P21 activated kinase 4 (PAK4) inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a compound as shown in a formula (I), or a pharmaceutically acceptable salt, a stereoisomer, a hydrate, a deuterated compound or a prodrug thereof, a pharmaceutical composition containing the compounds and the pharmaceutically acceptable salt, the stereoisomer, the hydrate, the deuterated compound or the prodrug thereof, and application of the compound or the pharmaceutical composition in preparation of a PAK4 inhibitor or in preparation of a medicine for preventing and / or treating PAK4-mediated related diseases. According to the present invention, the compound has significant PAK4 inhibition activity, provides good anti-tumor cell proliferation effect at the cellular level, and can be used for treating PAK4-mediated related diseases.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, particularly to the field of PAK4 inhibitors. Specifically, this invention relates to compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, hydrates, deuterated derivatives or prodrugs thereof, and pharmaceutical compositions containing them, and the use of the above compounds or pharmaceutical compositions in the preparation of PAK4 inhibitors, or in the preparation of medicaments for the prevention and / or treatment of PAK4-mediated diseases. Background Technology

[0002] p21-activated kinases (PAKs) are a class of evolutionarily conserved serine / threonine protein kinases, downstream targets of Rho family proteins, and involved in many important cellular activities. In mammals, the PAK family consists of six members. Based on their amino acid sequence similarity, domain structural characteristics, and activation mechanisms, PAKs are divided into two main classes: class I PAKs (PAK1-3) and class II PAKs (PAK4-6). They share high structural similarity, all consisting of three domains: an N-terminal guanosine triphosphate (GTP) binding domain, a highly conserved C-terminal serine / threonine kinase domain, and a proline-rich region. PAK1 and PAK4 are the most extensively studied members of the PAK family in recent years, while current research on p21-activated kinases is increasingly shifting towards PAK4, a representative member of class II PAKs.

[0003] PAK4 kinase is a 591-amino acid protein encoded by a gene located at position 19 of human chromosome 19. Human PAK4 is approximately 68 kDa. Its N-terminal regulatory region contains a GTPase-binding domain (GBD) and an autoinhibition domain (AID), while the C-terminus contains a kinase domain. Between the N- and C-termini is a proline-rich region (PXXP). To date, PAK4 has been shown to promote tumorigenesis by regulating many aspects of cancer markers, playing important roles in cell proliferation and survival, tumor metastasis, tumor cell angiogenesis, immune response, and metabolism.

[0004] Currently, there are no PAK4 inhibitors on the market domestically or internationally. Pfizer's PF-375830978 had to be terminated in Phase I clinical trials due to low bioavailability, poor pharmacokinetic properties, and failure to significantly inhibit the growth of human solid tumors. JK-50561 (structure undisclosed) developed by Beijing Zhuokai Biotechnology Co., Ltd., and KPT-9274 developed by Karyopharm Therapeutics, are both in Phase I clinical trials. Therefore, the development of small-molecule PAK4 inhibitors has significant clinical application value for tumor immunotherapy.

[0005] Summary of the Invention

[0006] According to one aspect of the invention, an object of the invention is to provide a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated product, or prodrug thereof.

[0007]

[0008] The A ring portion is selected from saturated or unsaturated three- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or from three- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0009] The B ring moiety is selected from substituted or unsubstituted saturated or unsaturated three- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated three- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted three- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” means that the group is substituted with 1 to 4 R3s, wherein the R3s are selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, and C3-C6 cycloalkyl;

[0010] The C-ring moiety is selected from substituted or unsubstituted saturated or unsaturated three- to seven-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated three- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted saturated or unsaturated three- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” means that the group is substituted by 1 to 3 R4s, wherein the R4s are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C5 alkoxy, halogen-substituted C1-C5 alkyl, and C3-C6 cycloalkyl;

[0011] R1 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C5 alkyl, C1-C5 alkoxy, and C3-C7 cycloalkyl;

[0012] R2 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl;

[0013] W is selected from -CH2-, -O-, -S-, (carbonyl), -N(Ra)-, (sulfinyl), wherein Ra is selected from H, deuterium or C1-C5 alkyl.

[0014] Preferably, the A ring portion is selected from saturated or unsaturated four- to six-membered cycloalkyl groups, C6-C... 10 Aryl, saturated or unsaturated four- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or saturated or unsaturated four- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0015] More preferably, the A ring portion is selected from saturated or unsaturated five- to six-membered cycloalkyl groups, saturated or unsaturated five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, or five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S.

[0016] Preferably, the B ring moiety is selected from substituted or unsubstituted saturated or unsaturated five- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl group, substituted or unsubstituted, is a saturated or unsaturated five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, or a substituted or unsubstituted five- to ten-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” means that the group is substituted with 1 to 4 R3s, wherein the R3s are selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and C3-C6 cycloalkyl.

[0017] More preferably, the B ring moiety is selected from substituted or unsubstituted saturated or unsaturated five- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10The aryl, substituted or unsubstituted saturated or unsaturated five- to ten-membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to ten-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S, wherein “substituted” means that the group is substituted by one to four R3s, wherein R3 is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro-substituted propyl, fluoro-substituted isopropyl, chloro-substituted methyl, chloro-substituted ethyl, chloro-substituted propyl, chloro-substituted isopropyl, bromo-substituted methyl, bromo-substituted ethyl, bromo-substituted propyl, and bromo-substituted isopropyl.

[0018] Preferably, the C-ring moiety is selected from substituted or unsubstituted saturated or unsaturated four- to eight-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl group, substituted or unsubstituted saturated or unsaturated four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted four- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” means that the group is substituted by 1 to 4 R4 groups, wherein the R4 groups are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and C3-C6 cycloalkyl.

[0019] More preferably, the C-ring portion is selected from substituted or unsubstituted saturated or unsaturated four- to six-membered cycloalkyl groups, substituted or unsubstituted saturated or unsaturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, or substituted or unsubstituted four- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by one to four R4s, wherein the R4s are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro-substituted propyl, fluoro-substituted isopropyl, chloro-substituted methyl, chloro-substituted ethyl, chloro-substituted propyl, chloro-substituted isopropyl, bromo-substituted methyl, bromo-substituted ethyl, bromo-substituted propyl, bromo-substituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] More preferably, the C-ring portion is selected from Where n1 is an integer from 0 to 4, preferably n1 is 0, 1, 2, 3 or 4, and R4 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluorinated methyl, fluorinated ethyl, fluorinated propyl, fluorinated isopropyl, chlorosubstituted methyl, chlorosubstituted ethyl, chlorosubstituted propyl, chlorosubstituted isopropyl, bromosubstituted methyl, bromosubstituted ethyl, bromosubstituted propyl, bromosubstituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0021] Preferably, R1 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl.

[0022] Preferably, R2 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl.

[0023] Preferably, W is selected from -CH2-, -O-, (carbonyl), -N(R) a )-, where R a Selected from H and C1-C4 alkyl groups.

[0024] More preferably, W is (Carbonyl group).

[0025] Preferably, the compound represented by formula (I) according to the invention, or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug, is represented by formula (II) or formula (III):

[0026]

[0027] The definitions of ring B, ring C, R1, and R2 are the same as those in the previous formula (I) or their preferred definitions;

[0028] X is independently selected from N and CH;

[0029] Y is independently selected from N, NH, CH2, O, S, Se, NR b ;R b H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, tert-butyloxycarbonyl, and tri- to octyl heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S;

[0030] Z is independently selected from N, CH, and CR. c ;R c H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 Aryl groups, and tri- to octyl heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0031] Preferably, Y is independently selected from N, NH, CH2, and NR. b ;R b H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C6-C 10 Aryl, tert-butyloxycarbonyl, and four- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S;

[0032] More preferably, Y is independently selected from N, NH, CH2, NR b ;R b It is H, C1-C4 alkyl, or tert-butoxycarbonyl.

[0033] Preferably, Z is independently selected from N, CH, and CR. c ;R c H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl groups, and four to six heteroaryl groups containing one to three heteroatoms selected from N, O, and S.

[0034] More preferably, Z is independently selected from N and CH.

[0035] In a specific embodiment, the compound represented by formula (I), or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug, is selected from the following structures:

[0036]

[0037]

[0038]

[0039] According to a second aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), formula (II) or formula (III) according to the invention, or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated product or prodrug thereof, and a pharmaceutically acceptable carrier.

[0040] According to a third aspect of the invention, another object of the invention is to provide the use of compounds represented by formula (I), formula (II) or formula (III) according to the invention, or pharmaceutically acceptable salts, stereoisomers, hydrates, deuterated derivatives or prodrugs thereof, in the preparation of PAK4 inhibitors, or in the preparation of medicaments for the prevention and / or treatment of PAK4-mediated diseases.

