Compounds as FAK inhibitors and their uses

Abstract

The present invention discloses a compound and its use as FAK inhibitor.Specifically, the present invention relates to a compound of general formula (1), its preparation method, and the use of the compound of general formula (1) and its isomer, crystal, pharmaceutically acceptable salt, hydrate or solvate as FAK inhibitor.The compound of the present invention, and its isomer, crystal, pharmaceutically acceptable salt, hydrate or solvate can be used to prepare medicine for treating or preventing the related disease mediated by FAK. [Case 1] TIFF2025507732000196.tif31168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202210190680.2, filed on February 28, 2022, and Chinese Patent Application No. 202210800802.2, filed on July 6, 2022, which are incorporated by reference in their entireties herein.

[0002] The present invention relates to the field of pharmaceutical chemistry, and in particular to a group of compounds having inhibitory activity against focal adhesion kinase (FAK kinase), their pharma- ceutically acceptable salts, and pharmaceutical compositions thereof, as well as the use of said compounds, their pharma- ceutically acceptable salts, and pharmaceutical compositions thereof in the treatment or prevention of related diseases mediated by FAK. [Background technology]

[0003] Focal adhesion kinase (FAK) is a member of the non-receptor tyrosine kinase family located at cell-cell junctions. When extracellular matrix (ECM) binds to integrin receptors on the cell membrane surface, FAK is activated, thereby upregulating downstream signaling pathways of the integrin receptor. Autophosphorylation of Tyr397 of FAK is a biomarker of FAK kinase activity. Studies have shown that FAK plays an important role in cell survival, proliferation, adhesion, migration, and invasion (McLean et al., 2005, Nat Rev cancer, 5:505-515). FAK expression and activity are upregulated by cancer cells, thereby promoting cancer cell proliferation and invasion and increasing tumor metastasis in vivo.

[0004] FAK mRNA levels are highly expressed in approximately 37% of ovarian cancer cells and 26% of breast cancer cells. FAK inhibitors inhibit tumor cell proliferation and invasion. When FAK kinase function is inhibited, breast cancer metastasis is significantly reduced. In addition to promoting cancer cell function, FAK mediates the activation of various signal transduction pathways downstream of angiogenic factors and is involved in the proliferation, migration, and differentiation of vascular endothelial cells. The specific absence of FAK in vascular endothelial cells indicates that FAK maintains vascular stability during development. Thus, FAK inhibitors can be used to antagonize pathological angiogenesis. Thus, FAK inhibitors can antagonize tumor development and progression directly and indirectly by suppressing tumor cell function and antiangiogenesis, and are used to treat tumors. In addition to cancer, FAK inhibitors can also be used in non-cancer indications associated with pathological vascular proliferation, such as retinal diseases.

[0005] Currently, there are no FAK inhibitors on the market. A series of pyrimidine compounds that function as FAK inhibitors have been reported in International Publication No. 2010058032A2, and BI853520, a highly selective FAK inhibitor, is currently in Phase I clinical trials. [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2010058032A2 [Non-patent literature]

[0007] [Non-Patent Document 1] McLean et al., 2005, Nat Rev cancer, 5:505-515 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides compounds and their uses as FAK inhibitors. [Means for solving the problem]

[0009] (overview) The present invention provides a compound represented by formula (1), or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In general formula (1), Ring A is a (C3-C6)cycloalkyl or a (3-membered to 6-membered)heterocycloalkyl, and the (C3-C6)cycloalkyl or the (3-membered to 6-membered)heterocycloalkyl each independently comprises 1, 2, 3, or 4 R a may be optionally substituted with; Y is -O-, -NR a -OR-CR a R b - and; L is selected from -CH2-, -O-, or -S-; Ring B is selected from a (3-membered to 18-membered)heterocycloalkyl, a (C3-C18)cycloalkyl, a (6-membered to 18-membered)aryl, or a (5-membered to 18-membered)heteroaryl, wherein the (3-membered to 18-membered)heterocycloalkyl, the (C3-C18)cycloalkyl, the (6-membered to 18-membered)aryl, or the (5-membered to 18-membered)heteroaryl are each independently selected from n R 2 may be optionally substituted with; X is a chemical bond, [ka] is selected from * represents the bond to ring B; G is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a Rb , -C(O)R a , -CO2R a , -CONR a R b , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C15) cycloalkyl, (3-membered to 15-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein the (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-membered to 14-membered) heterocycloalkyl, the (C6-C14) aryl, or the (5-membered to 14-membered) heteroaryl are each independently one, two, three, or four R c may be optionally substituted with; R 1 is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO2R a , -CONR a R b , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-membered to 14-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein the (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-membered to 14-membered) heterocycloalkyl, the (C6-C14) aryl, or the (5-membered to 14-membered) heteroaryl are each independently one, two, three, or four R c may be optionally substituted with; R 2 is -H, -D, halogen, hydroxy, amino, cyano, nitro, -ORa , -NR a R b , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-membered to 14-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein the (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-membered to 14-membered) heterocycloalkyl, the (C6-C14) aryl, or the (5-membered to 14-membered) heteroaryl are each independently one, two, three, or four R c or two R 2 are bonded to the same atom, the two R 2 may form one oxo group; R 3 is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR 3a , -NR 3a R 3b , -C(O)R 3a , -CO2R 3a , -S(O) p R 3a , -S(O) p NR 3a R 3b , -CONR 3a R 3b , -C(=NR 3a )-NR 3b R 3c , -NR 3a COR 3b , -NR 3a CONR 3b R 3c , -NR 3a CO2R 3b , -NR 3a S(O) p NR 3b R 3c , -NR 3a S(O) p R 3b, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-membered to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5-membered to 14-membered)heteroaryl, -(C1-C8)alkylene-(C1-C8)alkoxy, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-membered to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl; R a and R b are each independently -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-membered to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5-membered to 14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-membered to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl, The (C1-C8)alkyl, the (C1-C8)alkoxy, the (C1-C8)haloalkyl, the (C2-C8)alkenyl, the (C2-C8)alkynyl, the (C3-C14)cycloalkyl, the (3-membered to 14-membered)heterocycloalkyl, the (C6-C14)aryl, the (5-membered to 14-membered)heteroaryl, the -(C1-C8)alkylene-(C3-C14)cycloalkyl, the -(C1-C8)alkylene-(3-membered to 14-membered)heterocycloalkyl, the -(C1-C8)alkylene-(C6-C14)aryl, or the -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl each independently represents 1, 2, 3, or 4 R c or R a and R btogether with the atoms bonded thereto, form a (C3-C6) cycloalkyl group or a (3-membered to 6-membered) heterocycloalkyl group, and the (C3-C6) cycloalkyl group or the (3-membered to 6-membered) heterocycloalkyl group each independently comprises 1, 2, 3 or 4 R c may be optionally substituted with; R c is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR xa , -NR xa R xb , -(CH2) m OR xa , -(CH2) m NR xa R xb , -C(O)R xa , -CO2R xa , (CH2) m S(O) p R xa , -S(O) p NR xa R xb , -(CH2) m CONR xa R xb , -C(=NR xa )-NR xb R xc , -NR xa COR xb , -NR xa CONR xb R xc , -NR xa CO2R xb , -NR xa S(O) p NR xb R xc , -NR xa S(O) p R xb, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-membered to 14-membered) heterocycloalkyl, (C6-C14) aryl, (5-membered to 14-membered) heteroaryl, -(C1-C8) alkylene-(C1-C8) alkoxy, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-membered to 14-membered) heterocycloalkyl, -(C1-C8) aryl wherein the (C1-C8)alkylene, the (C1-C8)alkoxy, the (C1-C8)haloalkyl, the (C2-C8)alkenyl, the (C2-C8)alkynyl, the (C3-C14)cycloalkyl, the (3-membered to 14-membered)heterocycloalkyl, the (C6-C14)aryl, or the (5-membered to 14-membered)heteroaryl are each independently selected from 1, 2, 3, or 4 R 3c or two R c are bonded to the same atom, the two R c may form one oxo; R xa , R xb , and R xc are each independently -H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-membered to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5-membered to 14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-membered to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl; R 3a , R 3b and R 3care each independently -H, -D, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-membered to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5-membered to 14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-membered to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl; p is an integer of 0, 1 or 2; m is an integer of 0, 1, 2 or 3; n is an integer of 0, 1, 2, or 3.

[0010] In another preferred embodiment of the present invention, in general formula (1), L is -CH2- or -O-.

[0011] In another preferred embodiment, in the general formula (1), ring A is (C3-C6)cycloalkyl or (3-membered to 6-membered)heterocycloalkyl, wherein the (C3-C6)cycloalkyl or the (3-membered to 6-membered)heterocycloalkyl each independently represents 1, 2, 3, or 4 of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -(CH2)2OCH3, -CH2SO2CH3, -CH2CONH2, -CH2CON(CH3)2, [ka] said substituent is preferably -H, -D, -F, -OCH3, -OCF3, -CH3, -CD3, -CH2F, -CHF2, or -CF3; said substituent is more preferably -H, -D, or -F; said substituent is more preferably -H; said substituent is more preferably -D and said substituent is more preferably -F.

[0012] In another preferred embodiment, in the general formula (1), ring A is preferably [ka] where: * represents a ring attached to Y; A is more preferably [ka] A is more preferably [ka] A is more preferably [ka] and A is more preferably [ka] It is.

[0013] In another preferred embodiment, in the general formula (1), ring B is selected from (6- to 12-membered)aryl or (5- to 14-membered)heteroaryl, wherein the (6- to 12-membered)aryl or the (5- to 14-membered)heteroaryl is selected from n R 2 may be optionally substituted with

[0014] In another preferred embodiment, in the general formula (1), ring B is [ka] Ring B is preferably [ka] Ring B is more preferably [ka] Ring B is more preferably [ka] where: * teeth, [ka] Represents a bond to.

[0015] In another preferred embodiment, in the general formula (1), G is -H, -D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, or (5-membered to 15-membered) heterocycloalkyl, wherein the (C1-C6) alkyl, the (C1-C6) alkoxy, the (C1-C6) haloalkyl, or the (5-membered to 15-membered) heterocycloalkyl is 1, 2 , 3, or 4 -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -NHCH3, -N(CH3)2, -C(O)NH2, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -(CH2)2OCH3, -CH2SO2CH3, -CH2CONH2, -CH2CON(CH3)2, [ka] or two substituents attached to the same atom may form an oxo group.

[0016] In another preferred embodiment, in the general formula (1), G is -H, (C1-C3) alkyl, or (6- to 12-membered) heterocycloalkyl, wherein the (C1-C3) alkyl or the (6- to 12-membered) heterocycloalkyl is selected from 1, 2, 3, or 4 of -H, -D, -F, -CH3, -CD3, -CH2CH3, -OCH3, -N(CH3)2, -(CH2)2OCH3, -CH2SO2CH3, -CH2CONH2, -CH2CON(CH3)2, [ka] or two substituents attached to the same atom may form an oxo group.

[0017] In another preferred embodiment, in the general formula (1), G is -H, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2N(CH3)2, [ka] [ka] G is preferably selected from H, [ka] It is.

[0018] In another preferred embodiment, in the general formula (1), X is a chemical bond, [ka] X is preferably a chemical bond, [ka] X is more preferably a chemical bond, [ka] and X is more preferably [ka] and X is more preferably [ka] X is more preferably a chemical bond; * represents a bond to ring B.

[0019] In another preferred embodiment, in the general formula (1), R 1is -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -NHCH3, -N(CH3)2, -C(O)NH2, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, or [ka] Selected from; R 1 is preferably -F, -Cl, -Br, -CN, -NO2, -CF3, -C(O)NH2, or [ka] ;R 1 is preferably -F, -Cl, -Br, -CN, or -CF; R 1 is more preferably -F; R 1 is more preferably -Cl; R 1 is more preferably -Br; R 1 is more preferably -CN; R 1 is more preferably -CF3.

[0020] In another preferred embodiment, in the general formula (1), R 2is -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCF3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-membered to 6-membered)heterocycloalkyl, (C6-C10)aryl, or (5-membered to 10-membered)heteroaryl, wherein said (C1-C3)alkyl, said (C1-C3)alkoxy, said (C1-C3)haloalkyl, said ( the (C2-C4)alkenyl, the (C2-C4)alkynyl, the (C3-C6)cycloalkyl, the (3-membered to 6-membered)heterocycloalkyl, the (C6-C10)aryl, or the (5-membered to 10-membered)heteroaryl may each independently be optionally substituted with one, two, three, or four of -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -NHCH3, -N(CH3)2, -C(O)NH2, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, or -CF3; or two R 2 are bonded to the same atom, the two R 2 may form one oxo group.

[0021] In another preferred embodiment, in the general formula (1), R 2 -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -NHCH3, -N(CH3)2, -C(O)NH2, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, [ka] Selected from; R 2 is preferably -H, -D, -F, -Cl, -OH, -OCH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CF3, [ka] ;R 2 is more preferably -H, -F, -Cl, -OH, -OCH3, -OCF3, -CH2CH3, -CH(CH3)2, [ka] It is.

[0022] In another preferred embodiment, in the general formula (1), R 3 is selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -NO2, -OCH3, -NHCH3, -N(CH3)2, -C(O)NH2, -OCH2CH3, -OCF3, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, or -CF3; R 3 is preferably selected from -H, -D, -F, -CH3, -CD3, or -CF3; R 3 is more preferably selected from -H, -D, or -F; R 3 is more preferably selected from -H; R 3 is more preferably selected from -D; R 3 is more preferably selected from -F.

[0023] In some embodiments, the present invention provides a compound represented by formula (2), or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, A, L, B, X, G, R 1 , R 2 , n, and R 3 is as defined above, and R a is selected from H, D, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C3-C6) cycloalkyl, as exemplified in the detailed description.

[0024] In some embodiments, the present invention provides a compound represented by formula (3), or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, A, L, B, R 1 , R 2 , n, and R 3 is as defined above, and R a is selected from H, D, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, and are exemplified in the detailed description.

[0025] In some embodiments, the present invention provides a compound represented by formula (4), or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, A, L, B, X, G, R 1 , and R 2 are as defined above and exemplified in the detailed description.)

