-oxazol-3-yl)methoxy]phenyl)prop-2-yn-1-yl)-3-[(3R)-piperidin-3-yl]urea (Compound 115-7, 48 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), trimethylsilyl isocyanate (69.13 mg, 0.60 mmol), ethyldiisopropylamine (77.54 mg, 0.60 mmol) were added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the compound 115 (15 mg) was obtained by concentration, purification on a silica gel column (ethyl acetate / methanol = 5 / 1), and high performance liquid purification under the following conditions (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 44% B ~ 44% B, 16 min; detection wavelength: 254 nm / 214 nm; retention time (min): 7.2-8.0).

[0549] MS: (ESI, m / z): 452.2 [M+H] + , RT (min): 1.626

[0550] 1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.25 (m, 1H), 7.07 - 6.98 (m, 3H), 6.75 (t, 1H), 6.32 (d, 1H), 5.89 (s, 2H), 5.16 (s, 2H), 4.09 (d, 2H), 3.93 - 3.80 (m, 2H), 3.57 - 3.47 (m, 2H), 2.97 (t, 1H), 2.44 - 2.36 (m, 4H), 2.03 - 1.86 (m, 1H), 1.82 - 1.69 (m, 1H), 1.69 - 1.57 (m, 1H), 1.43 - 1.25 (m, 1H), 0.93 - 0.81 (m, 2H), 0.69 - 0.57 (m, 2H).

[0551] Biological evaluation

[0552] Test Example 1

[0553] Test Name: SLC6A19 Isoleucine transport assay

[0554] Cell line generation and maintenance:

[0555] Flp-In™-CHO™ cell lines were purchased from Thermo Fisher Scientific. Stable cell lines were generated by transfection of TMEM27 and hSLC6A19 encoding plasmids using standard protocols followed by antibiotic selection. The cell lines were used to generate inducible expression of cell lines with TMEM27 and expressing hSLC6A19. Stable cells were maintained in DMEM / F12 (Thermo Fisher) supplemented with 10% fetal bovine serum, 800 pg / ml G418, 2 mM L-glutamine.

[0556] Buffer preparation:

[0557] 1. Component A (FLIPR Membrane Potential Assay Kit)

[0558] 2. Component B: 20 mm HEPES in 1x HBSS buffer, pH 7.4 adjusted with 1 N NaOH.

[0559] Compound preparation:

[0560] 1. Dissolve compounds in DMSO to make 10 mM stock solutions, aliquot and store at -20 °C.

[0561] 2. Dilute compounds in buffer to the highest concentration of the test 10000 nM, 2-fold dilution.

[0562] a) JNT-517 final test concentrations: 10000, 5000, 2500, 1250, 625, 312.5, 156.3, 78.1, 39.1, 19.5 nM.

[0563] b) Test compound final test concentrations: 10000, 5000, 2500, 1250, 625, 312.5, 156.3, 78.1, 39.1, 19.5 nM.

[0564] Seeding of cells into 384 well cell culture plates

[0565] 1. TMEM27 / hSLC6A19 CHO cells were cultured with cell culture medium (F12, 10% FBS, 800 μg / ml G418, 2 mM L-glutamine).

[0566] 2. When the cells reached 80% confluency, the cells were detached with 0.25% trypsin. The cell density was measured and the cells were diluted to 1.0 x 10 6 cells / mL with culture medium.

[0567] 3. 20 μL of cells were added to each well of a 384 well black assay plate (pre-coated with poly-D-lysine or matrix) and incubated overnight at 37°C, 5% CO2.

[0568] Assay:

[0569] 1. On the day of the assay, wash the plates several times with component B and make the contents of the component A vial completely dissolve to a total volume of 10 mL.

[0570] 2. Centrifuge the cells gently to remove the cell plate medium and add 20 μL of component B and 20 μL of buffer to each well and incubate for 30 minutes at room temperature.

[0571] 3. After incubation, add 10 μL of 5x final concentration of compound to the assay plate and add 10 μL of 6x final concentration of L-isoleucine to a final concentration of 10 mM. Read the plate for 15 minutes. Read the fluorescence values using FLIPR (510-545 / 565-625 excitation / emission wavelengths, 5 minutes).

[0572] Data analysis:

[0573] % Inhibition = 100 - (compound well reading - low reading control well reading) / (high reading control well reading - low reading control well reading) x 100

[0574] High reading control well: 0.1% DMSO; Low reading control well: 10 μM JNT-517.