[0041] Among them, the diseases associated with PAK4 are selected from acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, prostate cancer and liver cancer, as well as neurodegenerative diseases, such as Alzheimer's disease.

[0042] According to a fourth aspect of the invention, another object of the invention is to provide a method for preventing and / or treating diseases associated with PAK4, the method comprising administering to a subject in need an effective amount of a compound represented by formula (I), formula (II) or formula (III) according to the invention, or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative or prodrug or pharmaceutical composition according to the invention.

[0043] Beneficial effects

[0044] This invention introduces several novel compounds with significant PAK4 inhibitory activity based on their novel core structures, which exhibit good anti-tumor cell proliferation effects at the cellular level and can be used to treat PAK4-mediated diseases. Detailed Implementation

[0045] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0046] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0047] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0048] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0049] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0050] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0051] definition

[0052] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, isomers can be prepared by asymmetric synthesis. This disclosure further covers the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0053] When listing a series of values, the intention is to cover every value within that range and every subrange. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0054] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 7 carbon atoms ("C"). 1- (C7 alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C7 alkyl"). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-6 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-10 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0055] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("tri- to deca-cyclic cycloalkyl") and zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C..."). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group"). An example C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example is C... 3-8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. An example C 3-10 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group may be monocyclic (“monocyclic cycloalkyl”) or contain fused rings, bridged rings, or spirocyclic systems, such as bicyclic systems (“bicyclic cycloalkyl”), and may be saturated or partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the number of carbons continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of the carbocyclic group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C… 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0056] "Heterocyclic group" refers to a group having a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 6-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided that the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic group can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the linkage of a heterocycle as defined above with one or more carbocyclic groups is on the carbocyclic group or the heterocycle, or ring systems in which a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3-6 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-6 membered heterocyclic group.

[0057] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having 6-10 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-10 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10"Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl group is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is an unsubstituted C 6-10 Aryl. In some embodiments, the aryl group is a substituted C. 6-10 Aryl.

[0058] "Heteroaryl" refers to a group having a 3-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) containing a cyclic carbon atom and 1-3 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0059] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0060] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems also aims to encompass rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" means a group containing no double or triple bonds, i.e., entirely composed of single bonds.

[0061] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0062] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic acids and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0063] The term "hydrate" refers to a compound that is bound to water. Typically, the number of water molecules contained in a hydrate of a compound is proportional to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. The given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0064] The term "stereoisomer" or "tautomer" refers to a compound in which two or more interconvertions result from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0065] It should also be understood that compounds with the same molecular formula but different properties, different atomic bonding sequences, or different spatial arrangements of atoms are called "isomers". Isomers with different atomic spatial arrangements are called "stereoisomers".

[0066] The term "prodrug" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, and which possesses pharmaceutical activity in vivo. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds described herein, in both their acid and acid derivative forms, are active, but the acid-sensitive forms generally offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release. Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic side groups of the compounds described herein are specific prodrugs. In some cases, it is necessary to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, and C7-C8 compounds described herein may be preferred. 12 Substituted aryl esters and C7-C 12 Arylalkyl esters.

[0067] The term "inhibition" or "inhibitor" refers to the ability of a compound to reduce, slow down, stop, or prevent the activity of a particular biological process.

[0068] The terms “composition” and “formulation” are used interchangeably.

[0069] The term "subject" to be administered refers to a person (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)). "Patient" refers to a human subject who requires treatment for a disease.

[0070] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0071] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0072] The term "effective amount" or "therapeutic effective amount" for the compounds described herein refers to an amount sufficient to elicit the desired biological response (i.e., to treat the condition). As will be understood by those skilled in the art, the effective amount of the compounds described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the route of administration, and the age and health status of the subject. In some embodiments, the effective amount is a therapeutic effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of the compound described herein in a single dose. In some embodiments, the effective amount is a combined amount of the compound described herein in multiple doses.

[0073] In addition, unless otherwise stated, all reagents disclosed below were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Shanghai Titan Technology Co., Ltd., and Sinopharm Chemical Reagent Co., Ltd. All solvents were purchased from the Titan Technology Exploration Platform. Sample-related analytical data were determined using the following equipment: the SepaBean machine T (SPBT02000200-1) used for column chromatography was purchased from Changzhou Sante Technology Co., Ltd.; all silica gel plates used for monitoring chemical reactions were purchased from Shanxi Nuotai Biotechnology Co., Ltd.; low-resolution mass spectrometry was performed using Waters (Arc HPLC); and proton and carbon NMR data were obtained using a BRUKER AVANCE NEO 500M.

[0074] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0075] The compound represented by formula (I) of this application can be prepared by those skilled in the art by replacing, adding or reducing relevant reactants, reaction conditions, etc., according to the synthesis method of the specific compound in the following examples and according to conventional synthesis methods of the prior art.

[0076] Example: Compound preparation method:

[0077] Example 1

[0078] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride (compound 1)

[0079]

[0080] Reaction 1:

[0081]

[0082] Step 1: Preparation of N-[(2,2-dimethylpropionyl)oxy]benzamide

[0083] O-neovalerylhydroxylamine trifluoromethanesulfonate (2000 mg, 7.48 mmol) and sodium carbonate (1580 mg, 14.96 mmol) were placed in a 100 mL reaction flask. Ethyl acetate (12 mL) and water (6 mL) were added under ice bath conditions, and the reaction was carried out at room temperature for 1 hour. Then, benzoyl chloride (1050 mg, 7.48 mmol) was added dropwise under ice bath conditions, and the reaction was stirred at room temperature. When the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 5 / 1, v / v) to obtain 1400 mg of a white solid, with a yield of 85%. LCMS (ESI) [M+H] + =222.

[0084] Reaction 2:

[0085]

[0086] Step 2: Preparation of methyl 4-methyl-1-oxoyne-2H-isoquinoline-3-carboxylate

[0087] N-[(2,2-dimethylpropionyl)oxy]benzamide (512 mg, 2 mmol), methyl butyryl-2-acetylacetate (231 mg, 2.4 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (37 mg, 0.06 mmol), and sodium carbonate (424 mg, 4 mmol) were placed in a 20 mL reaction tube, and ethanol (4 mL) was added. The mixture was stirred at room temperature for 2 hours. When the reaction was complete as determined by TLC, the mixture was filtered to obtain 392 mg of a white solid, with a yield of 90%. LCMS (ESI) [M+H] + =219.

[0088] Reaction 3:

[0089]

[0090] Step 3: Preparation of methyl 1-chloro-4-methylisoquinoline-3-carboxylate

[0091] 390 mg (1.79 mmol) of methyl 4-methyl-1-oxoylide-2H-isoquinoline-3-carboxylate was placed in a 50 mL reaction tube, followed by 10 mL of toluene and then 823 mg (5.37 mmol). The mixture was stirred in an ice bath, and triethylamine (18 mg, 0.18 mmol) was added dropwise. The mixture was heated to 90 °C and stirred overnight. After the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 6 / 1, v / v) to obtain 312 mg of a white solid, with a yield of 74%. LCMS (ESI) [M+H] + =236.

[0092] Reaction 4:

[0093]

[0094] Step 4: Preparation of 1-chloro-4-methylisoquinoline-3-carboxylic acid

[0095] 1-Chloro-4-methylisoquinoline-3-carboxylate (310 mg, 1.32 mmol) and sodium hydroxide (317 mg, 7.92 mmol) were placed in a 100 mL reaction flask, and ethanol (10 mL) and water (10 mL) were added. The mixture was stirred overnight at room temperature. When the reaction was complete as determined by TLC, the pH was adjusted to 6, and the solvent was removed by vacuum distillation, yielding 585 mg of a white powdery solid, with a yield of 99%. LCMS (ESI) [M+H] + =222.

[0096] Reaction 5:

[0097]

[0098] Step 5: Preparation of 4-[(1-chloro-4-methylisoquinoline-3-yl)carbonyl]piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0099] 1-Chloro-4-methylisoquinoline-3-carboxylic acid (200 mg, 0.90 mmol), piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (140 mg, 0.75 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (342 mg, 0.90 mmol), and triethylamine (318 mg, 3.15 mmol) were placed in a 50 mL reaction tube, and dichloromethane (5 mL) was added. The mixture was stirred overnight at room temperature. When the reaction proceeded completely as determined by TLC, the mixture was extracted, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 2 / 1, v / v) to obtain 240 mg of a white solid, in 82% yield. LCMS (ESI)

[0100] [M+H] + =390.

