Heterocyclic compound, pharmaceutical composition comprising the same, preparation method therefor, and use thereof

Abstract

To provide a heterocyclic compound for preventing or treating a disease or condition related to RET activity, a pharmaceutical composition comprising the same, a preparation method therefor, and a use thereof.SOLUTION: Provided is a compound having the structure of formula (I), wherein ring A is selected from C6-10 aromatic rings and 5- to 6-membered heteroaromatic rings, ring B is selected from C3-8 cycloalkyl groups and 4- to 11-membered heterocyclic groups, and X1 is selected from CH and N.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel heterocyclic compounds, pharmaceutical compositions containing same, processes for their preparation, and their use in the prevention or treatment of diseases or conditions associated with RET (Rearranged during transfection) activity. [Background technology]

[0002] Protein kinases are a type of enzyme that catalyzes the phosphorylation of proteins. By mediating cell signaling processes, protein phosphorylation regulates the physiological activities of cells, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. Malfunction of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes.

[0003] RET is a proto-oncogene, and the encoded RET protein is a transmembrane receptor tyrosine protein kinase consisting of three parts: a cysteine-rich cadherin-like extracellular domain (for binding ligands), a transmembrane domain, and an intracellular domain with tyrosine kinase activity. Activated RET protein can induce cell proliferation, migration, and differentiation by activating multiple downstream signaling pathways, including the RAS / RAF / ERK pathway, the PI3K / Akt pathway, and the JNK pathway. Alterations (mutations or fusions) in the RET gene and abnormal expression of the wild-type RET gene result in abnormal activation of the RET protein, and hyperactivation of signaling pathways is one of the main mechanisms of carcinogenesis. Abnormally activated RET protein is involved in the proliferation and invasion of different tumor cells through multiple types of signaling pathways, thereby affecting the development and development of tumors. Alterations in the RET gene have more pronounced effects on downstream cascades. Among them, RET gene mutations are mainly associated with medullary thyroid cancer and papillary thyroid cancer, and RET gene fusions are mainly associated with non-small cell lung cancer and chronic myeloid leukemia. Therefore, inhibiting RET activity is of great medical value (Nature Reviews Cancer, 2014, 14(3): 173-86).

[0004] RET inhibitors have great potential for treating and preventing various diseases (e.g., tumors, irritable bowel syndrome, etc.). At present, there are five compounds in clinical trials, and compounds from several companies are in the preclinical research stage. However, currently, no inhibitors that primarily target RET are available on the market. Therefore, it is necessary to develop new highly efficient and low-toxicity RET inhibitors to meet clinical needs. Detailed Description of the Invention

[0005] The present invention provides novel heterocyclic compounds which have a good inhibitory effect on RET and also have good pharmacokinetic properties, safety, and the like.

[0006] One aspect of the present invention provides a compound of formula I, a stereoisomer, tautomer, or mixtures thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound. [ka] (Of these, ring A is C 6-10 is selected from an aromatic ring and a 5- or 6-membered heteroaromatic ring; Ring B is C 3-8 is selected from cycloalkyl and 4- to 11-membered heterocyclic groups; X 1 is selected from CH and N,

[0007] R 1 is H, halogen, hydroxy, cyano group, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy), C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups and -NR 20a R 20b wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl and heterocyclic groups are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy and C 1-4 Heteroalkyl (e.g., C 1-4 alkoxy),

[0008] R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, 5-10 membered heteroaryl and -C(=O)R 21wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0009] R 3 and R 4 is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy) and C 3-6 and cycloalkyl, wherein the alkyl, heteroalkyl (e.g., alkoxy), and cycloalkyl are each optionally selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; and when m is greater than 1, two R 3 Optionally, C together with the atom to which they are attached 3-6 and / or when n is greater than 1, two R 4 Optionally, C together with the atom to which they are attached 3-6 may form a cycloalkyl or 4-10 membered heterocyclic group,

[0010] L is -O-, -S-, -S(O)-, -S(O) 2 -, -N=CR 21 -, -N(R 23a )-C(O)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6Alkenylene, C 2-6 Alkynylene, [ka] wherein the alkylene, heteroalkylene, alkenylene and alkynylene are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy) and C 3-8 or L is -N(R 23a )-and

[0011] R 5 is hydroxy, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR23a R 23b , -NR 23a C(=O)R 23b , -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b wherein the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups;

[0012] R 20a , R 20b , R 23a , R 23b , R 23c , R 24a , R 25a and R 25b are independently H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl or R 20a and R 20b , R 23a and R 23b , or R 25a and R 25b along with the atoms to which they are connected. and forming a 3-8 membered cycloalkyl or heterocyclic group, each of said alkyl, alkoxy, cycloalkyl and heterocyclic groups optionally containing OH, CN, halogen, NO 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl and C 1-4 may be substituted with one or more substituents selected from haloalkoxy;

[0013] R 30a, R 30b , R 33a , R 33b , R 34a , R 35a and R 35b are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 selected from haloalkoxy;

[0014] R 21 , R 22 , R 31 and R 32 are each independently C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each optionally selected from OH, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and u is 0, 1, 2, 3 or 4; However, ring B is a piperazine ring, and X 1 If CH, then R 2 is 4-CF 3 -pyridin-2-yl or 4-CN-pyridin-2-yl.

[0015] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, which may, optionally, further comprise one or more pharma- ceutically acceptable carriers.

[0016] Another aspect of the present invention provides the use of a compound according to the present invention, a stereoisomer, tautomer, or mixtures thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RET activity.

[0017] Another aspect of the present invention provides a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutical composition as described above, for preventing or treating a disease or condition associated with RET activity.

[0018] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with RET activity, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above. Another aspect of the present invention provides methods for preparing the compounds of the present invention. [Brief description of the drawings]

[0019] [Figure 1] 1 shows the results of an in vivo efficacy test of compound 17 and a comparative compound BLU-667 performed on a subcutaneously transplanted TT cell tumor model of medullary thyroid cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition

[0021] Unless otherwise defined below, the meaning of all technical and scientific terms used herein is intended to be the same as that generally understood by those skilled in the art. The term technology used herein refers to technology generally understood by those skilled in the art, and includes those technical modifications or equivalent technical replacements that are obvious to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are still provided to better explain the present invention.

[0022] The terms "including," "including," "having," "containing," or "involving," and other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, but other unlisted elements or method steps need not necessarily be present (i.e., these terms also include the terms "consisting essentially of" and "consisting of").

[0023] As used herein, the term "alkyl" is defined as a straight-chain or branched, saturated aliphatic hydrocarbon. In certain embodiments, an alkyl group has 1-12, e.g., 1-6, carbon atoms. For example, as used herein, "C 1-6 Alkyl" and "C 1-4The term "alkyl" refers to straight or branched chain groups having 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally containing one or more (e.g., 1-3) suitable substituents, such as halogen (in which case the group is referred to as a "haloalkyl") (e.g., CH 2 F, CHF 2 , C.F. 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , C.H. 2 CF 3 , C.H. 2 Cl or -CH 2 CH 2 CF 3 It may be replaced by "C 1-4 The term "alkyl" means a straight or branched aliphatic hydrocarbon chain of 1-4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "alkylene" refers to the corresponding divalent group, e.g., "C 1-8 Alkylene", "C 1-6 Alkylene", "C 1-4 Alkylene, etc., specific examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -or-CH(CH 3 )-), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), but are not limited to, butylene, pentylene, hexylene, etc. Said alkylene may be optionally substituted with one or more (e.g., 1-3) of the same or different substituents.

[0024] As used herein, the term "heteroalkyl" refers to an alkyl having one or more skeletal atoms selected from atoms other than carbon, such as, for example, oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, and which may be optionally substituted. 1-6 Heteroalkyl) refers to the number of carbons in the chain, in this example 1-6 carbon atoms. For example, -CH 2 OCH 2 CH 3 The group is C 3 The bond to the rest of the molecule may be through a heteroatom or a carbon atom in the heteroalkyl chain. The term "heteroalkylene" refers to the corresponding divalent radical, e.g., "C 1-6 Heteroalkylene, C 1-4 Heteroalkylene.

[0025] As used herein, the term "haloalkyl" means an alkyl substituted with one or more (e.g., 1-3) of the same or different halogen atoms, including, for example, "C 1-8 Haloalkyl", "C 1-6 Haloalkyl" and "C 1-4 "Haloalkyl" refers to haloalkyl having 1-8 carbon atoms, 1-6 carbon atoms, and 1-4 carbon atoms, respectively, e.g., -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 etc.

[0026] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which a hydrogen atom is replaced with one or more hydroxy, e.g., C 1-4 Hydroxyalkyl or C 1-3Hydroxyalkyl: examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH 3 , -C(CH 3 ) 2 Including, but not limited to, OH, etc.

[0027] As used herein, the term "alkoxy" refers to an alkyl group (as defined above) having an oxygen atom inserted at any suitable position, preferably C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 It is an alkoxy. 1-6 Representative examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, -CH 2 -OCH 3 and the like, wherein said alkoxy may be optionally substituted with one or more (eg, 1-3) of the same or different substituents.

[0028] As used herein, the term "alkyleneoxy" refers to a divalent alkoxy, e.g., -OCH 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH 2 O-, -CH 2 CH 2 O-, wherein the alkyleneoxy may be optionally substituted with one or more (eg, 1 to 3) of the same or different substituents.

[0029] As used herein, the term “alkenyl” means a linear or branched monovalent hydrocarbon radical, containing one or more double bonds and having 2-6 carbon atoms ("C 2-6 The alkenyl has, for example, -CH=CH 2 , -CH2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds according to the invention contain alkenyl, said compounds can be present in the form of pure E (entgegen), pure Z (zusammen) or any mixture thereof. The term "alkenylene" refers to the corresponding divalent radical, e.g. "C 2-6 alkenylene", "C 2-4 Alkenylene, and specific examples thereof include -CH=CH-, -CH 2 CH=CH-, -C(CH 3 )=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, and the like.

[0030] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Said alkynyl may be optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. The term "alkynylene" refers to the corresponding divalent group, such as "C 2-8 alkynylene," "C 2-6 alkynylene," "C 2-4 alkynylene, etc. [ka] and the like, and said alkynylene may be optionally substituted with one or more (eg, 1 to 3) of the same or different substituents.

[0031] As used herein, the term "fused ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.

[0032] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.

[0033] As used herein, the term "bridged ring" means a ring system formed by two or more cyclic structures sharing two atoms that are not directly bonded to each other.

[0034] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring group, including, but not limited to, monocyclic alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicycloalkyl, including spiro ring, fused or bridged ring systems (i.e., spirocycloalkyl, fused alkyl and bridged cycloalkyl, e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.). In the present invention, cycloalkyl may be optionally substituted with one or more (e.g., 1 to 3) of the same or different substituents. The carbon atom in cycloalkyl may be optionally substituted with an oxo group (i.e., forming C=O). "C 3-8 The term "cycloalkyl" refers to a cycloalkyl having 3-8 ring-forming carbon atoms, e.g., C 3-6 Cycloalkyl may be, for example, a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or may be, for example, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Fused Cycloalkyl, C 5-6Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 It may also be a bicycloalkyl, such as a fused cycloalkyl.

[0035] As used herein, the term "cycloalkoxy" means -O-cycloalkyl, where cycloalkyl is as defined above. Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0036] As used herein, the term "heterocyclic group" or "heterocycle" refers to a monocyclic or polycyclic (e.g., fused, spiro, or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, including, but not limited to, oxygen, nitrogen, and sulfur atoms, which carbon atoms and heteroatoms in the heterocyclic group may be optionally substituted with an oxo group (e.g., C=O, S(=O) or S(=O)). 2 (Forming).

[0037] As used herein, the term "4- to 11-membered heterocyclic group" means a heterocyclic group containing 4-11 ring atoms, including 4- to 10-membered heterocyclic groups, 4- to 9-membered heterocyclic groups, 4- to 8-membered heterocyclic groups, etc. , 4-7 membered heterocyclic group, 5-6 membered heterocyclic group, 3-8 membered heterocyclic group, 3-7 membered heterocyclic group, 4-7 membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered sulfur-containing heterocyclic group, etc., and the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" may each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. Illustrative examples of 4-11 membered heterocyclic groups include oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (e.g., [ka] These include, but are not limited to, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.

[0038] As used herein, the term "heterocyclic group" includes fused ring structures, and the point of attachment of the fused ring structure to another group may be on any ring of the fused ring structure. Thus, the heterocyclic group in the present invention further includes, for example, 3-7 membered (mono) heterocyclic group fused 3-7 membered (mono) heterocyclic group, 3-7 membered (mono) heterocyclic group fused (mono) cycloalkyl, 3-7 membered (mono) heterocyclic group fused C 4-6 Heterocyclic fused heterocyclic groups such as (mono)cycloalkyl, heterocyclic fused cycloalkyl, monoheterocyclic fused monoheterocyclic group, monoheterocyclic fused monocycloalkyl, illustrative examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentaazacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidyl, pyrrolidinopiperazinyl, piperidinomorpholinyl, [ka] Including, but not limited to: As used herein, the term "heterocyclic group" includes bridged heterocyclic groups and spiro heterocyclic groups.

[0039] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., one, two, three or four) heteroatoms (e.g., oxygen, nitrogen and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly bonded, including, but not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, and the like, for example: [ka] The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", and "sulfur-containing bridged heterocycle" may further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0040] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more (e.g., one, two, three or four) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) in which two or more saturated rings share one ring atom, including, but not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., such as, for example, [ka] The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle", and "sulfur-containing spiro heterocycle" may optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiro heterocycle" refers to a spiro heterocycle having a total of 6 to 10 ring atoms, at least one of which is a nitrogen atom.

[0041] In the present invention, the heterocyclic group may be condensed with an aryl to form a condensed ring structure, and examples of the condensed ring structure include: [ka] Including but not limited to:

[0042] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system. 6-12 The term "aryl (aromatic ring)" means an aryl (aromatic ring) having 6-12 carbon atoms, preferably C 6-10 Aryl (aromatic ring), preferably phenyl or naphthyl. Aryl may optionally have one or more (e.g., 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO 2 , C 1 -C 6 It may be substituted with alkyl.

[0043] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryls and bicyclic or polycyclic ring systems having at least one heteroaromatic ring (aromatic ring system having at least one heteroatom) and may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example, 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms in the heteroaryl may be optionally substituted with oxo (e.g., C=O, S(=O) or S(=O). 2 (Forming).

[0044] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" refers to a heteroaryl (heteroaromatic ring) having 5-10 (e.g., 5-6) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl" and "sulfur-containing heteroaryl" each may optionally have one or more other heteroatoms selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, as well as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered fused ring groups containing these.

[0045] As used herein, the term "heteroaryl" includes fused ring structures, and the point of attachment of said fused ring structure to other groups may be on any ring of the fused ring structure. Thus, heteroaryl in the present invention further includes (mono)heteroaryl-fused (mono)heteroaryl, (mono)heteroaryl-fused (mono)aryl, (mono)heteroaryl-fused (mono)heterocyclic group and (mono)heteroaryl-fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl-fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl-fused phenyl, 5-6 membered (mono)heteroaryl-fused 5-6 membered (mono)heterocyclic group or 5-6 membered (mono)heteroaryl-fused C 4-6 (mono)cycloalkyl (e.g., 5-6 membered heteroaryl fused cyclobutyl, 5-6 membered heteroaryl fused cyclopentyl, or 5-6 membered heteroaryl fused cyclohexyl), illustrative examples of which include indolyl, isoindolyl, indazolyl, benzimidazole, quinolyl, isoquinolyl, [ka] These include, but are not limited to: As used herein, the term “halo” or “halogen” is defined to include F, Cl, Br, or I.

[0046] The term "substituted" means the selective replacement of one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom with the specified group, provided that the substitution does not exceed the specified atom's normal valence for that case, and that such substitution results in the formation of a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0047] When a substituent is described as being "optionally substituted...," the substituent can be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) can be replaced individually and / or together with any independently selected substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) can each be replaced with any independently selected substituent.

[0048] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other groups, and thus each substituent can be the same or different from another (other) substituent.

[0049] As used herein, the term "one or more" means, under reasonable conditions, one or more than one, for example, two, three, four, five or ten. Unless otherwise specified, as used herein, the point of attachment of a substituent may be at any suitable position on the substituent. When a substituent bond is depicted as a bond connecting two atoms through a ring, then such substituent may be bonded to any ring-forming atom in that substitutable ring.

[0050] The present invention further includes all pharma- ceutically acceptable isotopically labeled compounds that are the same as the compounds of the present invention, except that one or more atoms have been replaced with an atom having the same atomic number as the compounds of the present invention, but with an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Illustrative examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H), isotopes of carbon (e.g., 11 C. 13 C and 14 C), isotopes of chlorine (e.g. 36 Cl), isotopes of fluorine (e.g. 18 F), isotopes of iodine (e.g. 123 I and 125 I), nitrogen isotopes (e.g., 13 N and 15 N), isotopes of oxygen (e.g. 15 O. 17 O and 18 O), phosphorus isotopes (e.g. 32 P), and isotopes of sulfur (e.g. 35 Certain isotopically labeled compounds of the present invention (e.g., doped with a radioactive isotope) are used in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to dope and easy to detect. 11 C. 18 F, 15 O and 13Substitution with N) is used to probe substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by analogous methods as described in the appended schemes and / or examples and preparations, substituting the appropriate isotopically labeled reagents in place of the previously used non-labeled reagents. Pharmaceutically acceptable solvates of the invention include those in which the solvent of crystallization can be isotopically substituted, e.g., D 2 O, acetone-d 6 or DMSO-d 6 Includes.

[0051] The term "stereoisomer" refers to an isomer formed by at least one asymmetric center. From compounds having one or more (e.g., one, two, three or four) asymmetric centers, exo / meso mixtures, simple enantiomers, diastereomeric mixtures and simple diastereomers can be prepared. Certain molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (usually called tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in equilibrium in solution as the following tautomers: [ka]

[0052] As will be understood, the scope of the present application thus includes all of the isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0053] In this specification, [ka] The chemical bonds of the compounds of the present invention can be drawn using a solid line. Drawing bonds to asymmetric carbon atoms using a solid line indicates the inclusion of all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, racemic mixture, etc.). Drawing bonds to asymmetric carbon atoms using a solid wedge line or a dashed wedge line indicates the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedge lines are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, it is intended that the compounds of the present invention can exist in the form of stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit one or more types of heterogeneity and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs). The present invention includes all possible crystalline forms or polymorphs of the compounds according to the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0054] Cocrystals consist of active molecules of a drug and molecules of other physiologically acceptable acids, bases, salts, or non-ionic compounds bound in the same crystal lattice by hydrogen bonds, pi-pi stacking, van der Waals forces, and other non-covalent bonds.

[0055] It should also be understood that a compound of the present invention may be present in free form for treatment, or in the form of its pharmaceutically acceptable derivative, if appropriate.In the present invention, pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salt, ester, solvate, N-oxide, metabolite or prodrug, which can directly or indirectly provide the compound of the present invention, its metabolite or residue after administration to a patient in need thereof.Therefore, when referring to the "compound of the present invention" in this specification, it is also intended to include the above-mentioned various derivative forms of the compound.

[0056] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts, such as hexafluorophosphate, meglumine salt, etc. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0057] As used herein, the term "ester" refers to an ester derived from a compound represented by each general formula in this application, including a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the compound according to the present invention as a free acid or alcohol). The compound according to the present invention may itself be an ester.

[0058] The compounds according to the invention may exist as solvates, preferably hydrates, in which the compounds according to the invention contain polar solvents that are components of the crystal lattice of said compounds, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric proportions.

[0059] Those skilled in the art should understand that not all nitrogen-containing heterocycles can form N-oxides, since nitrogen requires an available lone pair of electrons to be oxidized to an oxide. Those skilled in the art should be aware of the nitrogen-containing heterocycles that can form N-oxides. The reader should also be aware that tertiary amines can form N-oxides. Synthetic methods for producing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, oxidation of heterocycles and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. Methods for producing these N-oxides have been widely described and reviewed in the literature, for example in TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750, ARKatritzky and AJ Boulton, Eds., Academic Press, and GWH Cheeseman and ESG Werstiuk, Advances in Organic Synthesis, Vol. 1, pp 748-750. in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0060] Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in the body when the compounds of the invention are administered. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Thus, the invention includes metabolites of the compounds of the invention, including compounds prepared by a process in which a compound of the invention is contacted with a mammal for a time sufficient to produce a metabolic product thereof.

[0061] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are specific derivatives of the compounds of the present invention, which may or may not have less pharmacological activity themselves, that can be converted, for example, by hydrolysis, to the compounds of the present invention having the desired activity when administered into or onto the body. Typically, such prodrugs are functional derivatives of the aforementioned compounds that are easily converted in vivo to the desired therapeutically active compound. For further information on the use of prodrugs, see Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention are prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in Design of Prodrugs, H. Bundgaard (Elsevier, 1985)) for appropriate functional groups present in the compounds of the present invention.

[0062] The present invention further includes the compounds of the present invention having a protecting group. In any process for preparing the compounds of the present invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art. The term "about" means within ±10% of the numerical value, preferably within ±5%, and more preferably within ±2%. compound

[0063] One aspect of the present invention is a compound of formula I, a stereoisomer, tautomer, or mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or mixture thereof of said compound. In some cases, prodrugs are provided. [ka] (Of these, ring A is C 6-10 is selected from an aromatic ring and a 5- or 6-membered heteroaromatic ring; Ring B is C 3-8 is selected from cycloalkyl and 4- to 11-membered heterocyclic groups; X 1 is selected from CH and N,

[0064] R 1 is H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy), C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups and -NR 20a R 20b wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl and heterocyclic groups are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy and C 1-4 Heteroalkyl (e.g., C 1-4 alkoxy),

[0065] R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, 5-10 membered heteroaryl and -C(=O)R 21wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0066] R 3 and R 4 is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy) and C 3-6 and cycloalkyl, wherein the alkyl, heteroalkyl (e.g., alkoxy), and cycloalkyl are each optionally selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; and when m is greater than 1, two R 3 Optionally, C together with the atom to which they are attached 3-6 and / or when n is greater than 1, two R 4 Optionally, C together with the atom to which they are attached 3-6 may form a cycloalkyl or 4-10 membered heterocyclic group,

[0067] L is -O-, -S-, -S(O)-, -S(O) 2 -, -N=CR 21 -, -N(R 23a )-C(O)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6Alkenylene, C 2-6 Alkynylene, [ka] wherein the alkylene, heteroalkylene, alkenylene and alkynylene are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy) and C 3-8 or L is -N(R 23a )-and

[0068] R 5 is hydroxy, halogen, CN, NO 2 , C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR23a R 23b , -NR 23a C(=O)R 23b , -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b wherein the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups;

[0069] R 20a , R 20b , R 23a , R 23b , R 23c , R 24a , R 25a and R 25b are independently H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl or R 20a and R 20b , R 23a and R 23b or R 25a and R 25b together with the atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclic group, and the alkyl, alkoxy, cycloalkyl and and the heterocyclic group are each optionally selected from OH, CN, halogen, NO 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl and C 1-4 may be substituted with one or more substituents selected from haloalkoxy;

[0070] R 30a , R30b , R 33a , R 33b , R 34a , R 35a and R 35b are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 selected from haloalkoxy;

[0071] R 21 , R 22 , R 31 and R 32 are each independently C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each optionally selected from OH, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and u is 0, 1, 2, 3 or 4; However, ring B is a piperazine ring, and X 1 If CH, then R 2 is 4-CF 3 -pyridin-2-yl or 4-CN-pyridin-2-yl.

[0072] In one embodiment, ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring, preferably ring A is a benzene ring, a thiazole ring, a pyridine ring, a pyrazine ring or a pyrimidine ring, more preferably ring A is [ka] and X at the position marked with *. 1 is connected to the ring in which it is present, and is connected to ring B at the position marked with **.

[0073] In one embodiment, ring B is C 3-6 cycloalkyl or a 5-7 membered heterocyclic group, preferably, ring B is a piperidine ring, a piperazine ring, an azepane bridged ring or a diazepane bridged ring, more preferably, ring B is [ka] and is connected to ring A at the position marked * and to L at the position marked **. In one embodiment, X 1 is CH or N, preferably X 1 is N.

[0074] In one embodiment, R 1 is H, halogen, hydroxy, cyano group, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 and cycloalkyl and 4-10 membered heterocyclic groups, each of which may optionally be selected from hydroxy, halogen, CN, NO, 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy and C 1-4 Heteroalkyl (e.g., C 1-4 alkoxy).

[0075] In one embodiment, R 1 is C 1-4 Alkyl, 5-membered nitrogen-containing heterocyclic groups and C 1-4 Heteroalkyl (e.g., C 1-4 alkoxy), wherein the alkyl, heterocyclic and heteroalkyl (e.g., alkoxy) are each optionally selected from hydroxy, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy and C 1-3 Heteroalkyl (e.g., C 1-4 Optionally, the aryl group may be substituted with one or more substituents selected from the group consisting of aryl, ...

[0076] In one embodiment, R 1 is C 1-3 Alkyl (e.g., methyl), pyrrolidinyl (e.g., pyrrolidin-1-yl) and C 1-3 It is selected from alkoxy (eg, ethoxy).

[0077] In one embodiment, R 2 is C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl and -C(=O)R 21 wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl and C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkyl.

[0078] In one embodiment, R 2 is C 1-3 Alkyl, 5-6 membered heteroaryl and -C(=O)CH 3 wherein the alkyl and heteroaryl are each optionally selected from hydroxy, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Heteroalkyl and C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkyl.

[0079] In one embodiment, R 2 is C 1-3 Alkyl (e.g., methyl), -C(=O)CH 3 , thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl and pyridyl, each of which may optionally be selected from hydroxy, halogen, CN, C 1-3 Alkyl (e.g., methyl), C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Heteroalkyl (e.g., C 1-3 Alkoxy) and C 3-6 cycloalkyl, preferably R 2 is a methyl-substituted pyrazolyl (e.g., 5-methyl-1H-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl), a cyclopropyl-substituted pyrazolyl (e.g., 5-cyclopropyl-1H-pyrazol-3-yl) or -C(O)CH 3 It is.

[0080] In one embodiment, R 3 and R4 is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C 1-4 Alkyl and C 1-4 alkoxy, wherein the alkyl and alkoxy are each optionally selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; and when m is greater than 1, two R 3 Optionally, C together with the atom to which they are attached 3-6 and / or when n is greater than 1, two R 4 Optionally, C together with the atom to which they are attached 3-6 It may form a cycloalkyl or a 4-10 membered heterocyclic group.

[0081] In one embodiment, R 3 and R 4 is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C 1-3 Alkyl and C 1-3 alkoxy, wherein the alkyl and alkoxy are each optionally selected from halogen, CN and C 1-3 and when m is greater than 1, two R 3 Optionally, C together with the atom to which they are attached 3-6 and / or when n is greater than 1, two R 4 Optionally, C together with the atom to which they are attached 3-6 It may form a cycloalkyl or a 4-10 membered heterocyclic group.

[0082] In one embodiment, R 3 and R 4 is absent or, at each occurrence, independently F, Cl, CN, OH, C1-3 Alkyl and C 1-3 alkoxy, preferably R 3 and R 4 does not exist.

[0083] In some embodiments, L is -O-, -S-, -C(O)-, -N(R 23a )-C(O)-, -C(O)-N(R 23c )-, C 1-4 Alkylene, C 1-4 Heteroalkylene, [ka] wherein the alkylene and heteroalkylene are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy) and C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkyl.