[0575] IC50values were calculated using GraphPad Prism 9 software 50 (nM) and the effect-dose curve of the compound was plotted.

[0576] Table A Biological activity data of the compounds of the present application

[0577]

[0578]

[0579]

[0580] Experimental conclusion

[0581] The above data show that the representative compounds of the present application have good SLC6A19 inhibitory activity.

[0582] Test Example 2 Pharmacokinetic study of the test compound in beagle dogs

[0583] Experimental method

[0584] On the day of administration, the test substance was prepared using a prescription of 5% DMSO + 5% Solutol + 90% Saline. The prepared administration solution was reserved.

[0585] The intravenous injection IV group was administered at a dose of 0.5 mg / kg, and the oral gavage PO group was administered at a dose of 2 mg / kg. The animals were fasted overnight before administration.

[0586] Before administration, the body weight of the animals was measured, and the administration amount was calculated according to the body weight. The animals were administered once on the day of administration. At 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, venous blood (about 1 mL each time) was collected from the appropriate position, placed in EDTA-K2 anticoagulant blood collection tubes, centrifuged at 4000 rpm for 10 min (4°C), and the plasma was separated within 1 h. The plasma was extracted into labeled EP tubes (the label should at least indicate the project code, animal number, collection time point, collection date, etc.), and stored at -80°C for testing. The blood collection and centrifugation process were operated under ice bath conditions. The animals were fed 3 h after administration, and free water was provided. The concentration of the test substance in the plasma of beagle dogs was detected by using a verified LC-MS / MS method.

[0587] Experimental results

[0588] The pharmacokinetic study of the compounds in beagle dogs in the present application was determined by the above experiment, and the results are shown in Table B.

[0589] Table B Experimental results of pharmacokinetic study of test compounds in beagle dogs (IV 0.5 mpk / PO 2 mpk)

[0590]

[0591]

[0592] Experimental conclusion

[0593] The representative compounds of the present application have good PK properties in beagle dogs, and have lower clearance rate and longer half-life compared with the control compounds. It can be seen that, by structural optimization, the present application significantly improves the metabolic stability of the compounds, and further improves the drugability of the compounds.

[0594] Test Example 3 Pharmacokinetic study of test compounds in cynomolgus monkeys

[0595] Experimental method

[0596] On the day of administration, the test substance was prepared using a 5% DMSO+5% Solutol+90% Saline prescription, and the administration solution was prepared for standby.

[0597] The intravenous injection IV group was administered at a dose of 0.5 mg / kg, and the oral gavage PO group was administered at a dose of 2 mg / kg. The animals were fasted overnight before administration.

[0598] Before administration, the body weight of the animals was weighed, the administration amount was calculated according to the body weight, and the IV and PO administration was performed once on the administration day. At the time points of 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, venous blood (about 1 mL each time) was collected from the appropriate position, placed in an EDTA-K2 anticoagulant blood collection tube, centrifuged at 4000 rpm for 10 min (4℃), and the plasma was separated within 1 h, extracted into an EP tube with a label (the label should at least indicate the special code, animal number, collection time point, collection date, etc.), and stored at -80℃ for testing. The blood collection to centrifugation process was operated under ice bath conditions. Food was given 3 h after administration, and water was given freely. The LC-MS / MS method was used to detect the concentration of the test substance in the plasma of cynomolgus monkeys.

[0599] Experimental results

[0600] The pharmacokinetic study of the compounds in cynomolgus monkeys in the present application was determined by the above experiment, and the results are shown in Table C.

[0601] Table C Experimental results of pharmacokinetic study of test compounds in cynomolgus monkeys (IV 0.5 mpk / PO 2 mpk)

[0602]

[0603]

[0604] Experimental conclusion

[0605] The representative compounds of the present application have good PK properties in cynomolgus monkeys, and have more excellent oral exposure and bioavailability compared with the control compounds. It can be seen that, by structure optimization, the present application significantly improves the in-vivo pharmacokinetic properties of the compounds, and improves the drugability of the compounds.