[0101] Reaction 6:

[0102]

[0103] Step 6: Preparation of 5-cyclopropyl-3-({4-methyl-3-[(4-{[(2-methylprop-2-yl)oxy]carbonyl}piperazin-1-yl)carbonyl]isoquinoline-1-yl}amino)pyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester

[0104] 5-Cyclopropyl-1H-pyrazole-3-amine (1000 mg, 8.12 mmol) was placed in a 100 mL reaction flask, and 20 mL of dichloromethane was added. Potassium hydroxide (3.64 g, 65 mmol) was added in portions under ice bath conditions, followed by di-tert-butyl dicarbonate (2130 mg, 9.24 mmol). The reaction was allowed to proceed for 2-3 hours. Once the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 4 / 1, v / v) to obtain 1510 mg of a white solid, with a yield of 83%.

[0105] 4-[(1-chloro-4-methylisoquinoline-3-yl)carbonyl]piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (200 mg, 0.51 mmol), 3-amino-5-cyclopropylpyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester (151 mg, 0.76 mmol), bis(dibenzylacetone)palladium(0) (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (29 mg, 0.05 mmol), and cesium carbonate (166 mg, 0.51 mmol) were placed in a 50 mL reaction tube, and 5 mL of ultra-dry 1,4-dioxane was added. The atmosphere was purged with nitrogen, and the mixture was stirred at room temperature for 10 minutes. Then the temperature was raised to 80 °C, and the reaction was allowed to proceed for 3-4 hours. After the reaction of the starting materials was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 2 / 1, v / v) to obtain 182 mg of a yellow solid, with a yield of 62%. LCMS (ESI) [M+H] + =577.

[0106] Reaction 7:

[0107]

[0108] Step 6: Preparation of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone

[0109] {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone (174 mg, 0.47 mmol) was placed in a 100 mL reaction flask, and 30 mL of anhydrous methanol was added. A 4M solution of 1,4-dioxane hydrogen chloride was then added dropwise, and the mixture was heated to 50 °C and reacted overnight. When the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, yielding 164 mg of a pale yellow solid (90% yield). LCMS (ESI) [M+H] + =377. 1H NMR(500MHz,DMSO-d6)δ12.13(s,1H),9.68(s,2H),9.10(d,J=8.0Hz,1H),8 .15(d,J=8.1Hz,1H),8.04(t,J=7.4Hz,1H),7.88(t,J=7.6Hz,1H),6.32(s, 1H),3.98–3.88(m,2H),3.62–3.57(m,2H),3.17–3.26(m,2H),3.02–3.12(m ,2H),2.45(s,3H),2.04–1.98(m,1H),1.02–1.00(m,2H),0.81–0.78(m,2H).

[0110] Example 2

[0111] Synthesis of {4-methyl-1-[(5-methyl-1H-pyrazol-3-yl)amino]isoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride (compound 2)

[0112]

[0113] Except for replacing 3-amino-5-cyclopropylpyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester with 3-amino-5-methylpyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 50 mg of a pale yellow solid in 85% yield. LCMS (ESI) [M+H] + =351. 1 H NMR (500MHz, DMSO-d6) δ11.93(s,1H),9.62(s,2H),9.04(d,J=8.4Hz,1H),8.15(d,J=8.3Hz,1H),8.03(t,J=7.6Hz,1H),7.88(t,J =7.7Hz,1H),6.43(s,1H),3.61–3.54(m,2H),3.42–3.35(m,2H),3.28–3.20(m,2H),3.13–3.03(m,2H),2.46(s,3H),2.33(s,3H).

[0114] Example 3

[0115] Synthesis of (4-aminohexahydropyridin-1-yl){1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl} methyl ketone hydrochloride (compound 3)

[0116]

[0117] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (hexahydropyridin-4-ylamino)methane-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 75 mg of a pale yellow solid in 95% yield. LCMS (ESI) [M+H] + =391.

[0118] Example 4

[0119] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]isoquinoline-3-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0120]

[0121] Reaction 1:

[0122]

[0123] Step 1: Synthesis of methyl 1-chloroisoquinoline-3-carboxylate

[0124] 500 mg (2.46 mmol) of methyl 1-oxoylide-2H-isoquinoline-3-carboxylate was placed in a 50 mL reaction tube, followed by 10 mL of toluene and then 943 mg (6.15 mmol). The mixture was stirred in an ice bath, and triethylamine (25 mg, 0.25 mmol) was added dropwise. The mixture was heated to 90 °C and stirred overnight. After the reaction was complete as determined by TLC, the solvent was removed under reduced pressure, and the mixture was purified by rapid separation column chromatography (petroleum ether / ethyl acetate 5 / 1, v / v) to obtain 951 mg of a white solid, with a yield of 87%. LCMS (ESI) [M+H] + =222.

[0125] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 50 mg of a pale yellow solid in 80% yield. LCMS (ESI) [M+H] + =377. 1H NMR(500MHz, Methanol-d4)δ8.80(s,1H),8.17–8.13(m,1H),8.05–7.99(m,1H),7.95–7.88(m,1H),7.85(d,J=7.7Hz,1H),6.12(d,J=8.8Hz,1H), 4.54(t,J=17.5Hz,2H),3.71–3.53(m,2H),3.52–3.39(m,2H),3.33(s,1H) ),2.02–1.93(m,1H),1.46(s,3H),1.12–1.07(m,2H),0.82–0.78(m,2H).

[0126] Example 5

[0127] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-propylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0128]

[0129] Except for replacing methyl butyronitrile with propyl butyronitrile, the target compound was synthesized according to the method of Example 1, yielding 46 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =351. 1 H NMR (500MHz, Methanol-d4) δ8.73(d,J=7.9Hz,1H),8.25(d,J=7.7Hz,1H),8.11(d,J=7.1Hz,1H),7.94(t,J=7.1Hz,1H),6.20(s,1H),4.35–3.69(m,4H),3 .55–3.40(m,2H),3.34–3.28(m,2H),2.95(s,2H),2.10–2.04(m,1H),1.73(d ,J=7.1Hz,2H),1.18–1.10(m,2H),1.07(t,J=6.5Hz,3H),0.94–0.88(m,2H).

[0130] Example 6

[0131] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]isoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0132]

[0133] Except for replacing methyl butyronitrile with propyl butyronitrile, the target compound was synthesized according to the method of Example 4, yielding 46 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =363. 1 H NMR (500MHz, DMSO-d6) δ12.61(s,1H),9.76(s,2H),9.29(d,J=8.4Hz,1H),8.18–8.11(m,1H),8.11–

[0134] 8.02(m,1H),8.01–7.93(m,1H),7.90(s,1H),6.38(d,J=14.5Hz,1H),3.98–3.95(m ,4H),3.25–3.21(m,4H),2.06–2.01(m,1H),1.07–0.99(m,2H),0.84–0.77(m,2H).

[0135] Example 7

[0136] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-6-fluoro-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0137]

[0138] Except for replacing benzoyl chloride with 4-fluorobenzoyl chloride, the target compound was synthesized according to the method of Example 1, yielding 72 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =395. 1 H NMR(500MHz,DMSO-d6)δ11.87(s,1H),9.58(s,2H),9.14(dd,J=9.3,5.3Hz, 1H),7.93(dd,J=10.5,2.6Hz,1H),7.83–7.79(m,1H),6.31(s,1H),3.91(d, J=29.3Hz,2H),3.58(d,J=5.8Hz,2H),3.31(dd,J=18.0,9.5Hz,2H),3.07(m ,2H),2.43(s,3H),2.08–2.00(m,1H),1.08–1.03(m,2H),0.92–0.77(m,2H).

[0139] Example 8

[0140] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylpyrido[4,3-c]pyridin-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0141]

[0142] Except for replacing benzoyl chloride with pyridine-4-carbonyl chloride, the target compound was synthesized according to the method of Example 1, yielding 72 mg of a pale yellow solid in 90% yield. LCMS(ESI)[M+H] + =378. 1 H NMR(500MHz,Methanol-d4)δ9.90(s,1H),9.00(d,J=10.5Hz,2H),6.34(s,1H),4.20(s,2H),3.81 –3.60(m,2H),3.51(s,2H),3.23(s,2H),2.73(s,3H),2.18–2.13(m,1H),1.30–1.21(m,2H),1.06–

[0143] 0.97(m,2H).