[0084] In some embodiments, L is -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-3 Alkylene, C 1-3 Heteroalkylene, [ka] wherein the alkylene and heteroalkylene are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Heteroalkyl (e.g., C 1-3 Alkoxy) and C 3-6cycloalkyl, of which R 23a and R 23b is H or C 1-3 It is preferably alkyl.

[0085] In some embodiments, L is -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-3 Alkylene, [ka] wherein the alkylene is optionally selected from hydroxy, halogen, CN, C 1-3 Alkyl and C 1-3 Preferably, L is -CH 2 -, -CH(CH 3 )-, -O-, -C(O )-, [ka] -C(O)NH- or [ka] It is.

[0086] In certain embodiments, R 5 is hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O) 2R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b wherein the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups.

[0087] In one embodiment, R 5 is C 3-6 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, each of which is optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b Among these, the cycloalkyl, cycloa Alkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups.

[0088] In one embodiment, R 5 is C 6-10 aryl and 5-6 membered heteroaryl, each of which is optionally selected from hydroxy, halogen, CN, NO2 , C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Heteroalkyl (e.g., C 1-3 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -C(=O)R 31 , -C(=O)NR 33a R 33b and -NR 33a C(=O)R 33b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups.

[0089] In one embodiment, R 5 is selected from phenyl and 5-6 membered heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, imidazolyl or thiazolyl), wherein the phenyl and heteroaryl are each optionally selected from hydroxy, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3Heteroalkyl (e.g., C 1-3 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-8 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl, thiazolyl or cyclopentapyrazolyl), -NR 30a R 30b , -OR 31 , -C(=O)R 31 , -C(=O)NR 33a R 33b and -NR 33a C(=O)R 33b wherein the cycloalkyl, cycloalkoxy, heterocyclic and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Heteroalkyl (e.g., C 1-3 Alkoxy), C 3-6 Cycloalkyl, C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups.

[0090] In one embodiment, R 5 is selected from phenyl, pyridyl, pyrazolyl and thiazolyl, each of which is optionally selected from halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-8 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl, thiazolyl or cyclopentapyrazolyl), -NR 30aR 30b AND -OR 31 wherein the heterocyclic group and the heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 It may be substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups. 5 Optionally, halogen (e.g. For example, fluorine or chlorine), CN, C 1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Haloalkyl (e.g., trifluoromethyl), C 1-3 Alkoxy (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 Phenyl, pyridyl, pyrazolyl or thiazolyl, optionally substituted with one or more substituents selected from cycloalkoxy (e.g., cyclopropoxy) and 5-6 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl or thiazolyl), wherein the 5-6 membered heteroaryl is optionally further substituted with halogen (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl, ethyl, or isopropyl), C 1-3 Haloalkyl (e.g., fluoromethyl), C 1-3 Hydroxyalkyl (e.g., hydroxymethyl or hydroxypropyl), C 1-3 Alkoxy (e.g., methoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy (eg, cyclopropoxy or cyclobutoxy).

[0091] In one embodiment, R 5 is selected from phenyl, pyridyl, pyrazolyl and thiazolyl, each of which is optionally selected from halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-6 membered heteroaryl (e.g., pyridyl group, pyrrolyl group, furyl, pyrazolyl group, oxazolyl group, imidazolyl group or thiazolyl group), -NR 30a R 30b AND -OR 31 wherein the heterocyclic group and the heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, C 3-6 It may be substituted with one or more substituents selected from cycloalkyl and 4- to 6-membered heterocyclic groups. 5 is optionally halogen (e.g., fluorine or chlorine), CN, C 1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Haloalkyl (e.g., trifluoromethyl), C 1-3 Alkoxy (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 Phenyl, pyridyl, pyrazolyl or thiazolyl, optionally substituted with one or more substituents selected from cycloalkoxy (e.g., cyclopropoxy) and 5-membered heteroaryl (e.g., pyrazolyl, imidazolyl or thiazolyl), wherein the 5-membered heteroaryl is optionally further substituted with halogen (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl), C 1-3It may be optionally substituted with one or more substituents selected from hydroxyalkyl (eg, hydroxymethyl or hydroxypropyl).

[0092] In one embodiment, R 20a , R 20b , R 23a , R 23b , R 23c , R 24a , R 25a and R 25b are independently H, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-8 cycloalkyl or R 20a and R 20b , R 23a and R 23b , or R 25a and R 25b together with the atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclic group, said alkyl, alkoxy, cycloalkyl and heterocyclic groups each optionally containing OH, CN, halogen, NO 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl and C 1-4 It may be optionally substituted with one or more substituents selected from haloalkoxy.

[0093] In one embodiment, R 20a , R 20b , R 23a , R 23b , R 23c , R 24a , R 25a and R 25b are independently H, C 1-4 Alkyl or C 1-4 It is an alkoxy.

[0094] In one embodiment, R 23a and R 23b are independently H, C 1-3Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl or R 23a and R 23b are C together with the C atom to which they are attached. 3-6 and forming a cycloalkyl or heterocyclic group, each of said alkyl, alkoxy, cycloalkyl and heterocyclic groups optionally containing halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 It may be optionally substituted with one or more substituents selected from haloalkoxy.

[0095] In one embodiment, R 21 , R 22 , R 31 and R 32 are each independently C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic groups, each of which may optionally be selected from OH, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups. In one embodiment, R 21 , R 22 , R 31 and R 32 are each independently C 1-4 It is selected from alkyl.

[0096] In one embodiment, R 30a , R 30b , R 33a , R 33b , R 34a , R 35a and R35b are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and C 1-4 It is selected from haloalkoxy.

[0097] In one embodiment, R 30a , R 30b , R 33a , R 33b , R 34a , R 35a and R 35b are independently H and C 1-4 It is selected from alkyl. In some embodiments, m is 0. In certain embodiments, n is 0, 1 or 2. In certain embodiments, t is 0 or 1. In certain embodiments, u is 0 or 1. In one embodiment, the compounds of the present invention have the structure shown in formula IA: [ka] (Of these, R 1 and R 2 is as defined in formula I above,

[0098] R 5 is C 6-12 aryl and 5-10 membered heteroaryl, among which (1) the C 6-12 Aryl is optionally C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 membered heteroaryl, -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30aS(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33 a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkoxy, aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO. 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Cycloalkyl C 3-6 may be substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups;

[0099] R 23a , R 30a , R 30b , R 31 , R 32 , R 33a , R 33b , R 34a , R 35a and R 35b is as defined in formula I above, and R 23a is preferably H or C 1-3 It is an alkyl group.

[0100] In one embodiment, R 5 is C 6-12 aryl and 5-10 membered heteroaryl, among which (1) the C 6-12 Aryl is optionally C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 membered heteroaryl, -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkoxy, aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b may be substituted with one or more substituents selected from the following: , cycloalkoxy, heterocyclic group, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 Optionally substituted with one or more substituents selected from cycloalkyl 4-10 membered heterocyclic groups,

[0101] R 23a , R 30a , R 30b , R 31 , R 32 , R 33a , R 33b , R 34a , R 35a and R 35b is as defined in formula I above, and R 23a is preferred but C 1-3 It is an alkyl group. In certain embodiments, the compounds of the present invention have the structure shown in formula IB: [ka] (Of these, R 1 , R 2 , R 5 and R 23a is as defined in formula I above, and R 23a is preferably H or C 1-3 It is an alkyl group. In certain embodiments, the compounds of the present invention have the structure shown in formula IC. [ka]

[0102] (Of these, X 1 If CH, then R 1 , R 2 , R 5 and R 23a is as defined in formula I above, and R 23a is preferably H or C 1-3 is alkyl, and X 1 If N, then R 1 , R 2 , R 5 and R 23a is as defined in formula IA above. In one embodiment, the compounds of the present invention have the structure shown in formula ID. [ka] (Of these, R 1 , R 2 , R 23a , R 23b and t is as defined in Formula I above. and X 1 If CH, then R 5 is as defined in formula I above, and X 1 If N, then R 5 is C 6-12 aryl or 5-10 membered heteroaryl,

[0103] (i) When t is 0, the C 6-12 The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups;

[0104] (ii) When t is 1, (1) the C 6-12 Aryl is optionally hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from a cycloalkyl and a 4- to 10-membered heterocyclic group. 2 , C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O)2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; R 30a , R 30b , R 31 , R 32 , R 33a , R 33b , R 34a , R 35a and R 35b is as defined in formula I above. In certain embodiments, compounds of the invention have the structure shown in formula IE: [ka] (Of these, R 1 , R 2 , R 5 , R 23a , R 23b , X 1 and t are as defined in formula ID above.) In certain embodiments, compounds of the invention have the structure shown in formula IF. [ka] (Of these, R 1 , R 2 , R 5 , R 23a , R 23b and X 1 is as defined in the preceding paragraph under formula ID, R 4 is as defined in formula I above and is preferably C 1-3 Alkyl or C 1-3 is an alkoxy; R 23c , H, C 1-3 Alkyl or C 1-3 alkoxy, wherein the alkyl and alkoxy are each optionally selected from OH, CN, halogen, C 1-4 Alkoxy and C 1-4 hydroxyalkyl; u is 0 or 1, and n is 0 or 1.

[0105] In one embodiment, the compounds of the present invention have the structure shown in formula IG: [ka] (Of these, X 1 is CH or N, R 1 , R 2 and R 4 is as defined in formula I above, and R 4 is preferably C 1-3 Alkyl or C 1-3 is an alkoxy; n is 0 or 1, R 5 is C 6-12 aryl and 5-10 membered heteroaryl, among which (1) the C 6-12 Aryl is optionally C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 membered heteroaryl, -S(=O)R32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkoxy, aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO. 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12Aryl, 5-10 membered heteroaryl, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O) 2 R 32 , -S(=O)NR 30a R 30b , -S(=O) 2 NR 30a R 30b , -NR 30a S(=O)R 30b , -NR 30a S(=O) 2 R 30b , -C(=O)R 31 , -C(=O)NR 33a R 33b , -NR 33a C(=O)R 33b , -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO 2 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy), C 3-6 may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; R 30a , R 30b , R 31 , R 32 , R 33a , R 33b , R 34a , R 35a and R 35b is as defined in formula I above. In one embodiment, the compounds of the present invention have the structure shown in Formula I, in which: Ring A is [ka] and X at the position marked with *. 1 is connected to the ring in which it is present, and is connected to ring B at the position marked with **; Ring B is [ka] and is connected to ring A at the position marked with * and to L at the position marked with **; X 1 is N,

[0106] R 1 is C 1-3 Alkyl (e.g., methyl), pyrrolidinyl (e.g., pyrrolidin-1-yl) and C 1-3 alkoxy (e.g., ethoxy);

[0107] R 2 is a methyl-substituted pyrazolyl (e.g., 5-methyl-1H-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl), a cyclopropyl-substituted pyrazolyl (e.g., 5-cyclopropyl-1H-pyrazol-3-yl) or -C(O)CH 3 and R 3 and R 4 does not exist, L is CH 2 -, -CH(CH 3 )-, -O-, -C(O)-, [ka] -C(O)NH- or [ka] and

[0108] R 5 is optionally halogen (e.g., fluorine or chlorine), CN, C1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Haloalkyl (e.g., trifluoromethyl), C 1-3 Alkoxy (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 Phenyl, pyridyl, pyrazolyl or thiazolyl, optionally substituted with one or more substituents selected from cycloalkoxy (e.g., cyclopropoxy) and 5-6 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl or thiazolyl), wherein the 5-6 membered heteroaryl is optionally further substituted with halogen (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl, ethyl, or isopropyl), C 1-3 Haloalkyl (e.g., fluoromethyl), C 1-3 Hydroxyalkyl (e.g., hydroxymethyl or hydroxypropyl), C 1-3 Alkoxy (e.g., methoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl) and C 3-6 It may be optionally substituted with one or more substituents selected from cycloalkoxy (eg, cyclopropoxy or cyclobutoxy). The present invention encompasses any combination of the above embodiments. In one embodiment, the compound of the present invention is [ka] [ka] [ka] [ka] [ka] Including but not limited to: Manufacturing method In one embodiment, compounds of formula IA can be synthesized by the method depicted in Scheme A below. [ka]

[0109] (Of these, Hal 1 and Hal 2 are each independently F, Cl, Br or I, and preferably Hal 1 is F, Cl, Br or I, and Hal 2 is Cl, Br or I,

[0110] R 1 H, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C 1-6 Alkoxy), C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl and heterocyclic groups are each optionally selected from halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 1-4 Heteroalkyl (e.g., C 1-4 alkoxy),

[0111] R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 and selected from cycloalkyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl, each of which is optionally selected from hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C1-4 Haloalkoxy, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0112] R 23a , H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are each optionally selected from OH, CN, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl and C 1-4 may be substituted with one or more substituents selected from haloalkoxy; R 20a and R 20b is as defined in formula I above, and R 5 is as defined in formula IA above.

[0113] Compounds IA-1 and R 2 -NH 2 in the presence of a base by a substitution or coupling reaction (e.g., Buchwald reaction, Suzuki reaction, or Ullmann reaction) to produce compound IA-2.

[0114] In the substitution reaction, examples of the base that can be used include: t BuONa, t BuOk, t BuOLi, Cs 2 CO 3 , DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3and the usable solvent is, for example, t-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP, and the reaction temperature is 40° C.-140° C.

[0115] In the Buchwald reaction, usable catalysts include, for example, Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(dba) 2 , PdCl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(acac) 2 or Pd(allyl) 2 The available ligands are PPh 3 , XPhos, SPhos, RuPhos, XantPhos, Dppf, BINOL, BINAP or Pcy 3 and the like. Usable bases include, for example, t BuONa, t BuOk, t BuOLi, Cs 2 CO 3 , LiHMDS, LDA, NaHMDS, KHMDS, K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 and the usable solvent is, for example, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP, and the reaction temperature is 40° C.-140° C.

[0116] In the Suzuki reaction, usable catalysts include, for example, Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 and usable bases include, for example, Cs 2 CO 3 , K 3 PO 4 , Na2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 and usable solvents include, for example, 1,4-dioxane / H 2 O, DMF / H 2 O, DMSO / H 2 O or CH 3 CN / H 2 O and the reaction temperature is 60°C-120°C.

[0117] In the Ullmann reaction, usable catalysts include, for example, CuCl, CuBr, CuI or Cu 2 O, usable ligands are, for example, salicylaldoxime, cyclohexanediamine, N,N'-dimethylethylenediamine, TMEDA or ethylenediamine, usable bases are, for example, t BuONa, t BuOk, t B uOLi, Cs 2 CO 3 , LiHMDS, LDA, NaHMDS, KHMDS, K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 and usable solvents are, for example, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP, and the reaction temperature is 40° C.-140° C.

[0118] Step 2: reacting compounds IA-3 and IA-4 in the presence of a base to produce compound IA-5 Examples of bases that can be used include: t BuONa, t BuOk, t BuOLi, Cs 2 CO 3 , DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K 3 PO4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 Usable solvents include, for example, t-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO, or NMP. The reaction temperature is 40°C-140°C.

[0119] Step 3: Reacting compound IA-5 with a boron-containing reagent to produce compound IA-6 Usable boron-containing reagents include, for example, B 2 (pin) 2 Usable catalysts include, for example, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 or Pd(dppf) 2 Cl 2 DCM. Usable bases include, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 is 。 Usable solvents include, for example, 1,4-dioxane, DMF, DMSO, or CH 3 CN. The reaction temperature is 50℃-120℃.

[0120] Step 4: coupling compound IA-2 with IA-6 (e.g., Suzuki reaction) to produce compound IA-7 Usable catalysts include, for example, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 or Pd(dppf) 2 Cl 2 DCM. Usable bases include, for example, Cs 2 CO 3 , K 3 PO4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 is 。 Usable solvents include, for example, 1,4-dioxane, DMF, DMSO, CH 3 CN or any of the above solvents and H 2 The reaction temperature is 50° C.-120° C. Step 5: Compound IA-8 is produced by removing the protecting group from compound IA-7 under acidic conditions. Possible acids are, for example, HCl in 1,4-dioxane, HCl in EA or TFA in DCM. The reaction temperature is 0° C.-80° C. Step 6: Reductive amination of compound IA-8 with compound IA-9 to produce compound IA

[0121] Usable solvents include, for example, methanol, ethanol, THF, DCM, DCE, DMA, or mixtures of these with acetic acid in any ratio. Usable reducing agents include, for example, NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 The reaction temperature is 0° C.-80° C. In one embodiment, the reaction may be carried out in the presence of a base or an acid, and the base is, for example, TEA or DIPEA, and the acid is, for example, AcOH, HCl, or Ti(O i P) 4 It is. In certain embodiments, compounds of formula IA may be synthesized by the method depicted in Scheme B below. [ka] (Of these, Hal 2 , R 1 , R 2 , R 5 and R 23a is as defined in Scheme A above.)

[0122] Step 1: Compound IA-5 is deprotected under acidic conditions to produce compound IA-10 Possible acids are, for example, HCl in 1,4-dioxane, HCl in EA or TFA in DCM. The reaction temperature is 0° C.-80° C. Step 2: Reductive amination of compounds IA-10 and IA-9 to produce compound IA-11 Usable bases include, for example, DIPEA or TEA. Usable reducing agents include, for example, NaBH 3 CN or NaBH(OAc) 3 The solvent that can be used is, for example, MeOH, EtOH or DCE. The reaction temperature is 0°C to 80°C.

[0123] Usable solvents include, for example, methanol, ethanol, THF, DCM, DCE, DMA, or mixtures of these with acetic acid in any ratio. Usable reducing agents include, for example, NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 The reaction temperature is 0° C.-80° C. In an embodiment, the reaction may be carried out in the presence of a base or an acid, the base being, for example, TEA or DIPEA, and the acid being, for example, AcOH, HCl, or Ti(O i P) 4 It is.

[0124] Step 3: Reacting compound IA-11 with a boron-containing reagent to produce compound IA-12 Usable boron-containing reagents include, for example, B 2 (pin) 2 Usable catalysts include, for example, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 or Pd(dppf) 2 Cl 2 DCM. Usable bases include, for example, Cs 2 CO 3 , K 3 PO4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 Usable solvents include, for example, 1,4-dioxane, DMF, DMSO, or CH 3 CN. The reaction temperature is 50℃-120℃.

[0125] Step 4: coupling compound IA-12 with IA-2 (e.g., Suzuki reaction) to produce compound IA Usable catalysts include, for example, Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 or Pd(dppf) 2 Cl 2 DCM. Usable bases include, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 Usable solvents include, for example, 1,4-dioxane, DMF, DMSO, CH 3 CN or any of the above solvents and H 2 O. The reaction temperature is 50° C.-120° C. In one embodiment, the compound of formula IB can be synthesized by the method shown in Scheme C below. [ka] (Of these, Hal 1 , Hal 2 , R 1 , R 2 , R 5 , R 23a is as defined in Scheme A above.)

[0126] Compounds IB-1 and R 2 -NH 2and in the presence of a base by a substitution or coupling reaction (e.g., Buchwald reaction, Suzuki reaction, Ullmann reaction) to produce compound IB-2. The reaction conditions are as in Scheme A, Step 1 to prepare compounds of formula IA. Step 2: coupling compound IB-2 with IA-12 (e.g., Suzuki reaction) to produce compound IB The reaction conditions are as in step 4 of Scheme A to prepare compounds of formula IA. In certain embodiments, compounds of formula IC can be synthesized by the method depicted in Scheme D below. [ka] (Of these, Hal 1 , Hal 2 , R 1 , R 2 , R 5 and R 23a is as defined in Scheme A of the preceding sentence, and X 1 is selected from CH and N.

[0127] Compounds IC-1 and R 2 -NH 2 in the presence of a base by a substitution or coupling reaction (e.g., Buchwald reaction, Suzuki reaction, or Ullmann reaction) to produce compound IC-2. The reaction conditions are as in Scheme A, Step 1 to prepare compounds of formula IA. Step 2: Reacting compound IC-3 with a boron-containing reagent to produce compound IC-4 The reaction conditions are as in step 3 of Scheme A to prepare compounds of formula IA. Step 3: coupling compound IC-2 with IC-4 (e.g., Suzuki reaction) to produce compound IC-5 The reaction conditions are as in step 4 of Scheme A to prepare compounds of formula IA. Step 4: Compound IC-5 is deprotected under acidic conditions to produce compound IC-6 The reaction conditions are as in step 5 of Scheme A to prepare compounds of formula IA. Step 5: Reductive amination of compound IC-6 with IA-9 to produce compound IC The reaction conditions are as in step 6 of Scheme A to prepare compounds of formula IA. In one embodiment, compounds of formula ID can be synthesized by the method depicted in Scheme E below. [ka] (Of these, R 1 and R 2 is as defined in Scheme A above, R 5 is as defined in the preceding paragraph under formula ID,

[0128] R 23a and R 23b are independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or R 23a and R 23b form together with the C atom to which they are attached a 3-8 membered cycloalkyl or heterocyclic group, said alkyl, alkoxy, cycloalkyl and heterocyclic groups each optionally containing CN, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl and C 1-4 haloalkoxy; X 1 is selected from CH and N, and t is either 0 or 1.) Compounds IC-6 and ID-1 are subjected to a condensation reaction to produce compound ID.

[0129] Examples of the condensing agent that can be used include HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU, and PyBOP. Examples of the base that can be used include TEA, DIPEA, t BuOk, t BuONa, t BuOLi, NaH, NaOH, Cs 2 CO 3 , K 3 PO 4 or Na 2 CO 3 Usable solvents include, for example, THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH 3 CN, 1,4-dioxane or toluene. The reaction temperature is 0°C-120°C. For example, room temperature.

[0130] Alternatively, compound ID-1 is first reacted with an acylating agent to produce an acyl halide, which is then reacted with compound IC-6, optionally in the presence of a base, to produce a compound of formula ID. Examples of acylating agents that can be used include thionyl chloride or oxalyl chloride. The reaction can also be carried out under a small amount of DMF catalysis. Examples of bases that can be used include TEA or DIPEA. Examples of solvents that can be used include THF, DCM, DCE, CH 3 CN, 1,4-dioxane or toluene. The reaction temperature is 0°C-100°C. In one embodiment, compounds of formula IE can be synthesized by the method depicted in Scheme F below. [ka] (Of these, R 1 , R 2 , R 5 , R 23a , R 23b and t is as defined in Scheme E above; X1 is selected from CH and N, and Hal 2 is F, Cl, Br or I, preferably Hal 2 is Cl, Br or I. Step 1: coupling compound IC-2 with IA-6 (e.g., Suzuki reaction) to produce compound IE-1 The reaction conditions are the same as those of step 4 in scheme A for preparing the compound of formula IA. Step 2: Compound IE-2 is prepared by removing the protecting group from compound IE-1 under acidic conditions. The reaction conditions are the same as those of step 5 in scheme A for preparing the compound of formula IA. Step 3: condensation reaction of compound IE-2 with ID-1 to produce compound IE The reaction conditions are as in Scheme E to prepare compounds of formula ID. In certain embodiments, compounds of formula IF can be synthesized by the method depicted in Scheme G below. [ka] (Of these, R 1 , R 2 , R 23a , R 23b and R 5 is as defined in Scheme E above, X 1 is selected from CH and N,

[0131] R 4 is absent or is hydroxy, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Heteroalkyl (e.g., C 1-6 alkoxy),

[0132] R 23c , H, C 1-3 Alkyl or C 1-3and alkoxy, wherein the alkyl and alkoxy are each optionally selected from OH, CN, halogen, C 1-4 Alkoxy and C 1-4 hydroxyalkyl; Hal 2 is F, Cl, Br or I, preferably Hal 2 is Cl, Br or I, u is 0 or 1, and n is 0 or 1. Step 1: coupling compound IC-2 with IF-1 (e.g., Suzuki reaction) to produce compound IF-2 The reaction conditions are as in step 4 of scheme A for preparing the compound of formula IA. Step 2: Condensation reaction of compound IF-3 with an amine to produce compound IF-4 The reaction conditions are as in Scheme E to produce compounds of formula ID. Step 3: Compound IF-4 is deprotected under acidic conditions to produce compound IF-5 The reaction conditions are as in step 5 of scheme A for preparing the compound of formula IA. Step 4: Compound IF is prepared by nucleophilic substitution reaction of compounds IF-2 and IF-5 in the presence of a base. The reaction conditions are as in step 2 of Scheme A for preparing the compound of formula IA. In one embodiment, the compound of formula IG can be synthesized by the method shown in Scheme H below. [ka] (Of these, R 1 and R 2 is as defined in Scheme A above, X 1 is selected from CH and N, R 4 , H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 heteroalkyl; R 5 is as defined in formula IG above, and n is 0 or 1.

[0133] Compounds IG-1 and R 5 Step 1: Mitsunobu reaction with -OH to produce compound IG-2 Usable reaction reagents include, for example, PPh 3 , PMe 3 , DIAD, DEAD or DBAD. Usable solvents include aprotic solvents such as THF, ethyl ether, DCM, DMF or toluene. The reaction temperature is -20°C to 100°C, for example, room temperature.

[0134] Step 2: Compound IG-3 is produced by removing the protecting group from compound IG-2 under acidic conditions. The acid that can be used is, for example, a solution of HCl in 1,4-dioxane, a solution of HCl in EA, or a solution of TFA in DCM, or the reaction is carried out in a mixture of a solution of the acid and any solvent selected from, for example, THF, MeOH, and EtOH. The reaction temperature is 0° C.-80° C. Step 3: Compound IF-2 and IG-3 are subjected to a nucleophilic substitution reaction in the presence of a base to produce compound IG. The reaction conditions are as in step 2 of Scheme A to prepare the compound of formula IA. Drug Compositions, Formulations and Methods of Treatment

[0135] In one embodiment, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition may further comprise one or more pharma- ceutically acceptable carriers.

[0136] In some embodiments, the present invention provides a pharmaceutical formulation, which is preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gas formulation. In some embodiments, the pharmaceutical composition may also include one or more other therapeutic agents. In certain embodiments, the drug composition or formulation is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.

[0137] In one embodiment, the present invention provides the use of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a drug composition as described above, or a drug formulation according to the present invention, in the manufacture of a medicament for preventing or treating a disease or condition associated with RET activity.

[0138] In one embodiment, the present invention provides the use of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a drug composition as described above, or a drug formulation according to the present invention, in the manufacture of a medicament for modulating (e.g., decreasing or inhibiting) RET activity.

[0139] In one embodiment, the present invention provides a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation according to the present invention, for preventing or treating a disease or condition associated with RET activity.

[0140] In one embodiment, the present invention provides a method for preventing or treating a disease or condition related to RET activity, the method comprising administering to an individual in need thereof an effective amount of a compound according to the present invention, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a drug composition as described above, or a drug formulation according to the present invention. In one embodiment, the disease or condition associated with RET activity is preferably cancer, tumor, or irritable bowel syndrome.

[0141] In certain embodiments, the cancer or tumor is more preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), colon cancer, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.

[0142] As used herein, a "pharmaceutical acceptable carrier" means a diluent, adjuvant, excipient, or vehicle with which a therapeutic is administered that is compatible, within the scope of reasonable medical judgment, with contact with the tissues of humans and / or other animals and does not present excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0143] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharma- ceutically acceptable carriers are, for example, those described in Remington's Pharmaceutical Sciences (1990). The pharmaceutical compositions according to the invention can act systemically and / or locally and for this purpose they can be administered by any suitable route. In these administration routes, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form. As used herein, the term "effective amount" refers to an amount that, upon administration, reduces the severity of one or more of the diseases being treated. Refers to the amount of a compound that relieves some symptoms to some extent.

