TW202246263A - Hpk1 kinase inhibitor compounds - Google Patents

Hpk1 kinase inhibitor compounds Download PDF

Info

Publication number
TW202246263A
TW202246263A TW111110674A TW111110674A TW202246263A TW 202246263 A TW202246263 A TW 202246263A TW 111110674 A TW111110674 A TW 111110674A TW 111110674 A TW111110674 A TW 111110674A TW 202246263 A TW202246263 A TW 202246263A
Authority
TW
Taiwan
Prior art keywords
alkyl
compound
pharmaceutically acceptable
alkylene
halogen
Prior art date
Application number
TW111110674A
Other languages
Chinese (zh)
Inventor
陳宇鋒
呂萌
楊寒
程萬里
武朋
劉燦豐
陳凱旋
王友平
何南海
Original Assignee
大陸商杭州阿諾生物醫藥科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大陸商杭州阿諾生物醫藥科技有限公司 filed Critical 大陸商杭州阿諾生物醫藥科技有限公司
Publication of TW202246263A publication Critical patent/TW202246263A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a compound of formula (I) having the activity of inhibiting HPK1 kinase and a pharmaceutical composition comprising the compound. The present invention also provides the use of the compound in the prevention and/or treatment of cancer, tumor, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

HPK1激酶抑制劑化合物 HPK1 Kinase Inhibitor Compounds

本發明涉及一種雜環化合物，具體地涉及一種高活性的HPK1激酶抑制劑及其用途。 The invention relates to a heterocyclic compound, in particular to a highly active HPK1 kinase inhibitor and its application.

本申請要求於2021年3月23日提交到中國國家智慧財產權局的發明名稱為“HPK1激酶抑制劑化合物”的中國專利申請202110308954.9的優先權，其內容通過引用以整體併入本文。 This application claims the priority of the Chinese patent application 202110308954.9 with the invention title "HPK1 Kinase Inhibitor Compound" submitted to the China National Intellectual Property Office on March 23, 2021, the contents of which are incorporated herein by reference in its entirety.

HPK1是MAP4K家族的成員之一，主要在造血系統細胞中表達，並且充當T細胞增殖和信號傳導的細胞內負調節物。抗原刺激T細胞後促使胞漿中的接頭蛋白SLP-76被招募到脂膜TCR複合體上，為信號轉導相關激酶提供結合位點來實現TCR介導的信號傳遞而誘導T細胞啟動。在這一過程中HPK1被酪氨酸激酶Lck和Zap70磷酸化而啟動，參與調節T細胞受體蛋白相互作用。HPK1通過磷酸化接頭蛋白SLP-76的Ser376位點，使得SLP-76與支架蛋白14-3-3ε結合進而通過蛋白酶體被降解，而這一效應使得SLP-76與信號轉導相關激酶結合減少而阻斷了TCR信號轉導，繼而抑制T細胞啟動和增值。另一方面，HPK1還參與了調控樹突狀細胞(Dendritic Cells,DC)的成熟及啟動，特別是抑制了DC細胞中協助T細胞啟動相關蛋白如CD80，CD86及MHC複合物等的表達，進而影響DC調節T細胞啟動的作用；而活化的DC對腫瘤抗原的呈遞及DC和T細胞的相互協作是抗腫瘤免疫系統中最重要的環節之一。此外在腫瘤微 環境中存在大量免疫抑制性的分子如PGE2和TGF-β，這些因數介導的免疫抑制作用也與HPK1有重要聯繫。總體而言，特異性靶向抑制HPK1的小分子化合物可以改善T細胞功能，增強DC細胞功能，並同時逆轉腫瘤免疫抑制微環境，通過多途徑來發揮增強抗腫瘤免疫效應，從而實現抑制腫瘤生長的作用。然而，目前尚缺乏有效的HPK1激酶活性抑制劑。 HPK1, one of the members of the MAP4K family, is mainly expressed in cells of the hematopoietic system and acts as an intracellular negative regulator of T cell proliferation and signaling. After antigen stimulation of T cells, the adapter protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to achieve TCR-mediated signal transmission and induce T cell activation. In this process, HPK1 is activated by phosphorylation of tyrosine kinases Lck and Zap70, and participates in the regulation of T cell receptor protein interaction. HPK1 phosphorylates the Ser376 site of the adapter protein SLP-76, allowing SLP-76 to bind to the scaffold protein 14-3-3ε and then be degraded by the proteasome, and this effect reduces the binding of SLP-76 to signal transduction-related kinases And blocked TCR signal transduction, and then inhibited T cell initiation and proliferation. On the other hand, HPK1 is also involved in regulating the maturation and activation of dendritic cells (Dendritic Cells, DC), especially inhibiting the expression of proteins such as CD80, CD86 and MHC complexes in DC cells that assist T cell activation, and then Influencing the role of DC in regulating the initiation of T cells; and the presentation of activated DC to tumor antigens and the mutual cooperation between DC and T cells are one of the most important links in the anti-tumor immune system. In addition, in tumor micro There are a large number of immunosuppressive molecules such as PGE2 and TGF-β in the environment, and the immunosuppressive effects mediated by these factors are also closely related to HPK1. In general, small molecular compounds that specifically target and inhibit HPK1 can improve T cell function, enhance DC cell function, and reverse the tumor immunosuppressive microenvironment at the same time, and enhance the anti-tumor immune effect through multiple channels, so as to inhibit tumor growth role. However, there is still a lack of effective inhibitors of HPK1 kinase activity.

因此，現有技術中仍迫切需要有效的HPK1激酶活性抑制劑，以便為抗腫瘤提供更多有效的選擇。 Therefore, there is still an urgent need for effective HPK1 kinase activity inhibitors in the prior art, so as to provide more effective options for anti-tumor.

本發明意外發現了一種具有抑制HPK1激酶活性的式(I)化合物以及其藥學上可接受的鹽、同位素衍生物或立體異構體。因此，在第一個方面，本發明提供了具有式(I)結構的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體： The present invention unexpectedly discovers a compound of formula (I) and its pharmaceutically acceptable salt, isotope derivative or stereoisomer having the activity of inhibiting HPK1 kinase. Therefore, in a first aspect, the present invention provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer:

Figure 111110674-A0202-12-0002-3
其中R1表示氫、(C1-C6)烷基或(C3-C8)環烷基；R2表示氫、(C1-C6)烷基、鹵素、氰基、-ORa或(C1-C6)鹵代烷基；R3表示氫、鹵素、-ORa、(C1-C6)烷基、(C1-C6)鹵代烷基、羥基(C1-C6)烷基、(C2-C6)烯基、-(C0-C6亞烷基)(C3-C8)環烷基、-(C0-C6亞烷基)(4-8元)雜環烷基、-(C0-C6亞烷基)(C3-C8)環烷基氧基、-(C0-C6亞烷基)(4-8 元)雜環烷基氧基；A表示
Figure 111110674-A0202-12-0003-4
、
Figure 111110674-A0202-12-0003-5
、
Figure 111110674-A0202-12-0003-6
、、
Figure 111110674-A0202-12-0003-7
、
Figure 111110674-A0202-12-0002-3
 Wherein R 1 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl; R 2 represents hydrogen, (C 1 -C 6 ) alkyl, halogen, cyano, -OR a Or (C 1 -C 6 ) haloalkyl; R 3 represents hydrogen, halogen, -OR a , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, hydroxyl (C 1 -C 6 ) Alkyl, (C 2 -C 6 )alkenyl, -(C 0 -C 6 alkylene)(C 3 -C 8 )cycloalkyl, -(C 0 -C 6 alkylene)(4-8 Member) heterocycloalkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 ) cycloalkyloxy, -(C 0 -C 6 alkylene) (4-8 member) heterocycle Alkyloxy; A means
Figure 111110674-A0202-12-0003-4
,
Figure 111110674-A0202-12-0003-5
,
Figure 111110674-A0202-12-0003-6
,,
Figure 111110674-A0202-12-0003-7
,

Figure 111110674-A0202-12-0003-8
B表示-(C0-C6)亞烷基-、-O-(C1-C6)烷基-、-S-(C1-C6)烷基-、-S(O)-(C1-C6)烷基-；R4和R4’各自獨立地表示氫、(C1-C6)烷基、(C2-C6)烯基或鹵素；或者R4與R4’一起和與之相連的碳原子形成3-6元環，該環中還可以任意地含有0、1或2個選自N、O、S的雜原子；R5表示氫、C1-C6烷基、鹵代(C1-C6)烷基、(C3-C6)烯基、(C3-C8)環烷基、鹵代(C3-C8)環烷基、(4-8元)雜環烷基、鹵代(4-8元)雜環烷基、-(C0-C6)亞烷基-ORa、-(C0-C6)亞烷基-COORa或者-(C0-C6)亞烷基-C(O)NRaRa’；；R6和R6’各自獨立地表示氫、C1-C6烷基、(C1-C6)鹵代烷基、(C2-C6)烯基、鹵素或-(C0-C6)亞烷基-ORa；
Figure 111110674-A0202-12-0003-8
 B represents -(C 0 -C 6 )alkylene-, -O-(C 1 -C 6 )alkyl-, -S-(C 1 -C 6 )alkyl-, -S(O)-( C 1 -C 6 ) alkyl-; R 4 and R 4 ' each independently represent hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or halogen; or R 4 and R 4 ' to form a 3-6-membered ring together with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, S; R 5 represents hydrogen, C 1 -C 6 alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkyl, (4-8 membered) heterocycloalkyl, halogenated (4-8 membered) heterocycloalkyl, -(C 0 -C 6 )alkylene-OR a , -(C 0 -C 6 )alkylene -COOR a or -(C 0 -C 6 )alkylene-C(O)NR a R a ';; R 6 and R 6' each independently represent hydrogen, C 1 -C 6 alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, halogen or -(C 0 -C 6 )alkylene-OR a ;

或者R6與R6’一起和與之相連的碳原子形成3-6元環，該環中還可以任意地含有0、1或2個選自N、O、S的雜原子；X1表示N或者CR7；其中R7表示氫、鹵素、(C1-C6)烷基、(C1-C6)鹵代烷基、(C2-C6)烯基、-(C0-C6亞烷基)(C3-C8)環烷基、-(C0-C6亞烷基)(4-10元)雜環烷基、-(C0-C6亞烷基)(C6-C10)芳基、-(C0-C6亞烷基)(5-10)元雜芳基，或者，當X1表示CR7時，R7可以與相鄰的R3一起形成(5-10元)環烷基或者(5-10元)雜環烷基，其任選地被鹵素取代；RM和RN各自獨立地表示氫、(C1-C6)烷基、(C1-C6)鹵代烷基，或者 RM和RN一起和與之相連的碳原子環合成3-6元環，該環中還可以任意地含有0、1或2個選自O、N、S的雜原子，其任選地被鹵素取代；進一步地，該環還可以任意地被0、1或2個選自鹵素、ORa的取代基所取代；且RM和RN不同時為氫；其中Ra，Rb表示氫或(C1-C6)烷基；m、n表示0、1、2、3。 Or R 6 and R 6' form a 3-6-membered ring together with the carbon atom connected to it, and the ring can also optionally contain 0, 1 or 2 heteroatoms selected from N, O, and S; X 1 represents N or CR 7 ; where R 7 represents hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, -(C 0 -C 6 Alkylene) (C 3 -C 8 ) cycloalkyl, -(C 0 -C 6 alkylene) (4-10 member) heterocycloalkyl, -(C 0 -C 6 alkylene) (C 6 -C 10 )aryl, -(C 0 -C 6 alkylene)(5-10) membered heteroaryl, or, when X 1 represents CR 7 , R 7 can form together with adjacent R 3 (5-10 membered) cycloalkyl or (5-10 membered) heterocycloalkyl, which is optionally substituted by halogen; R M and R N each independently represent hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, or R M and R N together form a 3-6-membered ring with the carbon atom ring connected to it, and the ring can optionally contain 0, 1 or 2 members selected from O, Heteroatoms of N and S, which are optionally substituted by halogen; further, the ring can be optionally substituted by 0, 1 or 2 substituents selected from halogen, OR a ; and R M and R N are different When it is hydrogen; wherein R a and R b represent hydrogen or (C 1 -C 6 ) alkyl; m, n represent 0, 1, 2, 3.

在本發明的優選技術方案中，A表示

Figure 111110674-A0202-12-0004-75
，其中Ra表示氫或(C1-C6)烷基。在本發明的優選技術方案中，R1表示(C1-C6)烷基。在本發明的優選技術方案中，R2表示氫、鹵素或(C1-C6)烷基或者鹵代(C1-C6)烷基。在本發明的優選技術方案中，X1表示N或者CH。 In the preferred technical solution of the present invention, A represents
Figure 111110674-A0202-12-0004-75
, wherein R a represents hydrogen or (C 1 -C 6 ) alkyl. In a preferred technical solution of the present invention, R 1 represents (C 1 -C 6 ) alkyl. In a preferred technical solution of the present invention, R 2 represents hydrogen, halogen or (C 1 -C 6 ) alkyl or halogenated (C 1 -C 6 ) alkyl. In a preferred technical solution of the present invention, X1 represents N or CH.

在本發明的優選技術方案中，R3表示-ORa、(C1-C6)烷基或者(C3-C8)環烷基。在本發明的優選技術方案中，R4和R4’各自獨立地表示氫。在本發明的優選技術方案中，R5表示氫、(C1-C6)烷基或者(C3-C8)環烷基。在本發明的優選技術方案中，R6和R6’各自獨立地表示氫、鹵素、(C1-C6)烷基或者(C1-C6)鹵代烷基。 In a preferred technical solution of the present invention, R 3 represents -OR a , (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl. In a preferred technical solution of the present invention, R 4 and R 4' each independently represent hydrogen. In a preferred technical solution of the present invention, R 5 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl. In a preferred technical solution of the present invention, R 6 and R 6' each independently represent hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl.

在本發明的優選技術方案中，R7表示氫、鹵素、(C1-C6)烷基、(C1-C6)鹵代烷基、-(C0-C6亞烷基)(C3-C8)環烷基或者-(C0-C6亞烷基)(4-10元)雜環烷基。在本發明的優選技術方案中，m表示1或2。在本發明的優選技術方案中，n表示1或2。在本發明的優選技術方案中，m表示1，n表示2。 In the preferred technical solution of the present invention, R 7 represents hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 )cycloalkyl or -(C 0 -C 6 alkylene)(4-10 membered)heterocycloalkyl. In the preferred technical solution of the present invention, m represents 1 or 2. In the preferred technical solution of the present invention, n represents 1 or 2. In the preferred technical solution of the present invention, m represents 1, and n represents 2.

特別優選地，本發明提供了如下具體化合物： Particularly preferably, the present invention provides the following specific compounds:

Figure 111110674-A0202-12-0004-9
Figure 111110674-A0202-12-0004-9

Figure 111110674-A0202-12-0005-10
Figure 111110674-A0202-12-0005-10

Figure 111110674-A0202-12-0006-11
Figure 111110674-A0202-12-0006-11

Figure 111110674-A0202-12-0007-80
Figure 111110674-A0202-12-0007-80

Figure 111110674-A0202-12-0008-13
Figure 111110674-A0202-12-0008-13

Figure 111110674-A0202-12-0009-14
Figure 111110674-A0202-12-0009-14

Figure 111110674-A0202-12-0010-15
Figure 111110674-A0202-12-0010-15

Figure 111110674-A0202-12-0011-16
Figure 111110674-A0202-12-0011-16

在另一方面，本發明還提供了一種藥物組合物，其包含本發明所述的化合物以及藥學上可用的載體。 In another aspect, the present invention also provides a pharmaceutical composition, which comprises the compound described in the present invention and a pharmaceutically acceptable carrier.

在又一方面，本發明還提供了一種本發明的化合物或者藥物組合物在製備用於預防和/或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病或免疫介導性疾病的藥物中的用途。 In yet another aspect, the present invention also provides a compound or pharmaceutical composition of the present invention in the preparation of drugs for the prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases use.

特別注意的是，在本文中，當提及具有特定結構式的“化合物”時，一般地還涵蓋其立體異構體、非對映異構體、對映異構體、外消旋混合物和同位素衍生物。 It is particularly noted that, herein, when referring to a "compound" having a specific structural formula, it generally also covers its stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives.

本領域技術人員公知，一種化合物的鹽、溶劑合物、水合物是化合物的替代性存在形式，它們都可以在一定條件下轉化為所述化合物，因此，特別注意的是在本文中當提到一種化合物時，一般地還包括它的可藥用鹽，進而還包括其溶劑合物和水合物。 It is well known to those skilled in the art that a compound's salt, solvate, and hydrate are alternative forms of the compound, and they can all be converted into the compound under certain conditions. A compound generally includes its pharmaceutically acceptable salt, and further includes its solvate and hydrate.

相似地，在本文中當提到一種化合物時，一般地還包括其前藥、代謝產物和氮氧化物。 Similarly, when referring to a compound herein, its prodrugs, metabolites and nitroxides are also generally included.

本發明所述的可藥用鹽可使用例如以下的無機酸或有機酸而形成：“可藥用鹽”是指這樣的鹽，在合理的醫學判斷範圍內，其適用於接觸人和較低等動物的組織，而沒有不適當的毒性、刺激性、過敏反應等，稱得上合理的受益/風險比。可以在本發明化合物的最終分離和純化期間原位製備所述鹽，或單獨通過將游離堿或游離酸與合適的試劑反應製備所述鹽，如下概述。例如，游離堿官能團可以與合適的酸反應。此外，當本發明的化合物帶有酸性部分時，其合適的可藥用鹽可包括金屬鹽，例如鹼金屬鹽(如鈉鹽或鉀鹽)；和鹼土金 屬鹽(如鈣鹽或鎂鹽)。可藥用的無毒酸加成鹽的示例是氨基與無機酸(例如，鹽酸、氫溴酸、磷酸、硫酸和高氯酸)或有機酸(例如，醋酸、草酸、馬來酸、酒石酸、檸檬酸、琥珀酸或丙二酸)形成的鹽，或通過使用現有技術中的其他方法如離子交換形成的鹽。其他可藥用鹽包括己二酸鹽、海藻酸鈉、抗壞血酸鹽、天門冬氨酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡萄糖酸鹽、hernisulfate、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、撲酸鹽、果膠酸鹽、過硫酸鹽、3-苯丙酸鹽、磷酸鹽、苦味鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一酸鹽、戊酸鹽等。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽等。其他可藥用鹽包括(適當時)無毒銨鹽、季銨鹽和用反離子形成的銨陽離子，例如，鹵化物、氫氧化物、羧酸鹽、硫酸鹽、磷酸鹽、硝酸鹽、低級烷基磺酸鹽和芳基磺酸鹽。 The pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids: "Pharmaceutically acceptable salt" means a salt which, within the scope of reasonable medical judgment, is suitable for use in contact with humans and lower Such animal tissues, without undue toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free alkali or free acid with a suitable reagent, as outlined below. For example, free alkali functional groups can be reacted with a suitable acid. In addition, when the compound of the present invention bears an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (such as sodium or potassium salts); and alkaline earth metal salts; Salts (such as calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, lemon 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, sodium alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphor Sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate salt, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, Persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonic acid salt, undecanoate, pentanoate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkanes sulfonates and aryl sulfonates.

本發明的可藥用鹽可通過常規方法製備，例如通過將本發明的化合物溶解於與水可混溶的有機溶劑(例如丙酮、甲醇、乙醇和乙腈)，向其中添加過量的有機酸或無機酸水溶液，以使得鹽從所得混合物中沉澱，從中除去溶劑和剩餘的游離酸，然後分離所沉澱的鹽。 The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (such as acetone, methanol, ethanol and acetonitrile), adding an excess of organic acid or inorganic Aqueous acid solution, so that the salt is precipitated from the resulting mixture, the solvent and remaining free acid are removed therefrom, and the precipitated salt is isolated.