[0026] In some embodiments, the present invention provides a compound represented by formula (5) or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, A, L, B, R 1 , R 2 , and n are as defined above and exemplified in the detailed description.

[0027] In some embodiments, the present invention provides a compound represented by formula (5a) to formula (5i), or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0028] [ka] (In the formula, L, X, G, R 1 , R 2 , n, and R 3 is as defined above, and R a is selected from H, D, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C3-C6) cycloalkyl, as exemplified in the detailed description.

[0029] In some embodiments, the present invention provides compounds of general formula (6a) to general formula (6i) or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, L, X, G, R 1 , R 2 , and n are as defined above and exemplified in the detailed description.

[0030] In some embodiments, the present invention provides compounds of general formula (7a) to general formula (7r) or an isomer thereof, a crystalline form thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. [ka] (In the formula, X, G, R 1 , R 2 , and n are as defined above and exemplified in the detailed description.

[0031] In another specific embodiment of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] has one of the following:

[0032] Another object of the present invention is to provide a pharmaceutical composition containing a pharma- ceutically acceptable carrier, diluent and / or excipient, and, as an active ingredient, the compound of general formula (1) of the present invention or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0033] The present invention further aims to provide the use of the compound of general formula (1) of the present invention, or its isomer, its crystal, its pharma- ceutically acceptable salt, its hydrate or its solvate, or the above pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with FAK protein kinase.The disease is preferably cancer, and the cancer is blood cancer or solid cancer, preferably ovarian cancer, melanoma, breast cancer, head and neck cancer, pancreatic cancer, non-small cell lung cancer, colon cancer, prostate cancer, oral cancer, esophageal cancer, mesothelioma, myeloma, leukemia, and cancer metastasis of these cancers.

[0034] The present invention further contemplates to provide a method for treating, regulating or preventing a related disease mediated by FAK protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present invention, or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or the above pharmaceutical composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0036] (Synthesis of Compounds) Methods for preparing the compound of the general formula (1) of the present invention are specifically described below, but these specific methods do not limit the present invention in any way.

[0037] The compounds of general formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Furthermore, the solvents, temperatures and other reaction conditions described herein may be varied. The starting materials for the synthesis of the compounds may be obtained synthetically or may be commercially available. The compounds described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 thEd., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd Ed., (Wiley 1999). General methods for preparing compounds may be modified by using appropriate reagents and conditions to introduce various groups into the molecular formulas described herein.

[0038] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the following description. In addition, the compounds of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), where the compound of general formula (1) can be prepared using the following general reaction schemes 1 to 4.

[0039] General reaction scheme 1

[0040] [ka]

[0041] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 1, where R 1 , R 2 , R 3, X, L, Y, G, A, B, and n are as defined above. As shown in General Reaction Scheme 1, compound 1-1 is reacted with compound 1-2 under alkaline conditions to give compound 1-3, compound 1-3 is oxidized to give compound 1-4, and compound 1-4 is reacted with compound 1-5 under appropriate conditions to give target compound (1).

[0042] General reaction scheme 2

[0043] [ka]

[0044] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 2, where R 1 , R 2 , R 3 , X, L, Y, G, A, B, and n are as defined above. As shown in General Reaction Scheme 2, compound 1-1 is coupled with compound 1-6 to give compound 1-7, compound 1-7 is oxidized to give compound 1-8, and compound 1-8 is reacted with compound 1-5 under appropriate conditions to give the target compound (1).

[0045] General reaction scheme 3

[0046] [ka]

[0047] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 3, where R 1 , R 2 , R 3 , X, L, Y, G, A, B, and n are as defined above. As shown in General Reaction Scheme 3, compound 1-4 is reacted with compound 1-9 under appropriate conditions to give compound 1-10, compound 1-10 is hydrolyzed to give compound 1-11, and compound 1-11 is condensed with fragment S1 to give target compound (1).

[0048] General reaction scheme 4

[0049] [ka]

[0050] Embodiments of compounds of general formula (1) can be prepared according to General Reaction Scheme 4, where R 1 , R 2 , R 3 , X, L, Y, G, A, B, and n are as defined above. As shown in General Reaction Scheme 4, compound Int is reacted with compound 1-12 under appropriate conditions to give compound 1-13, and compound 1-13 is reacted with compound 1-5 under appropriate conditions to give target compound (1).

[0051] Further forms of the compound

[0052] As used herein, the term "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties of a compound, e.g., when administered to an individual, the substance does not cause undesirable biological effects or adverse interactions with any of its components.

[0053] The term "pharmaceutical acceptable salt" refers to a form of a compound that does not cause significant irritation to the receiving organism or abolish the biological activity and properties of the compound. In a specific embodiment, a pharmaceutical acceptable salt is obtained by reacting a compound of the general formula with an acid or base, where the acid or base is selected from the group consisting of those listed in Stahl and Wermuth, Handbook of Pharmaceutical Salts: properties, Selection, and Use, 1 st Ed., (Wiley, 2002), but are not limited to these.

[0054] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, compounds described herein may exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0055] In other specific examples, the compound of general formula (1) is prepared in different forms, including but not limited to amorphous, pulverized, and nanoparticle forms. Furthermore, the compound of general formula (1) may be a polymorph, including crystalline forms. A polymorph includes different lattice arrangements of the same elements of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystalline form.

[0056] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0057] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 The deuterated pharmaceutical composition may be labeled with a radioisotope such as 1,2-dihydro-1,3-trifluoroethylene (1H-tetrafluoroethylene) or 1,2-dihydro-1,3-trifluoroethylene (1H-tetrafluoroethylene). As another example, deuterium may be used to replace a hydrogen atom to form a deuterated compound. The bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon. Compared to non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have the advantages of reduced toxic effects and side effects, improved pharmaceutical stability, enhanced efficacy, and increased pharmaceutical in vivo half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0058] Explanation of terms Unless otherwise indicated, the terms used herein, including those described in the specification and claims, are defined as follows. It should be noted that in this specification and the appended claims, the singular forms "a" and "an" include the plural unless otherwise indicated. Conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used unless otherwise indicated. As used herein, "or" or "and" means "and / or" unless otherwise indicated.

[0059] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups with straight and branched chain groups containing 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, are preferred. As used herein, "alkyl" includes unsubstituted alkyl and substituted alkyl, particularly alkyl substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH,i Pr, n Pr, i Bu, n Bu, or t is selected from Bu.

[0060] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0061] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon double bond, including straight-chain or branched groups containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred.

[0062] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl as defined above.

[0063] Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups with a carbon-carbon triple bond, including straight-chain and branched groups, containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred.

[0064] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl as defined above.

[0065] Unless otherwise noted, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic); partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Cycloalkyls may include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings) and spirocycles. In some embodiments, cycloalkyls are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring carbon atoms of cycloalkyls may be optionally oxidized to form oxo or thio groups. Cycloalkyls further include cycloalkylene. In some embodiments, cycloalkyls include 0, 1, or 2 double bonds. In some embodiments, cycloalkyls include 1 or 2 double bonds (partially unsaturated cycloalkyls). In some embodiments, cycloalkyl may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0066] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl as defined above.

[0067] Unless otherwise indicated, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO, and t- BuO.

[0068] Unless otherwise specified, "aryl" refers to an aromatic hydrocarbon group that is monocyclic or polycyclic. For example, a monocyclic aryl ring may be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0069] Unless otherwise noted, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of said aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0070] Unless otherwise noted, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, phenanthrylene, and the like.

[0071] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), said heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl include pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [ka] These include, but are not limited to:

[0072] Unless otherwise stated, "heterocycloalkyl" refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus, which may optionally include one or more alkenylenes as part of the ring structure. Partially unsaturated heterocycloalkyls may be referred to as "heterocycloalkenyls" when the heterocycloalkyl contains at least one double bond, and "heterocycloalkynyls" when the heterocycloalkyl contains at least one triple bond. Heterocycloalkyls may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused or bridged rings). In some embodiments, heterocycloalkyls are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl contains 0-3 double bonds. In some embodiments, a heterocycloalkyl contains 0-2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also called partially unsaturated heterocycles) that have one or more aromatic rings fused (i.e., sharing bonds) to the heterocycloalkyl ring, e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyls that contain fused aromatic rings may be bonded through any ring atom, including the ring atoms of the fused aromatic rings.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl,. [ka] [ka] These include, but are not limited to:

[0073] Unless otherwise indicated, "heterocycloalkylidene" means a divalent heterocycloalkyl group as defined above.

[0074] Unless otherwise noted, "oxo" means =O. For example, a carbon is replaced with an oxo to form a group called "carbonyl." [ka] "; the group formed when sulfur is replaced by one oxo is "sulfinyl [ka] " and the group formed when sulfur is replaced by two oxos is "sulfonyl [ka] "

[0075] Unless otherwise stated, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a radical name indicates that the radical is partially or fully halogenated, i.e., substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

[0076] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0077] Unless otherwise expressly stated, the word "comprise" or variations thereof, such as "having" or "containing," means the inclusion of a specified element or integer, or group of elements or integers, and does not mean the exclusion of other elements or integers, or group of elements or integers (to the exclusion of other elements or integers, or group of elements or integers).

[0078] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are bonded to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0079] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0080] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked, for example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0081] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0082] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0083] Unless otherwise indicated, the absolute configuration of a stereocenter is represented by a solid wedge bond. [ka] and wedge-shaped dashed bond [ka] The relative configuration of the stereocenters is represented by a straight solid bond [ka] and straight dashed bond [ka] It is represented by the wavy line. [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0084] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0085] Specific pharmaceutical and medical terms The term "acceptable" as used herein means that a formulation component or active ingredient does not have an excessive and deleterious effect on the general health of the treated subject.

[0086] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, may result from or be associated with administration.

[0087] "Active ingredient" refers to compounds of general formula (1) and pharma- ceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may exist may exist depending on the properties of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0088] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0089] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0090] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of material, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0091] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0092] therapeutic use The present invention provides a method for treating diseases including, but not limited to, related diseases involving FAK protein kinase (e.g., cancer) using a compound of general formula (1) or a pharmaceutical composition of the present invention.

[0093] In some embodiments, a method of treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of structural general formula (1). In some embodiments, the cancer is associated with FAK kinase. In some embodiments, the compound of general formula (1) may be used in combination with other anti-cancer agents. In some embodiments, the compound of general formula (1) may be used in combination with a PD-1 inhibitor. In other embodiments, the cancer is a hematological and solid cancer, including, but not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases. In other embodiments, the cancer is ovarian cancer, melanoma, breast cancer, head and neck cancer, pancreatic cancer, non-small cell lung cancer, colon cancer, prostate cancer, oral cancer, esophageal cancer, mesothelioma, myeloma, leukemia, and cancer metastases of these cancers.

[0094] Route of administration The compound of the present invention and its pharmaceutically acceptable salt can be prepared into various formulations containing a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0095] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use and have sufficient purity and low toxicity. "Compatible" as used herein means that the components of the composition are capable of being mixed together with the compounds of the present invention without significantly reducing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0096] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0097] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0098] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric substances and wax-based substances.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0099] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0100] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0101] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0102] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0103] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required as required.

[0104] The compound of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, and the dosage is a pharma- ceutical effective dose. For a 60 kg human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage will take into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0105] The features described in the present invention or the features described above in the embodiments can be combined in any combination. All features disclosed herein can be used in any composition, and the various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise stated, the features disclosed herein are merely generic examples of equivalent or similar features. EXAMPLES

[0106] (Detailed Description) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference only and describe specific examples. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0107] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was expressed by volume.

[0108] In the present invention, the following abbreviations are used: ACN is acetonitrile; AcOH is acetic anhydride; Acetone is acetone; (Boc)2O is di-tert-butyl dicarbonate; BPO is benzoyl peroxide; CDCl3 is deuterated chloroform; CD3I is deuterated iodomethane; DCM is dichloromethane; DIPEA is diisopropylethylamine; Diox is 1,4-dioxane; DMF is N,N-dimethylformamide; DMAP is 4-(dimethylamino)pyridine; DMSO is dimethylsulfoxide; DPPA is diphenyl ether. nylphosphoryl azide; DCE, 1,2-dichloroethane; EA, ethyl acetate; Et2O, diethyl ether; EtMgBr, ethyl magnesium bromide; Flash, flash preparative medium pressure liquid chromatography; Hexane, n-hexane; HOBt, 1-hydroxybenzotriazole; EDCI, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HCl, hydrochloric acid; HPLC, high performance liquid chromatography; H2, hydrogen; h, time; HOBt, 1-hydroxybenzotriazole; HC HO is formaldehyde; IPA is isopropanol; K2CO3 is potassium carbonate; KOAc is potassium acetate; K3PO4 is potassium phosphate; LiOH is lithium hydroxide; LC-MS is high performance liquid chromatography-mass spectrometry; min is minutes; MeOH is methanol; mL is milliliters; MS is mass spectrometry; MsOH is methanesulfonic acid; m-CPCA is m-chloroperbenzoic acid; n-BuLi is n-butyl lithium; NaBH4 is sodium borohydride; n-BuOH is n-butanol; NH3 / THF is tetrahydrofuran of ammonia. Perhydrofuran solution: NMP is N-methylpyrrolidone; NMR is nuclear magnetic resonance; NBS is N-bromosuccinimide; NaBH(OAc)3 is sodium triacetoxyborohydride; Oxone is potassium peroxymonosulfate; Pd / C is palladium on carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); PE is petroleum ether; Py is pyridine; pre-TLC is preparative silica gel thin layer chromatography;Pd(dppf)2Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; pre-HPLC is preparative high performance liquid chromatography; PPTS is pyridinium p-toluenesulfonate; TFA is trifluoroacetic acid; T3P is 1-propanephosphonic anhydride; TLC is thin layer chromatography; Tf2O is trifluoromethanesulfonic anhydride; Ti(i-PrO)4 is tetraisopropyl titanate; TEA is triethylamine; t-BuOH is tert-butanol; toluene is methylbenzene; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos is 2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl.