[0144] Dosage regimens may be adjusted to provide the best desired response. For example, a single injection may be administered, or several doses may be administered over time, or the dosage may be proportionally increased or decreased according to the exigencies of the therapeutic situation. As noted, dosage values ​​vary with the type and severity of the condition to be alleviated, and may include single or multiple administrations. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0145] The amount of the compound of the present invention administered depends on the individual being treated, the severity of the disease or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician. In general, an effective dosage is about 0.0001 to about 50 mg per kg of body weight per day. In some cases, a dosage not exceeding the lower limit of the above range may be sufficient, while in other cases, a larger dosage may be used without causing adverse side effects, provided that the larger dosage is divided into several smaller dosages to be administered throughout the day. The compound of the present invention may be contained or used in a pharmaceutical composition in an amount of about 0.01 mg to about 1000 mg.

[0146] Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating or inhibiting the progression of the disease or condition to which the term applies, or one or more symptoms of such disease or condition, or preventing such disease or condition, or one or more symptoms of such disease or condition.

[0147] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease as described hereinabove) or normal individuals. In the present invention, a "non-human animal" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, including, for example, non-human primates, domestic and / or farm animals (e.g., sheep, dogs, cats, dairy cows, pigs, etc.).

[0148] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more other therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or neoplastic diseases). In some embodiments, the methods of the present invention may further comprise administering one or more other therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or neoplastic diseases). Working Example The present invention will be further described below in combination with examples, but the presentation of these examples is not intended to limit the scope of the present invention. The abbreviations used herein have the following meanings:

number

number

[0149] The compounds of the present invention can be isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC, and / or flash column chromatography, and their structures are 1 The reaction was confirmed by 1 H NMR and / or MS. Reaction monitoring was performed by TLC or LC-MS. 1H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model no. AVACE III HD 400MHz) was adopted. The LC / MS used was Aglient 1260 Infinity / Aglient 6120 Quadrupole. TLC used silica gel GF254 as the stationary phase.

[0150] Column chromatography typically used 200–300 mesh silica gel (Qingdao Haiyang Chemical Co., Ltd) as the stationary phase. Flash column chromatography was performed using a Biotage flash column chromatograph. Prep-HPLC was performed using Agilent 1260, Waters 2489 and A GeLai 3500 model chromatograph was used. Microwave reactions were carried out using a Biotage Initiator microwave reactor. In the following examples, unless otherwise specified, reaction temperatures are room temperature (15-30° C.).

[0151] Reagents used herein were purchased from companies such as Acros Organics, Aldrich Chemical Company or Topbiochem Technology Co., Ltd.

[0152] Example 1: 2-(6-(6-benzyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 1) [ka] Step 1: Preparation of tert-butyl 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 1c)

[0153] Compounds 1a (1.50 g) and 1b (1.77 g) were added sequentially to a 100 mL single-neck flask, followed by DMSO (20.0 mL) and K2 CO 3 (5.83 g) was added in order, and the mixture was heated to 90° C. under nitrogen protection and stirred for 20 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel flash column chromatography (PE:EA=5:1) to obtain compound 1c (2.03 g). MS m / z (ESI): 354.1 [M+H] + .

[0154] Step 2: Preparation of tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 1d)

[0155] Compound 1c (2.03g), B 2 (pin) 2- (4.01g), KOAc (1.55g ), 1,4-dioxane (15.0 mL) and Pd(dppf)Cl 2 ·DCM (644.67 mg) were added in sequence to a 100 mL one-neck flask and the reaction was heated to 90 °C under nitrogen protection. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel flash. The product was separated and purified by column chromatography (DCM:MeOH=15:1) to give compound 1d (2.11 g). MS m / z (ESI): 402.3 [M+H] + .

[0156] Step 3: Preparation of tert-butyl 3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Compound 1f)

[0157] Compound 1e (950 mg) was dissolved in 1,4-dioxane (50.0 mL), and compound 1d (2.11 g) and Cs were added in that order. 2 CO 3 (3.15 g) and water (5.0 mL) were added, followed by Pd(dppf)Cl 2 Add DCM (477.83mg) and heat to 90℃ under nitrogen protection for 14h. After completion of the reaction, cool the reaction solution to room temperature, dilute with water (100mL) and extract with EA (60mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain compound 1f (587.0mg). MS m / z (ESI): 463.3[M+H] + .

[0158] Step 4: Preparation of 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1g)

[0159] Compound 1f (1.36 g) was dissolved in DCM (20.0 mL), and TFA (20.0 mL) was added. The reaction was carried out under nitrogen protection at room temperature. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the mixture was separated and purified by Prep-HPLC to obtain the trifluoroacetate salt of compound 1g (587.0 mg). MS m / z (ESI): 363.3 [M+H] + .

[0160] Step 5: Preparation of 2-(6-(6-benzyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1)

[0161] The trifluoroacetate salt of compound 1g (31.58 mg) and compound 1h (27.74 mg) were dissolved in MeOH (0.5 mL), and TEA (8.46 mg) and sodium cyanoborohydride (26.27 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 1 (11.0 mg). MS m / z (ESI): 453.2 [M+H] + .

[0162] 1 H NMR (400MHz, DMSO-d 6 )δ12.15(br,1H),9.67(s,1H),9.12(d,J=2.4Hz,1H),8.44(dd,J=8.8,2.4Hz,1H),7.43-7.21(m,5H),6.78(d,J =8.8Hz,2H),6.30(br,1H),3.98-3.57(m,8H),2.72-2.61(m,1H),2.33(s,3H),2.24(s,3H),1.72-1.64(m,1H).

[0163] Example 2: 2-(6-(6-(4-Methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 2) [ka]

[0164] The trifluoroacetate salt of compound 1g (30.0 mg) and compound 2a (33.81 mg) were dissolved in MeOH (0.5 mL), and TEA (8.12 mg) and sodium cyanoborohydride (25.21 mg) were added in turn, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 2 (15.0 mg). MS m / z (ESI): 483.3 [M+H] + .

[0165] 1H NMR (400MHz, DMSO-d 6 )δ12.14(br,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),7.26(d,J=8.8Hz,2H),6.88-6.76(m,4H) ),6.30(br,1H),3.79-3.72(m,7H),3.58-3.53(m,4H),2.59-2.55(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0166] Example 3: 2-(6-(6-((6-chloropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 3) [ka]

[0167] The trifluoroacetate salt of compound 1g (30.0 mg) and compound 3a (35.15 mg) were dissolved in MeOH (0.5 mL), and TEA (8.12 mg) and sodium cyanoborohydride (25.21 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by Prep-HPLC to obtain compound 3 (20.0 mg). MS m / z (ESI): 488.2 [M+H] + .

[0168] 1 H NMR (400MHz, DMSO-d 6 )δ12.12(br,1H),9.67(s,1H),9.11(d,J=2.0Hz,1H),8.46-8.42(m,2H),7.87-7.80(m,1H),7.50-7.47(m,1H),6. 80-6.77(m,2H),6.31(br,1H),4.01-3.52(m,8H),2.66-2.57(m,1H),2.33(s,3H),2.26(s,3H),1.69-1.62(m,1H).

[0169] Example 4: 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 4) [ka] Step 1: Preparation of 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 4a)

[0170] Compound 1c (460.0 mg) was dissolved in DCM (5.0 mL) under nitrogen protection, TFA (5.0 mL) was added, and the mixture was reacted at room temperature for 2 h until the raw material was completely converted. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, washed with saturated sodium carbonate solution, extracted with DCM (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4a (250.0 mg). MS m / z (ESI): 254.0 [M + H] + .

[0171] Step 2: Preparation of 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (compound 4c)

[0172] Compounds 4a (250.0 mg) and 4b (275.0 mg) were dissolved in DCE (5.0 mL) and diluted with NaBH(OAc) 3 (1.06 g) was added and reacted at room temperature for 10 h. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (PE:EA = 10:1-1:3) to obtain compound 4c (320.0 mg). MS m / z (ESI): 375.1 [M + H] + .

[0173] Step 3: Preparation of 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 4d)

[0174] Compound 4c (332.0 mg) was dissolved in 1,4-dioxane (5.0 mL) and then 2 (pin) 2 (619.76 mg) and KOAc (237.11 mg) were added, and Pd(dppf)Cl was added under the protection of nitrogen. 2 DCM (99.65 mg) was added and heated to 90°C for 4h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (DCM:MeOH = 10:1) to obtain compound 4d (320.0 mg). MS m / z (ESI): 423.3 [M+H] + .

[0175] Step 4: 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6 - Preparation of diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 4)

[0176] Compound 4d (129.8 mg) was dissolved in 1,4-dioxane (5.0 mL), and then compound 1e (55 mg) and Cs were added. 2 CO 3 (149 mg) and water (5.0 mL), and then cooled to 100° C. under the protection of nitrogen. 2DCM (27.93 mg) was added and heated to 90°C for 5 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 4 (18.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0177] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1 H),8.07(d,J=2.0Hz,1H),7.68(dd,J=8.4,2.4Hz,1H),6.78-6.75(m,3H),6.30 (br,1H),3.82(s,3H),3.74(d,J=11.6Hz,2H),3.66(d,J=6.0Hz,2H),3.61-3. 45(m,4H),2.53-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.57(d,J=8.0Hz,1H).

[0178] Example 5: 2-(6-(6-((5-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 18) [ka]

[0179] Compound 1g trifluoroacetate (35.00 mg) and compound 18a (27.75 mg) were added to methanol (1.0 mL), and triethylamine (6.83 mg) and sodium cyanoborohydride (17.00 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 18 (6.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0180] 1 H NMR (400MHz, DMSO-d 6 )δ12.13(br,1H),9.65(s,1H),9.12(d,J=2.2Hz,1H),8.43(dd,J=8.92,2.32Hz,1H),8.21(s,1H),8.16-8.12(m,2H),7.35-7.31(m ,1H),6.77(d,J=9.0Hz,1H),6.31(br,1H),3.81(s,3H),3.78-3.69(m,4H),3.59(br,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3 H), 1.59 (d, J = 8.36 Hz, 1H).

[0181] Example 6: 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 17) [ka] Step 1: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 17a)

[0182] Compound 8c (2.0 g), hydrochloride salt of 91a (1.58 g) and potassium carbonate (4.45 g) were added in order to DMF (15 mL) and heated to 80° C. and stirred for 14 h. The reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (50 mL×2). The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated and purified by silica gel flash column chromatography (PE:EA=10:1) to obtain compound 17a (0.81 g). MS m / z (ESI): 192.1 [M+H] + .

[0183] Step 2: Preparation of 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 17)

[0184] The trifluoroacetate salt of compound 1g (22.82 mg) and compound 17a (27.47 mg) were added to methanol (1.0 mL), triethylamine (4.45 mg) and sodium cyanoborohydride (13.86 mg) were added in order, and the reaction was carried out at room temperature for 14 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by Prep-HPLC to obtain compound 17 (7.0 mg). MS m / z (ESI): 538.3 [M+H] + .

[0185] 1 H NMR (400MHz, DMSO-d 6)δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.16Hz,1H),8.67(dd,J=4.54,0.64Hz,1H),8.4 3(dd,J=8.94,2.28Hz,1H),8.41(d,J=1.68,1H),7.98(dd,J=8.48Hz,2.121H),7.92(d,J =4.28,1H),7.87(d,J=8.4,1H),6.78(d,J=9.0Hz,2H),6.31(br,1H),3.78-3.71(m,4H), 3.68-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.36Hz,1H).

[0186] Example 7: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 16) [ka]

[0187] The trifluoroacetate salt of compound 1g (35.0 mg) and compound 16a (35.1 mg) were added to methanol (0.5 mL), and triethylamine (9.5 mg) and sodium cyanoborohydride (29.4 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 16 (15.0 mg). MS m / z (ESI): 468.2 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz ,1H),8.38(s,1H),7.63(dd,J=7.6,1.6Hz,1H),7.18(d,J=8.0Hz,1H),6.77 (d,J=8.8Hz,2H),6.29(br,1H),3.83-3.64(m,4H),3.63-3.45(m,4H),2.57 -2.52(m,1H),2.43(s,3H),2.33(s,3H),2.26(s,3H),1.58(d,J=8.0Hz,1H).

[0189] Example 8: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((2-methylthiazol-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 15) [ka]

[0190] The trifluoroacetate salt of compound 1g (35.0 mg) and compound 15a (36.8 mg) were added to methanol (0.5 mL), and triethylamine (9.5 mg) and sodium cyanoborohydride (29.4 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 15 (16.0 mg). MS m / z (ESI): 474.2 [M+H] + .

[0191] 1 H NMR (400MHz, DMSO-d 6)δ12.19(br,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),8.17(s,1H),7.46(s,1H),6.76(d,J=8.8Hz,1H),6 .29(br,1H),3.78-3.66(m,6H),3.64-3.51(m,2H),2.59(s,3H),2.49-2.44(m,1H),2.33(s,3H),2.25(s,3H),1.57(d,J=8.4Hz,1H).

[0192] Example 9: 2-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 49) [ka]

[0193] Step 1: Preparation of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (compound 49b)

[0194] In a reaction bottle, compound 49a (2.00 g), B 2 (pin) 2 (4.09 g), KOAc (1.58 g), 1,4-dioxane (15.0 mL) and Pd(dppf)Cl 2 ·DCM (657.43mg) was added, and the mixture was heated to 90℃ under nitrogen protection for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30mL), and extracted with EA (40mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel flash column chromatography (DCM:MeOH=15:1) to obtain compound 49b (2.77g). MS m / z (ESI): 390.3[M+H] + .

[0195] Step 2: Preparation of tert-butyl 4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazine-1-carboxylate (compound 49c)

[0196] Compound 1e (1.30 g) was dissolved in 1,4-dioxane (50.0 mL), and then compound 49b (2.80 g) and Cs were added. 2 CO 3 (3.44 g) and water (2.0 mL) were added, Furthermore, Pd(dppf)Cl 2 Add DCM (647.3mg) and heat to 90℃ under nitrogen protection for 4 hours. After completion of the reaction, cool the reaction solution to room temperature, add water (100mL) to dilute, and extract with EA (60mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 49c (587.0mg). MS m / z (ESI): 451.3[M+H] + .

[0197] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine (compound 49d)

[0198] Compound 49c (2.7 g) was dissolved in DCM (20.0 mL), and TFA (20.0 mL) was added. The mixture was reacted at room temperature for 4 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the mixture was separated and purified by Prep-HPLC to obtain the trifluoroacetate salt of compound 49d (761.0 mg). MS m / z (ESI): 351.2 [M+H] + .

[0199] Step 4: Preparation of 2-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 49)

[0200] The trifluoroacetate salt of compound 49d (35.0 mg) and compound 4b (38.9 mg) were added to methanol (0.5 mL), and triethylamine (9.3 mg) and sodium cyanoborohydride (28.8 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 49 (25.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0201] 1 H NMR (400MHz, DMSO-d 6 )δ12.20(br,1H),9.65(s,1H),9.03(d,J=2.4Hz,1H),8.36(dd,J=8.8,2.0Hz,1H),8.09(d,J=2.0Hz,1H),7.68(dd,J=8.4,2.4Hz, 1H),6.94-6.78(m,3H),6.29(br,1H),3.84(s,3H),3.64-3.56(m,4H),3.49(s,2H),2.49-2.44(m,4H),2.31(s,3H),2.24(s,3H).

[0202] Example 10: 2-(6-(4-(4-Methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 23) [ka]

[0203] The trifluoroacetate salt of compound 49d (35.0 mg) and compound 2a (38.9 mg) was added to methanol (0.5 mL), and then triethylamine (9.3 mg) and sodium cyanoborohydride (28.8 mg) were added in order, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 23 (18.0 mg). MS m / z (ESI): 471.3 [M+H] + .

[0204] 1 H NMR (CD 3 OD,400MHz)δ9.07(d,J=2.4Hz,1H),8.45(dd,J=8.8,2.4Hz,1H),8.28(s,1H),7.42-7.35(m,2H),7.02-6.9 2(m,3H),6.76(s,1H),6.26(s,1H),3.99(s,2H),3.82(s,7H),3.08-3.00(m,4H),2.40(s,3H),2.31(s,3H).

[0205] Example 11: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((4-methylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 21) [ka]

[0206] The trifluoroacetate salt of compound 1g (35.0 mg) and compound 21a (27.52 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.08 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 21 (10.0 mg). MS m / z (ESI): 468.3 [M+H] + .

[0207] 1 H NMR (400MHz, DMSO-d 6)δ11.93(s,1H),9.61(s,1H),9.07(d,J=1.2Hz,1H),8.39(dd,J=8.8,2.2Hz,1H ),8.35(s,1H),8.25(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),7.01-6.63(m,2H) ,6.27(br,1H),3.82-3.69(m,2H),3.63(d,J=6.4Hz,2H),3.59-3.42(m,4H),2. 52-2.46(m,1H),2.28(s,3H),2.25(s,3H),2.21(s,3H),1.53(d,J=8.4Hz,1H).

[0208] Example 12: 2-(6-(6-(2-fluoro-5-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 96) [ka]

[0209] The trifluoroacetate salt of compound 1g (30.0 mg) and compound 96a (19.41 mg) were dissolved in MeOH (0.5 mL), and TEA (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence and reacted at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by Prep-HPLC to obtain compound 96 (10.0 mg). MS m / z (ESI): 501.2 [M+H] + .

[0210] 1 H NMR (400MHz, DMSO-d 6)δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.43(dd,J=9.2,2.4Hz,1H),7.06(t,J=9.2Hz,1H),7.03-7.00(m,1H),6.83-6.78(m,1H) ),7.03-6.64(m,2H),6.32(br,1H),3.77-3.71(m,7H),3.58-3.53(m,4 H),2.58-2.53(m,1H),2.33(s,3H),2.25(s,3H),1.58(d,J=8.4Hz,1H).

[0211] Example 13: (6-Methoxypyridin-3-yl)(4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazin-1-yl)ketone (Compound 110) [ka]

[0212] Compound 110a (16.5 mg), HATU (53.2 mg) and DIPEA (41.7 mg) were added to DMF (3.0 mL) and reacted at room temperature for 5 min. Then, trifluoroacetate salt of compound 49d (50.0 mg) was added and reacted at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with EA, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 110 (19.0 mg). MS m / z (ESI): 486.3 [M+H] + .

[0213] 1 H NMR (400MHz, DMSO-d 6 )δ12.01(br,1H),9.69(s,1H),9.08(d,J=2.2Hz,1H),8.41(dd,J=9.0,2.3Hz,1H), 8.34(d,J=2.1Hz,1H),7.84(dd,J=8.5,2.3Hz,1H),7.12-6.63(m,3H),6.30(s,1H), 3.92(s,3H),3.72(s,8H),2.34(s,3H),2.26(s,3H).

[0214] Example 14: 2-(6-Methoxypyridin-3-yl)-1-(4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one (Compound 111) [ka]

[0215] Compound 111a (18.0 mg), HATU (53.2 mg) and DIPEA (41.7 mg) were added to DMF (3.0 mL) and reacted at room temperature for 5 min. Then, trifluoroacetate salt of compound 49d (50.0 mg) was added and reacted at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with EA, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 111 (6.0 mg). MS m / z (ESI): 500.3 [M+H] + .

[0216] 1 H NMR (400MHz, DMSO-d 6 )δ12.02(br,1H),9.68(s,1H),9.06(d,J=2.3Hz,1H),8.39(dd,J=9.0,2.3Hz,1H),8.02(d,J=2.2Hz,1H),7.56(dd,J=8.5,2.4Hz,1 H),6.94(d,J=9.0Hz,1H),6.90-6.69(m,2H),6.27(s,1H),3.83(s,3H),3.74(s,2H),3.70-3.59(m,8H),2.32(s,3H),2.25(s,3H).

[0217] Example 15: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(4-methylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 80) [ka]

[0218] The trifluoroacetate salt of compound 1g (30 mg) and compound 80a (22.70 mg) were added to methanol (0.5 mL), and triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 80 (10.0 mg). MS m / z (ESI): 467.3 [M+ H] + .

[0219] 1 H NMR (400MHz, DMSO-d 6 )δ12.16(s,1H),9.66(s,1H),9.11(d,J=2.2Hz,1H),8.43(dd,J=8.9,2.3Hz,1H),7.22(d,J=7.9Hz,2H),7.11(d,J=7.9Hz,2H),6.76(d,J=9.0 Hz,2H),6.31(br,1H),3.78-3.65(m,4H),3.64-3.49(m,4H),2.60-2.4 9(m,1H),2.33(s,3H),2.27(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0220] Example 16: 5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-2-cyanopyridine (compound 117) [ka]

[0221] Compound 1g trifluoroacetate (30 mg) and compound 117a (24.96 mg) were added to methanol (0.5 mL), and triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 117 (2.0 mg). MS m / z (ESI): 479.2 [M+H] + .

[0222] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.2Hz,1H),8.74(d,J=1.2Hz,1H),8.43(dd,J=8.9,2.3Hz,1H),8.01(dt,J=17.2,5.0Hz,2H),6.77 (d,J=9.0Hz,2H),6.32(br,1H),3.81-3.66(m,6H),3.65-3.52(m,2H),2.61-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.4Hz,1H).

[0223] Example 17: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 118) [ka]

[0224] The trifluoroacetate salt of compound 1g (30 mg) and compound 118a (43.48 mg) were added to methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 118 (6.0 mg). MS m / z (ESI): 522.3 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.74(s,1H),8.43(dd,J=8.9,2.3Hz,1H),8.06(d,J=7.1Hz,1H),7.84(d,J=8.1Hz,1H),6 .77(d,J=9.0Hz,2H),6.30(br,1H),3.84-3.65(m,6H),3.60-3.48(m,2 H),2.61-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.61(d,J=8.4Hz,1H).

[0226] Example 18: 6-Methyl-2-(6-(6-((6-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 62) [ka]

[0227] The trifluoroacetate salt of compound 1g (30 mg) and compound 62a (46.49 mg, except that 4-fluoropyrazole was replaced with 4-methylpyrazole, the rest was prepared according to the synthesis method of compound 17a in Example 6) were added to methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in turn, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 62 (6.0 mg). MS m / z (ESI): 534.2 [M+H] + .

[0228] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.2Hz,1H),8.44(dd,J=8.9,2.3Hz,1H ),8.37(m,2H),7.93(dd,J=8.5,2.2Hz,1H),7.82(d,J=8.4Hz,1H),7.62(s,1H) ,6.78(d,J=9.0Hz,2H),6.30(br,1H),3.83-3.67(m,4H),3.66-3.50(m,4H),2. 60-2.52(m,1H),2.33(s,3H),2.26(s,3H),2.11(s,3H),1.59(d,J=8.4Hz,1H).

[0229] Example 19: 2-(6-(6-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 60) [ka]

[0230] The trifluoroacetate salt of compound 1g (30 mg) and compound 60a (43.00 mg) were added to methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 60 (11.0 mg). MS m / z (ESI): 520.2 [M+H] + .

[0231] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.59(dd,J=2.6,0.5Hz,1H),8.46-8.42(dd, J=8.8,2.4Hz,1H),8.41-8.39(d,J=2.0Hz,1H),7.97(dd,J=8.4,2.2Hz,1H),7.88(d,J=8.4Hz,1H) ,7.81(d,J=1.0Hz,1H),6.78(d,J=9.0Hz,2H),6.56(dd,J=2.5,1.7Hz,1H),6.29(br,1H),3.82-3. 68(m,4H),3.67-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0232] Example 20: 2-(6-(6-((5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 98) [ka]

[0233] Compound 1g trifluoroacetate (35.0 mg) and compound 98a (36.24 mg) were added to methanol (0.5 mL), and triethylamine (9.77 mg) and sodium cyanoborohydride (30.34 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 98 (15.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0234] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(br,1H),9.66(s,1H),9.12(d,J=2.2Hz,1H),8.45-8.41(m,3H),7.73-7.65(m,1H),6.77(d,J=9.0Hz,2H),6.29(br,1H) ,3.74(t,J=8.7Hz,4H),3.64(s,2H),3.58(d,J=6.5Hz,2H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0235] Example 21: 2-(6-(6-((5-chloropyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 69) [ka]

[0236] Compound 1g trifluoroacetate (35.0 mg) and compound 69a (41.0 mg) were added to methanol (0.5 mL), and triethylamine (9.77 mg) and sodium cyanoborohydride (30.34 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 69 (16.0 mg). MS m / z (ESI): 488.2 [M+H] + .

[0237] 1 H NMR (400MHz, DMSO-d 6 )δ12.01(br,1H),9.66(s,1H),9.11(d,J=2.2Hz,1H),8.50(d,J=2.3Hz,1H),8.43(dd,J=8.9,2.3Hz,1H),7.89(dd,J=8 .4,2.5Hz,1H),7.52(d,J=8.4Hz,1H),6.76(d,J=9.0Hz,2H),6.30(s,1H),3.79(d,J=11.7Hz,2H),3.73(d,J=5.9 Hz,2H),3.65(s,2H),3.57(d,J=10.0Hz,3H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0238] Example 22: 2-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 67) [ka]

[0239] Compound 1g trifluoroacetate (30 mg) and compound 67a (25.90 mg) were added to methanol (0.5 mL), and triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 67 (10.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d 6))δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.1Hz,1H),8.43(dd,J=8.9,2.3Hz,1H ),8.16(dd,J=2.8,0.6Hz,1H),7.39(d,J=8.3Hz,1H),7.35(dd,J=8.6,2.9Hz,1H), 6.76(d,J=9.0Hz,2H),6.30(s,1H),3.85-3.77(m,5H),3.69(d,J=5.9Hz,2H),3.60 -3.47(m,4H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.58(d,J=8.4Hz,1H).

[0241] Example 23: 2-(6-(6-(4-ethoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 41) [ka]

[0242] Compound 1g trifluoroacetate (30 mg) and compound 41a (28.37 mg) were added to methanol (0.5 mL), and triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 41 (15.0 mg). MS m / z (ESI): 497.3 [M+H] + .

[0243] 1 H NMR (400MHz, DMSO-d 6)δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz ,1H),7.22(d,J=8.8Hz,2H),6.88-6.76(m,4H),6.32(br,1H),3.98(q,J=6.9 Hz,2H),3.68(dd,J=30.7,8.6Hz,4H),3.51(d,J=30.4Hz,4H),2.59-2.55(m, 1H),2.33(s,3H),2.26(s,3H),1.56(d,J=8.3Hz,1H),1.31(t,J=7.0Hz,3H).

[0244] Example 24: 2-(6-(6-(1-(4-methoxyphenyl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 50) [ka]

[0245] Compound 1g trifluoroacetate (30 mg) and compound 50a (28.37 mg) were added to methanol (0.5 mL), and triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 50 (15.0 mg). MS m / z (ESI): 497.3 [M+H] + .

[0246] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.63(s,1H),9.11(d,J=2.1Hz,1H),8.42(dd,J=8.9,2.2H z,1H),7.25(d,J=8.6Hz,2H),7.02-6.57(m,4H),6.30(br,1H),3.97-3.77( m,2H),3.72(s,3H),3.67-3.50(m,2H),3.50-3.36(m,2H),2.49-2.39(m,2 H),2.33(s,3H),2.26(s,3H),1.51(d,J=8.3Hz,1H),1.12(d,J=6.2Hz,3H).

[0247] Example 25: 2-(6-(6-(4-fluorobenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 83) [ka]

[0248] Compound 1g trifluoroacetate (35.0 mg) and compound 83a (18.2 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 83 (26.0 mg). MS m / z (ESI): 471.2 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.64(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=9.2,2.4Hz,1H),7.93-7.35(m,2H),7.13-7.09(m,2H),6.83(br,1H),6.76 (d,J=9.2Hz,1H),6.30(br,1H),3.74-3.66(m,4H),3.62-3.53(m,4H),2.55-2.52(m,1H),2.32(s,3H),2.25(s,3H),1.57(d,J=8.4Hz,1H).