本發明所述的前體或代謝物可以是本領域公知的前體或代謝物，只要所述的前體或代謝物可通過體內代謝轉化形成目標化合物即可。例如“前藥”是指本發明化合物的那些前藥，在合理的醫學判斷範圍內，其適用於接觸人和更低等動物的組織，而沒有不適當 的毒性、刺激性、過敏反應等，稱得上合理的受益/風險比並且對其預期用途有效。術語“前藥”是指在體內迅速經轉化產生上述式的母體化合物的化合物，例如通過在體內代謝，或本發明化合物的N-去甲基化。 The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as the precursors or metabolites can be transformed into target compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue Toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit/risk ratio and effective for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by in vivo metabolism, or N-demethylation of a compound of the invention.

本發明所述的“溶劑合物”意指本發明化合物與一個或多個溶劑分子(無論有機的還是無機的)的物理締合。該物理締合包括氫鍵。在某些情形中，例如當一個或多個溶劑分子納入結晶固體的晶格中時，溶劑化物將能夠被分離。溶劑化物中的溶劑分子可按規則排列和/或無序排列存在。溶劑合物可包含化學計量或非化學計量的溶劑分子。“溶劑合物”涵蓋溶液相和可分離的溶劑合物。示例性溶劑合物包括但不限於水合物、乙醇合物、甲醇合物和異丙醇合物。溶劑化方法是本領域公知的。 "Solvate" as used herein means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

本發明所述的“立體異構”分為構象異構和構型異構，構型異構還可分為順反異構和旋光異構(即光學異構)，構象異構是指具有一定構型的有機物分子由於碳、碳單鍵的旋轉或扭曲而使得分子各原子或原子團在空間產生不同的排列方式的一種立體異構現象，常見的有烷烴和環烷烴類化合物的結構，如環己烷結構中出現的椅式構象和船式構象。“立體異構體”是指當本發明化合物含有一個或多個不對稱中心，因而可作為外消旋體和外消旋混合物、單一對映異構體、非對映異構體混合物和單一非對映異構體。本發明化合物有不對稱中心，每個不對稱中心會產生兩個光學異構體，本發明的範圍包括所有可能的光學異構體和非對映異構體混合物和純的或部分純的化合物。本發明所述的化合物可以以互變異構體形式存在，其通過一個或多個雙鍵位移而具有不同的氫的連接點。例如，酮和它的烯醇形式是酮-烯醇互變異構體。各互變異構體及其混合物都包括在本發明的化合物中。所有式(I)化合物的對映異構體、非對映異構體、外消旋體、內消旋體、順反異構體、互變異構體、幾何異構體、差向異構體及其 混合物等，均包括在本發明範圍中。 "Stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), conformational isomerism refers to having A stereoisomerism phenomenon in which the atoms or atomic groups of molecules of a certain configuration are arranged in different ways in space due to the rotation or twisting of carbon and carbon single bonds. The common structures are alkane and cycloalkane compounds, such as The chair and boat conformations that occur in the cyclohexane structure. "Stereoisomer" means when a compound of the present invention contains one or more asymmetric centers and is thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single Diastereomers. The compound of the present invention has an asymmetric center, and each asymmetric center can produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogens by displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereoisomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers of all compounds of formula (I) Body and its Mixtures and the like are included in the scope of the present invention.

本發明的“同位素衍生物”是指在本專利中化合物被同位素標記的分子。通常用作同位素標記的同位素是：氫同位素，2H和3H；碳同位素：11C、13C和14C；氯同位素：35Cl和37Cl；氟同位素：18F；碘同位素：123I和125I；氮同位素：13N和15N；氧同位素：15O,17O和18O和硫同位素35S。這些同位素標記化合物可以用來研究藥用分子在組織中的分佈情況。尤其是氘3H和碳13C，由於它們容易標記且方便檢測，運用更為廣泛。某些重同位素，比如重氫(2H)，的取代能增強代謝的穩定性，延長半衰期從而達到減少劑量的目而提供療效優勢的。同位素標記的化合物一般從已被標記的起始物開始，用已知的合成技術如同合成非同位素標記的化合物一樣來完成其合成。 The "isotopic derivatives" of the present invention refer to molecules that are labeled with isotopes of the compounds in this patent. Isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium 3 H and carbon 13 C are more widely used because of their easy labeling and convenient detection. The substitution of some heavy isotopes, such as deuterium ( 2 H), can enhance the stability of metabolism, prolong the half-life and thus achieve the purpose of reducing the dose and provide therapeutic advantages. Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.

本發明還提供了本發明化合物在製備用於預防和/或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病或免疫介導性疾病的藥物中的用途。 The present invention also provides the use of the compound of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.

此外，本發明提供了用於預防和/或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病、神經退行性疾病、注意力相關疾病或免疫介導性疾病的藥物組合物，其包含本發明化合物作為活性成分。 In addition, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the present invention compounds as active ingredients.

此外，本發明提供了一種用於預防和/或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病、神經退行性疾病、注意力相關疾病或免疫介導性疾病的方法，其包括向有此需要的哺乳動物施用本發明化合物。 In addition, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the A compound of the invention is administered to a mammal in need thereof.

炎症性疾病、自身免疫性疾病和免疫介導性疾病的代表性實例可包括但不限於，關節炎、類風濕性關節炎、脊柱關節炎、痛風性關節炎、骨關節炎、幼年型關節炎、其他關節炎性病症、狼瘡、系統性紅斑狼瘡(Systemic Lupus Erythematosus,SLE)、皮膚相關疾病、銀屑病、濕疹、皮炎、過敏性皮膚炎、疼痛、肺病、肺部炎症、 成人呼吸窘迫綜合征(Acute respiratory distress syndrome,ARDS)、肺結節病、慢性肺部炎症性疾病、慢性阻塞性肺病(Chronic Obstruction Pulmonary Disease,COPD)、心血管疾病、動脈粥樣硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注損傷、炎性腸病、克羅恩病、潰瘍性結腸炎、腸易激綜合征、哮喘、乾燥綜合征、自身免疫甲狀腺疾病、蕁麻疹(風疹)、多發性硬化、硬皮症、器官移植排斥、異種移植、特發性血小板減少性紫癜(Idiopathic thrombocytopenic purpura,ITP)、帕金森病、阿爾茲海默病、糖尿病相關疾病、炎症、***性疾病、過敏性鼻炎、過敏性支氣管炎、過敏性鼻竇炎、白血病、淋巴瘤、B細胞淋巴瘤、T細胞淋巴瘤、骨髓瘤、急性淋巴性白血病(Acute lymphocytic leukemia,ALL)、慢性淋巴性白血病(Chronic Lymphocytic Leukemia,CLL)、急性髓性白血病(Acute myeloid leukemia,AML)、慢性髓性白血病(Chronic Myeloid Leukemia,CML)、毛細胞白血病、何傑金氏病、非何傑金淋巴瘤、多發性骨髓瘤、骨髓增生異常綜合征(Myelodysplastic syndromes,MDS)、骨髓增生性腫瘤(Myeloproliferative Neoplasm,MPN)、彌漫性大B細胞淋巴瘤和濾泡性淋巴瘤。 Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other Arthritis Conditions, Lupus, Systemic Lupus Erythematosus (SLE), Skin Related Diseases, Psoriasis, Eczema, Dermatitis, Atopic Dermatitis, Pain, Lung Disease, Lung Inflammation, Adult respiratory distress syndrome (Acute respiratory distress syndrome, ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (Chronic Obstruction Pulmonary Disease, COPD), cardiovascular disease, atherosclerosis, myocardial infarction, Congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), Multiple sclerosis, scleroderma, organ transplant rejection, xenograft, Idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease , allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B cell lymphoma, T cell lymphoma, myeloma, acute lymphocytic leukemia (Acute lymphocytic leukemia, ALL), chronic lymphocytic leukemia ( Chronic Lymphocytic Leukemia (CLL), Acute myeloid leukemia (AML), Chronic Myeloid Leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple Myeloma, myelodysplastic syndromes (Myelodysplastic syndromes, MDS), myeloproliferative neoplasms (Myeloproliferative Neoplasm, MPN), diffuse large B-cell lymphoma and follicular lymphoma.

癌症或腫瘤的代表性實例可包括但不限於，皮膚癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、結腸癌、肺癌、骨癌、腦癌、神經細胞瘤、直腸癌、結腸癌、家族性腺瘤性息肉性癌、遺傳性非息肉性結直腸癌、食管癌、唇癌、喉癌、下嚥癌、舌癌、唾液腺癌、胃癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、卵巢癌、宮頸癌、子宮體癌、子宮內膜癌、絨毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒細胞白 血病(CML)、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(Diffuse Large B-cell Lymphoma,DLBCL)、肝細胞癌、膽囊癌、支氣管癌、小細胞肺癌、非小細胞肺癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、脈絡膜黑素瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤或漿細胞瘤。 Representative examples of cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer , colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophagus cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL ), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myeloid leukemia Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (Diffuse Large B-cell Lymphoma, DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, Multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma , Ewing sarcoma, or plasmacytoma.

當將本發明化合物或其可藥用鹽與另外的用於治療癌症或腫瘤的抗癌劑或免疫檢查點抑制劑組合施用時，本發明化合物或其可藥用鹽可提供增強的抗癌作用。 When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anticancer effects .

用於治療癌症或腫瘤的抗癌劑的代表性實例可包括但不限於細胞信號轉導抑制劑、苯丁酸氮芥、美法侖、環磷醯胺、異環磷醯胺、白消安、卡莫司汀、洛莫司汀、鏈脲佐菌素、順鉑、卡鉑、奧沙利鉑、達卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他濱、巰基嘌呤、氟達拉濱、長春堿、長春新堿、長春瑞濱、紫杉醇、多西紫杉醇、拓撲替康、伊立替康、依託泊苷、曲貝替定、更生黴素、多柔比星、表柔比星、道諾黴素、米托蒽醌、博來黴素、絲裂黴素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林類似物、甲地孕酮、強的松、***、甲潑尼龍、沙利度胺、干擾素α、亞葉酸鈣、西羅莫司、西羅莫司脂化物、依維莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、達拉菲尼、達可替尼、達努塞替、達沙替尼、多維替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依魯替尼、埃克替尼、伊馬替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、馬賽替尼、momelotinib、莫替沙尼、來那替尼、尼祿替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普納替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、盧梭利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、 tivantinib、替沃紮尼、托法替尼、曲美替尼、凡德他尼、維利帕尼、威羅菲尼、維莫德吉、volasertib、阿侖單抗、貝伐單抗、貝倫妥單抗維多汀、卡妥索單抗、西妥昔單抗、地諾單抗、吉妥珠單抗、伊匹單抗、尼妥珠單抗、奧法木單抗、帕尼單抗、利妥昔單抗、托西莫單抗、曲妥珠單抗、PI3K抑制劑、CSF1R抑制劑、A2A和/或A2B受體拮抗劑、IDO抑制劑、抗PD-1抗體、抗PD-L1抗體、LAG3抗體、TIM-3抗體及抗CTLA-4抗體或其任意組合。 Representative examples of anticancer agents useful in the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan , carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, Gemcitabine, mercaptopurine, fludarabine, vincristine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin Bixin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, Megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus ester, everolimus, alfatinib Ni, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib , dacomitinib, danucitinib, dasatinib, multivitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, Lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motezanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, Quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vimodegib, volasertib, alemtuzumab, bevacizumab, bevacizumab Rentuzumab vedotin, catumaxumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitum Monoclonal antibody, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and/or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti- PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody or any combination thereof.

當將本發明化合物或其可藥用鹽與另外的用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑組合施用時，本發明化合物或其可藥用鹽可提供增強的治療作用。 Compounds of the present invention, or pharmaceutically acceptable salts thereof, provide enhanced therapeutic effect.

用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑的代表性實例可包括但不限於，甾體藥物(例如，強的松、氫化波尼松、甲基氫化波尼松、可的松、羥基可的松、倍他米松、***等)、甲氨蝶呤、來氟米特、抗TNFα劑(例如，依那西普、英夫利昔單抗、阿達利單抗等)、鈣調神經磷酸酶抑制劑(例如，他克莫司、吡美莫司等)和抗組胺藥(例如，苯海拉明、羥嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，並且選自其中的至少一種治療劑可包含於本發明藥物組合物中。 Representative examples of therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases can include, but are not limited to, steroidal agents (e.g., prednisone, prednisone, prednisone, methylphenidate, Cortisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (eg, etanercept, infliximab, adalib monoclonal antibody, etc.), calcineurin inhibitors (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebazan Tin, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them can be included in the pharmaceutical composition of the present invention.

本發明的化合物或其可藥用鹽可作為活性成分通過口服或腸胃外施用，其有效量的範圍為在哺乳動物包括人(體重約70kg)的情況下0.1至2000mg/kg體重/天、優選1至1000mg/kg體重/天，並且每天以單次或4次分次劑量，或者遵循/不遵循預定時間施用。活性成分的劑量可根據多個相關因素(例如待治療物件的情況、疾病類型和嚴重性、施用速率和醫生意見)進行調整。在某些情況下，小於以上劑量的量可能是合適的。如果不引起有害的副作用則可使用大於以上劑量的量並且該量可以每天以分次劑量施用。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2000 mg/kg body weight/day in mammals including humans (about 70 kg in body weight), preferably 1 to 1000 mg/kg body weight/day and administered in single or 4 divided doses per day, or with or without a scheduled time. The dose of the active ingredient may be adjusted according to a number of relevant factors such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration and the opinion of the physician. In some cases, amounts less than the above dosages may be appropriate. Amounts greater than the above doses may be used if no deleterious side effects are caused and such amounts may be administered in divided doses daily.

除此之外，本發明還提供了一種預防和/或治療腫瘤、癌症、病毒感染、器官移植排斥、神經退行性疾病、注意力相關疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳動物施用本發明的化合物或本發明的藥物組合物。 In addition, the present invention also provides a method for preventing and/or treating tumors, cancers, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases or autoimmune diseases, which includes A mammal is administered a compound of the invention or a pharmaceutical composition of the invention.

可根據常規方法中的任何一種將本發明藥物組合物配製成用於口服施用或腸胃外施用(包括肌內、靜脈內和皮下途徑、瘤內注射)的劑型，例如片劑、顆粒、粉末、膠囊、糖漿、乳劑、微乳劑、溶液或混懸液。 The pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) according to any of conventional methods, such as tablets, granules, powders , capsules, syrups, emulsions, microemulsions, solutions or suspensions.

用於口服施用的本發明藥物組合物可通過將活性成分與例如以下的載體混合來製備：纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石、表面活性劑、助懸劑、乳化劑和稀釋劑。在本發明的注射組合物中採用的載體的實例是水、鹽溶液、葡萄糖溶液、葡萄糖樣溶液(glucose-like solution)、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性劑、助懸劑和乳化劑。 Pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with carriers such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, stearic acid, Magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier and diluent. Examples of carriers employed in the injectable compositions of the present invention are water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, Fatty acids, fatty acid esters, glycerides, surfactants, suspending and emulsifying agents.

本發明描述示例性實施方案的過程中，本發明的其它特徵將變得顯而易見，給出所述實施方案用於說明本發明而不意欲成為其限制，以下實施例使用本發明所公開的方法製備、分離和表徵。 Other features of the invention will become apparent in the course of the description of exemplary embodiments of the invention which are given to illustrate the invention and are not intended to be limiting thereof, the following examples were prepared using the methods disclosed in the invention , separation and characterization.

可以用有機合成領域的技術人員已知的多種方式來製備本發明的化合物，可使用下述方法以及有機合成化學領域中已知的合成方法或通過本領域技術人員所瞭解的其變化形式來合成本發明化合物。優選方法包括但不限於下文所述的這些。在適用於所使用試劑盒材料和適用於所實現轉變的溶劑或溶劑混合物中實施反應。有機合成領域的技術人員將理解，分子上存在的官能性與所提出的轉變一致。這有時需要加以判斷改變合成步驟的順序或原料以獲得期望的本發明化合物。 The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis and can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art Compounds of the invention. Preferred methods include, but are not limited to, those described below. Reactions are performed in solvents or solvent mixtures appropriate to the kit materials used and to the transformations effected. Those skilled in the art of organic synthesis will appreciate that the functionality present on the molecule is consistent with the proposed transitions. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.

術語 the term

如果無另外說明，用於本發明申請，包括說明書和申請專利範圍中的術語，定義如下。必須注意，在說明書和所附的申請專利範圍中書中，如果文中無另外清楚指示，單數形式“一個”包括複數意義。如果無另外說明，使用質譜、核磁、高效液相層析法(High Performance Liquid Chromatography,HPLC)、蛋白化學、生物化學、重組Deoxyribonucleic acid，脫氧核醣核酸(DNA)技術和藥理的常規方法。在本發明中，如果無另外說明，使用“或”或“和”指“和/或”。 Unless otherwise stated, the terms used in the application of the present invention, including the specification and scope of claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular form "a" and "an" include plural references unless the context clearly indicates otherwise. If not stated otherwise, conventional methods of mass spectrometry, nuclear magnetic resonance, High Performance Liquid Chromatography (HPLC), protein chemistry, biochemistry, recombinant Deoxyribonucleic acid, deoxyribonucleic acid (DNA) techniques and pharmacology are used. In the present invention, the use of "or" or "and" means "and/or" if not stated otherwise.

在說明書和申請專利範圍中，給定化學式或名稱應涵蓋所有立體和光學異構體及其中存在上述異構體的外消旋物。除非另外指明，否則所有手性(對映異構體和非對映異構體)和外消旋形式均在本發明範圍內。所述化合物中還可存在C=C雙鍵、C=N雙鍵、環系統等的許多幾何異構體，且所有上述穩定異構體均涵蓋於本發明內。本發明描述了本發明化合物的順式-和反式-(或E-和Z-)幾何異構體，且其可分離成異構體的混合物或分開的異構體形式。本發明化合物可以光學活性或外消旋形式加以分離。用於製備本發明化合物和其中製備的中間體的所有方法均視為本發明的部分。在製備對映異構體或非對映異構體產物時，其可通過常規方法(例如通過色譜或分段結晶)進行分離。取決於方法條件，以游離(中性)或鹽形式獲得本發明的終產物。這些終產物的游離形式和鹽均在本發明的範圍內。如果需要的話，則可將化合物的一種形式轉化成另一種形式。可將游離堿或酸轉化成鹽；可將鹽轉化成游離化合物或另一種鹽；可將本發明異構體化合物的混合物分離成單獨的異構體。本發明化合物、其游離形式和鹽可以多種互變異構體形式存在，其中氫原子轉置到分子的其它部分 上且由此分子的原子之間的化學鍵發生重排。應當理解的是，可存在的所有互變異構體形式均包括在本發明內。 In the specification and claims, a given chemical formula or name shall cover all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed within the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention and which may be isolated as a mixture of isomers or as separated isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All methods used to prepare the compounds of the invention and intermediates prepared therein are considered part of the invention. When preparing enantiomeric or diastereomeric products, they may be separated by customary methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. The free forms and salts of these end products are within the scope of the present invention. A compound can be converted from one form to another, if desired. Free alkali or an acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the invention can be separated into the individual isomers. The compounds of the present invention, their free forms and salts, may exist in various tautomeric forms in which the hydrogen atom is transposed to other parts of the molecule Rearrangement of the chemical bonds on and thus between the atoms of the molecule. It is to be understood that all tautomeric forms which may exist are included within the present invention.