[0109] Synthesis of intermediate IntA: [ka]

[0110] Synthesis of A-2: A-1 (25.0 g, 149 mmol) and MeOH (300 mL) were added to a 1 L one-neck flask, and concentrated H2SO4 (9.20 g, 93.8 mmol) was added dropwise at room temperature. The mixture was heated to 80 °C and stirred under argon atmosphere for 16 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated. H2O (300 mL) was added to the residue. The resulting mixture was extracted with EA (600 mL) and liquid separation was performed. The organic phase was washed with saturated sodium chloride solution (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white product (27.0 g, yield: 99.7%).

[0111] Synthesis of A-3: A-2 (27.0 g, 148 mmol), pyridine (35.2 g, 445 mmol) and DCM (400 mL) were added to a 1 L three-neck flask. The mixture was cooled to 0-5 °C in an ice bath, and Tf2O (54.4 g, 193 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 h. After the completion of the reaction was detected by LC-MS, H2O (300 mL) was added to the mixture to quench the reaction, and liquid separation was performed. The aqueous phase was then extracted with DCM (400 mL). The organic phases were combined, washed with saturated sodium chloride solution (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain a brown oily product (25.0 g, yield: 53.7%). ESI-MS m / z: 315.2 [M+H] + . 1 H NMR: (400MHz, CDCl3) δ = 7.38 (t, J=8.4 Hz, 1H), 6.89 (dd, J=8.4, 10.9 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 3H).

[0112] Synthesis of A-4: A-3 (25.0 g, 79.6 mmol), Zn(CN)2 (6.54 g, 55.7 mmol), and DMF (250 mL) were added to a 500 mL one-neck flask. After the mixture was purged with argon, Pd(PPh3)4 (9.19 g, 7.96 mmol) was added. The mixture was heated to 80 °C and stirred under argon atmosphere for 3 h. After the completion of the reaction was detected by LC-MS, H2O (200 mL) was added to the mixture to quench the reaction. The resulting mixture was extracted with EA (400 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (400 mL x 2), and concentrated. The residue was purified by column chromatography to give a white solid product (9.00 g, yield: 59.2%). ESI-MS m / z: 192.1 [M+H] + .

[0113] Synthesis of A-5: A-4 (9.00 g, 47.1 mmol), Et2O (120 mL), and Ti(i-PrO)4 (14.7 g, 51.8 mmol) were added to a 500 mL three-neck flask. The mixture was cooled to 0-5 °C in an ice bath, and then EtMgBr (3 M, 31.4 mL, 94.2 mmol) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 h. After completion of the reaction was detected by LC-MS, saturated aqueous ammonium chloride solution (400 mL) was added dropwise to the mixture at 0-5 °C to quench the reaction. The resulting mixture was extracted with EA (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (200 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (2.50 g, yield: 28.1%). ESI-MS m / z: 190.0 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ = 8.37 (s, 1H), 7.48 (t, J=7.9 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.89 - 3.79 (m, 3H), 1.44 - 1.27 (m, 4H).

[0114] Synthesis of A-6: A-5 (2.50 g, 13.2 mmol) and THF (60 mL) were added to a 250 mL three-neck flask. After the mixture was purged with argon, NaH (793 mg, 19.8 mmol, 60% purity) was added in one portion at room temperature. After the addition, the mixture was stirred at room temperature for 0.5 h, and then MeI (3.75 g, 26.4 mmol) was added. The mixture was stirred at room temperature for another 1.5 h. After the completion of the reaction was detected by LC-MS, the mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution (100 mL) at 0-10 °C. The resulting mixture was extracted with EA (100 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (2.00 g, yield: 74.5%). ESI-MS m / z: 204.1 [M+H] + .

[0115] Synthesis of IntA: A-6 (1.80 g, 8.86 mmol) and DCM (30 mL) were added to a 250 mL three-neck flask. The mixture was cooled to 0-5 °C in an ice bath under argon atmosphere, and BBr3 (13.3 mL, 1 Min DCM, 13.3 mmol) was added dropwise. After the dropwise addition was complete, the mixture was stirred at room temperature for 16 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated. DCM (100 mL) was added to the residue, which was then quenched with water (50 mL) at 0-10 °C. Sodium bicarbonate was then carefully added to adjust the pH to neutral. Liquid separation was performed. The aqueous phase was extracted with DCM (100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (100 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (1.40 g, yield: 83.5%). ESI-MS m / z: 190.0 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ = 9.56 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 2.75 - 2.68 (m, 3H), 1.70 - 1.57 (m, 2H), 1.34 - 1.18 (m, 2H).

[0116] Synthesis of intermediate IntB: [ka]

[0117] Synthesis of B-2: B-1 (8 g, 45.7 mmol), Et2O (120 mL), and Ti(i-PrO)4 (14.3 g, 50.3 mmol) were added to a 250 mL three-neck flask. The mixture was cooled to 0-5 °C in an ice bath, and EtMgBr (3 M, 30.5 mL, 91.5 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the completion of the reaction was detected by LC-MS, saturated aqueous ammonium chloride solution (200 mL) was added dropwise to the mixture at 0-5 °C to quench the reaction. The resulting mixture was extracted with EA (200 mL × 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (200 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (1.6 g, yield: 20.1%). ESI-MS m / z: 174.0 [M+H] + .

[0118] Synthesis of B-3: B-2 (1.6 g, 9.24 mmol) and THF (48 mL) were added to a 250 mL three-neck flask. After the mixture was purged with argon, NaH (554 mg, 13.86 mmol, 60% purity) was added in one portion at room temperature. After the addition, the mixture was stirred at room temperature for 0.5 h, and then MeI (2.63 g, 18.5 mmol) was added. The mixture was stirred at room temperature for another 1.5 h. After the completion of the reaction was detected by LC-MS, the mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution (50 mL) at 0-10 °C. The resulting mixture was extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (1.42 g, yield: 82.1%). ESI-MS m / z: 188.1 [M+H] + .

[0119] Synthesis of IntB: B-3 (1.4 g, 7.48 mmol), benzoyl peroxide (194 mg, 0.8 mmol), and carbon tetrachloride (42 mL) were added to a 250 mL one-neck flask. After the mixture was purged with argon, NBS (1.46 g, 8.2 mmol) was added at room temperature. After the addition, the mixture was heated to 80° and stirred for 16 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated and the residue was purified by Flash to give a light brown solid product (1.02 g, yield: 51.3%). ESI-MS m / z: 266.1 / 268.1[M+H] + .

[0120] Synthesis of intermediate IntC: [ka]

[0121] Synthesis of C-2: C-1 (18 g, 0.10 mol), DMF (400 mL), cesium carbonate (81.5 g, 0.25 mol), and 1,2-diiodoethane (33.8 g, 0.12 mol) were added to a 1 L one-neck flask. The mixture was stirred at room temperature under argon atmosphere for 20 h. After the completion of the reaction was detected by LC-MS, EA (200 mL) / PE (400 mL) and water (400 mL) were added to the mixture. The mixture was stirred and the liquid was separated. The organic phase was washed twice with saturated aqueous sodium chloride solution (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a light brown oily product (17.5 g, yield: 79.5%). ESI-MS m / z: 221.2 [M+H] + .

[0122] Synthesis of C-3: C-2 (17.5 g, 79.5 mmol), THF (200 mL), MeOH (100 mL), water (100 mL), and lithium hydroxide monohydrate (16.8 g, 0.4 mol) were added to a 1 L one-neck flask. The mixture was stirred at room temperature under argon atmosphere for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated to about half its volume and the pH was adjusted to 3-4 with 2N HCl. The resulting mixture was extracted twice with EA (200 mL x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a light brown oily product (14.3 g, yield: 88.1%). ESI-MS m / z: 207.2 [M+H] + .

[0123] Synthesis of C-4: C-3 (14.1 g, 69 mmol), isopropanol (200 mL) and DIPEA (22.3 g, 172.5 mmol) were added to a 1 L three-neck flask. The mixture was purged with argon, and then diphenylphosphoryl azide (22.8 g, 82.8 mmol) was added dropwise in an ice bath. After the dropwise addition was completed, the mixture was stirred at room temperature for 20 min. The mixture was heated to 50 °C and stirred for another 20 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated. EA (200 mL) and water (200 mL) were added to the residue. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted with EA (50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (100 mL × 2), and concentrated. The residue was purified by column chromatography to give a colorless oily product (7.6 g, yield: 41.8%). ESI-MS m / z: 264.3 [M+H] + .

[0124] Synthesis of C-5: C-4 (7.6 g, 28.86 mmol), DCM (200 mL), and P2O5 (16.3 g, 115 mmol) were added to a 500 mL one-neck flask. The mixture was heated to 50 °C and stirred under argon atmosphere for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was cooled and slowly poured into ice water (200 mL). After the mixture was stirred for 30 min, liquid separation was performed. The organic phase was then washed twice with saturated aqueous sodium chloride solution (100 mL × 2) and concentrated. The residue was purified by column chromatography to obtain a light brown oily product (3.2 g, yield: 54.6%). ESI-MS m / z: 204.2 [M+H] + .

[0125] Synthesis of C-6: C-5 (3.2 g, 15.7 mmol) and THF (65 mL) were added to a 250 mL three-neck flask. After the mixture was purged with argon, NaH (793 mg, 19.8 mmol, 60%) was added in one portion at room temperature. After the addition, the mixture was stirred at room temperature for 0.5 h, and then MeI (3.75 g, 26.4 mmol) was added. The mixture was stirred at room temperature for another 1.5 h. After the completion of the reaction was detected by LC-MS, the mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution (100 mL) at 0-10 °C. The resulting mixture was extracted with EA (100 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (2.2 g, yield: 64.6%). ESI-MS m / z: 218.3 [M+H] + .

[0126] Synthesis of IntC: C-6 (2.2 g, 10.12 mmol) and DCM (30 mL) were added to a 250 mL three-neck flask. The mixture was cooled to 0-5 °C in an ice bath under argon atmosphere, and BBr3 (20.2 mL, 1 M in DCM, 20.2 mmol) was added dropwise. After the dropwise addition was complete, the mixture was stirred at room temperature for 16 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated. DCM (100 mL) was added to the residue, which was then quenched with water (50 mL) at 0-10 °C. Sodium bicarbonate was then carefully added to adjust the pH to neutral. Liquid separation was performed. The aqueous phase was extracted with DCM (100 mL). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 2), and concentrated. The residue was purified by column chromatography to give a brown solid product (1.45 g, yield: 70.5%). ESI-MS m / z: 204.2 [M+H] + .

[0127] Example 1: Synthesis of N-methyl-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (Compound 1) [ka] [ka]

[0128] 1-1 synthesis: IntA (1.19 g, 6.29 mmol) and 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (1.51 g, 6.60 mmol) were dissolved in N,N-dimethylformamide (15 mL), and anhydrous potassium carbonate (2.17 g, 15.72 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction was detected by LC-MS, the reaction solution was poured into water (150 mL), and a large amount of solid precipitated. The resulting mixture was stirred at room temperature for 30 minutes and then filtered. The filter cake was washed with water and dried under vacuum to obtain a white solid crude product (2.39 g, yield: 100%). ESI-MS m / z: 382.1 [M+H] + .

[0129] Synthesis of 1-2: The above crude product 1-1 (2.39 g, 6.29 mmol) was dissolved in DCM (25 mL), and m-CPBA (2.12 g, 12.3 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h under argon atmosphere, and then m-CPBA (2.12 g, 12.3 mmol) was added. The mixture was stirred at room temperature for another 2 h. After the completion of the reaction was detected by LC-MS, the resulting mixture was filtered. DCM (100 mL) and saturated sodium thiosulfate solution (50 mL) were added to the filtrate, and the mixture was stirred at room temperature for 20 min. Liquid separation was performed. The organic phase was then washed with saturated sodium thiosulfate solution (50 mL) and saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on 100-200 mesh silica gel (elution gradient PE / EA=2:1→DCM / EA=2:1) ​​to give a white solid product (1.67 g, yield: 64.2%). ESI-MS m / z: 414.1 [M+H] + .

[0130] Synthesis of compound 1 The above compound 1-2 (69 mg, 0.167 mmol) and 4-amino-N-methylbenzamide (30 mg, 0.2 mmol) were dissolved in ultra-dry tert-butanol (5 mL) and camphorsulfonic acid (46 mg, 0.2 mmol) was added. The mixture was heated at reflux under argon atmosphere for 24 h. After the completion of the reaction was detected by LC-MS, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution to quench the reaction. The resulting mixture was concentrated under reduced pressure. The residue was purified by Flash and lyophilized to give a white solid product (17 mg, yield: 21.1%). ESI-MS m / z: 484.1 [M+H] + .

[0131] Example 2: Synthesis of 3-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide (compound 3) [ka] [ka]

[0132] Synthesis of 3-1: 4-Amino-3-methoxybenzoic acid (500 mg, 3.0 mmol) and 1-methylpiperidin-4-amine (350 mg, 3.0 mmol) were dissolved in DMF (10 mL), and HOBt (607 mg, 4.5 mmol), EDCI (863 mg, 4.5 mmol) and TEA (900 mg, 8.9 mmol) were added. The mixture was stirred at room temperature for 16 h. After the completion of the reaction was detected by LC-MS, water (50 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed twice with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid product (708 mg, yield: 90.0%). ESI-MS m / z: 264.2 [M+H] + .

[0133] Synthesis of compound 3: Compounds 1-2 (138 mg, 334 μmol) and 3-1 (88 mg, 334 μmol) were dissolved in overdried tert-butanol (5 mL), and camphorsulfonic acid (92 mg, 0.4 mmol) was added. The mixture was heated to reflux under an argon atmosphere for 24 hours. After completion of the reaction was detected by LC-MS, saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction solution to quench the reaction. The resulting mixture was concentrated under reduced pressure. The residue was purified by Flash and lyophilized to give a white solid product (33.4 mg, yield: 16.3%). ESI-MS m / z: 564.3 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.25 (s, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 6.30 - 6.21 (m, 1H), 4.07 (m, 1H), 3.88 (s, 3H), 3.17 (d, J = 12.0 Hz, 2H), 2.69 (s, 3H), 2.51 (s, 3H), 2.46 (t, J = 11.8 Hz, 2H), 2.08 (d, J = 12.9 Hz, 2H), 1.88 (q, J = 12.0 Hz, 2H), 1.60 (t, J = 7.0 Hz, 2H), 1.44 (t, J = 4.1 Hz, 2H).