[0250] Example 26: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(4-(trifluoromethyl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 84) [ka]

[0251] Compound 1g trifluoroacetate (35.0 mg) and compound 84a (25.6 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 84 (17.0 mg). MS m / z (ESI): 521.2 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d 6 )δ11.90(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=8.8,2.4Hz,1H),7.66(d,J=8.0,2H),7.58(d,J=8.4, 2H),6.94(br,1H),6.76(d,J=9.2Hz,1H),6.30(br,1H),3.74-3.57(m,8H),2.57-2.55(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0253] Example 27: 4-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)benzonitrile (compound 85) [ka]

[0254] Compound 1g trifluoroacetate (35.0 mg) and compound 85a (19.3 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 85 (12.0 mg). MS m / z (ESI): 478.2 [M+H] + .

[0255] 1 H NMR (400MHz, DMSO-d 6 )δ12.08(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=9.2,2.4Hz,1H),7.77(d,J=8.4,2H),7.56(d,J=8.0,2H),6.89(b r,1H),6.76(d,J=8.8Hz,1H),6.30(br,1H),3.74-3.56(m,8H),2.59-2.58(m,1H),2.33(s,3H),2.25(s,3H),1.61(d,J=8.4Hz,1H).

[0256] Example 28: 2-(6-(6-(4-(1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 86) [ka] Step 1: 4-(1H-pyrazol-1-yl)benzaldehyde (compound 86b) manufacturing

[0257] Compound 83a (1.0 g) and 86a (0.8 g) were added to DMF (10.0 mL), anhydrous potassium carbonate (2.2 g) was added, and the mixture was heated to 120° C. for 16 h until the raw material was completely converted. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, extracted with EA (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 86b (1.1 g). MS m / z (ESI): 173.1 [M+H] + .

[0258] Step 2: Preparation of 2-(6-(6-(4-(1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 86)

[0259] Compound 1g trifluoroacetate (35.0 mg) and compound 86b (25.3 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 86 (12.0 mg). MS m / z (ESI): 519.2 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6 )11.97(s,1H),9.65(s,1H),9.12(d,J=2.4Hz,1H),8.46-8.42(m,2H),7.77-7.72(m,3H),7.45(d,J=8.8Hz,2H),6.89(br,1H),6.77(d,J =9.2Hz,1H),6.52(t,J=2.0Hz,1H),6.30(br,1H),3.77-3.59(m,8H),2.56-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0261] Example 29: 2-(6-(6-(4-chlorobenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 82) [ka]

[0262] Compound 1g trifluoroacetate (35.0 mg) and compound 82a (20.6 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 82 (26.0 mg). MS m / z (ESI): 487.2 [M+H] + .

[0263] 1 H NMR (400MHz, DMSO-d 6 )δ12.21(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),7.41-7.36(m,4H),6.86(br,1H),6.7 6(d,J=9.2Hz,1H),6.30(br,1H),3.75-3.63(m,8H),2.60-2.56(m,1H),2.33(s,3H),2.25(s,3H),1.63(d,J=8.4Hz,1H).

[0264] Example 30: 2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 91) [ka] Step 1: Preparation of 4-(4-fluoro-1H-pyrazol-1-yl)benzaldehyde (compound 91b)

[0265] Compound 83a (0.1 g) and 91a (0.1 g) were dissolved in DMF (5.0 mL), potassium t-butoxide (0.3 g) was added, and the mixture was heated to 120° C. for 16 h until the raw material was completely converted. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, extracted with EA (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 91b (60 mg). MS m / z (ESI): 190.1 [M+H] + .

[0266] Step 2: Preparation of 2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 91)

[0267] Compound 1g trifluoroacetate (35.0 mg) and compound 91b (27.9 mg) were added to methanol (0.5 mL), and triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 91 (23.0 mg). MS m / z (ESI): 537.3 [M+H] + .

[0268] 1 H NMR (400MHz, DMSO-d 6 )11.97(s,1H),9.63(s,1H),9.12(d,J=2.4Hz,1H),8.61(d,J=4.8Hz,1H),8.43(dd,J=8.8,2.0Hz,1H),7.8 0(d,J=4.0Hz,1H),7.71(d,J=8.8Hz,2H),7.46(d,J=6.8Hz,2H),6.89(br,1H),6.77(d,J=8.8Hz,1H),6.30( br,1H),3.76-3.59(m,8H),2.56-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0269] Example 31: 6-Methyl-2-(6-(6-(4-(4-methyl-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 88) [ka] Step 1: Preparation of 1-(4-(1,3-dioxolan-2-yl)phenyl)-4-methyl-1H-pyrazole (compound 88c)

[0270] Compound 88a (300 mg), 88b (161.3 mg), trans-N,N'-dimethyl-1,2-cyclohexanediamine (74.5 mg), CuI (50.0 mg) and cesium carbonate (1.71 g) were added to DMF (5.0 mL) and reacted at 115 °C under nitrogen protection for 7 h. 2 The reaction was quenched with O (10 mL) and extracted with EA (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 88c (120 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA = 3:1). MS m / z (ESI): 231.2 [M + H] + . Step 2: Preparation of 4-(4-methyl-1H-pyrazol-1-yl)benzaldehyde (compound 88d)

[0271] Concentrated hydrochloric acid (1.5 mL) was dissolved in compound 88c (120 mg) in THF (10 mL) and H 2 The mixture was added dropwise to a 250 mL / min solution of 1,000 mol / L and heated to 65° C. for 1.5 h. After completion of the reaction, the reaction solution was cooled in an ice bath and saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH value of the reaction solution to about 8. The THF solvent was removed under reduced pressure and extracted with DCM (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Compound 88d (90 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=5:1). MS m / z (ESI): 187.1 [M+H] + .

[0272] Step 3: 6-Methyl-2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine Preparation of lysine-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 88)

[0273] The trifluoroacetate salt of compound 1g (35.0 mg) and compound 88d (54.0 mg) were added to methanol (0.5 mL), and triethylamine (9.8 mg) and sodium cyanoborohydride (30.3 mg) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 88 (10.0 mg). MS m / z (ESI): 533.3 [M+H] + .

[0274] 1H NMR(400MHz,DMSO)δ11.98(s,1H),9.66(s,1H),9.14(s,1H),8.45(d,J=8.4H z,1H),8.23(s,1H),7.71(d,J=8.0Hz,2H),7.54(s,1H),7.44(d,J=8.0Hz,2H) ,6.97-6.65(m,2H),6.32(br,1H),3.82-3.67(m,4H),3.65-3.50(m,4H),2.6 2-2.55(m,1H),2.35(s,3H),2.27(s,3H),2.11(s,3H),1.60(d,J=8.0Hz,1H).

[0275] Example 32: 2-(6-(6-((6-(3,4-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 121) [ka] Step 1: Preparation of 2-(3,4-dimethyl-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (compound 121c)

[0276] Compound 121a (300 mg), 121b (188.0 mg), trans-N,N'-dimethyl-1,2-cyclohexanediamine (74.2 mg), CuI (49.7 mg) and cesium carbonate (1.70 g) were added to DMF (5.0 mL) and reacted for 5 h at 120 °C under nitrogen protection. 2 The reaction was quenched with O (10 mL) and extracted with EA (10 mLx3). The organic phases were combined, washed with water (10 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography Compound 121c (305 mg) was obtained by separation and purification using HPLC (PE:EA=4:1). MS m / z (ESI): 246.1 [M+H] + . Step 2: Preparation of 6-(3,4-dimethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 121d)

[0277] Concentrated hydrochloric acid (2.0 mL) was added dropwise to a solution of compound 121c (305 mg) in THF (10 mL), and the mixture was heated to 65° C. and reacted for 1.5 h. After completion of the reaction, the reaction solution was cooled in an ice bath, and potassium carbonate was slowly added to adjust the pH value to about 8, and extracted with EA (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 121d (200 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=4:1). MS m / z (ESI): 202.2 [M+H] + .

[0278] Step 3: Preparation of 2-(6-(6-((6-(3,4-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 121)

[0279] Compound 1g trifluoroacetate (40.4 mg) and compound 121d (53.4 mg) were added to methanol (0.5 mL), and triethylamine (8.7 mg) and sodium cyanoborohydride (26.9 mg) were added in sequence, and the mixture was reacted at 20° C. for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 121 (3.0 mg). MS m / z (ESI): 548.3 [M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d 6)δ11.96(s,1H),9.63(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),8 .32(d,J=1.6Hz,1H),8.27(s,1H),7.88(dd,J=8.4,2.4Hz,1H),7.79-7.70(m,1H), 7.03-6.60(m,2H),6.29(br,1H),3.83-3.70(m,4H),3.66-3.47(m,4H),2.58-2.52 (m,1H),2.33(s,3H),2.25(s,3H),2.19(s,3H),2.02(s,3H),1.58(d,J=8.4Hz,1H).

[0281] Example 33: 2-(6-(6-((5-fluoropyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 70) [ka]

[0282] The trifluoroacetate salt of compound 1g (30 mg) and compound 70a (23.63 mg) were The mixture was added to methanol (0.5 mL), and then triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 70 (12.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d 6))δ11.97(br,1H),9.64(s,1H),9.11(d,J=2.2Hz,1H),8.43(dd,J=9.6,2.7Hz,2H ),7.69(td,J=8.8,3.0Hz,1H),7.54(dd,J=8.7,4.7Hz,1H),6.77(d,J=9.0Hz,2H), 6.31(s,1H),3.80(d,J=11.9Hz,2H),3.72(d,J=5.9Hz,2H),3.64(s,2H),3.56(d,J =10.2Hz,2H),2.57-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0284] Example 34: 2-(6-(6-((6-(3-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 63) [ka]

[0285] The trifluoroacetate salt of compound 1g (30 mg) and compound 63a (47.47 mg, except that 4-fluoropyrazole was replaced with 3-fluoropyrazole, the rest was prepared according to the synthesis method of compound 17a in Example 6) were added to methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in sequence, and the mixture was stirred at 20° C. for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 63 (10.0 mg). MS m / z (ESI): 538.2 [M+H] + .

[0286] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.55(m,1H),8.47-8. 38(m,2H),7.98(d,J=8.6Hz,1H),7.70(d,J=8.4Hz,1H),6.80(d,J=8.0Hz, 2H),6.56(dd,J=8,4Hz,1H),6.29(br,1H),3.84-3.68(m,4H),3.67-3.47( m,4H),2.60-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.2Hz,1H).

[0287] Example 35: 2-(6-(6-((6-(4-fluoro-1H-imidazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 64) [ka] Step 1: Preparation of 5-(1,3-dioxolan-2-yl)-2-(4-fluoro-1H-imidazol-1-yl)pyridine (compound 64b)

[0288] Compound 64a (230 mg), 121a (86 mg), N,N'-dimethylethylenediamine (38 mg), CuI (83 mg) and cesium carbonate (425 mg) were added to DMF (1 mL) and heated to 115°C under nitrogen protection for 3 h. The reaction was quenched with water and extracted with EA. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound 64b (120 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 236.1 [M+H] + . Step 2: Preparation of 6-(4-fluoro-1H-imidazol-1-yl)nicotinaldehyde (compound 64c)

[0289] Concentrated hydrochloric acid (12N, 3.0 mL) was added dropwise to a solution of compound 64b (120 mg) in THF (10 mL) and water (10 mL), and the mixture was reacted at room temperature for 18 h. After completion of the reaction, the pH value of the reaction solution was adjusted to about 8 with saturated sodium bicarbonate solution, and the mixture was extracted with EA and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to give compound 64c (60 mg) crude product, which was used directly in the next reaction without purification. MS m / z (ESI): 192.1 [M+H] + .

[0290] Step 3: Preparation of 2-(6-(6-((6-(4-fluoro-1H-imidazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 64)

[0291] Compound 1g trifluoroacetate (30 mg) and compound 64c (47.47 mg) were added to methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in sequence, and the mixture was stirred at 20° C. for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 64 (10.0 mg). MS m / z (ESI): 538.2 [M+H] + .

[0292] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.2Hz,1H),8.44(dd,J=9.1,2.4Hz,2H),8. 28(m,1H),7.99(d,J=8.4Hz,1H),7.76-7.74(d,J=8.0Hz,1H),7.69-7.67(dd,J=8.4, 1.6Hz,1H),6.86(br,1H),6.77(d,J=9.2Hz,1H),6.30(br,1H),3.78-3.71(m,4H),3. 67-3.51(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0293] Example 36: 2-(6-(6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 52) [ka]

[0294] Compound 1g (320 mg), compound 52a (181.17 mg, except that 6-bromonicotinaldehyde was replaced with 1-(6-bromopyridin-3-yl)ethanone, the rest was prepared according to the synthesis method of compound 17a in Example 6) and tetraisopropyl titanate (752.81 mg) were added to dry THF (25 mL), purged with nitrogen three times, and then stirred at 75 ° C for 24 h. Then, sodium triacetoxyborohydride (935.64 mg) was added to the system in batches, and dry THF (15 mL) was added, followed by stirring at 75 ° C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, separated and purified by flash column chromatography (MeOH:DCM = 1:9) to obtain crude compound 52, and then separated and purified by Prep-HPLC to obtain compound 52 (90.0 mg). MS m / z (ESI): 552.3 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d 6 )δ11.96(s,1H),9.63(s,1H),9.12(d,J=2.1Hz,1H),8.66(d,J=4.4Hz,1H),8.46-8.39(m,2H ),8.01(dd,J=8.5,2.0Hz,1H),7.90(dd,J=14.7,6.2Hz,2H),6.82(br,1H),6.75(d,J=12.0Hz ,1H),6.27(br,1H),3.96-3.82(m,2H),3.77(q,J=6.1Hz,1H),3.63(m,1H),3.49-3.37(m,3H ),2.55-2.51(m,1H),2.33(s,3H),2.25(s,3H),1.55(d,J=8.4Hz,1H),1.23(d,J=6.2Hz,3H).

[0296] Example 37: 2-(6-(6-((6-(3-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 120) [ka]

[0297] The trifluoroacetate salt of compound 1g (30 mg) and compound 120a (22.95 mg, prepared according to the synthesis method of compound 64c in Example 35, except that the starting material 4-fluoroimidazole was replaced with 3-cyclopropylpyrazole) were placed in methanol (0.5 mL), and triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg) were added in sequence, and the mixture was stirred at 20° C. for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 120 (13.0 mg). MS m / z (ESI): 560.3 [M+H] + .

[0298] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.2Hz,1H),8.44(dd,J=8.9,2.4Hz,2H),8.35(d,J=1.3Hz ,1H),7.92(dd,J=8.5,1.8Hz,1H),7.78(d,J=8.4Hz,1H),6.8(br,1H),6.78(d,J=9.0Hz,1H),6.28 (br,1H),6.26(d,J=2.5Hz,1H),3.81-3.66(m,4H),3.67-3.52(m,4H),2.58-2.53(m,1H),2.33(s, 3H),2.26(s,3H),2.03-1.95(m,1H),1.59(d,J=8.4Hz,1H),0.98-0.91(m,2H),0.79-0.73(m,2H).

[0299] Example 38: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 119) [ka] Step 1: Preparation of 4-((6-methylpyridin-3-yl)oxy)piperidine-t-butyl 1-carboxylate (Compound 119b)

[0300] Compound 119a (100 mg), N-Boc-4-hydroxypiperidine (276.65 mg) and triphenylphosphine (480.18 mg) were dissolved in dry THF (5 mL). The mixture was cooled to 0°C. DIAD (370.21 mg) was added dropwise to the system, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the system was concentrated under reduced pressure and purified by flash column chromatography (PE:EA=1:1) to obtain compound 119b (65 mg). MS m / z (ESI): 293.2 [M+H] + . Step 2: Preparation of 2-methyl-5-(piperidin-4-yloxy)pyridine (compound 119c)

[0301] Compound 119b (65 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 2 mL) and THF (1 mL) and stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give compound 119c hydrochloride (54 mg). MS m / z (ESI): 193.2 [M+H] + .

[0302] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrimidin-4-amine (compound 119)

[0303] Compound 119c hydrochloride (50 mg), compound 119d (50 mg) and potassium carbonate (73 mg) were added to DMF (2 mL), heated to 100° C. and stirred for 16 h. After completion of the reaction, the reaction solution was cooled to room temperature. Water (30 mL) was added to dilute the mixture, and the mixture was extracted with EA (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Compound 119 (13 mg) was obtained by separation and purification by Prep-HPLC. MS m / z (ESI): 457.3 [M+H] + .

[0304] 1 H NMR (400MHz, DMSO-d 6 )δ11.96(s,1H),9.63(s,1H),9.04(d,J=2.4Hz,1H),8.37(dd,J=9.0,2.4Hz,1H),8.1 9(d,J=2.9Hz,1H),7.38(dd,J=8.5,3.0Hz,1H),7.18(d,J=8.5Hz,1H),6.96(d,J=9.1 Hz,1H),6.82(s,1H),6.28(s,1H),4.72-4.65(m,1H),4.13-4.01(m,2H),3.49-3.40( m,2H),2.40(s,3H),2.32(s,3H),2.25(s,3H),2.06-1.98(m,2H),1.69-1.58(m,2H).

[0305] Example 39: 2-(6-(6-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 89) [ka] Step 1: Preparation of 1-(4-(1,3-dioxolan-2-yl)phenyl)-3-fluoro-1H-pyrazole (compound 89b)

[0306] Compound 89a (80 mg), 88a (212.92 mg), N,N'-dimethylethylenediamine (81.94 mg), cesium carbonate (908.55 mg) and CuI (177.02 mg) were added in order to DMF (6 mL) and heated to 110 °C and stirred for 12 h. The reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by flash column chromatography (PE:EA = 63:37) to obtain compound 89b (35 mg). MS m / z (ESI): 235.1 [M + H] + . Step 2: Preparation of 4-(3-fluoro-1H-pyrazol-1-yl)benzaldehyde (compound 89c)

[0307] Compound 89b (35 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 2 mL) and DCM (1 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give compound 89c (28 mg). MS m / z (ESI): 191.1 [M+H] + .

[0308] Step 3: Preparation of 2-(6-(6-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 89)

[0309] Compound 89c (14.37 mg), the trifluoroacetate salt of compound 1g (30 mg), triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg) were added in this order to methanol (0.5 mL) and stirred at room temperature for 36 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (0.1 mL). The reaction solution was concentrated and pre-purified by preparative TLC (DCM:MeOH=10:1) to obtain 5 mg of crude product (R f =0.15-0.25) was obtained, and separated and purified by Prep-HPLC to obtain compound 89 (4 mg). MS m / z (ESI): 537.3 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.3Hz,1H),8.49-8.39(m,2H),7.68(d,J=8.6Hz,2H),7.46(d,J=8.5Hz,2H),6.78(d,J=9.0Hz,2H ),6.31(dd,J=5.8,2.6Hz,2H),3.80-3.67(m,4H),3.64-3.48(m,4H),2.59-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0311] Example 40: 6'-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-[2,3'-bipyridine]-6-amine (compound 6) [ka] Step 1: Preparation of t-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (compound 6b)

[0312] Compound 6a (2.4 g) was dissolved in dry THF (50 mL), NaH (988.39 mg, purity 60%) was added in batches, and the mixture was stirred for 10 min. Di-tert-butyl dicarbonate (5.39 g) was added dropwise, and the mixture was stirred for 2 h at 25° C. under nitrogen protection. Water was added to the reaction solution to quench the reaction, and the reaction solution was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 6b (3.95 g) was obtained by separation and purification by silica gel column chromatography (PE:EA=5:1). Step 2: Preparation of t-butyl 3-((6-bromo-4-methylpyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (compound 6d)

[0313] Compound 6c (1.0 g), 6b (864.65 mg), palladium acetate (89.47 mg), xantphos (461.20 mg), and cesium carbonate (2.60 g) were added in order to 1,4-dioxane (10 mL), and stirred at 95°C for 2 h under nitrogen protection. LC-MS was used to monitor that the reaction of the raw materials had progressed completely and the target product was produced. The reaction solution was cooled to room temperature, filtered, and concentrated. Compound 6d (415 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=3:1). MS m / z (ESI): 367 [M+H] + . Step 3: Preparation of 6-bromo-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyridin-2-amine (compound 6e)

[0314] Compound 6d (300 mg) was added to a solution of hydrogen chloride in 1,4-dioxane (4N, 2 mL) and stirred at 25° C. for 1 h. It was directly concentrated to dryness, and methanol (5 mL) was added to dissolve the crude product. Then triethylamine (1 mL) was added and stirred at room temperature for 15 min. The reaction solution was concentrated and purified by silica gel flash column chromatography (DCM:MeOH=97:3) to give compound 6e (145 mg). MS m / z (ESI): 267 [M+H] + .

[0315] Step 4: Preparation of 6'-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-[2,3'-bipyridine]-6-amine (compound 6)

[0316] In a reaction bottle, compound 6e (30 mg), 10f (85 mg), and Na 2 CO 3 (27.85mg), Pd(PPh 3 ) 4 (12.98mg), H 2 O (1 mL) and 1,4-dioxane (5 mL) were added, and the mixture was purged with nitrogen three times, and then stirred at 95° C. for 5 h. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with EA. The organic layer was collected, washed with water and saturated saline, dried over anhydrous sodium sulfate, suction filtered, concentrated, pre-purified by preparative TLC (DCM:MeOH=9:1), and separated and purified by Prep-HPLC to obtain compound 6 (6 mg). MS m / z (ESI): 537.3 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d 6)δ11.63(s,1H),9.02(s,1H),8.86(d,J=2.3Hz,1H),8.67(dd,J=4.5,0.6Hz,1H),8.41(d,J=1 .7Hz,1H),8.21(dd,J=8.9,2.4Hz,1H),7.98(dd,J=8.5,2.2Hz,1H),7.92(d,J=4.3Hz,1H),7.8 6(d,J=8.4Hz,1H),7.03(s,1H),6.88(s,1H),6.77(d,J=9.0Hz,1H),6.22(s,1H),3.81-3.69( m,4H),3.66-3.53(m,4H),2.58-2.53(m,1H),2.26(s,3H),2.22(s,3H),1.59(d,J=8.4Hz,1H).

[0318] Example 41: 2-(6-(6-((6'-methoxy-[2,3'-bipyridin]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 7) [ka] Step 1: Preparation of 5-(1,3-dioxolan-2-yl)-6'-methoxy-2,3'-bipyridine (compound 7b)

[0319] In a reaction bottle, compound 7a (499 mg), 121a (500 mg), and Na 2 CO 3 (691mg), Pd(PPh 3 ) 4 (126mg), H 2 O (3 mL) and 1,4-dioxane (17 mL) were added, and the mixture was replaced with nitrogen three times, and then stirred at 95° C. for 5 h. After the reaction was completed, the mixture was concentrated to dryness. Compound 7b (350 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=1:1). Step 2: Preparation of 6'-methoxy-[2,3'-bipyridine]-5-formaldehyde (compound 7c)

[0320] Concentrated hydrochloric acid (12N, 3.0mL) was added dropwise to a solution of compound 7b (200mg) in THF (11mL) and water (9mL), and the mixture was reacted at room temperature for 18h. After completion of the reaction, the pH value of the reaction solution was adjusted to about 10 with potassium carbonate solution, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Compound 7c (60mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=2:1). MS m / z (ESI):215.1[M+H] + .

[0321] Step 3: Preparation of 2-(6-(6-((6'-methoxy-[2,3'-bipyridin]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 7)

[0322] The trifluoroacetate salt of compound 1g (50 mg) and compound 7c (67.44 mg) were added to methanol (0.5 mL), and triethylamine (10.62 mg) and sodium cyanoborohydride (32.97 mg) were added in sequence, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 7 (10.0 mg). MS m / z (ESI): 561.3 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d 6)δ11.98(br,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.86(d,J=2.2Hz,1H),8.60(d,J=1.5Hz, 1H),8.44(dd,J=8.9,2.3Hz,1H),8.36(dd,J=8.7,2.5Hz,1H),7.90(d,J=8.1Hz,1H),7.83(dd,J =8.2,2.1Hz,1H),6.85(dd,J=56.9,8.8Hz,3H),6.33(s,1H),3.91(s,3H),3.75(dd,J=20.2,8.9 Hz,4H),3.65-3.49(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0324] Example 42: 2-(6-(6-((5'-fluoro-2'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 8) [ka] Step 1: Preparation of 5-fluoro-2-methylpyridine-3-boronic acid pinacol (compound 8b)

[0325] In a reaction bottle, add bis(pinacolato)diboron (1.20 g), compound 8a (300 mg), and Pd(dppf)Cl. 2 DCM (128.93 mg), potassium acetate (464.85 mg) and dry 1,4-dioxane (10 mL) were added and heated to 100 °C under nitrogen protection and stirred for 4 h. After the reaction was completed, it was filtered. Water was added to dilute the filtrate and extracted with EA. The organic phase was washed twice with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and separated and purified by silica gel flash column chromatography (PE:EA = 1:1). Purification gave compound 8b (300 mg). MS m / z (ESI): 238.2 [M+H] + .

[0326] Step 2: Preparation of 2-(6-(6-((6-bromopyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 8d)

[0327] The trifluoroacetate salt of compound 1g (200 mg) and compound 8c (195.20 mg) were placed in methanol (10 mL) and triethylamine (42.48 mg) was added at room temperature with stirring. After stirring for 30 min, sodium cyanoborohydride (131.89 mg) was added and stirred at 20°C for 16 h. LC-MS monitoring showed that the product peak was evident. Compound 8d (220 mg) was obtained by separation and purification with silica gel flash column chromatography (DCM:MeOH=10:1). MS m / z (ESI): 532.1 [M+H] + .

[0328] Step 3: Preparation of 2-(6-(6-((5'-fluoro-2'-methyl-[2,3'-bipyridin]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 8)

[0329] In a reaction bottle, compound 8b (222.63 mg), 8d (100 mg), and Na 2 CO 3 (69.87mg), Pd(PPh 3 ) 4 (32.55 mg), water (1 mL) and 1,4-dioxane (5 mL) were added and stirred under nitrogen protection at 95° C. for 5 h. After the reaction was completed, the solvent was removed by rotary evaporation, pre-purified by preparative TLC (DCM:MeOH=9:1), and separated and purified by Prep-HPLC to obtain compound 8 (25 mg). MS m / z (ESI): 563.3 [M+H] + .

[0330] 1H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.66(s,1H),9.13(d,J=2.2Hz,1H),8.66(d,J=1.5Hz,1H),8.51(d,J=2.9Hz,1 H),8.44(dd,J=8.9,2.3Hz,1H),7.90(dd,J=8.1,2.1Hz,1H),7.76(dd,J=9.5,2.8Hz,1H),7.62 (d,J=8.0Hz,1H),6.81(br,1H),6.79(d,J=9.0Hz,1H),6.32(br,1H),3.85-3.71(m,4H),3.70- 3.51(m,4H),2.61-2.53(m,1H),2.51(s,3H),2.33(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0331] Example 43: 6-Methyl-2-(6-(6-((6-(5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 9) [ka]

[0332] The trifluoroacetate salt of compound 1g (30 mg) and compound 9a (17.68 mg, prepared according to the synthesis method of compound 64c in Example 35, except that the starting material 4-fluoroimidazole was replaced with 5-methylpyrazole) were placed in methanol (0.5 mL), and triethylamine (8.38 mg) was added. After stirring for 30 min, sodium cyanoborohydride (19.78 mg) was added and stirred at 20° C. for 16 h. LC-MS monitoring showed that the reaction of the raw materials was complete, and the product peak was clear. Compound 9 (7 mg) was obtained by separation and purification by Prep-HPLC. MS m / z (ESI): 534.3 [M+H] + .