[0144] Example 9

[0145] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-6-methoxy-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0146]

[0147] Except for replacing benzoyl chloride with p-methoxybenzoyl chloride, the target compound was synthesized according to the method of Example 1, yielding 45 mg of a pale yellow solid in 88% yield. LCMS(ESI)[M+H] + =407. 1 H NMR(500MHz,DMSO-d6)δ10.20(s,3H),9.54(s,2H),8.66(s,1H),7.28(s,1H),3.97(s,3H),3.93(d,J=6.5Hz,2H ),3.48(s,2H),3.22(s,2H),3.01(s,2H),2.37(s,3H),1.99–1.86(m,1H),0.98–0.89(m,2H),0.74–0.68(m,2H).

[0148] Example 10

[0149] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0150]

[0151] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 30 mg of a pale yellow solid in 70% yield. LCMS (ESI) [M+H] + =391. 1 H NMR(500MHz, Methanol-d4)δ8.72(d,J=8.4Hz,1H),8.24(dd,J=8.4,2.4Hz,1H),8.13–8.08(m,1H),8.00–7.89(m,1H), 6.12(s,1H),3.71–3.48(m,3H),2.58(d,J=1.9Hz,3H),2.06–2.01(m,1H),1.67–1.38(m,2H),1.35–1.23(m,2H),1.16–

[0152] 1.04(m,2H), 0.94–0.75(m,2H).

[0153] Example 11

[0154] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}[(2R)-2-methylpiperazin-1-yl]methyl ketone hydrochloride

[0155]

[0156] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 30 mg of a pale yellow solid in 70% yield. LCMS (ESI) [M+H] + =391. 1H NMR (500MHz, DMSO-d6) δ12.15(s,1H),9.91(d,J=11.2Hz,1H),9.52(d,J=11.1Hz,1H ),9.12(d,J=8.4Hz,1H),8.16(d,J=7.5Hz,1H),8.05(t,J=8.0Hz,1H),7.88(t,J=8.0 1H),6.36(s,1H),3.56–3.29(m,3H),3.21–3.16(m,3H),3.04–2.99(m,1H).2.4 4(s,3H),2.07–2.02(m,1H),1.41(s,3H),1.07–0.96(m,2H),0.84–0.81(m,2H).

[0157] Example 12

[0158] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}[(3S)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0159]

[0160] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2S)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 190 mg of a pale yellow solid in 96% yield. LCMS (ESI) [M+H] + =391. 1 H NMR (500MHz, DMSO-d6) δ12.22(s,1H),9.82(s,2H),9.12(d,J=8.2Hz,1H),8.16(d,J=8.2Hz,1H),8.06(t,J=7.6Hz,1H), 7.90(t,J=7.6Hz,1H),6.31(s,1H),4.48(s,1H),3.78–3.66(m,2H),3.54(s,3H),3.47–3.36(m,2H),2.46(s,3H),2.05–

[0161] 1.99(m,1H),1.35–1.31(m,2H),1.03–1.02(m,2H),0.85–0.76(m,2H).

[0162] Example 13

[0163] Synthesis of (4-methyl-1-{[5-(2-methylpropyl-2-yl)-1H-pyrazol-3-yl]amino}isoquinoline-3-yl)(piperazin-1-yl)methyl ketone hydrochloride

[0164]

[0165] Except for replacing 5-cyclopropyl-1H-pyrazole-3-amine with 5-(2-methylpropyl-2-yl)-1H-pyrazole-3-amine, the target compound was synthesized according to the method of Example 1, yielding 170 mg of a pale yellow solid in 81% yield. LCMS (ESI) [M+H] + =393. 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),9.73(s,2H),9.21(s,1H),8.13(s,1H),8.03(s,1H),7.87(s ,1H),6.42(s,1H),3.89(s,2H),3.61(s,2H),3.50(s,3H),3.23(s,2H),3.11(s,2H),1.28(s,9H).

[0166] Example 14

[0167] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}[(3R)-3-ethylpiperazin-1-yl]methyl ketone hydrochloride

[0168]

[0169] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-ethylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 40 mg of a pale yellow solid in 83% yield. LCMS (ESI)

[0170] [M+H] + =405. 1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),9.96–9.48(m,2H),9.05(d,J=8.4Hz,1H),8.1 7(d,J=8.3Hz,1H),8.06(t,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),6.32(s,1H),4.53( s,1H),3.80–3.67(m,4H),3.57(s,3H),3.53–3.47(m,2H),3.27–3.24(m,2H),3.10– 3.01(m,1H),2.48(s,3H),2.07–2.01(m,1H),1.06–1.04(m,2H),0.85–0.82(m,2H).

[0171] Example 15

[0172] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-ethylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0173]

[0174] Except for replacing methyl butyronitrile with ethyl butyronitrile, the target compound was synthesized according to the method of Example 1, yielding 46 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =391. 1 H NMR(500MHz,DMSO-d6)δ11.86(s,1H),9.66(s,2H),9.03(d,J=8.4Hz,1H),8.17(d,J =8.3Hz,1H),8.00(t,J=7.7Hz,1H),7.84(t,J=7.7Hz,1H),6.33(s,1H),4.00–3.93( m,2H),3.68–3.48(m,2H),3.34–3.18(m,2H),3.05–3.00(m,2H),2.89(q,J=7.2Hz,2 H),2.06–2.01(m,1H),1.19(t,J=7.4Hz,3H),1.08–0.98(m,2H),0.90–0.76(m,2H).

[0175] Example 16

[0176] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylisoquinoline-3-yl}[(2S)-2-methylpiperazin-1-yl]methyl ketone hydrochloride

[0177]

[0178] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3S)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 39 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =391. 1H NMR(500MHz,DMSO-d6)δ11.78(s,1H),9.81(d,J=9.0Hz,1H),9.38(d,J=11.5Hz,1H) ,9.01(d,J=8.4Hz,1H),8.14(d,J=8.3Hz,1H),8.03(t,J=7.7Hz,1H),7.87(t,J=7.7H z,1H),6.33(s,1H),3.59–3.57(m,1H),3.39(s,2H),3.27–3.23(m,2H),3.03(s,2H) ,2.45(s,3H),2.06–2.00(m,1H),1.41(s,3H),1.07–1.01(m,2H),0.84–0.80(m,2H).

[0179] Example 17

[0180] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5,6,7,8-tetradeuteryl-4-methylisoquinoline-3-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0181]

[0182] Except for replacing benzoyl chloride with deuterated benzoyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 70 mg of a pale yellow solid in 85% yield. LCMS (ESI) [M+H] + =395. 1 H NMR (500MHz, Methanol-d4)δ

[0183] 6.17(d,J=4.9Hz,1H),3.71–3.59(m,4H),3.45–3.33(m,5H),2.57(s,3H),2 .07–2.01(m,1H),1.52–1.41(m,1H),1.14–1.13(m,2H),0.91–0.87(m,2H).

[0184] Example 18

[0185] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5,6,7,8-tetradeuteryl-4-methylisoquinoline-3-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0186]

[0187] Except for replacing benzoyl chloride with deuterated benzoyl chloride, the target compound was synthesized according to the method of Example 1, yielding 70 mg of a pale yellow solid in 85% yield. LCMS (ESI) [M+H] + =381. 1 H NMR(500MHz,DMSO-d6)δ12.35(s,1H),9.73(s,2H),6.34(s,1H),3.93(s,2H),3.69–3.58(m,2H),3.30– 3.19(m,2H),3.14–2.96(m,2H),2.47(s,3H),2.06–2.00(m,1H),1.08–1.00(m,2H),0.87–0.78(m,2H).

[0188] Example 19

[0189] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5,6,7,8-tetradeuteryl-4-methylisoquinoline-3-yl}[(2R,5R)-2,5-dimethylpiperazin-1-yl]methyl ketone hydrochloride

[0190]

[0191] Except for replacing benzoyl chloride with deuterated benzoyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R,5R)-2,5-dimethylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 53 mg of a pale yellow solid in 96% yield. LCMS (ESI) [M+H] + =409. 1 H NMR(500MHz,Methanol-d4)δ6.17(s,1H),5.19(s,1H),4.81–3.42(m,5H),3.37(s,3H) ),2.54(s,3H),2.07–2.02(m,1H),1.59(s,3H),1.14–1.13(m,2H),0.93–0.79(m,2H).

[0192] Example 20

[0193] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5,6,7,8-tetradeuteryl-4-methylisoquinoline-3-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0194]

[0195] Except for replacing benzoyl chloride with deuterated benzoyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 76 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =407. 1 H NMR(500MHz,Methanol-d4)δ6.16(s,1H),4.82–4.67(m,1H),4.49–4.25(m,1H),4.03(s,1H),3.91–3.88(m,1H),3.73–3.57(m, 2H),2.55(s,3H),2.34–2.26(m,1H),2.18–2.13(m,2H),2.08–2.02(m,1H),1.94(s,1H),1.19–1.11(m,2H),0.92–0.85(m,2H).