[0134] Using different starting materials, the target compounds 2, 4, and 5 in Table 1 were obtained by the same synthesis method as in Example 2.

[0135] [Table 1]

[0136] Example 3: Synthesis of 2-fluoro-5-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)benzamide (Compound 8) [ka] [ka]

[0137] Synthesis of 8-1: 2-Fluoro-5-methoxy-4-nitrobenzoic acid (610 mg, 2.08 mmol), tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 2.08 mol), HOBt (420 mg, 3.1 mmol), EDCI (598 mg, 3.1 mmol), and DIPEA (1.1 mL) were added to DMF (10 mL). The mixture was purged with argon and stirred at room temperature for 20 h. After completion of the reaction was detected by LC-MS, water (20 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min and then filtered. The filter cake was washed with water and dried under vacuum to give the product (930 mg, yield: >100%). ESI-MS m / z: 438.2 [M+H] + .

[0138] Synthesis of 8-2: The above 8-1 (930 mg, crude product, 2.08 mmol) was added to EA (10 mL). After complete dissolution, 4M HCl / Diox (10 mL, 40 mmol) was added. After completion of the reaction was detected by LC-MS, the mixture was concentrated to dryness. EA (20 mL) and saturated sodium bicarbonate solution (20 mL) were added to the residue. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted twice with EA (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give a tan oily product (508 mg, yield: 72.4%). ESI-MS m / z: 338.1 [M+H] + .

[0139] Synthesis of 8-3: The above compound 8-2 (508 mg, 1.51 mmol) was added to THF (10 mL). Glacial acetic acid (136 mg, 2.265 mmol) and aqueous formaldehyde (147 mg, 37%, 1.8 mmol) were added at room temperature. The mixture was stirred at room temperature for 30 min. Then, NaBH(OAc)3 (479 mg, 2.26 mmol) was added, and the mixture was stirred at room temperature for another 20 h. After the completion of the reaction was detected by LC-MS, EA (20 mL) and saturated sodium bicarbonate solution (20 mL) were added to the mixture. After the mixture was stirred for 20 min, liquid separation was performed. The aqueous phase was extracted twice with EA (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product (630 mg, yield: >100%) as a brown oil. ESI-MS m / z: 352.1 [M+H] + .

[0140] Synthesis of 8-4: The above 8-3 (630 mg, crude product, 1.51 mmol) and 10% wet Pd / C (100 mg, containing 50-55% water) were added to MeOH (20 mL). The mixture was purged with hydrogen three times and vigorously stirred at room temperature under atmospheric pressure for 20 h. After completion of the reaction was detected by LC-MS, the mixture was filtered through diatomaceous earth. The filter cake was rinsed with MeOH, and the filtrate was concentrated to dryness to give the product as a white solid (433 mg, yield: 89%). ESI-MS m / z: 322.1 [M+H] + .

[0141] Synthesis of compound 8: The above compound 8-4 (50 mg, 0.156 mmol) and 1-2 (59 mg, 0.142 mmol) were added to isopropanol (5 mL). TFA (18 mg, 0.156 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 3 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (9 mg, yield: 9.7%). ESI-MS m / z: 655.3 [M+H] + .

[0142] Using different starting materials, the target compounds 6, 7, and 9 to 34 in Table 2 were obtained by the same synthesis method as in Example 3.

[0143] [Table 2-1] [Table 2-2]

[0144] Example 4: Synthesis of 3-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzamide (compound 35) [ka] [ka]

[0145] Synthesis of 35-1: 3-Methoxy-4-nitrobenzoic acid (835 mg, 5.0 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.0 g, 5.0 mol), HOBt (1.01 g, 7.5 mmol), EDCI (1.45 g, 7.5 mmol), and DIPEA (2.66 mL) were added to DMF (20 mL). The mixture was purged with argon and stirred at room temperature for 20 h. After completion of the reaction was detected by LC-MS, water (40 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min and then filtered. The filter cake was washed with water and dried under vacuum to give the product (1.59 g, yield: 91%). ESI-MS m / z: 350.2 [M+H] + .

[0146] Synthesis of 35-2: Compound 35-1 (700 mg, 2.0 mmol) and 1-2 (744 mg, 1.8 mmol) from above were added to over-dried tert-butanol (20 mL). TFA (228 mg, 2.0 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (319 mg, yield: 26%). ESI-MS m / z: 683.3 [M+H] + .

[0147] Synthesis of compound 35: The above compound 35-2 (310 mg, 0.454 mmol) was added to DCM (10 mL). TFA (456 mg, 4.0 mmol) was added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 5 h. After the reaction was essentially complete by LC-MS, saturated sodium bicarbonate solution (10 mL) was added to the mixture to quench the reaction, and liquid separation was performed. The aqueous phase was extracted with DCM (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product (280 mg, yield: 107%). Approximately 30 mg of the crude product was subjected to pre-TLC (DCM:MeOH=10:1) purification to obtain a white solid product (11 mg). ESI-MS m / z: 582.2 [M+H] + .

[0148] Example 5: Synthesis of 3-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzamide (compound 36) [ka] [ka]

[0149] Synthesis of compound 36: The above compound 35 (50 mg, crude product, 0.086 mmol) and anhydrous potassium carbonate (36 mg, 0.26 mmol) were added to DMF (2 mL). CD3I (12 mg, 0.083 mmol) was added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 2 h. After the reaction was essentially complete by LC-MS, the mixture was purified by Flash and lyophilized to give a white solid product (16 mg, yield: 31%). ESI-MS m / z: 600.2 [M+H] + . 1H-NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.25 (s, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 6.31 - 6.24 (m, 1H), 4.07 (m, 1H), 3.86 (s, 3H), 3.19 (d, J = 12.0 Hz, 2H), 2.63 (s, 3H), 2.46 (t, J = 11.8 Hz, 2H), 2.12 (d, J = 12.9 Hz, 2H), 1.81 (q, J = 12.0 Hz, 2H), 1.62 (t, J = 7.0 Hz, 2H), 1.45 (t, J = 4.1 Hz, 2H).

[0150] Using different starting materials, the target compounds 37 to 48 in Table 3 were obtained by the same synthesis methods as in Examples 4 and 5.

[0151] [Table 3]

[0152] Using different starting materials, the target compounds 49 to 73 and the target compounds 77 to 91 in Table 4 were obtained by referring to the same synthesis methods as in Examples 2 and 3.

[0153] [Table 4-1] [Table 4-2] [Table 4-3]

[0154] Example 6: Synthesis of 4'-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 74) [ka] [ka]

[0155] Synthesis of compound 74-1: tert-Butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (614 mg, 2.0 mmol) and 1-2 (744 mg, 1.8 mmol) were added to over-dried tert-butanol (20 mL). TFA (228 mg, 2.0 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated and the residue was purified by Flash and lyophilized to give an off-white solid product (623 mg, yield: 54.0%). ESI-MS m / z: 641.2 [M+H] + .

[0156] Synthesis of compound 74: The above compound 74-1 (600 mg, 0.936 mmol) was added to DCM (20 mL). TFA (1.14 g, 10 mmol) was added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 5 h. After the reaction was essentially completed by LC-MS, saturated sodium bicarbonate solution (20 mL) was added to the mixture to quench the reaction, and liquid separation was performed. The aqueous phase was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product (412 mg, yield: 81.4%). Approximately 30 mg of the crude product was subjected to pre-TLC (DCM:MeOH=10:1) purification to obtain a white solid product (9 mg). ESI-MS m / z: 541.2 [M+H] + .

[0157] Example 7: Synthesis of 2-(4-(3-methoxy-4-((4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N,N-dimethylacetamide (Compound 75) [ka] [ka]

[0158] Synthesis of compound 75: The above compound 74 (54 mg, crude product, 0.1 mmol) and anhydrous potassium carbonate (36 mg, 0.26 mmol) were added to DMF (2 mL). 2-Chloro-N,N-dimethylacetamide (10 mg, 0.082 mmol) was added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 2 h. After the reaction was essentially complete by LC-MS, the mixture was purified by Flash and lyophilized to give a white solid product (11 mg, yield: 21%). ESI-MS m / z: 626.2 [M+H] + .

[0159] Example 8: Synthesis of 4'-(2-((2-methoxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 76) [ka]

[0160] Compound 74 and 1-bromo-2-methoxyethane were used as starting materials, and compound 76 was obtained according to the synthesis method of Example 75.

[0161] Example 9: Synthesis of 4'-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 92) [ka] [ka]

[0162] Synthesis of 92-1: 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (500 mg, 3.286 mmol), DPPA (1.4 g, 4.929 mmol), and TEA (665 mg, 6.572 mmol) were added to tert-butanol (10 mL). The mixture was purged with argon, heated to 80° C., and stirred for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated. The residue was purified by Flash extraction, drying, and concentration to give an off-white solid product (294 mg, yield: 33%). ESI-MS m / z: 224.0 [M+H] + .

[0163] Synthesis of 92-2: The above compound 92-1 (294 mg, 1.3 mmol) and TFA (2 mL) were added to DCM (3 mL). The mixture was stirred at room temperature for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated and the residue was purified by Flash and lyophilized to give an off-white solid product (200 mg, yield: >100%). ESI-MS m / z: 124.0 [M+H] + .

[0164] Synthesis of compound 92: The above compound 92-2 (34 mg, 0.145 mmol) and 1-2 (50 mg, 0.121 mmol) were added to over-dried tert-butanol (2 mL). TFA (14 mg, 0.121 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated, and the residue was purified by HPLC and lyophilized to give an off-white solid product (10 mg, yield: 18.1%). ESI-MS m / z: 457.1 [M+H] + .

[0165] Using different starting materials, the target compounds 93 to 98 in Table 5 were obtained according to the same synthesis method as in Example 9.

[0166] [Table 5]

[0167] Example 10: Synthesis of 3-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide (Compound 99) [ka] [ka]

[0168] Synthesis of 99-1: IntB (1 g, 3.76 mmol), bis(pinacolato)diboron (1.91 g, 7.52 mmol), and potassium acetate (1.32 g, 15 mmol) were added to methylbenzene (50 mL). The mixture was purged with argon, and then Pd(dppf)2Cl2 (292 mg, 0.4 mmol) was added. The mixture was heated to 50° C. and stirred under argon atmosphere for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was purified by column chromatography to obtain the product (740 mg, yield: 62.8%). ESI-MS m / z: 314.1 [M+H] + .

[0169] Synthesis of 99-2: The above compound 99-1 (740 mg, 2.363 mmol), 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (648 mg, 2,835 mmol), and potassium phosphate (1.5 g, 7.09 mmol) were added to Diox (20 mL) / water (4 mL). The mixture was purged with argon, and then Pd(dppf)2Cl2 (270 mg, 0.37 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 16 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated and the residue was purified by Flash to give the product (435 mg, yield: 48.5%). ESI-MS m / z: 380.2 [M+H] + .

[0170] Synthesis of 99-3: The above compound 99-2 (430 mg, 1.133 mmol) was added to a mixture of THF (10 mL) / water (2 mL), followed by the addition of Oxone (2.8 g, 4.533 mmol). The mixture was stirred at room temperature for 6 h. After the completion of the reaction was detected by LC-MS, water (20 mL) was added to the system, followed by extraction with EA (20 mL). The organic phase was washed twice with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product (490 mg, yield: >100%) as a light brown solid. ESI-MS m / z: 412.2 [M+H]+ .

[0171] Synthesis of compound 99: The above compound 99-3 (53 mg, 0.13 mmol) and 3-1 (41 mg, 0.156 mmol) were added to over-dried tert-butanol (5 mL), and TFA (23 mg, 0.2 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 5 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (11 mg, yield: 14.2%). ESI-MS m / z: 595.2 [M+H] + .

[0172] Example 11: Synthesis of 2-fluoro-5-methoxy-4-(4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide (Compound 100) [ka]

[0173] Using 4-amino-2-fluoro-5-methoxybenzoic acid and compound 99-3 as starting materials, compound 100 was obtained according to the same synthesis method as in Example 99.

[0174] Example 12: Synthesis of 3-methoxy-4-((4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)benzamide (Compound 101) [ka] [ka]

[0175] Synthesis of 101-1: The above compound 99-3 (318 mg, 0.65 mmol) and methyl 4-amino-3-methoxybenzoate (141 mg, 0.78 mmol) were added to over-dried tert-butanol (10 mL), and TFA (114 mg, 1.0 mmol) was added at room temperature. The mixture was purged with argon, heated to 80° C., and stirred for 5 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (192 mg, yield: 57.6%). ESI-MS m / z: 513.2 [M+H] + .

[0176] Synthesis of 101-2: The above compound 101-1 (180 mg, 0.351 mmol) was added to THF (5 mL) / MeOH (2 mL) / water (2 mL) and lithium hydroxide monohydrate (147 mg, 3.51 mmol) was added at room temperature. The mixture was stirred at room temperature for 6 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated to a small volume and water (10 mL) was added. The pH was adjusted to 2-3 with 2N HCl aqueous solution, and the resulting mixture was extracted three times with EA (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a light brown solid product (142 mg, yield: 81.2%). ESI-MS m / z: 499.2 [M+H] + .

[0177] Synthesis of 101-3: The above compound 101-2 (50 mg, 0.10 mmol), tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (24 mg, 0.10 mol), HOBt (21 mg, 0.155 mmol), EDCI (30 mg, 0.155 mg), and DIPEA (39 mg, 0.302 mmol) were added to DMF (5 mL). The mixture was purged with argon and stirred at room temperature for 20 h. After the completion of the reaction was detected by LC-MS, water (10 mL) was added to the mixture, and the resulting mixture was extracted three times with EA (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a light brown solid product (80 mg, yield: >100%, crude product). ESI-MS m / z: 721.3 [M+H] + .

[0178] Synthesis of 101-4: The above compound 101-3 (80 mg, crude product, 0.10 mmol) was added to DCM (5 mL), and TFA (114 mg, 1 mmol) was added at room temperature. The mixture was stirred at room temperature under argon atmosphere for 5 h. After the completion of the reaction was detected by LC-MS, the mixture was quenched by adding saturated sodium bicarbonate solution (5 mL) and the liquid was separated. The aqueous phase was extracted with DCM (10 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product (63 mg, yield: 100%). ESI-MS m / z: 621.2 [M+H] + .