[0333] 1 H NMR (400MHz, DMSO-d 6 )δ11.99(s,1H),9.67(s,1H),9.14(d,J=2.1Hz,1H),8.49(d,J=2.4Hz,1H),8.45(dd,J=9.2, 2.4Hz,1H),8.38(d,J=1.6Hz,1H),7.94(dd,J=8.5,2.1Hz,1H),7.81(d,J=8.4Hz,1H),6.83(b r,1H),6.79(d,J=9.2Hz,1H),6.38(d,J=2.4Hz,1H),6.33(br,1H),3.85-3.71(m,4H),3.69-3 .51(m,4H),2.61-2.55(m,1H),2.35(s,3H),2.30(s,3H),2.27(s,3H),1.61(d,J=8.4Hz,1H).

[0334] Example 44: N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methylpyrimidin-4-amine (compound 10) [ka] Step 1: Preparation of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidin-4-amine (compound 10c)

[0335] Compound 10b (1.0 g) and 10a (755.53 mg) were dissolved in ethanol (20.00 mL) and N,N-diisopropylethylamine (1590.00 mg) was added, and the mixture was heated to 70° C. under the protection of nitrogen and stirred for 48 h. The reaction solution was concentrated under reduced pressure and diluted with EA (300.00 mL). The organic phase was washed three times with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. It was filtered and concentrated, and separated and purified by silica gel column chromatography (DCM:MeOH=9:1) to give compound 10c (820.00 mg). MS m / z (ESI): 250.1 [M+H] +Step 2: Preparation of 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 10d)

[0336] Compound 1c (1180.00 mg) was dissolved in a mixed solvent of methanol (5.00 mL) and DCM (10.00 mL), and a solution of hydrogen chloride in 1,4-dioxane (4N, 6.00 mL) was slowly added dropwise under an ice bath, followed by stirring at 25° C. for 16 h. The reaction solution was concentrated under reduced pressure to give compound 10d hydrochloride (1040.00 mg). MS m / z (ESI): 254.0 [M+H] + .

[0337] Step 3: Preparation of 3-(5-bromopyridin-2-yl)-6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (compound 10e)

[0338] The hydrochloride salt of compound 10d (300.00 mg) and compound 17a (297.04 mg) were The mixture was dissolved in 1,2-dichloroethane (10.00 mL) and triethylamine (104.82 mg) was slowly added dropwise. After stirring for 10 min, acetic acid (31.10 mg) was added dropwise and stirred for 30 min. Sodium triacetoxyborohydride (878.21 mg) was added and stirred at 25° C. for 20 h. A saturated aqueous solution of ammonium chloride was added to the reaction solution to quench the reaction, diluted with water, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 10e (363.00 mg) was obtained by separation and purification using silica gel column chromatography (PE:EA=1:1). MS m / z (ESI): 429.1 [M+H] + .

[0339] Step 4: Preparation of 6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 10f)

[0340] Compound 10e (187.00 mg) and bis(pinacolato)diboron (221.23 mg) were dissolved in 1,4-dioxane (15.00 mL) and potassium acetate (106.88 mg), Pd(dppf)Cl 2 ·DCM (35.57 mg) was added, and the mixture was heated to 95 °C under nitrogen protection and stirred for 5 h. The reaction mixture was diluted with EA (100.00 mL) and washed with water three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 10f (100.00 mg). MS m / z (ESI): 477.3 [M + H] + .

[0341] Step 5: Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methylpyrimidin-4-amine (compound 10)

[0342] Compounds 10c (26.21 mg) and 10f (50.00 mg) were dissolved in 1,4-dioxane (4.00 mL) and sequentially mixed with Pd(PPh 3 ) 4(18.19 mg) and aqueous sodium carbonate solution (33.38 mg dissolved in 1.00 mL of water) were added, and the mixture was heated to 95° C. under nitrogen protection and stirred for 12 h. After completion of the reaction, the reaction solution was diluted with EA (20.00 mL) and washed with water three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by Prep-HPLC to obtain compound 10 (9.00 mg). MS m / z (ESI): 564.3 [M+H] + .

[0343] 1 H NMR (400MHz, DMSO-d 6 )δ12.02(s,1H),9.64(s,1H),9.11(d,J=2.4Hz,1H),8.67(dd,J=4.8,0.8Hz,1H),8.42(dd,J=9 .2,2.0Hz,2H),7.99(dd,J=8.4,2.0Hz,1H),7.92(dd,J=4.4,0.8Hz,1H),7.87(d,J=8.4Hz,1H) ,6.78(d,J=9.2Hz,2H),6.18(br,1H),3.79-3.71(m,4H),3.64-3.53(m,4H),2.56-2.51(m,1H) ,2.33(s,3H),1.95-1.89(m,1H),1.60(d,J=8.4Hz,1H),0.97-0.92(m,2H),0.75-0.69(m,2H).

[0344] Example 45: 2-(6-(6-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 11) [ka] Step 1: Preparation of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (compound 11b)

[0345] Compound 11a (1.0 g), 121a (1.74 g), N,N'-dimethylethylenediamine (664.83 mg), CuI (1.44 g) and cesium carbonate (7.37 g) were added to DMF (30 mL) and heated to 98 °C under nitrogen protection for 16 h. The reaction was quenched by adding water to the reaction solution and extracted with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 11b (0.69 g) was obtained by separation and purification by silica gel column chromatography (PE:EA = 3:1). MS m / z (ESI): 246.2 [M + H] + . Step 2: Preparation of 6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 11c)

[0346] Hydrochloric acid (2N, 3.0mL) was added dropwise to a solution of compound 11b (250mg) in THF (6mL) and reacted at room temperature for 3h. After completion of the reaction, the reaction solution was cooled under ice bath. Potassium carbonate was slowly added to adjust the pH value to about 8, and extracted with EA (10mLx3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 11c (150mg) was obtained by separation and purification by silica gel column chromatography (PE:EA=3:1).

[0347] Step 3: Preparation of 2-(6-(6-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 11)

[0348] Compound 1g (30 mg) and compound 11c (25 mg) were placed in methanol (1 mL), and acetic acid (5 mg) was added, and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (15.6 mg) was added, and the mixture was reacted at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the crude product was pre-purified by preparative TLC (DCM:MeOH=96:4), which was further separated and purified by Prep-HPLC to obtain compound 11 (7 mg). MS m / z (ESI): 548.3 [M+H] + .

[0349] 1 H NMR (400MHz, DMSO-d 6 ))δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.44(dd,J=8.9,2.2Hz,1H) ,8.37(d,J=1.8Hz,1H),7.91(dd,J=8.5,2.2Hz,1H),7.74(d,J=8.4Hz,1H),6.96-6 .67(m,2H),6.31(s,1H),6.09(s,1H),3.85-3.68(m,4H),3.66-3.49(m,4H),2.56( s,3H),2.54(s,1H),2.33(s,3H),2.26(s,3H),2.19(s,3H),1.60(d,J=8.5Hz,1H).

[0350] Example 46: 2-(6-(6-((6-(5-isopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 12) [ka] Step 1: Preparation of 5-(1,3-dioxolan-2-yl)-2-(5-isopropyl-1H-pyrazol-1-yl)pyridine (compound 12b)

[0351] Compound 12a (210.68 mg), 121a (400 mg), N,N'-dimethylethylenediamine (153.27 mg), cesium carbonate (1.13 g) and CuI (331.13 mg) were added in order to DMF (10 mL), heated to 110 ° C and stirred for 3 h. The reaction solution was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel flash column chromatography (PE:EA = 55:45) to obtain compound 12b (300 mg). MS m / z (ESI): 260.2 [M + H] + . Step 2: Preparation of 6-(5-isopropyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 12c)

[0352] Compound 12b (300.00 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 6 mL) and DCM (4 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (PE:EA=80:20) to give compound 12c (120 mg). MS m / z (ESI): 216.2 [M+H] + .

[0353] Step 3: Preparation of 2-(6-(6-((6-(5-isopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 12)

[0354] Compound 12c (26.73 mg), 1g (30 mg) and sodium cyanoborohydride (26.01 mg) were added in order to a mixed solvent of methanol (1 mL) and acetic acid (0.1 mL), heated to 40° C. and stirred for 16 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (0.1 mL). The reaction solution was concentrated, separated and purified by Prep-HPLC to obtain the trifluoroacetate salt of compound 12 (15 mg), and separated by MPLC to obtain the free form of compound 12 (8 mg). MS m / z (ESI): 562.3 [M+H] + . MPLC Conditions:

[0355] Instrument model: Biotage Isolera Prime2.3.1, Column: Agel a Technologies C18 spherical 20-35um 100A, 12g, column temperature: 25℃, flow rate: 15.0mL / min, detection wavelength: 254nm, elution gradient: (0min: 0%A, 100%B; 3.0min: 0%A, 100%B; 20min: 80%A, 20%B), mobile phase A: 100% acetonitrile, mobile phase B: 0.5% ammonium bicarbonate aqueous solution, compound recovery time: 10.4min-11.8min.

[0356] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.16-9.09(m,1H),8.49-8.40(m,2H),8.36(d,J=1.9Hz,1H) ,7.93(dd,J=8.5,2.3Hz,1H),7.81(dd,J=8.4,0.7Hz,1H),6.78(d,J=9.0Hz,2H),6.42(d,J =2.5Hz,1H),6.33(s,1H),3.83-3.68(m,4H),3.66-3.50(m,4H),2.99(p,J=6.9Hz,1H),2.5 9-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.27(s,3H),1.25(s,3H).

[0357] Example 47: 2-(6-(6-(4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 25) [ka]

[0358] Step 1: Preparation of 2-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole (compound 25b)

[0359] Compound 25a (206.83 mg), compound 121a (400 mg), N,N'-dimethylethylenediamine (153.27 mg), cesium carbonate (1.13 g) and CuI (331.13 mg) were added in order to DMF (10 mL), heated to 110 °C and stirred for 12 h. The reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound 25b (525 mg). MS (ESI, m / z): 258.2 [M + H] + . Step 2: Preparation of 6-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)nicotinaldehyde (compound 25c)

[0360] Compound 25b (315 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 10 mL) and DCM (10 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (PE:EA=80:20) to give compound 25c (200 mg). MS m / z (ESI): 214.2 [M+H] + .

[0361] Step 3: 2-(6-(6-(4-(5,6-dihydrocyclopenta[c]pyrazole Preparation of -2(4H)-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 25)

[0362] Compound 25c (29.42 mg), 1g (50 mg), and sodium cyanoborohydride (43.35 mg) were added to a mixed solvent of methanol (0.5 mL) and acetic acid (0.05 mL), and the mixture was heated to 40° C. and stirred for 16 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (0.1 mL). The reaction solution was concentrated, separated and purified by Prep-HPLC to obtain the trifluoroacetate salt of compound 25 (25 mg), which was further separated by MPLC to obtain the free form of compound 25 (15 mg). MS m / z (ESI): 560.3 [M+H] + . MPLC Conditions:

[0363] Instrument type: Biotage Isolera Prime2.3.1, Column: Agela Technologies C18 spherical 20-35um 100A, 12g, Column temperature: 25°C, Flow rate: 15.0mL / min, Detection wavelength: 254nm, Elution gradient: (0min: 0%A, 100%B; 3.0min: 0%A, 100%B; 20min: 80%A, 20%B), Mobile phase A: 100% acetonitrile, Mobile phase B: 0.5% ammonium bicarbonate aqueous solution, Compound recovery time: 11.4min-12.8min.

[0364] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.65(s,1H),9.15-9.10(m,1H),8.44(dd,J=8.9,2.3Hz,1H),8.35-8.30( m,1H),8.19(d,J=1.2Hz,1H),7.89(dd,J=8.5,2.3Hz,1H),7.76(dd,J=8.4,0.7Hz,1H),6.7 8(d,J=9.0Hz,2H),6.31(s,1H),3.82-3.69(m,4H),3.66-3.50(m,4H),2.74-2.62(m,4H), 2.57-2.54(m,2H),2.38(q,J=7.4Hz,2H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0365] Example 48: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methanone (compound 26) [ka] Step 1: Preparation of methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinate (compound 26b)

[0366] Compounds 26a (1 g) and 91a (478.08 mg) were dissolved in acetonitrile (20 mL). Then, salicylaldoxime (129.96 mg), cesium carbonate (3.77 g) and cuprous oxide (132.47 mg) were added in order, and the mixture was heated to 85°C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was adjusted to about pH=5 by adding dilute hydrochloric acid. Silica gel was added and the mixture was stirred, and the mixture was separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain compound 26b (602 mg). MS m / z (ESI): 221.9 [M+H] + . Step 2: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid (compound 26c)

[0367] Compound 26b (580 mg) was dissolved in THF (10 mL) and H 2 2H2O (5 mL), and then NaOH (314.66 mg) was added and stirred at 25 °C for 14 h. After completion of the reaction, the reaction solution was adjusted to pH = 5 by adding dilute hydrochloric acid and extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 26c (312 mg). MS m / z (ESI): 208.1 [M+H] + .

[0368] Step 3: Preparation of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methanone (compound 26)

[0369] Compound 26c (20 mg) was placed in DMF (5 mL), and HBTU (29.41 mg), DIPEA (37.43) and 1g trifluoroacetate (50.60 mg) were added in sequence and stirred at 25 °C for 1 h. Water (25 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to give compound 26 (25 mg). MS m / z (ESI): 551.8 [M + H] + .

[0370] 1H NMR(400MHz,DMSO)δ11.97(s,1H),9.65(s,1H),9.04(s,1H),8.77-8.73(m,2H),8.38(dd,J= 8.8,2.0Hz,1H),8.25(dd,J=8.4,2.0Hz,1H),8.03(d,J=4.4Hz,1H),7.97(d,J=8.8Hz,1H),7. 05-6.47(m,2H),6.27(br,1H),4.96(s,1H),4.67(s,1H),4.17(d,J=9.6Hz,1H),3.80-3.65(m ,2H),3.63-3.50(m,1H),2.92-2.82(m,1H),2.31(s,3H),2.24(s,3H),1.72(d,J=8.4Hz,1H).

[0371] Example 49: 2-(6-(6-((6-(5-cyclobutoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 27) [ka] Step 1: Preparation of t-butyl 3-hydroxy-1H-pyrazole-1-carboxylate (compound 27b)

[0372] In a reaction bottle, compound 27a (500 mg), Boc 2 O (1.30 g), TEA (1.81 g) and DMAP (145.31 mg) were added, and THF (20 mL) was added. The reaction mixture was stirred at room temperature for 16 h, and the yellow turbidity gradually became clear. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure and separated and purified by silica gel flash column chromatography (DCM:MeOH=20:1) to obtain compound 27b (425 mg). Step 2: Preparation of t-butyl 3-cyclobutoxy-1H-pyrazole-1-carboxylate (compound 27d)

[0373] Compounds 27b (360 mg), 27c (215.71 mg) and PPh3 (776.71 mg) was dissolved in toluene (10 mL) and cooled in an ice-water bath. DIAD (628.74 mg) was added, and the mixture was heated to 110° C. under nitrogen protection and reacted for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE=1:20) to obtain compound 27d (374 mg). Step 3: Preparation of 3-cyclobutoxy-1H-pyrazole (compound 27e)

[0374] Compound 27d (374 mg) was dissolved in methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (4N, 3 mL) was added. The mixture was reacted at room temperature under nitrogen protection. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure to obtain the hydrochloride salt of compound 27e (280 mg). MS m / z (ESI): 139.1 [M+H] + . Step 4: Preparation of 2-(5-cyclobutoxy-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (compound 27f)

[0375] A reaction bottle was charged with compound 121a (315 mg), the hydrochloride salt of compound 27e (239 mg), and Cs 2 CO 3 (675.94 mg) and DMF (10 mL) were added and stirred until homogenous. Then, N,N'-dimethylethylenediamine (48.77mg) and CuI (52.68mg, 273.84μmol) were added, and the mixture was heated to 100℃ under the protection of nitrogen for 14h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30mL), and extracted with EA (40mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE=1:1) to obtain compound 27f (300mg). MS m / z (ESI): 287.9[M+H] + . Step 5: Preparation of 6-(5-cyclobutoxy-1H-pyrazol-1-yl)nicotinaldehyde (compound 27g)

[0376] Compound 27f (300 mg) was dissolved in THF (5 mL), hydrochloric acid (2N, 5 mL) was added to the solution, and the reaction was allowed to proceed at room temperature for 8 h. After completion of the reaction, the reaction solution was diluted with water (20 mL) and saturated NaHCO 3 The pH was adjusted to 7-8 with aqueous solution, and extracted with EA (40mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE=1:15) to obtain compound 27g (140mg). MS m / z (ESI): 243.9[M+H] + .

[0377] Step 6: Preparation of 2-(6-(6-((6-(5-cyclobutoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 27)

[0378] Compound 1g (65 mg), 27g (50.66 mg), and tetraisopropyl titanate (195.65 mg) were dissolved in dry THF (3 mL), heated to 75° C., and reacted for 1 h. Sodium triacetoxyborohydride (182.37 mg) was added to the reaction bottle, and reacted for 18 h while maintaining the temperature at 75° C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (20 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by Prep-HPLC to obtain compound 27 (20 mg). MS m / z (ESI): 589.9 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.66(s,1H),9.13(d,J=2.4Hz,1H),8.44(dd,J=8.8,2.4Hz,1H),8.40(d,J=2.4Hz,1H),8.33( d,J=2.0Hz,1H),7.91(dd,J=8.4,2.4Hz,1H),7.66(d,J=8.4Hz,1H),7.12-6.69(m,2H),6.49-6.14(m,1H),6.0 2(d,J=2.8Hz,1H),4.90(p,J=7.6Hz,1H),3.83-3.73(m,2H),3.73-3.66(m,2H),3.65-3.47(m,4H),2.60-2.53 (m,1H),2.46-2.38(m,2H),2.33(s,3H),2.26(s,3H),2.13-2.03(m,2H),1.82-1.73(m,1H),1.67-1.56(m,2H).

[0380] Example 50: 2-(6-(6-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((6-(4-chloro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 2 8 / Compound 28') [ka]

[0381] Step 1: Preparation of 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine and 2-(4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (Compound 28b / Compound 28b')

[0382] The nitrogen was protected with compounds 121a (202.0 mg), 28a (102.3 mg), CuI (167.2 mg), N,N'-dimethylethylenediamine (77.3 mg), and Cs 2 CO 3 (856.1 mg) was dissolved in DMF (5.0 mL) and heated to 120° C. to react until the raw material was completely converted. After the reaction was completed, the reaction solution was washed with saturated aqueous sodium carbonate and extracted with EA (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by preparative TLC to give a mixture of compounds 28b and 28b′ (230.0 mg). MS m / z (ESI): 266.0 [M+H] + .

[0383] Step 2: Preparation of 6-(4-chloro-3-methyl-1H-pyrazol-1-yl)nicotinaldehyde and 6-(4-chloro-5-methyl-1H-pyrazol-1-yl)nicotinaldehyde (Compound 28c / Compound 28c')

[0384] A mixture of compounds 28b and 28b' (230.0 mg) was added to a mixed solvent of concentrated hydrochloric acid (3 mL), THF (10 mL) and water (10 mL) and reacted at 25°C until the raw material was completely converted. The reaction solution was concentrated to dryness under reduced pressure to obtain a mixture of compounds 28c and 28c' (39.0 mg). MS m / z (ESI): 222.1 [M+H] + .

[0385] Step 3: Preparation of 2-(6-(6-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((6-(4-chloro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 28 / Compound 28')

[0386] A mixture of compounds 28c and 28c' (29.0 mg) and trifluoroacetate of compound 1g The acid salt (30.0 mg) was placed in methanol (0.5 mL), and triethylamine (6.4 mg) and sodium cyanoborohydride (19.8 mg) were added in sequence, and the reaction was allowed to proceed at room temperature until the raw material was completely converted. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 28 (2.0 mg, recovery time 5.6-6.0 min), MS m / z (ESI): 568.2 [M+H]. + , and compound 28' (1.0 mg, collection time 5.0-5.4 min), MS m / z (ESI): 568.2 [M+H]+ obtained.

[0387] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.64(s,1H),9.13(d,J=2.0Hz,1H),8.69(s,1H),8.45(d,J=8. 0Hz,1H),8.40(s,1H),7.98(d,J=8.8Hz,1H),7.82(d,J=8.4Hz,1H),6.89(d,J= 8.8Hz,1H),6.76-6.67(m,1H),6.38-6.23(m,1H),3.80-3.55(m,8H),2.62-2.5 8(m,1H),2.34(s,3H),2.28(s,3H),2.27(s,3H),1.61(d,J=8.0Hz,1H)(Compound 28).

[0388] 1 H NMR (400MHz, DMSO-d 6 )δ12.03(s,1H),9.68(s,1H),9.18(d,J=2.4Hz,1H),8.51(d,J=2.4Hz,1H),8.48(d ,J=2.4Hz,1H),8.05(dd,J=8.4,2.4Hz,1H),7.90(s,1H),7.83(d,J=8.4Hz,1H),6.8 5(d,J=9.2Hz,1H),6.82-6.69(m,1H),6.43-6.29(m,1H),3.86-3.56(m,8H),2.63(s ,3H),2.62-2.58(m,1H),2.39(s,3H),2.31(s,3H),1.66(d,J=8.4Hz,1H)(Compound 28').

[0389] Example 51: 2-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 29) [ka] Step 1: Preparation of t-butyl 4-((5-fluoropyridin-3-yl)oxy)piperidine-1-carboxylate (compound 29b)

[0390] The nitrogen was protected to give compound 29a (425.6 mg), N-Boc-4-hydroxypiperidine (505.0 mg) and PPh 3 (1.3 g) was dissolved in dry THF (5.0 mL), cooled to 0° C., DIAD (1.0 g) was added dropwise, and the temperature was gradually raised to 25° C., and the reaction was continued until the raw material was completely converted. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the compound 29b (736.2 mg) was obtained by separation and purification by column chromatography. MS m / z (ESI): 297.1 [M+H] + . Step 2: Preparation of 3-fluoro-5-(piperidin-4-yloxy)pyridine (compound 29c) hydrochloride

[0391] Compound 29b (555.5 mg) was added to a solution of hydrogen chloride in 1,4-dioxane (4N, 20 mL) and reacted at 25° C. until the starting material was completely converted. The reaction solution was concentrated to dryness under reduced pressure to give compound 29c hydrochloride (390.0 mg). MS m / z (ESI): 197.1 [M+H] + .

[0392] Step 3: Preparation of 2-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 29)

[0393] The hydrochloride salt of compound 29c (86.0 mg), compound 119d (55.5 mg) and K 2 CO 3 (122.7 mg) was added to DMF (5 mL) and heated to 125° C. to react until the raw material was completely converted. After the reaction was completed, the reaction solution was washed with saturated aqueous sodium carbonate and extracted with EA (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to give compound 29 (17.0 mg). MS m / z (ESI): 460.9 [M+H] + .

[0394] 1 H NMR (400MHz, DMSO-d 6 )δ12.41(s,1H),11.12(s,1H),8.97(d,J=2.4Hz,1H),8.31(dd,J=9.2,2.4Hz,1H ),8.25(t,J=1.6Hz,1H),8.20(d,J=2.4Hz,1H),7.59(dt,J=11.6,2.4Hz,1H),7. 14(d,J=9.2Hz,1H),6.90-6.80(m,2H),4.87-4.81(m,1H),4.19-4.13(m,2H),3. 85-3.73(m,2H),2.47(s,3H),2.28(s,3H),2.11-2.05(m,2H),1.72-1.63(m,2H).

[0395] Example 52: 2-(6-(6-((R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 52-1 / Compound 52-2) [ka]

[0396] Compound 52 (100 mg) was resolved by chiral Prep-HPLC to obtain compound 52-1 (retention time 6.788 min) and compound 52-2 (retention time 10.115 min). The two compounds are defined separately based on the retention time before and after the chiral resolution. This resulted in compound 52-1 (14 mg, ee: 98.85%), MS m / z (ESI): 55 2.3[M+H] +, Compound 52-2 (20 mg, ee:99.22%), MS m / z (ESI): 552.3 [M+H] + obtained. Chiral HPLC separation conditions:

[0397] Instrument type: Shimadzu LC-20AD, column: CHIRALPAK IE (IE00CD-RH008), 0.46 cm I.D. × 15 cm L, column temperature: 35°C, flow rate: 1.0 mL / min, detection wavelength: 254 nm, mobile phase: MeOH:CAN:DEA = 80:20:0.1 (V / V / V); the peak generation time of compound 52-1 was 6.788 min, and the peak generation time of compound 52-2 was 10.115 min.

[0398] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.66(d,J=4.6Hz,1H),8.43(d,J=2Hz,1H),8.41 (d,J=2.4Hz,1H),8.01(dd,J=8.5,1.9Hz,1H),7.90(dd,J=16.8,6.4Hz,2H),6.82(br,1H),6.75(d,J= 8.8Hz,1H),6.29(br,1H),3.95-3.81(m,2H),3.77(q,J=6.1Hz,1H),3.63(s,1H),3.53-3.38(m,3H), 2.55-2.53(m,1H),2.32(s,3H),2.25(s,3H),1.55(d,J=8.4Hz,1H),1.22(d,J=6.2Hz,3H).(Compound 52-1)

[0399] 1 H NMR (400MHz, DMSO-d 6)δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.66(d,J=4.6Hz,1H),8.43(d,J=2Hz,1H),8.41 (d,J=2.4Hz,1H),8.00(dd,J=8.5,1.9Hz,1H),7.89(dd,J=16.8,6.4Hz,2H),6.82(br,1H),6.75(d,J= 8.8Hz,1H),6.27(br,1H),3.95-3.81(m,2H),3.76(q,J=6.1Hz,1H),3.62(s,1H),3.53-3.38(m,3H), 2.55-2.51(m,1H),2.32(s,3H),2.25(s,3H),1.54(d,J=8.4Hz,1H),1.21(d,J=6.2Hz,3H).(Compound 52-2)

[0400] Example 53: 2-(6-(6-((6-(5-cyclopropoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 30) [ka] Step 1: Preparation of t-butyl 3-cyclopropoxy-1H-pyrazole-1-carboxylate (compound 30b)

[0401] Compound 27b (300 mg), 30a (141.89 mg) and triphenylphosphine (640.09 mg) were added to toluene (10 mL) and cooled to 0° C. DIAD (493.51 mg) was added dropwise and the mixture was heated to 110° C. and reacted for 6 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel flash column chromatography (PE:EA=23:77) to obtain compound 30b (60 mg). Step 2: Preparation of 3-cyclopropoxy-1H-pyrazole (compound 30c)

[0402] Compound 30b (102 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 2 mL) and THF (2 mL) and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to give compound 30c hydrochloride (73 mg). MS m / z (ESI): 125.1 [M+H] + . Step 3: Preparation of 2-(5-cyclopropoxy-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (compound 30d)

[0403] Compound 30c hydrochloride (69.81 mg), compound 121a (100 mg), N,N'-dimethylethylenediamine (38.32 mg), cesium carbonate (424.87 mg) and CuI (82.78 mg) were added in order to DMF (10 mL), heated to 110 °C and stirred for 3 h. The reaction solution was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 30d (80 mg). MS m / z (ESI): 273.9 [M + H] + Step 4: Preparation of 6-(5-cyclopropoxy-1H-pyrazol-1-yl)nicotinaldehyde (compound 30e)

[0404] Compound 30d (80 mg) was added to a mixture of hydrogen chloride in 1,4-dioxane (4N, 3 mL) and EA (2 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and diluted with DCM (30 mL). It was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 30e (55 mg). ) was obtained. MS m / z (ESI): 229.9 [M+H] + .