除非另有定義，本發明的取代基的定義是各自獨立而非互相關聯的，例如對於取代基中Ra(或者Ra’)而言，其在不同的取代基的定義中是各自獨立的。具體而言，對於Ra(或者Ra’)在一種取代基中選擇一種定義時，並不意味著該Ra(或者Ra’)在其他取代基中都具有該相同的定義。更具體而言，例如(僅列舉非窮舉)對於NRaRa’中，當Ra(或者Ra’)的定義選自氫時，其並不意味著在-C(O)-NRaRa’中，Ra(或者Ra’)必然為氫。 Unless otherwise defined, the definitions of substituents in the present invention are independent and not interrelated, for example, for R a (or R a ') in the substituent, they are independent in the definitions of different substituents . Specifically, when one definition is selected for R a (or R a ') in one substituent, it does not mean that the R a (or R a ') has the same definition in other substituents. More specifically, for example (but not exhaustively) for NR a R a ', when the definition of R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR In a R a ', R a (or R a ') must be hydrogen.

除非另有定義，否則當取代基被標注為“任意取代的”時，所述取代基選自例如以下取代基，諸如烷基、環烷基、芳基、雜環基、鹵素、羥基、烷氧基、氧代、烷醯基、芳基氧基、烷醯基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基團(其中2個氨基取代基選自烷基、芳基或芳基烷基)、烷醯基氨基、芳醯基氨基、芳烷醯基氨基、取代的烷醯基氨基、取代的芳基氨基、取代的芳烷醯基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺醯基、芳基磺醯基、芳基烷基磺醯基、磺醯氨基例如-SO2NH2、取代的磺醯氨基、硝基、氰基、羧基、氨基甲醯基例如-CONH2、取代的氨基甲醯基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有兩個選自烷基、芳基或芳基烷基的取代基的情況、烷氧基羰基、芳基、取代的芳基、胍基、雜環基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、呱啶基、嗎啉基、呱嗪基、高呱嗪基等和取代的雜環基。 Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkane Oxygen, oxo, alkyloxy, aryloxy, alkyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (where 2 amino substituents selected from alkyl, aryl or arylalkyl), alkylamino, arylamino, aralkanylamino, substituted alkanylamino, substituted arylamino, substituted aralkanylamino , thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl Acyl, sulfonylamino such as -SO 2 NH 2 , substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH 2 , substituted carbamoyl such as -CONH alkyl, -CONH Aryl, -CONHarylalkyl or the case of nitrogen with two substituents selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, Heterocyclic groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazine and substituted heterocyclic groups.

本文使用的術語“烷基”或“亞烷基”意欲包括具有指定碳原子數的支鏈和直鏈飽和脂族烴基團。例如，“C1-C6烷基”表示具有1個至6個碳原子的烷基。烷基的實例包括但不限於甲基(Me)、 乙基(Et)、丙基(例如正丙基和異丙基)、丁基(例如正丁基、異丁基、叔丁基)和戊基(例如正戊基、異戊基、新戊基)。優選的烷基是C1-C6烷基。優選的亞烷基是C0-C6亞烷基或C1-C6亞烷基。 The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C 1 -C 6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), and Pentyl (eg n-pentyl, isopentyl, neopentyl). Preferred alkyl groups are C 1 -C 6 alkyl groups. Preferred alkylene is C 0 -C 6 alkylene or C 1 -C 6 alkylene.

術語“烯基”表示含一個或多個雙鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如，“C2-C6烯基”含有兩個至六個碳原子。烯基包括但不限於例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。優選的烯基是(C3-C6)烯基。 The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. A preferred alkenyl group is (C 3 -C 6 )alkenyl.

術語“炔基”表示含一個或多個三鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如，“C2-C6炔基”含有兩個至六個碳原子。代表性炔基包括但不限於例如乙炔基、1-丙炔基、1-丁炔基等。 The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, "C2 - C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

術語“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(例如正丙氧基和異丙氧基)和叔丁氧基。類似地，“烷基硫基”或“硫代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的烷基；例如甲基-S-和乙基-S-。優選的烷氧基是C1-C6烷氧基。 The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C 1 -C 6 alkoxy" (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; eg methyl-S- and ethyl-S-. Preferred alkoxy groups are C 1 -C 6 alkoxy groups.

術語“羰基”是指由碳和氧兩種原子通過雙鍵連接而成的有機官能團(C=O)。 The term "carbonyl" refers to an organic functional group (C=O) consisting of two atoms, carbon and oxygen, joined by a double bond.

術語“芳基”，單獨或作為較大部分諸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有總計5至12個環成員的單環、二環或三環的環系統，其中所述系統中的至少一個環為芳族的且其中所述系統中的每個環含有3至7個環成員。在本發明的某些實施方案中，“芳基”是指芳族環系統，其包括但不限於苯基、聯苯基、茚滿基、1-萘基、2-萘基和四氫萘基。術語“芳烷基”或“芳基烷基”是指連接至芳基環的烷基殘基。非限制性實例包括苄基、苯乙基等。稠合的芳基可在環烷基環或芳族環的合適位置上連接至另一基團。例從環系統中畫 出的虛線表明鍵可連接至任意合適的環原子。優選的芳基是C6-C10芳基。 The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 12 ring members , a bicyclic or tricyclic ring system, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Examples Dashed lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom. Preferred aryl groups are C 6 -C 10 aryl groups.

術語“環烷基”是指單環或二環的環狀烷基，優選具有3至8個環成員。單環的環狀烷基指C3-C8的環狀烷基，包括但不限於環丙基、環丁基、環戊基、環己基和降莰烷基。支化環烷基諸如1-甲基環丙基和2-甲基環丙基包括在“環烷基”的定義中。二環的環狀烷基包括橋環、螺環或融合環的環烷基。 The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members. Monocyclic cyclic alkyl refers to C 3 -C 8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro, or fused ring cycloalkyls.

術語“環烯基”是指單環或二環的環狀烯基，優選具有3至8個環成員。單環的環狀烯基指C3-C8的環狀烯基，包括但不限於環丙烯基、環丁烯基、環戊烯基、環己烯基和降莰烯基。支化環烯基諸如1-甲基環丙烯基和2-甲基環丙烯基包括在“環烯基”的定義中。二環的環狀烯基包括橋環、螺環或融合環的環狀烯基。 The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group, preferably having 3 to 8 ring members. Monocyclic cyclic alkenyl refers to C 3 -C 8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included within the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups.

“鹵代”或“鹵素”包括氟、氯、溴和碘。“鹵代烷基”意欲包括具有指定碳原子數且取代有1個或多個鹵素(優選1個、2個或3個鹵素)的支鏈和直鏈飽和脂族烴基團。鹵代烷基的實例包括但不限於氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。鹵代烷基的實例還包括意欲包括具有指定碳原子數(優選1至6個碳原子)且取代有1個或多個氟原子的支鏈和直鏈飽和脂族烴基團的“氟烷基”。 "Halo" or "halogen" includes fluoro, chloro, bromo and iodo. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with 1 or more halogens, preferably 1, 2 or 3 halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and Heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (preferably 1 to 6 carbon atoms) substituted with 1 or more fluorine atoms.

“鹵代烷氧基”或“鹵代烷基氧基”表示具有指定數量碳原子(優選1至6個碳原子)的經氧橋連接的如上文所定義的鹵代烷基。例如，“鹵代C1-C6烷氧基”意欲包括C1、C2、C3、C4、C5、C6鹵代烷氧基。鹵代烷氧基的實例包括但不限於三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。類似地，“鹵代烷基硫基”或“硫代鹵代烷氧基”表示具有指定數量碳原子(優選1至6個碳原子)的經硫橋連接的如上文所定義的鹵代烷基；例如三氟甲基-S-和五氟乙基-S-。 "Haloalkoxy" or "haloalkyloxy" denotes a haloalkyl group as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through an oxygen bridge. For example, "haloC 1 -C 6 alkoxy" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a haloalkyl group as defined above having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through a sulfur bridge; for example trifluoromethane -S- and pentafluoroethyl-S-.

本發明內容中，當提到一些取代基團時使用Cx1-Cx2 的表述，這表示所述取代基團中的碳原子數可以是x1至x2個。例如，C0-C8表示所述基團含有0、1、2、3、4、5、6、7或8個碳原子，C1-C8表示所述基團含有1、2、3、4、5、6、7或8個碳原子，C2-C8表示所述基團含有2、3、4、5、6、7或8個碳原子，C3-C8表示所述基團含有3、4、5、6、7或8個碳原子，C4-C8表示所述基團含有4、5、6、7或8個碳原子，C0-C6表示所述基團含有0、1、2、3、4、5或6個碳原子，C1-C6表示所述基團含有1、2、3、4、5或6個碳原子，C2-C6表示所述基團含有2、3、4、5或6個碳原子，C3-C6表示所述基團含有3、4、5或6個碳原子。 In the context of the present invention, the expression C x1 -C x2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2. For example, C 0 -C 8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 1 -C 8 means that the group contains 1, 2, 3 , 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 3 -C 8 means that the The group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C 4 -C 8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C 0 -C 6 means that the The group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C 1 -C 6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C 2 -C 6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C 3 -C 6 means that the group contains 3, 4, 5 or 6 carbon atoms.

本發明內容中，當提到環狀基團(例如芳基、雜芳基、環烷基和雜環烷基)時使用“x1-x2元環”的表述，這表示該基團的環原子數可以是x1至x2個。例如，所述3-12元環狀基團可以是3、4、5、6、7、8、9、10、11或12元環，其環原子數可以是3、4、5、6、7、8、9、10、11或12個；3-6元環表示該環狀基團可以是3、4、5或6元環，其環原子數可以是3、4、5或6個；3-8元環表示該環狀基團可以是3、4、5、6、7或8元環，其環原子數可以是3、4、5、6、7或8個；3-9元環表示該環狀基團可以是3、4、5、6、7、8或9元環，其環原子數可以是3、4、5、6、7、8或9個；4-7元環表示該環狀基團可以是4、5、6或7元環，其環原子數可以是4、5、6或7個；5-8元環表示該環狀基團可以是5、6、7或8元環，其環原子數可以是5、6、7或8個；5-12元環表示該環狀基團可以是5、6、7、8、9、10、11或12元環，其環原子數可以是5、6、7、8、9、10、11或12個；6-12元環表示該環狀基團可以是6、7、8、9、10、11或12元環，其環原子數可以是6、7、8、9、10、11或12個。所述環原子可以是碳原子或雜原子，例如選自N、O和S的雜原子。當所述環是雜環時，所述雜環可以含有1、2、3、4、5、6、7、8、9、10或更多個環雜原子，例如選自N、O和S的雜原子。 In the context of the present invention, when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the ring atoms of the group The number can be x1 to x2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6-membered ring means that the cyclic group can be 3, 4, 5 or 6-membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 A membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 A membered ring means that the cyclic group can be a 4, 5, 6 or 7-membered ring, and the number of ring atoms can be 4, 5, 6 or 7; a 5-8-membered ring means that the cyclic group can be 5, 6, 7 or 8-membered ring, the number of ring atoms can be 5, 6, 7 or 8; 5-12 membered ring means that the ring group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the ring group can be 6, 7, 8, 9, 10, 11- or 12-membered rings may have 6, 7, 8, 9, 10, 11 or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example selected from N, O and S. When the ring is heterocyclic, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S of heteroatoms.

本發明內容中，一個或更多個鹵素可以各自獨立地選自氟、氯、溴和碘。 In the context of the present invention, one or more halogens may be each independently selected from fluorine, chlorine, bromine and iodine.

術語“雜芳基”意指穩定的3元、4元、5元、6元、或7元芳香單環或芳香二環或7元、8元、9元、10元、11元、12元芳香多環雜環，其為完全不飽和的、部分不飽和的，且其含有碳原子和1個、2個、3個或4個獨立地選自N、O和S的雜原子；且包括任何以下多環基團，其中上文所定義的任意雜環與苯環稠合。氮和硫雜原子可任選地被氧化。氮原子為取代的或未取代的(即N或NR，其中R為H或如果被定義，則為另一取代基)。雜環可在得到穩定結構的任何雜原子或碳原子處連接至其側基。如果所得化合物是穩定的，則本文所述的雜環基可在碳或氮原子上被取代。雜環中的氮可任選地被季銨化。優選地，當雜環中S和O原子的總數超過1時，則這些雜原子彼此不相鄰。優選地，雜環中S和O原子的總數不大於1。當使用術語“雜環”時，其意欲包括雜芳基。芳雜基的實施例包括但不限於吖啶基、氮雜環丁基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並***基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH-哢唑基、哢啉基、色滿基、色烯基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃並[2,3-b]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑並吡啶基、假吲哚基(indolenyl)、二氫吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑並吡啶基、異噁唑基、異噁唑並吡啶基、亞甲基二氧基苯基、嗎啉基、二氮雜萘基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑並吡啶基、噁唑烷基、萘嵌間二氮雜苯基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、 吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑並吡啶基、吡唑基、噠嗪基、吡啶並噁唑基、吡啶並咪唑基、吡啶並噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑並吡啶基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫噸基、喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、二氫吲哚基、1H-吲唑基、苯並咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫-喹啉基、2,3-二氫-苯並呋喃基、色滿基、1,2,3,4-四氫-喹喔啉基和1,2,3,4-四氫-喹唑啉基。術語“雜芳基”還可以包括由上述所定義的“芳基”與單環“雜芳基”所形成的聯芳基結構，例如但不限於“-苯基聯吡啶基-”、“-苯基聯嘧啶基”、“-吡啶基聯苯基”、“-吡啶基聯嘧啶基-”、“-嘧啶基聯苯基-”；其中本發明還包括含有例如上述雜環的稠環和螺環化合物。 The term "heteroaryl" means a stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-, 8-, 9-, 10-, 11-, 12-membered Aromatic polycyclic heterocycles that are fully unsaturated, partially unsaturated, and contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include Any of the following polycyclic groups in which any heterocyclic ring as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzooxa Azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-oxazolyl, oxalinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolinyl, Indolazinyl, indolyl, 3H-indolyl, isatinoyl (isatinoyl), isobenzofuryl, isochromanyl, isoindazolyl, isodihydroindolyl, isoindolyl, iso Quinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, diazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperonyl, pteridinyl, Purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl , pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinine Cyclo, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2 ,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, Thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1, 3,4-Triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl , Benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-Dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "- "Phenyl bipyrimidyl", "-pyridyl biphenyl", "-pyridyl bipyrimidyl-", "-pyrimidyl biphenyl-"; wherein the present invention also includes condensed rings containing, for example, the above-mentioned heterocycles and Spiro compounds.

本文使用的術語“雜環烷基”指的是一個單環雜環烷基體系，或為一個二環雜環烷基體系，同時還包括螺雜環或橋雜環烷基。單環的雜環烷基指的是3-8元或4-8元、且至少含一個選自O、N、S、P的飽和或不飽和但不為芳香性的環狀烷基體系。二環雜環烷基體系指的是一個雜環烷基稠合到一個苯基、或一個環烷基、或一個環烯基、或一個雜環烷基、或一個雜芳基上。 As used herein, the term "heterocycloalkyl" refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycle or bridged heterocycloalkyl. Monocyclic heterocycloalkyl refers to a 3-8-membered or 4-8-membered, and contains at least one saturated or unsaturated but not aromatic cyclic alkyl system selected from O, N, S, and P. A bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl.

本文使用的術語“橋環烷基”指的是共用兩個或兩個以上碳原子的多環化合物。可分為二環橋環烴及多環橋環烴。前者由兩個脂環共用兩個以上碳原子所構成；後者是由三個以上的環組成的 橋環烴。 The term "bridged cycloalkyl" as used herein refers to polycyclic compounds sharing two or more carbon atoms. Can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is composed of more than three rings Bridged ring hydrocarbon.

本文使用的術語“螺環烷基”指的是單環之間共用一個碳原子(稱螺原子)的多環烴。 The term "spirocycloalkyl" as used herein refers to polycyclic hydrocarbons in which monocyclic rings share one carbon atom (called a spiro atom).

本文使用的術語“橋環雜基”指的是共用兩個或兩個以上碳原子的多環化合物，該環中至少含一個選自O、N、S原子。可分為二環橋環雜環及多環橋雜環。 The term "bridged ring heterogroup" used herein refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one atom selected from O, N, and S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

本文使用的術語“雜螺環基”指的是單環之間共用一個碳原子(稱螺原子)的多環烴，該環中至少含一個選自O、N、S原子。 The term "heterospirocyclyl" used herein refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between monocyclic rings, and the ring contains at least one atom selected from O, N, and S.

本文中所用的術語“取代”意指至少一個氫原子被非氫基團替代，條件是維持正常化合價且所述取代得到穩定的化合物。本文所用的環雙鍵為在兩個相鄰環原子之間形成的雙鍵(例如C=C、C=N或N=N)。 The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and that the substitution results in a stable compound. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (eg, C=C, C=N or N=N).

在本發明化合物上存在氮原子(例如胺)的情形下，可通過使用氧化劑(例如mCPBA和/或過氧化氫)進行處理來將這些氮原子轉化成N-氧化物以獲得本發明的其它化合物。因此，所顯示和要求保護的氮原子視為均涵蓋所顯示氮及其N-氧化物以獲得本發明衍生物。 Where nitrogen atoms (e.g. amines) are present on compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention . Accordingly, both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.

當任何變數在化合物的任何組成或式中出現一次以上時，其每次出現時的定義均獨立於其在其它每種情況下出現時的定義。因此，例如如果顯示基團取代有0-3個R，則所述基團可任選地取代有至多三個R基團，且在每次出現時R獨立地選自R的定義。此外，取代基和/或變數的組合僅在上述組合可產生穩定的化合物時才容許存在。 When any variable occurs more than one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each occurrence is independently selected from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

本文使用的術語“患者”是指通過本發明的方法進行治療的有機體。這類有機體優選包括但不限於哺乳動物(例如鼠類、猿/猴、馬、牛、豬、犬、貓等)且最優選是指人類。 The term "patient" as used herein refers to an organism being treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, murine, simian, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.

本文使用的術語“有效量”意指將會引起例如研究人員或臨床醫師所尋求的組織、系統、動物或人的生物學或醫學回應的藥物或藥劑(即本發明化合物)的量。此外，術語“治療有效量”意指這樣的量：與未接受上述量的相應受試者相比，所述量導致改善的治療、治癒、預防或減輕疾病、病症或副作用，或降低在疾病或病症的進展速度。有效量可以一個或多個給藥、施用或劑量給予且不意欲被特定的製劑或給藥途徑限制。該術語還包括在其範圍內的增強正常生理機能的有效量。 As used herein, the term "effective amount" means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response sought by, eg, a researcher or clinician in a tissue, system, animal or human. Furthermore, the term "therapeutically effective amount" means an amount which results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the or the rate of disease progression. An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.

本文使用的術語“治療”包括導致改善病症、疾病、障礙等的任何效果，例如減輕、減少、調節、改善或消除，或改善其症狀。 As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the symptoms thereof.

術語“藥用”在本文中用於指如下那些化合物、物質、組合物和/或劑型：在合理醫學判斷的範圍內，其適於與人類和動物的組織接觸使用而無過高毒性、刺激性、過敏反應和/或其它問題或併發症，並與合理的益處/風險比相稱。 The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms: within the scope of sound medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity, irritation sex, allergic reactions, and/or other problems or complications, commensurate with a reasonable benefit/risk ratio.

本文使用的短語“藥用載體”意指藥用物質、組合物或媒介物，諸如液體或固體填充劑、稀釋劑、賦形劑、製造助劑(例如潤滑劑、滑石、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸)或溶劑包囊物質，其涉及將主題化合物從一個器官或身體的部分攜帶或運送至另一個器官或身體的部分。每種載體在與製劑的其它成分相容和對患者無害的意義上必須是“可接受的”。 The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g. lubricant, talc, magnesium stearate, , calcium stearate, or zinc stearate, or stearic acid) or solvent-encapsulated substances involved in the carrying or transport of a subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

術語“藥物組合物”意指包含本發明化合物與至少一種其它藥用載體的組合物。“藥用載體”是指本領域中通常接受用於將生物活性劑遞送至動物(具體為哺乳動物)的介質，包括(即)佐劑、賦形劑或媒介物，諸如稀釋劑、防腐劑、填充劑、流動調控劑、崩解劑、潤濕劑、乳化劑、懸浮劑、增甜劑、矯味劑、芳香劑、抗細菌劑、抗真菌劑、潤滑劑和分散劑，這取決於給藥模式和劑型的性質。 The term "pharmaceutical composition" means a composition comprising a compound of the present invention together with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, including (ie) adjuvants, excipients or vehicles, such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the given The mode of administration and the nature of the dosage form.