[0179] Synthesis of compound 101: The above compound 101-3 (63 mg, 0.1 mmol) was added to DCE (5 mL), and glacial acetic acid (12 mg, 0.2 mmol) and aqueous formaldehyde (41 mg, 37%, 0.5 mmol) were added at room temperature. The mixture was stirred at room temperature for 30 min. Then, NaBH(OAc)3 (106 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for another 2 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by HPLC and lyophilized to give an off-white solid product (9 mg, yield: 14.2%). ESI-MS m / z: 635.3 [M+H] + .

[0180] Using different starting materials, the target compounds 102 to 113 in Table 6 were obtained by referring to the same synthesis method as in Example 12.

[0181] [Table 6]

[0182] Example 13: Synthesis of 4-((5-chloro-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 114) [ka] [ka]

[0183] Synthesis of 114-1: IntA (378 mg, 2.0 mmol) and 2,4,5-trichloropyrimidine (403 mg, 2.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (828 mg, 6.0 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction was detected by LC-MS, the reaction solution was poured into water (20 mL), and a large amount of solid precipitated. After stirring at room temperature for 30 minutes, the mixture was filtered. The filter cake was washed with water and then dried under vacuum to obtain a white solid crude product (544 mg, yield: 80.9%). ESI-MS m / z: 336.0 [M+H] + .

[0184] Synthesis of compound 114: The above crude product 114-1 (50 mg, 0.149 mmol) was dissolved in DCM (25 mL), and m-CPBA (2.12 g, 12.3 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h under argon atmosphere, and m-CPBA (2.12 g, 12.3 mmol) was added. The mixture was stirred at room temperature for another 2 h. After the completion of the reaction was detected by LC-MS, the resulting mixture was filtered. DCM (100 mL) and saturated sodium thiosulfate solution (50 mL) were added to the filtrate, and the mixture was stirred at room temperature for 20 min. Liquid separation was performed. The organic phase was then washed with saturated sodium thiosulfate solution (50 mL) and saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on 100-200 mesh silica gel (elution gradient PE / EA=2:1→DCM / EA=2:1) ​​to give a white solid product (1.67 g, yield: 64.2%). ESI-MS m / z: 414.1 [M+H] + .

[0185] Synthesis of compound 114: The above crude product 114-1 (50 mg, 0.149 mmol) and 3-1 (47 mg, 0.18 mmol) were dissolved in over-dried tert-butanol (5 mL), and TFA (23 mg, 0.2 mmol) was added. The mixture was heated to reflux under argon atmosphere for 24 h. After the completion of the reaction was detected by LC-MS, saturated sodium bicarbonate solution (5 mL) was added to the reaction solution to quench the reaction. The resulting mixture was concentrated under reduced pressure. The residue was purified by Flash and lyophilized to give a white solid product (12 mg, yield: 14.3%). ESI-MS m / z: 563.0 [M+H] + .

[0186] Using different starting materials, the target compounds 115 to 118 in Table 7 were obtained according to the same synthesis method as in Example 13.

[0187] [Table 7]

[0188] Example 14: Synthesis of 4'-(2-((5-fluoro-2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 119) [ka] [ka]

[0189] Synthesis of 119-1: The above compound 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (375 mg, 1.5 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (446 mg, 2.0 mmol), and K3PO4 (636 mg, 3.0 mmol) were added to Diox (10 mL) and water (4 mL). The mixture was purged with argon, and then Pd(dppf)2Cl2 (140 mg, 0.15 mmol) was added. The mixture was heated to 80° C. and stirred under argon atmosphere for 20 h. After completion of the reaction was detected by LC-MS, the mixture was filtered. The filter cake was washed with EA (40 mL), and water (20 mL) was added to the filtrate. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (20 mL). The organic phases were combined, washed with saturated sodium chloride solution, and concentrated. The residue was purified by column chromatography to give the product (256 mg, yield: 64%). ESI-MS m / z: 267.1 [M+H] + .

[0190] Synthesis of 119-2: The above compound 119-2 (256 mg, 0.962 mmol) and 10% Pd / C (54 mg) were added to MeOH (10 mL). The mixture was purged with H2 three times and stirred at room temperature under normal pressure for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purple oily product (253 mg, yield: 100%). ESI-MS m / z: 239.1 [M+H] + .

[0191] Synthesis of compound 119: The above compound 119-2 (76 mg, 0.20 mmol) and 1-2 (82 mg, 0.20 mmol) were added to Diox (5 mL) and TFA (25 mg, 0.22 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 3 h. The product was detected by LC-MS. The mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (13 mg, yield: 11.4%). ESI-MS m / z: 572.2 [M+H] + .

[0192] Example 15: Synthesis of 4'-((2-((5-fluoro-2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 120) [ka] [ka]

[0193] Synthesis of 120-1: The above compound 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (770 mg, 3.079 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (697 mg, 3.079 mmol), Xantphos (178 mg, 0.308 mmol), and cesium carbonate (2.0 g, 6.158 mmol) were added to Diox (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (141 mg, 0.154 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered. The filter cake was washed with EA (40 mL), and water (20 mL) was added to the filtrate. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (20 mL). The organic phases were combined, washed with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography to give the product (890 mg, yield: 73.1%). ESI-MS m / z: 396.2 [M+H] + .

[0194] Synthesis of 120-2: The above compound 120-1 (400 mg, 1.012 mmol) and TFA (1 mL) were added to DCM (2 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (701 mg, yield: >100%). ESI-MS m / z: 296.1 [M+H] + .

[0195] Synthesis of 120-3: The above compound 120-2 (701 mg, crude, 1.012 mmol) and DIPEA (404 mg, 3.135 mmol) were added to THF (10 mL) / MeOH (2 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (137 mg, 2.276 mmol) and aqueous formaldehyde (100 mg, 37%, 1.23 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (434 mg, 2.049 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow solid product (305 mg, yield: 97.5%). ESI-MS m / z: 310.1 [M+H] + .

[0196] Synthesis of 120-4: The above compound 120-3 (305 mg, 0.987 mmol) and 10% Pd / C (34 mg) were added to MeOH (10 mL). The mixture was purged with H2 three times and stirred at room temperature under normal pressure for 2 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black oily product (303 mg, yield: 100%). ESI-MS m / z: 280.1 [M+H] + .

[0197] Synthesis of compound 120: The above compound 120-4 (135 mg, 0.483 mmol) and 1-2 (200 mg, 0.483 mmol) were added to Diox (10 mL) and TFA (66 mg, 0.58 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 3 h. The reaction product was detected by LC-MS. The mixture was concentrated, and the residue was purified by Flash and lyophilized to give an off-white solid product (35 mg, yield: 11.8%). ESI-MS m / z: 613.2 [M+H] + .

[0198] Example 16: Synthesis of 4'-((2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 121) [ka] [ka]

[0199] Synthesis of 121-1: The above compound 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (1.0 g, 4.0 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (733 mg, 4.0 mmol), Xantphos (231 mg, 0.4 mmol), and cesium carbonate (2.6 g, 8.0 mmol) were added to Diox (20 mL). The mixture was purged with argon, and then Pd2(dba)3 (183 mg, 0.20 mmol) was added. The mixture was heated to 100° C. and stirred under argon atmosphere for 20 hours. After the completion of the reaction was detected by LC-MS, the mixture was filtered. The filter cake was washed with DCM (50 mL), and water (50 mL) was added to the filtrate. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with DCM (50 mL). The organic phases were combined, washed with saturated sodium chloride solution, and concentrated. The residue was purified by Flash to give a yellow solid product (715 mg, yield: 50.7%). ESI-MS m / z: 353.2 [M+H] + .

[0200] Synthesis of 121-2: The above compound 121-1 (715 mg, 2.03 mmol) and 10% Pd / C (70 mg) were added to MeOH (10 mL). The mixture was purged with H2 three times and stirred at room temperature under normal pressure for 4 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black solid product (641 mg, yield: 98%). ESI-MS m / z: 323.2 [M+H] + .

[0201] Synthesis of compound 121 The above compound 121-2 (510 mg, 1.582 mmol) and 1-2 (654 mg, 1.582 mmol) were added to t-BuOH (10 mL) and MsOH (273 mg, 2.847 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by Flash and the impure product was further purified by preparative HPLC and lyophilized to give an off-white solid product (405 mg, yield: 39%). ESI-MS m / z: 656.3 [M+H] + .

[0202] Using different starting materials, the target compounds 122 to 129 in Table 8 were obtained by referring to the same synthesis methods as in Example 7, Example 8, Example 15 and Example 16.

[0203] [Table 8]

[0204] Example 17: Synthesis of 4'-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 130) [ka] [ka]

[0205] Synthesis of 130-1: Compound 2,4-dichloro-5-cyclopropylpyrimidine (500 mg, 2.646 mmol) and IntA (500 mg, 2.646 mmol) were added to DMF (5 mL), and the mixture was cooled to 0-5 °C in an ice bath under argon atmosphere. Potassium carbonate (750 mg, 5.435 mmol) was then added. The mixture was stirred at 0-5 °C for 30 min, then heated to room temperature and stirred for another 5 h. After completion of the reaction was detected by LC-MS, water (10 mL) was added to the mixture. The resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and dried under vacuum to obtain the product (622 mg, yield: 68.8%). ESI-MS m / z: 342.1 [M+H] + .

[0206] Synthesis of compound 130: The above compound 130-1 (100 mg, 0.293 mmol) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (78 mg, 0.352 mmol) were added to t-BuOH (5 mL) and MsOH (51 mg, 0.531 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by Flash and the impure product was further purified by pre-TLC to give an off-white solid product (15 mg, yield: 9.72%). ESI-MS m / z: 527.2 [M+H] + .

[0207] Example 18: Synthesis of 4'-((5-cyclopropyl-2-((2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 131) [ka] [ka]

[0208] Synthesis of 131-1: The above compound 4-fluoro-2-methoxy-1-nitrobenzene (794 mg, 4.64 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1 g, 4.42 mmol), and anhydrous potassium carbonate (1.3 g, 9.28 mmol) were added to acetonitrile (10 mL). The mixture was purged with argon, heated to 85 °C, and stirred for 40 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated. EA (20 mL) and water (20 mL) were added to the residue. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (20 mL). The organic phases were combined, washed with saturated sodium chloride solution, and concentrated. The residue was purified by column chromatography to give the product (1.5 g, yield: 90%). ESI-MS m / z: 378.2 [M+H] + .

[0209] Synthesis of 131-2: The above compound 131-1 (680 mg, 1.8 mmol) and TFA (2 mL) were added to DCM (4 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated. EA (5 mL) and PE (5 mL) were added to the residue. The resulting mixture was stirred at room temperature for 30 min and filtered. The filter cake was dried under vacuum to give a yellow solid product (730 mg, yield: >100%). ESI-MS m / z: 278.1 [M+H] + .

[0210] Synthesis of 131-3: The above compound 131-2 (730 mg, 1.8 mmol) and DIPEA (233 mg, 1.8 mmol) were added to THF (20 mL) / MeOH (4 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (216 mg, 3.6 mmol) and aqueous formaldehyde (175 mg, 37%, 2.16 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (763 mg, 3.6 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow foamy solid product (516 mg, yield: 98%). ESI-MS m / z: 292.1 [M+H] + .

[0211] Synthesis of 131-4: The above compound 131-3 (512 mg, 1.757 mmol) and 10% Pd / C (50 mg) were added to MeOH (10 mL). The mixture was purged with H2 three times and stirred at room temperature under normal pressure for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black oily product (460 mg, yield: 100%). ESI-MS m / z: 262.1 [M+H] + .

[0212] Synthesis of compound 131: The above compounds 130-1 (100 mg, 0.293 mmol) and 131-4 (92 mg, 0.352 mmol) were added to t-BuOH (5 mL) and MsOH (51 mg, 0.531 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by Flash, and the impure product was further purified by pre-HPLC and lyophilized to give an off-white solid product (13 mg, yield: 7.83%). ESI-MS m / z: 567.3 [M+H] + .

[0213] Example 19: Synthesis of 4-((5-chloro-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidin-2-yl)amino)-2-fluoro-5-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)benzamide (Compound 132) [ka] [ka]

[0214] Synthesis of 8-1: 2-Fluoro-5-methoxy-4-nitrobenzoic acid (1.22 g, 4.16 mmol), tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 4.16 mol), HOBt (840 mg, 6.2 mmol), EDCI (1.2 g, 6.2 mmol), and DIPEA (2.2 mL) were added to DMF (20 mL). The mixture was purged with argon and stirred at room temperature for 20 h. After completion of the reaction was detected by LC-MS, water (40 mL) was added to the mixture. The resulting mixture was stirred at room temperature for 30 min and then filtered. The filter cake was washed with water and dried under vacuum to give the product (1.9 g, yield: >100%). ESI-MS m / z: 438.2 [M+H] + .

[0215] Synthesis of 132-2: The above compound 8-1 (900 mg, 2.06 mmol) and 10% Pd / C (90 mg) were added to MeOH / THF (10 mL / 10 mL). The mixture was purged with H2 three times and then stirred at room temperature under normal pressure for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a light gray foamy solid product (880 mg, yield: >100%). ESI-MS m / z: 408.2 [M+H] + .

[0216] Synthesis of 132-3: The above compound 132-2 (315 mg, 0.773 mmol), compound 114-1 (200 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to obtain a tan solid product (95 mg, yield: 22.6%). ESI-MS m / z: 707.3 [M+H] + .

[0217] Synthesis of 132-4: The above compound 132-3 (95 mg, 0.134 mmol) and TFA (0.3 mL) were added to DCM (5 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (172 mg, yield: >100%). ESI-MS m / z: 607.2 [M+H] + .

[0218] Synthesis of compound 132: The above compound 132-4 (172 mg, crude, 0.134 mmol) and DIPEA (168 mg, 1.3 mmol) were added to THF (5 mL) / MeOH (1 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (16 mg, 0.27 mmol) and aqueous formaldehyde (17 mg, 37%, 0.204 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (57 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated and the residue was purified by Flash to give an off-white solid product (32 mg, yield: 38.4%). ESI-MS m / z: 621.2 [M+H] + .