[0196] Example 21

[0197] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5,6,7,8-tetradeuteryl-4-methylisoquinoline-3-yl}[(3S,5R)-3,5-dimethylpiperazin-1-yl]methyl ketone hydrochloride

[0198]

[0199] Except for replacing benzoyl chloride with deuterated benzoyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2S,6R)-2,6-dimethylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 60 mg of a pale yellow solid in 88% yield. LCMS (ESI) [M+H] + =409. 1 H NMR(500MHz,DeuteriumOxide)δ5.64(s,1H),4.11–2.58(m,6H),2.33(s,3H),1.74–1 .68(m,1H),1.40(d,J=6.4Hz,3H),1.07(s,3H),1.00–0.92(m,2H),0.66–0.54(m,2H).

[0200] Example 22

[0201] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylthiopheno[3,2-c]pyridin-6-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0202]

[0203] Except for replacing benzoyl chloride with 3-thiophenecarboxyl chloride, the target compound was synthesized according to the method of Example 1, yielding 40 mg of a pale yellow solid in 88% yield. LCMS (ESI) [M+H] + =383. 1 H NMR(500MHz, Methanol-d4)δ8.11(d,J=5.3Hz,1H),8.06(d,J=5.4Hz,1H),6.06(s,1H),3.88–4.13 (m,4H),3.57–3.38(m,4H),2.53(s,3H),2.09–2.04(m,1H),1.16–1.18(m,2H),0.94–0.87(m,2H).

[0204] Example 23

[0205] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0206]

[0207] Except for replacing benzoyl chloride with 3-furanoyl chloride, the target compound was synthesized according to the method of Example 1, yielding 34 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =367. 1 H NMR(500MHz, Methanol-d4)δ8.16(d,J=2.5Hz,1H),7.56–7.31(m,1H),5.99(s,1H),4.21–3.64(m,4H ),3.61–3.37(m,4H),2.50(d,J=6.1Hz,3H),2.09–2.04(m,1H),1.21–1.13(m,2H),0.92–0.90(m,2H).

[0208] Example 24

[0209] Synthesis of {7-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylfurano[2,3-c]pyridin-5-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0210]

[0211] Except for replacing benzoyl chloride with 2-furanoyl chloride, the target compound was synthesized according to the method of Example 1, yielding 34 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =367. 1 H NMR(500MHz,Methanol-d4)δ8.23(d,J=1.9Hz,1H),7.22(d,J=2.0Hz,1H),6.01(s,1H),4 .18–3.38(m,8H),2.47(s,3H),2.12–2.07(m,1H),1.24–1.16(m,2H),0.99–0.92(m,2H).

[0212] Example 25

[0213] Synthesis of {7-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methylthiopheno[2,3-c]pyridin-5-yl}(piperazin-1-yl)methyl ketone hydrochloride

[0214]

[0215] Except for replacing benzoyl chloride with 3-thiophenecarboxyl chloride, the target compound was synthesized according to the method of Example 1, yielding 51 mg of a pale yellow solid in 92% yield. LCMS (ESI) [M+H] + =383. 1 H NMR(500MHz,Deuterium Oxide)δ7.87(s,1H),7.38(s,1H),5.36(s,1H),3.93(s,2H),3.52–3.27(m,4H),3 .05(s,2H),2.24(s,3H),1.90–1.55(m,1H),1.15–0.77(m,2H),0.73–0.20(m,2H).

[0216] Example 26

[0217] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,7-dimethylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0218]

[0219] Except for replacing benzoyl chloride with 5-methylthiophene-3-carboxyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 120 mg of a pale yellow solid in 93% yield. LCMS (ESI) [M+H] + =411. 1 H NMR(500MHz,DeuteriumOxide)δ7.16(s,1H),5.62(s,1H),4.55(s,1H),3.78–3.16(m,7H),2.50( s,3H),2.26(s,3H),1.80–1.74(s,1H),1.52–1.05(m,1H),1.03–0.99(m,2H),0.68–0.65(m,2H).

[0220] Example 27

[0221] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,3,7-trimethylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0222]

[0223] Except for replacing benzoyl chloride with 4,5-dimethylthiophene-3-carboxyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 50 mg of a pale yellow solid in 89% yield. LCMS (ESI) [M+H] + =425. 1 H NMR(500MHz,DeuteriumOxide)δ5.85(s,1H),4.56(s,1H),3.69–3.61(m,1H),3.60–3.53(m,1H),3.50–3.47(m,1H),3.18–3. 00(m,1H),2.44(d,J=14.5Hz,6H),2.28(s,3H),1.90–1.84(m,1H),1.29–1.22(m,1H),1.06–0.96(m,2H),0.72–0.71(m,2H).

[0224] Example 28

[0225] Synthesis of {1-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-methyl-6,7,8,9-tetrahydrocyclohexano[1',2':4,5]thieno[3,2-c]pyridin-3-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0226]

[0227] Except for replacing benzoyl chloride with 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 80 mg of a pale yellow solid in 79% yield. LCMS (ESI) [M+H] + =451. 1 H NMR(500MHz,Deuterium Oxide)δ5.80(s,1H),4.53(s,1H),3.70–3.52(m,2H),3.50–3.40(m,1H),3.26(s,3H),3.22–2.98(m,1H),2.95–2.85(m,2H) ,2.83–2.73(m,2H),2.26(s,3H),1.91–1.64(m,5H),1.40(s,1H),1.12–1.06(m,1H),1.04–1.00(m,2H),0.75–0.62(m,2H).

[0228] Example 29

[0229] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylthieno[3,2-c]pyridin-6-yl}[(2R)-2-methylpiperazin-1-yl]methyl ketone hydrochloride

[0230]

[0231] Except for replacing benzoyl chloride with 3-thiophenecarboxyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 70 mg of a pale yellow solid in 91% yield. LCMS (ESI) [M+H] + =397. 1H NMR(500MHz,Deuterium Oxide)δ7.79(t,J=5.3Hz,1H),7.58(dd,J=8.3,5.3Hz,1H),5.64(d,J=8.8Hz,1H),4.29–2.57(m, 7H), 2.31 (d, J = 3.5Hz, 3H), 1.86–1.81 (m, 1H), 1.38 (s, 3H), 1.07–0.99 (m, 2H), 0.76–0.66 (m, 2H).

[0232] Example 30

[0233] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-3,7-dimethylthiopheno[3,2-c]pyridin-6-yl}[(2R)-2-methylpiperazin-1-yl]methyl ketone hydrochloride

[0234]

[0235] Reaction 1:

[0236]

[0237] Step 1: Preparation of 4-methylthiophene-3-formyl chloride

[0238] 4-Methylthiophene-3-carboxylic acid (1 g, 7.03 mmol) was placed in a 100 mL reaction flask, and 15 mL of dichloromethane and 50 μL of DMF were added. Oxaloyl chloride was added dropwise under ice bath conditions, and the mixture was then moved to room temperature for 3-4 hours. When the reaction was complete as detected by TLC, the solvent was removed under reduced pressure, and the next step was carried out directly.

[0239] Except for replacing benzoyl chloride with 4-methylthiophene-3-carboxyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 70 mg of a pale yellow solid in 91% yield. LCMS (ESI) [M+H] + =411. 1 H NMR(500MHz,DeuteriumOxide)δ7.43(s,1H),5.84(s,1H),3.67–3.03(m,7H),2.58(s,3 H),2.28(s,3H),1.86–1.81(m,1H),1.37(s,3H),1.08–0.96(m,2H),0.79–0.60(m,2H).

[0240] Example 31

[0241] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}[(2R)-2-methylpiperazin-1-yl]methyl ketone hydrochloride

[0242]

[0243] Except for replacing benzoyl chloride with 3-furanoyl chloride and piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 1, yielding 60 mg of a pale yellow solid in 87% yield. LCMS (ESI) [M+H] + =381. 1 H NMR(500MHz, Methanol-d4)δ8.16(d,J=2.0Hz,1H),7.42(d,J=2.0Hz,1H),5.99(s,1H),4.76–4.66(m,1 H),3.86–3.38(m,5H),3.29–3.18(m,1H),2.47(s,3H),2.06(s,1H),1.53(d,J=6.5Hz,3H),1.20–1.15(m 2H),0.94–0.88(m,2H).