[0606] The structure of the control compound described in the present application is as follows:

[0607]

[0608] The above has carried out exemplary description to the implementation mode of the technical scheme of the present application. It should be understood that the protection scope of the present application is not limited to the above-mentioned implementation modes. Any modification, equivalent replacement, improvement, etc. made by the person skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, deuterated form, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof: in, Y1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; each R b The same or different, independently selected from CN, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: OH, NH2, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, S(=O)2R b2 or C(=O)R b3 ; Each R b1 The same or different, independently selected from oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R b4 Substituted with the following groups: OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R b2 、R b3 The same or different, independently selected from H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; each R b4 The same or different, independently selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; L1 is absent or selected from unsubstituted or optionally substituted by one, two or more selected from oxo (=O), OH, NH2, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 C substituted by a cycloalkyl or 3-6 membered heterocyclic group 1-12 alkylene; R2, R3 are the same or different and are independently selected from H, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; 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 6-14 Arylene or 5-14 membered heteroarylene; X1 is selected from CH or N; Each R a The same or different, independently selected from oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: OH, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, methylene (=CH2), C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, NH2, S(=O)2R a2 or C(=O)R a3 ; or, two R attached to the same carbon atom a Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group consisting of one, two or more R a1 Substituted ring system: C 3-14 carbocyclic or 3-14 membered heterocyclic ring; or, two R a Together with the carbon atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R a1 Substituted ring system: C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 aromatic ring or 5-14 membered heteroaromatic ring; or, two non-adjacent R a connected with their terminal groups to form a group which is unsubstituted or optionally substituted with one, two or more R a1 Substituted C 1-3 alkylene; each R a1 The same or different, independently selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R a2 、R a3 The same or different, independently selected from H, OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R1 is selected from any one of the following groups: (i) 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 6-14 Aryl or 5-14 membered heteroaryl; (ii) COR 11 ; R 11 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: H, OH, -NR 12 R 13 、C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group; R 12 、R 13 The same or different, independently selected from H, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl; (iii) R 14 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 16 )(R 17 ), C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic group; R 16 、R 17 The same or different, independently selected from H, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl; or, R 16 、R 17 Together with the nitrogen atom to which it is attached, it forms a 3-14 membered nitrogen-containing heterocyclic ring; R 15 Selected from H, CN, unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: OH, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; (iv) X2 is selected from O or NR X2 ; R X2 Selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R 18 Selected from H, CN, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic group; R 19 Selected from H, CN, unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 110 )(R 111 ), C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R 110 、R 111 The same or different, independently selected from H, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; Each R c The same or different, independently selected from D, oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 Substituted with the following groups: OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, NH2, S(O)2H or COH; each R c1 The same or different, independently selected from oxo (=O), OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 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, deuterated form, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, wherein: n is selected from 0 or 1; Preferably, n is 1; Preferably, L2 is absent; Preferably, R2 is selected from H; Preferably, R3 is selected from cyclopropyl; Preferably, L1 is selected from methylene; Preferably, m is selected from 0, 1 or 2; Preferably, m is selected from 0 or 1; Preferably, each R a The same or different, independently selected from oxo (=O), CN, halogen, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, methylene (=CH2), C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; or, two R a Together with the carbon atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R a1 Substituted ring system: C 3-6 Carbocyclic or 3-6 membered heterocyclic ring; each R a1 the same or different, independently selected from CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, each R a are the same or different and are independently selected from CN, halogen (e.g. F, Cl, Br), OH, a methylene group which is unsubstituted or optionally substituted with one or two halogens (e.g. =CF2, =CHF); or two R attached to adjacent carbon atoms a Together with the carbon atoms to which they are respectively attached, they form a cyclopropane ring; Preferably, Selected from The "*" side is connected to L2, and the "#" side is connected to R1.