[0219] Example 20: Synthesis of 4-((5-chloro-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidin-2-yl)amino)-3-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)benzamide (Compound 133) [ka]

[0220] Using 3-methoxy-4-nitrobenzoic acid as a starting material, the target compound 133 was obtained according to the same synthesis method as in Example 132.

[0221] Example 21: Synthesis of 4'-((5-chloro-2-((5-fluoro-2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 134) [ka] [ka]

[0222] The above compound 114-1 (80 mg, 0.238 mmol) and 119-2 (68 mg, 0.286 mmol) were added to t-BuOH (5 mL) and MsOH (34 mg, 0.354 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by Flash, and the impure product was further purified by pre-HPLC and lyophilized to give an off-white solid product (16 mg, yield: 12.5%). ESI-MS m / z: 538.2 [M+H] + .

[0223] Example 22: Synthesis of 4'-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 135) [ka] [ka]

[0224] Synthesis of 135-1 tert-Butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (237 mg, 0.773 mmol), compound 114-1 (200 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to give a tan solid product (198 mg, yield: 54.9%). ESI-MS m / z: 606.2 [M+H] + .

[0225] Synthesis of 135-2: The above compound 135-1 (198 mg, 0.327 mmol) and TFA (0.5 mL) were added to DCM (10 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (271 mg, yield: >100%). ESI-MS m / z: 506.2 [M+H]+.

[0226] Synthesis of compound 135: The above compound 135-2 (141 mg, crude, 0.17 mmol) and DIPEA (168 mg, 1.3 mmol) were added to THF (5 mL) / MeOH (1 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (20 mg, 0.33 mmol) and aqueous formaldehyde (17 mg, 37%, 0.204 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (72 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow solid product (47 mg, yield: 53.2%). ESI-MS m / z: 520.2 [M+H] + .

[0227] Example 23: Synthesis of 4'-((5-chloro-2-((2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 136) [ka] [ka]

[0228] Synthesis of 136-2 The above compound 131-1 (500 mg, 1.325 mmol) and 10% Pd / C (50 mg) were added to MeOH / THF (10 mL / 4 mL). The mixture was purged with H2 three times and then stirred at room temperature under normal pressure for 2 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black foamy solid product (450 mg, yield: 96%). ESI-MS m / z: 348.1 [M+H] + .

[0229] Compound 114-1: Compound 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) and IntA (516 mg, 2.73 mmol) were added to DMF (5 mL), and the mixture was cooled to 0-5 °C in an ice bath under argon atmosphere. Potassium carbonate (755 mg, 5.46 mmol) was then added. The mixture was stirred at 0-5 °C for 1 h. After the completion of the reaction was detected by LC-MS, water (10 mL) was added to the mixture. The resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and dried under vacuum to obtain the product (836 mg, yield: 91%). ESI-MS m / z: 336.0 [M+H] + .

[0230] Synthesis of 136-3: The above compound 136-2 (269 mg, 0.773 mmol), compound 114-1 (200 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to obtain a tan solid product (110 mg, yield: 28%). ESI-MS m / z: 647.3 [M+H] + .

[0231] Synthesis of 136-4: The above compound 136-3 (110 mg, 0.17 mmol) and TFA (0.3 mL) were added to DCM (5 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (241 mg, yield: >100%). ESI-MS m / z: 547.2 [M+H] + .

[0232] Synthesis of compound 136: The above compound 136-4 (241 mg, crude, 0.17 mmol) and DIPEA (168 mg, 1.3 mmol) were added to THF (5 mL) / MeOH (1 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (20 mg, 0.33 mmol) and aqueous formaldehyde (17 mg, 37%, 0.204 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (72 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow solid product (79 mg, yield: 82.8%). ESI-MS m / z: 561.3 [M+H] + .

[0233] Example 24: Synthesis of 4'-((5-chloro-2-((5-fluoro-2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 137) [ka] [ka]

[0234] Synthesis of 137-1: The above compound 120-1 (1.2 g, 3.0 mmol) and 10% Pd / C (120 mg) were added to MeOH / THF (10 mL / 10 mL). The mixture was purged with H2 three times and then stirred at room temperature under normal pressure for 20 h. After the completion of the reaction detected by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black foamy solid product (1.1 g, yield: 98%). ESI-MS m / z: 366.2 [M+H] + .

[0235] Synthesis of 137-2: The above compound 137-1 (283 mg, 0.774 mmol), compound 114-1 (200 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to give a tan gummy product (213 mg, yield: 46%). ESI-MS m / z: 665.4 [M+H] + .

[0236] Synthesis of 137-3: The above compound 137-2 (213 mg, 0.32 mmol) and TFA (0.5 mL) were added to DCM (5 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (361 mg, yield: >100%). ESI-MS m / z: 565.3 [M+H] + .

[0237] Synthesis of compound 137: The above compound 137-3 (361 mg, crude, 0.32 mmol) and DIPEA (223 mg, 1.73 mmol) were added to THF (5 mL) / MeOH (1 mL). The mixture was stirred at room temperature for 10 min. Then, glacial acetic acid (40 mg, 0.67 mmol) and aqueous formaldehyde (32 mg, 37%, 0.384 mmol) were added, and the mixture was stirred at room temperature for 20 min. Then, NaBH(OAc)3 (136 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow solid product (143 mg, yield: 77.1%). ESI-MS m / z: 579.3 [M+H] + .

[0238] Using different starting materials, the target compounds 138 to 152 in Table 9 were obtained by referring to the same synthesis methods as in Example 23 and Example 24.

[0239] [Table 9]

[0240] Example 25: Synthesis of 4'-((5-chloro-2-((2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 153) [ka] [ka]

[0241] Synthesis of 153-1: 3-Methoxy-4-nitrobenzaldehyde (1.81 g, 10.0 mmol), ethylene glycol (5 mL), PPTS (1.26 g, 5.0 mmol) and methylbenzene (50 mL) were added to a 100 mL one-neck flask. The mixture was purged with argon, heated to 130 °C, refluxed to remove moisture and stirred for 20 h. After completion of the reaction was detected by LC-MS, the mixture was cooled, washed with water (50 mL) and the aqueous phase was extracted with methylbenzene (50 mL). The organic phases were combined, washed twice with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a brown oil (1.78 g, yield: 79%). ESI-MS m / z: 226.1 [M+H] + .

[0242] Synthesis of 153-2: The above compound 152-1 (1.78 g, 7.90 mmol) and 10% Pd / C (200 mg) were added to MeOH (100 mL). The mixture was purged with H2 three times, then stirred at room temperature under normal pressure for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was filtered. The filtrate was concentrated to dryness, and the residue was purified by column chromatography to obtain a light brown oily product (1.33 g, yield: 86.2%). ESI-MS m / z: 196.1 [M+H] + .

[0243] Synthesis of 153-3: The above compound 153-2 (174 mg, 0.893 mmol), compound 114-1 (200 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to give a tan gummy product (232 mg, yield: 78.7%). ESI-MS m / z: 495.1 [M+H] + .

[0244] Synthesis of 153-4: The above compound 153-3 (232 mg, 0.469 mmol) and 1N HCl (1.0 mL) were added to acetone / water (10 mL / 3 mL). The mixture was purged with argon, heated to 60° C., and stirred for 5 h. After completion of the reaction was detected by LC-MS, EA (10 mL) and water (20 mL) were added to the mixture. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (10 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (198 mg, yield: 93.6%). ESI-MS m / z: 451.1 [M+H] + .

[0245] Synthesis of compound 153: The above compound 153-4 (45 mg, 0.10 mmol), N-methylpiperazine (20 mg, 0.2 mmol) and glacial acetic acid (24 mg, 0.4 mmol) were added to THF (5 mL) and the mixture was stirred at room temperature for 15 min. Then NaBH(OAc)3 (85 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated and the residue was purified by Flash to give an off-white solid product (11 mg, yield: 20.6%). ESI-MS m / z: 535.2 [M+H] + .

[0246] Using different starting materials, the target compounds 154 to 156 in Table 10 were obtained according to the same synthesis method as in Example 25.

[0247] [Table 10]

[0248] Example 26: Synthesis of 4'-((5-chloro-2-((2-methoxy-4-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 157) [ka] [ka]

[0249] Synthesis of 157-1: The above compound 4-fluoro-2-methoxy-1-nitrobenzene (855 mg, 5.0 mmol), azetidin-3-ol (730 mg, 10.0 mmol), and anhydrous potassium carbonate (2.07 g, 15 mmol) were added to acetonitrile (50 mL). The mixture was purged with argon, heated to 85° C., and stirred for 20 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated. EA (20 mL) and water (20 mL) were added to the residue. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (20 mL). The organic phases were combined, washed with saturated sodium chloride solution, and concentrated. The residue was purified by column chromatography to give the product (793 mg, yield: 71.4%). ESI-MS m / z: 223.0 [M+H] + .

[0250] Synthesis of 157-2: The above compound 157-1 (793 mg, 3.569 mmol), ethylene glycol (2 mL), PPTS (448 mg, 1.784 mmol), and methylbenzene (30 mL) were added to a 100 mL one-neck flask. The mixture was purged with argon, heated to 130 °C, refluxed to remove water, and stirred for 20 h. After the completion of the reaction was detected by LC-MS, the mixture was cooled, washed with water (50 mL), and the aqueous phase was extracted with methylbenzene (50 mL). The organic phases were combined, washed twice with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a brown solid product (685 mg, yield: 72.1%). ESI-MS m / z: 267.1 [M+H] + .

[0251] Synthesis of 157-3: The above compound 157-2 (685 mg, 2.573 mmol) and 10% Pd / C (100 mg) were added to MeOH (30 mL). The mixture was purged with H2 three times and stirred at room temperature under atmospheric pressure for 20 h. After the reaction was completed by LC-MS, the mixture was filtered and the filtrate was concentrated to dryness to give a purplish black solid product (715 mg, yield: >100%). ESI-MS m / z: 237.1 [M+H]+.

[0252] Synthesis of 157-4: The above compound 157-3 (715 mg, 2.573 mmol), compound 114-1 (672 mg, 2.0 mmol), Xantphos (116 mg, 0.2 mmol), and anhydrous potassium phosphate (1.272 g, 6.0 mmol) were added to methylbenzene (50 mL). The mixture was purged with argon, and then Pd2(dba)3 (93 mg, 0.1 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to give a tan gummy product (546 mg, yield: 50.9%). ESI-MS m / z: 536.2 [M+H] + .

[0253] Synthesis of 157-5: The above compound 157-4 (546 mg, 1.019 mmol) and 1N HCl (2.0 mL) were added to acetone / water (30 mL / 10 mL). The mixture was purged with argon, heated to 60° C., and stirred for 5 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to about half the volume, and EA (30 mL) and water (20 mL) were added to the residue. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (30 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (387 mg, yield: 77.2%). ESI-MS m / z: 492.1 [M+H] + .

[0254] Synthesis of compound 157: The above compound 157-5 (49 mg, 0.10 mmol), N-methylpiperazine (20 mg, 0.2 mmol) and glacial acetic acid (24 mg, 0.4 mmol) were added to THF (5 mL), and the mixture was stirred at room temperature for 15 min. Then, NaBH(OAc)3 (85 mg, 0.4 mmol) was added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give an off-white solid product (16 mg, yield: 27.8%). ESI-MS m / z: 576.2 [M+H] + .

[0255] Using different starting materials, the target compounds 158 to 173 in Table 11 were obtained by referring to the same synthesis methods as in Example 23 and Example 26.

[0256] [Table 11]

[0257] Example 27: Synthesis of 4-((5-bromo-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 174) [ka] [ka]

[0258] Synthesis of 174-2: 2-Fluoro-5-methoxy-4-nitrobenzoic acid (610 mg, 2.08 mmol), 1-methylpiperidin-4-amine (260 mg, 2.29 mol), HOBt (420 mg, 3.1 mmol), EDCI (598 mg, 3.1 mmol), and DIPEA (1.1 mL) were added to DMF (10 mL). The mixture was purged with argon and stirred at room temperature for 20 h. After completion of the reaction was detected by LC-MS, water (20 mL) and EA (30 mL) were added to the mixture. The resulting mixture was stirred and liquid separation was performed. The aqueous phase was extracted with EA (30 mL). The organic phases were combined, washed twice with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a brown oil (530 mg, yield: 81.9%). ESI-MS m / z: 312.1 [M+H] + .

[0259] Synthesis of 174-3: The above 174-2 (530 mg, crude product, 1.703 mmol) and 10% Pd / C (50 mg, containing 50%-55% water) were added to MeOH (20 mL). The mixture was purged with hydrogen three times and vigorously stirred at room temperature under atmospheric pressure for 20 h. After completion of the reaction was detected by LC-MS, the mixture was filtered through diatomaceous earth. The filter cake was rinsed with MeOH, and the filtrate was concentrated to dryness to give a light gray solid product (483 mg, yield: 100%). ESI-MS m / z: 282.1 [M+H] + .

[0260] Synthesis of 174-1: Compound 2,4-dichloro-5-bromopyrimidine (455 mg, 2.0 mmol) and IntA (378 mg, 2.0 mmol) were added to DMF (5 mL), and the mixture was cooled to 0-5 °C in an ice bath under argon atmosphere. Potassium carbonate (553 mg, 4.0 mmol) was then added. The mixture was stirred at 0-5 °C for 1 h. After the completion of the reaction was detected by LC-MS, water (10 mL) was added to the mixture. The resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and then dried under vacuum to obtain the product (667 mg, yield: 87.6%). ESI-MS m / z: 380.0 [M+H] + .

[0261] Synthesis of compound 174 The above compound 174-1 (50 mg, 0.131 mmol) and 174-3 (42 mg, 0.148 mmol) were added to tert-butanol (3 mL), and TFA (19 mg, 0.169 mmol) was added at room temperature. The mixture was purged with argon, heated to 95 °C, and stirred for 8 h. The reaction product was detected by LC-MS. The mixture was concentrated, and the residue was purified by Flash, followed by preparative HPLC, and lyophilized to give an off-white solid product (5 mg, yield: 6.1%). ESI-MS m / z:625.1 [M+H] + .