[0244] Example 32

[0245] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-3,7-dimethylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0246]

[0247] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 30, yielding 120 mg of a pale yellow solid in 93% yield. LCMS (ESI) [M+H] + =411. 1 H NMR(500MHz,Methanol-d4)δ7.63(s,1H),6.18(s,1H),3.71–3.36(m,7H),2.82(s,3H),2 .48(s,3H),2.11–2.06(m,1H),1.64–1.38(m,2H),1.24–1.15(m,2H),0.96–0.89(m,2H).

[0248] Example 33

[0249] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0250]

[0251] Except for replacing (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 29, yielding 95 mg of a pale yellow solid in 90% yield. LCMS (ESI) [M+H] + =397. 1 H NMR(500MHz,Deuterium Oxide)δ7.73(d,J=5.5Hz,1H),7.50(d,J=5.5Hz,1H),5.57(s,1H),4.65–4.40(m,1H),3.71–2.98(m,7H) ,2.29(s,3H),1.80–1.74(m,1H),1.41(s,1H),1.13–1.05(m,1H),1.04–0.98(m,2H),0.74–0.56(m,2H).

[0252] Example 34

[0253] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0254]

[0255] Except for replacing (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 23, yielding 70 mg of a pale yellow solid in 87% yield. LCMS (ESI) [M+H] + =381. 1 H NMR(500MHz,Deuterium Oxide)δ7.89(s,1H),6.99(s,1H),5.59(s,1H),4.14–2.95(m,8H),2.29(s,3H),1.83 –1.79(m,1H),1.39(s,1H),1.13–1.06(m,1H),1.05–0.95(m,2H),0.70–0.67(m,2H).

[0256] Example 35

[0257] {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}(3,6-diazabicyclo[3.1.1]hept-3-yl)methyl ketone hydrochloride

[0258]

[0259] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 23, yielding 40 mg of a pale yellow solid in 89% yield. LCMS (ESI) [M+H] + =379. 1 H NMR(500MHz,Deuterium Oxide)δ7.87(d,J=2.2Hz,1H),6.98(d,J=2.3Hz,1H),5.64(s,1H),4.58(t,J=5.7Hz,1H),4.43–4.26(m,2H),4.13(d,J=14.6Hz,1H),3.91(d,J=13. 5Hz,1H),3.74(d,J=13.5Hz,1H),3.06–3.01(m,1H),2.32(s,3H),1.96(d ,J=11.1Hz,1H),1.87–1.80(m,1H),1.10–0.94(m,2H),0.74–0.71(m,2H).

[0260] Example 36

[0261] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,7-dimethylthiopheno[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0262]

[0263] Except for replacing 4-methylthiophene-3-carboxylic acid with 5-methylthiophene-3-carboxylic acid and (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 30, yielding 65 mg of a pale yellow solid in 93% yield. LCMS (ESI) [M+H] + =423. 1HNMR(500MHz,Deuterium Oxide)δ7.14(s,1H),5.63(s,1H),4.56(d,J=14.6Hz,1H),4.28(d,J=6.7Hz,1H),3.92(d,J=8.0Hz,2H),3.70–3.58(m,1H),3.46(d,J=15.0Hz,1H) ,3.37(d,J=16.0Hz,1H),2.52(s,3H),2.24(s,3H),2.20–2.10(m,1H),2. 04–1.98(m,2H),1.85–1.81(m,1H),1.07–0.98(m,2H),0.81–0.58(m,2H).

[0264] Example 37

[0265] {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-methyl-7-(2-methylpropyl)thiopheno[3,2-c]pyridine-6-

[0266] Synthesis of [(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0267]

[0268] Except for replacing 4-methylthiophene-3-carboxylic acid with 5-methylthiophene-3-carboxylic acid, methyl butyronitrile with ethyl 5-methylhexano-2-acetylonitrile, and (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 30, yielding 150 mg of a pale yellow solid in 87% yield. LCMS (ESI) [M+H] + =453. 1 H NMR(500MHz,Deuterium Oxide)δ7.11(s,1H),5.75(s,1H),4.61–4.50(m,1H),3.85–3.15(m,5H),2.57(s,3H),2.33(s,1H) ,1.92–1.88(m,1H),1.80–1.72(m,1H),1.44(s,1H),1.05(d,J=5.5Hz,3H),0.74(d,J=6.5Hz,6H).

[0269] Example 38

[0270] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methoxy-2-methylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0271]

[0272] Except for replacing 4-methylthiophene-3-carboxylic acid with 5-methylthiophene-3-carboxylic acid, methyl butyronitrile with ethyl 3-methoxypropane-2-acetylonitrile, and (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 30, yielding 150 mg of a pale yellow solid in 87% yield. LCMS (ESI) [M+H] + =441. 1 H NMR(500MHz,Deuterium Oxide)δ7.04(s,1H),4.58(s,1H),4.46(d,J=10.2Hz,2H),3.64–3.37(m,3H),3.35(s,3H),3.20( s,1H),2.46(s,3H),1.88–1.82(m,1H),1.46–1.37(m,1H),1.10–1.05(m,3H),0.83–0.63(m,2H).

[0273] Example 39

[0274] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}(2,6-diazaspiro[3,3]hept-2-yl)methyl ketone hydrochloride

[0275]

[0276] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 2,6-diazaspiro[3.3]heptane-2-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 23, yielding 65 mg of a pale yellow solid in 89% yield. LCMS (ESI) [M+H] + =379. 1 H NMR(500MHz,Deuterium Oxide)δ7.96(s,1H),7.06(s,1H),5.59(s,1H),4.54–3.71(m,8H),2.37(s,3H),1.82–1.77(m,1H),1.07–0.94(m,2H),0.70–0.60(m,2H).

[0277] Example 40

[0278] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-8-yl)methyl ketone hydrochloride

[0279]

[0280] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 23, yielding 65 mg of a pale yellow solid in 86% yield. LCMS (ESI) [M+H] + =423. 1 H NMR(500MHz,Deuterium Oxide)δ7.93(d,J=2.2Hz,1H),7.02(d,J=2.2Hz,1H),5.36(s,1H),4.65–3.75(m,1H),3.60–3.32(m,3H),3 .16–2.94(m,2H),2.32(s,3H),2.27–2.00(m,4H),1.84–1.80(m,1H),1.05–1.02(m,2H),0.71–0.68(m,2H).

[0281] Example 41

[0282] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}[(3R)-3-(dimethylamino)tetrahydro-1H-pyrrolo-1-yl]methyl ketone hydrochloride

[0283]

[0284] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with (3R)-3-(dimethylamino)tetrahydropyrrole, the target compound was synthesized according to the method of Example 23, yielding 41 mg of a pale yellow solid in 64% yield. LCMS (ESI) [M+H] + =381. 1H NMR(500MHz,Deuterium Oxide)δ7.89(s,1H),7.00(d,J=5.5Hz,1H),4.95(s,1H),4.15–3.98(m,1H),3.81(s,2H),3.66(s,1H),3.53–3.42(m,1H),3.26(s,1H),2.85–

[0285] 2.65(m,2H),2.57(s,1H),2.54–2.39(m,1H),2.34(d,J=4.0Hz,3H),2.2 5–2.07(m,1H),1.84–1.77(m,1H),1.06–0.96(m,2H),0.70–0.65(m,2H).

[0286] Example 42

[0287] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylfurano[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0288]

[0289] Except for replacing piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 23, yielding 20 mg of a pale yellow solid in 93% yield. LCMS (ESI) [M+H] + =393. 1 H NMR(500MHz,Deuterium Oxide)δ7.90(s,1H),6.99(s,1H),4.55(m,2H),4.31–4.22(m,1H),3.93(d,J=6.4Hz,1H),3.70–3.5 8(m,1H),3.53–3.33(m,2H),2.30(s,3H),2.22–1.49(m,5H),1.05–1.03(m,2H),0.81–0.58(m,2H).

[0290] Example 43

[0291] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-(methoxymethyl)-2-methylthiopheno[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0292]

[0293] Except for replacing (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 38, yielding 30 mg of a pale yellow solid in 74% yield. LCMS (ESI) [M+H] + =453. 1 H NMR(500MHz,Deuterium Oxide)δ7.07(s,1H),4.61–4.38(m,3H),4.28(d,J=6.8Hz,1H),3.90(d,J=6.7Hz,1H),3.54(d,J=14.3Hz,1H),3.45(d,J=15.5Hz,1H),3.3 5(s,3H),3.32–3.27(m,1H),2.51(s,3H),2.20–2.14(m,1H),2.10–1.95(m,2H),1.89–1.80(m,2H),1.13–1.03(m,2H),0.77–0.72(m,2H).