特定藥學及醫學術語 Certain pharmaceutical and medical terms

術語“可接受的”，如本文所用，指一個處方組分或活性成分對一般治療目標的健康沒有過分的有害影響。 The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

術語“癌症”，如本文所用，指一種不能控制的細胞的異常生長，並且在某種條件下能夠轉移(傳播)。這種類型的癌症包括但不限於，實體腫瘤(如膀胱、腸、腦、胸、子宮、心臟、腎、肺、淋巴組織(淋巴瘤)、卵巢、胰腺或其它內分泌器官(如甲狀腺)、***、皮膚(黑色素瘤)或血液瘤(如非白血性白血病)。 The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood cancer (such as non-leukemic leukemia).

術語“聯合給藥”或其類似術語，如本文所用，指將幾種所選的治療藥物給一個病人用藥，以相同或不同的給藥方式在相同或不同的時間給藥。 The term "administration in combination" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration at the same or different times.

術語“增強”或“能增強”，如本文所用，指預期的結果能夠在效價或是持續時間方面都有增加或延長。因此，在增強藥物的治療效果方面，術語“能增強”指藥物在系統中有提高或延長效價或持續時間的能力。本文所用的“增效值”，指在理想的系統中，能夠最大限度地的增強另外一個治療藥物的能力。 The term "enhancing" or "capable of enhancing", as used herein, means that the desired result can be increased or prolonged, either in potency or duration. Thus, in relation to enhancing the therapeutic effect of a drug, the term "capable of potentiating" refers to the ability of the drug to increase or prolong its potency or duration in the system. As used herein, "potency value" refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.

術語“免疫性疾病”指對內源性或外源性抗原產生的不良或有害反應的疾病或症狀。結果通常會造成細胞的功能障礙、或因此而破壞並造成機能障礙、或破壞可能產生免疫症狀的器官或組織。 The term "immune disease" refers to a disease or condition of an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually dysfunction of the cells, or destruction thereof and dysfunction, or destruction of organs or tissues that may produce immune symptoms.

術語“試劑盒”與“產品包裝”是同義詞。 The terms "kit" and "product packaging" are synonymous.

術語“受試者”或“病人”包括哺乳動物和非哺乳動物。哺乳動物包括但不限於，哺乳類：人、非人靈長類如猩猩、猿及猴類；農業動物如牛、馬、山羊、綿羊、豬；家畜如兔、狗；實驗動物包括齧齒類，如大鼠、小鼠及豚鼠等。非哺乳類動物包括但不限於，鳥、魚等。在一優選例中，所選哺乳動物是人。 The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; domestic animals such as rabbits and dogs; experimental animals include rodents, such as Rats, mice and guinea pigs etc. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred embodiment, the selected mammal is a human.

術語“治療”、“治療過程”或“療法”如本文所用，包括 緩和、抑制或改善疾病的症狀或狀況；抑制併發症的產生；改善或預防潛在代謝綜合症；抑制疾病或症狀的產生，如控制疾病或情況的發展；減輕疾病或症狀；使疾病或症狀減退；減輕由疾病或症狀引起的併發症，或預防和/或治療由疾病或症狀引起的徵兆。 The term "treatment", "course of treatment" or "therapy" as used herein includes Alleviate, inhibit, or ameliorate the symptoms or condition of a disease; inhibit the development of complications; ameliorate or prevent underlying metabolic syndrome; inhibit the development of a disease or symptom, such as controlling the development of a disease or condition; alleviate a disease or symptom; cause a disease or symptom to subside ; Alleviate the complications caused by the disease or symptoms, or prevent and/or treat the symptoms caused by the diseases or symptoms.

如本文所用，某一化合物或藥物組合物，給藥後，可以使某一疾病、症狀或情況得到改善，尤指其嚴重度得到改善，延遲發病，減緩病情進展，或減少病情持續時間。無論固定給藥或臨時給藥、持續給藥或斷續給藥，可以歸因於或與給藥有關的情況。 As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

給藥途徑 Route of administration

適合的給藥途徑包括但不限於，口服、靜脈注射、直腸、氣霧劑、非腸道給藥、眼部給藥、肺部給藥、經皮給藥、***給藥、耳道給藥、鼻腔給藥及局部給藥。此外，僅作舉例說明，腸道外給藥，包括肌肉注射、皮下注射、靜脈注射、髓內注射、心室注射、腹膜內注射、***內注射、及鼻內注射。 Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration. In addition, by way of example only, parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

在一方面，此處描述的化合物給藥方式是局部的而不是全身性的給藥方式。在特定的具體實施例中，長效製劑通過植入給藥(例如皮下或肌肉)或通過肌肉注射。此外，在另一具體化實施例中，藥物通過靶向藥物給藥系統來給藥。例如，由器官特異性抗體包裹的脂質體。在這種具體實施例中，所述脂質體被選擇性的導向特定器官並吸收。 In one aspect, the compounds described herein are administered locally rather than systemically. In certain embodiments, the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Additionally, in another embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are selectively directed to and taken up by specific organs.

藥物組合物和劑量 Pharmaceutical Composition and Dosage

本發明還提供藥用組合物，其包含治療有效量的與一種或多種藥用載體(添加劑)和/或稀釋劑一起配製的一種或多種本發明的化合物，和任選的一種或多種上述其它治療劑。可通過任意合適方式給予本發明化合物以用於任意上述用途，例如口服，諸如片劑、丸劑、粉劑、顆粒劑、酏劑、酊劑、懸浮液(包括奈米懸浮液、微懸浮液、噴霧乾燥的分散液)、糖漿和乳液；經舌下；含服；經腸胃外，諸如通過皮 下、靜脈內、肌內或胸骨內注射或輸注技術(例如以無菌可注射水性或非水性溶液或懸浮液形式)；經鼻，包括向鼻膜給藥，諸如通過吸入噴霧；局部，諸如以乳膏劑或軟膏劑形式；或經直腸，諸如以栓劑形式；或經瘤內注射。它們可單獨給藥，但通常使用基於所選給藥途徑和標準藥學實踐選擇的藥物載體給藥。 The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more of the above-mentioned other therapeutic agent. The compounds of the invention may be administered for any of the above uses by any suitable means, e.g. orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as through the skin Intravenous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g. in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as with In the form of a cream or ointment; or rectally, such as in suppository form; or by intratumoral injection. They can be administered alone, but generally will be administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

根據本領域技術人員認識範圍內的諸多因素來調配藥用載體。這些因素包括，但不限於：所調配活性劑的類型和性質；含有活性劑的組合物所要給藥的受試者；組合物的預期給藥途徑；及所靶向的治療適應症。藥用載體包括水性和非水性液體介質及各種固體和半固體劑型。 Pharmaceutical carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

上述載體可包括除活性劑外的諸多不同成分和添加劑，上述其它成分出於本領域技術人員公知的各種原因包括於製劑中，例如穩定活性劑、黏合劑等。關於合適的藥用載體和載體選擇中所涉及的因素的描述可參見多個容易獲得的來源，例如Allen L.V.Jr.et al.Remington：The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。 Such carriers may include many different ingredients and additives other than the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, and the like. A description of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.

當然，本發明化合物的劑量方案取決於已知因素而有所變化，諸如具體藥劑的藥效學特性及其給藥模式和途徑；接受者的物種、年齡、性別、健康狀況、醫學病狀和重量；症狀的性質和程度；同時治療的種類；治療頻率；給藥途徑、患者的腎和肝功能及期望效應。根據一般指導，當用於指定效應時，各活性成分的日口服劑量應為約0.001mg/天至約10-5000mg/天，優選地為約0.01mg/天至約1000mg/天，且最優選地為約0.1mg/天至約250mg/天。在恆速輸注期間，靜脈內最優選劑量應為約0.01mg/kg/分鐘至約10mg/kg/分鐘。本發明化合物可以單一日劑量給藥，或可以每日兩次、三次或四次的分開劑量給藥總日劑量。 Dosage regimens for the compounds of this invention will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the recipient's species, age, sex, health, medical condition and Weight; nature and extent of symptoms; type of concomitant therapy; frequency of treatment; route of administration, patient's renal and hepatic function, and desired effects. As a general guide, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably From about 0.1 mg/day to about 250 mg/day. The most preferred dose intravenously will be about 0.01 mg/kg/minute to about 10 mg/kg/minute during a constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

所述化合物通常以與根據預期給藥形式(例如口服 片劑、膠囊劑、酏劑和糖漿劑)適當地選擇且與常規藥學實踐相符合的合適藥物稀釋劑、賦形劑或載體(在本文中統稱為藥物載體)的混合物形式進行給藥。 The compounds are usually given in the form according to the intended administration (e.g. oral Tablets, capsules, elixirs and syrups) are suitably selected and are administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) consistent with conventional pharmaceutical practice.

適於給藥的劑型(藥物組合物)可含有約1毫克至約2000毫克活性成分/劑量單位。在這些醫藥組合物中，以組合物的總重量計，活性成分通常將以約0.1-95重量%的量存在。 Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

用於口服給藥的典型膠囊劑含有至少一種本發明化合物(250mg)、乳糖(75mg)和硬脂酸鎂(15mg)。使該混合物穿過60目網篩，並包裝成1號明膠膠囊。 A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packed into size 1 gelatin capsules.

典型的可注射製劑可如下製備：以無菌方式將至少一種本發明化合物(250mg)置於瓶中、以無菌方式凍乾並密封。為進行使用，將瓶內容物與2mL生理鹽水混合，以產生可注射製劑。 A typical injectable formulation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a vial, lyophilizing in a sterile manner and sealing. For use, the vial contents are mixed with 2 mL of normal saline to produce an injectable formulation.

本發明範圍包括(單獨或與藥物載體組合)包含治療有效量的至少一種本發明化合物作為活性成分的藥物組合物。任選地，本發明化合物可單獨使用、與本發明其它化合物組合使用或與一種或多種其它治療劑(例如抗癌劑或其它藥學活性物質)組合使用。 Included within the scope of the present invention are pharmaceutical compositions comprising (alone or in combination with a pharmaceutical carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

不考慮所選擇的給藥路徑，通過本領域技術人員已知的常規方法來將本發的化合物(其可以合適的水合形式使用)和/或本發明的藥物組合物配製成藥用劑量形式。 Irrespective of the chosen route of administration, the compounds of the invention (which may be used in suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art .

可改變活性成分在本發明的藥物組合物中的實際劑量水準，從而獲得對於實現特定患者的期望的治療回應、組成和給藥模式有效的而對患者無毒的活性成分量。 Actual dosage levels of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient without being toxic to the patient.

選定的劑量水準會取決於多種因素，包括所用的本發明的特定化合物或其酯、鹽或醯胺的活性；給藥路徑；給藥時間；所用的特定化合物的***速率；吸收速率和程度；治療的持續時間；與所用的特定化合物組合使用的其它藥物、化合物和/或物質；所治療的患者的年齡、性別、重量、狀況、一般健康和先前的醫學史等醫 學領域公知的因素。 The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption; Duration of treatment; other drugs, compounds, and/or substances used in combination with the particular compound used; age, sex, weight, condition, general health, and previous medical history of the patient being treated factors known in the scientific field.

具有本領域普通技術的醫生或獸醫可容易地確定並開出有效量的所需藥物組合物。例如，為了達到所期望的治療效果，醫師或獸醫可在低於所需的水準開始藥物組合物中所用的本發明化合物的較量，並逐步增加劑量直至實現所期望的效果。通常，合適日劑量的本發明化合物將是有效產生治療效果的最低劑量的化合物的量。此種有效劑量通常取決於上述因素。通常，口服、靜脈內、腦室內和皮下劑量的用於患者的本發明化合物的範圍為約0.01至約50mg/kg體重/天。如果需要的話，有效日劑量的活性化合物可以兩個、三個、四個、五個、六個或更多個亞劑量在一天當中的適當的間隔分別給藥，任選地呈單位劑型形式。在本發明的某些方面中，服藥為每天一次給藥。 A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be that amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors mentioned above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention to patients range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.

雖然本發明化合物可單獨給藥，但優選以藥物製劑(組合物)形式給予化合物。 Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical formulations (compositions).

試劑盒/產品包裝 Kit/Product Packaging

為了用於上述適應症的治療，試劑盒/產品包裝也在此進行描述。這些試劑盒可以由輸送器、藥包或容器盒組成，容器盒可被劃分成多格，以容納一種或多種容器，如管形瓶、試管及類似物等，每個容器中包含所述方法中的單獨一種成分。合適的容器包括瓶子，管形瓶，注射器和試管等。容器由可接受的玻璃或塑膠等材料製作而成。 Kits/product packaging are also described herein for use in the treatment of the above indications. These kits may consist of transporters, packs, or container boxes that may be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing the method a single component in . Suitable containers include bottles, vials, syringes, test tubes and the like. Containers are made of acceptable materials such as glass or plastic.

舉例來講，容器可裝有一種或多種在此所述的化合物，化合物可能以藥物組分形式存在，也可能與在本文中所述的其它成分組成混合物體存在。容器可有一個無菌輸出口(例如容器可為靜脈輸液包或瓶，瓶塞可被皮下注射器針頭刺破)。這樣的試劑盒可帶有一種化合物，及本文中所述的使用方法的說明、標籤或操作說明。 For example, a container may contain one or more compounds described herein, either as a pharmaceutical composition or in admixture with other ingredients described herein. The container can have a sterile outlet (eg, the container can be an IV bag or bottle, the stopper of which can be pierced by a hypodermic needle). Such a kit may contain a compound, and instructions for use, labels or instructions for use described herein.

一個典型的試劑盒可包括一種或多種容器，為適應商業推廣和使用者對化合物使用的需求，每個容器裝有一種或多種材 料(如試劑，也可以是濃縮的母液，和/或器械)。這些材料包括但不局限於緩衝液，稀釋液，濾器，針頭，注射器，輸送器，包，容器，瓶和/或試管，附有內容清單和/或使用說明書，內置包裝也附有說明書。整套的說明都要包括在內。 A typical kit may include one or more containers, each containing one or more Materials (such as reagents, which may also be concentrated stock solutions, and/or devices). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, transporters, bags, containers, bottles and/or test tubes, accompanied by a list of contents and/or instructions for use, and inner packaging also accompanied by instructions. Instructions for the entire set are to be included.

標籤可顯示在容器上或與容器緊密相關。標籤出現在容器上即指標籤字母、數位或其它特徵被黏貼、鑄模、刻在容器上；標籤也可出現在裝有多種容器的容器盒或運輸盒內，如在產品插頁中。一個標籤可用來提示內容物的某種特定治療用途。標籤也可標示內容物使用說明，諸如在上述方法中描述的。 Labels can be displayed on or closely associated with the container. The appearance of the label on the container means that the label letters, numbers or other features are pasted, molded, or engraved on the container; the label can also appear in the container box or shipping box containing various containers, such as in the product insert. A label may be used to indicate a specific therapeutic use of the contents. The label may also bear instructions for use of the contents, such as described in the methods above.

在本說明書中被描述的所有特徵(包括任何所述的請求項、摘要和圖)，和/或任何方法或過程中涉及的所有步驟，均有可能以任意一種組合存在，除非某些特徵或步驟在同一組合中是相互排斥的。 All features described in this specification (including any stated claims, abstracts and drawings), and/or all steps involved in any method or process, may exist in any combination, unless certain features or Steps are mutually exclusive in the same combination.

本發明提到的上述特徵，或實施例提到的特徵可以任意組合。本案說明書所揭示的所有特徵可與任何組合物形式並用，說明書中所揭示的各個特徵，可以任何可提供相同、均等或相似目的的替代性特徵取代。因此除有特別說明，所揭示的特徵僅為均等或相似特徵的一般性例子。 The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

下面結合具體實施例，進一步闡述本發明。應理解，這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未注明具體條件的實驗方法，通常按照常規條件或按照製造廠商所建議的條件。除非另外說明，否則所有的百分數、比率、比例、或份數按重量計。 Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

本發明中的重量體積百分比中的單位是本領域技術人員所熟知的，例如是指在100毫升的溶液中溶質的重量。除非另行定義，文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外，任何與所記載內容相似或均等的方法及材料皆可應 用於本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。 The unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of solute in 100 ml of solution. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials that are similar or equivalent to those described can be used used in the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

通用過程general process

未包括製備途徑時，本發明所用原料與試劑均為已知產品，可以按照本領域已知的方法合成，或者可通過購買市售產品獲得。使用的市售試劑均不需進一步純化。 When the preparation route is not included, the raw materials and reagents used in the present invention are known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. All commercially available reagents were used without further purification.

室溫是指20-30℃。 Room temperature means 20-30°C.

如反應實施例中無特殊說明，則反應均在氮氣氛下進行。氮氣氛是指反應瓶連接一個約1L的氮氣氣球。 Unless otherwise specified in the reaction examples, the reactions were all carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to a nitrogen balloon of about 1 L connected to the reaction flask.

氫化反應通常抽真空，充入氫氣，反復操作3次。氫氣氛是指反應瓶連接一個約1L的氫氣氣球。 The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere means that the reaction bottle is connected with a hydrogen balloon of about 1L.

微波反應使用Biotage® Initiator+微波反應器。 Microwave reaction using Biotage ® Initiator+ Microwave Reactor.

本發明化合物的結構是通過核磁共振(Nuclear Magnetic Resonance,NMR)和質譜(Mass Spectrometry,MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用(Bruker AscendTM 500型)核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，內標為四甲基矽烷(TMS)。以下簡寫用於NMR信號的多重性：s=單峰，brs=寬峰，d=二重峰，t=三重峰，m=多重峰。耦合常數以J值列出，以Hz測量。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (Nuclear Magnetic Resonance, NMR) and mass spectrometry (Mass Spectrometry, MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use (Bruker Ascend TM 500 type) NMR instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal Labeled as Tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.

LC-MS的測定使用Thermo液質聯用儀(UltiMate 3000+MSQ PLUS)。HPLC的測定使用Thermo高壓液相色譜儀(UltiMate 3000)。反相製備色譜使用Thermo(UltiMate 3000)反相製備色譜儀。快速柱層析使用艾傑爾(FS-9200T)自動過柱機，矽膠預裝柱使用三泰SEPAFLASH®預裝柱。薄層層析矽膠板用煙臺黃海HSGF254或青島GF254矽膠板，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The determination of LC-MS used Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS). For HPLC measurement, a Thermo high pressure liquid chromatograph (UltiMate 3000) was used. Reverse-phase preparative chromatography Thermo (UltiMate 3000) reverse-phase preparative chromatography was used. The flash column chromatography uses Agel (FS-9200T) automatic column passing machine, and the silica gel prepacked column uses Santai SEPAFLASH® prepacked column. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications of thin-layer chromatography separation and purification products are 0.4mm~0.5mm.