[0262] Using different starting materials, the target compound 175 and the target compound 176 in Table 12 were obtained by following the same synthesis method as in Example 27.

[0263] [Table 12]

[0264] Example 28: Synthesis of 4'-((5-bromo-2-((2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (Compound 177) [ka] [ka]

[0265] Synthesis of compound 177 The above compound 174-1 (50 mg, 0.131 mmol) and 131-4 (41 mg, 0.157 mmol) were added to t-BuOH (5 mL) and MsOH (25 mg, 0.260 mmol) was added at room temperature. The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by Flash, and the impure product was further purified by pre-HPLC and lyophilized to give an off-white solid product (9 mg, yield: 11.3%). ESI-MS m / z: 605.2 [M+H] + .

[0266] Using different starting materials, the target compounds 178 to 191 in Table 13 were obtained according to the same synthesis method as in Example 28.

[0267] [Table 13-1] [Table 13-2]

[0268] Example 29: Synthesis of 4-((5-cyano-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 192) [ka] [ka]

[0269] Synthesis of 192-1: Compound 2,4-dichloro-5-cyanopyrimidine (696 mg, 4.0 mmol) and IntA (756 mg, 4.0 mmol) were added to DMF (10 mL), and the mixture was cooled to 0-5 °C in an ice bath under argon atmosphere. Potassium carbonate (1.11 g, 8.0 mmol) was then added. The mixture was stirred at 0-5 °C for 1 h. After the completion of the reaction was detected by LC-MS, water (20 mL) was added to the mixture. The resulting mixture was stirred for 15 min and filtered. The filter cake was washed with water and purified by column chromatography to obtain an off-white solid product (747 mg, yield: 57.2%). ESI-MS m / z: 327.0 [M+H] + .

[0270] Synthesis of compound 192: The above compound 192-1 (50 mg, 0.153 mmol) and 3-1 (48 mg, 0.184 mmol) were added to tert-butanol (3 mL), and TFA (35 mg, 0.306 mmol) was added at room temperature. The mixture was purged with argon, heated to 95 °C, and stirred for 8 h. The reaction product was detected by LC-MS. The mixture was concentrated, and the residue was purified by preparative HPLC and lyophilized to give an off-white solid product (16 mg, yield: 18.9%). ESI-MS m / z: 554.3 [M+H] + .

[0271] Using different starting materials, the target compounds 193 to 195 in Table 14 were obtained according to the same synthesis method as in Example 29.

[0272] [Table 14]

[0273] Example 30: Synthesis of 2-((2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)-4-((2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindoline]-4'-yl)oxy)pyrimidine-5-carbonitrile (Compound 196) [ka] [ka]

[0274] Synthesis of compound 196: The above compound 192-1 (50 mg, 0.153 mmol) and 131-4 (41 mg, 0.157 mmol) were added to t-BuOH (5 mL) at room temperature, followed by the addition of MsOH (25 mg, 0.260 mmol). The mixture was purged with argon, heated to 90 °C, and stirred for 6 h. The reaction product was detected by LC-MS. The mixture was concentrated. The residue was purified by pre-HPLC and lyophilized to give an off-white solid product (14 mg, yield: 16.6%). ESI-MS m / z: 552.3 [M+H] + .

[0275] Using different starting materials, the target compounds 197 to 202 in Table 15 were obtained according to the same synthesis method as in Example 30.

[0276] [Table 15]

[0277] Example 31: Synthesis of 4'-((5-chloro-2-((2-methoxy-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)pyrimidin-4-yl)oxy)-2'-methylspiro[cyclobutane-1,1'-isoindolin]-3'-one (Compound 203) [ka] [ka]

[0278] Synthesis of 203-1 Compound 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) and IntC (555 mg, 2.73 mmol) were added to DMF (5 mL), and the mixture was cooled to 0-5 °C in an ice bath under argon atmosphere. Potassium carbonate (755 mg, 5.46 mmol) was then added. The mixture was stirred at 0-5 °C for 1 h. After the completion of the reaction was detected by LC-MS, water (10 mL) was added to the mixture. The resulting mixture was stirred for 15 min and filtered. The filter cake was washed with water and dried under vacuum to obtain the product (767 mg, yield: 80.4%). ESI-MS m / z: 350.0 [M+H] + .

[0279] Synthesis of 203-3: The above compound 136-2 (269 mg, 0.773 mmol) and compound 203-1 (208 mg, 0.595 mmol), Xantphos (69 mg, 0.119 mmol), and anhydrous potassium phosphate (379 mg, 1.785 mmol) were added to methylbenzene (10 mL). The mixture was purged with argon, and then Pd2(dba)3 (54 mg, 0.06 mmol) was added. The mixture was heated to 100 °C and stirred under argon atmosphere for 8 h. After the completion of the reaction was detected by LC-MS, the mixture was directly loaded onto a column and purified by silica gel column chromatography to give a tan solid product (136 mg, yield: 34.6%). ESI-MS m / z: 661.3 [M+H] + .

[0280] Synthesis of 203-4: The above compound 203-3 (130 mg, 0.197 mmol) and TFA (0.3 mL) were added to DCM (5 mL). The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was detected by LC-MS, the mixture was concentrated to give the crude product (211 mg, yield: >100%). ESI-MS m / z: 560.2 [M+H] + .

[0281] Synthesis of compound 203: The above compound 203-4 (50 mg, crude, 0.047 mmol) and DIPEA (46 mg, 0.36 mmol) were added to THF (5 mL) / MeOH (1 mL). The mixture was stirred at room temperature for 10 min. Glacial acetic acid (6 mg, 0.10 mmol) and aqueous formaldehyde (8 mg, 37%, 0.10 mmol) were added, and the mixture was stirred at room temperature for 20 min. NaBH(OAc)3 (36 mg, 0.17 mmol) was then added, and the mixture was stirred at room temperature for another 1 h. After the completion of the reaction was detected by LC-MS, the mixture was concentrated, and the residue was purified by Flash to give a yellow solid product (7 mg, yield: 25.9%). ESI-MS m / z:575.2 [M+H] + .

[0282] Using different starting materials, the target compounds 204 to 218 in Table 16 were obtained according to the same synthesis method as in Example 31.

[0283] [Table 16]

[0284] Nuclear magnetic resonance data for some of the compounds of this patent are shown in Table 17 below.

[0285] [Table 17-1] [Table 17-2] [Table 17-3]

[0286] Biological Example 1: Assay of the inhibitory activity of the compounds of the present invention against the FAK enzyme Compounds serially diluted in DMSO were mixed with FAK recombinant protein. The mixture was left at room temperature for 10 minutes, and then biotin-labeled TK substrate (TK) and ATP were added. After 40 minutes of reaction at room temperature, Sa-XL665 and Crytate-labeled TK antibody were added. After 1 hour of incubation at room temperature, the fluorescence intensities at 615 nm and 665 nm were measured. The ratio of the fluorescence intensities at 665 nm and 615 nm was calculated. The inhibition rate and IC of the compounds were compared with the DMSO control group. 50 The results are shown in Table 18 below.

[0287] [Table 18-1] [Table 18-2]

[0288] Biological Example 2: Assay of the inhibitory activity of the compounds of the present invention against PC3 cell proliferation 2D activity assay: 1200 PC3 cells were seeded in a 96-well plate. After overnight adhesion culture, serially diluted compounds were added. 72 hours after addition, Cell Titer-Lumi (Beyotime C0068XL) was added and the intracellular ATP content was measured. Cell proliferation was evaluated and the IC of the compound that inhibited cell proliferation was calculated. 50 was calculated.

[0289] 3D activity assay: PC3 cells were seeded in 96-well plates at 1200 cells / well and cultured in 3D. Cell proliferation was measured 14 days after adding serially diluted compounds. The inhibition rate and IC 50 was calculated.

[0290] The 2D / 3D inhibitory activity of the compounds of the present invention against PC3 cells is shown in Table 19 below.

[0291] [Table 19-1] [Table 19-2]

[0292] As can be seen from the data in the above table, the compounds of the present invention showed virtually no inhibitory activity against PC3 2D cells, but showed very strong inhibitory activity against PC3 3D cells, and the activity of most of the compounds was equal to or significantly stronger than that of the control compound BI853520.

[0293] Biological Example 3: Assay of inhibition of PC3 cell adhesion by compounds of the present invention PC3 cells were seeded at 8000 cells / well. The cells were treated with compounds and the number of adherent cells was counted 4 hours later. The inhibition rate and IC 50 The results are shown in Table 20 below.

[0294] [Table 20]

[0295] As can be seen from the data in the above table, inhibition of PC3 cell hypoadhesion by some of the compounds of the present invention was significantly superior to that by the control compound.

[0296] Biological Example 4: Assay for inhibition of Y397 phosphorylation by compounds of the present invention PC3 cells were seeded at 8000 cells / well. Three hours after the cells were treated with the compounds, the phosphorylation level of the FAK397 site in the cells was measured by ELISA using an antibody that specifically recognizes phosphorylation at the FAK397 site. The inhibition rate and IC50 The results are shown in Table 21 below.

[0297] [Table 21]

[0298] Biological Example 5: In vivo pharmacokinetic studies of compounds of the invention Female CD-1 mice aged 7–10 weeks were administered 2 mg / kg intravenously and 10 mg / kg orally, respectively. Mice were fasted for at least 12 h prior to dosing, fed 4 h after dosing, and allowed free access to water throughout the experiment.

[0299] On the day of the experiment, animals in the intravenous administration group received a single injection of the corresponding compound at a dose of 10 mL / kg via the tail vein, and animals in the oral administration group received a single injection of the corresponding compound at a dose of 10 mL / kg via intragastric injection. Before administration, the animals were weighed, and the dose was calculated according to their body weight. The sampling time points were 0.083 hours, 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Approximately 200 μL of whole blood was collected from the orbital venous plexus at each time point and used to prepare plasma for concentration measurement by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Plasma concentrations were processed using the non-compartmental model of Winnolin pharmacokinetic software, and pharmacokinetic parameters were calculated using the log-linear trapezoidal method.

[0300] [Table 22]

[0301] Biological Example 6: In vivo efficacy assays for compounds of the invention Human pancreatic cancer Mia PaCa-2 cells were cultured in a conventional manner in 1640 medium containing 10% fetal bovine serum in a 37°C / 5% CO2 incubator. After subculture, cells were harvested when they reached the desired amount. 7Mia PaCa-2 cells were injected into the left dorsal side of each nude mouse until the tumors were 100–200 mm 3 After the animals had grown to adulthood, they were randomly divided into groups for administration. The administration groups were as follows: 1) vehicle control group (8 mice), 2) control compound group and test compound group (8 mice each). The vehicle control group mice were intragastrically administered with 0.5% CMC-Na twice a day, and the compound group mice were intragastrically administered with 0.5% MC-Tween-80 suspension once a day. The tumor volume and body weight of the mice were measured every Tuesday and Thursday, and the nude mice were sacrificed on the 21st day after administration. The tumor growth inhibition ability of the compounds was evaluated by tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the administration group - tumor volume on day 1 of the treatment group) / (administration volume on day 28 of the control group - tumor volume on day 1 of the control group). The toxicity of the compounds was evaluated based on the body weight of the mice.

[0302] Miapaca-2 in vivo experiment The groups are as follows: 1) solvent control group, 2) control compound BI853520 group, 3) control compound B group, 4) compound 4 group, 5) compound 79 group, 6) compound 136 group, 7) compound 137 group, 8) compound 117 group, and 9) compound 178 group. The results are shown in Table 23 below.

[0303] [Table 23]

[0304] As can be seen from the above in vivo experimental results, the compounds of the present invention exhibited significant inhibitory effects on tumor growth in the human pancreatic cancer MiaPaCa-2 model, and had significant advantages over the control compounds. In addition, all compounds showed good toxicity resistance.

[0305] Biological Example 7: In vivo efficacy assays for compounds of the invention Human prostate cancer PC3 cells were cultured in a conventional manner in 1640 medium containing 10% fetal bovine serum in a 37°C / 5% CO2 incubator. After subculture, cells were harvested when they reached the desired amount. 7PC3 cells were injected into the left dorsal side of each nude mouse until the tumors were 100–200 mm 3 After the animals had grown to adulthood, they were randomly divided into groups for administration. The groups were as follows: 1) vehicle control group (8 mice), 2) control compound group and test compound group (8 mice each). The vehicle control group mice were intragastrically administered with 0.5% CMC-Na twice a day, and the compound group mice were intragastrically administered with 0.5% MC-Tween-80 suspension once a day. The tumor volume and body weight of the mice were measured every Tuesday and Thursday, and the nude mice were sacrificed on the 21st day after administration. The tumor growth inhibition ability of the compounds was evaluated by tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the treatment group - tumor volume on day 1 of the treatment group) / (administration volume on day 28 of the control group - tumor volume on day 1 of the control group). The toxicity of the compounds was evaluated based on the body weight of the mice.

[0306] PC3 in vivo experiment The groups were as follows: 1) solvent control, 2) control compound BI853520, 3) compound 4, 4) compound 73, 5) compound 79, 6) compound 120, 7) compound 136, and 8) compound 137. The results are shown in Table 24 below.

[0307] [Table 24]

[0308] As can be seen from the above in vivo experimental results, the compounds of the present invention exhibited significant inhibitory effects on tumor growth in human prostate cancer PC-3 model, and had significant advantages over the control compounds. In addition, all compounds showed good toxicity resistance.

[0309] Biological Example 8: In vivo efficacy assays for compounds of the invention Female BALB / c mice (6 weeks old, 18–22 g) provided by Vital River Laboratory Animal Technology Co., Ltd. (China) were used after 1 week of quarantine and acclimation. All animals were housed in a room at 23 ± 2°C and 50 ± 5% relative humidity, with artificial lighting from 8:00 to 20:00 every day and air exchanged 13–18 times per hour. Standard laboratory chow and water were available ad libitum.