[0405] Step 5: Preparation of 2-(6-(6-((6-(5-cyclopropoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 30)

[0406] Compound 30e (40 mg), 1g (40 mg), and tetraisopropyl titanate (26.01 mg) were placed in a 5 mL reaction bottle, dried THF (2 mL) was added, and the mixture was heated to 75° C. and stirred for 16 h. Then, sodium triacetoxyborohydride (26.01 mg) was added, and the mixture was stirred at 75° C. for 8 h. The reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (0.1 mL) was added to quench the reaction. The reaction solution was concentrated and pre-purified by preparative TLC (DCM:MeOH=10:1) to obtain 25 mg of crude product (R f =0.35-0.45), which was then separated and purified by Prep-HPLC to obtain compound 30 (10 mg). MS m / z (ESI): 575.9 [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d 6 )δ11.95(s,1H),9.62(s,1H),9.12(d,J=2.3Hz,1H),8.46-8.41(m,2H),8.34(d,J=2.2Hz, 1H),7.92(dd,J=8.4,2.2Hz,1H),7.67(d,J=8.4Hz,1H),6.78(d,J=9.0Hz,2H),6.29(s,1H ),6.17(d,J=2.7Hz,1H),4.10(tt,J=6.0,3.2Hz,1H),3.84-3.68(m,4H),3.66-3.48(m,4H ),2.60-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H),0.79-0.68(m,4H).

[0408] Example 54: 2-(6-(6-((6-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 31) [ka] Step 1: Preparation of methyl 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-3-carboxylate (compound 31b)

[0409] In a reaction bottle, compound 121a (2.0 g), 31a (1.12 g), and Cs 2 CO 3 (5.72 g), trans-N,N'-dimethylcyclohexanediamine (504.72 mg), CuI (337.89 mg) and DMF (10 mL) were added and heated to 90 °C under nitrogen protection for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE = 20:80) to obtain compound 31b (2.2 g). MS m / z (ESI): 276.0 [M + H] + . Step 2: Preparation of (1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 31c)

[0410] Compound 31b (2.2 g) was dissolved in THF (20 mL) and the temperature was lowered to -20°C. LiAlH 4 (464.31 mg) was slowly added in batches and reacted for 15 min while maintaining the temperature. After the reaction was completed, EA (1 mL) was slowly added dropwise to remove excess LiAlH 4The reaction was then quenched by adding water (1 mL) dropwise, diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE = 50:50) to give compound 31c (1.24 g). MS m / z (ESI): 248.0 [M + H] + . Step 3: Preparation of 5-(1,3-dioxolan-2-yl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridine (compound 31d)

[0411] Dry DCM (20 mL) was cooled to -40°C under nitrogen protection, and bis(2-methoxyethyl)aminosulfur trifluoride (2.86 g) was slowly added dropwise. Compound 31c (0.8 g) in DCM solution (20 mL) was added dropwise to the reaction solution, and the reaction solution was gradually warmed to 25°C and reacted for 20 h. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and bubbled. After the release of was completed, it was extracted with DCM (20mLx3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE=20:80) to give compound 31d (200mg). MS m / z (ESI): 249.9[M+H] + . Step 4: Preparation of 6-(3-(fluoromethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 31e)

[0412] Compound 31d (200 mg) was dissolved in THF (5 mL), and hydrochloric acid (2N, 2.3 mL) was added to the solution and reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was diluted with water (20 mL) and saturated NaHCO 3 The pH was adjusted to 7-8 with aqueous solution. It was directly concentrated and separated and purified by silica gel flash column chromatography (EA:PE=15:85) to obtain compound 31e (110 mg). MS m / z (ESI): 206.0 [M+H] +.

[0413] Step 5: Preparation of 2-(6-(6-((6-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 31)

[0414] Compound 1g (87 mg), 31e (110 mg), and tetraisopropyl titanate (278.46 mg) were dissolved in dry THF (10 mL), heated to 75 ° C., and reacted for 8 h. The reaction solution was cooled to 25 ° C., sodium triacetoxyborohydride (259.57 mg) was added to the reaction bottle, and reacted for 12 h while maintaining the temperature at 25 ° C. Water (1 mL) was added dropwise to quench the reaction, and the mixture was concentrated and then pre-purified by silica gel flash column chromatography (DCM:MeOH = 90:10), and further separated and purified by Prep-HPLC to obtain compound 31 (25 mg). MS m / z (ESI): 551.8 [M + H] + .

[0415] 1 H NMR (400MHz, DMSO-d 6 )δ9.63(s,1H),9.13(d, J =2.0Hz,1H),8.62(d, J =2.4Hz,1H),8.49-8.39(m,2H),8.15(s,1H),7.99(dd, J =8.4,1.6Hz,1H),7.90-7.84(m,1H),7.07-6.74(m,2H),6.70(s,1H),6.30(br,1H),5.53(s,1H),5.4 1(s,1H),3.81-3.73(m,4H),3.67-3.58(m,4H),2.63-2.53(m,1H),2.34(s,3H),2.26(s,3H),1.61(d, J = 8.4Hz, 1H).

[0416] Example 55: 2-(6-(6-((6-(5-ethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 46) [ka] Step 1: Preparation of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 46a)

[0417] Compound 86a (2g) was placed in 3,4-dihydropyran (6mL), and TFA (334.97mg) was added, and the mixture was heated to 100℃ and stirred for 16h. Water (100mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with EA (50mLx3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA=60:1-10:1) to obtain compound 46a (2.4g). MS m / z (ESI): 153.2[M+H] + . Step 2: Preparation of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 46b)

[0418] Compound 46a (2 g) was placed in dry THF (30 mL), and n-butyl lithium (2.5 M, 6.31 mL) was added at -78 ° C., and the mixture was stirred for 1 h. Then, ethyl iodide (3.07 g) was slowly added at -78 ° C., and the mixture was slowly warmed to room temperature and stirred for 5 h. Methanol (50 mL) was added to the reaction solution to quench the reaction, and silica gel was directly added and stirred, and the mixture was separated and purified by column chromatography (PE:EA = 40:1 to 5:1) to obtain compound 46b (721 mg). MS m / z (ESI): 181.0 [M + H] + . Step 3: Preparation of 5-ethyl-1H-pyrazole (compound 46c)

[0419] Compound 46b (721 mg) was placed in MeOH (7 mL) and hydrogen chloride in 1,4-dioxane (4N, 1 mL) was added and stirred at 25° C. for 1 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and extracted with EA (80 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried by rotary evaporation to give compound 46c (185 mg). MS m / z (ESI): 97.1 [M+H] + . Step 4: Preparation of 5-(1,3-dioxolan-2-yl)-2-(5-ethyl-1H-pyrazol-1-yl)pyridine (compound 46d)

[0420] Compound 121a (401 mg) and 46c (184.31 mg) were dissolved in DMF (15 mL). Then, N,N-dimethylethylenediamine (153.39 mg), cesium carbonate (1.7 g) and CuI (331.96 mg) were added in order, and the mixture was heated to 110 °C under the protection of nitrogen and stirred for 10 h. Water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA = 40:1 to 3:1) to obtain compound 46d (199 mg). MS m / z (ESI): 245.9 [M + H] + . Step 5: Preparation of 6-(5-ethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 46e)

[0421] Compound 46d (200 mg) was dissolved in THF (4 mL) and H 22H2O (2 mL), and hydrogen chloride in 1,4-dioxane (4N, 1 mL) was added, and the mixture was stirred at 25° C. for 5 h. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with EA (50 mL×3). The organic phases were combined, washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA=40:1-3:1) to obtain compound 46c (91 mg). MS m / z (ESI): 202.1 [M+H] + .

[0422] Step 6: Preparation of 2-(6-(6-((6-(5-ethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 46)

[0423] Compound 1g (40.93 mg), 46e (25 mg) and tetraisopropyl titanate (128.41 mg) were added to dry THF (10 mL), purged with nitrogen three times, and then stirred at 75° C. for 10 h. Then, sodium triacetoxyborohydride (119.69 mg) was added in batches, followed by stirring at 75° C. for 6 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 46 (8 mg). MS m / z (ESI): 547.9 [M+H] + .

[0424] 1 H NMR (400MHz, DMSO-d 6)δ11.98(s,1H),9.65(s,1H),9.12(d,J=2.0Hz,1H),8.47(d,J=2.4Hz,1H),8.44(dd,J=9.20,2. 4Hz,1H),8.36(d,J=1.6Hz,1H),7.93(dd,J=8.4,2.0Hz,1H),7.81(d,J=8.4Hz,1H),7.20-6.69(m ,2H),6.40(d,J=2.8Hz,1H),6.32(s,1H),3.83-3.68(m,4H),3.66-3.53(m,4H),2.66(q,J=7.6Hz ,2H),2.61-2.53(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.4Hz,1H),1.23(t,J=7.6Hz,3H).

[0425] Example 56: 2-(6-(6-((6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 122) [ka] Step 1: Preparation of 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 122a)

[0426] Compound 91a (500 mg) was added to 3,4-dihydropyran (2.5 mL), and TFA (129.96 mg) was added, and the mixture was heated to 100° C. and stirred for 16 h. Water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (50 mL×3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA=50:1-10:1) to obtain compound 122a (901 mg). MS m / z (ESI): 171.1 [M+H] + . Step 2: Preparation of 4-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 122b)

[0427] Compound 122a (900 mg) was placed in dry THF (10 mL), and n-butyl lithium (2.5 M, 2.33 mL) was added at -78 ° C., and the mixture was stirred for 1 h. Then, methyl iodide (1.13 g) was slowly added at -78 ° C., and the mixture was gradually warmed to room temperature and stirred for 3 h. Methanol was added to the reaction liquid to quench the reaction, and the reaction was extracted with EA (80x3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (DCM:MeOH = 60:1 to 10:1) to obtain compound 122b (845 mg) as a pale yellow liquid. MS m / z (ESI): 185.0 [M+H] + . Step 3: Preparation of 4-fluoro-5-methyl-1H-pyrazole (compound 122c)

[0428] Compound 122b (800 mg) was placed in MeOH (7 mL) and hydrogen chloride in 1,4-dioxane (4N, 7 mL) was added and stirred at 25° C. for 1 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and extracted with EA (80 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 122c (300 mg). MS m / z (ESI): 101.2 [M+H] + . Step 4: Preparation of 5-(1,3-dioxolan-2-yl)-2-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridine (compound 122d)

[0429] Compounds 121a (300 mg) and 122c (143.58 mg) were dissolved in DMF (15 mL ), and N,N-dimethylethylenediamine (114.75 mg), cesium carbonate (1.27 g) and CuI (248.35 mg) were added in order, and the mixture was heated to 110°C under the protection of nitrogen and stirred for 10 h. Water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA = 50:1 to 10:1) to obtain compound 122d (254 mg). MS m / z (ESI): 249.9 [M+H] + . Step 5: Preparation of 6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 122e)

[0430] Compound 122d (240 mg) was dissolved in THF (5 mL) and H 2 2H2O (2 mL), a solution of hydrogen chloride in 1,4-dioxane (4N, 991.74 uL) was added, and the mixture was stirred at 25° C. for 5 h. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL) and extracted with EA (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 122e (55 mg). MS m / z (ESI): 205.9 [M+H] + .

[0431] Step 6: Preparation of 2-(6-(6-((6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 122)

[0432] Compound 1g (101 mg), 122e (51.98 mg) and tetraisopropyl titanate (288.01 mg) were added to dry THF (25 mL), purged with nitrogen three times, and then stirred at 75° C. for 10 h. Then, sodium triacetoxyborohydride (268.46 mg) was added in batches, followed by stirring at 75° C. for 6 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 122 (22 mg). MS m / z (ESI): 551.8 [M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d 6 )δ11.99(s,1H),9.65(s,1H),9.13(d,J=4.0Hz,1H),8.57(d,J=4.8Hz,1H),8.44 (dd,J=8.8,2.0Hz,1H),8.37(s,1H),7.94(dd,J=8.4,1.6Hz,1H),7.80(d,J=8.4 Hz,1H),6.97-6.74(m,2H),6.31(s,1H),3.81-3.69(m,4H),3.66-3.52(m,4H),2 .59-2.53(m,1H),2.33(s,3H),2.28(s,3H),2.24(s,3H),1.59(d,J=8.4Hz,1H).

[0434] Example 57: 2-(6-(6-((6-(1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 123) [ka] Step 1: Preparation of t-butyl 2-(5-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate (compound 123b)

[0435] Compound 123a (1.13 g), 8c (1.0 g), tetra(triphenylphosphine)palladium (310.62 mg) and sodium carbonate (1.71 g) were added to 1,4-dioxane (60 mL) and water (15 mL), and the mixture was heated to 95° C. under the protection of nitrogen for 14 h. After the reaction was completed, the mixture was concentrated to remove a part of the organic solvent, and extracted with EA. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA=5:1) to obtain compound 123b (1.25 g).

[0436] Step 2: Preparation of t-butyl 2-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrrole-1-carboxylate (compound 123c)

[0437] Compound 1g (50 mg), 123b (37.57 mg) and tetraisopropyl titanate (156.84 mg) were added to dry THF (5 mL) and stirred at 72°C for 18 h. Sodium triacetoxyborohydride (146.19 mg) was added and reacted at 72°C for 4 h. After completion of the reaction, the product was directly purified by silica gel column chromatography (DCM:MeOH=93:7) to obtain compound 123c (40 mg). MS m / z (ESI): 618.9 [M+H] + .

[0438] Step 3: Preparation of 2-(6-(6-((6-(1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 123)

[0439] A solution of hydrogen chloride in 1,4-dioxane (4N, 2.0 mL) was added dropwise to a solution of compound 123c (40 mg) in methanol (2 mL) and reacted at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, and excess potassium carbonate was added and stirred at room temperature for 0.5 h to liberate the hydrochloride salt. After filtration, the mixture was concentrated under reduced pressure and separated and purified by Prep-HPLC to obtain compound 123 (22 mg). MS m / z (ESI): 518.9 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),11.43(s,1H),9.66(s,1H),9.12(d,J=2.1Hz,1H),8.49-8.35(m,2 H),7.70(d,J=7.9Hz,1H),7.61(d,J=8.2Hz,1H),6.93-6.59(m,4H),6.31(s,1H),6. 12(dd,J=5.7,2.5Hz,1H),3.85-3.68(m,4H),3.65-3.49(m,4H),2.59-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.2Hz,1H).

[0441] Example 58: 2-(6-(6-((6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 124) [ka] Step 1: Preparation of 4-fluoro-3-iodo-1H-pyrazole (compound 124a)

[0442] 4-Fluoropyrazole (1.5 g), NIS (4.31 g) and chloroform (30 mL) were added in order to a reaction bottle, and the mixture was stirred at 80° C. for 7 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, directly added with silica gel and stirred, and then separated and purified by flash silica gel column chromatography (PE:EA=4:1) to obtain compound 124a (1.2 g). MS m / z (ESI): 213 [M+H] + . Step 2: Preparation of 5-(1,3-dioxolan-2-yl)-2-(4-fluoro-3-iodo-1H-pyrazol-1-yl)pyridine (compound 124b)

[0443] Compound 121a (576.33 mg), 124a (354 mg), cesium carbonate (1.63 g) and DMF (15 mL) were added to a reaction bottle in that order and stirred at 90° C. for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (20 mL) and extracted with EA. The organic phase was washed with water three times, dried over anhydrous sodium sulfate, filtered, concentrated and purified by C. 18 Compound 124b (300 mg) was obtained by separation and purification using a column (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 68:32). MS m / z (ESI): 362 [M+H] + .

[0444] Step 3: Preparation of 2-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)-5-(1,3-dioxolan-2-yl)pyridine (compound 124c)

[0445] In a reaction bottle, add cyclopropylboronic acid (89.20 mg), compound 124b (125 mg), palladium acetate (15.54 mg), potassium phosphate (257.17 mg), trimethylsilyl phosphate (1.0 mg), and 1,2-dichlorophenyl ether (1.0 mg). Cyclohexylphosphine (9.71 mg), toluene (5 mL) and water (1 mL) were added and stirred at 90°C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, silica gel was added directly and stirred, and the mixture was separated and purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 124c (70 mg). MS m / z (ESI): 276 [M+H] + . Step 4: Preparation of 6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 124d)

[0446] Compound 124c (70 mg) was dissolved in a mixture of THF (8 mL) and water (8 mL), and concentrated hydrochloric acid (5 mL, 37%) was added dropwise and stirred at 25° C. for 18 h. After the reaction was completed, a part of the solvent was removed by rotary evaporation, and the pH of the reaction solution was adjusted to about 9 with saturated aqueous sodium bicarbonate solution, and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (PE:EA=3:1) to obtain compound 124d (18 mg). MS m / z (ESI): 232 [M+H] + .

[0447] Step 5: Preparation of 2-(6-(6-((6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 124)

[0448] Compound 124d (18 mg), 1g (31.04 mg), isopropyl titanate (88.50 mg) and dry THF (5 mL) were added in order to a reaction bottle, and the mixture was stirred at 75° C. for 18 h under the protection of nitrogen. Then, sodium triacetoxyborohydride (82.49 mg) was added in batches, followed by stirring at 75° C. for 6 h. After the reaction was completed, a part of the solvent was removed by rotary evaporation, the pH of the reaction solution was adjusted to about 9 with saturated sodium bicarbonate solution, and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and pre-purified by preparative TLC (DCM:MeOH=9:1), and separated and purified by Prep-HPLC to obtain compound 124 (15 mg). MS m / z (ESI): 577.9 [M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.55(d,J=4.6Hz,1H),8.44(dd,J=8.9,2.2Hz ,1H),8.35(d,J=1.5Hz,1H),7.93(dd,J=8.5,2.0Hz,1H),7.76(d,J=8.5Hz,1H),6.82(br,1H),6.7 9(d,J=12Hz,1H),6.30(br,1H),3.84-3.75(m,4H),3.73-3.49(m,4H),2.59-2.53(m,1H),2.33(s, 3H),2.26(s,3H),2.02-1.93(m,1H),1.59(d,J=8.4Hz,1H),1.03-0.95(m,2H),0.94-0.86(m,2H).

[0450] Example 59: 2-(6-(6-((R)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 125-1 / Compound 125-2) [ka] Step 1: Preparation of 1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone (compound 125b)

[0451] Compound 86a (328.18 mg), 125a (500 mg) and cesium carbonate (1.57 g) were added in order to DMSO (5 mL), heated to 100° C. and stirred for 2 h. The reaction solution was cooled to room temperature, diluted with water, and extracted with EA. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (PE:EA=50:50) to obtain compound 125b (364 mg). MS m / z (ESI): 188.1 [M+H] + .

[0452] Step 2: Preparation of 2-(6-(6-(1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 125)

[0453] Compound 125b (309.90 mg), 1g (400 mg) and tetraisopropyl titanate (1.25 g) were placed in a 250 mL reaction bottle, dry THF (20 mL) was added, and the mixture was heated to 75 ° C and stirred for 16 h. Then, sodium triacetoxyborohydride (1.17 g) was added and stirred at 75 ° C for 2 h. The reaction solution was cooled to room temperature, and the reaction was quenched by adding saturated aqueous ammonium chloride solution (3 mL). The reaction solution was concentrated and separated and purified by silica gel flash column chromatography (DCM:MeOH = 9:1) to obtain compound 125 (270 mg). MS m / z (ESI): 533.9 [M + H] + .

[0454] Step 3: Preparation of 2-(6-(6-((R)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 125-1 / Compound 125-2)

[0455] Compound 125 (250 mg) was resolved by chiral Prep-HPLC to give compound 125-1 (retention time 7.647 min) and compound 125-2 (retention time 11.638 min). The two compounds were defined separately based on the retention time before and after chiral resolution, and no stereochemical identification was performed. This resulted in compound 125-1 (101 mg, ee: 100%), MS m / z (ESI): 533.9 [M+H] + , Compound 125-2 (100mg, ee:99.93%), MS m / z (ESI):533.9[M+H] + obtained. Chiral HPLC separation conditions

[0456] Instrument type: Shimadzu LC-20AD, column: CHIRALPAK IE-3 (IE30CD-UL006), 0.46 cm I.D. × 15 cm L, column temperature: 25°C, flow rate: 1.0 mL / min, detection wavelength: 254 nm, mobile phase: MeOH:ACN:DEA = 70:30:0.1 (V / V / V), peak generation time of compound 125-1 was 7.647 min, and peak generation time of compound 125-2 was 11.638 min.

[0457] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.3Hz,1H),8.59(s,1H),8.47-8.39(m,2H),7.99(d ,J=6.4Hz,1H),7.89(d,J=7.4Hz,1H),7.81(s,1H),6.75(d,J=9.0Hz,2H),6.56(s,1H),6.31 (s,1H),3.96-3.83(m,2H),3.75(d,J=3.3Hz,1H),3.63(s,1H),3.54-3.36(m,3H),2.57-2.5 3(m,1H),2.33(s,3H),2.25(s,3H),1.54(d,J=6.9Hz,1H),1.22(d,J=2.5Hz,3H).(Compound 125-1)

[0458] 1 H NMR (400MHz, DMSO-d 6)δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.3Hz,1H),8.59(d,J=2.6Hz,1H),8.47-8.39(m,2H),8.00( dd,J=8.5,2.2Hz,1H),7.90(d,J=8.4Hz,1H),7.81(d,J=1.6Hz,1H),6.75(d,J=9.0Hz,2H),6.57(t,J= 2.1Hz,1H),6.31(s,1H),3.96-3.83(m,2H),3.76(q,J=6.2Hz,1H),3.63(s,1H),3.54-3.36(m,3H),2 .57-2.53(m,1H),2.33(s,3H),2.25(s,3H),1.55(d,J=8.4Hz,1H),1.23(d,J=6.1Hz,3H).(Compound 125-2)

[0459] Example 60: 2-(6-(6-((6-(4-fluoromethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 126) and (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 127) [ka] Step 1: Preparation of ethyl 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (compound 126b)

[0460] In a reaction bottle, compound 121a (3.0 g), 126a (1.86 g), and Cs 2 CO 3(8.67 g), trans-N,N'-dimethylcyclohexanediamine (757.08 mg), CuI (506.84 mg) and DMF (15 mL) were added and heated to 90 °C under nitrogen protection for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE = 20:80) to obtain compound 126b (3.31 g). MS m / z (ESI): 290.0 [M + H] + . Step 2: Preparation of 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 126c)

[0461] Compound 126b (3.31 g) was dissolved in THF (30 mL) and the temperature was lowered to -20°C. LiAlH 4 (651.40 mg, 16.99 mmol) was slowly added in batches and the reaction was allowed to proceed for 15 min while maintaining the temperature. After the reaction was completed, EA (2 mL) was slowly added dropwise to remove excess LiAlH 4 The reaction was then quenched by adding water (1 mL) dropwise, diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE=50:50) to give compound 126c (2.30 g). MS m / z (ESI): 248.0 [M+H] + . Step 3: Preparation of 5-(1,3-dioxolan-2-yl)-2-(4-(fluoromethyl)-1H-pyrazol-1-yl)pyridine (compound 126d)

[0462] Dry DCM (30 mL) was cooled to -40°C under nitrogen protection, and diethylaminosulfur trifluoride (6.06 g) was slowly added dropwise. Compound 126c (2.30 g) in DCM (30 mL) was added dropwise to the reaction solution, and the reaction solution was slowly heated to 25°C and reacted for 20 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution, and after the release of air bubbles was completed, it was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel flash column chromatography (EA:PE = 20:80) to obtain compound 126d (684 mg). MS m / z (ESI): 249.9 [M + H] + . Step 4: Preparation of 6-(4-(fluoromethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 126e)

[0463] Compound 126d (684 mg) was dissolved in THF (10 mL), hydrochloric acid (1N, 5 mL) was added to the solution, and the reaction was carried out at 25° C. for 16 h. After the reaction was completed, the reaction solution was diluted with water (20 mL) and saturated NaHCO 3 The pH was adjusted to 7-8 with aqueous solution. It was directly concentrated to remove THF, and DCM (30 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated to give compound 126e (460 mg). MS m / z (ESI): 206.0 [M+H] + .

[0464] Step 5: Preparation of 2-(6-(6-((6-(4-fluoromethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 126) and (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 127)

[0465] Compound 1g (200 mg), 126e (182 mg), and tetraisopropyl titanate (640 mg) were dissolved in dry THF (40 mL), heated to 75° C., and reacted for 8 hours. The reaction solution was cooled to 25° C., sodium triacetoxyborohydride (597 mg) was added to the reaction bottle, and reacted for 12 hours while maintaining the temperature at 25° C. Water (1 mL) was added dropwise to quench the reaction, and the mixture was concentrated and then separated and pre-purified by silica gel flash column chromatography (DCM:MeOH=90:10) to obtain a crude product (a mixture of compounds 126 and 127), which was then separated and purified by Prep-HPLC to obtain compound 126 (21 mg):MS m / z (ESI): 552.3 [M+H] + , Compound 127 (19mg):MS m / z (ESI):550.3[M+H] + obtained.

[0466] 1 H NMR (400MHz, DMSO-d 6 )δ12.00(br,1H),9.65(s,1H),9.13(d, J =2.2Hz,1H),8.77(d, J =3.2Hz,1H),8.44(dd, J =8.8,2.2Hz,2H),7.99(dd, J =8.4,2.0Hz,1H),7.94(s,1H),7.91-7.96(m,1H),6.95-6.69(m,2H),6.30(br,1H),5.46(s,1H),5.3 4(s,1H),3.82-3.70(m,4H),3.68-3.52(m,4H),2.59-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d, J =8.4Hz,1H).(Compound 126)

[0467] 1 H NMR (400MHz, DMSO-d 6 )δ12.04(br,1H),9.66(s,1H),9.13(d, J =2.2Hz,1H),8.52-8.35(m,3H),7.95(dd, J =8.4,1.6Hz,1H),7.88-7.81(m,1H),7.73(s,1H),6.99-6.64(m,2H),6.31(br,1H),5.05(br,1H),4.4 5(s,2H),3.93-3.70(m,4H),3.67-3.51(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d, J =8.4Hz,1H).(Compound 127)

[0468] Example 61: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 128) [ka] Step 1: Preparation of 6-(1H-pyrrol-2-yl)nicotinaldehyde (compound 128a)

[0469] A solution of hydrogen chloride in 1,4-dioxane (4N, 6.0 mL) was added dropwise to a solution of compound 123b (500 mg) in methanol (10 mL) and reacted at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, and excess potassium carbonate was added and stirred at room temperature for 0.5 h to liberate the hydrochloride salt. After filtration, the mixture was concentrated under reduced pressure and separated and purified by silica gel column chromatography (PE:EA=4:1) to obtain compound 128a (250 mg). MS m / z (ESI): 173.0 [M+H] + . Step 2: Preparation of 5-(1,3-dioxolan-2-yl)-2-(1H-pyrrol-2-yl)pyridine (compound 128b)

[0470] Compound 128a (250 mg), ethylene glycol (180 mg) and p-toluenesulfonic acid (27.6 mg) were added to toluene (15 mL) and reacted under reflux for 18 h. After completion of the reaction, the reaction solution was diluted with EA and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 128b (290 mg). MS m / z (ESI): 217.0 [M+H] + . Step 3: Preparation of 5-(1,3-dioxolan-2-yl)-2-(1-methyl-1H-pyrrol-2-yl)pyridine (compound 128c)

[0471] Compound 128b (250 mg) was dissolved in dry DMF (5 mL), and under the protection of nitrogen, NaH (138.7 mg, purity 60%) was added at 0° C. and stirred for 15 min. Methyl iodide (820 mg) was added and reacted at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into saturated saline, extracted with EA, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA=5:1) to obtain compound 128c (125 mg). MS m / z (ESI): 231.0 [M+H] + . Step 4: Preparation of 6-(1-methyl-1H-pyrrol-2-yl)nicotinaldehyde (compound 128d)

[0472] Dilute hydrochloric acid (2N, 2.0mL) was added dropwise to a solution of compound 128c (110mg) in THF (4.0mL) and reacted at room temperature for 3h. After completion of the reaction, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, and excess potassium carbonate was added and stirred at room temperature for 0.5h to liberate the hydrochloride salt. After filtration, the mixture was concentrated under reduced pressure and separated and purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 128d (75mg).