本發明中一些中間體的合成方法如下： The synthetic method of some intermediates in the present invention is as follows:

中間體1Intermediate 1

Figure 111110674-A0202-12-0035-17
Figure 111110674-A0202-12-0035-17

中間體1由以下步驟製備： Intermediate 1 was prepared by the following steps:

Figure 111110674-A0202-12-0035-18
Figure 111110674-A0202-12-0035-18

第一步：將1-甲基-3,5-二硝基吡啶-2-酮Int-1a(1.0g,5.02mmol)溶於甲醇(50mL)中，依次加入氨甲醇溶液(7mol/L，8.61mL,60.27mmol)和1-甲基呱啶-4-酮Int-1b(625mg,5.52mmol)。反應混合物加熱至50℃攪拌5小時。冷卻至室溫後靜置48小時，減壓濃縮反應液，殘餘物加入乙酸乙酯(50mL)後過濾。濾液減壓濃縮後得到紅色固體Int-1c(1.0g)，直接用於下一步反應。ESI-MS(m/z)：194.4[M+H]+；1H NMR(500MHz,DMSO-d 6)δ 9.14(d,J=2.5Hz,1H),8.36(d,J=2.5Hz,1H),3.64(s,2H),3.02(t,J=6.0Hz,2H),2.74(t,J=6.0Hz,2H),2.39(s,3H)。 Step 1: Dissolve 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0g, 5.02mmol) in methanol (50mL), add ammonia methanol solution (7mol/L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol). The reaction mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, it was allowed to stand for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain a red solid Int-1c (1.0 g), which was directly used in the next reaction. ESI-MS(m/z): 194.4[M+H] + ; 1 H NMR(500MHz,DMSO- d 6 )δ 9.14(d, J =2.5Hz,1H), 8.36(d, J =2.5Hz, 1H), 3.64(s, 2H), 3.02(t, J =6.0Hz, 2H), 2.74(t, J =6.0Hz, 2H), 2.39(s, 3H).

第二步：將上一步得到的化合物Int-1c(1.0g)溶於甲醇(30mL)中，加入10% Pd-C(400mg)，在氫氣氛圍下室溫反應6小時。過濾 除去鈀碳，濾液濃縮得到黃色固體Int-1d(800mg，收率94.70%)。ESI-MS(m/z)：164.2[M+H]+。 The second step: the compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), 10% Pd-C (400 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere for 6 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain a yellow solid Int-1d (800 mg, yield 94.70%). ESI-MS (m/z): 164.2 [M+H] + .

第三步：將化合物Int-1d(100mg,0.61mmol)溶於醋酸(3mL)中，加入N-溴代丁二醯亞胺(109mg,0.61mmol)，反應混合物在室溫下攪拌1小時。加入飽和碳酸氫鈉水溶液淬滅反應直至不產生氣泡，水相用甲醇/二氯甲烷(1/20,50mL×2)萃取，合併有機相，無水硫酸鈉乾燥，過濾濃縮得到化合物Int-1e(38mg，收率25%)。ESI-MS(m/z)：242.3[M+H]+；1H NMR(500MHz,DMSO-d 6)δ 6.77(s,1H),5.25(s,2H),3.37(s,2H),2.69(t,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.32(s,3H)。 Step 3: Compound Int-1d (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg, 0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-1e ( 38mg, yield 25%). ESI-MS (m/z): 242.3[M+H] + ; 1 H NMR (500MHz, DMSO- d 6 ) δ 6.77(s,1H),5.25(s,2H),3.37(s,2H), 2.69(t, J =6.0Hz, 2H), 2.60(t, J =6.0Hz, 2H), 2.32(s, 3H).

第四步：將化合物Int-1e(37mg,0.15mmol)溶於甲醇(1mL)中，加入碘化亞銅(3mg，0.015mmol)，1，10-菲囉啉(3mg，0.03mmol)和碳酸銫(99mg,0.30mmol)。反應混合物置換氮氣後用微波加熱至100℃攪拌2小時。反應冷卻至室溫，濃縮反應液，殘餘物用製備型薄層層析純化(甲醇/二氯甲烷/三乙胺=1/10/0.1)得到黃色固體Int-1(20mg，收率67%)。ESI-MS(m/z)：194.5[M+H]+；1H NMR(500MHz,DMSO-d 6)δ 6.54(s,1H),4.68(s,2H),3.80(s,3H),3.30(s,2H),2.64(t,J=5.6Hz,2H),2.59(t,J=5.7Hz,2H),2.31(s,3H)。 Step 4: Dissolve compound Int-1e (37mg, 0.15mmol) in methanol (1mL), add cuprous iodide (3mg, 0.015mmol), 1,10-phenanthroline (3mg, 0.03mmol) and carbonic acid Cesium (99 mg, 0.30 mmol). The reaction mixture was replaced with nitrogen and heated to 100° C. with microwave and stirred for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by preparative thin-layer chromatography (methanol/dichloromethane/triethylamine=1/10/0.1) to obtain a yellow solid Int-1 (20mg, yield 67% ). ESI-MS (m/z): 194.5[M+H] + ; 1 H NMR (500MHz, DMSO- d 6 )δ 6.54(s,1H),4.68(s,2H),3.80(s,3H), 3.30(s, 2H), 2.64(t, J =5.6Hz, 2H), 2.59(t, J =5.7Hz, 2H), 2.31(s, 3H).

中間體2Intermediate 2

Figure 111110674-A0202-12-0036-19
Figure 111110674-A0202-12-0036-19

中間體2由以下步驟製備： Intermediate 2 was prepared by the following steps:

Figure 111110674-A0202-12-0037-20
Figure 111110674-A0202-12-0037-20

第一步：將化合物Int-1e(230mg,0.94mmol)溶於乙醇(2mL)中，加入碘化亞銅(18mg,0.095mmol)，1，10-菲囉啉(34mg,0.18mmol)和碳酸銫(619mg,1.90mmol)。反應混合物置換氮氣後用微波加熱至100℃攪拌5小時。反應冷卻至室溫，過濾，濾液濃縮，殘餘物用矽膠柱層析純化(甲醇/二氯甲烷/三乙胺=1/50/0.1)得到黃色固體Int-2(113mg，收率57%)。ESI-MS(m/z)：208.5[M+H]+。 The first step: Dissolve compound Int-1e (230mg, 0.94mmol) in ethanol (2mL), add cuprous iodide (18mg, 0.095mmol), 1,10-phenanthroline (34mg, 0.18mmol) and carbonic acid Cesium (619 mg, 1.90 mmol). The reaction mixture was replaced with nitrogen and heated to 100° C. with microwave and stirred for 5 hours. The reaction was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane/triethylamine=1/50/0.1) to obtain a yellow solid Int-2 (113mg, yield 57%) . ESI-MS (m/z): 208.5 [M+H] + .

中間體3Intermediate 3

Figure 111110674-A0202-12-0037-21
Figure 111110674-A0202-12-0037-21

中間體3由以下步驟製備： Intermediate 3 was prepared by the following steps:

Figure 111110674-A0202-12-0037-22
Figure 111110674-A0202-12-0037-22

第一步：將化合物Int-1e(100mg，0.41mmol)和三甲基環三硼氧烷(148mg，1.19mmol)溶於二氧六環(1.5mL)和水(0.15mL)中，加入碳酸鉀(171mg，1.24mmol)，Pd(dppf)Cl2(30mg,0.041mmol)。反應體系置換氮氣後用微波加熱至140℃攪拌1小時。反應冷卻至室溫，反應混合物用矽藻土過濾，濾液濃縮。殘餘物用矽膠柱層析純化(甲醇/二氯甲烷=1/20)得到黃色固體Int-3(50mg，收率68%)。ESI-MS(m/z)：178.6[M+H]+。 The first step: Dissolve compound Int-1e (100mg, 0.41mmol) and trimethylboroxane (148mg, 1.19mmol) in dioxane (1.5mL) and water (0.15mL), add carbonic acid Potassium (171 mg, 1.24 mmol), Pd(dppf)Cl2 (30 mg , 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 140°C by microwave and stirred for 1 hour. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane=1/20) to obtain Int-3 (50 mg, yield 68%) as a yellow solid. ESI-MS (m/z): 178.6 [M+H] + .

中間體4Intermediate 4

Figure 111110674-A0202-12-0038-23
Figure 111110674-A0202-12-0038-23

中間體4由以下步驟製備： Intermediate 4 was prepared by the following steps:

Figure 111110674-A0202-12-0038-24
Figure 111110674-A0202-12-0038-24

第一步：將化合物Int-1e(350mg,1.45mmol)和乙烯基三氟硼酸鉀(387mg,2.89mmol)溶於1,4-二氧六環(1.5mL)和水(0.15mL)中，加入碳酸鉀(399mg,2.89mmol)和Pd(dppf)Cl2(105mg,0.14mmol)。反應體系置換氮氣後用微波反應器加熱至120℃攪拌1小時。反應冷卻至室溫後，用矽藻土過濾，濾液濃縮，殘留物用柱層析分離(甲醇/二氯甲烷=1/20)得到黃色固體Int-4a(136mg，收率49%)。ESI-MS(m/z)：190.7[M+H]+；1H NMR(500MHz,CDCl3)δ 6.85(dd,J=17.2,11.0Hz,1H),6.66(s,1H),6.16(dd,J=17.3,1.9Hz,1H),5.49(dd,J=11.0,1.9Hz,1H),3.67-3.63(m,2H),3.55(s,2H),3.00(t,J=6.1Hz,2H),2.80(t,J=6.1Hz,2H),2.49(s,3H)。 The first step: Dissolve compound Int-1e (350mg, 1.45mmol) and potassium vinyltrifluoroborate (387mg, 2.89mmol) in 1,4-dioxane (1.5mL) and water (0.15mL), Potassium carbonate (399 mg, 2.89 mmol) and Pd(dppf)Cl2 (105 mg , 0.14 mmol) were added. After the reaction system was replaced with nitrogen, it was heated to 120°C with a microwave reactor and stirred for 1 hour. After the reaction was cooled to room temperature, it was filtered with celite, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to obtain a yellow solid Int-4a (136 mg, yield 49%). ESI-MS (m/z): 190.7[M+H] + ; 1 H NMR (500MHz, CDCl 3 ) δ 6.85 (dd, J =17.2, 11.0Hz, 1H), 6.66(s, 1H), 6.16( dd, J =17.3,1.9Hz,1H),5.49(dd, J =11.0,1.9Hz,1H),3.67-3.63(m,2H),3.55(s,2H),3.00(t, J =6.1Hz ,2H), 2.80(t, J =6.1Hz,2H), 2.49(s,3H).

第二步：將化合物Int-4a(60mg,0.31mmol)溶於甲醇(5mL)中，加入10%鈀碳(20mg)，混合物在氫氣氛圍下室溫攪拌1小時。反應液用矽藻土過濾，濾液濃縮得到中間體4(37mg，收率61%)。ESI-MS(m/z)：192.7[M+H]+。 Step 2: Compound Int-4a (60 mg, 0.31 mmol) was dissolved in methanol (5 mL), 10% palladium on carbon (20 mg) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain intermediate 4 (37 mg, yield 61%). ESI-MS (m/z): 192.7 [M+H] + .

中間體5Intermediate 5

Figure 111110674-A0202-12-0039-25
Figure 111110674-A0202-12-0039-25

中間體5由以下步驟製備： Intermediate 5 was prepared by the following steps:

Figure 111110674-A0202-12-0039-26
Figure 111110674-A0202-12-0039-26

第一步：將化合物Int-1e(100mg,0.41mmol)溶於甲苯(3mL)和水(0.3mL)的混合溶劑中，加入環丙基硼酸(42mg,0.49mmol)，磷酸鉀(306mg,1.45mmol)，三環己基膦(23mg,0.082mmol)和醋酸鈀(9mg,0.041mmol)。反應體系置換氮氣後加熱至100℃攪拌18小時。反應冷卻至室溫後，反應液用矽藻土過濾，濾液濃縮，殘留物用柱層析分離(甲醇/二氯甲烷=1/20)得到黃色固體Int-5(61mg，收率72%)。ESI-MS(m/z)：204.2[M+H]+。 The first step: Dissolve compound Int-1e (100mg, 0.41mmol) in a mixed solvent of toluene (3mL) and water (0.3mL), add cyclopropylboronic acid (42mg, 0.49mmol), potassium phosphate (306mg, 1.45 mmol), tricyclohexylphosphine (23mg, 0.082mmol) and palladium acetate (9mg, 0.041mmol). The reaction system was replaced with nitrogen, heated to 100°C and stirred for 18 hours. After the reaction was cooled to room temperature, the reaction solution was filtered with diatomaceous earth, the filtrate was concentrated, and the residue was separated by column chromatography (methanol/dichloromethane=1/20) to obtain a yellow solid Int-5 (61 mg, yield 72%) . ESI-MS (m/z): 204.2 [M+H] + .

中間體6Intermediate 6

Figure 111110674-A0202-12-0039-27
Figure 111110674-A0202-12-0039-27

中間體6由以下步驟製備： Intermediate 6 was prepared by the following steps:

Figure 111110674-A0202-12-0040-28
Figure 111110674-A0202-12-0040-28

第一步：將N-叔丁氧羰基-4-呱啶酮Int-6a(4.4g，22.1mmol)和1-甲基-3，5-二硝基-2-吡啶酮Int-1a(4.0g，20.1mmol)溶於甲醇(150mL)中，加入氨甲醇溶液(7N，34.4mL，240.8mmol)。氮氣保護下60℃攪拌6小時。反應液降至室溫，繼續攪拌2天。LCMS監測反應結束，反應液濃縮，加入乙酸乙酯(150mL)，攪拌半小時後過濾，濾液濃縮得到黃色固體Int-6b(5.1g，產率91%)。ESI-MS(m/z)：280.1[M+H]+。 The first step: N-tert-butoxycarbonyl-4-piperidone Int-6a (4.4g, 22.1mmol) and 1-methyl-3,5-dinitro-2-pyridone Int-1a (4.0 g, 20.1 mmol) was dissolved in methanol (150 mL), and ammonia methanol solution (7N, 34.4 mL, 240.8 mmol) was added. Stir at 60°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and stirring was continued for 2 days. LCMS monitored the completion of the reaction, the reaction solution was concentrated, ethyl acetate (150 mL) was added, stirred for half an hour and then filtered, the filtrate was concentrated to obtain a yellow solid Int-6b (5.1 g, yield 91%). ESI-MS (m/z): 280.1 [M+H] + .

第二步：將化合物Int-6b(5.0g，17.9mmol)，溶於甲醇(50mL)中，加入10%鈀/碳(500mg)。混合物在氫氣氛圍下(氫氣球)室溫攪拌16小時。反應結束後，反應液過濾，濾液濃縮得到淡黃色固體Int-6c(3.7g，產率84%)。ESI-MS(m/z)：250.2[M+H]+。 The second step: Compound Int-6b (5.0 g, 17.9 mmol) was dissolved in methanol (50 mL), and 10% palladium on carbon (500 mg) was added. The mixture was stirred at room temperature under an atmosphere of hydrogen (hydrogen balloon) for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a pale yellow solid Int-6c (3.7 g, yield 84%). ESI-MS (m/z): 250.2 [M+H] + .

第三步：將化合物Int-6c(3.7g，14.8mmol)溶於DMF(20mL)中，加入N-溴代丁二醯亞胺(2.78g，15.6mmol)和醋酸(370mg)。反應混合物室溫攪拌2小時，LCMS監測反應結束。加水(100mL)，用乙酸乙酯萃取水相(150mL*3)，有機相合併，飽和食鹽水洗滌， 無水硫酸鈉乾燥，過濾濃縮，殘餘物後通過矽膠柱層析分離得到黃色固體Int-6d(3.6g，產率74%)。ESI-MS(m/z)：328.2[M+H]+。 The third step: Compound Int-6c (3.7g, 14.8mmol) was dissolved in DMF (20mL), and N-bromosuccinimide (2.78g, 15.6mmol) and acetic acid (370mg) were added. The reaction mixture was stirred at room temperature for 2 hours, and the completion of the reaction was monitored by LCMS. Add water (100mL), extract the aqueous phase (150mL*3) with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and the residue is separated by silica gel column chromatography to obtain Int-6d as a yellow solid (3.6 g, 74% yield). ESI-MS (m/z): 328.2 [M+H] + .

第四步：將化合物Int-6d(500mg，1.53mmol)溶於甲醇(5mL)中，加入甲醇鈉甲醇溶液(5N，0.33mL，1.65mmol)。反應混合物用微波加熱至100℃攪拌3小時。反應冷至室溫，反應液濃縮，殘餘物通過矽膠柱層析分離得到黃色固體Int-6(330mg，產率77%)。ESI-MS(m/z)：280.2[M+H]+。 Step 4: Compound Int-6d (500mg, 1.53mmol) was dissolved in methanol (5mL), and sodium methoxide in methanol (5N, 0.33mL, 1.65mmol) was added. The reaction mixture was heated to 100° C. with microwave and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow solid Int-6 (330 mg, yield 77%). ESI-MS (m/z): 280.2 [M+H] + .

實施例1 Example 1

3-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)嘧啶-4-基)氨基)-N,2,2-三甲基丙醯胺 3-((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-diazin-3-yl)amino)pyrimidine -4-yl)amino)-N,2,2-trimethylpropanamide

Figure 111110674-A0202-12-0041-29
Figure 111110674-A0202-12-0041-29

化合物1由以下步驟製備： Compound 1 was prepared by the following steps:

Figure 111110674-A0202-12-0041-30
Figure 111110674-A0202-12-0041-30

第一步：將Boc-3-氨基-2,2-二甲基-丙酸1a(50mg，0.23mmol)和 甲胺鹽酸鹽(77mg，1.15mmol)溶於N，N-二甲基甲醯胺(5mL)中，依次加入HATU(105mg，0.27mmol)和N，N-二異丙基乙胺(297mg，2.30mmol)，反應混合物在室溫下攪拌14小時。TLC檢測原料1a轉化完全。反應混合物加水(5mL)稀釋，用乙酸乙酯萃取(15mL * 3)。有機相合併，飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾濃縮，得到化合物1b的粗品，直接用於下一步反應。 Step 1: Dissolve Boc-3-amino-2,2-dimethyl-propionic acid 1a (50mg, 0.23mmol) and methylamine hydrochloride (77mg, 1.15mmol) in N , N -dimethylformaldehyde To amide (5 mL), HATU (105 mg, 0.27 mmol) and N , N -diisopropylethylamine (297 mg, 2.30 mmol) were sequentially added, and the reaction mixture was stirred at room temperature for 14 hours. TLC detected complete conversion of starting material 1a . The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude compound 1b , which was directly used in the next reaction.

第二步：將上一步得到的化合物1b的粗品溶於鹽酸二氧六環溶液(4mol/L，5mL)中，反應液在室溫下攪拌2小時，TLC顯示化合物1b反應完全。反應液減壓濃縮，得到化合物1c的粗品，直接用於下一步反應。 The second step: the crude compound 1b obtained in the previous step was dissolved in dioxane hydrochloride solution (4mol/L, 5mL), and the reaction solution was stirred at room temperature for 2 hours. TLC showed that the compound 1b was completely reacted. The reaction solution was concentrated under reduced pressure to obtain the crude compound 1c , which was directly used in the next reaction.

第三步：將上一步得到的化合物1c的粗品溶於異丙醇(5mL)中，加入2，4，5-三氯嘧啶1d(40mg，0.21mmol)和N，N-二異丙基乙胺(84mg，0.65mmol)。反應液升溫至90℃攪拌過夜，LCMS檢測化合物1d反應完全。反應液減壓濃縮，殘餘物通過矽膠柱層析純化(石油醚/乙酸乙酯=2/1)得到化合物1e(52mg，三步反應收率82%)。ESI-MS(m/z)：278.4[M+H]+。 The third step: the crude product of compound 1c obtained in the previous step was dissolved in isopropanol (5 mL), and 2,4,5-trichloropyrimidine 1d (40 mg, 0.21 mmol) and N , N -diisopropylethyl Amine (84 mg, 0.65 mmol). The reaction solution was warmed up to 90° C. and stirred overnight. LCMS detected that the reaction of compound 1d was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 1e (52 mg, yield of three-step reaction 82%). ESI-MS (m/z): 278.4 [M+H] + .