[0310] Mouse colon cancer MC38 cells were cultured in a conventional manner in 1640 medium containing 10% fetal bovine serum at 37°C / 5% CO2 incubator. After subculture, cells were harvested when they reached the desired amount. 6 MC38 cells were injected subcutaneously into the right flank of BALB / c mice to form tumors. 3 After the animals had grown to 100 mm Hg, they were randomly divided into a vehicle control group, a test compound alone group, a test compound + PD-1 combination group, and a PD-1 alone group (Bio X Cell), and then treatment was started. Tumor volumes were measured with calipers on days 3, 7, 10, 14, 17, and 21 after treatment.

[0311] The tumor growth inhibition ability of the compound was evaluated by tumor growth inhibition rate (TGI) = 1 - (tumor volume of the treatment group on day 28 - tumor volume of the treatment group on day 1) / (administration volume of the control group on day 28 - tumor volume of the control group on day 1). The toxicity of the compound was evaluated based on the body weight and condition of the mice.

[0312] MC38 in vivo experiment The groups are as follows: 1) solvent control group, 2) control compound BI853520 group, 3) PD-1 monoclonal antibody group, 4) compound 79 group, 5) compound 136 group, 6) compound 120 group, 7) compound 79 group + PD-1 monoclonal antibody group, 8) compound 136 group + PD-1 monoclonal antibody group, 9) compound 120 group + PD-1 monoclonal antibody group, and 10) control compound BI853520 + PD-1 monoclonal antibody group. The results are shown in Table 25 below.

[0313] [Table 25]

[0314] As can be seen from the above-mentioned in vivo experimental results, the combination of the compounds of the present invention with PD-1 monoclonal antibody showed a relatively good inhibitory effect on tumor growth in the mouse colon cancer MC-38 model, while the control compounds showed virtually no combined effect on this model.In addition, all the compounds showed good toxicity resistance.

[0315] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. 【Chemistry 1】 (In general formula (1), Ring A is a (C3-C6)cycloalkyl or a (3- to 6-membered)heterocycloalkyl, wherein said (C3-C6)cycloalkyl or said (3- to 6-membered)heterocycloalkyl each independently contains 1, 2, 3, or 4 R ａ optionally substituted with; Y is —O—, —NR ａ -or-CR ａ R ｂ - and; L is -CH ２ -, -O-, or -S-; Ring B is selected from a (3- to 18-membered)heterocycloalkyl, a (C3-C18)cycloalkyl, a (C6-C18)aryl, or a (5- to 18-membered)heteroaryl, wherein said (3- to 18-membered)heterocycloalkyl, said (C3-C18)cycloalkyl, said (C6-C18)aryl, or said (5- to 18-membered)heteroaryl are each independently selected from n R ２ optionally substituted with; X is a chemical bond, 【Chemistry 2】 and ＊ represents the bond to ring B; G is -H, -D, halogen, hydroxy, amino, cyano, nitro, or -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ , -CONR ａ R ｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C15) cycloalkyl, (3-membered to 15-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein said (C1-C8) alkyl, said (C1-C8) alkoxy, said (C1-C8) haloalkyl, said (C2-C8) alkenyl, said (C2-C8) alkynyl, said (C3-C15) cycloalkyl, said (3-membered to 15-membered) heterocycloalkyl, said (C6-C14) aryl, or said (5-membered to 14-membered) heteroaryl are each independently selected from 1, 2, 3, or 4 R ｃ optionally substituted with; R １ is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ , -CONR ａ R ｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-membered to 14-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein said (C1-C8) alkyl, said (C1-C8) alkoxy, said (C1-C8) haloalkyl, said (C2-C8) alkenyl, said (C2-C8) alkynyl, said (C3-C14) cycloalkyl, said (3-membered to 14-membered) heterocycloalkyl, said (C6-C14) aryl, or said (5-membered to 14-membered) heteroaryl are each independently selected from 1, 2, 3, or 4 R ｃ optionally substituted with; R ２ is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-membered to 14-membered) heterocycloalkyl, (C6-C14) aryl, or (5-membered to 14-membered) heteroaryl, wherein said (C1-C8) alkyl, said (C1-C8) alkoxy, said (C1-C8) haloalkyl, said (C2-C8) alkenyl, said (C2-C8) alkynyl, said (C3-C14) cycloalkyl, said (3-membered to 14-membered) heterocycloalkyl, said (C6-C14) aryl, or said (5-membered to 14-membered) heteroaryl are each independently selected from 1, 2, 3, or 4 R ｃ or two R ２ are bonded to the same atom, the two R ２ may form one oxo group; R ３ is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR ３ａ , -NR ３ａ R ３ｂ , -C(O)R ３ａ , -CO ２ R ３ａ , -S(O) ｐ R ３ａ , -S(O) ｐ NR ３ａ R ３ｂ , -CONR ３ａ R ３ｂ , -C(=NR ３ａ )-NR ３ｂ R ３ｃ , -NR ３ａ COR ３ｂ , -NR ３ａ CONR ３ｂ R ３ｃ , -NR ３ａ CO ２ R ３ｂ , -NR ３ａ S (O) ｐ NR ３ｂ R ３ｃ , -NR ３ａ S (O) ｐ R ３ｂ , (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3- to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5- to 14-membered)heteroaryl, -(C1-C8)alkylene-(C1-C8)alkoxy, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3- to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5- to 14-membered)heteroaryl; R ａ and R ｂ are each independently -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3- to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5- to 14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3- to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5- to 14-membered)heteroaryl, wherein The (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3- to 14-membered) heterocycloalkyl, the (C6-C14) aryl, the (5- to 14-membered) heteroaryl, the -(C1-C8) alkylene-(C3-C14) cycloalkyl, the -(C1-C8) alkylene-(3- to 14-membered) heterocycloalkyl, the -(C1-C8) alkylene-(C6-C14) aryl, or the -(C1-C8) alkylene-(5- to 14-membered) heteroaryl each independently represent 1, 2, 3, or 4 R ｃ optionally substituted with R ａ and R ｂ together with the atoms to which they are bonded form a (C3-C6) cycloalkyl group or a (3- to 6-membered) heterocycloalkyl group, and the (C3-C6) cycloalkyl group or the (3- to 6-membered) heterocycloalkyl group each independently contain 1, 2, 3, or 4 R ｃ optionally substituted with; R ｃ is -H, -D, halogen, hydroxy, amino, cyano, nitro, -OR ｘａ , -NR ｘａ R ｘｂ , -(CH ２ ) ｍ OR ｘａ , -(CH ２ ) ｍ NR ｘａ R ｘｂ , -C(O)R ｘａ , -CO ２ R ｘａ , (CH ２ ) ｍ S (O) ｐ R ｘａ , -S(O) ｐ NR ｘａ R ｘｂ , -(CH ２ ) ｍ CONR ｘａ R ｘｂ , -C(=NR ｘａ )-NR ｘｂ R ｘｃ , -NR ｘａ COR ｘｂ , -NR ｘａ CONR ｘｂ R ｘｃ , -NR ｘａ CO ２ R ｘｂ , -NR ｘａ S (O) ｐ NR ｘｂ R ｘｃ , -NR ｘａ S (O) ｐ R ｘｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3- to 14-membered) heterocycloalkyl, (C6-C14) aryl, (5- to 14-membered) heteroaryl, -(C1-C8) alkylene-(C1-C8) alkoxy, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3- to 14-membered) heterocycloalkyl, -(C1-C8) aryl and -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-membered to 14-membered)heteroaryl, wherein said (C1-C8)alkyl, said (C1-C8)alkoxy, said (C1-C8)haloalkyl, said (C2-C8)alkenyl, said (C2-C8)alkynyl, said (C3-C14)cycloalkyl, said (3-membered to 14-membered)heterocycloalkyl, said (C6-C14)aryl, or said (5-membered to 14-membered)heteroaryl are each independently selected from 1, 2, 3, or 4 R ３ｃ or two R ｃ are bonded to the same atom, the two R ｃ may form an oxo; R ｘａ , R ｘｂ , and R ｘｃ are each independently —H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3- to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5- to 14-membered)heteroaryl, —(C1-C8)alkylene-(C3-C14)cycloalkyl, —(C1-C8)alkylene-(3- to 14-membered)heterocycloalkyl, —(C1-C8)alkylene-(C6-C14)aryl, or —(C1-C8)alkylene-(5- to 14-membered)heteroaryl; R ３ａ , R ３ｂ and R ３ｃ are each independently -H, -D, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3- to 14-membered)heterocycloalkyl, (C6-C14)aryl, (5- to 14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3- to 14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5- to 14-membered)heteroaryl; p is an integer of 0, 1 or 2; m is an integer of 0, 1, 2, or 3; n is an integer of 0, 1, 2, or 3.

2. In the general formula (1), L is —CH ２ - or -O-, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof according to claim 1.

3. In general formula (1), ring A is (C3-C6) cycloalkyl or (3- to 6-membered) heterocycloalkyl, wherein the (C3-C6) cycloalkyl or the (3- to 6-membered) heterocycloalkyl each independently contains 1, 2, 3, or 4 of -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -(CH ２ ) ２ OCH ３ , -CH ２ SO ２ CH ３ , -CH ２ CONH ２ , -CH ２ CON (CH ３ ) ２ , 【Transformation 3】 2. The compound of claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, optionally substituted with:

4. In the general formula (1), ring A is 【Chemistry 4】 where: ＊ represents a bond to Y, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

5. In the general formula (1), the ring B is selected from a (6- to 12-membered) aryl or a (5- to 14-membered) heteroaryl, and the (6- to 12-membered) aryl or the (5- to 14-membered) heteroaryl is selected from n R ２ 2. The compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which may be optionally substituted by:

6. In the general formula (1), ring B is 【Transformation 5】 and Ring B is preferably 【Transformation 6】 and Ring B is more preferably 【Transformation 7】 and Ring B is more preferably 【Transformation 8】 where: ＊ but, 【Chemistry 9】 6. The compound of claim 5, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein

7. In general formula (1), G is -H, -D, (C1 to C6) alkyl, (C1 to C6) alkoxy, (C1 to C6) haloalkyl, or (5 to 15 membered) heterocycloalkyl, wherein the (C1 to C6) alkyl, the (C1 to C6) alkoxy, the (C1 to C6) haloalkyl, or the (5 to 15 membered) heterocycloalkyl is selected from the group consisting of 1, 2, 3, or 4 of -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -NHCH ３ , -N(CH ３ ) ２ , —C(O)NH ２ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -(CH ２ ) ２ OCH ３ , -CH ２ SO ２ CH ３ , -CH ２ CONH ２ , -CH ２ CON (CH ３ ) ２ , 【Chemistry 10】 or two substituents attached to the same atom may form an oxo group, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

8. In the general formula (1), G is —H, (C1-C3) alkyl, or (6- to 12-membered) heterocycloalkyl, wherein the (C1-C3) alkyl or the (6- to 12-membered) heterocycloalkyl is selected from the group consisting of 1, 2, 3, or 4 of —H, —D, —F, —CH ３ , -CD ３ , -CH ２ CH ３ , -OCH ３ , -N(CH ３ ) ２ , -(CH ２ ) ２ OCH ３ , -CH ２ SO ２ CH ３ , -CH ２ CONH ２ , -CH ２ CON (CH ３ ) ２ , 【Chemistry 11】 or two substituents attached to the same atom may form an oxo group, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

9. In the general formula (1), G is —H, —CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ N (CH ３ ) ２ , 【Chemistry 12-1】 【Chemistry 12-2】 9. The compound according to claim 8, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, selected from:

10. In the general formula (1), X is a chemical bond, 【Chemistry 13】 X is preferably a chemical bond, 【Chemistry 14】 and X is more preferably a chemical bond, 【Chemistry 15】 and X is more preferably 【Chemistry 16】 and X is more preferably 【Chemistry 17】 X is more preferably a chemical bond; ＊ represents a bond to ring B, or an isomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof.

11. In general formula (1), R １ is -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -NHCH ３ , -N(CH ３ ) ２ , —C(O)NH ２ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , or -CF ３ is selected from: R １ Preferably, —F, —Cl, —Br, —CN, or —NO ２ , -CF ３ or —C(O)NH ２ and R １ is preferably —F, —Cl, —Br, —CN, or —CF ３ and R １ is more preferably —F; R １ is more preferably —Cl; R １ is more preferably —Br; R １ is more preferably —CN; R １ More preferably, -CF ３ 2. The compound according to claim 1, wherein:

12. In general formula (1), R ２ is -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCF ３ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , -N(CH ２ CH ３ ) ２ , (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3- to 6-membered) heterocycloalkyl, (C6-C10) aryl, or (5- to 10-membered) heteroaryl, wherein the (C1-C3) alkyl, the (C1-C3) alkoxy, the (C1-C3) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the (3- to 6-membered) heterocycloalkyl, the (C6-C10) aryl, or the (5- to 10-membered) heteroaryl are each independently -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -NHCH ３ , -N(CH ３ ) ２ , —C(O)NH ２ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , or -CF ３ or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which is optionally substituted with one, two, three or four of:

13. In general formula (1), R ２ is -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -NHCH ３ , -N(CH ３ ) ２ , —C(O)NH ２ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , [Chemistry 18] is selected from: R ２ is preferably —H, —D, —F, —Cl, —OH, or —OCH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ , 【Chemistry 19】 and R ２ More preferably, —H, —F, —Cl, —OH, —OCH ３ , -OCF ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , 【Chemistry 20】 13. The compound according to claim 12, wherein:

14. In general formula (1), R ３ is -H, -D, -F, -Cl, -Br, -I, -OH, -NH ２ , -CN, -NO ２ , -OCH ３ , -NHCH ３ , -N(CH ３ ) ２ , —C(O)NH ２ , -OCH ２ CH ３ , -OCF ３ , -CH ３ , -CD ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , or -CF ３ is selected from: R ３ is preferably —H, —D, —F, or —CH ３ , -CD ３ , or -CF ３ and R ３ is more preferably -H, -D, or -F; R ３ is more preferably —H; R ３ is more preferably -D; R ３ is more preferably —F, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof according to claim 1.

15. The compound has the following structure: 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 【Chemistry 21-7】 【Chemistry 21-8】 【Chemistry 21-9】 【Chemistry 21-10】 or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein

16. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, the compound according to claim 1 or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

17. Use of the compound of claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in the preparation of a medicament for treating a disease associated with FAK kinase.

Images