[0294] Example 44

[0295] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-(methoxymethyl)thieno[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0296]

[0297] Except for replacing 5-methylthiophene-3-carboxylic acid with thiophene-3-carboxylic acid, the target compound was synthesized according to the method of Example 38, yielding 81 mg of a pale yellow solid in 91% yield. LCMS (ESI) [M+H] + =439. 1H NMR(500MHz,DeuteriumOxide)δ7.74(d,J=5.6Hz,1H),7.49(d,J=5.6Hz,1H),4.57–4.4 8(m,3H),4.28(d,J=6.7Hz,1H),3.90(d,J=6.7Hz,1H),3.54(d,J=14.5Hz,1H),3.46(d, J=14.5Hz,1H),3.37(s,3H),3.30–2.72(m,1H),3.26(s,1H),2.20–2.15(m,1H),2.09–2 .07(m,1H),2.02–1.95(m,1H),1.89–1.82(m,2H),1.13–1.05(m,2H),0.76–0.73(m,2H).

[0298] Example 45

[0299] Synthesis of [4-(1H-pyrazol-3-ylamino)-2,7-dimethylthiopheno[3,2-c]pyridin-6-yl][(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0300]

[0301] Except for replacing 5-cyclopropyl-1H-pyrazole-3-amine with 3-aminopyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 26, yielding 45 mg of a pale yellow solid in 82% yield. LCMS(ESI)[M+H] + =371. 1 H NMR(500MHz,Deuterium Oxide)δ7.83–7.46(m,1H),7.42–7.18(m,1H),6.26–5.77(m,1H),4.64–4.33(m,1H),3.67–3.62(m,2H) ,3.58–3.35(m,3H),3.26(s,3H),3.12(q,J=7.3Hz,1H),2.55(d,J=13.6Hz,3H),2.29(d,J=14.9Hz,3H).

[0302] Example 46

[0303] {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-(methoxymethyl)-2-methylthiopheno[3,2-c]pyridine-6-

[0304] Synthesis of [(3R)-3,4-dimethylpiperazin-1-yl]methyl ketone hydrochloride

[0305]

[0306] Except for replacing 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-1,2-dimethylpiperazine, the target compound was synthesized according to the method of Example 43, yielding 10 mg of a pale yellow solid in 47% yield. LCMS (ESI) [M+H] + =455. 1 H NMR(500MHz,Methanol-d4)δ7.70(s,1H),6.07(s,1H),4.70(s,2H),4.37–3.49(m,3H),3.46(s,3H),3.38–3.37(m,1H ),3.33(s,3H),3.02(s,3H),2.73(s,3H),2.11–2.05(m,1H),1.93–1.25(m,3H),1.22–1.16(m,2H),0.95–0.85(m,2H).

[0307] Example 47

[0308] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-methylthiopheno[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0309]

[0310] Except for replacing (3R)-3-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 29, yielding 40 mg of a pale yellow solid in 89% yield. LCMS (ESI) [M+H] + =409. 1 H NMR(500MHz,Deuterium Oxide)δ7.79(d,J=5.5Hz,1H),7.57(d,J=5.5Hz,1H),5.65(s,1H),4.57(d,J=14.6Hz,1H),4.28(d,J=6.6Hz,1H),3.91(d,J=5.0Hz,1H),3.69–3.5 8(m,1H),3.47(d,J=14.2Hz,1H),3.38(d,J=14.5Hz,1H),2.31(s,3H),2. 24–1.96(m,3H),1.85–1.78(m,2H),1.09–0.97(m,2H),0.72–0.70(m,2H).

[0311] Example 48

[0312] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-ethylthiopheno[3,2-c]pyridin-6-yl}(3,8-diazabicyclo[3.2.1]oct-3-yl)methyl ketone hydrochloride

[0313]

[0314] Except for replacing methyl butyronitrile with ethyl butyronitrile, the target compound was synthesized according to the method of Example 47, yielding 86 mg of a pale yellow solid in 94% yield. LCMS (ESI) [M+H] + =423. 1 H NMR(500MHz,DeuteriumOxide)δ7.72(d,J=6.0Hz,1H),7.50(d,J=6.0Hz,1H),5.66(d,J=4.1Hz,1H) ,4.53(d,J=14.5Hz,1H),4.29(d,J=6.7Hz,1H),3.91(d,J=6.6Hz,1H),3.59(d,J=14.4Hz,1H),3.46 (d,J=14.0Hz,1H),3.36(d,J=14.4Hz,1H),2.66(d,J=9.1Hz,2H),2.23–2.13(m,1H),2.12–2.04(m, 1H),2.02–1.96(m,1H),1.87–1.75(m,2H),1.20–1.16(m,3H),1.08–0.95(m,2H),0.72–0.60(m,2H).

[0315] Example 49

[0316] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-(methoxymethyl)thiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0317]

[0318] Except for replacing 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 44, yielding 65 mg of a pale yellow solid in 98% yield. LCMS (ESI) [M+H] + =427. 1H NMR(500MHz,Deuterium Oxide)δ7.68(s,1H),7.44(s,1H),5.34(s,1H),4.65–4.45(m,3H),3.71–3.39(m,3H),3.36(s,3H), 3.32–2.91(m,3H),1.84–1.78(m,1H),1.42(d,J=6.5Hz,1H),1.08–1.06(m,2H),0.81–0.63(m,2H).

[0319] Example 50

[0320] Synthesis of {4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-ethylthiopheno[3,2-c]pyridin-6-yl}[(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0321]

[0322] Except for replacing 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropyl-2-yl ester with (2R)-2-methylpiperazine-1-carboxylic acid-2-methylpropyl-2-yl ester, the target compound was synthesized according to the method of Example 48, yielding 75 mg of a pale yellow solid in 88% yield. LCMS (ESI) [M+H] + =411. 1 H NMR(500MHz,Deuterium Oxide)δ7.76(d,J=5.5Hz,1H),7.55(d,J=5.5Hz,1H),5.66(s,1H),4.65–4.50(m,1H),3.75–3.39(m,4H),3.30–3.21(m,3H),2.81–2.56 (d,J=8.5Hz,2H),1.84–1.79(m,1H),1.50–1.32(m,1H),1.17(t,J=7.6Hz,3H),1.12–1.06(m,1H),1.05–0.98(m,2H),0.71–0.68(m,2H).

[0323] Example 51

[0324] Synthesis of [2,7-dimethyl-4-(pyridin-3-ylamino)thiopheno[3,2-c]pyridin-6-yl][(3R)-3-methylpiperazin-1-yl]methyl ketone hydrochloride

[0325]

[0326] Except for replacing 3-aminopyrazole-1-carboxylic acid-2-methylpropyl-2-yl ester with pyridine-3-amine, the target compound was synthesized according to the method of Example 45, yielding 35 mg of a pale yellow solid in 67% yield. LCMS(ESI)[M+H] + =382. 1 H NMR(500MHz,Deuterium Oxide)δ9.11(d,J=11.4Hz,1H),8.34(d,J=7.8Hz,1H),8.15(d,J=5.5Hz,1H),7.73(dd,J=8.9,5.6Hz,1H),7.19(d,J=5.0Hz,1H) ,4.59(d,J=14.0Hz,1H),3.65–3.52(m,2H),3.48–3.40(m,1H),3.30–3.26(m,3H),2.53(s,3H),2.27(s,3H),1.40–1.04(m,3H).

[0327] Experimental Example 1: PAK4 Enzyme Activity Assay

[0328] Using Invitrogen's Z′-LYTE TM The Kinase Assay Kit – Ser / Thr 20 Peptide PAK4 Enzyme Activity Assay Kit is used to detect the inhibitory activity of analyte compounds on PAK4 enzyme activity. The specific steps are as follows:

[0329] 1) Add 2.5 μL of 4× test compound (containing 4% DMSO) to the compound treatment group. Set up an enzyme control group, a 100% phosphorylation control group and a 0% phosphorylation control group. Add 2.5 μL of 4% DMSO buffer to each of the above control groups.

[0330] 2) PAK4 enzyme was purchased from Promega. An enzyme / substrate peptide mixture was prepared to achieve a final substrate peptide concentration of 2 μM and an enzyme concentration of 0.5-2 ng / μL. 5 μL of the enzyme / substrate peptide mixture was added to the compound treatment group, the enzyme control group, and the 0% phosphorylation control group. 5 μL of phosphorylated substrate peptide was added to the 100% phosphorylation control group.

[0331] 3) Add 2.5 μL of ATP solution (final concentration of 4 μM) to the compound treatment group and the enzyme control group, and add the same volume of buffer to the other control groups. The final reaction system volume is 10 μL.