[0473] Step 5: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 128)

[0474] Compound 1g (40 mg), 128d (25 mg) and tetraisopropyl titanate (125 mg) were added to dry THF (5 mL) and stirred at 72°C for 10 h. Then, sodium triacetoxyborohydride (117 mg) was added and reacted at 72°C for 6 h. After the reaction was completed, the mixture was directly pre-purified by silica gel column chromatography (DCM:MeOH=93:7), and further separated and purified by Prep-HPLC to obtain compound 128 (34 mg). MS m / z (ESI): 532.9 [M+H] + .

[0475] 1 H NMR (400MHz, CD 3OD) δ9.14(d,J=2.1Hz,1H),8.59-8.43(m,2H),7.78(dd,J=8.2,2.2Hz,1H),7.55 (d,J=8.2Hz,1H),6.85(d,J=9.0Hz,1H),6.81-6.65(m,2H),6.50(dd,J=3.7,1.8 Hz,1H),6.35(s,1H),6.10(dd,J=3.7,2.7Hz,1H),4.02-3.77(m,7H),3.77-3.59 (m,4H),2.73(d,J=6.3Hz,1H),2.41(s,3H),2.32(s,3H),1.71(d,J=8.8Hz,1H).

[0476] Example 62: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(thiazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 129) [ka] Step 1: Preparation of 4-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)thiazole (compound 129b)

[0477] Compound 129a (325 mg), 121a (200 mg) and tetra(triphenylphosphine)palladium (50 mg) were added to toluene (10 mL) and reacted at 120° C. for 6 hours. After the reaction was completed, the reaction solution was concentrated to dryness and purified by silica gel column chromatography ( Compound 129b (115 mg) was obtained after separation and purification with PE:EA=2:1). MS m / z (ESI): 235.1 [M+H] + . Step 2: Preparation of 6-(thiazol-4-yl)nicotinaldehyde (compound 129c)

[0478] Dilute hydrochloric acid (2.0 mL, 3N) was added dropwise to a solution of compound 129b (115 mg) in THF (3.0 mL) and reacted at room temperature for 15 h. After completion of the reaction, saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to adjust the pH of the solution to about 10, and then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 129c (83 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 191.1 [M+H] + .

[0479] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(thiazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 129)

[0480] Compound 1g (50 mg), 129c (26.2 mg) and tetraisopropyl titanate (156.8 mg) were added to dry THF (5 mL) and reacted for 10 h with stirring at 72 ° C., and then sodium triacetoxyborohydride (146.2 mg) was added and reacted for 6 h at 72 ° C. After the reaction was completed, the crude product was directly purified by silica gel column chromatography (DCM:MeOH = 8:1), and then separated and purified by Prep-HPLC to obtain compound 129 (51 mg). MS m / z (ESI): 537.3 [M + H] + .

[0481] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.66(s,1H),9.22(d,J=2.1Hz,1H),9.13(d,J=2.1Hz,1H),8.58(d,J=1.6Hz,1H),8.44(dd ,J=8.9,2.3Hz,1H),8.29(d,J=2.0Hz,1H),8.06(d,J=8.0Hz,1H),7.88(dd,J=8.1,2.2Hz,1H),7.01-6.64(m ,2H),6.33(s,1H),3.87-3.49(m,8H),2.61-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0482] Example 63: 2-(6-(6-([[2,2'-bipyridin]-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 130) [ka] Step 1: Preparation of 5-(1,3-dioxolan-2-yl)-2,2′-bipyridine (compound 130b)

[0483] Compound 130a (320 mg), 121a (200 mg) and tetra(triphenylphosphine)palladium (50 mg) were placed in toluene (10 mL) and subjected to a microwave reaction at 120° C. for 4 h. After completion of the reaction, the reaction solution was concentrated to dryness, and the mixture was separated and purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain compound 130b (100 mg). MS m / z (ESI): 229.1 [M+H] + . Step 2: Preparation of [2,2'-bipyridine]-5-formaldehyde (compound 130c)

[0484] Dilute hydrochloric acid (5.0 mL, 3N) was added dropwise to a solution of compound 130b (100 mg) in THF (5.0 mL) and reacted at room temperature for 15 h. After completion of the reaction, saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to adjust the pH of the solution to about 10, and then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 130c (45 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 185.2 [M+H] + .

[0485] Step 3: Preparation of 2-(6-(6-([[2,2'-bipyridin]-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 130)

[0486] Compound 1g (50 mg), 130c (25.4 mg) and tetraisopropyl titanate (156.8 mg) were added to dry THF (5 mL) and reacted for 10 h with stirring at 72 ° C., and sodium triacetoxyborohydride (146.2 mg) was added and reacted for 6 h at 72 ° C. After the reaction was completed, the crude product was directly purified by silica gel column chromatography (DCM:MeOH = 10:1), and then separated and purified by Prep-HPLC to obtain compound 130 (40 mg). MS m / z (ESI): 531.3 [M + H] + .

[0487] 1 H NMR (400MHz, DMSO-d 6 )δ11.97(s,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.75-8.57(m,2H) ,8.44(dd,J=8.9,2.3Hz,1H),8.35(dd,J=9.7,8.2Hz,2H),7.93(ddd,J=8.3,5.9,1.9Hz,2H),7.44(ddd,J=7.5,4.8,1.1Hz,1H),7.08-6.57(m,2 H),6.31(s,1H),3.82-3.57(m,8H),2.63-2.56(m,1H),2.33(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0488] Example 64: 2-(6-(6-((6-(5-fluoro-1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 131) [ka] Step 1: Preparation of 6-(5-fluoro-1H-pyrrol-2-yl)nicotinaldehyde (compound 131a)

[0489] Compound 128a (200 mg) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (432 mg, selective fluorine reagent) were added to acetonitrile (15 mL) and subjected to a microwave reaction at 70°C for 10 min. After completion of the reaction, the reaction solution was concentrated to dryness, and separated and purified by silica gel column chromatography (PE:EA=5:1) to obtain compound 131a (60 mg). MS m / z (ESI): 191.1 [M+H] + .

[0490] Step 2: Preparation of 2-(6-(6-((6-(5-fluoro-1H-pyrrol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 131)

[0491] Compound 1g (50 mg), 131a (26.2 mg) and tetraisopropyl titanate (156.8 mg) were added to dry THF (5 mL) and reacted for 10 h with stirring at 72 ° C., and sodium triacetoxyborohydride (146.2 mg) was added and reacted for 6 h at 72 ° C. After completion of the reaction, the product was directly crudely purified by silica gel column chromatography (DCM:MeOH = 8:1), and then separated and purified by Prep-HPLC to obtain compound 131 (9 mg). MS m / z (ESI): 537.3 [M + H] + .

[0492] 1 H NMR (400MHz, DMSO-d 6)δ12.06(s,1H),11.98(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.43(dd,J =8.9,2.3Hz,1H),8.39(d,J=1.3Hz,1H),7.74-7.65(m,1H),7.57(d,J=8.2Hz, 1H),6.92-6.72(m,2H),6.57(t,J=4.2Hz,1H),6.31(s,1H),5.57(t,J=3.8Hz, 1H),3.76(d,J=11.2Hz,2H),3.70(d,J=5.7Hz,2H),3.63-3.52(m,4H),2.60-2 .55(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.2Hz,1H).

[0493] Example 65: 2-(6-(6-((6-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 132) [ka] Step 1: Preparation of 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinaldehyde (compound 132b)

[0494] Compound 132a (2.24 g), 8c (1 g), tetra(triphenylphosphine)palladium (310.6 mg) and 1,4-dioxane (20 mL) were added in a reaction bottle in order, and a solution of sodium carbonate (1.71 g) in water (5 mL) was added, and the mixture was reacted for 5 h under nitrogen protection at 95 ° C. with stirring. After the reaction was completed, water was added to dilute the mixture and extracted with EA (20 mL × 3). The organic phases were combined, washed once with water and saturated brine in order, dried over anhydrous sodium sulfate, filtered, concentrated and separated and purified by flash column chromatography (DCM:MeOH = 96:4) to obtain compound 132b (1.14 g).

[0495] Step 2: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 132c)

[0496] Compound 1g (500 mg) and 132b (477.8 mg) were dissolved in DMA (10 mL) and reacted at 25° C. with stirring for 2 h. Then sodium triacetoxyborohydride (1.17 g) was added and reacted at 25° C. with continued stirring for 16 h. After completion of the reaction, it was quenched by adding water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 132c (697 mg). MS m / z (ESI): 604.3 [M+H] + .

[0497] Step 3: Preparation of 2-(6-(6-((6-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 132)

[0498] Compound 132c (697 mg) was dissolved in MeOH (15 mL) and TFA (0.86 mL) was added dropwise and reacted at 25° C. for 16 h. After completion of the reaction, saturated sodium bicarbonate solution was added to quench the reaction, and the pH of the solution was adjusted to about 9. The mixture was concentrated to remove methanol, diluted with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 132 (279 mg). MS m / z (ESI): 521.3 [M+H] + .

[0499] 1 H NMR (400MHz, DMSO-d 6)δ13.48(s,0.3H, tautomer 1),13.01(s,0.7H,tautomer 2),11.98(s,1H),9.66(s,1H),9. 13(d,J=2.2Hz,1H),8.52(s,1H),8.44(dd,J=8.9,2.3Hz,1H),8.01-7.64(m,3H),7. 01-6.59(m,3H),6.32(br,1H),3.85-3.68(m,4H ),3.68-3.45(m,4H),2.60-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0500] Example 66: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(5-methylfuran-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 133) [ka] Step 1: Preparation of 6-(5-methylfuran-2-yl)nicotinaldehyde (compound 133b)

[0501] In the reaction bottle, compound 133a (203.1 mg), 8c (200 mg), and Na 2 CO 3 (341.9 mg), tetra(triphenylphosphine)palladium (62.1 mg), water (2.5 mL) and 1,4-dioxane (10 mL) were added and reacted for 2 hours with stirring at 95°C. After completion of the reaction, the reaction solution was cooled to room temperature and directly separated and purified by silica gel column chromatography (PE:EA=87:13) to obtain compound 133b (124 mg). MS m / z (ESI): 188.1 [M+H] + .

[0502] Step 2: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(5-methylfuran-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 133)

[0503] Compound 133b (23.2 mg), 1g (30 mg) and DMA (1 mL) were added to the reaction bottle in order and reacted for 2 h with stirring at 25° C. Then sodium triacetoxyborohydride (70.2 mg) was added and reacted for 16 h with continued stirring at 25° C. After the reaction was completed, the reaction solution was separated and purified by Prep-HPLC to obtain compound 133 (9 mg). MS m / z (ESI): 534.3 [M+H] + .

[0504] 1 H NMR (400MHz, DMSO-d 6 )δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.2Hz,1H),8.48(d,J=1.5Hz,1H),8 .44(dd,J=8.9,2.3Hz,1H),7.78(dd,J=8.2,2.1Hz,1H),7.60(d,J=8.1Hz,1H) ,6.96(d,J=4.5Hz,1H),6.84(br,1H),6.78(d,J=9.0Hz,1H),6.31(br,1H),6. 25(dd,J=3.2,1.0Hz,1H),3.82-3.68(m,4H),3.68-3.45(m,4H),2.60-2.53(m ,1H),2.36(s,3H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0505] Example 67: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 134) [ka] Step 1: Preparation of 2-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)oxazole (compound 134b)

[0506] Compound 121a (300.0 mg) and 134a (467.0 mg) were dissolved in toluene (15.0 mL), and tetra(triphenylphosphine)palladium (75.3 mg) was added, and the mixture was stirred at 120° C. for 12 h under nitrogen protection. The reaction mixture was concentrated under reduced pressure, diluted with EA (200.0 mL), and the organic phase was washed with water three times and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA=7:3) to obtain compound 134b (78.0 mg). MS m / z (ESI): 219.1 [M+1] + . Step 2: Preparation of 6-(oxazol-2-yl)nicotinaldehyde (compound 134c)

[0507] Compound 134b (78.0 mg) was dissolved in a mixed solvent of THF (2.0 mL) and water (2.0 mL), and concentrated hydrochloric acid (1.0 mL, 12 N) was slowly added dropwise, and the mixture was stirred at 25° C. for 8 h. The reaction solution was adjusted to alkaline with an aqueous potassium carbonate solution, and extracted with EA (100.0 mL). The organic phase was washed with water three times, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (DCM:MeOH=9:1) to obtain compound 134c (51.0 mg). MS m / z (ESI): 175.1 [M+1] + .

[0508] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidin-4-amine (compound 134)

[0509] Compound 134c (28.8 mg) and 1g (30.0 mg) were dissolved in N,N-dimethylacetamide (1.0 mL) and stirred at 25° C. for 1 h. Then, sodium triacetoxyborohydride (70.2 mg) was added to the reaction system and stirred at 25° C. for 12 h. The reaction solution was diluted with EA (20 mL), washed with water three times, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by Prep-HPLC to obtain compound 134 (17.0 mg). MS m / z (ESI): 521.3 [M+1] + .

[0510] 1 H NMR (400MHz, DMSO-d 6 )δ12.00(s,1H),9.68(s,1H),9.14(d,J=2.4Hz,1H),8.66(s,1H),8.45 (dd,J=9.2,2.4Hz,1H),8.29(s,1H),8.06(d,J=8.4Hz,1H),7.95(d,J=8.0Hz,1H),7.45(s,1H),6.79(br,1H),6.78(d,J=8.8Hz ,1H),6.32(br,1H),3.79-3.75(m,4H),3.67-3.60(m,4H),2.58-2.56(m,1H),2.34(s,3H),2.26(s,3H),1.61(d,J=8.0Hz,1H).

[0511] Example 68: 2-(6-(6-((6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 135) [ka] Step 1: Preparation of 5-(1,3-dioxolan-2-yl)-2-(1H-pyrazol-4-yl)pyridine (compound 135b)

[0512] Compounds 121a (1.0 g) and 135a (1.0 g) were dissolved in 1,4-dioxane (30 mL) and H 2 HO (6 mL) and then Pd(dppf)Cl 2 (130mg) and K 2 CO 3 (1.5 g) was added and stirred at 95° C. for 2 h under nitrogen protection. After the reaction was completed, the temperature was lowered in an ice-water bath and filtered through diatomaceous earth. The filtrate was concentrated to dryness, separated and purified by MPLC to obtain compound 135b (452 ​​mg). MS m / z (ESI): 218.2 [M+H] + . MPLC Conditions:

[0513] Instrument type: Biotage Isolera Prime2.3.1; Column: Agela Technologies C18 spherical 20-35um 100A, 120g, Column temperature: 25°C, Flow rate: 30.0mL / min, Detection wavelength: 254nm, Elution gradient: (0min: 20%A, 80%B; 3.0min: 20%A, 80%B; 25min: 90%A, 10%B), Mobile phase A: Acetonitrile, Mobile phase B: 0.05% TFA aqueous solution. Step 2: Preparation of 5-(1,3-dioxolan-2-yl)-2-(1-isopropyl-1H-pyrazol-4-yl)pyridine (compound 135d)

[0514] Compound 135b (100 mg) and Cs 2 CO 3 (374.9 mg) was placed in dry DMF (10 mL), and compound 135c (195.6 mg) was added and stirred at 80° C. for 12 h. After completion of the reaction, water (100 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted with EA. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE:EA=1:1) to obtain compound 135d (52 mg). MS m / z (ESI): 260.0 [M+H] + . Step 3: Preparation of 6-(1-isopropyl-1H-pyrazol-4-yl)nicotinaldehyde (compound 135e)

[0515] Compound 135d (240 mg) was dissolved in THF (4 mL) and H 2 2H2O (2 mL) and HCl in 1,4-dioxane (4N, 1 mL) was added and stirred at 25 °C for 5 h. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 135e (40 mg). MS m / z (ESI): 216.1 [M+H].

[0516] Step 4: Preparation of 2-(6-(6-((6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 135)

[0517] Compound 1g (40 mg), 135e (26.1 mg) and tetraisopropyl titanate (31.4 mg) were added to dry THF (25 mL) and stirred at 75°C for 10 h under nitrogen protection. Sodium triacetoxyborohydride (23.4 mg) was then added to the reaction system and stirred at 75°C for 6 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 135 (2.1 mg). MS m / z (ESI): 562.1 [M+H] + .

[0518] 1 H NMR (400MHz, DMSO-d 6)δ11.98(s,1H),9.67(s,1H),9.12(d,J=2.0Hz,1H),8.56-8.39(m,2H),8.32(s,1H) ),7.97(s,1H),7.71(dd,J=8.0,2.0Hz,1H),7.59(d,J=8.0Hz,1H),7.05-6.65(m,2 H),6.33(s,1H),4.64-4.36(m,1H),3.94-3.63(m,4H),3.64-3.45(m,4H),2.62-2. 50(m,1H),2.31(s,3H),2.29(s,3H),1.56(d,J=8.0Hz,1H),1.45(d,J=6.4Hz,6H).

[0519] Example 69: 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-5-yl)propan-2-ol (compound 136) [ka]

[0520] Step 1: Preparation of 2-(1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 136a)

[0521] Compound 31b (200 mg) was placed in dry THF (10 mL) and cooled in a dry ice ethanol bath for 15 min. Then, methylmagnesium bromide in ethyl ether (3N, 0.65 mL) was slowly added dropwise and reacted for 15 min while maintaining the temperature, and then the temperature was raised to room temperature and reacted for 4 h. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (1 mL), diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 136a (200 mg). MS m / z (ESI): 276.1 [M+H] +. Step 2: Preparation of 6-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 136b)

[0522] Compound 136a (200 mg) was placed in THF (5 mL) and hydrochloric acid (2N, 4.5 mL) was added, followed by stirring at 25° C. for 12 h. The reaction mixture was adjusted to pH 7-8 by adding saturated aqueous sodium bicarbonate solution, and extracted with EA (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 136b (165 mg). MS m / z (ESI): 232.1 [M+H] + .

[0523] Step 3: Preparation of 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-5-yl)propan-2-ol (compound 136)

[0524] Compound 136b (50.5 mg) and compound 1g (30 mg) were placed in DMA (3 mL) and stirred at room temperature for 1 h under nitrogen protection. Then, sodium triacetoxyborohydride (101 mg) was added and reacted overnight while maintaining room temperature. After completion of the reaction, water (60 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Pre-HPLC to obtain compound 136 (12 mg). MS m / z (ESI): 578.3 [M + H] + .

[0525] 1 H NMR (400MHz, DMSO-d 6)δ12.14(br,1H),9.67(s,1H),9.12(d,J=2.0Hz,1H),8.50-8.41(m,2H),8.41-8.35(m,1H),7.99-7.92(m, 1H),7.82(d,J=8.4Hz,1H),6.79(d,J=9.2Hz,2H),6.52(d,J=2.4Hz,1H),6.31(br,1H),5.10(s,1H),3.82-3 .70(m,4H),3.68-3.55(m,4H),2.61-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.49(s,6H).

[0526] Example 70: (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 137) [ka] Step 1: Preparation of 6-(3-(hydroxymethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 137a)

[0527] Compound 31c (189 mg) was placed in THF (5 mL) and diluted hydrochloric acid (2N, 5 mL) was added and stirred at 25° C. for 2 h. The reaction mixture was adjusted to pH 7-8 by adding saturated aqueous sodium bicarbonate solution and extracted with EA (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 137a (157 mg). MS m / z (ESI): 204.1 [M+H] + .

[0528] Step 2: Preparation of (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 137)

[0529] Compound 137a (50.5 mg) and compound 1g (50 mg) were added to DMA (2 mL) and stirred at room temperature for 1 h under nitrogen protection. Then, sodium triacetoxyborohydride (159 mg) was added and reacted overnight while maintaining room temperature. After the reaction was completed, water (60 mL) was added to the reaction solution to quench the reaction, and the reaction was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Pre-HPLC to obtain compound 137 (10 mg). MS m / z (ESI): 550.3 [M + H] + .

[0530] 1 H NMR (400MHz, DMSO-d 6 )δ12.00(s,1H),9.68(s,1H),9.13(d,J=2.0Hz,1H),8.52(d,J=2.4Hz,1H),8 .44(dd,J=8.8,2.4Hz,1H),8.38(d,J=2.4Hz,1H),7.94(dd,J=8.4,2.0Hz,1H) ,7.82(d,J=8.4Hz,1H),7.06-6.65(m,2H),6.51(d,J=2.4Hz,1H),6.29(br,1H ),5.26(t,J=6.0Hz,1H),4.53(d,J=5.6Hz,2H),3.81-3.69(m,4H),3.67-3.49 (m,4H),2.59-2.53(m,1H),2.34(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0531] Example 71: 2-(6-(6-((6-(4-fluoro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 138) [ka] Compound 138 was prepared in accordance with the synthetic method of Example 56. MS m / z (ESI): 551.8 [M+H] + . Separation method:

[0532] The prep-HPLC purification of the compounds in Examples 1-51, 53-58, and 60-71 was carried out on an Aglient 1260, Waters 2489, or GeLai 3500 HPLC, the column temperature was 25° C., and the detection wavelength was 214 nm, 254 nm, or 280 nm. Other separation conditions are shown in the table below:

number

number

number

number

number

number

number

number

[0533] The following intermediate compounds in the examples were purified by GeLai 3500 HPLC, the column temperature was 25° C., the detection wavelength was 214 nm, 254 nm or 280 nm, and other separation conditions were as shown in the table below:

number

[0534] Test method: The inhibitory activity of the compounds of the present invention against wild-type RET enzyme, mutant RET enzyme (RET-V804M, RET-V804L, RET-M918T) and fused RET enzyme (RET-CCDC6) was measured according to the instructions of the HTRF KinEASE-TK kit (Cisbio). Each RET enzyme was pre-incubated with various concentrations of test compounds at room temperature for 30 min, and then the substrate and adenosine triphosphate (ATP) were added to start the reaction. After incubation at room temperature for 40 min, TK antibody-cryptate and streptavidin-XL665 were added, and the detection was performed after incubation at room temperature for 45 min. The vehicle group (DMSO) was used as a negative control, and the buffer group (without RET enzyme) was used as a blank control, and the relative inhibitory activity percentage (i.e., inhibition rate) of each concentration of the compound was calculated according to the following formula. Relative inhibitory activity percentage = 1-(compound concentration-blank control) / (negative control-blank control)*100%

[0535] The percentage of relative inhibitory activity of each compound at each concentration was plotted against the compound concentration, and the curve was fitted according to a four-parameter model to obtain the IC 50 The value was calculated. y=min+(max-min) / (1+(x / IC 50 )^(-Hillslope))

[0536] (wherein, y is the percentage of relative inhibitory activity, max and min are the maximum and minimum values ​​of the fitting curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.) Test Example 2: VEGFR2 Inhibition Test

[0537] Test method: The inhibitory activity of the compound of the present invention against VEGFR2 enzyme was measured according to the instructions of HTRF KinEASE-TK kit (Cisbio). VEGFR2 enzyme was pre-incubated with various concentrations of test compounds at room temperature for 30 min, and then substrate and adenosine triphosphate (ATP) were added to start the reaction. After incubation at room temperature for 40 min, TK antibody-cryptate and streptavidin-XL665 were added, and after incubation at room temperature for 45 min, detection was performed. The vehicle group (DMSO) was used as a negative control, and the buffer group (without VEGFR2 enzyme) was used as a blank control, and the following formula was used to calculate the inhibitory effect of the compound against VEGFR2 enzyme: The relative inhibitory activity percentage (i.e., inhibition rate) of each concentration of compound was calculated according to: Relative inhibitory activity percentage = 1-(compound concentration-blank control) / (negative control-blank control)*100%

[0538] The percentage of relative inhibitory activity of each compound at each concentration was plotted against the compound concentration, and the curve was fitted according to a four-parameter model to obtain the IC 50 The values ​​were calculated: y=min+(max-min) / (1+(x / IC 50 )^(-Hillslope))

[0539] (wherein, y is the percentage of relative inhibitory activity, max and min are the maximum and minimum values ​​of the fitting curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.) Test results: The test results are shown in Tables 1-4. [Table 1] It is clear from Table 1 that the compounds of the present invention have a clear inhibitory effect on the mutant RET enzyme. [Table 2] From Table 2, it is clear that the compounds of the present invention have a clear inhibitory effect on the RET-V804M enzyme. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0540] It is clear from Tables 3-1 to 3-5 that the compounds of the present invention have clear inhibitory effects on the RET-CCDC6 enzyme, the RET-M918T enzyme, the RET-V804M enzyme, the RET-V804L enzyme and the RET-WT enzyme. [Table 4]

[0541] In addition, the inhibitory IC of compound 11 against VEGFR2 was 50 was 158.02 ± 25.08 nM, and the inhibitory IC of compound 17 against VEGFR2 50 was measured to be 62.97±11.77 nM. The above results, combined with the inhibition rate data in Table 4, show that the compounds of the present invention have weak inhibition against VEGFR2 and have better selective inhibitory effect against RET enzyme compared to VEGFR2. Test Example 3: Pharmacokinetics and tissue distribution of the compound in rats

[0542] BLU-667 (prepared according to Example 5 of WO2017 / 079140A1) and Compound 17 were administered intragastrically (PO) to male SD rats, respectively, and the plasma concentrations and brain, lung and thyroid tissue concentrations of BLU-667 and Compound 17 in rats were measured to investigate the pharmacokinetic properties. The PO dose was 5 mg / kg, and the solvent was 0.5% MC (methylcellulose). PO administration was performed and blood samples were collected at different time points (0 h before administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration). The blood samples were anticoagulated with dipotassium ethylenediaminetetraacetate and centrifuged to obtain plasma samples, which were stored at -80°C. At 0.5 h, 2 h, 8 h and 24 h after PO administration, The rats were sacrificed by bleeding from the abdominal aorta, and the brain, lungs, and thyroid gland were collected and washed, and then homogenized with saline at a fixed ratio to obtain tissue samples, which were then stored at -80°C. Each plasma sample and tissue sample was treated with precipitated protein and analyzed by LC-MS / MS. The pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.3 software, and the results are shown in Table 5. [Table 5]

[0543] As shown by the data in Table 5, after intragastric administration of 5 mg / kg of BLU-667 and compound 17 to SD rats, the exposure of compound 17 in the target organ tissues of the brain, lung, and thyroid gland was better than that of BLU-667. Test Example 4: Efficacy test of compounds in mice

[0544] Study Objective: To evaluate the in vivo efficacy of Compound 17 and BLU-667 in a Balb / c-nu mouse model bearing human medullary thyroid carcinoma TT cell subcutaneous xenograft tumors.

[0545] Drug preparation: Compound 17 and BLU-667 were each dissolved in 0.1 M H 3 PO 4The HOAc solution was dissolved in 0.1M HOAc solution and a clear solution (pH: about 4.0) was prepared. 3 PO 4 The solution was administered PO or BID.