第四步：將化合物1e(52mg，0.18mmol)和中間體Int-1(36mg，0.18mmol)溶於1，4-二氧六環(5mL)中，依次加入BrettPhos G3 Pd(17mg，0.018mmol)、BrettPhos(10mg，0.018mmol)、碳酸銫(122mg，0.37mmol)。反應混合物氮氣置換後，在100℃下攪拌過夜。LCMS檢測化合物1e反應完全。反應液通過矽藻土過濾，濾液濃縮，殘餘物通過製備薄層層析純化(石油醚/乙酸乙酯=1/1)得到化合物1的粗品，再通過反向製備HPLC純化得到化合物1(6mg，收率7%)。ESI-MS(m/z)：434.2[M+H]+；1H NMR(500MHz,DMSO-d6) δ 8.18(s,1H),7.97(s,1H),7.69(d,J=4.5Hz,1H),7.65(s,1H),6.93(t,J=5.9Hz,1H),3.89(s,3H),3.53-3.48(m,4H),2.80-2.69(m,4H),2.59(s,3H),2.40(s,3H),1.11(s,6H)。 Step 4: Dissolve compound 1e (52mg, 0.18mmol) and intermediate Int-1 (36mg, 0.18mmol) in 1,4-dioxane (5mL), and add BrettPhos G3 Pd (17mg, 0.018mmol ), BrettPhos (10 mg, 0.018 mmol), cesium carbonate (122 mg, 0.37 mmol). After replacing the reaction mixture with nitrogen, it was stirred overnight at 100°C. LCMS detected that the reaction of compound 1e was complete. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain the crude product of compound 1 , and then purified by reverse preparative HPLC to obtain compound 1 (6mg , yield 7%). ESI-MS (m/z): 434.2[M+H] + ; 1 H NMR (500MHz, DMSO- d6 ) δ 8.18(s,1H),7.97(s,1H),7.69(d, J =4.5Hz ,1H),7.65(s,1H),6.93(t, J =5.9Hz,1H),3.89(s,3H),3.53-3.48(m,4H),2.80-2.69(m,4H),2.59( s,3H), 2.40(s,3H), 1.11(s,6H).

實施例2 Example 2

3-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)嘧啶-4-基)氨基)-N,2-二甲基丙醯胺 3-((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-diazin-3-yl)amino)pyrimidine -4-yl)amino)-N,2-dimethylpropanamide

Figure 111110674-A0202-12-0043-31
Figure 111110674-A0202-12-0043-31

用Boc-DL-3-氨基異丁酸替代實施例1第一步中的Boc-3-氨基-2,2-二甲基-丙酸1a，用類似的方法和反應步驟，可以得到化合物2。ESI-MS(m/z)：420.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.16(s,1H),7.94(s,1H),7.78(d,J=4.0Hz,1H),7.60(s,1H),7.20(t,J=5.8Hz,1H),3.89(s,3H),3.55-3.48(m,1H),3.41(d,J=7.2Hz,2H),3.37(s,1H),2.74(t,J=5.6Hz,2H),2.71-2.64(m,3H),2.57(d,J=4.5Hz,3H),2.34(s,3H),1.02(d,J=7.0Hz,3H)。 Substitute Boc-3-amino-2,2-dimethyl-propionic acid 1a in the first step of Example 1 with Boc-DL-3-aminoisobutyric acid, and use similar methods and reaction steps to obtain compound 2 . ESI-MS(m/z): 420.2[M+H] + ; 1 H NMR(500MHz, DMSO- d6 )δ 8.16(s,1H),7.94(s,1H),7.78(d, J =4.0Hz ,1H),7.60(s,1H),7.20(t, J =5.8Hz,1H),3.89(s,3H),3.55-3.48(m,1H),3.41(d, J =7.2Hz,2H) ,3.37(s,1H),2.74(t, J =5.6Hz,2H),2.71-2.64(m,3H),2.57(d, J =4.5Hz,3H),2.34(s,3H),1.02( d, J =7.0Hz, 3H).

實施例3 Example 3

3-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)嘧啶-4-基)氨基)-N,N,2,2-四甲基丙醯胺 3-((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-diazin-3-yl)amino)pyrimidine -4-yl)amino)-N,N,2,2-tetramethylpropionamide

Figure 111110674-A0202-12-0043-32
Figure 111110674-A0202-12-0043-32

用二甲胺鹽酸鹽替代實施例1第一步中的甲胺鹽酸鹽，用類似的方法和反應步驟，可以得到化合物3。ESI-MS(m/z)：448.2[M+H]+；1H NMR(500MHz,CDCl3)δ 8.36(s,1H),7.87(s,1H),7.27(s,1H),6.49(s,1H),3.98(s,3H),3.70(d,J=6.2Hz,2H),3.58(s,2H),3.05(s,6H),2.89(d,J=5.6Hz,2H),2.80(t,J=5.4Hz,2H),2.50(s,3H),1.35(s,6H)。 Compound 3 can be obtained by using dimethylamine hydrochloride instead of methylamine hydrochloride in the first step of Example 1, and using a similar method and reaction steps. ESI-MS (m/z): 448.2[M+H] + ; 1 H NMR (500MHz, CDCl 3 ) δ 8.36(s, 1H), 7.87(s, 1H), 7.27(s, 1H), 6.49( s,1H),3.98(s,3H),3.70(d, J =6.2Hz,2H),3.58(s,2H),3.05(s,6H),2.89(d, J =5.6Hz,2H), 2.80(t, J =5.4Hz, 2H), 2.50(s, 3H), 1.35(s, 6H).

實施例4 Example 4

3-((2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)-5-甲基嘧啶-4-基)氨基)-N,2,2-三甲基丙醯胺 3-((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalene-3-yl)amino)-5-methyl Pyrimidin-4-yl)amino)-N,2,2-trimethylpropionamide

Figure 111110674-A0202-12-0044-33
Figure 111110674-A0202-12-0044-33

化合物4由以下步驟製備： Compound 4 was prepared by the following steps:

Figure 111110674-A0202-12-0044-34
Figure 111110674-A0202-12-0044-34

第一步：將2,4-二氯-5-甲基-嘧啶(652mg，4mmol)和3-氨基-2,2-二甲基丙酸甲酯鹽酸鹽(670mg，4mmol)溶於異丙醇(15mL)之中，向上述反應液之中加入DIEA(1.55g,12.00mmol)。反應液在85℃ 下攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮後得到粗品，並通過柱色譜層析(石油醚/乙酸乙酯=1/1)得到無色油狀目標化合物4c(835mg，收率81%)。ESI-MS(m/z)：258.3[M+H]+。 The first step: 2,4-dichloro-5-methyl-pyrimidine (652mg, 4mmol) and 3-amino-2,2-dimethylpropanoic acid methyl ester hydrochloride (670mg, 4mmol) were dissolved in iso Among propanol (15 mL), DIEA (1.55 g, 12.00 mmol) was added to the above reaction solution. The reaction was stirred overnight at 85°C. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain a crude product, and the target compound 4c (835 mg, yield 81%) was obtained as a colorless oil by column chromatography (petroleum ether/ethyl acetate=1/1). ESI-MS (m/z): 258.3 [M+H] + .

第二步：將化合物4c(540mg，2.10mmol)溶解在四氫呋喃(10mL)和水(5mL)的混合溶液之中，向上述反應體系之中加入氫氧化鋰(100mg，4.19mmol)，反應液在室溫下攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮除去四氫呋喃，然後用1N鹽酸水溶液調節溶液pH值到3，生成的白色固體過濾乾燥得到化合物4d(340mg，收率66%)。ESI-MS(m/z)：244.3[M+H]+。 Second step: Dissolve compound 4c (540mg, 2.10mmol) in a mixed solution of tetrahydrofuran (10mL) and water (5mL), add lithium hydroxide (100mg, 4.19mmol) to the above reaction system, and the reaction solution was Stir overnight at room temperature. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to remove tetrahydrofuran, and then the pH value of the solution was adjusted to 3 with 1N aqueous hydrochloric acid solution, and the resulting white solid was filtered and dried to obtain compound 4d (340 mg, yield 66%). ESI-MS (m/z): 244.3 [M+H] + .

第三步：將化合物4d(121mg，0.5mmol)，甲胺鹽酸鹽(33mg，0.5mmol)，二異丙基乙胺(129mg，1mmol)和HATU(285mg，0.75mmol)溶解在二氯甲烷(8mL)之中，反應液在室溫下攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮後得到粗品，並經過柱色譜層析(二氯甲烷/乙酸乙酯=1/1)純化得到化合物4e(50mg，收率38%)。ESI-MS(m/z)：257.3[M+H]+。 The third step: compound 4d (121mg, 0.5mmol), methylamine hydrochloride (33mg, 0.5mmol), diisopropylethylamine (129mg, 1mmol) and HATU (285mg, 0.75mmol) were dissolved in dichloromethane (8 mL), the reaction was stirred overnight at room temperature. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane/ethyl acetate=1/1) to obtain compound 4e (50 mg, yield 38%). ESI-MS (m/z): 257.3 [M+H] + .

第四步：將化合物4e(50mg，0.19mmol)，Int-1(37mg，0.19mmol)，BrettPhos G3 Pd(17mg，0.019mmol)，Brettphos(20mg，0.038mmol)，碳酸銫(126mg，0.39mmol)溶解在二氧六環(10mL)之中，反應液在氮氣氛圍下110℃攪拌過夜。LCMS檢測原料轉化完全。將反應液過濾後旋乾，粗品經過反向製備HPLC純化得到化合物4(8mg，收率10%)。ESI-MS(m/z)：414.4[M+H]+；1H NMR(500MHz,DMSO-d 6)δ 8.36(s,1H),7.68(s,1H),7.60(q,J=4.6Hz,1H),7.20(s,1H),6.42(t,J=6.0Hz,1H),3.90(s,3H),3.54(d,J=6.0Hz,2H),3.43(s,2H),2.73(d,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.58(d,J=4.4Hz,3H),2.34 (s,3H),1.92(s,3H),1.11(s,6H)。 The fourth step: compound 4e (50mg, 0.19mmol), Int-1 (37mg, 0.19mmol), BrettPhos G3 Pd (17mg, 0.019mmol), Brettphos (20mg, 0.038mmol), cesium carbonate (126mg, 0.39mmol) It was dissolved in dioxane (10 mL), and the reaction solution was stirred overnight at 110° C. under a nitrogen atmosphere. Complete conversion of starting material was detected by LCMS. The reaction solution was filtered and spin-dried, and the crude product was purified by reverse preparative HPLC to obtain compound 4 (8 mg, yield 10%). ESI-MS (m/z): 414.4[M+H] + ; 1 H NMR (500MHz, DMSO- d 6 ) δ 8.36(s,1H),7.68(s,1H),7.60(q, J =4.6 Hz,1H),7.20(s,1H),6.42(t, J =6.0Hz,1H),3.90(s,3H),3.54(d, J =6.0Hz,2H),3.43(s,2H), 2.73(d, J =6.0Hz, 2H), 2.64(t, J =6.0Hz, 2H), 2.58(d, J =4.4Hz, 3H), 2.34 (s, 3H), 1.92(s, 3H), 1.11(s,6H).

實施例5 Example 5

5-氯-N2-(2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)-N4-((1-(甲磺醯)環丁基)甲基)嘧啶-2,4-二胺 5-Chloro-N2-(2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-phthalazin-3-yl)-N4-((1-( Methanesulfonyl)cyclobutyl)methyl)pyrimidine-2,4-diamine

Figure 111110674-A0202-12-0046-35
Figure 111110674-A0202-12-0046-35

化合物5由以下步驟製備： Compound 5 was prepared by the following steps:

Figure 111110674-A0202-12-0046-36
Figure 111110674-A0202-12-0046-36

第一步：將2,4,5-三氯嘧啶(46mg,0.25mmol)溶於異丙醇(2mL)中，然後向其中加入1-(甲磺醯)環丁基)甲胺鹽酸鹽5a(51mg,0.25mmol)和N,N-二異丙基乙胺(97mg,0.75mmol)，反應體系在25℃下攪拌16h。待反應結束後，濃縮反應液。殘餘物用矽膠柱層析純化(石油醚/乙酸乙酯=2/1)得到白色固體5b(48mg，收率58%)。ESI-MS(m/z)：310.1[M+H]+。 Step 1: Dissolve 2,4,5-trichloropyrimidine (46 mg, 0.25 mmol) in isopropanol (2 mL), and then add 1-(methylsulfonyl)cyclobutyl)methylamine hydrochloride to it 5a (51mg, 0.25mmol) and N,N-diisopropylethylamine (97mg, 0.75mmol), the reaction system was stirred at 25°C for 16h. After the reaction was completed, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain white solid 5b (48 mg, yield 58%). ESI-MS (m/z): 310.1 [M+H] + .

第二步：將化合物5b(48mg，0.16mmol)和Int-1(30mg，0.16mmol)溶於1,4-二氧六環(5mL)中，加入BrettPhos Pd G3(14mg，0.016mol)，BrettPhos(17mg，0.032mol)和碳酸銫(101mg，0.32mol)。反應體系置換氮氣後加熱至110℃攪拌18小時。待反應液冷卻至室溫，反應液用矽藻土過濾，濾液濃縮。殘餘物用反向製備HPLC純化 得到化合物5(6mg，收率8%)。ESI-MS(m/z)：467.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.02(s,1H),7.99(s,1H),7.84(s,1H),7.13-7.07(m,1H),3.98(d,J=6.0Hz,3H),3.87(s,3H),3.43(s,2H),2.93(s,3H),2.77-2.72(m,2H),2.67-2.61(m,2H),2.48-2.42(m,2H),2.34(s,3H),2.18-2.10(m,2H),1.90-1.80(m,2H)。 Second step: Dissolve compound 5b (48mg, 0.16mmol) and Int-1 (30mg, 0.16mmol) in 1,4-dioxane (5mL), add BrettPhos Pd G3 (14mg, 0.016mol), BrettPhos (17 mg, 0.032 mol) and cesium carbonate (101 mg, 0.32 mol). The reaction system was replaced with nitrogen and then heated to 110°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse preparative HPLC to obtain compound 5 (6 mg, yield 8%). ESI-MS (m/z): 467.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.02(s, 1H), 7.99(s, 1H), 7.84(s, 1H), 7.13-7.07(m,1H),3.98(d, J =6.0Hz,3H),3.87(s,3H),3.43(s,2H),2.93(s,3H),2.77-2.72(m,2H) ,2.67-2.61(m,2H),2.48-2.42(m,2H),2.34(s,3H),2.18-2.10(m,2H),1.90-1.80(m,2H).

實施例6 Example 6

1-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)嘧啶-4-基)氨基)甲基)-N-甲基環丁烷-1-甲醯胺 1-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-diazin-3-yl)amino) Pyrimidin-4-yl)amino)methyl)-N-methylcyclobutane-1-carboxamide

Figure 111110674-A0202-12-0047-38
Figure 111110674-A0202-12-0047-38

用1-(氨甲基)環丁烷羧酸甲酯和2,4,5-三氯嘧啶分別替代實施例4第一步中的2,2-二甲基-3-氨基丙酸甲酯4a和2,4-二氯-5-甲基嘧啶4b，用類似的方法和反應步驟，可以得到化合物6。ESI-MS(m/z)：446.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.30(s,1H),7.98(s,1H),7.77(s,1H),7.74(d,J=4.5Hz,1H),7.08(t,J=5.3Hz,1H),3.93(s,3H),3.70(d,J=5.8Hz,2H),2.89(s,3H),2.55(d,J=4.5Hz,3H),2.22(dd,J=20.1,9.2Hz,2H),2.02-1.96(m,2H),1.90-1.80(m,1H),1.75-1.67(m,1H)。 Replace the 2,2-dimethyl-3-aminopropionic acid methyl ester in the first step of Example 4 with 1-(aminomethyl)cyclobutanecarboxylic acid methyl ester and 2,4,5-trichloropyrimidine respectively 4a and 2,4-dichloro-5-methylpyrimidine 4b , using similar methods and reaction steps, compound 6 can be obtained. ESI-MS (m/z): 446.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.30(s, 1H), 7.98(s, 1H), 7.77(s, 1H), 7.74(d, J =4.5Hz, 1H), 7.08(t, J =5.3Hz, 1H), 3.93(s, 3H), 3.70(d, J =5.8Hz, 2H), 2.89(s, 3H), 2.55(d, J =4.5Hz,3H),2.22(dd, J =20.1,9.2Hz,2H),2.02-1.96(m,2H),1.90-1.80(m,1H),1.75-1.67(m, 1H).

實施例7 Example 7

3-((2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)-5-甲基嘧啶-4-基)氨基)-2,2-二甲基丙酸 3-((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalene-3-yl)amino)-5-methyl Pyrimidin-4-yl)amino)-2,2-dimethylpropionic acid

Figure 111110674-A0202-12-0048-39
Figure 111110674-A0202-12-0048-39

實施例8 Example 8

3-((2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-二氮雜萘-3-基)氨基)-5-甲基嘧啶-4-基)氨基)-2,2-二甲基丙醯胺 3-((2-((2-Methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthalene-3-yl)amino)-5-methyl Pyrimidin-4-yl)amino)-2,2-dimethylpropanamide

Figure 111110674-A0202-12-0048-40
Figure 111110674-A0202-12-0048-40

化合物7和8由以下步驟製備： Compounds 7 and 8 were prepared by the following steps:

Figure 111110674-A0202-12-0048-41
Figure 111110674-A0202-12-0048-41

第一步：將化合物4c(410mg，1.59mmol)，Int-1(338mg，1.75mmol)，碳酸銫(1.04g，3.18mmol)，Brettphos Pd G3(144mg，0.159mmol)，Brettphos(170mg，0.318mmol)溶解在二氧六環(20mL)之中，反應液在氮氣氛圍下110攝氏度攪拌16個小時。LCMS檢測原料轉 化完全。將反應液過濾，濾液濃縮後得到粗品並經過矽膠柱層析(二氯甲烷/甲醇=10/1)純化得到化合物7a(190mg，收率28%)。ESI-MS(m/z)：415.3[M+H]+。 The first step: compound 4c (410mg, 1.59mmol), Int-1 (338mg, 1.75mmol), cesium carbonate (1.04g, 3.18mmol), Brettphos Pd G3 (144mg, 0.159mmol), Brettphos (170mg, 0.318mmol ) was dissolved in dioxane (20 mL), and the reaction solution was stirred at 110 degrees Celsius for 16 hours under a nitrogen atmosphere. Complete conversion of starting material was detected by LCMS. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound 7a (190 mg, yield 28%). ESI-MS (m/z): 415.3 [M+H] + .

第二步：將化合物7a(15mg，0.036mmol)溶解在四氫呋喃(3mL)與水(3mL)的混合溶劑之中，然後向上述反應液之中加入氫氧化鋰(3mg，0.072mmol)，反應液在室溫下攪拌3小時。LCMS檢測原料轉化完全。反應液濃縮除去四氫呋喃，然後用1N鹽酸水溶液調節溶液pH值到3，將水溶液濃縮得到化合物7(15mg)。ESI-MS(m/z)：401.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.38(s,1H),7.69(s,1H),7.20(s,1H),6.40(d,J=6.3Hz,1H),3.90(s,3H),3.61(d,J=6.0Hz,3H),2.74-2.67(m,6H),2.37(s,3H),1.93(s,3H),1.12(s,6H)。 The second step: Dissolve compound 7a (15mg, 0.036mmol) in a mixed solvent of tetrahydrofuran (3mL) and water (3mL), then add lithium hydroxide (3mg, 0.072mmol) to the above reaction solution, and the reaction solution Stir at room temperature for 3 hours. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to remove THF, then the pH of the solution was adjusted to 3 with 1N aqueous hydrochloric acid solution, and the aqueous solution was concentrated to obtain compound 7 (15 mg). ESI-MS(m/z): 401.3[M+H] + ; 1 H NMR(500MHz,DMSO-d 6 )δ 8.38(s,1H),7.69(s,1H),7.20(s,1H), 6.40(d, J =6.3Hz,1H),3.90(s,3H),3.61(d, J =6.0Hz,3H),2.74-2.67(m,6H),2.37(s,3H),1.93(s ,3H), 1.12(s,6H).