[0332] 4) After reacting at room temperature for 1 hour, add 5 μL of reaction reagent to each well to identify and cleave the unphosphorylated substrate peptide. After reacting for 1 hour, add the stop solution to terminate the reaction.

[0333] 5) The plate was read using a microplate reader (Molecular Device, Sunnyvale, CA, USA). The excitation light was 400 nm, and the emission light was 445 nm for coumarin and 520 nm for fluorescein. The emission intensity ratio, phosphorylation percentage, and compound inhibition rate of each well were calculated according to the formula provided in the kit, as shown in Table 1 below.

[0334] Table 1. PAK4 enzyme inhibitory activity of the compounds

[0335]

[0336]

[0337] Note: 50 nmol inhibition rate (%) < 20: +; 20 < 50 nmol inhibition rate (%) < 50: ++; 50 < 50 nmol inhibition rate (%) < 80: +++; 50 nmol inhibition rate (%) > 80: ++++

[0338] Experiment Example 2: Compound Anti-tumor Cell Proliferation Experiment

[0339] The inhibitory activity of the compounds against tumor cell proliferation was evaluated using the CCK-8 (Cell Counting Kit-8) assay. Human colorectal cancer cells HCT-116 and human pancreatic cancer cells MIA PaCa-2 were used, both purchased from the American Type Culture Collection (Manassas, VA, USA). The specific steps are as follows:

[0340] 1) HCT-116 and MIA PaCa-2 tumor cells in the logarithmic growth phase were counted separately and seeded in 96 wells (Corning, NY, USA) at a density of 1500 cells / well.

[0341] 2) Incubate overnight in an incubator (37℃, 5% CO2), add 10 μL / well of different concentrations of the compound, set up 3 replicates for each concentration, and set up a solvent control group and a cell-free blank control group.

[0342] 3) After culturing in the incubator for 72 hours, add 20 μL of CCK-8 reagent (purchased from Heyuan Liji) to each well and continue to place the cells in the incubator until the OD value is between 0.8 and 1.2 when detected by the microplate reader at a wavelength of 450 nm. Read the plate and record the OD value.

[0343] 4) Calculate the inhibition rate of the compound according to the following formula (1):

[0344] Inhibition rate (%) = (OD) 对照组-OD 给药组 ) / OD 对照组 ×100……(1)

[0345] The results are shown in Table 2 below:

[0346] Table 2 shows the PAK4 cell inhibitory activity of some compounds.

[0347] compound HCT-116 MIA PaCa-2 4 ++ ++ 5 + + 6 +++ +++ 7 ++ ++ 8 + + 17 ++ ++ 18 ++ + 22 ++++ ++++ 23 +++ +++ 41 ++ ++ 42 ++++ ++++

[0348] Note: Proliferation inhibition activity IC50 50 >5μM:+; 2μM <IC 50 <5μM:++; 1μM <IC 50 <2μM:++; IC 50 <1μM:++++

[0349] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug thereof, in, The A ring portion is selected from saturated or unsaturated three- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or from three- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S. The B ring moiety is selected from substituted or unsubstituted saturated or unsaturated three- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated three- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted three- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by 1 to 4 R3s, wherein R3s are selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, and C3-C6 cycloalkyl; The C-ring moiety is selected from substituted or unsubstituted saturated or unsaturated three- to seven-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated three- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted saturated or unsaturated three- to ten-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by 1 to 3 R4s, wherein the R4s are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C5 alkoxy, halogen-substituted C1-C5 alkyl, and C3-C6 cycloalkyl; R1 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C5 alkyl, C1-C5 alkoxy, and C3-C7 cycloalkyl; R2 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl; W is selected from -CH2-, -O-, -S-, (carbonyl), -N(Ra)-, (sulfinyl), wherein Ra is selected from H, deuterium or C1-C5 alkyl.

2. The compound represented by formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug, characterized in that, Preferably, the A ring portion is selected from saturated or unsaturated four- to six-membered cycloalkyl groups, C6-C... 10 Aryl, saturated or unsaturated four- to six-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or saturated or unsaturated four- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; More preferably, the A ring portion is selected from saturated or unsaturated five- to six-membered cycloalkyl groups, saturated or unsaturated five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, or five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S. Preferably, the B ring moiety is selected from substituted or unsubstituted saturated or unsaturated five- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to ten-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by 1 to 4 R3s, wherein R3s are selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and C3-C6 cycloalkyl; More preferably, the B ring moiety is selected from substituted or unsubstituted saturated or unsaturated five- to ten-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated five- to ten-membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to ten-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by one to four R3s, wherein R3 is selected from hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro-substituted propyl, fluoro-substituted isopropyl, chloro-substituted methyl, chloro-substituted ethyl, chloro-substituted propyl, chloro-substituted isopropyl, bromo-substituted methyl, bromo-substituted ethyl, bromo-substituted propyl, and bromo-substituted isopropyl. Preferably, the C-ring moiety is selected from substituted or unsubstituted saturated or unsaturated four- to eight-membered cycloalkyl groups, or substituted or unsubstituted C6-C groups. 10 The aryl, substituted or unsubstituted saturated or unsaturated four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, or substituted or unsubstituted four- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by 1 to 4 R4s, wherein the R4s are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and C3-C6 cycloalkyl; More preferably, the C-ring portion is selected from substituted or unsubstituted saturated or unsaturated four- to six-membered cycloalkyl groups, substituted or unsubstituted saturated or unsaturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, or substituted or unsubstituted four- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S, wherein "substituted" means that the group is substituted by one to four R4s, wherein the R4s are selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro-substituted propyl, fluoro-substituted isopropyl, chloro-substituted methyl, chloro-substituted ethyl, chloro-substituted propyl, chloro-substituted isopropyl, bromo-substituted methyl, bromo-substituted ethyl, bromo-substituted propyl, bromo-substituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. More preferably, the C-ring portion is selected from Where n1 is an integer from 0 to 4, preferably n1 is 0, 1, 2, 3 or 4, and R4 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluorinated methyl, fluorinated ethyl, fluorinated propyl, fluorinated isopropyl, chlorosubstituted methyl, chlorosubstituted ethyl, chlorosubstituted propyl, chlorosubstituted isopropyl, bromosubstituted methyl, bromosubstituted ethyl, bromosubstituted propyl, bromosubstituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R1 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl; Preferably, R2 is selected from hydrogen, deuterium, hydroxyl, amino, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl; Preferably, W is selected from -CH2-, -O-, (carbonyl), -N(R) a )-, where R a Selected from H, C1-C4 alkyl groups; More preferably, W is (Carbonyl group).

3. The compound represented by formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug, characterized in that, The compound is represented by either formula (II) or formula (III): The definitions of the B ring portion, the C ring portion, R1, and R2 are the same as those in formula (I) of claim 1 or 2, or their preferred definitions; X is independently selected from N and CH; Y is independently selected from N, NH, CH2, O, S, Se, NR b ;R b H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, tert-butyloxycarbonyl, and tri- to octyl heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; Z is independently selected from N, CH, and CR. c ;R c H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl groups, and tri- to octyl heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S.

4. The compound represented by formula (I) according to claim 3, or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug, characterized in that, Preferably, Y is independently selected from N, NH, CH2, and NR. b ;R b H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C6-C 10 Aryl, tert-butyloxycarbonyl, and four- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; More preferably, Y is independently selected from N, NH, CH2, NR b ;R b It is H, C1-C4 alkyl, or tert-butoxycarbonyl; Preferably, Z is independently selected from N, CH, and CR. c ;R c H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl groups, and four- to six-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S; More preferably, Z is independently selected from N and CH.

5. The compound represented by formula (I) according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated derivative, or prodrug selected from the following structures:

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), (II) or (III) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated product or prodrug thereof, and a pharmaceutically acceptable carrier.

7. The use of a compound represented by formula (I), formula (II) or formula (III) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated product or prodrug thereof, in the preparation of a PAK4 inhibitor, or in the preparation of a medicament for the prevention and / or treatment of PAK4-mediated diseases.

8. The use according to claim 7, characterized in that, The diseases associated with PAK4 are selected from acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, prostate cancer, and liver cancer, as well as neurodegenerative diseases such as Alzheimer's disease.

9. A method for preventing and / or treating PAK4-mediated diseases, the method comprising administering to a subject in need an effective amount of a compound represented by formula (I), (II) or (III) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, hydrate, deuterated product or prodrug thereon, or a pharmaceutical composition according to claim 6.

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