3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, deuterated form, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: Y1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; each R b The same or different, independently selected from CN, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: OH, NH2, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, S(=O)2R b2 or C(=O)R b3 ; Each R b1 The same or different, independently selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R b2 、R b3 The same or different, independently selected from H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted groups include phenyl, naphthyl, or 5-10 membered heteroaryl; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or three R b Substituted phenyl, naphthyl or 5-6 membered heteroaryl (e.g., pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl); Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, thienyl; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl, naphthyl, pyridyl or pyrazolyl; Preferably, Y1 is selected from unsubstituted or optionally substituted with one, two or three R b substituted phenyl or pyridyl; Preferably, each R b The same or different, independently selected from CN, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, pyrazolyl; each R b1 The same or different, independently selected from CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, unsubstituted or optionally substituted with one, two or more R b4 Substituted groups: phenyl or 5-6 membered heteroaryl; each R b4 The same or different, independently selected from C 1-4 alkyl; Preferably, each R b The same or different, independently selected from CN, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, pyrazolyl; each R b1 The same or different, independently selected from CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 alkoxy; Preferably, each R b The same or different, independently selected from CN, halogen, unsubstituted or optionally substituted by one, two or more R b1 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; each R b1 The same or different, independently selected from CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 alkoxy; Preferably, each R b The same or different, independently selected from methyl, ethyl, isopropyl, cyclopropyl, phenyl, pyrazole Methylpyrazole (such as ), CN, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCF3 or Preferably, each R b The same or different, independently selected from methyl, isopropyl, cyclopropyl, phenyl, pyrazole Methylpyrazole (such as ), CN, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3 or OCF3; Preferably, each R b the same or different, independently selected from CN, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, OCH3 or OCF3; Preferably, Y1 is selected from Preferably, Y1 is selected from Preferably, Y1 is selected from Preferably, Y1 is selected from 4. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, deuterated form, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: R1 is selected from any one of the following groups: (i) unsubstituted or optionally substituted with one or two R c Substituted as follows: phenyl or 5-6 membered heteroaryl; (ii) COR 11 ; R 11 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -NR 12 R 13 、C 1-6 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -NR 12 R 13 or C 1-6 Alkyl; R 12 、R 13 The same or different, independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-6 Alkyl; preferably, R 12 、R 13 The same or different, independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl; (iii) R 14 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 16 )(R 17 ), C 1-6 Alkyl; R 16 、R 17 The same or different, independently selected from H or C 1-6 Alkyl; R 15 is selected from H, CN or OH; (iv) X2 is selected from O or NR X2 ; R X2 Selected from H or C 1-6 Alkyl; R 18 Selected from H or C 1-6 Alkyl; R 19 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: -N(R 110 )(R 111 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; R 110 、R 111 The same or different, independently selected from H or C 1-6 alkyl; Each R c The same or different, independently selected from D, OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, each R c The same or different, independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R1 is selected from any one of the following groups: (i) unsubstituted or optionally substituted with one or two R c Substituted pyrimidinyl (e.g. ), pyridazinyl (e.g. ); (ii) COR 11 ; R 11 Selected from unsubstituted or optionally substituted by one or two R c Substituted with the following groups: -NR 12 R 13 、C 1-4 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 Selected from unsubstituted or optionally substituted by one or two R c Substituted with the following groups: -NR 12 R 13 、C 1-4 Alkyl or C 3-6 Cycloalkyl; R 12 、R 13 The same or different, independently selected from H, C 1-4 Alkyl (e.g. -CH3, -CD3, -CH2CH3) or C 3-6 Cycloalkyl; preferably, R 12 、R 13 The same or different, independently selected from H or C 1-6 alkyl; (iii) R 14 Selected from -N(R 16 )(R 17 );R 16 、R 17 The same or different, independently selected from H or C 1-4 Alkyl; R 15 Selected from CN or OH; (iv) X2 is selected from O; R 18 Selected from H or C 1-4 Alkyl; R 19 Selected from C 1-4 alkyl; Each R c are identical or different and are independently selected from D, OH, CN, F, Cl, methyl, ethyl, n-propyl, isopropyl or tert-butyl; Preferably, each R c are identical or different and are independently selected from OH, CN, F, Cl, methyl, ethyl, n-propyl, isopropyl or tert-butyl; Preferably, R1 is selected from Preferably, R1 is selected from Preferably, R1 is selected from 5. The compound according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, deuterated form, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: The compound represented by formula (I) has the structure shown below: Among them, Y1, R2, R3, R a , X2, R 12 、R 13 、R 14 、R 15 、R 18 、R 19 , m has the definition as described in any one of claims 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, Y1, R a 、R 13 、R 15 、R 17 、R 18 、R 19 , m has the definition as described in any one of claims 1-4; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R a 、R b 、R 12 、R 13 , m has the definition as described in any one of claims 1-4; X is a halogen (e.g., F, Cl, Br); m1 is selected from 0, 1, 2, 3 or 4; preferably, m1 is selected from 0, 1 or 2; preferably, m1 is selected from 0 or 1; preferably, m1 is 0; preferably, m1 is 1.

6. The compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, deuterated form, 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 the compound of formula (I) according to any one of claims 1 to 6, comprising the following steps A: Step A: in, R1, R2, R3, R a , L1, L22, X1, 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, deuterated form, solvate, polymorph, pharmaceutically acceptable salt, or prodrug 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 preventively 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, deuterated form, 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 at least one of the compound of formula (I) according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, deuterated form, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament; Preferably, the use may be for preparing a medicament for treating or preventing a disease or condition mediated by SLC6A19; Preferably, the SLC6A19-mediated disease or disorder is phenylketonuria.

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