第三步：將化合物7(75mg，187umol)，氯化銨(142mg，0.37mmol)，HATU(142mg，0.37mmol),DIPEA(72mg，0.56mmol)溶解在DMF(8mL)之中，反應液在室溫下攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮得到粗品並經過反相製備HPLC純化得到化合物8(10mg，收率14%)。ESI-MS(m/z)：400.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.37(s,1H),7.69(s,1H),7.20(s,1H),6.97(s,1H),6.30(t,J=6.1Hz,1H),3.90(s,3H),3.53(d,J=6.0Hz,2H),3.44(s,2H),2.73(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),2.34(s,3H),1.92(s,3H),1.12(s,6H)。 The third step: compound 7 (75mg, 187umol), ammonium chloride (142mg, 0.37mmol), HATU (142mg, 0.37mmol), DIPEA (72mg, 0.56mmol) were dissolved in DMF (8mL), and the reaction solution was Stir overnight at room temperature. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by reverse-phase preparative HPLC to obtain compound 8 (10 mg, yield 14%). ESI-MS(m/z): 400.3[M+H] + ; 1 H NMR(500MHz,DMSO-d 6 )δ 8.37(s,1H),7.69(s,1H),7.20(s,1H), 6.97(s,1H),6.30(t, J =6.1Hz,1H),3.90(s,3H),3.53(d, J =6.0Hz,2H),3.44(s,2H),2.73(t, J =6.0Hz, 2H), 2.64(t, J =6.0Hz, 2H), 2.34(s, 3H), 1.92(s, 3H), 1.12(s, 6H).

實施例9 Example 9

1-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-萘啶-3-基)氨基)嘧啶4-基)氨基)甲基)-N-乙基環丁烷-1-甲醯胺 1-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidine 4 -yl)amino)methyl)-N-ethylcyclobutane-1-formamide

Figure 111110674-A0202-12-0050-42
Figure 111110674-A0202-12-0050-42

用1-(氨甲基)環丁烷羧酸甲酯和2,4,5-三氯嘧啶分別替代實施例4第一步中的2,2-二甲基-3-氨基丙酸甲酯4a和2,4-二氯-5-甲基嘧啶4b，然後在第三步用乙胺鹽酸鹽替換甲胺鹽酸鹽，用類似的方法和反應步驟，可以得到化合物9。ESI-MS(m/z)：460.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.17(s,1H),7.96(s,1H),7.72(t,J=5.5Hz,1H),7.63(s,1H),6.81(t,J=5.4Hz,1H),3.88(s,3H),3.71(d,J=5.6Hz,2H),3.44(s,2H),3.11-2.99(m,2H),2.75(t,J=5.9Hz,2H),2.64(t,J=5.8Hz,2H),2.34(s,3H),2.23(dd,J=18.7,9.9Hz,2H),1.98-1.90(m,2H),1.88-1.81(m,1H),1.76-1.68(m,1H),0.94(t,J=7.2Hz,3H)。 Replace the 2,2-dimethyl-3-aminopropionic acid methyl ester in the first step of Example 4 with 1-(aminomethyl)cyclobutanecarboxylic acid methyl ester and 2,4,5-trichloropyrimidine respectively 4a and 2,4-dichloro-5-methylpyrimidine 4b , and then replace methylamine hydrochloride with ethylamine hydrochloride in the third step. Compound 9 can be obtained by similar methods and reaction steps. ESI-MS (m/z): 460.2[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ 8.17(s, 1H), 7.96(s, 1H), 7.72(t, J = 5.5Hz ,1H),7.63(s,1H),6.81(t, J =5.4Hz,1H),3.88(s,3H),3.71(d, J =5.6Hz,2H),3.44(s,2H),3.11 -2.99(m,2H),2.75(t, J =5.9Hz,2H),2.64(t, J =5.8Hz,2H),2.34(s,3H),2.23(dd, J =18.7,9.9Hz, 2H), 1.98-1.90(m, 2H), 1.88-1.81(m, 1H), 1.76-1.68(m, 1H), 0.94(t, J =7.2Hz, 3H).

實施例10 Example 10

4-((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-萘啶-3-基)氨基)嘧啶-4-基)氨基)-3,3-二甲基丁酸 4-((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidine-4 -yl)amino)-3,3-dimethylbutanoic acid

Figure 111110674-A0202-12-0050-43
Figure 111110674-A0202-12-0050-43

化合物10由以下步驟製備： Compound 10 was prepared by the following steps:

Figure 111110674-A0202-12-0051-44
Figure 111110674-A0202-12-0051-44

第一步：將化合物10a(200mg，1.02mmol)與2,4,5-三氯嘧啶(43mg，1.33mmol)1d溶解在異丙醇(8mL)之中，向上述反應液之中加入DIPEA(264mg，2.04mmol)，反應液在室溫下攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮得到粗品並經過矽膠柱層析(石油醚/乙酸乙酯=3/1)純化得到無色油狀化合物10b(312mg，收率100%)。ESI-MS(m/z)：306.3[M+H]+。 The first step: Dissolve compound 10a (200mg, 1.02mmol) and 2,4,5-trichloropyrimidine (43mg, 1.33mmol) 1d in isopropanol (8mL), add DIPEA ( 264mg, 2.04mmol), the reaction solution was stirred overnight at room temperature. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain colorless oily compound 10b (312 mg, yield 100%). ESI-MS (m/z): 306.3 [M+H] + .

第二步：將化合物10b(360mg,1.18mmol)和Int-1(227mg，1.18mmol)溶解在二氧六環(10mL)之中，依次加入碳酸銫(766mg，2.35mmol)，Brettphos Pd G3(213mg，0.23mmol)和Brettphos(126mg,0.23mmol)，反應液在氮氣氛圍下110℃攪拌過夜。LCMS檢測原料轉化完全。將反應液濃縮得到粗品並經過矽膠柱層析(二氯甲烷/甲醇=10/1)純化得到棕色油10c(280mg，收率51%)。ESI-MS(m/z)：463.5[M+H]+。 Second step: Dissolve compound 10b (360mg, 1.18mmol) and Int-1 (227mg, 1.18mmol) in dioxane (10mL), add cesium carbonate (766mg, 2.35mmol) successively, Brettphos Pd G3 ( 213mg, 0.23mmol) and Brettphos (126mg, 0.23mmol), the reaction solution was stirred overnight at 110°C under nitrogen atmosphere. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain a brown oil 10c (280 mg, yield 51%). ESI-MS (m/z): 463.5 [M+H] + .

第三步：將化合物10c(260mg，0.56mmol)溶解在四氫呋喃(5mL)和水(5mL)的混合溶液之中，向上述反應液之中加入氫氧化鋰(23mg，0.56mmol)，反應液在室溫下攪拌四個小時。將反應液用1N鹽 酸水溶液酸化到pH=3，然後用乙酸乙酯萃取。將萃取後的水相濃縮得到粗品。將粗品用反相製備HPLC純化得到化合物10(3.59mg，收率1.47%)。ESI-MS(m/z)：435.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.13(s,1H),7.95(s,1H),7.62(s,1H),7.25(s,1H),3.88(s,2H),3.45(s,3H),3.38(s,2H),2.75(d,J=6.0Hz,2H),2.67(d,J=6.0Hz,2H),2.35(s,3H),2.15(s,2H),0.96(s,6H)。 The third step: Dissolve compound 10c (260mg, 0.56mmol) in a mixed solution of tetrahydrofuran (5mL) and water (5mL), add lithium hydroxide (23mg, 0.56mmol) to the above reaction solution, and the reaction solution was Stir at room temperature for four hours. The reaction solution was acidified to pH=3 with 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The extracted aqueous phase was concentrated to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC to obtain compound 10 (3.59 mg, yield 1.47%). ESI-MS (m/z): 435.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.13(s, 1H), 7.95(s, 1H), 7.62(s, 1H), 7.25(s,1H),3.88(s,2H),3.45(s,3H),3.38(s,2H),2.75(d, J =6.0Hz,2H),2.67(d, J =6.0Hz,2H ), 2.35(s,3H), 2.15(s,2H), 0.96(s,6H).

實施例11 Example 11

1-(((5氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-萘啶-3-基)氨基)嘧啶-4-基)氨基)甲基)-N-甲基環丙烷-1-甲醯胺 1-(((5chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidine-4 -yl)amino)methyl)-N-methylcyclopropane-1-formamide

Figure 111110674-A0202-12-0052-45
Figure 111110674-A0202-12-0052-45

用1-(氨甲基)環丙基甲酸乙酯和2,4,5-三氯嘧啶分別替代實施例4第一步中的2,2-二甲基-3-氨基丙酸甲酯4a和2,4-二氯-5-甲基嘧啶4b，用類似的方法和反應步驟，可以得到化合物11。ESI-MS(m/z)：432.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.03(s,1H),7.96(s,1H),7.81(s,1H),7.69(d,J=4.2Hz,1H),7.15(t,J=6.0Hz,1H),3.88(s,3H),3.67(d,J=5.9Hz,2H),3.38(s,2H),2.75(t,J=5.6Hz,2H),2.64(t,J=5.7Hz,2H),2.55(d,J=4.3Hz,3H),2.34(s,3H),0.93(dd,J=6.2,3.9Hz,2H),0.78(dd,J=6.5,4.0Hz,2H)。 Substitute 2,2-dimethyl-3-aminopropionic acid methyl ester 4a in the first step of Example 4 with 1-(aminomethyl) ethyl cyclopropanate and 2,4,5-trichloropyrimidine respectively And 2,4-dichloro-5-methylpyrimidine 4b , using similar methods and reaction steps, compound 11 can be obtained. ESI-MS (m/z): 432.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.03(s, 1H), 7.96(s, 1H), 7.81(s, 1H), 7.69(d, J =4.2Hz, 1H), 7.15(t, J =6.0Hz, 1H), 3.88(s, 3H), 3.67(d, J =5.9Hz, 2H), 3.38(s, 2H), 2.75(t, J =5.6Hz, 2H), 2.64(t, J =5.7Hz, 2H), 2.55(d, J =4.3Hz, 3H), 2.34(s, 3H), 0.93(dd, J =6.2 ,3.9Hz,2H),0.78(dd, J =6.5,4.0Hz,2H).

實施例12 Example 12

1-(((5-氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-萘啶-3-基)氨基)嘧啶-4-基)氨基)甲基)-N-甲基環戊烷-1-甲醯胺 1-(((5-chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidine- 4-yl)amino)methyl)-N-methylcyclopentane-1-formamide

Figure 111110674-A0202-12-0053-46
Figure 111110674-A0202-12-0053-46

用Boc-1-氨基甲基環戊烷羧酸替代實施例1第一步中的Boc-3-氨基-2,2-二甲基-丙酸1a，用類似的方法和反應步驟，可以得到化合物12。ESI-MS(m/z)：460.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.09(s,1H),7.96(s,1H),7.68(s,1H),7.66(d,J=4.7Hz,1H),6.83(t,J=5.6Hz,1H),3.88(s,3H),3.52(d,J=5.8Hz,2H),3.42(s,2H),2.75(t,J=5.9Hz,2H),2.64(t,J=5.7Hz,2H),2.57(d,J=4.4Hz,3H),2.34(s,3H),1.86(dt,J=7.7,5.5Hz,2H),1.61-1.55(m,6H)。 Replace Boc-3-amino-2,2-dimethyl-propionic acid 1a in the first step of Example 1 with Boc-1-aminomethylcyclopentane carboxylic acid, and use similar methods and reaction steps to obtain Compound 12 . ESI-MS (m/z): 460.2[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.09(s, 1H), 7.96(s, 1H), 7.68(s, 1H), 7.66(d, J =4.7Hz, 1H), 6.83(t, J =5.6Hz, 1H), 3.88(s, 3H), 3.52(d, J =5.8Hz, 2H), 3.42(s, 2H), 2.75(t, J =5.9Hz, 2H), 2.64(t, J =5.7Hz, 2H), 2.57(d, J =4.4Hz, 3H), 2.34(s, 3H), 1.86(dt, J =7.7 ,5.5Hz,2H), 1.61-1.55(m,6H).

實施例13 Example 13

1-(((5氯-2-((2-甲氧基-6-甲基-5,6,7,8-四氫-1,6-萘啶-3-基)氨基)嘧啶-4-基)氨基)甲基)環丁烷-1-羧酸 1-(((5chloro-2-((2-methoxy-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)pyrimidine-4 -yl)amino)methyl)cyclobutane-1-carboxylic acid

Figure 111110674-A0202-12-0053-47
Figure 111110674-A0202-12-0053-47

用4-(氨甲基)環丁烷羧酸甲酯鹽酸鹽替代實施例10第一步中的3,3-二甲基-4-氨基丁酸乙酯鹽酸鹽10a，用類似的方法和反應步驟，可以得到化合物13。ESI-MS(m/z)：433.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ 8.15(s,1H),7.97(s,1H),7.63(s,1H),7.01(t,J=6.1Hz,1H),3.88(s,3H),3.75(d,J=6.0Hz,2H),3.44(s,2H),2.75(t,J=5.8Hz,2H),2.66(t,J=5.8Hz,2H),2.35(s,3H),2.28-2.21(m,2H),2.06-1.99(m,2H),1.84-1.76(m,2H)。 Replace 3,3-dimethyl-4-aminobutyric acid ethyl ester hydrochloride 10a in the first step of embodiment 10 with 4-(aminomethyl)cyclobutanecarboxylic acid methyl ester hydrochloride, use similar Methods and reaction steps, compound 13 can be obtained. ESI-MS (m/z): 433.3[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.15(s, 1H), 7.97(s, 1H), 7.63(s, 1H), 7.01(t, J =6.1Hz, 1H), 3.88(s, 3H), 3.75(d, J =6.0Hz, 2H), 3.44(s, 2H), 2.75(t, J =5.8Hz, 2H), 2.66(t, J =5.8Hz, 2H), 2.35(s, 3H), 2.28-2.21(m, 2H), 2.06-1.99(m, 2H), 1.84-1.76(m, 2H).

根據以上實施例描述的合成路線和中間體的合成方法，製備得到了以下實施例化合物。 According to the synthetic routes and intermediate synthesis methods described in the above examples, the following examples of compounds were prepared.

Figure 111110674-A0202-12-0054-48
Figure 111110674-A0202-12-0054-48

Figure 111110674-A0202-12-0055-49
Figure 111110674-A0202-12-0055-49

Figure 111110674-A0202-12-0056-50
Figure 111110674-A0202-12-0056-50

HPK1抑制劑生物學篩選和結果 HPK1 Inhibitor Biological Screening and Results

試驗例1：化合物對HPK1激酶活性抑制能力的檢測(方法1)所需使用試劑如下 Test Example 1: The detection of compound's ability to inhibit HPK1 kinase activity (method 1) requires the following reagents

Figure 111110674-A0202-12-0056-51
Figure 111110674-A0202-12-0056-51

實驗步驟 Experimental procedure

具體操作如下：配置酶促反應體系緩衝液(10mM MOPS，pH 7.2，5mM β-glycerol-phosphate，10mM MgCl2，0.8mM EDTA，2mM EGTA，0.1mM DTT)；將測試的化合物(配於DMSO中1mM的化合物儲液)用緩衝液稀釋至為60uM最高濃度(包含6% DMSO)，並配置60μM濃度起始用包含6% DMSO的緩衝液進行5倍稀釋共計8個點的梯度濃度的化合物；隨後使用緩衝液將HPK1激酶稀釋至30nM。在Greiner 384孔微孔板(貨號：784075)中每孔加入2μl的HPK1激酶稀釋液，對照孔中補充2μl緩衝液；短暫離心後在反應孔中加入1μl的稀釋化合物，對照孔中加入1μl包含6% DMSO的緩衝液；短暫離心後置於25℃恆溫孵育箱(上海一恒科學儀器有限公司，貨號：LRH-150)中孵育20min。在每孔中加入3μl反應底物(溶解於蒸餾水中的10μM MBP和20μM ATP)，短暫離心後置於25℃恆溫孵育箱中孵育60min，採用ADP-Glo Kinase Assay Kit檢測酶促反應活性，ADP-Glo Kinase Assay Kit檢測都依據試劑盒的操作說明進行。資料採用化合物的半數抑制濃度IC50描述。 The specific operation is as follows: configure the enzymatic reaction system buffer (10mM MOPS, pH 7.2, 5mM β-glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); The compound stock solution) was diluted with buffer to the highest concentration of 60uM (containing 6% DMSO), and the 60μM concentration was initially diluted 5-fold with a buffer containing 6% DMSO for a total of 8 points of gradient concentration of the compound; then Dilute HPK1 kinase to 30 nM in buffer. in Greiner Add 2μl of HPK1 Kinase Diluent to each well of a 384-well microplate (Catalog No.: 784075), add 2μl of buffer to the control well; add 1μl of the diluted compound to the reaction well after short centrifugation, add 1μl to the control well containing 6% DMSO buffer; after brief centrifugation, place in a constant temperature incubator at 25°C (Shanghai Yiheng Scientific Instrument Co., Ltd., Cat. No.: LRH-150) and incubate for 20 minutes. Add 3 μl of reaction substrate (10 μM MBP and 20 μM ATP dissolved in distilled water) to each well, briefly centrifuge and incubate in a constant temperature incubator at 25°C for 60 min, and use the ADP-Glo Kinase Assay Kit to detect the enzymatic reaction activity, ADP -Glo Kinase Assay Kit detection is carried out according to the operating instructions of the kit. The data are described by the half inhibitory concentration IC50 of the compound.

Figure 111110674-A0202-12-0057-52
Figure 111110674-A0202-12-0057-52

上述結果表明，本發明的化合物對HPK1激酶活性具有優異的抑制能力。 The above results show that the compound of the present invention has excellent inhibitory ability to HPK1 kinase activity.

試驗例2：化合物對Jurkat細胞分泌細胞因數白介素-2(IL-2)激動能力的檢測及化合物對Jurkat細胞活力的影響(方法2) Test Example 2: Detection of Compounds on Jurkat Cells Secreting Cytokine Interleukin-2 (IL-2) and Effect of Compounds on Jurkat Cell Viability (Method 2)

所需使用試劑及細胞如下： The required reagents and cells are as follows:

實驗試劑： Experimental reagents:

Figure 111110674-A0202-12-0058-53
Figure 111110674-A0202-12-0058-53

實驗細胞： Experimental cells:

Figure 111110674-A0202-12-0058-55
Figure 111110674-A0202-12-0058-55

實驗步驟 Experimental procedure

具體操作如下：將化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI 1640培養基(此試驗中均含10% FBS)中，渦旋混勻後為最高濃度點。用0.2% DMSO培養基3倍逐漸稀釋化合物溶液，共8個濃度點。以含濃度為0.1% DMSO的RPMI 1640培養基溶液處理作為對照。在康寧96孔細胞培養板(貨號：3599)中每孔加入1×105 Jurkat E6-1細胞，隨後加入等量體積的化合物稀釋液，對照組加入含0.2% DMSO的RPMI 1640培養基，置於37℃細胞培養箱 (Thermo Fisher Scientific，型號：3111)孵育1h。隨後加入終濃度為1μg/ml Anti-human CD3 Antibody和1μg/ml Anti-human CD28 Antibody抗體，置於37℃細胞培養箱孵育24h，收集培養上清液，採用Human IL-2 DuoSet ELISA KIT檢測細胞上清液中的IL-2含量，Human IL-2 DuoSet ELISA檢測依據試劑盒的操作說明進行。IL-2分泌資料採用化合物的刺激信號與0.1% DMSO的信號的最高倍數比值描述；收集細胞，使用CellTiter-Glo® Luminescent Cell Viability Assay試劑盒檢測細胞活力，細胞活力資料採用化合物的半數抑制濃度IC50描述。 The specific operation is as follows: the compound powder was dissolved in DMSO to 10 mM, 2 μl of the compound was added to 998 μl of RPMI 1640 medium (contained 10% FBS in this test), and the highest concentration point was obtained after vortexing. The compound solution was gradually diluted 3 times with 0.2% DMSO medium, with a total of 8 concentration points. Treated with RPMI 1640 medium solution containing 0.1% DMSO as a control. Add 1×105 Jurkat E6-1 cells to each well of Corning 96-well cell culture plate (Catalog No.: 3599), then add an equal volume of compound dilution, add RPMI 1640 medium containing 0.2% DMSO to the control group, and place at 37 ℃ cell culture incubator (Thermo Fisher Scientific, model: 3111) for 1 h. Then add 1 μg/ml Anti-human CD3 Antibody and 1 μg/ml Anti-human CD28 Antibody at a final concentration of 1 μg/ml, incubate in a 37°C cell culture incubator for 24 hours, collect the culture supernatant, and use Human IL-2 DuoSet ELISA KIT to detect cells The IL-2 content in the supernatant was detected by Human IL-2 DuoSet ELISA according to the operating instructions of the kit. The IL-2 secretion data is described by the highest fold ratio between the stimulation signal of the compound and the signal of 0.1% DMSO; the cells are collected, and the cell viability is detected using the CellTiter-Glo® Luminescent Cell Viability Assay kit, and the cell viability data is used for the half inhibitory concentration IC50 of the compound describe.