[0546] Tumor measurements: Tumor diameters were measured twice a week with a caliper. Tumor volume was calculated as V = 0.5 × a × b 2 (a and b represent the long and short diameters of the tumor, respectively). The antitumor effect of the compound was evaluated by the tumor growth inhibition rate TGI (%) (TGI (%) = [(1-(mean tumor volume at the end of drug administration in the treatment group-mean tumor volume at the start of drug administration in the treatment group)) / (mean tumor volume at the end of treatment in the vehicle group-mean tumor volume at the start of treatment in the vehicle group)] x 100%). The results are shown in Figure 1.

[0547] Statistical analysis: Statistical analysis was performed using Prism Graphpad 5.0 software based on the relative tumor volume at the end of the study. Comparisons between multiple groups were analyzed by two-way ANOVA, and differences were considered significant when p<0.05.

[0548] Test results: In a TT nude mouse model of human medullary thyroid cancer, compound 17 had a significant antitumor effect at a dose of 5 mg / kg, and the antitumor effect tended to be dose-dependent. The antitumor effect of compound 17 at a dose of 5 mg / kg (T / C=17.44%, TGI=131.36%, p<0.05) was better than that of BLU-667 at a dose of 5 mg / kg (T / C=33.62%, TGI=88.82%, p<0.05). Relative tumor growth rate T / C (%) = T RTV / C RTV ×100%, where T RTV is the mean relative tumor volume of the test compound group, and C RTV is the relative tumor volume of the vehicle group, and the relative tumor volume RTV = V t / V 0 and V 0 is the mean tumor volume at the start of drug administration, and V t is the mean tumor volume measured on day t after drug administration.

[0549] The above examples are not intended to limit the scope of this application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and other publications) is incorporated herein by reference in its entirety.

Claims

1. A compound having the structure of Formula I, a stereoisomer, tautomer, or mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound. 【Chemistry 1】 (Of these, ring A is C ６－１０ is selected from an aromatic ring and a 5- to 6-membered heteroaromatic ring; Ring B is C ３－８ selected from cycloalkyl and 4- to 11-membered heterocyclic groups; X １ is selected from CH and N; R １ is H, halogen, hydroxy, cyano group, C １－６ Alkyl, C １－６ Heteroalkyl (e.g., C １－６ Alkoxy), C ３－８ Cycloalkyl, 4-10 membered heterocyclic group and -NR ２０ａ R ２０ｂ wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl and heterocyclic groups are each optionally selected from hydroxy, halogen, CN, NO ２， C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy and C １－４ Heteroalkyl (e.g., C １－４ alkoxy), R ２ is C １－６ Alkyl, C １－６ Heteroalkyl, C ３－８ Cycloalkyl, 4-10 membered heterocyclic group, 5-10 membered heteroaryl and -C(=O)R ２１ wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl and C ３－６ cycloalkyl, R ３ and R ４ is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C １－６ Alkyl, C １－６ Heteroalkyl (e.g., C １－６ Alkoxy) and C ３－６ and cycloalkyl, wherein said alkyl, heteroalkyl (e.g., alkoxy) and cycloalkyl are each optionally selected from halogen, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ haloalkoxy; and when m is greater than 1, two R ３ Optionally, together with the atom to which they are attached, ３－６ and / or when n is greater than 1, two R ４ Optionally, together with the atom to which they are attached, ３－６ may form a cycloalkyl or 4-10 membered heterocyclic group; L is -O-, -S-, -S(O)-, -S(O) ２ -, -N=CR ２１ -, -N(R ２３ａ )-C(O)-, C １－６ Alkylene, C １－６ Heteroalkylene, C ２－６ Alkenylene, C ２－６ Alkynylene, 【Chemistry 2】 wherein the alkylene, heteroalkylene, alkenylene and alkynylene are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkoxy, C １－６ Heteroalkyl (e.g., C １－６ Alkoxy) and C ３－８ or L is -N(R ２３ａ ) - and R ５ is hydroxy, halogen, CN, NO ２ , C １－６ Alkyl, C １－６ Heteroalkyl (e.g., C １－６ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ２０ａ R ２０ｂ , -OR ２１ , -SR ２１ , -S(=O)R ２２ , -S(=O) ２ R ２２ , -S(=O)NR ２０ａ R ２０ｂ , -S(=O) ２ N.R. ２０ａ R ２０ｂ , -NR ２０ａ S(=O)R ２０ｂ , -NR ２０ａ S (=O) ２ R ２０ｂ , -C(=O)R ２１ , -C(=O)NR ２３ａ R ２３ｂ , -NR ２３ａ C(=O)R ２３ｂ , -OC(=O)NR ２３ａ R ２３ｂ and -NR ２４ａ C(=O)NR ２５ａ R ２５ｂ wherein the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl, C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups; R ２０ａ , Ｒ２０ｂ , R ２３ａ , R ２３ｂ , R ２３ｃ , R ２４ａ , R ２５ａ and R ２５ｂ are each independently H, OH, or C １－６ Alkyl, C １－６ Alkoxy and C ３－８ cycloalkyl or R ２０ａ and R ２０ｂ , R ２３ａ and R ２３ｂ , or R ２５ａ and R ２５ｂ together with the atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclic group, said alkyl, alkoxy, cycloalkyl and heterocyclic groups each optionally containing OH, CN, halogen, NO ２ , C １－４ Alkyl, C １－４ Alkoxy, C １－４ Hydroxyalkyl, C １－４ Haloalkyl and Bi C １－４ may be substituted with one or more substituents selected from haloalkoxy; R ３０ａ , R ３０ｂ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy and C １－６ selected from haloalkoxy; R ２１ , R ２２ , R ３１ and R ３２ are each independently １－６ Alkyl, C １－６ Alkoxy, C ３－８ Cycloalkyl, 4-10 membered heterocyclic group, C ６－１２ aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each optionally selected from OH, halogen, CN, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ optionally substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; m is 0, 1, 2, 3 or 4, preferably 0; n is 0, 1, 2, 3 or 4, preferably 0, 1 or 2; t is 0, 1, 2, 3 or 4, preferably 0 or 1; and u is 0, 1, 2, 3 or 4, preferably 0 or 1; provided that ring B is a piperazine ring and X １ When is CH, R ２ is 4-CF ３ -pyridin-2-yl or 4-CN-pyridin-2-yl.

2. Ring A is a benzene ring or a 5- or 6-membered heteroaromatic ring; Preferably, ring A is a benzene ring, a thiazole ring, a pyridine ring, a pyrazine ring or a pyrimidine ring; More preferably, ring A is 【Chemistry 3】 At the position marked with *, １ is connected to the ring in which is present, and is connected to ring B at the position marked with **; and / or Ring B is C ３－６ cycloalkyl or a 5-7 membered heterocyclic group; Preferably, ring B is a piperidine ring, a piperazine ring, an azepane bridged ring or a diazepane bridged ring; More preferably, ring B is 【Chemistry 4】 and is linked to ring A at the position marked with * and to L at the position marked with **; and / or X １ is CH or N, preferably N; 2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

3. R １ is H, halogen, hydroxy, cyano group, C １－４ Alkyl, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl and 4-10 membered heterocycles groups, wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, and heterocyclic groups each optionally include hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy and C １－４ Heteroalkyl (e.g., C １－４ alkoxy), Preferably, R １ C １－４ Alkyl, 5-membered nitrogen-containing heterocyclic group and C １－４ Heteroalkyl (e.g., C １－４ alkoxy), wherein the alkyl, heterocyclic and heteroalkyl (e.g., alkoxy) are each optionally selected from hydroxy, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy and C １－３ Heteroalkyl (e.g., C １－３ alkoxy), More preferably, R １ C １－３ Alkyl (e.g., methyl), pyrrolidinyl (e.g., pyrrolidin-1-yl) and C １－３ alkoxy (e.g., ethoxy); and / or R ２ is C １－４ Alkyl, C １－４ Heteroalkyl, C ３－６ Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl and -C(=O)R ２１ wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl and C ３－６ may be substituted with one or more substituents selected from cycloalkyl; Preferably, R ２ C １－３ Alkyl, 5-6 membered heteroaryl and -C(=O)CH ３ wherein the alkyl and heteroaryl are each optionally selected from hydroxy, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl and C ３－６ may be substituted with one or more substituents selected from cycloalkyl; More preferably, R ２ C １－３ Alkyl (e.g., methyl), -C(=O)CH ３ , thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl and pyridyl, each of which may optionally be selected from hydroxy, halogen, CN, C １－３ Alkyl (e.g., methyl), C １－３ Haloalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl (e.g., C １－３ Alkoxy) and C ３－６ cycloalkyl, More preferably, R ２ is methyl-substituted pyrazolyl (e.g., 5-methyl-1H-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl), cyclopropyl-substituted pyrazolyl (e.g., 5-cyclopropyl-1H-pyrazol-3-yl) or -C(O)CH ３ That is, 3. A compound according to claim 1 or 2, a stereoisomer, tautomer, or mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

4. R ３ and R ４ is absent or, at each occurrence, independently represents hydroxy, halogen, CN, C １－４ Alkyl and C １－４ alkoxy, wherein the alkyl and alkoxy are each optionally selected from halogen, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ haloalkoxy; and when m is greater than 1, two R ３ Optionally, together with the atom to which they are attached, ３－６ and / or when n is greater than 1, two R ４ Optionally, together with the atom to which they are attached, ３－６ may form a cycloalkyl or 4-10 membered heterocyclic group; Preferably, R ３ and R ４ is absent or, at each occurrence, independently selected from hydroxy, halogen, CN, C １－３ Alkyl and C １－３ alkoxy, wherein the alkyl and alkoxy are each optionally selected from halogen, CN and C １－３ and when m is greater than 1, two R ３ Optionally, together with the atom to which they are attached, ３－６ and / or when n is greater than 1, two R ４ Optionally, together with the atom to which they are attached, ３－６ may form a cycloalkyl or 4-10 membered heterocyclic group; More preferably, R ３ and R ４ is absent or, at each occurrence, independently represents F, Cl, CN, OH, C １－３ Alkyl and C １－３ is selected from alkoxy, More preferably, R ３ and R ４ does not exist, A compound according to any one of claims 1 to 3, said compound stereoisomer, tautomer, or mixtures thereof, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

5. L is -O-, -S-, -C(O)-, -N(R ２３ａ )-C(O)-, -C(O)-N(R ２３ｃ ) -, C １－４ Alkylene, C １－４ Heteroalkylene, 【Chemistry 5】 wherein the alkylene and heteroalkylene are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy) and C ３－６ cycloalkyl, Preferably, L is -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C １－３ Alkylene, C １－３ Heteroalkylene, 【Chemistry 6】 wherein the alkylene and heteroalkylene are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl (e.g., C １－３ Alkoxy) and C ３－６ cycloalkyl, of which R ２３ａ and R ２３ｂ is H or C １－３ It is preferably alkyl, More preferably, L is -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C １－３ Alkylene, 【Chemistry 7】 wherein the alkylene is optionally selected from hydroxy, halogen, CN, C １－３ Alkyl and C １－３ may be substituted with one or more substituents selected from haloalkyl; More preferably, L is -CH ２ -, -CH(CH ３ )-, -O-, -C(O)-, 【Chemistry 8】 -C(O)NH- or 【Chemistry 9】 That is, A compound according to any one of claims 1 to 4, a stereoisomer, a tautomer, or a mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

6. R ５ is hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ２０ａ R ２０ｂ , -OR ２１ , -SR ２１ , -S(=O)R ２２ , -S(=O) ２ R ２２ , -S(=O)NR ２０ａ R ２０ｂ , -S(=O) ２ N.R. ２０ａ R ２０ｂ , -NR ２０ａ S(=O)R ２０ｂ , -NR ２０ａ S (=O) ２ R ２０ｂ , -C(=O)R ２１ , -C(=O)NR ２３ａ R ２３ｂ , -NR ２３ａ C(=O)R ２３ｂ , -OC(=O)NR ２３ａ R ２３ｂ and -NR ２４ａ C(=O)NR ２５ａ R ２５ｂ wherein the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl, C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups; Preferably, R ５ But, C ３－６ Cycloalkyl, 4-10 membered heterocyclic group, C ６－１２ aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are each optionally selected from hydroxy, halogen, C N, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl, C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups; More preferably, R ５ C ６－１０ aryl and 5-6 membered heteroaryl, each of which is optionally selected from hydroxy, halogen, CN, NO ２ , C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl (e.g., C １－３ Alkoxy), C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ and -NR ３３ａ C(=O)R ３３ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl, C ３－６ It may be substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups, and more preferably R ５ is selected from phenyl and 5-6 membered heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, imidazolyl or thiazolyl), wherein said phenyl and heteroaryl are each optionally selected from hydroxy, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl (e.g., C １－３ Alkoxy), C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-6 membered heterocyclic group, 5-8 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl, thiazolyl or cyclopentapyrazolyl), -NR ３０ａ R ３０ｂ , -OR ３１ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ and -NR ３３ａ C(=O)R ３３ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Heteroalkyl (e.g., C １－３ Alkoxy), C ３－６ Cycloalkyl, C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups; Even more preferably, R ５ is selected from phenyl, pyridyl, pyrazolyl and thiazolyl, each of which is optionally selected from halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Alkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-6 membered heterocyclic groups, 5-8 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl, thiazolyl or is cyclopentapyrazolyl), -NR ３０ａ R ３０ｂ and -OR ３１ wherein the heterocyclic group and the heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Haloalkoxy, C １－３ Alkoxy, C ３－６ Cycloalkyl, C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy and 4- to 6-membered heterocyclic groups; Most preferably, R ５ optionally halogen (e.g., fluorine or chlorine), CN, C １－３ Alkyl (e.g., methyl or ethyl), C １－３ haloalkyl (e.g., trifluoromethyl), C １－３ Alkoxy (e.g., methoxy or ethoxy), C ３－６ Cycloalkyl (e.g., cyclopropyl), C ３－６ Phenyl, pyridyl, pyrazolyl or thiazolyl, optionally substituted with one or more substituents selected from cycloalkoxy (e.g., cyclopropoxy) and 5-6 membered heteroaryl (e.g., pyridyl, pyrrolyl, pyrazolyl, furyl, oxazolyl, imidazolyl or thiazolyl), wherein the 5-6 membered heteroaryl is optionally further substituted with halogen (e.g., fluorine or chlorine), C １－３ Alkyl (e.g., methyl, ethyl or isopropyl), C １－３ haloalkyl (e.g., fluoromethyl), １－３ Hydroxyalkyl (e.g., hydroxymethyl or hydroxypropyl), C １－３ Alkoxy (e.g., methoxy), C ３－６ Cycloalkyl (e.g., cyclopropyl) and C ３－６ optionally substituted with one or more substituents selected from cycloalkoxy (e.g., cyclopropoxy or cyclobutoxy); A compound according to any one of claims 1-5, a stereoisomer, a tautomer, or a mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

7. R ２０ａ , R ２０ｂ , R ２３ａ , R ２３ｂ , R ２３ｃ , R ２４ａ , R ２５ａ and R ２５ｂ are each independently H, C １－４ Alkyl, C １－４ Alkoxy and C ３－８ cycloalkyl or R ２０ａ and R ２０ｂ , R ２３ａ and R ２３ｂ , or R ２５ａ and R ２５ｂ together with the atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclic group, said alkyl, alkoxy, cycloalkyl and heterocyclic groups each optionally containing OH, CN, halogen, NO ２ , C １－４ Alkyl, C １－４ Alkoxy, C １－４ Hydroxyalkyl, C １－４ Haloalkyl and C １－４ may be substituted with one or more substituents selected from haloalkoxy; Preferably, R ２０ａ , R ２０ｂ , R ２３ａ , R ２３ｂ , R ２３ｃ , R ２４ａ , R ２５ａ and R ２５ｂ are each independently H, C １－４ Alkyl or C １－４ is an alkoxy; In particular, R ２３ａ and R ２３ｂ are each independently H, C １－３ Alkyl, C １－３ Alkoxy and C ３－６ cycloalkyl or R ２３ａ and R ２３ｂ are C together with the C atom to which they are attached. ３－６ and forming a cycloalkyl or heterocyclic group, each of said alkyl, alkoxy, cycloalkyl and heterocyclic groups optionally containing halogen, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Hydroxyalkyl, C １－３ Haloalkyl and C １－３ may be substituted with one or more substituents selected from haloalkoxy; and / or R ２１ , R ２２ , R ３１ and R ３２ are each independently C １－４ Alkyl, C １－４ Alkoxy, C ３－８ cycloalkyl and 4-10 membered heterocyclic groups, each of which may optionally be selected from OH, halogen, CN, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ optionally substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; Preferably, R ２１ , R ２２ , R ３１ and R ３２ are each independently C １－４ is selected from alkyl, and / or R ３０ａ , R ３０ｂ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ are each independently H, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy and C １－４ selected from haloalkoxy; Preferably, R ３０ａ , R ３０ｂ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ are each independently H and C １－４ is selected from alkyl, A compound according to any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound.

8. The compound of claim 1 having the structure shown in any of Formulas I-A to I-G, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound: 【Chemistry 10】 (Of these, R ５ is C ６－１２ aryl and 5- to 10-membered heteroaryl, among which (1) the C ６－１２ Aryl is optionally C ３－６ Cycloalkoxy, C ６－１２ Aryl, 5-10 membered heteroaryl, -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkoxy, aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO, ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O) N.R. ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ Cycloalkyl, C ３－６ may be substituted with one or more substituents selected from cycloalkoxy and 4- to 10-membered heterocyclic groups; R １ , R ２ , R ２３ａ , R ３０ａ , R ３０ｂ , R ３１ , R ３２ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ is as defined in any one of claims 1 to 7, and R ２３ａ is H or C １－３ It is preferably alkyl. 【Chemistry 11】 (Of these, R １ , R ２ , R ５ and R ２３ａ is as defined in any one of claims 1 to 7, and R ２３ａ is H or C １－３ It is preferably alkyl. 【Chemistry 12】 (Of these, X １ When is CH, R １ , R ２ , R ５ and R ２３ａ is as defined in any one of claims 1 to 7, and R ２３ａ is H or C １－３ It is preferably alkyl, but X １ If N, then R １ , R ２ , R ５ and R ２３ａ is as defined above in formula IA. 【Chemistry 13】 (Of these, R １ , R ２ , R ２３ａ , R ２３ｂ and t is as defined in any one of claims 1 to 7, X １ When is CH, R ５ is as defined in any one of claims 1 to 7, and X １ If N, then R ５ is C ６－１２ aryl or 5-10 membered heteroaryl, (i) When t is 0, ６－１２ The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ optionally substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; (ii) when t is 1, (1) the C ６－１２ Aryl is optionally hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups. ２ , C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkoxy, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; R ３０ａ , R ３０ｂ , R ３１ , R ３２ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ is as defined in any one of claims 1 to 7. 【Chemistry 14】 (Of these, R １ , R ２ , R ５ , R ２３ａ , R ２３ｂ , X １ and t is as defined above in Formulas ID. 【Chemistry 15】 (Of these, R １ , R ２ , R ５ , R ２３ａ , R ２３ｂ and X １ is as defined above in formula ID; R ４ is as defined in any one of claims 1 to 7 and preferably C １－３ Alkyl or C １－３ is an alkoxy; R ２３ｃ is H, C １－３ Alkyl or C １－３ alkoxy, wherein the alkyl and alkoxy are each optionally selected from OH, CN, halogen, C １－４ Alkoxy and C １－４ hydroxyalkyl; u is 0 or 1, and n is 0 or 1. 【Chemistry 16】 (Of these, X １ is CH or N, R １ , R ２ and R ４ is as defined in any one of claims 1 to 7, and R ４ is preferably C １－３ Alkyl or C １－３ is an alkoxy; n is 0 or 1; R ５ is C ６－１２ aryl and 5- to 10-membered heteroaryl, among which (1) the C ６－１２ Aryl is optionally C ３－６ Cycloalkoxy, C ６－ １２ Aryl, 5-10 membered heteroaryl, -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkoxy, aryl and heteroaryl are each optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ and (2) the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halogen, CN, NO, ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, 4-10 membered heterocyclic group, C ６－１２ Aryl, 5-10 membered heteroaryl, -NR ３０ａ R ３０ｂ , -OR ３１ , -SR ３１ , -S(=O)R ３２ , -S(=O) ２ R ３２ , -S(=O)NR ３０ａ R ３０ｂ , -S(=O) ２ N.R. ３０ａ R ３０ｂ , -NR ３０ａ S(=O)R ３０ｂ , -NR ３０ａ S (=O) ２ R ３０ｂ , -C(=O)R ３１ , -C(=O)NR ３３ａ R ３３ｂ , -NR ３３ａ C(=O)R ３３ｂ , -OC(=O)NR ３３ａ R ３３ｂ and -NR ３４ａ C(=O)NR ３５ａ R ３５ｂ wherein the cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl (e.g., C １－４ Alkoxy), C ３－６ may be substituted with one or more substituents selected from cycloalkyl and 4- to 10-membered heterocyclic groups; R ３０ａ , R ３０ｂ , R ３１ , R ３２ , R ３３ａ , R ３３ｂ , R ３４ａ , R ３５ａ and R ３５ｂ is as defined in any one of claims 1 to 7.

9. The compound is 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 It is selected from 2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound.

10.

21. (Of these, Hal １ and Hal ２ are each independently F, Cl, Br or I, preferably Hal １ is F, Cl, Br or I, and Hal ２ is Cl, Br or I, R １ is H, cyano, C １－６ Alkyl, C １－６ Heteroalkyl (e.g., C １－６ Alkoxy), C ３－８ Cycloalkyl, 4-6 membered heterocyclic group and -NR ２０ａ R ２０ｂ wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl and heterocyclic groups are each optionally selected from halogen, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy and C １－４ Heteroalkyl (e.g., C １－４ alkoxy), R ２ is C １－６ Alkyl, C １－６ Heteroalkyl, C ３－８ and selected from cycloalkyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl, each of which is optionally selected from hydroxy, halogen, CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkoxy, C １－４ Heteroalkyl and C ３－６ may be substituted with one or more substituents selected from cycloalkyl; R ２３ａ is H, C １－６ Alkyl, C １－６ Alkoxy and C ３－８ Cycloalkyl wherein the alkyl, alkoxy and cycloalkyl are each optionally selected from OH, CN, halogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Hydroxyalkyl, C １－４ Haloalkyl and C １－４ and R ２０ａ , R ２０ｂ and R ５ is as defined in formula IA in claim 8. Compound I-A-1 and R ２ -NH ２ in the presence of a base to produce compound IA-2; Step 2: reacting compounds IA-3 and IA-4 in the presence of a base to produce compound IA-5; Step 3: reacting compound IA-5 with a boron-containing reagent to produce compound IA-6; Step 4 is reacting compound I-A-2 with I-A-6 to produce compound I-A-7; Step 5 is removing the protecting group from compound I-A-7 under acidic conditions to produce compound I-A-8; and Step 6: reacting compounds IA-8 and IA-9 to produce compound IA; A method comprising: or, 【Chemical 22】 (wherein each group is as defined in Scheme A above). Step 1: removing the protecting group from compound IA-5 under acidic conditions to produce compound IA-10; Step 2: reacting compounds IA-10 and IA-9 to produce compound IA-11; step 3, reacting compound IA-11 with a boron-containing reagent to produce compound IA-12; and Step 4: reacting compound IA-12 with IA-2 to produce compound IA; A method comprising: or, 【Chemistry 23】 (wherein each group is as defined in Scheme A above). Compound I-B-1 and R ２ -NH ２ in the presence of a base to produce compound I-B-2; and Step 2: reacting compound I-B-2 with IA-12 to produce compound I-B; A method comprising: or, 【Chemistry 24】 wherein each group is as defined in Scheme A above, and X １ is selected from CH and N. Compound I-C-1 and R ２ -NH ２ in the presence of a base to produce compound IC-2; Step 2: reacting compound IC-3 with a boron-containing reagent to produce compound IC-4; Step 3 is reacting compounds I-C-2 and I-C-4 to produce compound I-C-5; Step 4 is removing the protecting group from compound I-C-5 under acidic conditions to produce compound I-C-6; and Step 5: reacting compounds IC-6 and IA-9 to produce compound IC; A method comprising: or, 【Chemistry 25】 (Of these, R １ and R ２ is as defined in Scheme A, R ５ is as defined in formula ID in claim 8, R ２３ａ and R ２３ｂ are each independently H, C １－６ Alkyl, C １－６ Alkoxy and C ３－８ cycloalkyl or R ２３ａ and R ２３ｂ form together with the C atom to which they are attached a 3-8 membered cycloalkyl or heterocyclic group, said alkyl, alkoxy, cycloalkyl and heterocyclic groups each optionally being selected from CN, halogen, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Hydroxyalkyl, C １－４ Haloalkyl and C １－４ may be substituted with one or more substituents selected from haloalkoxy; X １ is selected from CH and N, and t is 0 or 1. A method comprising: or, 【Chemistry 26】 (Of these, R １ , R ２ , R ５ , R ２３ａ , R ２３ｂ and t is as defined in Scheme E; X １ is selected from CH and N, and Hal ２ is F, Cl, Br or I, preferably Hal ２ is Cl, Br or I. Step 1 is to react compound I-C-2 with I-A-6 to produce compound I-E-1; Step 2 is to remove a protecting group from compound I-E-1 under acidic conditions to produce compound I-E-2; and Step 3: carrying out a condensation reaction between compound IE-2 and ID-1 to produce compound IE; or, 【Chemical 27】 (Of these, R １ , R ２ , R ２３ａ , R ２３ｂ and R ５ is as defined in Scheme E; X １ is selected from CH and N; R ４ is absent or is hydroxy, CN, C １－６ Alkyl, C １－６ Haloalkyl and C １－６ Heteroalkyl (e.g., C １－６ alkoxy), R ２３ｃ is H, C １－３ Alkyl or C １－３ alkoxy, wherein the alkyl and alkoxy are each optionally selected from OH, CN, halogen, C １－４ Alkoxy and C １－４ hydroxyalkyl; Hal ２ is F, Cl, Br or I, preferably Hal ２ is Cl, Br or I, u is 0 or 1, and n is 0 or 1. Step 1 is reacting compound IC-2 with IF-1 to produce compound IF-2, and step 2 is reacting compound IF-3 with an amine to produce compound IF-4; Step 3: removing the protecting group from compound I-F-4 under acidic conditions to produce compound I-F-5; and Step 4: reacting compounds IF-2 and IF-5 in the presence of a base to produce compound IF; A method comprising: or, 【Chemistry 28】 (Of these, R １ and R ２ is as defined in Scheme A; X １ is selected from CH and N; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl and C １－６ heteroalkyl; R ５ is as defined above in formulas IG, and n is 0 or 1. Compound I-G-1 and R ５ Step 1 is reacting with —OH to produce compound I-G-2, Step 2 is removing the protecting group from compound I-G-2 under acidic conditions to produce compound I-G-3, and Step 3: Compound IF-2 is reacted with Compound IG-3 by nucleophilic substitution in the presence of a base to produce Compound IG; A method comprising: A method for producing the compound of claim 8.

11. A prophylactically or therapeutically effective amount of a compound according to any one of claims 1-9, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, The drug composition may optionally further comprise one or more pharma- ceutically acceptable carriers.

12. Use of a compound according to any one of claims 1-9, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotope derivative, a metabolite, or a prodrug of the compound, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for preventing or treating a disease or condition associated with RET activity, preferably, the disease or condition associated with RET activity is cancer or tumor, or irritable bowel syndrome; The cancer or tumor is more preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), colon cancer, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.

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