Figure 111110674-A0202-12-0059-56
Figure 111110674-A0202-12-0059-56

Figure 111110674-A0202-12-0060-57
Figure 111110674-A0202-12-0060-57

NA：表示未檢測到IL-2的釋放增強。 NA: Indicates that no enhanced release of IL-2 was detected.

上述結果表明，與對照相比，本發明化合物顯著增加了Jurkat細胞分泌的細胞因數白介素-2的水準，同時不對Jurkat的細胞活力有不利影響。 The above results show that, compared with the control, the compound of the present invention significantly increases the level of the cytokine interleukin-2 secreted by Jurkat cells without adversely affecting the viability of Jurkat cells.

試驗例3：化合物對人PBMC細胞分泌細胞因數白介素-2(IL-2)激動能力的檢測化合物對人PBMC細胞活力的影響(方法3) Test Example 3: Detection of compound's ability to secrete cytokine interleukin-2 (IL-2) from human PBMC cells Effect of compound on human PBMC cell viability (method 3)

所需使用試劑如下 The required reagents are as follows

Figure 111110674-A0202-12-0060-58
Figure 111110674-A0202-12-0060-58

實驗細胞來源資訊： Source information of experimental cells:

Figure 111110674-A0202-12-0060-59
Figure 111110674-A0202-12-0060-59

實驗步驟 Experimental procedure

具體操作如下：人PBMC按照標準操作從液氮中取出後，置於37℃水浴鍋中解凍復甦，將細胞用RPMI 1640培養基(此試驗中均含10% FBS)重懸，離心洗滌兩次；隨後將人PBMC細胞重懸於RPMI 1640培養基中備用。將化合物粉末用DMSO溶解至10mM，取2μl化合物加入到998μl RPMI 1640培養基中，渦旋混勻後為最高濃度點。用0.2% DMSO培養基3倍逐漸稀釋化合物溶液，共8個濃度點。以含濃度為0.1% DMSO的RPMI 1640培養基溶液處理作為對照。在康寧96孔細胞培養板(貨號：3599)中每孔加入1×105人PBMC細胞，隨後加入等量體積的化合物稀釋液，對照組加入含0.2% DMSO的RPMI 1640培養基，置於37℃細胞培養箱(Thermo Fisher Scientific，型號：3111)孵育1h。隨後加入終濃度為0.01μg/ml Anti-human CD3 Antibody和1μg/ml Anti-human CD28 Antibody抗體，置於37℃細胞培養箱孵育24h。採用Human IL-2 DuoSet ELISA KIT檢測細胞上清液中的IL-2含量，Human IL-2 DuoSet ELISA檢測依據試劑盒的操作說明進行。資料採用化合物的刺激信號與0.1% DMSO的信號的最高倍數比值描述。收集細胞，使用CellTiter-Glo® Luminescent Cell Viability Assay試劑盒檢測細胞活力，細胞活力資料採用化合物的半數抑制濃度IC50描述。 The specific operation is as follows: Human PBMCs were taken out of liquid nitrogen according to the standard operation, placed in a 37°C water bath to thaw and recover, the cells were resuspended in RPMI 1640 medium (both contained 10% FBS in this test), and washed twice by centrifugation; Human PBMC cells were then resuspended in RPMI 1640 medium for use. The compound powder was dissolved in DMSO to 10 mM, 2 μl of the compound was added to 998 μl of RPMI 1640 medium, and the highest concentration point was obtained after vortexing. The compound solution was gradually diluted 3 times with 0.2% DMSO medium, with a total of 8 concentration points. Treated with RPMI 1640 medium solution containing 0.1% DMSO as a control. Add 1×105 human PBMC cells to each well of Corning 96-well cell culture plate (product number: 3599), then add an equal volume of compound dilution, add RPMI 1640 medium containing 0.2% DMSO to the control group, and place the cells at 37°C Incubate for 1 h in an incubator (Thermo Fisher Scientific, model: 3111). Then add Anti-human CD3 Antibody and 1 μg/ml Anti-human CD28 Antibody at a final concentration of 0.01 μg/ml, and incubate for 24 hours in a 37°C cell culture incubator. The Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and the Human IL-2 DuoSet ELISA detection was performed according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulating signal of the compound to the signal of 0.1% DMSO. The cells were collected, and the cell viability was detected using the CellTiter-Glo® Luminescent Cell Viability Assay kit, and the cell viability data was described by the half inhibitory concentration IC50 of the compound.

Figure 111110674-A0202-12-0061-60
Figure 111110674-A0202-12-0061-60

Figure 111110674-A0202-12-0062-61
Figure 111110674-A0202-12-0062-61

NA：表示未檢測到IL-2的釋放增強。 NA: Indicates that no enhanced release of IL-2 was detected.

上述結果表明，與對照相比，本發明化合物顯著增加了PBMC細胞分泌的細胞因數白介素-2的水準，同時不對PBMC的細胞活力有不利影響。 The above results show that, compared with the control, the compound of the present invention significantly increases the level of cytokine interleukin-2 secreted by PBMC cells without adversely affecting the cell viability of PBMC cells.

Claims (16)

具有式I結構的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體： Compounds with the structure of formula I or pharmaceutically acceptable salts, isotopic derivatives, stereoisomers:
Figure 111110674-A0202-13-0001-81
Figure 111110674-A0202-13-0001-81
 其中 in R1表示氫、(C1-C6)烷基或(C3-C8)環烷基； R 1 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl; R2表示氫、(C1-C6)烷基、鹵素、氰基、-ORa或(C1-C6)鹵代烷基； R 2 represents hydrogen, (C 1 -C 6 ) alkyl, halogen, cyano, -OR a or (C 1 -C 6 ) haloalkyl; R3表示氫、鹵素、-ORa、(C1-C6)烷基、(C1-C6)鹵代烷基、羥基(C1-C6)烷基、(C2-C6)烯基、-(C0-C6亞烷基)(C3-C8)環烷基、-(C0-C6亞烷基)(4-8元)雜環烷基、-(C0-C6亞烷基)(C3-C8)環烷基氧基或-(C0-C6亞烷基)(4-8元)雜環烷基氧基； R 3 represents hydrogen, halogen, -OR a , (C 1 -C 6 )alkyl, (C 1 -C 6 )halogenated alkyl, hydroxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkene Group, -(C 0 -C 6 alkylene) (C 3 -C 8 ) cycloalkyl, -(C 0 -C 6 alkylene) (4-8 member) heterocycloalkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 ) cycloalkyloxy or -(C 0 -C 6 alkylene) (4-8 member) heterocycloalkyloxy; A表示
Figure 111110674-A0202-13-0001-63
、
Figure 111110674-A0202-13-0001-64
、
Figure 111110674-A0202-13-0001-65
、、
Figure 111110674-A0202-13-0001-66
、 A means
Figure 111110674-A0202-13-0001-63
,
Figure 111110674-A0202-13-0001-64
,
Figure 111110674-A0202-13-0001-65
,,
Figure 111110674-A0202-13-0001-66
,
Figure 111110674-A0202-13-0001-82
Figure 111110674-A0202-13-0001-82
 B表示-(C0-C6)亞烷基-、-O-(C1-C6)烷基-、-S-(C1-C6)烷基-或-S(O)-(C1-C6)烷基-； B represents -(C 0 -C 6 )alkylene-, -O-(C 1 -C 6 )alkyl-, -S-(C 1 -C 6 )alkyl- or -S(O)-( C 1 -C 6 )alkyl-; R4和R4’各自獨立地表示氫、(C1-C6)烷基、(C2-C6)烯基或鹵素； R 4 and R 4 ' each independently represent hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or halogen; 或者R4與R4’一起和與之相連的碳原子形成3-6元環，該環中還可以任意地含有0、1、2個選自N、O、S的雜原子； Or R 4 and R 4' form a 3-6-membered ring together with the carbon atom connected to it, and the ring can also optionally contain 0, 1, or 2 heteroatoms selected from N, O, and S; R5表示氫、C1-C6烷基、鹵代(C1-C6)烷基、(C3-C6)烯基、(C3-C8)環烷基、鹵代(C3-C8)環烷基、(4-8元)雜環烷基、鹵代(4-8元)雜環烷基、-(C0-C6)亞烷基-ORa、-(C0-C6)亞烷基-COORa或者-(C0-C6)亞烷基-C(O)NRaRa’； R 5 represents hydrogen, C 1 -C 6 alkyl, halo (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, halo (C 3 -C 8 ) cycloalkyl, (4-8 member) heterocycloalkyl, halogenated (4-8 member) heterocycloalkyl, -(C 0 -C 6 ) alkylene-OR a , -( C 0 -C 6 )alkylene-COOR a or -(C 0 -C 6 )alkylene-C(O)NR a R a '; R6和R6’各自獨立地表示氫、C1-C6烷基、(C1-C6)鹵代烷基、(C2-C6)烯基鹵素或-(C0-C6)亞烷基-ORa； R 6 and R 6' each independently represent hydrogen, C 1 -C 6 alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl halogen or -(C 0 -C 6 ) Alkyl- ORa ; 或者R6與R6’一起和與之相連的碳原子形成3-6元環，該環中還可以任意地含有0、1、2個選自N、O、S的雜原子； Or R 6 and R 6' form a 3-6-membered ring together with the carbon atom connected to it, and the ring can also optionally contain 0, 1, or 2 heteroatoms selected from N, O, and S; X1表示N或者CR7； X 1 represents N or CR 7 ; 其中，R7表示氫、鹵素、(C1-C6)烷基、(C1-C6)鹵代烷基、(C2-C6)烯基、-(C0-C6亞烷基)(C3-C8)環烷基、-(C0-C6亞烷基)(4-10元)雜環烷基、-(C0-C6亞烷基)(C6-C10)芳基、-(C0-C6亞烷基)(5-10)元雜芳基， Wherein, R 7 represents hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, -(C 0 -C 6 alkylene) (C 3 -C 8 ) cycloalkyl, -(C 0 -C 6 alkylene) (4-10 members) heterocycloalkyl, -(C 0 -C 6 alkylene) (C 6 -C 10 ) aryl, -(C 0 -C 6 alkylene) (5-10) membered heteroaryl, 或者，當X1表示CR7時，R7可以與相鄰的R3一起形成(5-10元)環烷基或者(5-10元)雜環烷基，其任選地被鹵素取代； Or, when X 1 represents CR 7 , R 7 can form (5-10 membered) cycloalkyl or (5-10 membered) heterocycloalkyl together with adjacent R 3 , which is optionally substituted by halogen; RM和RN各自獨立地表示氫、鹵素、(C1-C6)烷基或(C1-C6)鹵代烷基，或者RM和RN一起和與之相連的碳原子環合成3-6元環，該環中還可以任意地含有0、1、2個選自O、N、S的雜原子，其任選地被鹵素取代；且RM和RN不同時為氫； R M and R N each independently represent hydrogen, halogen, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl, or R M and R N are synthesized together with the carbon atom connected to it3 -6-membered ring, which can also optionally contain 0, 1, 2 heteroatoms selected from O, N, S, which are optionally substituted by halogen; and R M and R N are not hydrogen at the same time; 其中，Ra、Rb表示氫或(C1-C6)烷基； Wherein, R a and R b represent hydrogen or (C 1 -C 6 ) alkyl; m、n表示0、1、2或3。 m and n represent 0, 1, 2 or 3. 如請求項1所述的化合物或藥學上可接受的鹽、 同位素衍生物、立體異構體，其中，A表示
Figure 111110674-A0202-13-0003-90
。 The compound or pharmaceutically acceptable salt, isotope derivative, stereoisomer as described in Claim 1, wherein, A represents
Figure 111110674-A0202-13-0003-90
. 如請求項1或2所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R1表示(C1-C6)烷基。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as described in claim 1 or 2, wherein R 1 represents (C 1 -C 6 ) alkyl. 如請求項1-3中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R2表示鹵素、(C1-C6)烷基或者鹵代(C1-C6)烷基。 Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers according to any one of claims 1-3, wherein R 2 represents halogen, (C 1 -C 6 ) alkyl or halogenated (C 1 -C 6 )alkyl. 請求項1-4中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，X1表示N或者CH。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer according to any one of Claims 1-4 , wherein X represents N or CH. 請求項1-5中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R3表示-ORa、(C1-C6)烷基或者(C3-C8)環烷基。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer according to any one of claims 1-5, wherein R 3 represents -OR a , (C 1 -C 6 ) alkyl or ( C 3 -C 8 )cycloalkyl. 請求項1-6中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R4和R4’各自獨立地表示氫。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer according to any one of claims 1-6, wherein R 4 and R 4' each independently represent hydrogen. 請求項1-7中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R5表示氫、(C1-C6)烷基或者(C3-C8)環烷基。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer according to any one of claims 1-7, wherein R 5 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 8 ) cycloalkyl. 如請求項1-8中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中，R6和R6’各自獨立地表示氫、鹵素、(C1-C6)烷基或者(C1-C6)鹵代烷基。 Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers as described in any one of claims 1-8, wherein R 6 and R 6' each independently represent hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. 如請求項1-9中任一項所述的化合物或藥學上可 接受的鹽、同位素衍生物、立體異構體，其中，R7表示氫、鹵素、(C1-C6)烷基、(C1-C6)鹵代烷基、-(C0-C6亞烷基)(C3-C8)環烷基或者-(C0-C6亞烷基)(4-10元)雜環烷基。 Compounds or pharmaceutically acceptable salts, isotopic derivatives, and stereoisomers as described in any one of claim items 1-9, wherein R 7 represents hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, -(C 0 -C 6 alkylene) (C 3 -C 8 ) cycloalkyl or -(C 0 -C 6 alkylene) (4-10 member) hetero Cycloalkyl. 如請求項1-10中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中m表示1或2。 The compound or pharmaceutically acceptable salt, isotopic derivative, stereoisomer as described in any one of claims 1-10, wherein m represents 1 or 2. 如請求項1-11中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中n表示1或2。 The compound or pharmaceutically acceptable salt, isotopic derivative, stereoisomer as described in any one of claims 1-11, wherein n represents 1 or 2. 如請求項1-12中任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體，其中m表示1，n表示2。 The compound or pharmaceutically acceptable salt, isotopic derivative, or stereoisomer as described in any one of claims 1-12, wherein m represents 1, and n represents 2. 化合物，其具有以下結構： compound, which has the following structure:
Figure 111110674-A0202-13-0004-91
Figure 111110674-A0202-13-0004-91
Figure 111110674-A0202-13-0005-92
Figure 111110674-A0202-13-0005-92
Figure 111110674-A0202-13-0006-93
Figure 111110674-A0202-13-0006-93
Figure 111110674-A0202-13-0007-94
Figure 111110674-A0202-13-0007-94
Figure 111110674-A0202-13-0008-95
Figure 111110674-A0202-13-0008-95
Figure 111110674-A0202-13-0009-96
Figure 111110674-A0202-13-0009-96
Figure 111110674-A0202-13-0010-97
Figure 111110674-A0202-13-0010-97
 一種藥物組合物，其包括請求項1-14任一項所述的化合物或藥學上可接受的鹽、同位素衍生物、立體異構體以及藥學上可用的載體。 A pharmaceutical composition, which comprises the compound or pharmaceutically acceptable salt, isotope derivative, stereoisomer and pharmaceutically acceptable carrier described in any one of claims 1-14. 如請求項1-14任一項所述的化合物或藥學上可 接受的鹽、同位素衍生物、立體異構體或者請求項15所述的藥物組合物在製備用於預防和/或治療癌症、腫瘤、炎症性疾病、自身免疫性疾病或免疫介導性疾病的藥物中的用途。 Compound as described in any one of claims 1-14 or pharmaceutically available Accepted salts, isotope derivatives, stereoisomers, or the pharmaceutical composition described in Claim 15 are used in the preparation of prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases Uses in medicine.
TW111110674A 2021-03-23 2022-03-22 Hpk1 kinase inhibitor compounds TW202246263A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110308954.9 2021-03-23
CN202110308954 2021-03-23

Publications (1)

Publication Number Publication Date
TW202246263A true TW202246263A (en) 2022-12-01

Family

ID=83395188

Family Applications (1)

Application Number Title Priority Date Filing Date
TW111110674A TW202246263A (en) 2021-03-23 2022-03-22 Hpk1 kinase inhibitor compounds

Country Status (3)

Country Link
CN (3) CN116768888A (en)
TW (1) TW202246263A (en)
WO (1) WO2022199561A1 (en)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA80767C2 (en) * 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
JP2007537238A (en) * 2004-05-14 2007-12-20 ファイザー・プロダクツ・インク Pyrimidine derivatives for the treatment of abnormal cell proliferation
WO2008051547A1 (en) * 2006-10-23 2008-05-02 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors
WO2009122180A1 (en) * 2008-04-02 2009-10-08 Medical Research Council Pyrimidine derivatives capable of inhibiting one or more kinases
MX2012013274A (en) * 2010-05-21 2013-05-28 Chemilia Ab Novel pyrimidine derivatives.
EP3548479A1 (en) * 2016-11-30 2019-10-09 ARIAD Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
CN112451526A (en) * 2020-11-30 2021-03-09 深圳市人民医院 Application of MRT68921HCl

Also Published As

Publication number Publication date
CN116348117A (en) 2023-06-27
CN116768888A (en) 2023-09-19
CN116854687A (en) 2023-10-10
WO2022199561A1 (en) 2022-09-29

Similar Documents

Publication Publication Date Title
TWI723511B (en) Highly active sting protein agonist compound
TWI716976B (en) Highly active sting protein agonist
WO2019158070A1 (en) A2a and/or a2b receptor antagonist
WO2019228252A1 (en) Highly active csf1r inhibitor compound
US20230399327A1 (en) High activity hpk1 kinase inhibitor
JP7436630B2 (en) Adenosine receptor antagonist
JP7281834B2 (en) PD-L1 antagonist compounds
WO2023143501A1 (en) Wnt pathway inhibitor compound
TWI768781B (en) TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR
TW202246263A (en) Hpk1 kinase inhibitor compounds
US20220267350A1 (en) Adenosine receptor antagonist
CN115066423A (en) PD-L1 antagonist compounds
LU505117B1 (en) A pan-KRAS inhibitor compound
WO2024022365A1 (en) Wnt pathway inhibitor compound
TW202304906A (en) Highly active hpk1 kinase inhibitor
TWI810547B (en) Pd-l1 antagonist compound
WO2023005894A1 (en) Inhibitor compound for wnt pathway
WO2024060966A1 (en) Pan-kras inhibitor compound
TW202304434A (en) Highly active hpk1 kinase inhibitor
WO2023143546A1 (en) Wnt pathway inhibitor compounds
CN117903169A (en) Pan-KRAS inhibitor compound
CN117396482A (en) Wnt pathway inhibitor compound